Clinical trial NCT01691898
Conditions: Follicular Lymphoma Diffuse Large B-Cell Lymphoma
Sponsor: Genentech, Inc.
Start date: 2012-09-27; Completion date: 2019-02-07
Enrollment: 231 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multicenter, open-label study will evaluate the safety and efficacy of pinatuzumab vedotin (DCDT2980S) or polatuzumab vedotin (DCDS4501A) in combination with rituximab (RTX), as well as of polatuzumab vedotin in combination with obinutuzumab in participants with relapsed or refractory (r/r) follicular lymphoma (FL) and r/r diffuse large B-cell lymphoma (DLBCL).

Detailed description:

Arms: arm 1: For the first 2 cycles, RTX 375 milligrams per square meter (mg/m\^2) will be given by intravenous (IV) infusion on Day 1 and pinatuzumab vedotin 2.4 milligrams per kilogram (mg/kg) will be administered by IV infusion on Day 2 to Arm A participants (with r/r FL and DLBCL). In the absence of any infusion-related adverse events, RTX and pinatuzumab may be administered on the same day (Day 1) in subsequent cycles beginning with the third cycle. Participants who develop disease progression (PD) will be further treated with RTX 375 mg/m\^2 followed by polatuzumab vedotin 2.4 mg/kg IV infusion on Day 1, beginning no later than 42 days after the last dose of the prior study treatment until a second PD event relative to the tumor assessment, documenting PD on the initial study treatment, clinical deterioration, and/or intolerance to the crossover treatment for up to a maximum of 1 year (17 cycles on an every-21-day schedule). arm 2: For the first 2 cycles, RTX 375 mg/m\^2 will be given by IV infusion on Day 1 and polatuzumab vedotin 2.4 mg/kg will be administered by IV infusion on Day 2 to Arm B participants (with r/r FL and DLBCL). In the absence of any infusion-related adverse events, RTX and polatuzumab may be administered on the same day (Day 1) in subsequent cycles beginning with the third cycle. Participants who develop PD would be further treated with RTX 375 mg/m\^2 followed by pinatuzumab vedotin 2.4 mg/kg IV infusion on Day 1, beginning no later than 42 days after the last dose of the prior study treatment until a second PD event relative to the tumor assessment, documenting PD on the initial study treatment, clinical deterioration, and/or intolerance to the crossover treatment for up to a maximum of 1 year (17 cycles on an every-21-day schedule). arm 3: For the first 2 cycles, RTX 375 mg/m\^2 will be given by IV infusion on Day 1 and polatuzumab vedotin 1.8 mg/kg will be administered by IV infusion on Day 2 to Cohort C participants (with r/r FL). In the absence of any infusion-related adverse events, RTX and polatuzumab may be administered on the same day (Day 1) in subsequent cycles beginning with the third cycle for up to a maximum of 1 year (17 cycles on an every-21-day schedule) or significant toxicity, PD, or withdrawal from study. arm 4: For the first cycle, obinutuzumab will be given by IV infusion on Days 1, 8, and 15. Polatuzumab vedotin 1.8 mg/kg IV infusion will be given on Day 2 of the first cycle to Cohort E participants (with r/r FL and DLBCL). In the absence of any infusion-related adverse events, obinutuzumab and polatuzumab vedotin may be administered on the same day (Day 1) in subsequent cycles beginning with the second cycle up to a maximum of 8 cycles or significant toxicity, PD, or withdrawal from study. arm 5: For the first cycle, obinutuzumab will be given by IV infusion on Days 1, 8, and 15. Polatuzumab vedotin 1.8 mg/kg IV infusion will be given on Day 2 of the first cycle to Cohort G participants (with r/r FL). In the absence of any infusion-related adverse events, obinutuzumab and polatuzumab vedotin may be administered on the same day (Day 1) in subsequent cycles beginning with the second cycle of the dose-expansion period to cohort G participants up to a maximum of 8 cycles or significant toxicity, PD, or withdrawal from study. arm 6: For the first cycle, obinutuzumab will be given by IV infusion on Days 1, 8, and 15. Polatuzumab vedotin 1.8 mg/kg IV infusion will be given on Day 2 of the first cycle to Cohort H participants (with r/r DLBCL). In the absence of any infusion-related adverse events, obinutuzumab and polatuzumab vedotin may be administered on the same day (Day 1) in subsequent cycles beginning with the second cycle of the dose-expansion period to cohort H participants up to a maximum of 8 cycles or significant toxicity, PD, or withdrawal from study.
Interventions: intervention 1: Obinutuzumab intervention 2: Pinatuzumab Vedotin intervention 3: Polatuzumab Vedotin intervention 4: Rituximab
Intervention descriptions: intervention 1: Obinutuzumab 1000 mg will be administered by IV infusion on Days 1, 8, 15 of first 21-Day cycle and on Day 1 of subsequent 21-day cycles for up to 8 cycles. intervention 2: Pinatuzumab Vedotin 1.8 or 2.4 mg/kg administered by IV infusion on Day 1 or 2 of every 21-day cycle. intervention 3: Polatuzumab Vedotin 1.8 or 2.4 mg/kg administered by IV infusion on Day 1 or 2 of every 21-day cycle. intervention 4: RTX 375 mg/m\^2 administered by IV infusion on Day 1 of every 21-day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
Document Type:         Protocol, Amendments and SAP 
Official Title: 
A Randomized, Open-Label, Multicenter, Phase II Trial Evaluating the 
Safety and Activity of Pinatuzumab Vedotin (DCDT2980S) in 
Combination With Rituximab or Polatuzumab Vedotin (DCDS4501A) 
in Combination With Rituximab and a Non-Randomized Phase Ib/II 
Evaluation 
of 
Polatuzumab 
Vedotin 
in 
Combination 
With 
Obinutuzumab in Patients With Relapsed or Refractory B-Cell Non-
Hodgkin's Lymphoma 
NCT Number: 
NCT01691898 
Document Date: 
Protocol Amendment Version 4: 03-Oct-2017 
Protocol Amendment Version 3: 30-Apr-2015 
Protocol Amendment Version 2: 06-Nov-2014 
Protocol Amendment Version 1: 24-Jun-2013 
 
 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This is a Genentech, Inc., document that contains confidential information.  
It is intended solely for the recipient clinical investigator(s) and must not be disclosed to any other 
party.  This material may be used only for evaluating or conducting clinical investigations; any 
other proposed use requires written consent from Genentech, Inc.
DCDT2980S and DCDS4501A—Genentech, Inc.
Protocol GO27834, Version A4
PROTOCOL
TITLE:
A RANDOMIZED, OPEN-LABEL, MULTICENTER, 
PHASE II TRIAL EVALUATING THE SAFETY AND
ACTIVITY OF PINATUZUMAB VEDOTIN 
(DCDT2980S) IN COMBINATION WITH RITUXIMAB 
OR POLATUZUMAB VEDOTIN (DCDS4501A) IN 
COMBINATION WITH RITUXIMAB AND A NON-
RANDOMIZED PHASE IB/II EVALUATION OF 
POLATUZUMAB VEDOTIN IN COMBINATION WITH 
OBINUTUZUMAB IN PATIENTS WITH RELAPSED 
OR REFRACTORY B-CELL NON-HODGKIN’S 
LYMPHOMA
PROTOCOL NUMBER:
GO27834
VERSION NUMBER:
A4
EUDRACT NUMBER:
2011-004377-84
IND NUMBER:
107713
STUDY DRUG:
Pinatuzumab vedotin (DCDT2980S); 
polatuzumab vedotin (DCDS4501A)
MEDICAL MONITOR:
, M.D. 
SPONSOR:
Genentech, Inc.
DATE FINAL:
27 July 2012
DATES AMENDED:
Version A1: 24 June 2013
Version A2: 6 November 2014
Version A3: 30 April 2015
Version A4:  See electronic date stamp below.
 
03-Oct-2017 17:09:03
Title
Approver's Name
Company Signatory
Date and Time (UTC)


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PROTOCOL AMENDMENT, VERSION A4:
RATIONALE
Protocol GO27834 has been amended to implement the following changes:  

Language has been updated to include 18F-fluorodeoxyglucosepositron emission 
tomography (18F-FDG-PET; hereafter referred to as PET)/computed tomography 
(CT) scans as a response assessment. Lugano Response Criteria is based upon 
PET/CT as a modality.  PET/CT is a correction to comply with the standard Lugano 
Response Criiteria (Cheson 2014; Sections 2.1, 2.2.2, 2.3.1, 3.3.3., 3.3.4, 4.5.1.8, 
and 4.10.4, and Appendices C1 and C2).

Section 3.4.4 (Risks Associated with ADCETRIS[Brentuximab Vedotin]) has been 
deleted and other sections re-numbered accordingly.  Brentuximab is a drug 
produced by Seattle Genetics. It's safety profile was used as a benchmark for 
potential safety issues, but is now no longer considered relevant with the body of 
experience available for pinaturzumab (DCDT2980S) and polatuzumab 
(DCDS4501A).

Language has been updated to include second malignancies as an adverse event 
of special interest in all studies containing obinutuzumab (Section 5.1.3).

Language has been updated to state second malignancies will be recorded 
indefinitely (even if the study has been closed) for all subjects enrolled in the 
obinutuzumab containing cohorts and irrespective of new anti-lymphoma treatments 
(Sections 5.2.1. and 5.6 and Appendices A1, A2, and A3).

The Medical Monitor has changed and the contact information has been revised 
(Section 5.4.1).

Appendix A5 has been updated to correct visits to occur at 3-month and 6-month 
intervals as opposed to the erroneous footnote which notes "two-month" and 
"four-month" intervals.
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


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PROTOCOL AMENDMENT, VERSION A4:
SUMMARY OF CHANGES
PROTOCOL SYNOPSIS
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable.
SECTION 2.1:  PRIMARY OBJECTIVES
The primary objectives of this study are the following:

To assess the anti-tumor activity of the combination of DCDS4501A and 
obinutuzumab in patients with relapsed or refractory follicular NHL and DLBCL 
based on 18F-fluorodeoxyglucosepositron emission tomography (18F-FDG-PET; 
hereafter referred to as PET)/computed tomography (CT) CR at the end of 
treatment according to Independent Review Committee (IRC) per Lugano 2014 
response criteria
SECTION 2.2.2:  Activity Objectives
The secondary activity objectives for obinutuzumab-containing arms of the study are the 
following:

CR at end of treatment based on PET/CT alone, as determined by the investigator

Objective response (OR; CR or PR) at end of treatment based on PET/CT, alone as 
determined by investigator and IRC 

OR (CR or PR) at end of treatment based on CT only, as determined by the 
investigator and IRC

Best objective response (BOR, CR or PR) while on study based on PET/CT alone or 
CT only, as determined by the investigator
SECTION 2.3.1:  Efficacy Objectives
The exploratory efficacy objectives for this study are to evaluate the long-term outcome 
of obinutuzumab-treated patients according to Lugano 2014 response criteria, as 
measured by the following:

Duration of response based on PET/CT PET and/or CT scans, as determined by the 
investigator

Progression-free survival (PFS) based on PET/CT and/or CT scans, as determined 
by the investigator

Event-free survival (EFS) based on PET/CT and/or CT scans, as determined by the 
investigator


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SECTION 3.3.3:  Activity Outcome Measures
The following activity outcome measures will be assessed for obinutuzumab-containing 
cohorts (Cohorts E, G, and H) according to Lugano 2014 Response Criteria 
(Cheson et al. 2014):
The primary activity outcome measure will be assessed by: 

CR at end of treatment (68 weeks after Cycle 6 Day 1 or last dose of study 
medication) based on PET/CTalone, as determined by the IRC
The following secondary efficacy outcome measures will be assessed:

OR (CR or PR) at end of treatment based on PET/CT, alone as determined by the 
investigator and IRC 

BOR (CR or PR) while on study based on PET/CT alone or CT only, as determined 
by the investigator 
SECTION 3.3.4:  Exploratory Outcome Measures
The following exploratory efficacy outcome measures will be assessed:

DOR, defined as the time from the date of the first occurrence of a documented CR 
or PR to the date of disease progression, relapse, or death from any cause, for the 
subgroup of patients with a best overall response of CR or PR, based on PET/CT
and/or CT scans as determined by the investigator assessment.  For patients 
achieving a response who have not experienced disease progression, relapse, or 
died prior to the time of the analysis, the DOR will be censored on the date of last 
disease assessment.

PFS, defined as the time from date of randomization or first treatment (for 
G-containing arms) to the first occurrence of progression or relapse, or death from 
any cause , based on PET/CT and/or CT scans as determined by the investigator 
assessment.

EFS, defined as the time from date of randomization or first treatment (for 
G-containing arms) to any treatment failure including disease progression relapse, 
initiation of new anti-lymphoma therapy, or death from any cause, whichever occurs 
first, based on PET/CT and/or CT scans as determined by the investigator 
assessment
SECTION 3.4.4:  Risks Associated with ADCETRIS® (Brentuximab Vedotin)
An ADC using the same MMAE drug and linker as that used in DCDT2980S and 
DCDS4501A, but coupled to an antibody targeting the CD30 antigen (brentuximab 
vedotin, ADCETRIS, Seattle Genetics), was recently approved by the FDA for use in 
the treatment of specific subsets of patients with relapsed Hodgkin lymphoma and 
systemic anaplastic large cell lymphoma.  
The most common adverse reactions observed in studies with brentuximab vedotin 
(occurring in at least 20% of patients) were neutropenia, peripheral sensory neuropathy, 
fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, 
thrombocytopenia, cough, and vomiting.  


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Serious adverse reactions were reported in 31% of patients receiving ADCETRIS.  The 
most common occurring in 2% of patients included peripheral motor neuropathy, 
abdominal pain, septic shock, supraventricular arrhythmia, pain in extremity, and urinary 
tract infection.  In addition, John Cunningham (JC) virus infection resulting in progressive 
multifocal leukoencephalopathy (PML) and death has been reported.  
Because of the use of the same MMAE drug, it is possible that the adverse events 
observed with the use of brentuximab vedotin can also be observed with the use of 
DCDT2980S and DCDS4501A.  
Refer to the current version of the ADCETRISPrescribing Information for full and 
updated details.
SECTION 4.5.1.8:  Tumor Response Assessments
All measurable disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Response assessments will be assessed by the 
investigator, on the basis of physical examinations, CT scans, PET/CT scans, and/or 
MRI scans, and bone marrow examinations, using standard response criteria for NHL 
(Cheson et al. 2007; Cheson et al. 2014) (see Appendix C-1 and C-2).  Specific response 
assessment criteria differ between the rituximab-containing arms/cohorts and the 
obinutuzumab-containing cohorts (see Section 4.5.1.8a. and 4.5.1.8b).
a.
Radiographic Assessments for Patients on Rituximab-Containing
Arms/Cohorts
A PET/CT scan is required during screening for all patients with DLBCL.  An additional 
PET/CT scan in DLBCL patients with DLBCL should be obtained at the 6-month tumor 
assessment to ensure consistency of response assessment methodology at this 
timepoint for all patients.  PET/CT scans should additionally be obtained to confirm 
disappearance of metabolically active disease during study treatment and to confirm a 
CR upon discontinuation of study treatment.  
For patients with FL, PET/CT scans are not required but may be obtained on the basis 
of physician preference and if permitted by local health authorities.  Similarly, for patients 
with DLBCL, PET/CT scans on patients with FL should be obtained during screening; 
for patients whose tumors are PET positive during screening, an additional PET/CT
scan should be obtained at the 6-month tumor assessment.  PET/CT scans should 
additionally be obtained to confirm disappearance of metabolically active disease during 
study treatment and to confirm a CR upon discontinuation of study treatment. 
For all patients regardless of disease subtype, combined PET/CT-CT scans may be 
used instead of CT alone if performed with contrast and if collected with resolution 
sufficient to allow accurate and consistent comparison of target lesion measurements 
with subsequent PET/CT-CT scans.  If a PET/CT-CT scan is to be used during 


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screening, then PET/CT-CT scans should be performed for all subsequent tumor 
assessments in order to ensure their consistency across different timepoints.
b.
Radiographic Assessments for Patients on Obinutuzumab-Containing 
Cohorts
PET/CT scans should minimally extend from skull-base to mid-thigh.  Full-body PET 
scan should be performed when clinically appropriate.
PET/CT and CT scans are required for patients with follicular NHL and DLBCL patients 
at screening, after Cycle 4 of study treatment (i.e., between Cycle 4 Day 15 and Cycle 5 
Day 1), and at EOT.  The EOT response assessment should be performed 68 weeks 
after Cycle 8 Day 1 or last study treatment.  CT scans without PET scans will be 
obtained every 6 months for 2 years, with use of Lugano 2014 Response Criteria for 
NHL (see Appendix C-2).
d.
Schedule of Tumor Response Assessments for Rituximab-Containing 
Arms/Cohorts
Tumor response assessments will be performed every 3 months (1 week) from the 
initiation of study treatment until study treatment completion or early termination 
(e.g., between Days 14 and 21 of Cycles 4 and 8 for those patients receiving at least 
eight 21-day cycles of treatment).  The schedule of tumor assessments is independent 
of the study treatment dose schedule.  For patients enrolled in rituximab-containing 
arms/cohorts, the schedule of tumor response assessments is detailed in Appendix A-1.  
As stated above, for all patients with DLBCL enrolled in a rituximab-containing 
arm/cohort, PET/CT scans are required during the screening period and at the 6-month 
tumor assessment timepoint.
e.
Schedule of Tumor Response Assessments for 
Obinutuzumab-Containing Cohorts
All patients with follicular NHL and DLBCL enrolled in obinutuzumab-containing cohorts 
are required to have a combined PET/CT and CT scan at screening, after Cycle 4 of 
treatment, and at EOT.  The schedule for tumor response assessments for patients 
enrolled in obinutuzumab-containing cohorts is detailed in Appendix A-3.
SECTION 4.10.4:  Activity Analyses
For patients in the rituximab-containing arms/cohorts with DLBCL, primary assessment 
of tumor response will be based on diagnostic imaging scansfor example, CT and/or 
MRI scans and PET/CT scans. For patients with FL enrolled in the rituximab-containing 
arms/cohorts, primary assessment of response will be based on CT scans only; the 
assessment of response in patients with FL based on PET/CT scans will be performed 
for exploratory purposes only.


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SECTION 5.1.3:  Non Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor)Protocol-Defined Adverse Events 
of Special Interest/Non-Serious Expedited Adverse Events
Non-serious adverse events of special interest are required to be reported by the 
investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2 for reporting instructions), irrespective of regulatory seriousness 
criteria.  Adverse events of special interest for this study include the following:

Secondary malignancies 
SECTION 5.2.1:  Adverse Event Reporting Period
After initiation of study drug (the Genentech product[s] or other IMP), all new AEs and 
SAEs regardless of attribution will be collected until 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is later.  
After this period, investigators should report only SAEs that are felt to be related to prior 
study treatment with the exception of second malignancies (see Section 5.6).  Second 
malignancies will be recorded indefinitely (even if the study has ended) and irrespective 
of new anti-lymphoma treatment (NALT).
SECTION 5.4.1:  Reporting Requirements for Fatal/Life Threatening SAEs 
Related to Investigational Product
Medical Monitor Contact Information for sites in North America:
Medical Monitor:
, M.D.
Telephone No.:
Mobile Telephone No.:
SECTION 5.6:  POST STUDY ADVERSE EVENTS
The investigator should notify the study Sponsor of any death or other SAE occurring at 
any time after a patient has discontinued or terminated study participation if felt to be 
related to prior study treatment.  Second malignancies will be recorded indefinitely (even 
if the study has been closed) and irrespective of NALT.  The Sponsor should also be
notified if the investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a patient that participated in 
this study.  The investigator should report these events to Genentech Drug Safety on the 
study eCRF.  If the study eCRF is no longer available, the investigator should report the 
event directly to Genentech Drug Safety either by faxing or by scanning and emailing the 
Serious Adverse Event/Adverse Event of Special Interest Reporting Form with use of the 
fax number or email address provided below.
APPENDIX A1:  Study Flowchart:  Initial Study Treatment (Arms AB, 
Cohorts CD)
The study flowchart for initial study treatment has been revised to reflect the changes to 
the protocol.


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APPENDIX A2:  Study Flowchart:  Crossover Treatment (Patients 
Randomized to Arms A or B Only)
The study flowchart for crossover treatment has been revised to reflect the changes to 
the protocol.
APPENDIX A3:  Study Flowchart for Obinutuzumab-Containing Cohorts 
(E, GH):  Initial Study Treatment
The study flowchart for for obinutuzumab-containing cohorts has been revised to reflect 
the changes to the protocol.
APPENDIX A5:  Post-Treatment Follow-Up for Obinutuzumab-Containing 
Regimens (Cohorts E, G-H)
The post-treatment follow-up for obinutuzumab-containing regimens has been revised to 
reflect the changes to the protocol and to correct visit intervals.
APPENDIX C1:  Modified Response and Progression Criteria for NHL
Appendix C1 has been revised to reflect the changes to the protocol.
APPENDIX C2:  Revised Criteria for Response Assessment: The Lugano 
Classification (Cohorts E, GH)
Appendix C2 has been revised to reflect the changes to the protocol.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 18
PROTOCOL SYNOPSIS……………………………………………………………   19
1.
BACKGROUND .......................................................................................... 37
1.1
Background on Disease......................................................... 37
1.2
Background on the Molecules ............................................... 37
1.2.1
DCDT2980S .......................................................................... 37
1.2.1.1
Background and Preclinical Data........................................... 37
1.2.1.2
DCDT2980S Clinical Data ..................................................... 39
1.2.2
DCDS4501A.......................................................................... 42
1.2.2.1
Background and Preclinical Data........................................... 42
1.2.2.2
DCDS4501A Clinical Data..................................................... 45
1.2.3
Rituximab............................................................................... 48
1.2.4
Obinutuzumab ....................................................................... 49
1.2.4.1
Obinutuzumab Mechanism of Action ..................................... 49
1.2.4.2
Obinutuzumab Nonclinical Toxicology................................... 49
1.2.4.3
Obinutuzumab Nonclinical Efficacy ....................................... 50
1.2.4.4
Obinutuzumab Clinical Experience........................................ 51
1.2.4.5
Obinutuzumab Pharmacokinetics and 
Pharmacodynamics ............................................................... 52
1.3
Rationale for Doing this Study ............................................... 53
1.3.1
Rationale for Assessing ADC Dose of 1.8 mg/kg 
Combined with Rituximab in iNHL ......................................... 54
1.3.2
Rationale for Assessing DCDS4501A in 
Combination with Obinutuzumab in Relapsed or 
Refractory NHL...................................................................... 54
2.
OBJECTIVES.............................................................................................. 55
2.1
Primary Objectives ................................................................ 55
2.2
Secondary Objectives............................................................ 55
2.2.1
Safety Objectives................................................................... 55
2.2.2
Activity Objectives ................................................................. 56
2.2.3
Pharmacokinetic Objectives .................................................. 56
2.3
Exploratory Objectives........................................................... 56


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2.3.1
Efficacy Objectives ................................................................ 56
2.3.2
Biomarker Objectives............................................................. 57
2.3.3
Patient-Reported Outcomes Objective .................................. 57
2.3.4
Crossover Treatment Objective............................................. 57
3.
STUDY DESIGN......................................................................................... 57
3.1
Description of the Study......................................................... 57
3.1.1
Rituximab-Containing Regimens with 
DCDT2980S or DCDS4501A................................................. 59
3.1.1.1
Randomized Portion of the Study (Arms A 
and B) Closed to Enrollment............................................... 59
3.1.1.2
Non-Randomized Portion of the Study with 
Rituximab (Cohorts C and D)Closed to 
Enrollment ............................................................................. 59
3.1.2
All Patients on Rituximab-Containing 
Arms/Cohorts......................................................................... 60
3.1.3
Obinutuzumab-Containing Regimen with 
DCDS4501A (Cohorts E, G, and H) ...................................... 60
3.1.3.1
Obinutuzumab-Containing Regimen in Phase Ib: 
Safety Run-In (Cohort E) ....................................................... 61
3.1.4
Follicular NHL Patients for Rituximab-Containing 
Arms/Cohorts......................................................................... 61
3.1.5
Follicular NHL Patients for 
Obinutuzumab-Containing Cohorts ....................................... 62
3.1.6
DLBCL Patients for Rituximab-Containing 
Arms/Cohorts......................................................................... 62
3.1.7
DLBCL Patients for Obinutuzumab-Containing 
Cohorts.................................................................................. 63
3.1.8
Crossover Treatment (Randomized Patients in 
Arms A and B Only)............................................................... 63
3.2
Rationale for Study Design.................................................... 65
3.2.1
Rationale for the PK Sample Schedule ................................. 66
3.3
Outcome Measures ............................................................... 67
3.3.1
Safety Outcome Measures .................................................... 67
3.3.2
Pharmacokinetic/Pharmacodynamic Outcome 
Measures............................................................................... 67
3.3.3
Activity Outcome Measures................................................... 68


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3.3.4
Exploratory Outcome Measures ............................................ 69
3.4
Safety Plan ............................................................................ 69
3.4.1
Safety Run-In Analysis .......................................................... 70
3.4.2
Internal Monitoring Committee............................................... 71
3.4.3
Risks Associated with DCDT2980S and 
DCDS4501A.......................................................................... 72
3.4.3.1
Infusion-Related Events......................................................... 72
3.4.3.2
Tumor Lysis Syndrome.......................................................... 73
3.4.3.3
Bone Marrow Toxicity/Neutropenia........................................ 73
3.4.3.4
Immunogenicity ..................................................................... 73
3.4.3.5
Peripheral Neuropathy........................................................... 74
3.4.3.6
Reproductive Toxicity ............................................................ 74
3.4.3.7
Hyperglycemia....................................................................... 74
3.4.3.8
Hepatotoxicity........................................................................ 74
3.4.3.9
Commonly Reported Side Effects.......................................... 75
3.4.4
Risks Associated with Rituximab Therapy and 
Their Management ................................................................ 75
3.4.4.1
Infusion Reactions................................................................. 75
3.4.4.2
Management of Severe Infusion Reactions........................... 75
3.4.4.3
Tumor Lysis Syndrome.......................................................... 76
3.4.4.4
Hepatitis B Reactivation with Related Fulminant 
Hepatitis and Other Viral Infections ....................................... 76
3.4.4.5
Cardiovascular Events........................................................... 77
3.4.4.6
Bowel Obstruction and Perforation........................................ 77
3.4.4.7
Immunization ......................................................................... 77
3.4.5
Risks Associated with Obinutuzumab Therapy...................... 77
3.4.5.1
Infusion-Related Reactions and Hypersensitivity 
Reactions (Including Anaphylaxis)......................................... 78
3.4.5.2
Tumor Lysis Syndrome.......................................................... 78
3.4.5.3
Neutropenia........................................................................... 78
3.4.5.4
Thrombocytopenia................................................................. 79
3.4.5.5
Infection................................................................................. 79
3.4.5.6
Immunization ......................................................................... 80
3.4.5.7
Worsening of Preexisting Cardiac Condition ......................... 80


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3.5
Minimization of Bias............................................................... 80
3.6
Administrative Structure......................................................... 80
3.7
Compliance with Laws and Regulations ................................ 81
4.
MATERIALS AND METHODS .................................................................... 81
4.1
Patients.................................................................................. 81
4.1.1
Inclusion Criteria.................................................................... 81
4.1.2
Exclusion Criteria................................................................... 82
4.2
Method of Treatment Assignment.......................................... 83
4.3
Study Treatment.................................................................... 84
4.3.1
DCDT2980S and DCDS4501A.............................................. 84
4.3.1.1
Formulation and Storage ....................................................... 84
4.3.1.2
Dosage and Administration.................................................... 85
4.3.1.3
Dosage Modification .............................................................. 86
4.3.1.4
Schedule Modification............................................................ 87
4.3.1.5
Infusion Reaction................................................................... 87
4.3.1.6
Neutropenia........................................................................... 90
4.3.1.7
Peripheral Neuropathy........................................................... 91
4.3.1.8
Hyperglycemia....................................................................... 91
4.3.2
Rituximab............................................................................... 92
4.3.2.1
Formulation............................................................................ 92
4.3.2.2
Dosage, Administration, and Storage .................................... 92
4.3.2.3
Dosage Modification .............................................................. 93
4.3.2.4
Schedule Modification............................................................ 93
4.3.2.5
Infusion Reaction................................................................... 94
4.3.3
Obinutuzumab ....................................................................... 94
4.3.3.1
Formulation............................................................................ 94
4.3.3.2
Dosage, Administration, and Storage .................................... 94
4.3.3.3
Dosage Modification .............................................................. 96
4.3.3.4
Schedule Modification............................................................ 96
4.3.3.5
Thrombocytopenia................................................................. 97
4.3.3.6
Febrile Neutropenia ............................................................... 97
4.3.4
Investigational Medicinal Product Accountability ................... 98
4.4
Concomitant and Excluded Therapies................................... 98


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4.4.1
Concomitant Therapy ............................................................ 98
4.4.2
Excluded Therapy.................................................................. 99
4.5
Study Assessments ............................................................. 100
4.5.1
Definitions of Study Assessments ....................................... 100
4.5.1.1
Medical History and Demographics ..................................... 100
4.5.1.2
Vital Signs............................................................................ 100
4.5.1.3
Physical Examination .......................................................... 100
4.5.1.4
Laboratory Assessments ..................................................... 101
4.5.1.5
Electrocardiogram Assessments ......................................... 102
4.5.1.6
Pharmacokinetic and Pharmacodynamic 
Assessments ....................................................................... 103
4.5.1.7
Immunogenicity Assessments ............................................. 103
4.5.1.8
Tumor Response Assessments........................................... 104
4.5.1.9
Exploratory Research .......................................................... 107
4.5.1.10
Patient-Reported Outcomes ................................................ 108
4.5.2
Screening and Pretreatment Assessments.......................... 108
4.5.3
Assessments During Treatment .......................................... 109
4.5.4
Study Treatment Completion Visit ....................................... 109
4.5.5
Crossover Treatment Completion Visit ................................ 110
4.5.6
Follow-Up Assessments ...................................................... 110
4.5.6.1
Follow-Up Assessments for Rituximab-
Containing Regimens .......................................................... 111
4.5.6.2
Follow-Up Assessments for Obinutuzumab-
Containing Regimens .......................................................... 111
4.6
Patient Discontinuation........................................................ 111
4.6.1
Discontinuation from Treatment........................................... 111
4.6.2
Discontinuation from Study.................................................. 112
4.7
Study Discontinuation.......................................................... 112
4.8
Post-Trial Access................................................................. 112
4.9
Assay Methods.................................................................... 112
4.9.1
Total DCDT2980S/DCDS4501A Antibody ELISA................ 112
4.9.2
Antibody-Conjugated MMAE (MMAE Affinity 
Capture Enzyme-Release LC/MS-MS)................................ 112
4.9.3
Free MMAE LC-MS/MS....................................................... 113


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4.9.4
Rituximab ELISA ................................................................. 113
4.9.5
Obinutuzumab ELISA .......................................................... 113
4.9.6
Anti-Therapeutic Antibody ................................................... 113
4.9.7
Biomarker Assays................................................................ 113
4.10
Statistical Methods .............................................................. 113
4.10.1
Analysis of the Conduct of the Study................................... 113
4.10.2
Safety Analysis.................................................................... 114
4.10.3
Pharmacokinetic and Pharmacodynamic 
Analyses.............................................................................. 114
4.10.4
Activity Analyses.................................................................. 115
4.10.5
Exploratory Analyses........................................................... 116
4.10.6
Handling of Missing Data..................................................... 116
4.10.7
Determination of Sample Size ............................................. 116
4.11
Data Quality Assurance....................................................... 118
5.
ASSESSMENT OF SAFETY..................................................................... 118
5.1
Safety Parameters and Definitions ...................................... 118
5.1.1
Adverse Event ..................................................................... 118
5.1.2
Serious Adverse Event ........................................................ 119
5.1.3
Protocol-Defined Adverse Events of Special 
Interest/Non-Serious Expedited Adverse Events................. 120
5.2
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 120
5.2.1
Adverse Event Reporting Period ......................................... 120
5.2.2
Eliciting Adverse Events ...................................................... 121
5.2.3
Assessment of Severity and Causality of Adverse 
Events.................................................................................. 121
5.3
Procedures for Recording Adverse Events.......................... 123
5.3.1
Recording Adverse Events on the eCRF............................. 123
5.3.1.1
Diagnosis versus Signs and Symptoms............................... 123
5.3.1.2
Adverse Events Occurring Secondary to Other 
Events.................................................................................. 123
5.3.1.3
Persistent or Recurrent Adverse Events.............................. 123
5.3.1.4
Abnormal Laboratory Values ............................................... 124
5.3.1.5
Abnormal Vital Sign Values ................................................. 124


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5.3.1.6
Abnormal Liver Function Tests............................................ 125
5.3.1.7
Deaths ................................................................................. 125
5.3.1.8
Preexisting Medical Conditions............................................ 125
5.3.1.9
Worsening of Baseline Hematologic Malignancy................. 126
5.3.1.10
Hospitalization, Prolonged Hospitalization or 
Surgery................................................................................ 126
5.3.1.11
Pregnancy ........................................................................... 126
5.4
Expedited Reporting Requirements for Serious 
Adverse Events ................................................................... 127
5.4.1
Reporting Requirements for 
Fatal/Life-Threatening SAEs Related to 
Investigational Product ........................................................ 127
5.4.2
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest.................................................................... 127
5.5
Type and Duration of Follow-Up of Patients after 
Adverse Events ................................................................... 128
5.6
Post-Study Adverse Events................................................. 128
6.
INVESTIGATOR REQUIREMENTS.......................................................... 129
6.1
Study Initiation..................................................................... 129
6.2
Study Completion ................................................................ 130
6.3
Informed Consent Form....................................................... 131
6.4
Communication with the Institutional Review 
Board or Ethics Committee.................................................. 132
6.5
Study Monitoring Requirements .......................................... 132
6.6
Electronic Case Report Forms............................................. 132
6.7
Source Data Documentation................................................ 133
6.8
Use of Computerized Systems ............................................ 133
6.9
Study Medication Accountability.......................................... 134
6.10
Disclosure of Data ............................................................... 134
6.11
Retention of Records........................................................... 134
7.
REFERENCES ......................................................................................... 136


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LIST OF TABLES
Table 1
Management of Infusion-Related Symptoms for All Study 
Drugs .......................................................................................... 89
Table 2
Administration of First and Subsequent Infusions of 
Obinutuzumab............................................................................. 95
Table 3
Potential 90% Interval Estimates for the True Response 
Probability ................................................................................. 117
Table 4
Adverse Event Grading (Severity) Scale................................... 122
Table 5
Causal Attribution Guidance ..................................................... 122
LIST OF FIGURES
Figure 1
CD22 Expression Levels on B-Cell Tumor Cells......................... 38
Figure 2
CD79b Expression Levels on B-Cell Tumor Cells....................... 43
Figure 3a
Study Schema for Rituximab-Containing Arms/Cohorts 
(Closed to Enrollment) ................................................................ 58
Figure 3b
Study Schema for Obinutuzumab-Containing Arms/Cohorts ...... 58


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LIST OF APPENDICES
Appendix A1 Study Flowchart:  Initial Study Treatment (Arms AB, 
Cohorts CD)............................................................................ 139
Appendix A2 Study Flowchart:  Crossover Treatment (Patients 
Randomized to Arms A or B Only)............................................ 144
Appendix A3 Study Flowchart for Obinutuzumab-Containing Cohorts (E, 
GH):  Initial Study Treatment................................................... 147
Appendix A-4 Study Flowchart: Post-Treatment Follow-Up for 
Rituximab-Containing Regimens (Arms A-B, Cohorts CD) ..... 151
Appendix A-5 Study Flowchart: Post-Treatment Follow-Up for 
Obinutuzumab-Containing Regimens (Cohorts E, G-H) ........... 153
Appendix B-1 Serum and Plasma Pharmacokinetic Schedule for 
DCDT2980S/DCDS4501A and Rituximab, and ATA 
Schedule for DCDT2980S/DCDS4501A (For Patients 
Receiving Rituximab on Day 1 and 
DCDT2980S/DCDS4501A on Day 2 of Every Cycle) 
(Arms A-B, Cohorts C-D) .......................................................... 155
Appendix B-2 Serum and Plasma Pharmacokinetic Schedule for Rituximab 
and DCDT2980S/DCDS4501A, and ATA Schedule for 
DCDT2980S/DCDS4501A for Patients Receiving Rituximab 
and DCDT29808S/DCDS4501A on Day 1 of Every 
Cycle Beginning Cycle 3 (Arms A-B, Cohorts C-D)................... 157
Appendix B3 Serum and Plasma Pharmacokinetic, Blood 
Pharmacodynamic, and ATA Schedule for Obinutuzumab 
and DCDS4501A (Cohorts E, GH).......................................... 159
Appendix C-1 Modified Response and Progression Criteria for NHL .............. 161
Appendix C2 Revised Criteria for Response Assessment: The Lugano 
Classification (Cohorts E, GH) ................................................ 165
Appendix D
Anaphylaxis Management......................................................... 170
Appendix E
M. D. Anderson Symptom Inventory (MDASI)........................... 171
Appendix F
Recommendations for the Use of White Blood Cell Growth 
Factors...................................................................................... 173


DCDT2980S and DCDS4501A—Genentech, Inc.
18/Protocol GO27834, Version A4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A RANDOMIZED, OPEN-LABEL, MULTICENTER, 
PHASE II TRIAL EVALUATING THE SAFETY AND
ACTIVITY OF PINATUZUMAB VEDOTIN 
(DCDT2980S) IN COMBINATION WITH RITUXIMAB 
OR POLATUZUMAB VEDOTIN (DCDS4501A) IN 
COMBINATION WITH RITUXIMAB AND A 
NON-RANDOMIZED PHASE IB/II EVALUATION OF 
POLATUZUMAB VEDOTIN IN COMBINATION WITH 
OBINUTUZUMAB IN PATIENTS WITH RELAPSED 
OR REFRACTORY B-CELL NON-HODGKIN’S 
LYMPHOMA
PROTOCOL NUMBER:
GO27834
VERSION NUMBER:
A4
EUDRACT NUMBER:
201100437784
IND NUMBER:
107713
STUDY DRUG:
Pinatuzumab vedotin (DCDT2980S); 
polatuzumab vedotin (DCDS4501A)
MEDICAL MONITORS:
, M.D.
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Please return a copy of the form to the CRO Monitor at your site.  Please retain the 
original for your study files.


DCDT2980S and DCDS4501A—Genentech, Inc.
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PROTOCOL SYNOPSIS
TITLE:
A RANDOMIZED, OPEN-LABEL, MULTICENTER, PHASE II 
TRIAL EVALUATING THE SAFETY AND ACTIVITY OF 
PINATUZUMAB VEDOTIN (DCDT2980S) IN COMBINATION 
WITH RITUXIMAB OR POLATUZUMAB VEDOTIN 
(DCDS4501A) IN COMBINATION WITH RITUXIMAB AND A 
NON-RANDOMIZED PHASE Ib/II EVALUATION OF 
POLATUZUMAB VEDOTIN IN COMBINATION WITH 
OBINUTUZUMAB IN PATIENTS WITH RELAPSED OR 
REFRACTORY B-CELL NON-HODGKIN’S LYMPHOMA
PROTOCOL NUMBER:
GO27834
VERSION NUMBER:
A4
EUDRACT NUMBER:
2011-004377-84
IND NUMBER:
107713
STUDY DRUG:
Pinatuzumab vedotin (DCDT2980S); 
polatuzumab vedotin (DCDS4501A)
PHASE:
II
INDICATION:
Relapsed or refractory B-cell non-Hodgkin's lymphoma
SPONSOR:
Genentech, Inc.
Objectives
Primary Objectives
The primary objectives of this study are the following:

To assess the safety and tolerability of the combination of DCDT2980S and rituximab 
administered to patients with relapsed or refractory follicular non-Hodgkin’s lymphoma 
(NHL) and diffuse large B-cell lymphoma (DLBCL)

To assess the safety and tolerability of the combination of DCDS4501A and rituximab 
administered to patients with relapsed or refractory follicular NHL and DLBCL

To assess the safety and tolerability of the combination of DCDS4501A and obinutuzumab 
when administered to patients with relapsed or refractory follicular NHL or DLBCL

To assess the anti-tumor activity of the combination of DCDT2980S and rituximab in 
patients with relapsed or refractory follicular NHL and DLBCL

To assess the anti-tumor activity of the combination of DCDS4501A and rituximab in 
patients with relapsed or refractory follicular NHL and DLBCL

To assess the anti-tumor activity of the combination of DCDS4501A and obinutuzumab in 
patients with relapsed or refractory follicular NHL and DLBCL based on 
18F-fluorodeoxyglucosepositron emission tomography (18F-FDG-PET; hereafter referred 
to as PET)/computed tomography (CT) complete response (CR) at the end of treatment 
according to Independent Review Committee (IRC) per Lugano 2014 response criteria


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The secondary safety objectives of this study are the following:

To assess the incidence of antibody formation to DCDT2980S, DCDS4501A, and 
obinutuzumab as measured by the formation of anti-therapeutic antibodies (ATAs)

To compare the safety and tolerability of the combination of DCT2980S and rituximab and 
DCDS4501A and rituximab or obinutuzumab
Activity Objectives
The secondary activity objective for rituximab-containing arms of the study is the following:

To compare the anti-tumor activity of the combination of DCT2980S and rituximab and 
DCDS4501A and rituximab or obinutuzumab
The secondary activity objectives for obinutuzumab-containing arms of the study are the 
following:

CR at end of treatment based on PET/CT, as determined by the investigator

Objective response (OR; CR or partial response [PR]) at end of treatment based on 
PET/CT as determined by investigator and IRC 

CR at end of treatment based on CT only as determined by the investigator and IRC

OR (CR or PR) at end of treatment based on CT only, as determined by the investigator 
and IRC

Best objective response (BOR, CR or PR) while on study based on PET/CT or CT only, 
as determined by the investigator
Pharmacokinetic Objectives
The pharmacokinetic (PK) objectives of this study are the following:

To characterize the pharmacokinetics of DCDT2980S and rituximab in patients with 
relapsed or refractory NHL when the two drugs are given in combination

To characterize the pharmacokinetics of DCDS4501A and rituximab or obinutuzumab in 
patients with relapsed or refractory NHL when the two drugs are given in combination
Patient-Reported Outcome Objectives
The objective of this study related to assessment of patient-reported outcomes (PRO) is the 
following:

To assess patient-reported tolerability to study treatment and the impact of study treatment 
on patient functioning, on the basis of PRO in Rituximab cohorts only
Biomarker Objectives
The objectives of this study related to assessment of biologic markers are the following:

To make a preliminary assessment of biologic markers that might act as predictors of 
DCDT2980S rituximab combination anti-tumor activity and allow assessment of response 
in different prognostic subgroups of DLBCL and follicular NHL

To make a preliminary assessment of biologic markers that might act as predictors of 
DCDS4501Arituximab or obinutuzumab combination anti-tumor activity and allow 
assessment of response in different prognostic subgroups of DLBCL and follicular NHL
Study Design
Description of Study
This is a Phase Ib/II, multicenter, open-label study.  Up to approximately 246 patients with 
relapsed or refractory follicular lymphoma (FL) and DLBCL will be enrolled at approximately 
3040 investigative sites worldwide.  Additional patients may be enrolled in order to obtain 
additional safety and/or efficacy data. Arms A and B and Cohort C are no longer enrolling 
patients.


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For Obinutuzumab Cohorts:
Only investigational sites in the United States will enroll patients into Cohort E.  Investigational 
sites in the United States and worldwide will participate in Cohorts G and H.
The study will be composed of a randomized portion and a non-randomized portion, as 
described in the protocol.
Rituximab-Containing Regimens with DCDT2980S or DCDS4501A
Randomized Portion of the Study (Arms A and B)Closed to Enrollment
Following determination of eligibility, patients within each disease group will be randomized in a 
1:1 ratio to receive one of two treatments:

Arm A:  Rituximab (375 mg/m2) followed by DCDT2980S (2.4 mg/kg) every 21 days;

Arm B:  Rituximab (375 mg/m2) followed by DCDS4501A (2.4 mg/kg) every 21 days
The first day of treatment constitutes Day 1 of each cycle.  A typical cycle is 21 days in duration.
A dynamic hierarchical randomization scheme will be employed with respect to the following 
stratification factors:

For patients with FL (see the protocol for definitions)
Rituximab refractory disease (no response or disease relapse 6 months from last 
rituximab treatment) versus rituximab relapsed disease (disease relapse after 
response 6 months from last rituximab treatment)

For patients with DLBCL (see the protocol for definitions)
Second-line versus third-line (or beyond) therapy
For second-line patients, disease relapse or no objective response (CR, unconfirmed 
CR [CRu], or PR) <12 months from the start of initial therapy versus disease relapse, 
after initial objective response (CR, Cru, or PR), 12 months from start of initial 
therapy 
For third-line patients, failure to achieve a CR or progression < 6 months from start of 
most recent therapy versus CR or progression ≥6 months from start of most recent 
therapy
No formal testing comparing the two treatment arms in the randomized portion of the study is 
planned.
Non-Randomized Portion of the Study with Rituximab (Cohorts C and D)Closed to 
Enrollment
Only select investigator sites that have agreed to participate in the non-randomized portion of 
the study will enroll patients into these cohorts.
Patients with relapsed or refractory follicular NHL will be enrolled in Cohorts C and D to receive 
rituximab (375 mg/m2) combined with DCDT2980S or DCDS4501A at a dose of 1.8 mg/kg.  The 
first day of treatment constitutes Day 1 of each cycle.  A typical cycle will be 21 days in duration.
The opening of either or both cohorts will be at the Sponsor’s discretion and only after the 
enrollment of patients with FL into the randomized portion of the study is completed.  Patients 
will not be randomized to receive one treatment or the other.  It is anticipated that Cohort C 
and D will be opened sequentially.  
All Patients on Rituximab-Containing Arms/Cohorts
All patients on rituximab-containing regimens, regardless of assigned arm/cohort, will receive 
DCDT2980S or DCDS4501A and rituximab administered by intravenous (IV) infusion on a 
21-day cycle.  For the first two cycles, rituximab will be administered by IV infusion on Day 1 
and DCDT2980S or DCDS4501A will be administered by IV infusion on Day 2.  In the absence 
of any infusion-related adverse events, rituximab and DCDT2980S or DCDS4501A may be 
administered on the same day (Day 1) in subsequent cycles beginning with the third cycle.  In 
this instance, rituximab will be administered first, followed by DCDT2980S or DCDS4501A.  In 
certain circumstancesfor example, infusion-related reactions (IRRs) requiring interruption or 
slowing of infusion raterituximab may be administered over 2 days (e.g., Day 1 and Day 2 of 
the cycle); in this case, DCDT2980S or DCDS4501A may be administered on Day 2 following 
completion of the rituximab infusion or on Day 3 of the cycle.


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Patients may receive treatments for up to 1 year (17 cycles on an every-21-day schedule) if not 
discontinued because of significant toxicity, disease progression, or withdrawal from study.
Patients will be evaluated for safety and efficacy according to the Schedules of Assessments 
outlined in the protocol.  Initial response assessments in this study will be performed every 
3 months from the initiation of therapy until study treatment completion or early termination 
(e.g., between Days 14 and 21 of Cycles 4 and 8 for those patients receiving at least 
eight 21-day cycles of treatment).  Additional response assessments for patients who proceed 
to crossover treatment will be performed as described in the protocol; response assessments 
for patients who discontinue study treatment (both initially assigned treatment and crossover 
treatment) for reasons other than disease progression will be performed as described in the 
protocol.
Responses to study treatment will be based on investigator assessments.  In addition, tumor 
assessment data will be transmitted to an Independent Review Facility (IRF) for collection and 
possible independent review.
Obinutuzumab-Containing Regimens with DCDS4501A (Cohorts E, G, and H)Closed to 
Enrollment
DCDS4501A at 1.8 mg/kg will be given in combination with obinutuzumab to patients with 
relapsed or refractory follicular NHL and DLBCL in two stages: (1) safety run-in and 
(2) expansion.
Study treatment will be given in 21-day cycles for both follicular NHL and DLBCL.  Patients will 
be treated for up to a total of 8 cycles.  For the first cycle, obinutuzumab will be administered by 
IV infusion on Days 1, 8, and 15.  DCDS4501A will be given on Day 2 for Cycle 1.  In the
absence of any infusion-related adverse events, obinutuzumab and DCDS4501A may be 
administered on the same day (Day 1) in subsequent cycles beginning with the second cycle.  
If obinutuzumab and DCDS4501A are administered on the same day, the study drugs will be 
given sequentially.  Obinutuzumab will be administered first, followed by DCDS4501A.  In 
certain circumstancesfor example, IRRs requiring interruption or slowing of infusion 
rateobinutuzumab may be administered over 2 days (e.g., Day 1 and Day 2 of the cycle); 
in this case, DCDS4501A may be administered on Day 2 following completion of the 
obinutuzumab infusion.
Obinutuzumab-Containing Regimen in Phase Ib: Safety Run-In (Cohort E)
This portion of the study will consist of a safety run-in that will evaluate the safety of 
DCDS4501A at 1.8 mg/kg in combination with obinutuzumab in 6 patients (Cohort E).  The 
safety run-in is described in detail in the protocol.  
Obinutuzumab-Containing Regimens in Phase II:  Expansion Stage (Cohorts G and H)
After the safety run-in has demonstrated that DCDS4501A at 1.8 mg/kg in combination with 
obinutuzumab is safe to administer, patients will be enrolled into two expansion cohorts based 
on histology of follicular NHL or DLBCL (Cohorts G and H respectively).  Forty patients will be 
enrolled into each expansion cohort.  An additional cohort(s) may be added in the future.
Follicular NHL Patients for Rituximab-Containing Arms/Cohorts
Patients with relapsed or refractory follicular NHL will be enrolled into the study as defined by 
the following:

Relapsed to regimens containing rituximab, defined as documented history of response 
(CR, CRu, or PR) of 6 months in duration from completion of all prior rituximab-containing 
regimens.  A rituximab-containing regimen is defined as rituximab as a single agent during 
induction and/or maintenance or in combination with other agents during induction and/or 
maintenance.


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
Refractory to any prior regimen containing rituximab, defined as no response to or 
progression within 6 months of completion of the last dose of rituximab therapy (either as 
monotherapy or in combination with chemotherapy), including:
Patients with progressive disease while receiving rituximab monotherapy, 
rituximab combined with chemotherapy, or rituximab maintenance therapy; patients 
must have received at least one full dose (375 mg/m2) of rituximab.
Patients with no objective response (PR or CR) to a rituximab-containing regimen 
consisting of at least 4 weekly doses of rituximab monotherapy or at least 4 cycles of 
rituximab combined with chemotherapy
Patients with disease relapse, after having achieved an objective response, within 
6 months of completion of the last dose of rituximab therapy in a regimen consisting of 
at least four weekly doses of rituximab monotherapy or at least 4 cycles of rituximab 
combined with chemotherapy
Enrollment of patients with refractory disease as defined above may be limited to no greater 
than 60% of the total follicular NHL cohort, in order to avoid overrepresentation of the refractory 
disease population.
Follicular NHL Patients for Obinutuzumab-Containing Cohorts
Patients with relapsed or refractory follicular NHL will be enrolled into the study as defined by 
the following:

Relapsed to prior regimen(s) after having a documented history of response (CR, CRu, or 
PR) of 6 months in duration from completion of regimen(s)  

Refractory to any prior regimen, defined as no response to the prior therapy, or progression 
within 6 months of completion of the last dose of therapy
DLBCL Patients for Rituximab-Containing Arms/Cohorts
Patients with relapsed or refractory DLBCL who are determined by the investigator to be 
ineligible for high-dose therapy with autologous stem cell rescue/stem cell transplant (SCT) will 
be enrolled into the study as defined by the following:

Second-line SCT-ineligible patients with progressive disease or no response (stable 
disease [SD]) 12 months from start of initial therapy (second-line refractory)

Second-line SCT-ineligible patients with disease relapse after initial response 12 months 
from start of initial therapy (second-line relapsed)

Third-line (or beyond) SCT-ineligible patients with progressive disease or no response 
(SD) 6 months from start of prior therapy (third-line refractory)

Third-line (or beyond) SCT-ineligible patients with disease relapse after initial response 
6 months from start of prior therapy (third-line relapsed)
Enrollment into any of the above four categories may be limited to no greater than 40% of the 
DLBCL cohort—and to no more than 60% of the two refractory categories combined—to avoid 
overrepresentation of any specific subpopulation, refractory patients in particular.
DLBCL Patients for Obinutuzumab-Containing Cohorts
Patients with relapsed or refractory DLBCL who are determined by the investigator to be 
ineligible for high-dose therapy with autologous stem cell rescue/SCT as determined by the 
investigator will be enrolled into the study as defined by the following:

Second-line SCT-ineligible patients with progressive disease or no response 
(SD) 12 months from start of initial therapy (second-line refractory)

Second-line SCT-ineligible patients with disease relapse after initial response 12 months 
from start of initial therapy (second-line relapsed)

Third-line (or beyond) SCT-ineligible patients with progressive disease or no response 
(SD) 6 months from start of prior therapy (third-line refractory)

Third-line (or beyond) SCT-ineligible patients with disease relapse after initial response 
6 months from start of prior therapy (third-line + relapsed)


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Crossover Treatment (Randomized Patients in Arms A and B Only)
Patients randomized to Arm A or Arm B who develop progressive disease may be eligible to 
receive crossover treatment consisting of rituximab and the other antibody-drug conjugate 
(ADC) or the other ADC alonefor example, Arm B treatment for patients who have disease 
progression while receiving Arm A treatment, and vice versaprovided the following conditions 
are met:

Patients must not have experienced a toxicity requiring the discontinuation of 
DCDT2980S/DCDS4501A treatment OR experienced toxicity during the last dose of study 
treatment that would preclude treatment with the crossover regimen.
Patients who had modifications to dosing and/or schedule on the initial study treatment 
will be permitted to receive crossover treatment in the absence of toxicities on the 
modified dose and/or schedule.  The dose and schedule of crossover treatment will be 
determined by the investigator and the Medical Monitor.
Patients who had rituximab discontinued and continued on single-agent 
DCDT2980S/DCDS4501A treatment may receive crossover treatment of single-agent 
DCDS4501A/ DCDT2980S.

Patients must have radiographically documented disease progression.

Patients must meet all inclusion and exclusion criteria described in the Inclusion Criteria 
and Exclusion Criteria sections below, except for those related to prior rituximab treatment.

Acceptable toxicity:  All study drug–related adverse events from the initial study treatment 
must have decreased to Grade 1 or baseline grade on or before the first day of treatment 
on the crossover regimen.  Exceptions may be allowed after a careful assessment and 
discussion of the benefit-risk balance with the patient by the investigator and approval from
the Medical Monitor.

Administration of crossover treatment must be in the best interests of the patient as 
determined after a careful assessment and discussion of benefit-risk balance with the 
patient by the investigator and approval from the Medical Monitor.

A tumor biopsy (described in the protocol) will be required for patients with safely accessible 
site of disease, defined as requiring only local anesthesia and, in general, excluding the 
brain, lungs or any internal organs that may subject patients to significant risk. 
Patients for whom a safely accessible site of disease is not present may still receive 
crossover treatment without undergoing a biopsy.  Eligibility to receive crossover 
treatment should be discussed with and approved by the Medical Monitor.
A tumor biopsy of a safely accessible site of disease is optional for patients who are 
not eligible for study cross over. 
Patients who are determined to be eligible for study cross over will be treated as follows:

Assessments obtained at the initial study treatment discontinuation visit (described in the 
protocol) may be used as screening assessments for crossover treatment.  The following 
re-screening assessments must be repeated/obtained within 1 week prior to starting 
treatment on the crossover regimen, in order to re-establish baseline pretreatment clinical 
and disease status:  targeted physical exam, Eastern Cooperative Oncology Group (ECOG) 
status, and hematology and serum chemistry laboratory tests.
Re-screening tests for hepatitis B and C do not need to be performed unless there is 
clinical suspicion of hepatitis B and/or C positivity.
A radiographic tumor assessment must also be performed, unless already done to 
document disease progression, within 6 weeks prior to starting crossover treatment.

Crossover treatment will begin no later than 42 days after the last dose of the prior study 
treatment.
Patients will be treated with the crossover treatment until a second disease progression event 
relative to the tumor assessment, documenting progressive disease on the initial study 
treatment, clinical deterioration, and/or intolerance to the crossover treatment for up to a 
maximum of 1 year (17 cycles on an every-21-day schedule).  Patients will be evaluated for 
safety and efficacy according to the schedules of assessments outlined in the protocol.  


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Response assessments for patients who discontinue study treatment for reasons other than 
disease progression will be performed as described in the protocol. 
Clinical data and exploratory data derived from tumor biopsies obtained prior to crossover 
treatment will be monitored on an ongoing basis.  Genentech has the right to restrict or suspend 
enrollment into crossover treatment at any time.  Reasons for this may include, but are not 
limited to, the following:

The incidence or severity of adverse events during crossover treatment indicates a potential 
safety hazard to patients.

Patient enrollment into crossover treatment is unsatisfactory.

Data recording is inaccurate or incomplete. 

Patients who are enrolled into the non-randomized portion of the study (Cohorts C, D, E, G, 
and H) will not have the option to receive crossover treatment upon disease progression.
Number of Patients
Up to approximately 246 patients with relapsed or refractory FL and DLBCL will be enrolled at 
approximately 3040 investigative sites worldwide.  Additional patients may be enrolled in order 
to obtain additional safety and/or efficacy data. 
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form(s)

Age 18 years 

ECOG Performance Status of 0, 1, or 2

Life expectancy of at least 12 weeks

History of histologically documented relapsed or refractory Grades 13a FL or relapsed or 
refractory DLBCL

Availability of an archival or freshly biopsied tumor tissue sample must be confirmed for 
study enrollment.

Have a clinical indication for treatment as determined by the investigator

Must have at least one bidimensionally measurable lesion (1.5 cm in its largest dimension 
by computed tomography [CT] scan or magnetic resonance imaging [MRI])

Laboratory values (including patients with hepatic or renal involvement), as follows:
AST and ALT 2.5ULN
Total bilirubin 1.5ULN
Platelet count 75,000/mm3 (unless thrombocytopenia clearly due to marrow 
involvement of NHL and/or disease-related immune thrombocytopenia)
Absolute neutrophil count 1000/mm3 (without growth factor support, unless 
neutropenia clearly due to marrow involvement of NHL)
Total hemoglobin 9 g/dL (without transfusion support 14 days prior to screening, 
unless anemia clearly due to marrow involvement of NHL)
Serum creatinine 2.0 mg/dL or measured creatinine CL 50 mL/min

For female patients of childbearing potential and male patients with female partners of 
childbearing potential, agreement to use one highly effective form of nonhormonal 
contraception or two effective forms of nonhormonal contraception, including at least one 
method with a failure rate of 1% per year, through the course of study treatment and for 
12 months after the last dose of DCDT2980S, DCDS4501A, rituximab, or obinutuzumab 
(whichever is later) in women and at least 5 months after the last dose of DCDT2980S, 
DCDS4501A, rituximab, or obinutuzumab (whichever is later) in men


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A woman is considered not to be of childbearing potential if she is postmenopausal, 
defined by amenorrhea of 12 months duration and age 45 years, or has undergone 
hysterectomy and/or bilateral oophorectomy.
The following are considered highly effective forms of contraception:  1) true 
abstinence; 2) male sterilization (with post-procedure documentation of absence of 
sperm in the ejaculate).  For female patients, the sterilized male partner should be the 
sole partner.
The following are considered effective forms of contraception:  1) intrauterine device 
(IUD; copper IUD or hormonal IUDs only) or intrauterine system; 2) condom with 
spermicidal foam/gel/film/cream/suppository; 3) occlusive cap (diaphragm or 
cervical/vault cap) with spermicidal foam/gel/film/cream/suppository.
Males must agree to abstain from sperm donation for at least 5 months after the last 
dose of DCDT2980S or, DCDS4501A or, rituximab, or obinutuzumab (whichever is 
later).
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Prior use of any MAb, radioimmunoconjugate or ADC within 4 weeks before Cycle 1, Day 1

Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, 
or any investigational anti-cancer agent within 2 weeks prior to Cycle 1, Day 1
Adverse events except for sensory neuropathy from any previous treatments must be 
resolved or stabilized to Grade 2 prior to Cycle 1, Day 1.

Completion of autologous stem cell transplant within 100 days prior to Cycle 1, Day 1

Prior allogeneic stem cell transplant

Eligibility for autologous SCT (patients with relapsed or refractory DLBCL)

History of transformation of indolent disease to DLBCL

History of severe allergic or anaphylactic reactions to MAb therapy (or recombinant 
antibody-related fusion proteins)

History of other malignancy that could affect compliance with the protocol or interpretation 
of results
Patients with a history of curatively treated basal or squamous cell carcinoma of the 
skin or in situ carcinoma (e.g., of the cervix or breast) are allowed.  Patients with a 
malignancy that has been treated with curative intent will also be allowed if the 
malignancy has been in remission without treatment for 2 years prior to Cycle 1, 
Day 1.

Current or past history of CNS lymphoma

Current Grade 1 peripheral neuropathy

Evidence of significant, uncontrolled, concomitant diseases that could affect compliance 
with the protocol or interpretation of results, including significant cardiovascular disease 
(such as New York Heart Association Class III or IV cardiac disease, myocardial infarction 
within the last 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary 
disease (including obstructive pulmonary disease and history of bronchospasm)

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding 
fungal infections of nail beds) at study enrollment or any major episode of infection requiring 
treatment with IV antibiotics or hospitalization (relating to the completion of the course of 
antibiotics) within 4 weeks prior to Cycle 1, Day 1

Recent major surgery within 6 weeks prior to Cycle 1, Day 1, other than for diagnosis


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
Presence of positive test results for hepatitis B (hepatitis B surface antigen and/or total 
anti-HBc) or hepatitis C (HCV antibody)
Patients who are positive for anti-HBc are eligible only if polymerase chain reaction 
(PCR) is negative for HBV DNA and it is believed by both the investigator and Medical 
Monitor that it is in the patient’s best interest to participate. 
Patients who are positive for HCV antibody must be negative for HCV by PCR to be 
eligible for study participation.

Vaccination with a live vaccine within 28 days prior to treatment

Known history of HIV seropositive status

Women who are pregnant or lactating

Ongoing corticosteroid use 30 mg/day prednisone or equivalent
Patients receiving corticosteroid treatment 30 mg/day prednisone or equivalent must 
be documented to be on a stable dose prior to study enrollment and initiation of 
therapy
Length of Study
The length of study will be the time from screening of the first enrolled patient through 2 years 
after the Treatment Completion Visit for the last enrolled patient on an obinutuzumab-containing 
regimen.  The length of the study for the obinutuzumab-containing cohorts is expected to be 
approximately 48 months.
End of Study
The end of study is defined as the timepoint at which patients enrolled in the 
obinutuzumab-containing regimens in the study have had at least 2 years of follow-up from the 
time of the Treatment Completion Visit or have discontinued from the study.
Outcome Measures
Safety Outcome Measures
The safety and tolerability of the combination of DCDT2980S and rituximab and DCDS4501A 
and rituximab or obinutuzumab will be assessed using the following safety outcome measures:

Incidence, nature, and severity of adverse events

Incidence of anti-DCDT2980S, anti-DCDS4501A, or anti-obinutuzumab antibodies

Changes in vital signs

Changes in laboratory values
The determination of the DCDS4501A RP2D in combination with obinutuzumab will be 
assessed using the following primary safety outcome measures for the Phase Ib portion of the 
study:

Incidence and nature of DLTs

Incidence, nature, and severity of adverse events and serious adverse events

Changes in vital signs, physical findings, ECGs, and clinical laboratory values during and 
following study treatment administration
Pharmacokinetic/Pharmacodynamic Outcome Measures
The following PK parameters will be derived from the serum concentration–time profiles of total 
antibody (the sum of conjugated and unconjugated antibody), including rituximab or 
obinutuzumab, and plasma concentration-time profiles of antibody-conjugated monomethyl 
auristatin E (acMMAE) and free MMAE following administration of DCDT2980S or DCDS4501A, 
when appropriate, as data allow:

Total exposure (area under the concentration-time curve [AUC])

Maximum plasma and serum concentration (Cmax)

Clearance (CL)


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
Terminal half-life (t1/2)

Steady-state volume of distribution (Vss)
Compartmental, non-compartmental, and/or population methods may be used.  Other 
parameters, such as accumulation ratio and trough plasma and serum concentration (Cmin), may 
also be calculated.
The following PD outcome measures will be assessed when appropriate, as data allow:

Peripheral blood B-cell depletion and recovery.  For each visit at which CD19+ B-cell 
measurements are taken, B-cell data will be listed for each patient by dose level as follows:
Absolute blood cell counts
Percent change relative to the baseline blood counts
CD19+ B-cell recovery, defined as the timepoint when the values return to baseline 
levels or 50% of baseline levels
Activity Outcome Measures
The following activity outcome measures will be assessed for rituximab-containing arms/cohorts 
(Arms A and B, Cohort C):

Objective response, defined as a PR or CR

Duration of objective response, defined as the duration of time from the first occurrence of a 
documented objective response to time of relapse or death from any cause

Progression-free survival (PFS), defined as the duration from initial randomization to the 
first occurrence of progression or death within 30 days of the last administration of study 
drug, whichever occurs first

Overall survival (OS), defined as the duration from the date of randomization/enrollment to 
the date of death from any cause
Objective response and disease progression will be determined using standard criteria for NHL.
The following activity outcome measures will be assessed for obinutuzumab-containing cohorts 
(Cohorts E, G, and H) according to Lugano 2014 Response Criteria (Cheson et al. 2014):
The primary activity outcome measure will be assessed by: 

CR at end of treatment (68 weeks after Cycle 6 Day 1 or last dose of study medication) 
based on PET/CT, as determined by the IRC
The following secondary efficacy outcome measures will be assessed:

OR (CR or PR) at end of treatment based on PET/CT as determined by the investigator 
and IRC

CR at end of treatment based on CT only, as determined by the investigator and IRC 

OR (CR or PR) at end of treatment based on CT only as determined by the investigator and 
IRC 

BOR (CR or PR) while on study based on PET/CT or CT only, as determined by the 
investigator
Exploratory Outcome Measures
The exploratory outcome measures will include, but will not be limited to, the following: 

Confirmation and quantitation of CD22, CD79b, and CD20 expression levels in either 
archival or freshly obtained (when available) tumor specimens (tumor biopsies, 
bone marrow biopsies, peripheral blood) by immunohistochemistry/flow 
cytometry/quantitative reverse transcriptase polymerase chain reaction (qRT-PCR)

Additional assessments related to the understanding of the mechanism of action of 
DCDT2980S, DCDS4501A, rituximab, and obinutuzumab, mechanisms of resistance to 
DCDT2980S, DCDS4501A, rituximab, and obinutuzumab, and/or NHL pathogenesis may 
be included.


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
Treatment and disease symptom assessments using the M.D. Anderson Symptom 
Inventory (MDASI) in rituximab-containing cohorts only
The following exploratory efficacy outcome measures will be assessed:

DOR, defined as the time from the date of the first occurrence of a documented CR or PR 
to the date of disease progression, relapse, or death from any cause, for the subgroup of 
patients with a best overall response of CR or PR, based on PET/CT and/or CT scans as 
determined by the investigator assessment.  For patients achieving a response who have 
not experienced disease progression, relapse, or died prior to the time of the analysis, the 
DOR will be censored on the date of last disease assessment.

PFS, defined as the time from date of randomization or first treatment (for G-containing 
arms) to the first occurrence of progression or relapse, or death from any cause, based on 
PET/CT and/or CT scans as determined by the investigator assessment.

EFS, defined as the time from date of randomization or first treatment (for G-containing 
arms) to any treatment failure including disease progression relapse, initiation of new 
anti-lymphoma therapy, or death from any cause, whichever occurs first, based on PET/CT
and/or CT scans as determined by the investigator assessment

OS, defined as the time from the date of first treatment to the date of death from any cause
Investigational Medicinal Products
Test Product
Pinatuzumab Vedotin (DCDT2980S) and Polatuzumab Vedotin (DCDS4501A)
Patients will receive DCDT2980S or DCDS4501A at 1.8 mg/kg or 2.4 mg/kg by IV infusion on 
Day 1 or Day 2 for each cycle.  The total dose of DCDT2980S or DCDS4501A for each patient 
will be determined by the dose cohort to which the patient is assigned and depend on the 
patient’s weight within 96 hours prior to Day 1 of each cycle.
Rituximab
All patients in rituximab-containing arms/cohorts will receive DCDT2980S or DCDS4501A and 
rituximab administered by IV infusion on a 21-day cycle.  For the first two cycles, patients will 
receive rituximab 375 mg/m2 by IV infusion on Day 1 and DCDT2980S or DCDS4501A by IV 
infusion on Day 2.  In the absence of any infusion-related adverse events, rituximab 375 mg/m2
and DCDT2980S or DCDS4501A may be administered on the same day (Day 1) in subsequent 
cycles beginning with the third cycle.  In this case, rituximab will be administered first, followed 
by DCDT2980S or DCDS4501A.
Obinutuzumab
Patients in obinutuzumab-containing cohorts will receive DCDS4501A and obinutuzumab 
administered by IV infusion on a 21-day cycle.  For the first cycle, patients will receive 
obinutuzumab 1000 mg by IV infusion on Days 1, 8, and 15.  DCDS4501A will be given on 
Day 2 for Cycle 1.  In the absence of any infusion-related adverse events, obinutuzumab and 
DCDS4501A may be administered on the same day (Day 1) in subsequent cycles beginning 
with the second cycle.
Non-Investigational Medicinal Products
Not applicable.
Statistical Methods
The final analysis will be based on patient data collected until all patients discontinue from the 
study or the study is terminated by the Sponsor, whichever occurs first.  The analyses will be 
based on the safety evaluable population, defined as patients who received at least one dose of 
study treatment.  All summaries will be presented according to the disease-specific cohort, 
treatment group, and assigned dose level.
Analysis of the Conduct of the Study
Enrollment, major protocol violations, and reasons for discontinuations from the study will be 
summarized.
Demographic and baseline characteristics, such as age, sex, race/ethnicity, weight, duration of 
malignancy, and baseline ECOG Performance Status, will be summarized using means, 


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standard deviations, medians, and ranges for continuous variables and proportions for 
categorical variables.  All summaries will be presented overall and by treatment group, assigned 
dose level, and disease-specific cohort.
Study drug administration data will be listed by the disease-specific cohorts described in the 
protocol.  Any dose modifications will be flagged.  Means and standard deviations will be used 
to summarize the total doses of DCDT2980S, DCDS4501A, rituximab, and obinutuzumab
received.  All summaries will be presented by treatment group, assigned dose level, and 
disease-specific cohort.
Safety Analysis
Safety will be assessed through summaries of adverse events, changes in laboratory test 
results, changes in physical findings on physical examinations, and changes in vital signs.  All 
patients who receive any amount of DCDT2980S, DCDS4501A, rituximab, or obinutuzumab will 
be included in the safety analysis and will be assigned to the treatment group on the basis of 
the study treatment received.  Patients who have dose level changes from the initial assigned 
dose level will be summarized by the initial assigned dose level of DCDT2980S or DCDS4501A.
All adverse event data will be listed by study site, patient number, treatment group, 
disease-specific cohort, and cycle.  All adverse events occurring on or after treatment on Day 1 
of Cycle 1 will be summarized by mapped terms, appropriate thesaurus levels, and 
NCI CTCAE v4.0 toxicity grade.  In addition, all serious adverse events, including deaths will be 
listed separately and summarized.  
Selected laboratory data will be listed, with values outside of normal ranges identified.  The 
incidence of antibodies to DCDT2980S and DCDS4501A will be summarized.
Pharmacokinetic and Pharmacodynamic Analyses
Individual and mean serum concentrations of total DCDT2980S or DCDS4501A antibody 
(conjugated and unconjugated antibody) and rituximab or obinutuzumab and plasma 
concentrations of acMMAE and free MMAE versus time data will be tabulated and plotted by 
NHL disease subtype (relapsed or refractory follicular NHL or DLBCL).  The pharmacokinetics 
of the above analytes will be summarized by estimating the appropriate PK parameters 
(e.g., AUC, Cmax, CL, Vss, and t1/2).  Estimates for these parameters will be tabulated and 
summarized (mean, standard deviation, and range).  Non-compartmental, compartmental, 
and/or population methods will be used, as data allow. 
Exposure-response (safety and efficacy) analysis may be conducted with use of PK data and 
available drug effect (e.g., imaging, measures of tumor burden) and toxicity (e.g., clinical 
pathology) data, at the sponsor’s discretion.
In addition, population PK methods may be employed to manage sparse data and to investigate 
the effects of certain covariates on the pharmacokinetics of DCDT2980S and DCDS4501A, as 
data allow, and at the sponsor’s discretion.
Activity Analyses
Best overall response, duration of response, and PFS will be listed for all patients.
Overall response rate (ORR) from the initial study treatment will be calculated on the basis of 
data from patients who received study treatment.  Objective response is defined as CR or PR 
as determined by the investigator, on the basis of physical examinations, radiographic scans, 
and bone marrow examinations, using modified response criteria for NHL and confirmed by 
repeat assessments 4 weeks after initial documentation.  Any patient with insufficient data to 
determine response will be classified as a non-responder.
For patients in the rituximab-containing arms/cohorts with DLBCL, primary assessment of 
tumor response will be based on diagnostic imaging scansfor example, CT and/or MRI scans 
and PET/CT scans. For patients with FL enrolled in the rituximab-containing arms/cohorts, 
primary assessment of response will be based on CT scans only; the assessment of response 
in patients with FL based on PET/CT scans will be performed for exploratory purposes only.
For patients on obinutuzumab-containing cohorts, primary response assessment for both 
DLBCL and FL will be based on PET/CT scans using the updated 2014 Lugano Response 
Criteria. Patients in Cohorts E, G, and H will be evaluated with a PET/CT scan at screening, 
between Cycle 4 Day 15 and Cycle 5 Day 1, and at the end of treatment (6-8 weeks after 
completing treatment).  The efficacy analysis for these cohorts will, therefore, be different from 


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the analysis for Arms AB and Cohorts CD.  Subsequent imaging can be CT only.  Responses 
to study treatment will also be based on investigator assessments.
Among patients with an objective response, duration of response will be defined as the time 
from the initial documentation of a CR or PR to the time of disease progression or death.  If a 
patient does not experience death or disease progression before the end of the study, duration 
of response will be censored at the day of the last tumor assessment.
For the randomized portion of the study (Arms A and B), PFS is defined as the time from the 
date of randomization to the date of disease progression or death from any cause, whichever 
occurs first.  If a patient has not experienced progressive disease or death, PFS will be 
censored at the date of the last tumor assessment.  Patients with no post-baseline tumor 
assessment will be censored on the date of randomization.  For the non-randomized portion of 
the study (Cohorts C through H), PFS is defined as the time from the date of study enrollment to 
the date of disease progression or death from any cause, whichever occurs first.
For the randomized portion of the study (Arms A and B), OS is defined as the time from the date 
of randomization to the date of death from any cause.  For the non-randomized portion of the 
study (Cohorts C through H), OS is defined as the time from the date of study enrollment to date 
of death from any cause.
Exploratory Analyses
Assay results of possible predictive markers will be listed by treatment group and response 
status.
Frequencies and percentages of missing data for the PRO endpoints will be reported.  Dropouts 
(defined as patients withdrawing from treatment for reasons other than documented disease 
progression or death) will be summarized.
Summary statistics of the MDASI items, scales, and their changes from baseline will be 
calculated at each assessment timepoint.  The mean, standard error, and median of the 
absolute scores and the mean changes from baseline (and 95% CI) within and between study 
arms will be reported for the MDASI scales and single items, as well as the weekly averages of 
the worst symptom rating.  For change scores in the MDASI from baseline, patients without 
baseline scores will not be included in the analyses.  Line charts depicting the means and mean 
changes of subscales over time will be also provided.  
Repeated measures mixed-effects models will explore MDASI subscale scores with a baseline 
score and appropriate covariates added, as appropriate.
Handling of Missing Data
For the endpoint of objective response, patients without a post-baseline tumor assessment will 
be considered non-responders in the all-treated population analysis. 
For duration of response and PFS, data from patients who are lost to follow-up will be included 
in the analysis as censored observations on the last date that the patient is known to be 
progression free, defined as the date of the last tumor assessment, or, if no tumor assessments 
were performed, as the date of last study treatment plus 1 day.
Compliance to PRO data collection will be reported with summary statistics, including 
frequencies of reasons for non-compliance such as patient refusal to complete PRO data 
collection.  
Determination of Sample Size
For the randomized portion of the study (Arms A and B), a target of 120 patients will be enrolled 
in two separate cohorts of patients (40 in the follicular NHL cohort and 80 in the DLBCL cohort).  
The randomized portion of this study is non-comparative in nature.  No formal hypothesis 
testing is planned to compare the treatment arms.  Moreover, there is insufficient power to 
detect minimum clinically meaningful differences between the two treatment arms.  Genentech 
has judged the proposed sample size to provide sufficient precision in estimating the anti-tumor 
activity of DCDT2980S combined with rituximab or DCDS4501A combined with rituximab as 
measured by objective response.  For example, with the assumption of an observed response 
rate of 40%, a 90% confidence interval for the response rate would be approximately 22%58% 
(i.e., 40% 18%) for the follicular NHL cohort and approximately 27%53% (i.e., 40% 13%) 
for the DLBCL cohort.  With 40 patients, there is an 87% chance of observing at least one 
adverse event with a true incidence of 5%.


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For the non-randomized portions of the study (Cohorts C and D), approximately 20 patients will 
be enrolled into each arm, for a total of 40 patients.   With 20 patients under an observed 
response rate of 40%, the exact Clopper-Pearson 90% confidence interval for the response rate 
would be 22%61%.  With respect to the assessment of safety based upon a sample size of 
20 patients, the chance of observing at least one adverse event with a true incidence of 10% is 
88%.
For the obinutuzumab safety run-in cohort (Cohort E), 6 patients will be enrolled.  For the 
obinutuzumab expansion cohorts (Cohorts G and H), 40 patients with follicular NHL and 
40 patients with DLBCL will be enrolled at the RP2D to further evaluate safety and efficacy of 
the combination.  Table 3 in the protocol provides asymptotic 90% confidence intervals for the 
true probability of response for a range of observed proportions based upon a sample of 
40 patients.  A sample size of 40 patients is deemed sufficient to provide adequate precision on 
the point estimate and for the lower end of the 90% CI to rule out a clinically uninteresting rate 
of 45% assuming observed response rates of approximately 60% or higher (~24 responders 
observed among 40 patients).
Therefore, up to 252 patients may be enrolled in this study. 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
ac
antibody-conjugated
ADC
antibodydrug conjugate 
ADCC
antibody-dependent cellular cytotoxicity
ADCP
antibody-dependent cell-mediated phagocytosis
AE
adverse event
anti-HBc
hepatitis B core antibody
ASCO
American Society of Clinical Oncology
ATA
anti-therapeutic antibody
AUC
area under the concentration-time curve
AUC0-24
area under the concentration-time curve from 0 to 24 hours
AUCinf
area under the concentration-time curve from 0 to infinity
CDC
complement-dependent cytotoxicity 
CHOP
cyclophosphamide, doxorubicin, vincristine, and prednisone
CL
clearance 
CLL
chronic lymphocytic leukemia
Cmax
maximum plasma and serum concentration
Cmin
trough plasma and serum concentration
CR
complete response
CRu
unconfirmed response
CT
computed tomography (scan)
CTCAE
Common Terminology Criteria for Adverse Events
CVP
cyclophosphamide, vincristine, and prednisone
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DOR
duration of response
EC
ethics committee
eCRF
electronic Case Report Form 
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture 
EFS
event-free survival
EMA
European Medicines Agency
EORTC
European Organisation for Research and Treatment of 
Cancer
EOT
end of treatment
18F-FDG-PET
18F-fluorodeoxyglucosepositron emission tomography


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Abbreviation
Definition
FACS
fluorescence-activated cell sorting
FBS
fasting blood sugar
FDA
U.S. Food and Drug Administration
FDG
fluorodeoxyglucose
FL
follicular lymphoma
G
GA101 or obinutuzumab
G-CHOP
obinutuzumab, cyclophosphamide, doxorubicin, vincristine, 
and prednisone
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
HbsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HNSTD
highest non-severely toxic dose
HPW
highly purified water
ICH
International Council for Harmonisation
IgG1
immunoglobulin-G1 
IHC
immunohistochemistry
IL
interleukin
IMC
Internal Monitoring Committee
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
iNHL
indolent non-Hodgkin’s lymphoma
IP
interferon-inducible protein
IRB
Institutional Review Board
IRC
Independent Review Committee
IRF
Independent Review Facility
IRR
infusion-related reaction
ISH
in situ hybridization
IV
intravenous
IxRS
interactive voice or web-based response system
JC
John Cunningham
Kd
equilibrium dissociation constant
LC-MS/MS
liquid chromatography–tandem mass spectrometry
LMWH
low-molecular weight heparin
MCL
mantle cell lymphoma
MC-VC-PABC
maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl 


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Abbreviation
Definition
MDASI
M.D. Anderson Symptom Inventory
MMAE
monomethyl auristatin E 
MAb
monoclonal antibody
MRD
minimal residual disease
MRI
magnetic resonance imaging
MTD
maximum tolerated dose 
MZL
marginal zone lymphoma
NALT
new anti-lymphoma treatment
NCI
National Cancer Institute
NHL
non-Hodgkin’s lymphoma
NK
natural killer
NOAC
new oral anticoagulant
ORR
overall response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PE
polyethylene
PET
positron emission tomography
PD
pharmacodynamic
PFS
progression-free survival
PK
pharmacokinetic 
PML
progressive multifocal leukoencephalopathy
PP
polypropylene
PR
partial response
PRO
patient-reported outcomes
PVC
polyvinyl chloride
PUR
polyurethane
qRT-PCR
quantitative reverse transcriptase polymerase chain reaction
Q3W
every 3 weeks
R
rituximab
R-CHOP
rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone
RP2D
recommended Phase II dose
SAE
serious adverse event
SC
subcutaneous
SCID
severe combined immunodeficiency
SCT
stem cell transplant


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Abbreviation
Definition
SD
stable disease
SDV
source data verification
SmPC
Summary of Product Characteristics
STD10
severely toxic dose to 10%
SWFI
Sterile Water for Injection
t1/2
terminal half-life
TLS
tumor lysis syndrome 
TNF
tumor necrosis factor
ULN
upper limit of normal
Vss
steady-state volume of distribution


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1.
BACKGROUND
1.1
BACKGROUND ON DISEASE 
B-cell lymphoproliferative disorders are a heterogeneous group of malignancies, ranging 
from slow-growing indolent and incurable diseases with a median survival of 810 years 
(such as follicular non-Hodgkin’s lymphoma [NHL]) to more aggressive intermediate- to 
high-grade lymphomas (such as diffuse large-cell lymphoma), which can have a median 
survival of 6 months if left untreated or long-term remission in more than 50% of patients 
with appropriate treatment.  Diffuse large B-cell lymphoma (DLBCL) is the most common 
type of NHL accounting for approximately 30%40% of all new patients, whereas 
follicular lymphoma (FL) accounts for approximately 20%25% of new lymphomas.  
Despite advances in the clinical outcomes of patients with NHL using treatments such as 
the CD20-specific monoclonal antibody (MAb) rituximab (Rituxan®, MabThera®) in 
combination with chemotherapy, indolent B-cell malignancies remain incurable, as do 
approximately half of aggressive NHL patients.  Thus, there is still a need for treatments 
that can be combined with chemoimmunotherapy and can significantly extend 
disease-free and overall survival (OS) in these patients, with at least acceptable, if not 
superior, safety profiles.
1.2
BACKGROUND ON THE MOLECULES
1.2.1
DCDT2980S
1.2.1.1
Background and Preclinical Data
CD22 is a cell-surface antigen whose expression is restricted to all mature B cells except 
plasma cells.  It is expressed in a majority of the B cellderived malignancies, including 
nearly all NHL and chronic lymphocytic leukemia (CLL) samples tested (see Figure 1).  
Antibodies bound to CD22 are rapidly internalized, making CD22 ideally suited for 
targeted delivery of cytotoxic agents (Shan and Press 1995).  
DCDT2980S is an antibodydrug conjugate (ADC) that consists of a potent anti-mitotic 
agent, monomethyl auristatin E (MMAE) conjugated to a humanized immunoglobulin-G1 
(IgG1) anti-CD22 MAb, MCDT2219A, via a protease-labile linker, 
maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-VC-PABC).  
MMAE has a mode of action similar to vincristine, which is a component of standard 
chemotherapy used in lymphoma therapy.  This therapeutic approach takes advantage 
of the specific targeting capability of the antibody and the cytotoxic activity of MMAE.
Following internalization, the MMAE is deconjugated from DCDT2980S by lysosomal 
enzymes, binds to tubulin, and disrupts the microtubule network, resulting in inhibition of 
cell division and cell growth and induction of apoptosis (Doronina et al. 2003). 


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Figure 1
CD22 Expression Levels on B-Cell Tumor Cells
CLLchronic lymphocytic leukemia; DLBCLdiffuse large B-cell lymphoma; FLfollicular 
lymphoma; MCLmantle cell lymphoma; MFImean fluorescence intensity; MZLmarginal 
zone lymphoma.
CD22 expression levels (MFI) on B-cell tumor cells were assessed by flow cytometry in patients 
diagnosed with the following B-cell lymphomas:  CLL (n49), DLBCL (n59), FL (n58), 
MCL (n20), and MZL (n60). 
Comprehensive pharmacologic, pharmacokinetic (PK), pharmacodynamic (PD), and 
toxicology evaluations were conducted to support the use of DCDT2980S in clinical 
trials. DCDT2980S binds human CD22 with a high affinity (equilibrium dissociation 
constant [Kd] 1.70.2 nM) and showed similar binding affinity to cynomolgus monkey 
CD22.  No binding activity was observed with mouse and rat peripheral blood 
mononuclear cells (PBMCs).  
The unconjugated antibody MCDT2219A did not appear to induce antibody-dependent 
cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) in vitro.  
In contrast, DCDT2980S displayed potent and selective inhibition of cell proliferation in 
vitro (50% of the maximal inhibitory concentration [IC50] 0.33 nM) by cell viability 
assays.  Efficacy studies conducted in murine xenograft models of human lymphoma 
(CD22-positive WSU-DLCL2 and BJAB cell lines) showed that a single dose of 
DCDT2980S resulted in regression of tumor growth at doses ranging from 1 to 4 mg/kg.  
PD studies with DCDT2980S showed that a single dose of 16 mg/kg resulted in partial 
depletion of peripheral blood B cells in cynomolgus monkeys with a corresponding 
depletion in germinal center B cells in lymphoid tissue.
0
1000
2000
3000
CLL
DLBCL
FL
MCL
MZL
0
1000
2000
3000
CLL
DLBCL
FL
MCL
MZL


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The PK profiles of DCDT2980S were observed to be linear in rodents and moderately 
non-linear in cynomolgus monkeys over the tested dose range.  The non-linear 
clearance (CL) observed in cynomolgus monkeys with DCDT2980S is likely due to the 
contribution of B cell-mediated CL to the total CL.  The free MMAE concentrations in 
cynomolgus monkeys following DCDT2980S administration were generally 10,000 times 
lower than the concentration of DCDT2980S.  
Cynomolgus monkeys were selected as the most relevant nonclinical species for the 
toxicology and PK/PD studies of DCDT2980S, given the comparable sequence 
homology of human and cynomolgus monkey CD22, similar binding affinity of 
DCDT2980S to human and cynomolgus monkey CD22, and comparable tissue 
cross-reactivity in both human and cynomolgus monkey tissues.  DCDT2980S was well 
tolerated at doses of up to 3 mg/kg (highest non-severely toxic dose [HNSTD]) in 
monkeys and up to or greater than 10 mg/kg in rats (severely toxic dose to 10% [STD10] 
of rats 10 mg/kg).  Reversible bone marrow toxicity and associated hematopoietic 
changes were observed in both rats and monkeys treated with DCDT2980S or MMAE, 
suggesting that the toxicity of DCDT2980S is related to MMAE.  Additional effects on 
liver and lung in rats were minimal in severity and reversible and did not occur in 
cynomolgus monkeys, which may be due to differences in species sensitivity, exposure, 
and/or pharmacokinetics.  
Complete details of preclinical studies of DCDT2980S can be found in the DCDT2980S 
Investigator’s Brochure.
1.2.1.2
DCDT2980S Clinical Data
a.
Patient Enrollment
Both DCDT2980S monotherapy and combination therapy with rituximab have been 
studied in a Phase I study (Study DCT4862g) of patients with relapsed or refractory 
B-cell malignancies expected to express CD22, including indolent NHL, DLBCL, mantle 
cell lymphoma (MCL), and CLL.
All data presented herein is based on a data entry cutoff of 22 February 2013, with 
clinical data available from 65 patients with NHL (excluding patients with CLL) enrolled in 
dose-escalation and expansion cohorts.  These include 49 patients who were treated 
with single-agent DCDT2980S at doses ranging from 0.1 to 3.2 mg/kg administered 
intravenously every 21 days and 16 patients who were enrolled into two Phase Ib 
cohorts with DCDT2980S administered at doses of 1.8 mg/kg (5 patients) and 2.4 mg/kg 
(11 patients) in combination with 375 mg/m2 rituximab.
Enrollment into CLL dose escalation cohorts was closed on 31 May 2013.  Refer to the 
DCDT2980S Investigator Brochure for details regarding clinical data in CLL patients.


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b.
Pharmacokinetics
The pharmacokinetics of DCDT2980S have been characterized in the Phase I 
Study DCT4862g.  DCDT2980S was administered to patients with NHL at dose levels 
ranging from 0.1 to 3.2 mg/kg every 3 weeks (Q3W).  Three analytes were quantified:
antibody-conjugated MMAE (acMMAE), total antibody, and free MMAE. 
Preliminary PK analysis based on available data as of 22 June 2012 is summarized 
below.  
The mean value of CL estimates of acMMAE and total antibody of each dose level for 
doses of ≥1.0 mg/kg ranged from 17.6 to 21.3 mL/day/kg and from 10.5 to 
16.2 mL/day/kg, respectively.  Similar CL estimates for doses 1.0 mg/kg suggested 
dose-proportional increase of acMMAE and total antibody exposure.  CL estimates 
appeared to be slightly higher at doses 1.0 mg/kg (0.1, 0.25, and 0.5 mg/kg), although 
data from these dose levels are limited.  The CL of acMMAE was faster than that of total 
antibody at each dose level.  
In patients with NHL, the mean value of the steady-state volume of distribution (Vss) of 
acMMAE and total antibody of each dose level ranged from 69.2 to 130 mL/kg and from 
97.4 to 154 mL/kg, respectively, across the dose levels tested, approximating human 
serum volume.  Vss values did not appear to change substantially with dose.  The half-life 
for acMMAE and total antibody ranged from 2.9 to 7.0 days and from 4.4 to 13 days, 
respectively.  
For acMMAE and total antibody, the time to maximum concentration occurred 
immediately after infusion.  For free MMAE, the time to maximum concentration was 
approximately 2 to 3 days after infusion. Maximum plasma and serum concentration 
(Cmax) and area under the concentration-time curve from Time 0 to infinity (AUCinf) of free 
MMAE appeared to increase with dose across the dose levels tested.  A half-life of 
3-4 days for free MMAE was observed, which is relatively long and similar to that of its 
parent conjugate, suggesting formation ratelimited kinetics of free MMAE.  No 
accumulation of free MMAE is expected for the Q3W regimen.  The Cmax values of free 
MMAE in NHL patients were at least 100-fold lower than acMMAE concentrations at 
each dose level, suggesting a slow release of free MMAE from acMMAE and potentially 
fast elimination once it is formed. 
Preliminary comparisons of pharmacokinetics between patients with NHL and CLL (for 
which patients are enrolled into separate dose-escalation cohorts) treated with identical 
doses of DCDT2980S provide some insight into the factors that affect pharmacokinetics.  
Both acMMAE and total antibody were cleared faster in CLL patients than in NHL 
patients.  This observation is likely to be related to the high number of circulating B cells 
generally observed in CLL patients, which may result in significant target-mediated CL of 
DCDT2980S.  The free MMAE exposure in CLL patients was relatively low compared to 
that of its parent conjugate.  


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The exposure parameters (Cmax and AUCinf) of total antibody, acMMAE, and free MMAE 
were similar between DCDT2980S and DCDT2980S + rituximab at doses of 1.8 and 
2.4 mg/kg, based on preliminary data.  This observation suggests that when given in 
combination, rituximab does not impact the pharmacokinetics of DCDT2980S; the effect 
of DCDT2980S on rituximab pharmacokinetics will be assessed.
All observations will be verified with additional data from the ongoing Phase I study as 
well as this study. 
Refer to the DCDT2980S Investigator Brochure for complete and updated details.
c.
Safety
Dose Limiting Toxicity
Study DCT4862g utilizes a standard 33 dose-escalation cohort enrollment scheme.  
Patients enrolled into each dose-escalation cohort in Study DCT4862g have been 
observed for dose-limiting toxicities (DLT) for a minimum of 21 days after their first dose 
of DCDT2980S.  Any patient who did not complete the DLT observation period for any 
reason other than a DLT was replaced.
Separate dose-escalation cohorts enrolled patients with B-cell NHL and CLL.  For the 
NHL dose escalation, DLTs of Grade 4 neutropenia occurred in 1 patient out of 
3 DLT-evaluable patients in the 3.2 mg/kg single-agent cohort and 1 patient out of 
11 DLT-evaluable patients in the 2.4 mg/kg + rituximab cohort.  Consequently, 
DCDT2980S at 2.4 mg/kg was determined to be the recommended Phase II dose 
(RP2D) as both monotherapy and in combination with rituximab.  
For the CLL dose-escalation cohorts, one DLT was reported to date.  This Grade 5 event 
of febrile neutropenia resulted in the patient’s death.  Whereas the contribution of the 
study drug to the neutropenia could not be completely ruled out, other factors, including 
bone marrow involvement of disease that resulted in baseline anemia, thrombocytopenia 
and neutropenia, and clinical evidence of disease progression may have also played a 
contributory role.
Single-Agent DCDT2980S and DCDT2980S Combined with Rituximab in 
NHL
Forty-nine patients received single-agent DCDT2980S at a starting dose of 1.8 mg/kg 
(7 at 1.8 mg/kg, 42 at 2.4 mg/kg); 16 patients received DCDT2980S at a starting dose 
of 1.8 mg/kg in combination with rituximab (5 at 1.8 mg/kg, 11 at 2.4 mg/kg).  Overall 
the safety profile of DCDT2980S combined with rituximab did not differ from that of 
single-agent DCDT2980S.
Treatment-emergent hematologic and commonly reported nonhematologic adverse 
events for all grades in patients treated with single-agent DCDT2980S and DCDT2980S 
plus rituximab included neutropenia (29%), febrile neutropenia (3%), infection (system 
organ class; 43%), anemia (25%), thrombocytopenia (12%), peripheral neuropathy 


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(28%), diarrhea (40%), pyrexia (14%), nausea (34%), and fatigue (55%).  
Treatment-emergent Grade 3 adverse events included neutropenia (25%), febrile 
neutropenia (3%), infection (system organ class; 11%), anemia (5%), peripheral 
neuropathy (3%), diarrhea (5%), pyrexia (2%), and fatigue (3%).  Serious adverse 
events assessed by the treating investigator to be related to DCDT2980S were reported 
in 21% of patients.  Dose discontinuations for adverse events were reported in 20% of 
patients.
Refer to the DCDT2980S Investigator’s Brochure for complete and updated details 
related to safety.
d.
Efficacy in Non-Hodgkin’s Lymphoma
Investigator-based objective responses were observed in 17 of 43 (40%) patients treated 
with single-agent DCDT2980S and 5 of 15 (33%) patients treated with DCDT2980S 
combined with rituximab.  Among patients with relapsed or refractory DLBCL, 11 of 28 
(39%) objective responses (5 complete responses [CR] and 6 partial responses [PR]) 
were observed with single-agent DCDT2980S and 3 of 7 (43%; 2 CR, 1 PR) with 
DCDT2980S combined with rituximab.  Among patients with relapsed or refractory
indolent NHL (iNHL), 6 of 13 (46%) objective responses (2 CR, 4 PR) were observed 
with single-agent DCDT2980S and 1 of 4 (PR) with DCDT2980S combined with 
rituximab.  
Refer to the DCDT2980S Investigator Brochure for complete and updated details related 
to anti-tumor activity.
1.2.2
DCDS4501A
1.2.2.1
Background and Preclinical Data
CD79b is a cell-surface antigen whose expression is restricted to all mature 
B cells except plasma cells.  It is expressed in a majority of B cellderived malignancies, 
including nearly all NHL and CLL samples tested (see Figure 2) (Dornan et al. 2009).  
Antibodies bound to CD79b are rapidly internalized, making CD79b ideally suited 
for targeted delivery of cytotoxic agents (Polson et al. 2007, 2009).  
Similar to DCDT2980S, DCDS4501A is an ADC that contains a humanized 
immunoglobulin-G1 (IgG1) antihuman CD79b MAb (MCDS4409A) and MMAE linked 
through MC-VC-PABC.
Comprehensive pharmacologic, PK, PD, and toxicological evaluations were undertaken to 
support the entry of DCDS4501A into clinical trials.  Because DCDS4501A specifically 
recognizes CD79b on B cells of human but not on those of cynomolgus monkey, rat, or 
mouse, a surrogate ADC (DCDS5017A) that binds to cynomolgus monkey CD79b was 
generated to assess the antigen-dependent pharmacological, toxicological, and PK/PD 
activities in cynomolgus monkeys.  The structure, binding epitope, and binding affinity of 
the surrogate ADC are similar to those of DCDS4501A.


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Figure 2
CD79b Expression Levels on B-Cell Tumor Cells
CLLchronic lymphocytic leukemia; DLBCLdiffuse large B-cell lymphoma; 
FLfollicular lymphoma; MCLmantle cell lymphoma; MFImean fluorescence intensity; 
MZLmarginal zone lymphoma. 
CD79b expression levels (MFI) on B-cell tumor cells were assessed by flow cytometry in patients 
diagnosed with the following B-cell lymphomas:  CLL (n49), DLBCL (n59), FL (n58), 
MCL (n20), and MZL (n60).
DCDS4501A bound human CD79b with high affinity (Kd1.830.26 nM); the surrogate 
ADC also showed similar high binding affinity to cynomolgus monkey CD79b.  
DCDS4501A displayed potent and selective inhibition of tumor cell proliferation in vitro 
(IC500.071 nM0.01 nM) in cell viability assays.  Moderate ADCC but no CDC activity 
was observed with the unconjugated clinical candidate antibody MCDS4409A.  Both 
clinical and surrogate unconjugated antibodies showed no appreciable cytokine release 
when evaluated in in vitro cytokine release assays with PBMCs.  Moderate elevations 
in interleukin (IL)-1and interferon-inducible protein (IP)-10 were observed only with the 
unconjugated clinical antibody, however the clinical significance of these observations 
are not known because IL-1and IP-10 are not produced by B cells, are not involved in 
B-cell signaling through CD79b, and are not associated with cytokine-release syndromes 
in vivo.
Single intravenous (IV) doses of DCDS4501A resulted in inhibition of tumor growth in 
murine xenograft models of lymphoma.  Tumor regression was observed at doses 
ranging from 0.5 to 3 mg/kg.  In contrast, MCDS4409A showed no activity.  DCDS4501A 
administered at 5 mg/kg demonstrated better anti-tumor activity compared to a current 
standard-of-care regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, 
and prednisone [R-CHOP]) in xenograft models of NHL.  PD studies demonstrated that 
doses of the surrogate ADC ranging from 0.3 to 5 mg/kg resulted in a decrease of 


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peripheral blood B cells in cynomolgus monkeys.  A preferential decrease of proliferating 
B cells (CD20Ki67) compared to the resting B cells (CD20Ki67) ) by the surrogate 
ADC was demonstrated in cynomolgus monkeys, in line with the expected mechanism of 
action of an anti-mitotic agent, MMAE.
Due to B cellmediated CL, non-linear pharmacokinetics were observed with the 
surrogate ADC in cynomolgus monkeys following single IV doses of 0.33 mg/kg or four 
doses of 3 and 5 mg/kg given Q3W.  The total antibody exposure after the fourth dose 
increased approximately 1.2- to 1.5-fold compared to the first dose.  As expected, the 
toxicokinetic profile of the clinical ADC in rats and cynomolgus monkeys was linear in the 
tested dose range.  Consistent with the half-life of the clinical ADC, minimal 
accumulation was observed following weekly dosing in rats and no accumulation was 
observed following Q3W dosing in cynomolgus monkeys.  The free MMAE 
concentrations in plasma following administration of the clinical or surrogate ADCs were 
generally low and overall did not exceed 2 ng/mL, regardless of dose.  The overall 
incidence of anti-therapeutic antibodies (ATAs) was 20%67% following administration 
of the clinical or surrogate ADCs in cynomolgus monkeys; however, the ATAs did not 
appear to impact the toxicokinetic/PK parameter estimates.
In repeat-dose toxicity studies in rats and cynomolgus monkeys, DCDS4501A and 
the surrogate ADC were well tolerated in monkeys up to doses of 5 mg/kg and 3 mg/kg 
respectively, with 3 mg/kg considered the HNSTD.  In rats, DCDS4501A was well 
tolerated up to 6 mg/kg (STD1010 mg/kg).  The predominant antigen-independent 
findings associated with DCDS4501A or surrogate ADC exposure were reversible bone 
marrow toxicity and associated peripheral blood cell effects in both monkeys and rats.  
Administration of the surrogate ADC to monkeys also resulted in expected 
antigen-dependent reversible decreases in peripheral blood B cells and the 
disappearance of B-cell germinal centers in splenic lymphoid follicles at doses 3 mg/kg.  
Additional findings observed in rats but not in monkeys included thymic lymphoid 
depletion at 6 mg/kg, minimal to mild liver toxicities (at 6 mg/kg), lung toxicities at 
10 mg/kg in male animals only, and a slight increase in apoptosis and mitoses in multiple 
tissues, including skin and adnexa.  Hepatobiliary toxicity consisted of transient 
dose-dependent liver enzyme elevations accompanied by minimal to slight 
dose-dependent increases in mitotic figures/apoptosis in hepatocytes, sinusoidal cells, 
and bile duct epithelium as well as minimal to slight dose-dependent random focal 
hepatic necrosis.  Pulmonary toxicity was characterized by minimal to slight 
dose-dependent alveolar macrophage infiltration, sometimes accompanied by minimal to 
slight type II pneumocyte hyperplasia/hypertrophy.  These findings were consistent with 
the expected pharmacologic effect of MMAE on inducing mitotic arrest due to inhibition 
of tubulin polymerization.  Except for two individual instances (one female given 
10 mg/kg in the liver and one male given 10 mg/kg in the lung), these findings were 
completely reversible after a 6-week recovery period.  Non-reversible male reproductive 


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toxicity, characterized by degeneration of testicular seminiferous tubules, was observed 
in rats at all doses. 
Complete details of preclinical studies of DCDS4501A can be found in the DCDS4501A 
Investigator’s Brochure.
1.2.2.2
DCDS4501A Clinical Data
a.
Patient Enrollment
Both DCDS4501A monotherapy and combination therapy with rituximab are being 
studied in a Phase I study (Study DCS4968g) of patients with relapsed or refractory 
B-cell malignancies expected to express CD79b, including indolent NHL, DLBCL, MCL, 
and CLL.  
All data presented herein is based on a data entry cutoff of 28 February 2013, with 
clinical data available from 60 patients with NHL (excluding patients with CLL) enrolled in 
dose-escalation and expansion cohorts.  These include 51 patients who were treated 
with single-agent DCDS4501A ranging from 0.1 to 2.4 mg/kg administered intravenously 
every 21 days and 9 patients who were enrolled into a single Phase Ib cohort with 
DCDS4501A administered at a dose of 2.4 mg/kg in combination with 375 mg/m2
rituximab.
In the CLL dose-escalation cohorts, two DLTs were reported at the single-agent dose of 
1.8 mg/kg.  Enrollment into the CLL cohorts was stopped on 7 January 2013.  Refer to 
the DCDS4501A Investigator Brochure for details regarding clinical data in CLL patients.  
b.
Pharmacokinetics
The pharmacokinetics of DCDS4501A were characterized in the Phase I Study
DCDS4501A.  DCDS4501A was administered in patients with NHL at escalating doses 
of 0.1 to 2.4 mg/kg Q3W as monotherapy and following administration of rituximab in the 
Phase Ib cohort.  Three analytes were quantified: acMMAE, total antibody, and free 
MMAE. 
Preliminary PK analysis based on available data as of 22 June 2012 is summarized 
below.  The CL estimates of acMMAE and total antibody of each dose level is in the 
range of 14.9–21.2 mL/day/kg and 7.12–27.9 mL/day/kg, respectively.  CL estimates 
were similar across doses of 0.1–2.4 mg/kg tested, suggesting dose-proportional 
increase of acMMAE and total antibody exposure.  The CL of acMMAE was faster than 
that of total antibody at each dose level.  
The mean value of Vss of acMMAE and total antibody of each dose level ranged from 
61 to 80.8 mL/kg and from 59.4 to 114.3 mL/kg, respectively, across the dose levels 
tested, which approximated human serum volume. Vss values did not appear to change 
substantially with dose. The half-lives for acMMAE and total antibody are from 2.4 to 
5.5 days and 2.9 to 7 days, respectively. 


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In a single-agent dose-escalation study, for acMMAE and total antibody, the time to 
maximum concentration occurred immediately after infusion.  For free MMAE, the time to 
maximum concentration was approximately 2 to 3 days after infusion.  Cmax and AUCinf of 
free MMAE appear increased with dose across the dose levels.  A half-life of 3–4 days 
for free MMAE was observed, which is relatively long and similar to acMMAE and 
suggests formation ratelimited kinetics for free MMAE.  No accumulation of free MMAE 
is expected for the Q3W regimen.  The Cmax values of free MMAE in NHL patients were 
at least 100-fold lower compared with acMMAE concentrations at each dose level, 
suggesting a slow release of free MMAE from acMMAE and potentially fast elimination 
once it is formed.  
Preliminary comparisons of pharmacokinetics between patients with NHL and CLL (for 
which patients are enrolled into separate dose-escalation cohorts) treated with identical 
doses of DCDS4501A provide some insight into the factors that affect pharmacokinetics.  
Both acMMAE and total antibody were cleared faster in CLL patients than in NHL 
patients.  This observation is likely to be related to the high number of circulating B cells 
generally observed in CLL patients, which may result in significant target-mediated CL of 
DCDS4501A. The free MMAE exposure in CLL patients was relatively low compared 
with that of its parent conjugate.
To date, PK data for patients treated with DCDS4501A in combination with rituximab is 
limited.  Consequently, full comparison with single-agent DCDS4501A pharmacokinetics
is not possible.  On the basis of very limited data from 3 patients, total antibody 
pharmacokinetics was comparable between 2.4 mg/kg of DCDS4501A administered as 
a single agent and following rituximab administration, suggesting that when given in 
combination, rituximab does not affect the pharmacokinetics of DCDS4501A; the effect 
of DCDS4501A on rituximab pharmacokinetics will be assessed.  
All observations will be verified with additional data from the ongoing Phase I study as 
well as this study.
Refer to the DCDS4501A Investigator Brochure for complete and updated details.
c.
Safety
Dose-Limiting Toxicities
Study DCS4968g utilizes a standard 33 dose escalation cohort enrollment scheme.  
Patients enrolled into each dose-escalation cohort in Study DCS4968g have been 
observed for DLTs for a minimum of 21 days after their first dose of DCDS4501A.  
Any patient who did not complete the DLT observation period for any reason other than 
a DLT was replaced.
DLT of Grade 4 neutropenia occurred in 1 patient out of 10 DLT-evaluable patients in the 
2.4 mg/kg single-agent cohort and 1 patient out of 9 DLT-evaluable patients in the 
2.4 mg/kg rituximab cohort.  Doses of DCDS4501A greater than 2.4 mg/kg as 


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monotherapy or in combination with rituximab were not assessed.  Consequently, 
DCDS4501A at 2.4 mg/kg was therefore determined to be the RP2D as both 
monotherapy and in combination with rituximab.  
In the CLL dose-escalation cohorts, two DLTs were reported at the single-agent dose of 
1.8 mg/kg.  One patient had a Grade 4 neutropenia, and 1 patient had a Grade 4 
invasive fungal infection.  
Single-Agent DCDS4501A and DCDS4501A Combined with Rituximab
Fifty-two patients received single-agent DCDS4501A at a starting dose of 1.8 mg/kg 
(6 at 1.8 mg/kg, 45 at 2.4 mg/kg); an additional 9 patients received DCDS4501A at a 
dose of 2.4 mg/kg in combination with rituximab.  Overall, the safety profile of 
DCDS4501A combined with rituximab did not differ from that of single-agent 
DCDS4501A.
Treatment-emergent hematologic and commonly reported non-hematologic adverse 
events of all grades in patients treated with single-agent DCDS4501A and DCDS4501A 
plus rituximab included neutropenia (50%), febrile neutropenia (5%), infection (system 
organ class; 35%), anemia (13%), thrombocytopenia (18%), peripheral neuropathy 
(32%), diarrhea (43%), pyrexia (37%), nausea (35%), and fatigue (18%).  
Treatment-emergent Grade 3 adverse events included neutropenia (43%), febrile 
neutropenia (5%), infection (system organ class; 10%), anemia (8%), peripheral 
neuropathy (7%), diarrhea (3%), pyrexia (2%), and fatigue (5%).  Serious adverse 
events assessed by the treating investigator to be related to DCDS4501A were reported 
in 20% of patients. Dose discontinuations for adverse events were reported in 33% of 
patients.
Refer to the DCDS4501A Investigator’s Brochure for complete and updated details 
related to safety.  
d.
Efficacy
Investigator-based objective responses were observed in 28 of 49 (57%) patients treated 
with single-agent DCDS4501A and 7 of 9 patients (78%) treated with DCDS4501A 
combined with rituximab.  Among patients with relapsed or refractory DLBCL, objective 
responses were observed in 16 of 30 (53%; 4 CR, 12 PR) patients treated with 
DCDS4501A; 1 patient with DLBCL was treated with DCDS4501A combined with 
rituximab and achieved a PR.  Among patients with relapsed or refractory iNHL, 
objective responses were observed in 7 of 14 (50%; 2 CR, 5 PR) patients treated with 
single-agent DCDS4501A and 5 of 5 (100%; 2 CR, 3 PR) patients treated with 
DCDS4501A plus rituximab. 
Refer to the DCDS4501A Investigator’s Brochure for complete and updated details 
regarding anti-tumor activity.


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1.2.3
Rituximab
Rituximab has been shown to be an effective treatment for CD20-positive B-cell 
malignancies and is commonly used both as a single agent and in combination with 
cytotoxic chemotherapy.  Rituximab binds to CD20, a hydrophobic, transmembrane 
protein that is present on pre–B cells and mature B cells and in 90% of B-cell NHLs.  
It exerts its cytotoxic effects via complement-mediated B-cell lysis, ADCC, and induction 
of apoptosis (Cartron et al. 2004).
In the United States, rituximab has been approved by the U.S. Food and Drug 
Administration (FDA) for the following indications in NHL: as a single agent for the 
treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive 
B-cell NHL; for the treatment of relapsed or refractory, low-grade or follicular, 
CD20-positive B-cell NHL, including initial treatment weekly for eight doses and 
re-treatment (weekly for four doses) in patients who responded to an initial course of 
rituximab; for the treatment of low-grade, CD20-positive B-cell NHL, in combination with 
cyclophosphamide, vincristine, and prednisone (CVP) induction chemotherapy in 
previously untreated patients with follicular, CD20-positive NHL; as treatment in 
previously untreated patients with low-grade, CD20-positive NHL who achieve an 
objective response or stable disease (SD) following CVP induction; and as maintenance 
therapy for previously untreated follicular CD20-positive B-cell NHL after achieving a 
response to a regimen including chemotherapy and rituximab.
In the European Union, rituximab (MabThera®) is approved for the treatment of the 
following indications in NHL: treatment of patients with Stage III–IV follicular NHL who 
are chemotherapy-resistant or in their second or subsequent relapse after 
chemotherapy; treatment of patients with CD20-positive DLBCL in combination with 
cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy; as
front-line therapy in Stage III–IV follicular NHL in combination with CVP chemotherapy; 
as maintenance therapy in patients with relapsed or refractory, follicular NHL responding 
to induction treatment with CHOP or R-CHOP; and as maintenance treatment for 
patients with FL who have responded to initial treatment with rituximab plus 
chemotherapy.
Rituximab has also been approved for the treatment of CLL.  The European Medicines 
Agency (EMA) granted an approval for the use of rituximab in combination with 
chemotherapy for previously untreated CLL.  The FDA approved the use of rituximab in 
combination with fludarabine and cyclophosphamide for patients with previously 
untreated and previously treated CD20-positive CLL.  
Refer to the Rituximab Investigator’s Brochure for complete details regarding clinical 
data related to approved indications.  For rituximab safety information, refer to local 
rituximab prescribing information.


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1.2.4
Obinutuzumab
1.2.4.1
Obinutuzumab Mechanism of Action
Obinutuzumab ([G], also known as RO5072759, GA101, Gazyva, and Gazyvaro) is a 
humanized type II and glycoengineered anti-CD20 MAb, derived by humanization of the 
parental B-Ly1 mouse antibody and subsequent glycoengineering leading to the 
following characteristics (Mössner et al. 2010; Golay et al. 2013):

High-affinity binding to CD20 antigen on B cells

Type II binding mode to the CD20 antigen, leading to a more even distribution of 
bound antibody to the surface membrane of the B cell due to lack of CD20 
translocation into lipid rafts after antibody binding and low complement activation 
and low complement-dependent cytotoxicity related to the recognition of the CD20 
epitope 

Compared with the type I anti-CD20 antibodies rituximab or ofatumumab, increased 
ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) related to an 
improved binding of obinutuzumab to the different allotypes of FcRIIIa and FcRIIIb 
expressed by natural killer (NK) cells , monocytes/macrophages and neutrophils

Compared with rituximab, increased direct cell-death induction related to an elbow 
hinge amino exchange of the Fab region and type II binding of the CD20 epitope
Obinutuzumab received FDA approval in November 2013 and EMA approval in 
July 2014 on the basis of the CLL-11 Study BO21004 for patients with relapsed Chronic 
Lymphocytic Leukemia.  Obinutuzumab plus chlorambucil showed superiority over 
rituximab plus chlorambucil in all efficacy parameters such as overall response rate 
(ORR), complete remission rate (CRR), minimal residual disease (MRD), 
progression-free survival (PFS), event-free survival (EFS), and duration of response 
(DOR) (Goede et al. 2014).
Obinutuzumab is currently being explored in the treatment of lymphoid malignancies 
such as aggressive and indolent lymphomas (DLBCL, FL, and marginal zone lymphoma 
[MZL]).  Preliminary data suggest possible increased anti-lymphoma efficacy over 
rituximab, a hypothesis that is currently being explored in several randomized trials, 
including a Phase III study of R-CHOP versus G-CHOP in first-line treatment of DLBCL, 
a Phase III study of R-chemotherapy (CHOP, CVP, or bendamustine) followed by 
rituximab maintenance compared with G-chemotherapy (CHOP, CVP, or bendamustine) 
followed by obinutuzumab maintenance in first-line treatment of FL and MZL, and a 
Phase III study of obinutuzumab combined with bendamustine compared with 
bendamustine in patients with rituximab-refractory indolent NHL.
1.2.4.2
Obinutuzumab Nonclinical Toxicology
The nonclinical toxicology of obinutuzumab has been evaluated in repeat-dose studies in 
cynomolgus monkeys given weekly IV (30-minute infusion) up to 26 weeks in duration 
and weekly SC injections for 4 weeks in duration.  The high dose of 50 mg/kg in the 
26-week study resulted in a steady-state area under the concentration-time curve from 0 


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to 24 hours (AUC024) exposure of 341,000 ghr/mL, which is approximately 61-fold 
above that of the clinical exposure of 5584 ghr/mL.
Consistent with expected pharmacologic activity, obinutuzumab caused marked 
decreases in B cells, with corresponding lymphoid depletion in spleen and lymph nodes.  
Circulating CD40-positive mature B cells began to reverse after several months without 
treatment and maximally reversed to 7%152% of baseline by 37 weeks.  In addition, 
transient decreases in NK cells were observed; this finding is consistent with the 
pharmacologic effect of FcRIIIa binding.  Suspected opportunistic infections in as many 
as three unscheduled deaths were considered a possible secondary result of B-cell 
depletion.
Obinutuzumab was immunogenic in the cynomolgus monkey, which led to reduced 
systemic exposures in several animals and abrogation of the pharmacologic activity. 
Hypersensitivity reactions were noted that included systemic inflammation and infiltrates 
consistent with immune complexmediated hypersensitivity reactions such as 
arteritis/periarteritis, glomerulonephritis, and serosal/adventitial inflammation and led to 
unscheduled termination in six animals.
Both the clinical IV formulation and the SC formulation of obinutuzumab were locally well 
tolerated across studies.  No effects were present in male and female reproductive 
parameters included in the 26-week IV dose study.  No obinutuzumab-related effects 
were observed on CNS, respiratory, or cardiovascular function.
In vitro assays using undiluted human whole blood measured significant increases in 
cytokine secretion caused by obinutuzumab, indicating that obinutuzumab has an 
increased propensity to trigger first infusionrelated cytokine release in patients.
See the Obinutuzumab Investigator’s Brochure for details on the nonclinical studies.
1.2.4.3
Obinutuzumab Nonclinical Efficacy
Obinutuzumab has in vivo efficacy superior to rituximab in various human lymphoma 
xenograft models.  Both antibodies were tested in human SUDHL-4 cells (DLBCL model) 
injected subcutaneously in severe combined immunodeficient (SCID) beige mice.  
Rituximab administration was started when tumors were established and rapidly 
growing.  Results showed that rituximab at 10 mg/kg inhibited tumor growth compared 
with rituximab at 1 mg/kg; however, increasing the rituximab dose to 30 mg/kg did not 
result in increased efficacy and rituximab was not able to achieve complete tumor 
regression.  In contrast, obinutuzumab showed a dose-dependent increase in efficacy in 
the range of 130 mg/kg.  Results showed complete tumor regression in all animals and 
lasting tumor eradication in 9 of 10 animals at the highest dose of 30 mg/kg and in 
1 of 10 animals at a dose of 10 mg/kg.


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In another experiment, SUDHL4 xenografts in SCID mice were first treated with weekly 
rituximab 30 mg/kg. When the tumors became refractory to rituximab (Day 35), 
rituximab treatment was continued or changed to either weekly vehicle control or 
obinutuzumab 30 mg/kg. While tumors in control- and rituximab-treated mice continued 
to grow, obinutuzumab-treated mice showed control of tumor growth and lived until 
Day 61 when control or rituximab-treated mice had already been sacrificed.  
Additional studies have also shown similar results, with obinutuzumab treatment 
controlling tumor growth, whereas vehicle- and rituximab-treated tumors were not 
controlled (Mössner et al. 2010).
See the Obinutuzumab Investigator’s Brochure for details on the nonclinical studies.
1.2.4.4
Obinutuzumab Clinical Experience
As of July 2013, more than 1900 patients with CD20-positive malignant disease have 
been treated with obinutuzumab in clinical trials.  Clinical data for obinutuzumab are 
available from six clinical trials, including three Phase I and Phase II studies of 
obinutuzumab monotherapy, a Phase Ib chemotherapy combination study in NHL 
(Study BO21000), and two Phase III studies (Study BO21004 in CLL and 
Study GAO4753g in NHL).
Infusion-related reactions (IRRs), mostly Grades 1 and 2, are the most common adverse 
events observed during therapy.  IRRs have been associated predominantly with the first 
infusion, generally occurring early during the infusion, shortly after the infusion, or, in 
some cases, up to 24 hours after the completion of the infusion.  In a few patients, 
concurrent signs of laboratory tumor lysis syndrome (TLS) were observed.  The 
incidence and intensity of IRRs decreased strongly with subsequent infusions of 
obinutuzumab.  On the basis of preliminary observations, extensive tumor burden, tumor 
factors, and host factors may be predisposing factors for the occurrence of IRRs. The 
frequency and severity of IRRs is also reduced in lymphomas compared with CLL.
Other frequently observed adverse events include infections and neutropenia.
Grade 34 thrombocytopenia and neutropenia, including febrile neutropenia, have been 
reported with obinutuzumab, associated predominantly with treatment of CLL rather than 
NHL.  Given its anticipated mode of action, which results in profound B-cell depletion, 
obinutuzumab may be associated with an increased risk of infections during and after
treatment.
Data from Study BO20999 (obinutuzumab monotherapy) showed safety and efficacy of 
single-agent obinutuzumab in patients with relapsed indolent and aggressive 
lymphomas.  Responses were seen at both lower (400 mg) and higher (1600/800 mg) 
doses, although responses increased at the higher dose, with 54% of patients with 
indolent lymphoma and 32% of patients with aggressive lymphomas showing PR or CR 
at the end of treatment (EOT) (Morschhauser et al. 2013; Salles et al. 2013).  


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Study BO21000 (Phase Ib) evaluated obinutuzumab in combination with chemotherapy:  
obinutuzumab with fludarabine and cyclophosphamide and obinutuzumab with CHOP 
(Radford et al. 2013).  Both chemotherapy combinations were shown to be feasible in 
patients with previously untreated or relapsed or refractory FL, with response rates of 
90% for both regimens.  Safety was acceptable, with no new or unexpected adverse 
events observed.  The most common adverse event was neutropenia.
Data from obinutuzumab in combination with chlorambucil in CLL (Phase III 
Study BO21004) showed increased efficacy of this combination over 
rituximab-chlorambucil, with a hazard ratio of 0.39 for PFS.  IRRs were common (65% all 
grades, 20% Grade 34, no fatal IRRs) and neutropenia occurred at increased 
frequency with the combination therapy (33% Grade 35), but there was no increase in 
infections or treatment-related deaths (Goede et al. 2014).
See the Obinutuzumab Investigator’s Brochure for additional details on the clinical 
studies.
1.2.4.5
Obinutuzumab Pharmacokinetics and Pharmacodynamics
A two-compartment model comprising a time-varying CL pathway and a linear CL
pathway provides an adequate description of the pharmacokinetics of obinutuzumab 
following IV administration in Study BO20999 and Study BO21003.  Following the 
infusion of obinutuzumab, the elimination appears to be characterized by a linear CL
pathway that is dependent on time (i.e., starting at a typical value of 630 mL/day and 
then gradually decreasing to an asymptote of 60 mL/day at steady state).  Tumor burden 
may potentially contribute significantly to the CL of obinutuzumab, especially at the 
beginning of treatment when CD20-positive tumor cells are most abundant.  As tumor 
burden decreases, the CL reaches an asymptote, which is considered to be primarily a 
function of the proteolytic metabolic CL.  Some patients with a high tumor burden may 
appear to clear the drug from the plasma faster than patients with a low tumor burden 
because obinutuzumab binds to the CD20-positive tumor cells and is effectively 
removed from the plasma.  The CL of the drug will vary with time because repeated 
treatments with obinutuzumab will reduce the quantity of CD20-positive tumor cells.  The 
number of times obinutuzumab is administered during the first cycle of treatment may be 
expected to reduce the number of CD20-positive tumor cells, thus minimizing the impact 
of the time-varying CL pathway on obinutuzumab exposure.
Treatment with obinutuzumab resulted in extensive B-cell depletion, with all patients 
showing a reduction in B-cell counts to absolute zero at some stage of their treatment 
cycle.  Overall, there has been no notable increase in complement levels before and 
after infusion, but transient increases occurring during the administration of 
obinutuzumab have been observed in the levels of tumor necrosis factor (TNF)-, 
interleukin (IL)-6, IL-8, IL-10, and interferon (IFN)-.


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1.3
RATIONALE FOR DOING THIS STUDY
The goals of this study are to continue to assess the safety, tolerability, and biologic and 
clinical activity of the combinations of DCDT2980S and rituximab and DCDS4501A and 
rituximab in two specific NHL patient populations:  patients with relapsed or refractory 
follicular NHL and patients with relapsed or refractory DLBCL.  An additional goal of this 
study is to assess the safety, tolerability, and potential biologic and clinical activity of 
DCDS4501A in combination with obinutuzumab, an anti-CD20 antibody, in the 
aforementioned NHL patient populations.  These patients continue to have an extremely 
poor prognosis with no curative options available.  Consequently, new therapeutic 
options are needed.  
DCDT2980S, DCDS4501A, rituximab, and obinutuzumab each target antigens specific 
to B-cell malignancies including follicular NHL and DLBCL (see Figure 1  and Figure 2). 
The randomized component of the Phase II study design permits an assessment of the 
clinical benefit provided by each of these molecules in combination with rituximab, which 
has established clinical activity in B-cell malignancies both as monotherapy and in 
combination with chemotherapy.  Data from this study will help inform the feasibility of 
the combination regimens in earlier lines of therapy (e.g., as first-line therapy in newly 
diagnosed patients).  
The non-randomized component of the study will further evaluate the safety and 
tolerability and clinical activity of DCDS4501A in combination with obinutuzumab in 
patients with relapsed or refractory follicular lymphoma or DLBCL and will also provide 
preliminary evidence as to which anti-CD20 agent, rituximab or obinutuzumab, in 
combination with DCDS4501A, provides a better benefit-risk profile in the target 
population being studied. 
The feasibility of combining an ADC with rituximab has previously been tested clinically 
with the combination of another, different CD22-specific ADC, inotuzumab ozogamicin 
(CMC-544), with results suggesting that the addition of rituximab may have increased 
clinical activity without significant increase in toxicity over the ADC alone in patients with 
aggressive NHL (Fayad et al. 2006; Nam et al. 2009; Nina et al. 2010).  As noted in 
Section 1.2.1 and Section 1.2.2, the combinations of DCDT2980S and rituximab, and 
DCDS4501A and rituximab have been shown to have acceptable safety in patients with 
relapsed or refractory NHL in the Phase I studies (Studies DCT4862g and DCS4968g).  
Given the relatively poor prognosis of patients with relapsed or refractory hematologic 
malignancies that have failed standard therapies, the nonclinical toxicity profile 
associated with DCDT2980S and DCDS4501A treatment, and the clinical safety profile 
observed to date for both ADCs, the benefit-risk ratio of a clinical study of DCDT2980S 
and DCDS4501A, each combined with rituximab or obinutuzumab, is considered 
acceptable. 


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1.3.1
Rationale for Assessing ADC Dose of 1.8 mg/kg Combined 
with Rituximab in iNHL
On the basis of available Phase I data (see Section 1.2.1 and Section 1.2.2), both 
DCDT2980S and DCDS4501A as single agents and combined with rituximab have 
shown early signs of clinical activity in heavily pretreated patients with relapsed or
refractory NHL.  However, early evidence in the Phase I studies indicate that duration of 
study treatment may be limited by tolerability to ADC.  Specifically, for both ADCs, 
peripheral sensory neuropathy has been identified as a known risk (see Section 3.4.3.5).  
Notably, 4 of 7 and 5 of 11 discontinuations for adverse events in Studies DCT4862g 
and DCS4968g, respectively, were the result of peripheral neuropathy.  
Because of the chronic course and incurability of iNHL, treatment paradigms are 
increasingly emphasizing tolerability to treatment in addition to efficacy.  As both 
DCDT2980S and DCDS4501A have shown single-agent activity at the 1.8 mg/kg dose 
level (Advani et al. 2012; Palanca-Wessels et al. 2012), the purpose of enrolling 
additional cohorts of patients with FL is to determine whether lower doses of ADC in 
combination with standard doses of rituximab result in improved tolerability while 
maintaining efficacy in FL.  
In contrast to iNHL, treatment paradigms in relapsed or refractory aggressive 
lymphomas such as DLBCL continue to place a premium on anti-tumor activity and 
higher tolerance for treatment-related toxicity, given that the duration of disease control 
and survival are substantially shorter and that treatment options are extremely limited.  
Early Phase I data suggest lower rates of study treatment discontinuation for adverse 
events among patients with DLBCL compared with patients with iNHL.  Taken together 
with anti-tumor activity observed to date, the benefit-risk profile of the currently tested 
ADC dose of 1.8 mg/kg is considered acceptable to combine with rituxminab in the 
treatment of patients with iNHL.
1.3.2
Rationale for Assessing DCDS4501A in Combination with 
Obinutuzumab in Relapsed or Refractory NHL
The development of next-generation anti-CD20directed therapy may further enhance 
the efficacy of current standard regimens for NHL.  Obinutuzumab, also known as 
RO5072759, GA101, and Gazyva/Gazyvaro, a novel type II and glycoengineered 
anti-CD20 antibody, has shown superiority over rituximab in a Phase III trial in first-line 
CLL (Goede et al. 2014). Obinutuzumab is currently being compared with rituximab in 
two large Phase III studies in patients with newly diagnosed DLBCL (Study BO21005) 
and with previously untreated iNHL, including FL (Study BO21223).  Assuming these 
studies demonstrate greater clinical benefit with obinutuzumab- vs. rituximab-containing 
regimens, potentially altering the standard of care in NHL, it will be important to also 
assess the safety and efficacy of combining DCDS4501A with obinutuzumab-containing 
regimens.


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The goals of the non-randomized portion of the Phase Ib study are to assess the safety, 
tolerability, and potential biologic and clinical activity of DCDS4501A at 1.8 mg/kg in 
combination with obinutuzumab in patients with relapsed or refractory follicular NHL or 
DLBCL.  The RP2D, the Phase II dose-expansion portion of the study, will further 
evaluate the safety and tolerability and clinical activity of DCDS4501A at 1.8 mg/kg in 
combination with obinutuzumab in patients with relapsed or refractory follicular NHL or 
DLBCL.
2.
OBJECTIVES
2.1
PRIMARY OBJECTIVES
The primary objectives of this study are the following:

To assess the safety and tolerability of the combination of DCDT2980S and 
rituximab administered to patients with relapsed or refractory follicular NHL and 
DLBCL

To assess the safety and tolerability of the combination of DCDS4501A and 
rituximab administered to patients with relapsed or refractory follicular NHL and 
DLBCL

To assess the safety and tolerability of the combination of DCDS4501A and 
obinutuzumab when administered to patients with relapsed or refractory follicular 
NHL or DLBCL

To assess the anti-tumor activity of the combination of DCDT2980S and rituximab in 
patients with relapsed or refractory follicular NHL and DLBCL

To assess the anti-tumor activity of the combination of DCDS4501A and rituximab in 
patients with relapsed or refractory follicular NHL and DLBCL

To assess the anti-tumor activity of the combination of DCDS4501A and 
obinutuzumab in patients with relapsed or refractory follicular NHL and DLBCL
based on 18F-fluorodeoxyglucosepositron emission tomography (18F-FDG-PET; 
hereafter referred to as PET)/computed tomography (CT) CR at the end of 
treatment according to Independent Review Committee (IRC) per Lugano 2014 
response criteria
2.2
SECONDARY OBJECTIVES
2.2.1
Safety Objectives
The secondary safety objectives of this study are the following:

To assess the incidence of antibody formation to DCDT2980S, DCDS4501A, and 
obinutuzumab as measured by the formation of ATAs

To compare the safety and tolerability of the combination of DCT2980S and 
rituximab and DCDS4501A and rituximab or obinutuzumab


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2.2.2
Activity Objectives
The secondary activity objective for rituximab-containing arms of the study is the 
following:

To compare the anti-tumor activity of the combination of DCT2980S and rituximab 
and DCDS4501A and rituximab or obinutuzumab
The secondary activity objectives for obinutuzumab-containing arms of the study are the 
following:

CR at end of treatment based on PET/CT, as determined by the investigator

Objective response (OR; CR or PR) at end of treatment based on PET/CT, as 
determined by investigator and IRC 

CR at end of treatment based on CT only, as determined by the investigator and IRC

OR (CR or PR) at end of treatment based on CT only, as determined by the 
investigator and IRC

Best objective response (BOR, CR or PR) while on study based on PET/CT or CT 
only, as determined by the investigator
2.2.3
Pharmacokinetic Objectives
The PK objectives of this study are the following:

To characterize the pharmacokinetics of DCDT2980S and rituximab in patients with 
relapsed or refractory NHL when the two drugs are given in combination

To characterize the pharmacokinetics of DCDS4501A and rituximab or 
obinutuzumab in patients with relapsed or refractory NHL when the two drugs are 
given in combination
2.3
EXPLORATORY OBJECTIVES
2.3.1
Efficacy Objectives
The exploratory efficacy objectives for this study are to evaluate the long-term outcome 
of obinutuzumab-treated patients according to Lugano 2014 response criteria, as 
measured by the following:

Duration of response based on PET/CT and/or CT scans, as determined by the 
investigator

Progression-free survival (PFS) based on PET/CT and/or CT scans, as determined 
by the investigator

Event-free survival (EFS) based on PET/CT and/or CT scans, as determined by the 
investigator

Overall survival 


 
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2.3.2 
Biomarker Objectives 
The objectives of this study related to assessment of biologic markers are the following: 
• 
To make a preliminary assessment of biologic markers that might act as predictors 
of DCDT2980S + rituximab combination anti-tumor activity and allow assessment of 
response in different prognostic subgroups of DLBCL and follicular NHL 
• 
To make a preliminary assessment of biologic markers that might act as predictors 
of DCDS4501A + rituximab or obinutuzumab combination anti-tumor activity and 
allow assessment of response in different prognostic subgroups of DLBCL and 
follicular NHL 
 
2.3.3 
Patient-Reported Outcomes Objective 
The objective of this study related to assessment of patient-reported outcomes (PRO) is 
the following: 
• 
To assess patient-reported tolerability to study treatment and the impact of study 
treatment on patient functioning on the basis of PRO in Rituximab cohorts only 
 
2.3.4 
Crossover Treatment Objective 
The objective of this study related to assessment of crossover treatment is the following: 
• 
To preliminarily assess the safety, tolerability, and anti-tumor activity of DCDT2980S 
and DCDS4501A, either as a single-agent or in combination with rituximab, as 
crossover treatment following disease progression on initial study treatment. (Note:  
This objective applies only to patients enrolled in Arms A and B [see Section 3.1]) 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a Phase Ib/II, multicenter, open-label study.  Up to approximately 246 patients 
with relapsed or refractory FL and DLBCL will be enrolled at approximately 
30−40 investigative sites worldwide.  Additional patients may be enrolled in order to 
obtain additional safety and/or efficacy data.  Arms A and B and Cohort C are no longer 
enrolling patients. 
For Obinutuzumab Cohorts: 
Only investigational sites in the United States will enroll patients into Cohort E.  
Investigational sites in the United States and worldwide will participate in Cohorts G 
and H.   
The study will be composed of a randomized portion and a non-randomized portion, as 
illustrated in Figure 3. 


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Figure 3a Study Schema for Rituximab-Containing Arms/Cohorts (Closed 
to Enrollment)
Figure 3b
Study Schema for Obinutuzumab-Containing Arms/Cohorts
ADCantibody-drug conjugate; DLBCLdiffuse large B-cell lymphoma; FLfollicular lymphoma; 
GGA101/obinutuzumab; PDprogressive disease; r/rrelapsed or refractory; RTXrituximab.


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3.1.1
Rituximab-Containing Regimens with DCDT2980S or 
DCDS4501A
3.1.1.1
Randomized Portion of the Study (Arms A and B)Closed to 
Enrollment
Following determination of eligibility, patients within each disease group will be 
randomized in a 1:1 ratio to receive one of two treatments:

Arm A: Rituximab (375 mg/m2) followed by DCDT2980S (2.4 mg/kg) every 21 days;

Arm B: Rituximab (375 mg/m2) followed by DCDS4501A (2.4 mg/kg) every 21 days
The first day of treatment constitutes Day 1 of each cycle.  A typical cycle is 21 days in 
duration.
A dynamic hierarchical randomization scheme will be employed with respect to the 
following stratification factors:

For patients with FL (see Section 3.1.4 for definitions)
Rituximab refractory disease (no response or disease relapse 6 months from 
last rituximab treatment) versus rituximab relapsed disease (disease relapse 
after response 6 months from last rituximab treatment)

For patients with DLBCL (see Section 3.1.5 for definitions)
Second-line versus third-line (or beyond) therapy
For second-line patients, disease relapse or no objective response (CR,
unconfirmed CR [CRu], or PR) <12 months from the start of initial therapy versus 
disease relapse, after initial objective response (CR, unconfirmed response 
[CRu] or PR), 12 months from start of initial therapy 
For third-line patients, failure to achieve a CR or progression < 6 months from 
start of most recent therapy versus CR or progression ≥6 months from start of 
most recent therapy
No formal testing comparing the two treatment arms in the randomized portion of the 
study is planned.
3.1.1.2
Non-Randomized Portion of the Study with Rituximab 
(Cohorts C and D)Closed to Enrollment
Only select investigator sites that have agreed to participate in the non-randomized 
portion of the study will enroll patients into these cohorts.
Patients with relapsed or refractory follicular NHL will be enrolled in Cohorts C and D to 
receive rituximab (375 mg/m2) combined with DCDT2980S or DCDS4501A at a dose of 
1.8 mg/kg.  The first day of treatment constitutes Day 1 of each cycle.  A typical cycle will 
be 21 days in duration.


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The opening of either or both cohorts will be at the Sponsor’s discretion and only after 
the enrollment of patients with FL into the randomized portion of the study is completed.  
Patients will not be randomized to receive one treatment or the other.  It is anticipated 
that Cohort C and D will be opened sequentially.
3.1.2
All Patients on Rituximab-Containing Arms/Cohorts
All patients on rituximab-containing regimens, regardless of assigned arm/cohort, will 
receive DCDT2980S or DCDS4501A and rituximab administered by IV infusion on a 
21-day cycle.  For the first two cycles, rituximab will be administered by IV infusion on 
Day 1 and DCDT2980S or DCDS4501A will be administered by IV infusion on Day 2.  
In the absence of any infusion-related adverse events, rituximab and DCDT2980S or 
DCDS4501A may be administered on the same day (Day 1) in subsequent cycles 
beginning with the third cycle.  In this instance, rituximab will be administered first, 
followed by DCDT2980S or DCDS4501A.  In certain circumstancesfor example, IRRs
requiring interruption or slowing of infusion raterituximab may be administered over 
2 days (e.g., Day 1 and Day 2 of the cycle); in this case, DCDT2980S or DCDS4501A 
may be administered on Day 2 following completion of the rituximab infusion or on Day 3 
of the cycle.
Patients may receive treatments for up to 1 year (17 cycles on an every-21-day 
schedule) if not discontinued because of significant toxicity, disease progression, or 
withdrawal from study.
Patients will be evaluated for safety and efficacy according to the Schedules 
of Assessments outlined in Appendices A-1, A-2, and A-4.  Initial response assessments 
in this study will be performed every 3 months from the initiation of therapy until study 
treatment completion or early termination (e.g., between Days 14 and 21 of Cycles 4 
and 8 for those patients receiving at least eight 21-day cycles of treatment).  Additional 
response assessments for patients who proceed to crossover treatment 
(see Section 3.1.6) will be performed as described in Appendix A-2; response 
assessments for patients who discontinue study treatment (both initially assigned 
treatment and crossover treatment) for reasons other than disease progression will be 
performed as described in Appendix A-4.
Responses to study treatment will be based on investigator assessments.  In addition, 
tumor assessment data will be transmitted to an Independent Review Facility (IRF) for 
collection and possible independent review.
3.1.3
Obinutuzumab-Containing Regimen with DCDS4501A 
(Cohorts E, G, and H)
DCDS4501A at 1.8 mg/kg will be given in combination with obinutuzumab to patients 
with relapsed or refractory follicular NHL and DLBCL in two stages: (1) safety run-in and 
(2) expansion.


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Study treatment will be given in 21-day cycles for both follicular NHL and DLBCL.  
Patients will be treated for up to a total of 8 cycles.  For the first cycle, obinutuzumab will 
be administered by IV infusion on Days 1, 8, and 15.  DCDS4501A will be given on Day 
2 for Cycle 1.  In the absence of any infusion-related adverse events, obinutuzumab and 
DCDS4501A may be administered on the same day (Day 1) in subsequent cycles 
beginning with the second cycle.  If obinutuzumab and DCDS4501A are administered on 
the same day, the study drugs will be given sequentially.  Obinutuzumab will be 
administered first, followed by DCDS4501A.  In certain circumstancesfor example, 
IRRs requiring interruption or slowing of infusion rateobinutuzumab may be 
administered over 2 days (e.g., Day 1 and Day 2 of the cycle); in this case, DCDS4501A 
may be administered on Day 2 following completion of the obinutuzumab infusion.
3.1.3.1
Obinutuzumab-Containing Regimen in Phase Ib: Safety Run-In 
(Cohort E)
This portion of the study will consist of a safety run-in that will evaluate the safety of 
DCDS4501A at 1.8 mg/kg in combination with obinutuzumab in 6 patients (Cohort E).  
The safety run-in is described in detail in Section 3.4.  
Obinutuzumab-Containing Regimens in Phase II:  Expansion Stage 
(Cohorts G and H)
After the safety run-in has demonstrated that DCDS4501A at 1.8 mg/kg in combination 
with obinutuzumab is safe to administer, patients will be enrolled into two expansion 
cohorts based on histology of follicular NHL or DLBCL (Cohorts G and H, respectively). 
Forty patients will be enrolled into each expansion cohort. An additional cohort(s) may 
be added in the future.
3.1.4
Follicular NHL Patients for Rituximab-Containing 
Arms/Cohorts
Patients with relapsed or refractory follicular NHL will be enrolled into the study as 
defined by the following:

Relapsed as documented history of response (CR, CRu, or PR) of 6 months in 
duration from completion of all prior rituximab-containing regimens.  A 
rituximab-containing regimen is defined as rituximab as a single agent during 
induction and/or maintenance or in combination with other agents during induction 
and/or maintenance.

Refractory to any prior regimen containing rituximab, defined as no response to or 
progression within 6 months of completion of the last dose of rituximab therapy 
(either as monotherapy or in combination with chemotherapy), including:
Patients with progressive disease while receiving rituximab monotherapy, 
rituximab combined with chemotherapy, or rituximab maintenance therapy; 
patients must have received at least one full dose (375 mg/m2) of rituximab.


 
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Patients with no objective response (PR or CR) to a rituximab-containing regimen 
consisting of at least 4 weekly doses of rituximab monotherapy or at least 
4 cycles of rituximab combined with chemotherapy 
Patients with disease relapse, after having achieved an objective response, 
within 6 months of completion of the last dose of rituximab therapy in a regimen 
consisting of at least four weekly doses of rituximab monotherapy or at least 
4 cycles of rituximab combined with chemotherapy 
 
Enrollment of patients with refractory disease as defined above may be limited to no 
greater than 60% of the total follicular NHL cohort, in order to avoid overrepresentation 
of the refractory disease population. 
3.1.5 
Follicular NHL Patients for Obinutuzumab-Containing Cohorts 
Patients with relapsed or refractory follicular NHL will be enrolled into the study as 
defined by the following: 
• 
Relapsed to prior regimen(s) after having a documented history of response (CR, 
CRu, or PR) of ≥ 6 months in duration from completion of regimen(s)   
• 
Refractory to any prior regimen, defined as no response to the prior therapy, or 
progression within 6 months of completion of the last dose of therapy 
 
3.1.6 
DLBCL Patients for Rituximab-Containing Arms/Cohorts 
Patients with relapsed or refractory DLBCL who are determined by the investigator to be 
ineligible for high-dose therapy with autologous stem cell rescue/stem cell transplant 
(SCT) will be enrolled into the study as defined by the following: 
• 
Second-line SCT-ineligible patients with progressive disease or no response 
(SD) < 12 months from start of initial therapy (second-line refractory) 
• 
Second-line SCT-ineligible patients with disease relapse after initial response 
≥ 12 months from start of initial therapy (second-line relapsed) 
• 
Third-line (or beyond) SCT-ineligible patients with progressive disease or no 
response (SD) < 6 months from start of prior therapy (third-line + refractory) 
• 
Third-line (or beyond) SCT-ineligible patients with disease relapse after initial 
response ≥ 6 months from start of prior therapy (third-line + relapsed) 
 
Enrollment into any of the above four categories may be limited to no greater than 40% 
of the DLBCL cohort—and to no more than 60% of the two refractory categories 
combined—in order to avoid overrepresentation of any specific subpopulation, refractory 
patients in particular. 


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3.1.7
DLBCL Patients for Obinutuzumab-Containing Cohorts
Patients with relapsed or refractory DLBCL who are determined by the investigator to be 
ineligible for high-dose therapy with autologous stem cell rescue/SCT will be enrolled 
into the study as defined by the following:

Second-line SCT-ineligible patients with progressive disease or no response 
(SD) 12 months from start of initial therapy (second-line refractory)

Second-line SCT-ineligible patients with disease relapse after initial response 
12 months from start of initial therapy (second-line relapsed)

Third-line (or beyond) SCT-ineligible patients with progressive disease or no 
response (SD) 6 months from start of prior therapy (third-line refractory)

Third-line (or beyond) SCT-ineligible patients with disease relapse after initial 
response 6 months from start of prior therapy (third-line + relapsed)
3.1.8
Crossover Treatment (Randomized Patients in Arms A and B
Only)
Patients randomized to Arm A or Arm B who develop progressive disease may be 
eligible to receive crossover treatment consisting of rituximab and the other ADC or the 
other ADC alonefor example, Arm B treatment for patients who have disease 
progression while receiving Arm A treatment, and vice versaprovided the following 
conditions are met:

Patients must not have experienced a toxicity requiring the discontinuation of 
DCDT2980S/DCDS4501A treatment OR experienced toxicity during the last dose of 
study treatment that would preclude treatment with the crossover regimen.
Patients who had modifications to dosing and/or schedule on the initial study 
treatment will be permitted to receive crossover treatment in the absence of 
toxicities on the modified dose and/or schedule.  The dose and schedule of 
crossover treatment will be determined by the investigator and the Medical 
Monitor.
Patients who had rituximab discontinued and continued on single-agent 
DCDT2980S/DCDS4501A treatment may receive crossover treatment of 
single-agent DCDS4501A/ DCDT2980S.

Patients must have radiographically documented disease progression.

Patients must meet all inclusion and exclusion criteria described in Section 4.1.1
and Section 4.1.2, except for those related to prior rituximab treatment.

Acceptable toxicity:  All study drug–related adverse events from the initial study 
treatment must have decreased to Grade 1 or baseline grade on or before the first 
day of treatment on the crossover regimen.  Exceptions may be allowed after a 
careful assessment and discussion of the benefit-risk balance with the patient by the 
investigator and approval from the Medical Monitor.


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
Administration of crossover treatment must be in the best interests of the patient as
determined after a careful assessment and discussion of benefit-risk balance with 
the patient by the investigator and approval from the Medical Monitor.

A tumor biopsy (see Section 4.5.1.9) will be required for patients with safely 
accessible site of disease, defined as requiring only local anesthesia and, in 
general, excluding the brain, lungs or any internal organs that may subject patients 
to significant risk. 
Patients for whom a safely accessible site of disease is not present may still 
receive crossover treatment without undergoing a biopsy.  Eligibility to receive 
crossover treatment should be discussed with and approved by the Medical 
Monitor.
A tumor biopsy of a safely accessible site of disease is optional for patients who 
are not eligible for study cross over. 
Patients who are determined to be eligible for study cross over will be treated as follows:

Assessments obtained at the initial study treatment discontinuation visit 
(see Section 4.5.4) may be used as screening assessments for crossover treatment.  
The following re-screening assessments must be repeated/obtained within 1 week 
prior to starting treatment on the crossover regimen, in order to re-establish baseline 
pretreatment clinical and disease status:  targeted physical exam, Eastern 
Cooperative Oncology Group (ECOG) status, and hematology and serum chemistry 
laboratory tests.
Re-screening tests for hepatitis B and C do not need to be performed unless 
there is clinical suspicion of hepatitis B and/or C positivity.
A radiographic tumor assessment must also be performed, unless already done 
to document disease progression, within 6 weeks prior to starting crossover 
treatment.

Crossover treatment will begin no later than 42 days after the last dose of the prior 
study treatment.
Patients will be treated with the crossover treatment until a second disease progression 
event relative to the tumor assessment, documenting progressive disease on the initial 
study treatment, clinical deterioration, and/or intolerance to the crossover treatment for 
up to a maximum of 1 year (17 cycles on an every-21-day schedule).  Patients will be 
evaluated for safety and efficacy according to the schedules of assessments outlined in 
Appendices A-2.  Response assessments for patients who discontinue study treatment 
for reasons other than disease progression will be performed as described in 
Appendix A-4. 


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Clinical data and exploratory data derived from tumor biopsies obtained prior to 
crossover treatment will be monitored on an ongoing basis.  Genentech has the right to 
restrict or suspend enrollment into crossover treatment at any time.  Reasons for this 
may include, but are not limited to, the following:

The incidence or severity of adverse events during crossover treatment indicates a 
potential safety hazard to patients.

Patient enrollment into crossover treatment is unsatisfactory.

Data recording is inaccurate or incomplete. 

Patients who are enrolled into the non-randomized portion of the study (Cohorts C, 
D, E, G, and H) will not have the option to receive crossover treatment upon disease 
progression (see Section 3.2 for rationale).
3.2
RATIONALE FOR STUDY DESIGN
The primary rationale for the randomized non-comparative portion of the study is to 
assess clinical activity for the ADCs DCDT2980S and DCDS4501A in patients with 
relapsed or refractory NHL.  The study design ensures that the patient populations under 
study are balanced with respect to critical variables such as prior therapy and ensures 
consistent clinical assessment of safety and efficacy.  The collection and assessment of 
tumor tissue obtained prior to first study treatment and following progressive disease will 
provide further understanding of disease biology, possible mechanisms of resistance to 
the study treatment, and initial insights into tumor subtypes based on tumor biomarkers 
that are sensitive to study treatment.  Finally, the inclusion of study treatment crossover 
(see Section 3.1.8) will address important questions regarding efficacy and tolerability of 
a second ADC-rituximab combination following disease progression on the initial 
ADC-rituximab combination. 
The primary rationale for the non-randomized portion of the study (Cohorts C and D) is 
to assess the therapeutic index (i.e., the balance of efficacy and tolerability of 
DCDT2980S and DCDS4501A at a dose of 1.8 mg/kg in patients with relapsed or 
refractory follicular NHL).  An informal comparison between patients with follicular NHL 
treated at the two doses of the ADC will help determine if tolerability is improved at the 
lower ADC dose without substantial compromise of efficacy. 
The clinical feasibility of an ADC-rituximab combination regimen in patients with relapsed
or refractory NHL has been previously studied.  Results from studies of rituximab in 
combination with a different CD22-specific ADC, inotuzumab ozogamicin, demonstrated 
that when combined with rituximab, the ADC was able to be given at the single-agent 
MTD without the need for dose reduction of the ADC because of the lack of significant 
overlapping toxicity (Fayad et al. 2006; Nam et al. 2009; Nina et al. 2010).
DCDT2980S and DCDS4501A were both evaluated as single agents and in combination 
with rituximab in the Phase I studies Study DCT4862g and Study DCS4968g, 
respectively.  Results from these trials have determined an MTD of 2.4 mg/kg for 


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single-agent DCDT2980S and an RP2D of 2.4 mg/kg for single-agent DCDS4501A in 
patients with mixed NHL.  In addition, the RP2D of DCT2980S and DCDS4501 each in 
combination with rituximab (375 mg/m2) on an every-21-day schedule was determined 
to be 2.4 mg/kg.  
Study GO27834 will continue to assess the cumulative safety and longer-term tolerability 
of ADC-rituximab combination therapy.  Due to additional information about the benefit-
risk profile of DCDS4501A at the 2.4 mg/kg dose, the Sponsor is no longer pursuing the 
2.4 mg/kg dose of DCDS4501A in the obinutuzumab-containing cohorts.
The primary rationale for the non-randomized Phase Ib/II obinutuzumab-containing 
cohorts (Cohorts EH) is to assess safety and clinical activity for the combination of 
obinutuzumab and DCDS4501A in patients with relapsed/refractory NHL (Cohorts E, G, 
and H).  Obinutuzumab (also known as RO5072759, GA101 and Gazyva/Gazyvaro), 
a novel type II and glycoengineered anti-CD20 antibody, has shown superiority over 
rituximab in a Phase III trial in first-line CLL (Goede et al. 2014).  Obinutuzumab is 
currently being compared with rituximab in two large Phase III studies in patients with 
newly diagnosed DLBCL (Study BO21005) and previously untreated iNHL, including FL 
(Study BO21223).  Assuming these studies demonstrate greater clinical benefit with 
obinutuzumab- vs. rituximab-containing regimens, potentially altering the standard of 
care in NHL, it will be important to also assess the safety and efficacy of combining 
DCDS4501A with obinutuzumab-containing regimens.
Study drug dosing will occur on Days 1 or 2 of each 21-day (or 28-day) cycle to allow for 
recovery from potential bone marrow toxicity.
3.2.1
Rationale for the PK Sample Schedule
PK data obtained in this study will be important in informing potential future trials with 
this combination.  Given the likely changing effect of peripheral B-cell counts, tumor 
burden, and target antigen expression on target-mediated drug CL over multiple doses 
of DCDT2980S or DCDS4501A plus rituximab or obinutuzumab when the two drugs are 
given in combination, the drug levels of DCDT2980S or DCDS4501A-related analytes 
and rituximab or obinutuzumab will be assessed in this combination study.  
In Studies DCT4862g and DCS4968g, single-agent DCDT2980S and DCDS4501A 
administered by IV infusion every 21 days were evaluated at doses ranging from 0.1 to 
3.2 mg/kg for DCDT2980S and 0.1 mg/kg to 2.4 mg/kg for DCDS4501A in patients with 
NHL.  Intensive PK sampling of all patients in the ongoing Phase I studies will provide 
sufficient data to allow complete profiling of the distribution and elimination phases for 
DCDT2980S and DCDS4501A and the investigation of potential correlations between 
various PK parameters and efficacy and/or toxicity.  Consequently a reduced PK 
sampling scheme of DCDT2980S and DCDS4501A will be used in this study. 


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The PK data collected in this study will allow further characterization of the PK properties 
of DCDT2980S and DCDS4501A.  In addition, the DCDT2980S and DCDS4501A 
concentration results from this study will be compared with available data from the 
single-agent clinical studies to evaluate whether concurrent administration of rituximab 
affects the exposure of DCDT2980S and/or DCDS4501A.  
Rituximab serum concentration measurements from this study will be compared with 
PK data from historical rituximab clinical studies to evaluate whether the combination 
with DCDT2980S and/or DCDS4501A affects the pharmacokinetics of rituximab. 
Limited sampling of serum concentrations of obinutuzumab will be assessed and 
compared with historical data to evaluate potential PK interactions with DCDS4501A.
3.3
OUTCOME MEASURES
3.3.1
Safety Outcome Measures
The safety and tolerability of the combination of DCDT2980S and rituximab and 
DCDS4501A and rituximab or obinutuzumab will be assessed using the following safety 
outcome measures:

Incidence, nature, and severity of adverse events

Incidence of anti-DCDT2980S, anti-DCDS4501A, or anti-obinutuzumab antibodies

Changes in vital signs

Changes in laboratory values
3.3.2
Pharmacokinetic/Pharmacodynamic Outcome Measures
The following PK parameters will be derived from the serum concentration–time profiles 
of total antibody (the sum of conjugated and unconjugated antibody), including rituximab
or obinutuzumab, and plasma concentration-time profiles of acMMAE and free MMAE 
following administration of DCDT2980S or DCDS4501A, when appropriate, as data 
allow:

Total exposure (area under the concentration-time curve [AUC])

Maximum plasma and serum concentration (Cmax)

CL

Terminal half-life (t1/2)

Vss
Compartmental, non-compartmental, and/or population methods may be used.  Other 
parameters, such as accumulation ratio and trough plasma and serum concentration 
(Cmin), may also be calculated.


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The following PD outcome measures will be assessed when appropriate, as data allow:

Peripheral blood B-cell depletion and recovery.  For each visit at which CD19+ B-cell 
measurements are taken, B-cell data will be listed for each patient by dose level as 
follows:
Absolute blood cell counts
Percent change relative to the baseline blood counts
CD19+ B-cell recovery, defined as the timepoint when the values return to 
baseline levels or 50% of baseline levels

Assessment of the kinetics of circulating tumor DNA
3.3.3
Activity Outcome Measures
The following activity outcome measures will be assessed for rituximab-containing 
arms/cohorts (Arms A and B, Cohort C):

Objective response, defined as a PR or CR

Duration of objective response, defined as the duration of time from the first 
occurrence of a documented objective response to time of relapse or death from 
any cause

PFS, defined as the duration from randomization to the first occurrence of 
progression or death within 30 days of the last administration of study drug, 
whichever occurs first

OS, defined as the duration from the date of randomization/enrollment to the date of 
death from any cause
Objective response and disease progression will be determined using standard criteria 
for NHL (Cheson et al. 2007, 2014; see Appendix C-1 and Appendix C-2).
The following activity outcome measures will be assessed for obinutuzumab-containing 
cohorts (Cohorts E, G, and H) according to Lugano 2014 Response Criteria 
(Cheson et al. 2014):
The primary activity outcome measure will be assessed by: 

CR at end of treatment (68 weeks after Cycle 6 Day 1 or last dose of study 
medication) based on PET/CT, as determined by the IRC
The following secondary efficacy outcome measures will be assessed:

OR (CR or PR) at end of treatment based on PET/CT, as determined by the 
investigator and IRC 

CR at end of treatment based on CT only, as determined by the investigator 
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
OR (CR or PR) at end of treatment based on CT only, as determined by the 
investigator and IRC 

BOR (CR or PR) while on study based on PET/CT or CT only, as determined by the 
investigator 
3.3.4
Exploratory Outcome Measures
The exploratory outcome measures will include, but will not be limited to, the following: 

Confirmation and quantitation of CD22, CD79b, and CD20 expression levels in 
either archival or freshly obtained (when available) tumor specimens (tumor 
biopsies, bone marrow biopsies, peripheral blood) by immunohistochemistry/flow 
cytometry/quantitative reverse transcriptase polymerase chain reaction (qRT-PCR)

Additional assessments related to the understanding of the mechanism of action of 
DCDT2980S, DCDS4501A, rituximab, and obinutuzumab, e.g., assessment of 
circulating tumor DNA(ctDNA) to monitor response, mechanisms of resistance to 
DCDT2980S, DCDS4501A, rituximab, and obinutuzumab, and/or NHL pathogenesis 
may be included.

Treatment and disease symptom assessments using the M.D. Anderson Symptom 
Inventory (MDASI) in rituximab-containing cohorts only
The following exploratory efficacy outcome measures will be assessed:

DOR, defined as the time from the date of the first occurrence of a documented CR 
or PR to the date of disease progression, relapse, or death from any cause, for the 
subgroup of patients with a best overall response of CR or PR, based on PET/CT
and/or CT scans as determined by the investigator assessment.  For patients 
achieving a response who have not experienced disease progression, relapse, or 
died prior to the time of the analysis, the DOR will be censored on the date of last 
disease assessment.

PFS, defined as the time from date of randomization or first treatment (for 
G-containing arms) to the first occurrence of progression or relapse, or death from 
any cause , based on PET/CT and/or CT scans as determined by the investigator 
assessment.

EFS, defined as the time from date of randomization or first treatment (for 
G-containing arms) to any treatment failure including disease progression relapse, 
initiation of new anti-lymphoma therapy, or death from any cause, whichever occurs 
first, based on PET/CT and/or CT scans as determined by the investigator 
assessment

OS, defined as the time from the date of first treatment to the date of death from any 
cause
3.4
SAFETY PLAN 
See Section 5 (Assessment of Safety) for complete details of the safety evaluation for 
this study.


 
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Safety will be evaluated through the monitoring of the following: 
• 
Serious adverse events that are attributed to protocol-mandated interventions from 
the time of signing of the Informed Consent Form until the first dose of study 
treatment on Cycle 1, Day 1 
• 
All adverse events from Cycle 1, Day 1 until 30 days after the last dose of 
DCDT2980S, DCDS4501A, rituximab, or obinutuzumab, whichever is later, 
including doses that were administered as part of crossover treatment 
• 
All serious adverse events from Cycle 1, Day 1 until 30 days after the last dose of 
DCDT2980S, DCDS4501A, rituximab, or obinutuzumab, whichever is later, 
including doses that were administered as part of crossover treatment 
• 
All serious adverse events from the last dose of DCDT2980S, DCDS4501A, 
rituximab, or obinutuzumab, whichever is later, including doses that were 
administered as part of crossover treatment, and which are judged to be caused by 
DCDT2980S, DCDS4501A, rituximab, or obinutuzumab, regardless of time of onset 
• 
Measurements of protocol-specified hematology and clinical chemistry laboratory 
values 
• 
Measurements of protocol-specified vital signs 
• 
Assessment of ECGs 
• 
Assessment of physical findings on clinical physical examinations 
 
Patients who have an ongoing study drug−related adverse event will be followed until 
the event has resolved to baseline grade, the event is assessed by the investigator as 
stable, new anti-tumor treatment is initiated, the patient is lost to follow-up, the patient 
withdraws consent, it is determined that the study treatment or participation is not the 
cause of the adverse event, or the study is terminated. 
See Section 5.2.3 for assessment of causality for adverse events. 
3.4.1 
Safety Run-In Analysis 
As outlined in Figure 3b and Section 3.1.3.1, a safety run-in analysis (Cohort E) will be 
conducted by the Internal Monitoring Committee (IMC) to evaluate the combination of 
DCDS4501A at a dose of 1.8 mg/kg with obinutuzumab.  This analysis will include data 
from the first 6 patients treated through the safety observation period, from Cycle 1 
Day 1 to Cycle 2 Day 1 for a minimum of 21days.  Three patients will initially be enrolled, 
and then an additional 3 patients will be enrolled after the first 3 patients have safely 
completed the first cycle.  The decision to enroll an additional 3 patients will be made by 
the Sponsor’s Medical Monitor in consultation with the safety science leader, 
biostatistician, and participating investigators.  At the IMC’s discretion, and at any point 
during enrollment of the safety run-in, a decision could be made that more than 
6 patients are needed to evaluate safety.  Additional patients may also be enrolled at 
dose levels below 1.8 mg/kg of DCDS4501A (i.e., 1.4 mg/kg) based upon review of all 
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Safety summaries will be assessed at the safety run-in for SAEs; Grade 3-5 treatment-
related AEs; all AEs; all Grade 3-5 AEs; and AEs leading to treatment discontinuation or 
dose modification/interruption.

During the 6-patient safety run-in, if any patient experiences a treatment-related 
death, then the obinutuzumab-containing portion of the study will be closed to 
further recruitment.

During the 6-patient safety run-in:
If 2 or more of the first 3 patients enrolled experience Grade 4 febrile neutropenia 
or serious (i.e., SAE) documented infection requiring IV antibiotics in the 
presence of Grade 34 neutropenia, then the obinutuzumab-containing portion of 
the study will be closed to further recruitment
If 1 of the first 3 patients enrolled experiences Grade 4 febrile neutropenia or 
serious (i.e., SAE) documented infection requiring IV antibiotics in the presence 
of Grade 34 neutropenia, then an additional 3 patients will be recruited.  If 2 or 
more of these first 3 patients experience Grade 4 febrile neutropenia or serious 
(i.e., SAE) infection with Grade 34 neutropenia, then the 
obinutuzumab-containing portion of the study will be closed to further 
recruitment.
If 2 or more of the first 6 patients to be enrolled experiences Grade 4 febrile 
neutropenia or serious (i.e., SAE) documented infection requiring IV antibiotics in 
the presence of Grade 34 neutropenia, then the obinutuzumab-containing 
portion of the study will be closed to further recruitment.
Before the expansion portion of the study can begin (enrollment of 
Cohorts G and H), six patients must have completed the safety observation 
period (Cycle 1 Day 1 to Cycle 2 Day 1 for a minimum of 21 days) in the safety 
run-in (Cohort E).
3.4.2
Internal Monitoring Committee
This study will employ an Internal Monitoring Committee (IMC). The purpose of the IMC 
will be to make recommendations regarding study conduct on the basis of trial safety 
data to ensure patient safety while receiving study treatment.
The IMC will include the Roche/Genentech Medical Monitor, at least one other Clinical 
Science representative who is not directly involved in the study, a Drug Safety Scientist, 
a biostatistician, and a statistical programmer.  Representatives from other Sponsor 
functional areas may be included as additional ad hoc members. In addition to the 
ongoing assessment of the incidence and nature of adverse events, serious adverse 
events, and laboratory abnormalities by the Investigator and the Medical Monitor, the 
IMC will review the aforementioned data at least twice during the study. 


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Throughout the course of the study, the IMC will meet at regular intervals during the 
study and at the request of the Medical Monitor (e.g., on the basis of unexpected safety 
signals).  The IMC may make recommendations regarding study conduct, including, but 
not limited to, performing additional safety analyses, amending the study protocol, 
holding patient enrollment to one or both treatment arms pending further safety 
evaluations, holding/discontinuing study treatment, or terminating the study.
Specific operational details such as the committee’s composition, frequency and timing 
of meetings and members’ roles and responsibilities will be detailed in the IMC charter.
For Arms A and B: The first planned review will occur after approximately 10 patients 
are randomized and have at least 6 weeks follow-up, and the next formal review will 
occur when approximately 60 patients are randomized and have at least 6 weeks 
follow-up.
3.4.3
Risks Associated with DCDT2980S and DCDS4501A
The clinical safety profile of DCDT2980S and DCDS4501A based on clinical data 
obtained in the ongoing Phase I studies are summarized in Section 1.2.1.2 and 
Section 1.2.2.2.  Known and suspected risks, based on clinical data to date, are 
described below.  Guidelines regarding the management of these risks through dose 
and schedule modifications are described in Section 4.3.1.3 and Section 4.3.1.4.  
Refer also to the Investigator’s Brochure for complete and updated details.
3.4.3.1
Infusion-Related Events
Some MAbs may be associated with the development of allergic or anaphylactic 
reactions, to either the active protein or excipients.  True allergic or anaphylactic 
reactions are rare after the first dose of a product, as they require prior sensitization.  
Patients with true allergic or anaphylactic reactions should not receive further doses of 
the product.
MAbs may also be associated with reactions that are clinically indistinguishable from 
true allergic or anaphylactic reactions but are mediated through direct release of 
cytokines or other pro-inflammatory mediators.  Such reactions are often termed IRRs.  
IRRs typically occur with the first infusion of a MAb product and are generally less 
frequent and/or less severe with subsequent infusions.  They can often be managed by 
slowing the infusion rate and/or pre-treatment with various medications.
Allergic or anaphylactic reactions and IRRs typically begin during or within several hours
of completing the infusion.  The onset of symptoms may be rapid, and some reactions 
may be life threatening.
Patients should be monitored for these types of reactions during and after receiving 
DCDT2908S and DCDS4501A.  DCDT2980S and DCDS4501A should be administered 


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in an environment under close supervision of a physician and where full resuscitation 
facilities are immediately available.  Specific guidelines for additional precautions to be 
taken during and following DCDT2980S and DCDS4501A administration are provided in 
Section 4.3.1.5.
3.4.3.2
Tumor Lysis Syndrome
There is a potential risk of TLS if treatment with DCDT2980S or DCDS4501A results in 
the rapid destruction of a large number of tumor cells.  If any evidence of this occurs 
during the study, TLS prophylaxis measures will be instituted.  Patients who are 
considered to have a high tumor burden (e.g., lymphocyte count 25109/L) or bulky 
lymphadenopathy and who are considered to be at risk for TLS by the investigator will 
receive TLS prophylaxis (e.g., allopurinol 300 mg/day orally or a suitable alternative 
treatment according to institutional practice starting 1224 hours prior to study 
treatment) and must be well hydrated prior to the initiation of study treatment at Cycle 1, 
Day 1.  These patients should continue to receive repeated prophylaxis with allopurinol 
and adequate hydration prior to each subsequent infusion as deemed appropriate by the 
investigator.
3.4.3.3
Bone Marrow Toxicity/Neutropenia
Based on preclinical toxicity studies in rats and cynomolgus monkeys and clinical data 
from the ongoing Phase I Studies DCT4862g and DCS4968g, neutropenia has been 
identified as a known risk (adverse drug reaction) of both DCDT2908S and 
DCDS4501A.  Neutropenia and neutropenia-associated events were reversible but in 
some cases resulted in protocol-mandated dose reductions and/or delays.  
Adequate hematologic function should be confirmed before initiation of study treatment.  
Patients receiving study treatment will be regularly monitored for evidence of marrow 
toxicity with complete blood counts.  Study treatment may be delayed or modified due to 
hematologic toxicities, as described in Section 4.3.1.
The use of G-CSF for neutropenia is described in Section 4.3.1.6.  Transfusion support 
for anemia and thrombocytopenia is also permitted at the discretion of the treating 
physician.
Febrile neutropenia is commonly associated with myelotoxicity, which is considered a 
class effect of MMAE because it is commonly reported with ADCETRIS, other similar 
ADCs, and vincristine sulfate.
Clinical data show that among the most common SAEs reported in both DCS4968g and 
DCT4862g studies were febrile neutropenia and pyrexia.
3.4.3.4
Immunogenicity
As expected with any recombinant antibody, DCDT2980S, DCDS4501A, and 
obinutuzumab may elicit an immune response and patients may develop antibodies 


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against DCDT2980S, DCDS4501A, or obinutuzumab.  Patients will be closely monitored 
for any potential immune response to DCDT2980S, DCDS4501A, and obinutuzumab.  
Appropriate screening and confirmatory assays will be employed to detect ATAs at 
multiple timepoints before, during, and after treatment with DCDT2980S, DCDS4501A, 
and obinutuzumab.  Considering the historically low immunogenicity rate of rituximab in 
NHL patients, ATAs against rituximab will not be monitored in this study.
3.4.3.5
Peripheral Neuropathy
On the basis of clinical data from the ongoing Phase I Studies DCT4862g and 
DCS4968g and data from brentuximab vedotin studies, an anti-CD30-vc-MMAE ADC 
(see Section 3.4.2), peripheral neuropathy (sensory and motor) has been identified as a 
known risk (adverse drug reaction) for both DCDT2980S and DCDS4501A.
Careful clinical evaluation of patients for neuropathy should be conducted prior to 
initiation of study drug. Patients should be monitored for signs of peripheral neuropathy 
or worsening neuropathy and appropriate action taken per protocol guidelines.  Study 
treatment dose and schedule modifications for significant and prolonged neuropathic 
toxicity and dose-reduction are described in Section 4.3.1.7.  
3.4.3.6
Reproductive Toxicity
Adverse effects on human reproduction and fertility are anticipated with the 
administration of DCDT2980S and DCDS4501A, given the mechanism of action of 
MMAE.  Standard exclusion criteria will be used to ensure that patients of childbearing 
potential (male or female) are using adequate contraceptive methods. 
3.4.3.7
Hyperglycemia
Hyperglycemia has been observed in patients treated with DCDT2980S and 
DCDS4501A as well as with other ADCs using the same vc-MMAE platform.  Several 
patients given both DCDT2980S and DCDS4501A had abnormal fasting blood sugar 
(FBS) at screening with elevations of glucose following steroid administration prior to 
rituximab dose. Hyperglycemia has been reversible upon holding or discontinuing 
treatment of the ADCs and/or initiation or adjustment of anti-hyperglycemic medications.  
Emerging data suggest that hyperglycemia may occur more commonly in individuals 
with abnormal FBS values or known diabetes.  This is also reported for ADCETRIS
(2013 SmPC and 2013 USPI).
3.4.3.8
Hepatotoxicity
Elevations in transaminase and/or bilirubin levels requiring dose modifications and 
treatment discontinuations have been reported in the ongoing clinical studies.  


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3.4.3.9
Commonly Reported Side Effects
Other commonly reported side effects of both DCDT2980S or DCDS4501A in the 
Phase I clinical trials and within this study include fatigue, nausea, decreased appetite, 
vomiting, hair thinning or loss, joint pains, loss of appetite, diarrhea, muscle aches, 
constipation, increases in blood glucose, and headaches.
3.4.4
Risks Associated with Rituximab Therapy and Their 
Management
3.4.4.1
Infusion Reactions
In single-agent clinical trials of rituximab and in post-marketing surveillance studies, mild
to moderate infusion reactions consisting of fever and chills/rigors occurred in the 
majority of patients during the first rituximab infusion.  Other frequent infusion reaction 
signs and symptoms included nausea, pruritus, angioedema, asthenia, hypotension, 
headache, bronchospasm, throat irritation, rhinitis, urticaria, rash, vomiting, myalgia, 
dizziness, and hypertension.  These reactions generally occurred within 30120 minutes 
of beginning the first infusion, and they resolved with slowing or interruption of the 
rituximab infusion and with supportive care (diphenhydramine, 
acetaminophen/paracetamol, IV saline, meperidine, and vasopressors).  The incidence 
of infusion reactions was highest during the first infusion and decreased with each 
subsequent infusion.
Rituximab has caused severe infusion reactions.  In some cases, these reactions were 
fatal.  These severe reactions typically occurred during the first infusion with a time to 
onset of 30120 minutes.  Signs and symptoms of severe infusion reactions may include 
urticaria, hypotension, angioedema, hypoxia, or bronchospasm and may require 
interruption of rituximab administration.  The most severe manifestations and sequelae 
include pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, 
ventricular fibrillation, cardiogenic shock, and anaphylactic and anaphylactoid events 
(see Appendix D).  Approximately 80% of fatal infusion reactions occurred in association 
with the first infusion of rituximab.  Because of this, patients should receive 
premedication with acetaminophen/paracetamol, antihistamines, or corticosteroids, in 
accordance with standard clinical practice, prior to rituximab infusions.
3.4.4.2
Management of Severe Infusion Reactions
Administration of rituximab will occur in a setting with emergency equipment and staff
who are trained to monitor for and respond to medical emergencies.  The rituximab 
infusion should be interrupted for severe reactions on the basis of clinical judgment.  
Medications and supportive care measuresincluding, but not limited to, epinephrine, 
antihistamines, glucocorticoids, IV fluids, vasopressors, oxygen, bronchodilators and
acetaminophen/paracetamolshould be available for immediate use and instituted as 
medically indicated for use in the event of a reaction during administration.  


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In most cases, the infusion can be resumed at a 50% reduction in rate (e.g., from
100 mg/hr to 50 mg/hr) when symptoms have completely resolved.  Patients requiring 
close monitoring during all rituximab infusions include those with preexisting cardiac and 
pulmonary conditions, those with prior clinically significant cardiopulmonary adverse 
events, and those with high numbers of circulating malignant cells (25,000/L) with or 
without evidence of high tumor burden.
3.4.4.3
Tumor Lysis Syndrome
Rapid reductions in tumor volume followed by acute renal failure, hyperkalemia, 
hypocalcemia, hyperuricemia, or hyperphosphatemia have been reported within 
1224 hours after the first infusion of rituximab.  Rare instances of fatal outcome have 
been reported in the setting of TLS following treatment with rituximab.  The risks of TLS 
appear to be greater in patients with high tumor burden.  Patients deemed to be at high 
risk for TLS complications may, at the investigator’s discretion, receive their initial dose 
of rituximab over 2 consecutive days (see Section 4.3.2.3).  Correction of electrolyte 
abnormalities, monitoring of renal function and fluid balance, and administration of 
supportive care, including dialysis, should be initiated as indicated.  Following complete 
resolution of TLS complications, rituximab has been tolerated when re-administered in
conjunction with prophylactic therapy for TLS in a limited number of cases.
3.4.4.4
Hepatitis B Reactivation with Related Fulminant Hepatitis and 
Other Viral Infections
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death 
has been reported for some patients with hematologic malignancies treated with 
rituximab.  The majority of these patients received rituximab in combination with 
chemotherapy.  The median time to the diagnosis of hepatitis was approximately 
4 months after the initiation of rituximab and approximately 1 month after the last dose 
of rituximab.  Patients with serologic findings consistent with chronic HBV (hepatitis B 
surface antigen [HBsAg] positivity) or hepatitis C virus (HCV) infection (HCV RNA or 
antibody positivity) are ineligible for this study.  Patients who are not chronically infected 
with HBV but have serologic evidence of prior infection at baseline (IgG hepatitis B core 
antibody[anti-HBc] positive but HBV DNA negative) may be eligible (if believed to be in 
the patient’s best interest by the investigator and Medical Monitor) and would be 
monitored closely for perturbations in liver function during the period of rituximab 
treatment and every 24 weeks thereafter.  Such patients would also be required to 
receive prophylactic anti-viral therapy with lamivudine for at least 6 months after 
completion of rituximab therapy (Yeo et al. 2009).
Additional serious viral infections, new, reactivated, or exacerbated (e.g., infections 
caused by cytomegalovirus, varicella zoster virus, herpes simplex virus, West Nile virus, 
parvovirus B19, John Cunningham [JC] virus, and HCV) have been reported with 
rituximab, mainly in patients who had received rituximab in combination with 
chemotherapy or as part of a hematopoietic stem cell transplant.  Particular attention 
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such as high-dose chemotherapy and stem cell transplant.  JC virus infection resulting in 
PML and death has been observed in rituximab-treated patients with hematologic 
malignancies or with autoimmune diseases.  Most cases of progressive multifocal 
leukoencephalopathy (PML) were diagnosed within 12 months of the patient’s last 
infusion of rituximab.  Physicians should consider the diagnosis of PML in any patient 
presenting with new-onset neurologic manifestations.  Evaluation of PML includes, but is 
not limited to, consultation with a neurologist, brain magnetic resonance imaging (MRI), 
and lumbar puncture.  Physicians should discontinue rituximab (and DCDT2980S and/or 
DCDS4501A) and consider discontinuation or reduction of any immunosuppressive 
therapy in patients who develop PML.
3.4.4.5
Cardiovascular Events
Infusions should be discontinued in the event of serious or life-threatening cardiac 
arrhythmias.  Patients who develop clinically significant arrhythmias should undergo
cardiac monitoring during and after subsequent infusions of rituximab.  Patients with 
preexisting cardiac conditions, including arrhythmias and angina, who have had 
recurrences of these events during rituximab therapy should be monitored throughout
the infusion and the immediate post-infusion period.
3.4.4.6
Bowel Obstruction and Perforation
Abdominal pain, bowel obstruction, and perforation, in some cases leading to death, 
were observed in patients receiving rituximab in combination with chemotherapy for 
DLBCL.  In post-marketing reports, which include patients with low-grade or follicular 
NHL and patients with DLBCL, the mean time to onset of symptoms was 6 days
(range, 177 days) in patients with documented gastrointestinal perforation.  Complaints 
of abdominal pain, especially early in the course of treatment, should prompt a thorough 
diagnostic evaluation and appropriate treatment.  
3.4.4.7
Immunization
The safety of immunization with live viral vaccines following rituximab therapy has not 
been studied.  Patients who participate in this study may not receive either primary or 
booster with live virus vaccines for at least 28 days prior to initiation of rituximab or at 
any time during study treatment.  Investigators should review the status of potential 
study patients being considered for this study and follow the U.S. Centers for Disease 
Control and Prevention guidelines for adult with non-live vaccines intended to prevent 
infectious diseases prior to study therapy.
Refer to the Rituxan/MabThera(Rituximab) Package Insert/Summary of Product 
Characteristics (SmPC) for additional safety information.
3.4.5
Risks Associated with Obinutuzumab Therapy
No evidence available at the time of the approval of this protocol indicates that special 
warnings or precautions are appropriate other than those noted in the Obinutuzumab 
Investigator’s Brochure and as described in the following sections.


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3.4.5.1
Infusion-Related Reactions and Hypersensitivity Reactions 
(including Anaphylaxis)
The commonly experienced IRRs have been characterized by fever, chills, flushing, 
nausea, vomiting, hypotension, hypertension, fatigue, and other symptoms.
Respiratory infusion-related symptoms, such as hypoxia, dyspnea, bronchospasm, 
larynx and throat irritation, and laryngeal edema, have also been reported.  These IRRs 
were mostly mild or moderate (NCI CTCAE v4.0, Grade 1 and 2 events), and10% of 
the events were severe (Grade 3 events), occurring predominantly during the first hour 
of the infusion or shortly after the first infusion had finished.  The events resolved with 
the slowing or interruption of the infusion and supportive care.  The incidence and 
severity of IRRs decreased with subsequent infusions.  Extensive tumor burden 
predominantly localized in the blood circulation (e.g., high peripheral lymphocyte count in 
patients with CLL) may be a predisposing factor for the development of IRRs.
IRRs may be clinically indistinguishable from IgE-mediated allergic or anaphylactic 
reactions.
3.4.5.2
Tumor Lysis Syndrome
TLS has been reported with obinutuzumab administration.  Patients with a high tumor 
burden, including patients with a lymphocyte count 25109/L, particularly patients with 
B-cell CLL and MCL, are at increased risk for TLS and severe IRRs.  All patients with 
peripheral blood lymphocyte counts of 25109/L or bulky adenopathy must receive 
prophylaxis for TLS prior to the initiation of study treatment.  This includes appropriate 
hydration, consisting of fluid intake of approximately 3 L/day, starting 12 days prior to 
the first dose of obinutuzumab, and administration of allopurinol (300 mg/day orally) or a 
suitable alternative (i.e., rasburicase) treatment, starting at least 1224 hours prior to 
the first infusion of obinutuzumab (Cycle 1, Day 1).  All patients should then be carefully 
monitored during the initial weeks of treatment.  Patients still considered at risk for TLS 
because of persistently high tumor burden (i.e., peripheral blood lymphocyte counts 
25109/L) before the second and subsequent infusions of obinutuzumab should 
receive continuous TLS prophylaxis with allopurinol or a suitable alternative (i.e., 
rasburicase) and adequate hydration until the risk is abated, as determined by the 
investigator. For treatment of TLS, correct electrolyte abnormalities, monitor renal 
function and fluid balance, and administer supportive care, including dialysis as 
indicated.
3.4.5.3
Neutropenia
Cases of Grade 3 or 4 neutropenia, including febrile neutropenia, have been reported 
with obinutuzumab administration.  Grade 3 or 4 neutropenia has predominantly been 
observed in patients with CLL.  Patients who experience Grade 3 or 4 neutropenia 
should be monitored until neutrophil values return to at least Grade 2.  Use of G-CSF 
has been found to result in a rapid normalization of neutrophils, similar to what has been 
observed in patients treated with rituximab.  The use of G-CSF is allowed for treatment 


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of neutropenia in this study.  Primary prophylaxis with G-CSF is recommended 
according to the American Society of Clinical Oncology (ASCO), European Organisation 
for Research and Treatment of Cancer (EORTC), and European Society for Medical 
Oncology (ESMO) guidelines, namely for patients who are 60 years old and/or with 
co-morbidities (Lyman et al. 2004).  
3.4.5.4
Thrombocytopenia
Severe and life-threatening thrombocytopenia, including acute thrombocytopenia 
(occurring within 24 hours after the infusion), has been observed during treatment with 
obinutuzumab.  Fatal hemorrhagic events have also been reported in patients treated 
with obinutuzumab.  It seems that the first cycle is the greatest risk of hemorrhage in 
patients treated with obinutuzumab.  A clear relationship between thrombocytopenia and 
hemorrhagic events has not been established.  Patients treated with concomitant 
medication, which could possibly worsen thrombocytopenia-related events (e.g., platelet 
inhibitors and anticoagulants), may be at greater risk of bleeding.  Patients should be 
closely monitored for thrombocytopenia, especially during the first cycle; regular 
laboratory tests should be performed until the event resolves, and dose delays should be 
considered in case of severe or life-threatening thrombocytopenia.  Transfusion of blood 
products (i.e., platelet transfusion) according to institutional practice is at the discretion 
of the treating physician. 
3.4.5.5
Infection
On the basis of its anticipated mode of action, resulting in profound B-cell depletion, 
obinutuzumab may be associated with an increased risk of infections.  Infections have 
been reported in patients receiving obinutuzumab.  Therefore, obinutuzumab should not 
be administered to patients with active severe infections.
A “black-box” warning for obinutuzumab states that reactivation of hepatitis B as well as 
other serious viral infections (e.g., infections caused by cytomegalovirus, Varicella zoster 
virus, herpes simplex virus, JC virus, and HCV) that were new, reactivated, or 
exacerbated have been reported with the B celldepleting antibody rituximab mainly in 
patients who had received the drug in combination with chemotherapy or as part of a 
hematopoietic SCT.  The risk of such infections with obinutuzumab is unknown.  
Particular attention should be given to patients who have previously received significant 
immunosuppressive treatment, such as high-dose chemotherapy and SCT.
A “black-box” warning for obinutuzumab states that JC viral infection (including fatal) that 
resulted in PML with destructive infection of oligodendrocytes of the CNS white matte
have been reported in patients treated with anti-CD20 therapies, including rituximab and 
obinutuzumab.
The diagnosis of PML should be considered in any patient presenting with new-onset 
neurologic manifestations.  The symptoms of PML are unspecific and can vary 
depending on the affected region of the brain.  Motor involvement with corticospinal tract 


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findings, sensory involvement, cerebellar deficits, and visual field defects are common.  
Some syndromes regarded as cortical (e.g., aphasia or visual-spatial disorientation) 
can occur.
Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain
MRI, and lumbar puncture (cerebrospinal fluid testing for JC viral DNA). 
Therapy with obinutuzumab should be withheld during the investigation of potential PML 
and permanently discontinued in case of confirmed PML.  Discontinuation or reduction of 
any concomitant chemotherapy or immunosuppressive therapy should also be 
considered.  The patient should be referred to a neurologist for the diagnosis and 
management of PML.
3.4.5.6
Immunization
The safety of immunization with live virus vaccines following obinutuzumab therapy has 
not been studied.  Thus, vaccination with live virus vaccines is not recommended during 
treatment and until B-cell recovery.
3.4.5.7
Worsening of Preexisting Cardiac Condition
In patients with underlying cardiac disease and treated with obinutuzumab, adverse 
events such as angina pectoris, acute coronary syndrome, myocardial infarction, heart 
failure, and arrhythmias, including atrial fibrillation and tachyarrhythmia, have been 
observed.  These events may occur as part of an IRR and can be fatal.  Therefore, 
patients with a history of cardiac disease should be monitored closely.  In addition, these 
patients should be hydrated with caution to prevent a potential fluid overload.
3.5
MINIMIZATION OF BIAS
For the randomized, non-comparative, open-label portion of the study, patients were
randomly allocated to two treatment arms in a 1:1 ratio through use of an interactive 
voice or web-based response system (IxRS).  A dynamic stratified randomization 
scheme was employed to ensure balance in the stratification factors as specified in 
Section 3.1.  This portion of the study (Arms A and B) is now closed to enrollment.
3.6
ADMINISTRATIVE STRUCTURE 
Genentech, Inc., a member of the Roche group, will sponsor this study.  A Contract 
Research Organization (CRO) will be utilized to perform project management, study 
management, and clinical monitoring.  Genentech will conduct CRO oversight, approve 
patient eligibility, and perform dose escalation decision-making, medical monitoring, and 
statistical programming and analysis. An IMC (see Section 3.4) will provide an 
additional level of safety monitoring for the study. 
Approximately 40 study centers in the United States, Canada, and Europe will 
participate in the study to enroll approximately 252 patients.  Additional patients may be 
enrolled in order to obtain additional safety and/or efficacy data.


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Electronic data capture (EDC) will be utilized for this study.  An IxRS will be used to 
assign patient numbers.  A central laboratory will be used for sample management and 
storage until shipment to one of several specialty laboratories or Genentech for analysis.  
An IRF will be used for the collection and possible assessment of radiographic images 
from tumor assessments.  Additional vendors for ECG collection and possible analysis 
and for PRO collection and data entry will be used.
3.7
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in accordance with the FDA regulations, the International 
Conference on Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP), and 
applicable local, state, and federal laws, as well as other applicable country laws.
4.
MATERIALS AND METHODS
4.1
PATIENTS
4.1.1
Inclusion Criteria
Patients must meet the following criteria to be eligible for study entry:

Signed Informed 
Consent Form(s)

Age 18 years 

ECOG Performance Status of 0, 1, or 2

Life expectancy of at least 12 weeks

History of histologically documented relapsed or refractory Grades 13a FL or 
relapsed or refractory DLBCL

Availability of an archival or freshly biopsied tumor tissue sample must be confirmed 
for study enrollment.

Have a clinical indication for treatment as determined by the investigator

Must have at least one bidimensionally measurable lesion (1.5 cm in its largest 
dimension by CT scan or MRI)

Laboratory values (including patients with hepatic or renal involvement), as follows:
AST and ALT 2.5 ULN
Total bilirubin 1.5 ULN
Platelet count 75,000/mm3 (unless thrombocytopenia clearly due to marrow 
involvement of NHL and/or disease-related immune thrombocytopenia)
Absolute neutrophil count 1000/mm3 (without growth factor support, unless 
neutropenia clearly due to marrow involvement of NHL)
Total hemoglobin 9 g/dL (without transfusion support 14 days prior to 
screening, unless anemia clearly due to marrow involvement of NHL)
Serum creatinine 2.0 mg/dL or measured creatinine CL 50 mL/min


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
For female patients of childbearing potential and male patients with female partners 
of childbearing potential, agreement to use one highly effective form of nonhormonal
contraception or two effective forms of nonhormonal contraception, including at 
least one method with a failure rate of 1% per year, through the course of 
study treatment and for 12 months after the last dose of DCDT2980S,
DCDS4501A, rituximab, or obinutuzumab (whichever is later) in women and at least 
5 months after the last dose of DCDT2980S, DCDS4501A, rituximab, or 
obinutuzumab (whichever is later) in men
A woman is considered not to be of childbearing potential if she is 
postmenopausal, defined by amenorrhea of 12 months duration and age 
45 years, or has undergone hysterectomy and/or bilateral oophorectomy.
The following are considered highly effective forms of contraception:  1) true 
abstinence; 2) male sterilization (with post-procedure documentation of absence 
of sperm in the ejaculate).  For female patients, the sterilized male partner should 
be the sole partner.
The following are considered effective forms of contraception:  1) intrauterine 
device (IUD; copper IUD or hormonal IUDs only) or intrauterine system; 
2) condom with spermicidal foam/gel/film/cream/suppository; 3) occlusive cap 
(diaphragm or cervical/vault cap) with spermicidal 
foam/gel/film/cream/suppository.
Males must agree to abstain from sperm donation for at least 5 months after the 
last dose of DCDT2980S, DCDS4501A, rituximab, or obinutuzumab
(whichever is later).
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Prior use of any MAb, radioimmunoconjugate or ADC within 4 weeks before 
Cycle 1, Day 1

Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive 
therapy, or any investigational anti-cancer agent within 2 weeks prior to Cycle 1, 
Day 1
Adverse events except for sensory neuropathy from any previous treatments 
must be resolved or stabilized to Grade 2 prior to Cycle 1, Day 1.

Completion of autologous stem cell transplant within 100 days prior to Cycle 1, 
Day 1

Prior allogeneic stem cell transplant

Eligibility for autologous SCT (patients with relapsed or refractory DLBCL)

History of transformation of indolent disease to DLBCL

History of severe allergic or anaphylactic reactions to MAb therapy (or recombinant 
antibody-related fusion proteins)


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
History of other malignancy that could affect compliance with the protocol or 
interpretation of results
Patients with a history of curatively treated basal or squamous cell carcinoma of 
the skin or in situ carcinoma (e.g., of the cervix or breast) are allowed.  Patients 
with a malignancy that has been treated with curative intent will also be allowed if 
the malignancy has been in remission without treatment for 2 years prior 
to Cycle 1, Day 1.

Current or past history of CNS lymphoma

Current Grade 1 peripheral neuropathy

Evidence of significant, uncontrolled, concomitant diseases that could affect 
compliance with the protocol or interpretation of results, including significant 
cardiovascular disease (such as New York Heart Association Class III or IV cardiac 
disease, myocardial infarction within the last 6 months, unstable arrhythmias, or 
unstable angina) or significant pulmonary disease (including obstructive pulmonary 
disease and history of bronchospasm)

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection 
(excluding fungal infections of nail beds) at study enrollment or any major episode 
of infection requiring treatment with IV antibiotics or hospitalization (relating to the 
completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1

Recent major surgery within 6 weeks prior to Cycle 1, Day 1, other than 
for diagnosis

Presence of positive test results for hepatitis B (HBsAg and/or total anti-HBc) or 
hepatitis C (HCV antibody)
Patients who are positive for anti-HBc are eligible only if PCR is negative for HBV 
DNA and it is believed by both the investigator and Medical Monitor that it is in 
the patient’s best interest to participate. 
Patients who are positive for HCV antibody must be negative for HCV by PCR to 
be eligible for study participation.

Vaccination with a live vaccine within 28 days prior to treatment

Known history of HIV seropositive status

Women who are pregnant or lactating

Ongoing corticosteroid use 30 mg/day prednisone or equivalent
Patients receiving corticosteroid treatment 30 mg/day prednisone or equivalent 
must be documented to be on a stable dose prior to study enrollment and 
initiation of therapy
4.2
METHOD OF TREATMENT ASSIGNMENT
This is an open-label study.  After written informed consent has been obtained and 
preliminary eligibility has been established, the study site will submit documentation 
supporting eligibility to the Sponsor via facsimile and obtain the Sponsor’s approval to 


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enroll the patient.  Once the Sponsor reviews and approves the patient for enrollment, 
the patient number will be assigned via IxRS.
As described in Section 3.1.1.2, only select investigator sites that have agreed to 
participate in the non-randomized (Cohorts C and D) portion of the study will enroll 
patients into these cohorts.  Cohorts C and D will be opened sequentially following 
completion of the randomized portion of the study for patients with FL.
For obinutuzumab-containing cohorts (Cohorts E, G, and H), patients with either 
relapsed or refractory follicular NHL or relapsed or refractory DLBCL will be enrolled.  
After the safety run-in stage for DCDS4501A at 1.8 mg/kg in combination with 
obinutuzumab, the non-randomized dose-expansion portion of the study will enroll 
40 relapsed or refractory FL patients into Cohort G and 40 relapsed or refractory DLBCL 
patients into Cohort H.
Personnel responsible for performing PK and ATA assays will receive participants’ 
treatment assignments to identify appropriate PK and ATA samples to be analyzed in 
the appropriate corresponding assays. 
4.3
STUDY TREATMENT 
4.3.1
DCDT2980S and DCDS4501A
4.3.1.1
Formulation and Storage
a.
DCDT2980S
DCDT2980S will be provided as a lyophilized powder in a single-use 20-cc vial.  
The solution for reconstitution is Sterile Water for Injection (SWFI), and the reconstitution 
volume is 2.6 mL to yield a final concentration of 20 mg/mL DCDT2980S in 40 mM 
L-histidine hydrochloride, 240 mM sucrose, and 0.02% polysorbate 20, pH 6.0.
Reconstituted DCDT2980S should be further diluted with sterile 0.9% NaCl to a total 
volume of 250 mL.
DCDT2980S vials must be refrigerated at 2C8C (36F46F) upon receipt until use.  
DCDT2980S should not be used beyond the expiration date provided by the 
manufacturer.  Vial contents should not be frozen or shaken and should be protected 
from direct sunlight.  After reconstitution, DCDT2980S vials may be stored at room 
temperatures (8C25C [46F77F]) for up to 4 hours or at refrigerated 
temperatures (2C8C [36F46F]) for up to 8 hours prior to use.  Once DCDT2980S 
has been diluted with sterile 0.9% NaCl, the solution should be used within 4 hours at 
room temperature or within 8 hours at refrigerated temperature.  Vials are intended for 
single use only; therefore, any remaining solution should be discarded.
For further details, refer to the DCDT2980S Investigator’s Brochure.


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b.
DCDS4501A
DCDS4501A is provided as a liquid formulation and contains no preservatives.  Each 
single-use 20-cc vial is filled to deliver 100 mg of DCDS4501A.  The drug product is 
formulated as 10 mg/mL DCDS4501A in 20 mM L-histidine acetate, 240 mM sucrose, 
0.02% (w/v) polysorbate 20, pH 5.5. 
DCDS4501A will be administered to patients intravenously via syringe pump with an 
IV infusion set containing a 0.22µm in-line filter with a final volume of DCDS4501A 
determined by the dose and patient weight. 
DCDS4501A vials must be refrigerated at 2C8C (36F46F) upon receipt until use.  
DCDS4501A vials may be stored at room temperature (8°C25°C [46°F77°F]) for up 
to 8 hours.  DCDS4501A should not be used beyond the expiration date provided by the 
manufacturer.  Vial contents should not be frozen or shaken and should be protected 
from direct sunlight.  Vials are intended for single use only; therefore, any remaining 
solution should be discarded.
Once the DCDS4501A dose solution has been prepared, the solution should be used 
within 4 hours at room temperature (8 C25C [46F77F]) or within 8 hours 
refrigerated at 2°C8°C (36°F46°F).  Because the drug product contains no 
preservatives, the Sponsor recommends using DCDS4501A in a syringe and extension 
set as soon as possible to reduce the risk of microbial contamination.  
For further details, refer to the DCDS4501A Investigator Brochure.
4.3.1.2
Dosage and Administration
a.
DCDT2980S-Specific Information
DCDT2980S will be administered to patients by IV infusion.  Compatibility testing has 
shown that DCDT2980S is stable when diluted in polyvinyl chloride (PVC) bags to a 
concentration at or above 0.04 mg/mL in 0.9% NaCl diluent.  The drug product will be 
delivered following dilution in 0.9% NaCl with a final DCDT2980S concentration 
determined based on dose and patient weight.  The study drug will be diluted in a PVC 
bag and delivered using a 0.22 µm in-line filter on the IV infusion set.
Additional information/instructions regarding study drug administration will be provided in 
the Pharmacy Binder.
b.
DCDS4501A-Specific Information
DCDS4501A will be administered to patients intravenously via syringe pump with an 
IV infusion set containing a 0.22 µm in-line filter with a final volume of DCDS4501A 
determined by the dose and patient weight.  Compatibility testing has shown that 
DCDS4501A is stable both in syringes made of polypropylene (PP) and in standard 
extension sets with 0.22 µm in-line filter, when stored neat or diluted with 0.9% NaCl 
saline.  


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Additional information/instructions regarding study drug administration will be provided in 
the Pharmacy Binder.
c.
General Information
The total dose of DCDT2980S and DCDS4501A for each patient will depend on the 
patient’s weight within 96 hours prior to Day 1 of each cycle.  The patient weight 
obtained during screening may be used for dose determination at all treatment cycles; if 
the patient’s weight within 96 hours prior to Day 1 of a given treatment cycle differs 
by >10% from the weight obtained during screening, the new weight should be used to 
calculate the dose.
For both DCDT2980S and DCDS4501A, the initial dose will be administered to
well-hydrated (based on clinical judgment) patients over 90 (10) minutes.  
Premedication with acetaminophen or paracetamol (e.g., 5001000 mg) and 
diphenhydramine (e.g., 50C100 mg) per institutional standard practice may be 
administered prior to each infusion.  Administration of corticosteroids is permitted at the 
discretion of the treating physician.  Patients who do not receive premedications prior to 
the first dose of DCDT2980S and who develop an IRR during the first dose should 
receive premedications prior to subsequent doses (see Table 1).
The DCDT2980S/DCDS4501A infusion may be slowed or interrupted for patients 
experiencing infusion-associated symptoms.  Following the initial dose, patients will be 
observed for 90 minutes for fever, chills, rigors, hypotension, nausea, or other 
infusion-associated symptoms.  If the infusion is well-tolerated, subsequent doses of 
DCDT2980S/DCDS4501A may be administered over 30 (10) minutes, followed by a 
30-minute observation period post-infusion.  
For instructions on study drug preparation and administration, refer to the DCDT2980S 
and DCDS4501A Investigator Brochure.
4.3.1.3
Dosage Modification
Patients should be assessed clinically for toxicity prior to each dose using the 
NCI CTCAE v4.0 grading scale.  Dosing will occur only if a patient’s clinical assessment 
and laboratory test values are acceptable.  If scheduled dosing coincides with a holiday 
that precludes dosing, dosing should commence on the nearest following date, with 
subsequent dosing continuing on a 21-day schedule as applicable.
Specific guidelines around dosage modifications for neutropenia and peripheral 
neuropathy are detailed below in Section 4.3.1.6 and Section 4.3.1.7.  Patients who 
experience other treatment-related Grade 3 or 4 toxicity or laboratory abnormalities will 
be allowed to delay dosing of study treatment (both ADC and rituximab or 
obinutuzumab) for up to 2 weeks to allow for recovery.  Patients may continue to receive 
additional infusions of DCDT2980S or DCDS4501A per their treatment assignment 
provided that the toxicity has resolved to Grade 2 or 80% of the baseline value, 


 
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whichever is lower, within the 2−week delay period.  The decision for dose modification 
will be made on the basis of the investigator’s assessment of ongoing clinical benefit 
with continued study treatment and in consultation with the Medical Monitor.   
Once dose reductions of DCDT2980S or DCDS4501A are made for toxicity, dose 
re-escalation will not be allowed.   
If a patient develops unacceptable toxicity to DCDT2980S or DCDS4501A, requiring its 
discontinuation, single-agent rituximab may be continued on the basis of the 
investigator’s assessment of ongoing clinical benefit and with the approval of the 
Medical Monitor.  Patients enrolled in obinutuzumab-containing cohorts will not continue 
on single-agent obinutuzumab unless approved by the Medical Monitor. 
4.3.1.4 
Schedule Modification 
Patients in whom toxicities have not resolved to Grade ≤ 2 or ≥ 80% of baseline value, 
whichever is lower, may have their study treatment delayed by up to 2 weeks.  Dosing of 
both DCDT2980S or DCDS4501A and rituximab or obinutuzumab should be held during 
this period.  If all study drug−related toxicities have resolved sufficiently, the patient may 
resume DCDT2980S or DCDS4501A and rituximab or obinutuzumab dosing on the 
regular every-21-day schedule.   
A patient’s dosing may be changed to a 28-day cycle if it is felt by the investigator that 
changing a patient’s dosing regimen from 21-day to 28-day cycles would provide 
sufficient time for recovery from a transient and reversible toxicityfor example, 
cytopenia without requiring repeated treatment delays.  Modifications to the dosing 
schedule in this fashion must be made in consultation with and with the approval of the 
Medical Monitor. 
Patients who do not fulfill the criteria for continuation of dosing after the 2-week delay 
may be discontinued from study treatment and be followed for safety outcomes (see 
Section 4.5.6).  Exceptions on the basis of ongoing clinical benefit may be allowed 
following a careful assessment and discussion of risk versus benefit with the patient by 
the investigator and approval from the Medical Monitor.  
Specific guidelines around schedule modifications for neutropenia and peripheral 
neuropathy are detailed below in Section 4.3.1.6 and Section 4.3.1.7. 
4.3.1.5 
Infusion Reaction 
Patients will be monitored during and after each DCDT2980S/DCDS4501A infusion for 
90 minutes after the first infusion and for 30 minutes after subsequent infusions in the 
absence of infusion-related adverse events.  Patients who experience infusion-related 
symptoms should be managed as described in Table 1.  Precautions for suspected 
anaphylactic reaction during study drug infusions are provided in Appendix D. 


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In the event of a life-threatening IRR, which may include pulmonary or cardiac events, 
or an IgE-mediated anaphylactic reaction, administration of 
DCDT2980S/DCDS4501A should be immediately discontinued.  Patients who 
experience these reactions should receive aggressive symptomatic treatment and are 
not eligible to receive any additional study treatment.
Premedication prior to DCDT2980S/DCDS4501A with acetaminophen/paracetamol, 
antihistamines, or corticosteroids per standard clinical practice is permittedfor 
example, in patients with substantial tumor burden and where the risk of cytokine 
release syndrome is high.  In patients who do not receive premedication prior to any 
given dose of DCDT2980S/DCDS4501A and who develop any Grade 2 
infusion-related toxicity, premedication should be administered prior to subsequent 
doses. 


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Table 1
Management of Infusion-Related Symptoms for All Study Drugs
Infusion-Related 
Symptoms a
Guidance
Grade 12

Slow or hold infusion

Give supportive treatment b

Upon symptom resolution, may resume/escalate infusion rate at the 
investigator’s discretion c

Note: For Grade 2 wheezing or bronchospasm, patient must be 
premedicated for subsequent doses.  If symptoms recur with the same or 
greater severity, the infusion must be stopped immediately and study 
treatment permanently discontinued.
Grade 3

Discontinue infusion

Give supportive treatment b

Upon symptom resolution, may resume/escalate infusion rate at the 
investigator discretion c

Note:  If the same adverse event recurs with the same or greater severity, 
treatment must be permanently discontinued.

Note:  For Grade 3 hypotension or fever, patient must be premedicated 
before re-treatment.  If symptoms recur, then study drug must be 
permanently discontinued.

Note:  If patient has Grade 3 wheezing or bronchospasm at first occurrence, 
study treatment should be permanently discontinued.  
Grade 4

Discontinue infusion immediately, treat symptoms aggressively, and 
permanently discontinue patient from study treatment
IVintravenous; NCI CTCAENational Cancer Institute Common Terminology Criteria for 
Adverse Events.
a Refer to the NCI CTCAE v4.0 scale for the grading of symptoms.  Management of IgE-mediated 
allergic reactions should be as directed in the text preceding this table.
b Supportive treatment:  Patients should be treated with acetaminophen/paracetamol and an 
antihistamine such as diphenhydramine if they have not been received in the last 4 hours.  
IV saline may be indicated.  For bronchospasm, urticaria, or dyspnea, patients may require 
antihistamines, oxygen, corticosteroids (e.g., 100 mg IV prednisolone or equivalent), 
and/or bronchodilators.  Patients with hypotension requiring vasopressor support must be 
permanently discontinued from study drug.
c Infusion rate escalation after re-initiation:  Upon complete resolution of symptoms, the infusion 
may be resumed at 50% of the rate achieved prior to interruption.  In the absence of 
infusion-related symptoms, the rate of infusion may be escalated in increments of 50 mg/hr every 
30 minutes.


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4.3.1.6
Neutropenia
Because neutropenia is a known risk of DCDT2980S and DCDS4501A 
(see Section 3.4.3.3), the use of growth factor support (G-CSF) as prophylactic and 
therapeutic indications is permitted (see Appendix F) in order to allow continued dosing 
of DCDT2980S/DCDS4501A.  Dose modifications for patients who experience 
treatment-related Grade 34 neutropenia in the context of G-CSF usage are as follows:

Primary prophylaxis with G-CSF (i.e., prior to the first dose of 
DCDT2980S/DCDS4501A) is permitted for patients with clinical factors listed in 
Appendix F or who otherwise are considered at high risk for developing neutropenia 
on study treatment.

Patients who experience treatment-related Grade 34 neutropenia will be allowed to 
delay dosing of study treatment (both ADC and rituximab or obinutuzumab) for up to 
two weeks to allow for recovery.  Therapeutic G-CSF is permitted as clinically 
indicated (see Appendix F) and to facilitate neutrophil recovery to allow subsequent 
DCDT2980S/DCDS4501A dosing.

Subsequent dosing of DCDT2980S/DCDS4501A and rituximab/obinutuzumab is 
permitted provided that the neutropenia has resolved to Grade 2 or 80% of the 
baseline value, whichever is lower, within the 2-week period.  

If prophylactic G-CSF was not administered prior to the cycle in which the 
Grade 34 neutropenia developed, then prophylactic G-CSF may be administered 
prior to subsequent cycles without DCDT2980S/DCDS4501A dose reduction.  The 
dose schedule may be changed from 21-day to 28-day cycles to provide sufficient 
time for neutrophil recovery in subsequent cycles.  In the absence of prophylactic 
G-CSF or dose schedule modification, the dose of DCDT2980S/DCDS4501A in 
subsequent cycles should be reduced to 1.8 mg/kg for Arms A and B.  For Cohorts 
E, G, and H, patients will be given DCDS4501A at a dose of 1.8 mg/kg, and further 
dose reductions cannot be made.  

If Grade 34 neutropenia recurs with prophylactic G-CSF, the dose for subsequent 
DCDT2980S/DCDS4501A should be reduced to 1.8 mg/kg for Arms A and B.  
Prophylactic G-CSF and dose schedule modifications as described above are 
permitted in order to maintain the reduced DCDT2980S/DCDS4501A dose level and 
schedule.

If Grade 34 neutropenia recurs at the reduced dose despite the administration of 
prophylactic G-CSF, then the patient should be discontinued from study treatment.  

For patients enrolled into the non-randomized portion of the study (Cohorts C and D,
as well as Cohorts E, G, and H), dose reductions will not be allowed for neutropenia.  
Administration of therapeutic/prophylactic G-CSF and dose-schedule modifications 
as described above are allowed.  Patients who have persistent or recurrent 
Grade 34 neutropenia as defined above should be discontinued from study 
treatment.


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The determination of the dose and schedule modifications will be made on the basis of
the investigator’s assessment of ongoing clinical benefit with continuing study treatment 
and with the approval of the Medical Monitor.  
4.3.1.7
Peripheral Neuropathy
Peripheral neuropathy (sensory and/or motor) is a known risk of DCDT2980S and 
DCDS4501A (see Section 3.4.3.5).  For new or worsening drug-related Grade 2 or 3 
peripheral sensory and/or motor neuropathy, dosing should be held for up to 2 weeks
until peripheral neuropathy improves to Grade 1 or baseline grade.  Continuation of 
study treatment following dose delays beyond 2 weeks will require consultation with and 
approval of the Medical Monitor based on an assessment of the benefit-risk analysis of 
continuing to delay study treatment.
For patients enrolled in arms A or B following resolution of peripheral neuropathy
(sensory and/or motor), subsequent doses of DCDT2980S/DCDS4501A should be 
reduced to 1.8 mg/kg.  If worsening Grade 2 or 3 peripheral neuropathy (sensory and/or 
motor) recurs following dose reduction, study treatment should be discontinued.  For 
Grade 4 peripheral neuropathy (sensory and/or motor), study treatment should be 
discontinued. 
For patients enrolled into Cohorts C and D, dose modifications will not be allowed.  
Patients who have Grade 2 or 3 peripheral neuropathy (sensory and/or motor), as 
defined above, should be discontinued from study treatment.  
For patients enrolled in Cohorts E, G, or H, following resolution of Grade 2 or Grade 3 
peripheral neuropathy (sensory and/or motor), subsequent doses of DCDS4501A should 
be permanently reduced from 1.8 mg/kg to 1.4 mg/kg.  If worsening Grade 2 or Grade 3 
peripheral neuropathy (sensory and/or motor) recurs following dose reduction, study 
treatment should be discontinued.  For Grade 4 peripheral neuropathy (sensory and/or 
motor), study treatment should be discontinued.
4.3.1.8
Hyperglycemia
Hyperglycemia has been observed in patients treated with DCDT2980S and 
DCDS4501A as well as with other ADCs using the same vc-MMAE platform.  
Hyperglycemia has been reversible upon holding or discontinuing treatment of the ADCs 
and/or initiation of improved anti-hyperglycemic medications (see Section 3.4.3.7).  
For symptomatic fasting Grade 3 (250500 mg/dL) or asymptomatic Grade 4 
(500 mg/dL) hyperglycemia, medical management should be initiated immediately and 
consultation with a specialist should be considered.  If the hyperglycemia persists for 
1 week after initiation of management, dose modification, schedule modification, or 
discontinuation of study treatment should be considered.  In these cases, the study 
Medical Monitor should be consulted to assess the benefit-risk balance of continued 
study treatment.


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4.3.2
Rituximab
4.3.2.1
Formulation
Rituximab (Rituxan®/MabThera®) is a sterile, clear, colorless, preservative-free liquid 
concentrate for IV administration.  Rituximab is supplied at a concentration of 10 mg/mL 
in 500-mg (50-mL) single-use vials.  A single-unit, 500-mg carton contains one 50-mL 
vial of rituximab (10 mg/mL).  The product is formulated for IV administration in 
9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, and 0.7 mg/mL 
polysorbate 80, after reconstitution with SWFI.  The pH is adjusted to 6.5.  Vials are for 
single use.  Each vial and carton will contain a label (either single-panel or booklet) 
affixed to the vial or carton.  
4.3.2.2
Dosage, Administration, and Storage
Rituximab (Rituxan®, MabThera®) will be administered intravenously once per 3-week 
(or 4-week) cycle.  The infusion at 375 mg/m2 for each dose will be based on the 
patient’s body surface area at screening and will remain the same throughout the study.  
If a scheduled dose of rituximab falls outside of the 2-day window for reasons other 
than an adverse event, the site must notify and have a discussion with the Genentech 
Medical Monitor prior to rituximab administration.  Such dosing may not necessarily 
qualify as a protocol deviation, if deemed to be in the best interests of the patient, after 
consultation with the Medical Monitor and agreed to in advance by the Medical Monitor. 
Rituximab should not be administered as an IV push or bolus.  Infusion reactions may 
occur.  Premedication consisting of acetaminophen (or paracetamol), diphenhydramine 
(or other suitable antihistamine), and a single dose of hydrocortisone (e.g., up to 100 mg 
or an equivalent dose of methylprednisolone) may also be administered beginning with 
the first infusion, per standard clinical practice.  Premedication may attenuate infusion 
reactions.  Because transient hypotension may occur during rituximab infusion, 
consideration should be given to withholding antihypertensive medications for 12 hours
prior to rituximab infusion.  
a.
First Infusion
The rituximab solution for infusion should be administered intravenously at an initial rate 
of 50 mg/hr.  Rituximab should not be mixed or diluted with other drugs.  If infusion 
reactions do not occur, the infusion rate should be escalated in 50mg/hr increments 
every 30 minutes to a maximum of 400 mg/hr.  If an infusion reaction develops, 
the infusion should be temporarily slowed or interrupted.  The infusion can continue at 
one-half the previous rate upon improvement of patient symptoms.  
b.
Subsequent Infusions
If the patient tolerates the first infusion well, subsequent rituximab infusions may be 
administered at an initial rate of 100 mg/hr and increased in 100mg/hr increments at 
30-minute intervals to a maximum of 400 mg/hr, as tolerated.  If the patient does not 
tolerate the first infusion well, the guidelines for the first infusion should be followed.


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If a patient tolerates the first three cycles of study treatment without significant infusion 
reactions, rituximab may be administered as “rapid infusion” in accordance with local 
institutional guidelines.
c.
Storage
Rituximab vials must be stored at 2C8C (36C46F).  Rituximab vials should be 
stored in the outer carton in order to protect them from light.  Rituximab solution for 
infusion may be stored at 2C8C (36C46F) for 24 hours and has been shown to be 
stable for an additional 12 hours at room temperature.  However, because rituximab 
does not contain a preservative, diluted solutions should be stored refrigerated 
(2C8C).  No incompatibilities between rituximab and PVC or polyethylene (PE) bags 
have been observed.
See the Rituxan® (Rituximab) Package Insert or SmPC (in the European Union) for 
additional information.
4.3.2.3
Dosage Modification
There will be no rituximab dose modification in this study.  Patients at high risk for 
TLS complications (see Section 3.4.3.2) may, at the investigator’s discretion, receive 
their initial dose of rituximab over 2 consecutive days (e.g., 125 mg/m2 on Day 1, 
250 mg/m2 on Day 2; with DCDT2980S/DCDS4501A dose potentially delayed to Day 3).
Any NCI CTCAE (v4.0) toxicity Grade 3 in severity that is deemed related to rituximab 
treatment will require interruption of study treatment (both ADC and rituximab) until 
resolution to Grade 2 or 80% of baseline, whichever is lower.  Resumption of 
rituximab treatment may be considered in patients with resolution of toxicities to 
Grade 1 within 2 weeks at the discretion of the investigator, after consultation with the 
Medical Monitor.  Failure of such toxicities to resolve after 2-week delay in study 
treatment will require permanent discontinuation of rituximab.  Continuation of rituximab 
treatment may be permitted on the basis of ongoing clinical benefit following a careful 
assessment and discussion of risk versus benefit with the patient by the investigator and 
approval from the Medical Monitor.  
If a patient develops unacceptable toxicity to rituximab requiring its discontinuation, 
single-agent DCDT2980S or DCDS4501A may be continued on the basis of the 
investigator’s assessment of ongoing clinical benefit and with the approval of the Medical 
Monitor.
4.3.2.4
Schedule Modification
Patients in whom toxicities have not resolved (i.e., to Grade 1 or 80% of baseline) 
may have their study treatment delayed by up to 2 weeks.  If after the up to2-week 
delay, all study drugrelated toxicities have resolved sufficiently, the patient may receive 
the scheduled doses of rituximab.  In addition, a patient’s dosing may be changed to a 
28-day cycle if it is felt by the investigator and Medical Monitor that changing a patient’s 


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dosing regimen from 21-day to 28-day cycles would provide sufficient time for recovery 
from transient cytopenias without requiring repeated treatment delays.
Patients who do not fulfill the criteria for dosing after the additional 2 weeks have 
elapsed may be discontinued from study treatment and be followed for safety outcomes 
(see Section 4.5.1).  Exceptions on the basis of ongoing clinical benefit may be allowed 
following a careful assessment and discussion of risk versus benefit with the patient by 
the investigator and approval from the Medical Monitor.  In addition, delay of therapy 
because of toxicities not attributed to study drug may not require discontinuation and will 
be discussed with the Medical Monitor.
4.3.2.5
Infusion Reaction
Patients will be monitored during and after each rituximab infusion for 90 minutes after 
the first infusion and for 30 minutes after subsequent infusions in the absence of 
infusion-related adverse events.  Patients who experience infusion-related symptoms 
should be managed as directed in Table 1 (see Section 4.3.1.5).
In the event of a life-threatening IRR (which may include pulmonary or cardiac events) or 
IgE-mediated anaphylactic reaction to rituximab, rituximab should be discontinued and 
no additional rituximab should be administered.  Patients who experience these 
reactions should receive aggressive symptomatic treatment and should be discontinued 
from study treatment.
4.3.3
Obinutuzumab
4.3.3.1
Formulation
Obinutuzumab (GA101/Gazyva/Gazyvaro) is a clear, colorless to slightly brownish 
liquid, provided as a single 1000-mg dose liquid concentrate with a strength of 
25 mg/mL.  It is supplied in 50mL glass vials containing 40 mL of the 25 mg/mL liquid 
concentrate.  In addition to the antibody, the liquid also contains histidine/histidine-HCl, 
trehalose, poloxamer 188, and highly purified water (HPW).
4.3.3.2
Dosage, Administration, and Storage
Obinutuzumab will be administered by IV infusion as an absolute (flat) dose of 1000 mg 
in combination with DCDS4501A, as outlined in Section 3.1.3.  Obinutuzumab will be 
administered on Days 1, 8, and 15 of Cycle 1 and on Day 1 of Cycles 28 (see Table 2).  
No dose modifications of obinutuzumab are allowed.
All obinutuzumab infusions should be administered after premedication with oral 
acetaminophen and an antihistamine (see Section 4.4.1).  The prophylactic use of 
corticosteroids (e.g., 100 mg of IV prednisolone or equivalent) may also be considered 
for patients thought to be at high risk for IRRs, if deemed appropriate by the investigator,
and should be administered prior to the obinutuzumab infusion.  On Cycle 1 Day 1, it is 
recommended that oral prednisone, prednisolone, or methylprednisolone be given within 
12 hours as a premedication but at least 60 minutes prior to the obinutuzumab infusion.  


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Premedication with prednisone or prednisolone is mandatory in patients who had an IRR 
and should continue until IRRs no longer occur during antibody infusion.  For the 
management of IRRs and anaphylaxis, see Table 1 (Section 4.3.1.5).
If it is the strong preference of the investigator or of the site (e.g., for logistical reasons) 
or if the patient is at increased risk for an IRR (high tumor burden, high peripheral 
lymphocyte count), the administration of obinutuzumab infusion can be split over 2 days.
Table 2
Administration of First and Subsequent Infusions of 
Obinutuzumab
First Infusion (Cycle 1 Day 1)
Subsequent Infusions

Begin infusion at an initial rate of 50 mg/hr.

If no infusion-related or hypersensitivity 
reaction occurs, increase the infusion rate in 
50-mg/hour increments every 30 minutes to a 
maximum of 400 mg/hr.

If a reaction develops, stop or slow the 
infusion.  Administer medications and 
supportive care in accordance with 
institutional guidelines.  If reaction has 
resolved, resume the infusion at a 
50% reduction in rate (i.e., 50% of rate used 
at the time the reaction occurred).

If the patient experienced an infusion-related 
or hypersensitivity reaction during the prior 
infusion, use full premedication including 
100 mg prednisone/prednisolone (until no 
further IRR occurs), begin infusion at an 
initial rate of 50 mg/hr, and follow instructions 
for first infusion.

If the patient tolerated the prior infusion well 
(defined by absence of Grade 2 reactions 
during a final infusion rate of 100 mg/hr), 
begin infusion at a rate of 100 mg/hr.

If no reaction occurs, increase the infusion 
rate in 100-mg/hour increments every 
30 minutes, to a maximum of 400 mg/hr.

If a reaction develops, stop or slow the 
infusion.  Administer medications and 
supportive care in accordance with 
institutional guidelines.  If reaction has 
resolved, resume the infusion at a 
50% reduction in rate (i.e., 50% of rate used 
at the time the reaction occurred).
IRRinfusion-related reaction.
In all parts of the study, obinutuzumab must be administered in a clinical (inpatient or 
outpatient) setting.  Full emergency resuscitation facilities should be immediately 
available, and patients should be under the close supervision of the investigator at all 
times.  For the management of IRRs and anaphylaxis, see Table 1 (Section 4.3.1.5).
Obinutuzumab should be administered as a slow IV infusion through a dedicated line.  
IV infusion pumps should be used to control the infusion rate of obinutuzumab.  Do not 
administer as an IV push or bolus.  Administration sets with PVC, polyurethane (PUR), 
or PE as a product contact surface and IV bags with polyolefin (PO), polypropylene (PP), 
PVC, or PE as a product contact surface are compatible and can be used.  Do not use 
an additional in-line filter because of potential adsorption.


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The recommended storage conditions for obinutuzumab drug product are between 2°C 
and 8°C, protected from light.  For clinical formulation-specific and batch-specific 
instructions and information on in-use stability, see the packaging label.  
4.3.3.3
Dosage Modification
There will be no obinutuzumab dose modification in this study.  Patients at high risk for 
TLS complications (see Section 3.4.3.2) may, at the investigator’s discretion, receive 
obinutuzumab over 2 consecutive days (with DCDS4501A dose potentially delayed to 
Day 2 or Day 3).
Any NCI CTCAE (v4.0) toxicity Grade 3 in severity that is deemed related to 
obinutuzumab treatment will require interruption of study treatment (both DCDS4501A 
and obinutuzumab) until resolution to Grade 2 or 80% of baseline, whichever is lower.  
Resumption of obinutuzumab treatment may be considered in patients with resolution of 
toxicities to Grade 1 within 2 weeks at the discretion of the investigator, 
after consultation with the Medical Monitor.  Failure of such toxicities to resolve after 
2-week delay in study treatment will require permanent discontinuation of obinutuzumab.  
Continuation of study treatment following dose delays beyond 2 weeks will require 
consultation with and approval of the Medical Monitor based on an assessment of the 
benefit-risk analysis of continuing to delay study treatment.
If a patient develops unacceptable toxicity to obinutuzumab requiring its discontinuation, 
single-agent DCDS4501A will not be permitted.
4.3.3.4
Schedule Modification
Patients in whom toxicities have not resolved (i.e., to Grade 1 or 80% of baseline) 
may have their study treatment delayed by up to 2 weeks.  Dosing of both DCDS4501A 
and obinutuzumab should be held during this period.  If all study drugrelated toxicities 
have resolved to Grade1 or 80% of baseline, the patient may resume DCDS4501A 
and obinutuzumab dosing on the regular every21day schedule.  In addition, a 
patient’s dosing may be changed to a 28-day cycle if it is felt by the investigator and 
Medical Monitor that changing a patient’s dosing regimen from 21-day to 28-day cycles 
would provide sufficient time for recovery from transient cytopenias without requiring 
repeated treatment delays.
Patients who do not fulfill the criteria for dosing after the additional 2 weeks have 
elapsed may be discontinued from study treatment and be followed for safety outcomes 
(see Section 4.5.6).  Exceptions on the basis of ongoing clinical benefit may be allowed 
following a careful assessment and discussion of risk versus benefit with the patient by 
the investigator and approval from the Medical Monitor.  In addition, delay of therapy 
because of toxicities not attributed to study drug may not require discontinuation and will 
be discussed with the Medical Monitor.


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Specific guidelines around schedule modifications for thrombocytopenia and febrile 
neutropenia are detailed below in Section 4.3.3.5 and Section 4.3.3.6.
4.3.3.5
Thrombocytopenia
Thrombocytopenia is a known risk of obinutuzumab (see Section 3.4.5.4).  If the clinical 
condition of a patient requires the use of concomitant anticoagulants, the patient is at 
increased risk of bleeding when the platelet count is 20,000/L.  When possible, 
replace prior therapy with Vitamin K antagonists, such as warfarin, with low-molecular 
weight heparin (LMWH) or new oral anticoagulants (NOACs) before Cycle 1 Day 1.  
Clinical decision making may be adjusted depending on the patient-specific assessment 
of benefit and risk.
In the event of severe thrombocytopenia (platelet count 10,000/L) and/or symptomatic 
bleeding (irrespective of platelet count) in patients who are not receiving concomitant 
anticoagulants or platelet inhibitors:

Hold obinutuzumab until thrombocytopenia or symptomatic bleeding resolves.  If 
Cycle 1 Day 8 is delayed, then skip Day 8 and administer Day 15 as previously 
scheduled (if thrombocytopenia or symptomatic bleeding has resolved).  If Cycle 1 
Day 15 is delayed, then skip Day 15 dosing and administer Cycle 2 Day 1 of 
obinutuzumab and DCDS4501A as scheduled (if thrombocytopenia or symptomatic 
bleeding has resolved).
In the event of thrombocytopenia with platelet count 20,000/L and/or symptomatic 
bleeding (irrespective of platelet count) in patients who are receiving concomitant 
anticoagulants or platelet inhibitors:

Hold obinutuzumab until thrombocytopenia or symptomatic bleeding resolves. If 
Cycle 1 Day 8 is delayed, then skip Day 8 and administer Day 15 as previously 
scheduled (if thrombocytopenia or symptomatic bleeding has resolved).  If Cycle 1 
Day 15 is delayed, then skip Day 15 dosing and administer Cycle 2 Day 1 of 
obinutuzumab and DCDS4501A as scheduled (if thrombocytopenia or symptomatic 
bleeding has resolved).

For patients who are on LMWH or NOACs, when platelet count 20,000/L 
develops, reduce the dose of LMWH or NOACs used.

For patients who are on platelet inhibitors when thrombocytopenia with platelet 
count 20,000/L develops, consideration should be given to temporarily pausing
the use of platelet inhibitors.
4.3.3.6
Febrile Neutropenia  
In the event of febrile neutropenia or neutropenia with infection, hold obinutuzumab until 
febrile neutropenia or neutropenia with infection resolves.  

If Cycle 1 Day 8 is delayed long enough that the patient is approaching Day 15, then 
skip Day 8 and administer Day 15 as previously scheduled (if infection or fever has 
resolved)


 
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• 
If Cycle 1 Day 15 is delayed long enough that the patient approaching Cycle 2, then 
skip Day 15 dosing and administer Cycle 2 Day 1 of DCDS4501 as scheduled 
(if infection or fever has resolved) 
• 
Note:  Obinutuzumab Patients will receive DCDT2980S or DCDS4501A at 
1.8 mg/kg or 2.4 mg/kg by IV infusion on Day 1 or Day  should not be held for 
neutropenia without fever or infection 
 
4.3.4 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(pinatuzumab vedotin [DCDT2980S], polatuzumab vedotin [DCDS4501A], rituximab, and 
obinutuzumab) will be provided by the Sponsor where required by local health authority 
regulations.  The study site will acknowledge receipt of IMPs to confirm the shipment 
condition and content.  Any damaged shipments will be replaced.  
IMPs will be either disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. 
4.4 
CONCOMITANT AND EXCLUDED THERAPIES  
4.4.1 
Concomitant Therapy  
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, and nutritional supplements) used by a patient 
from 7 days prior to the screening evaluation to the end of study visits.  All concomitant 
medications should be reported to the investigator and recorded on the appropriate 
electronic Case Report Form (eCRF).  Patients who use oral contraceptives, 
hormone-replacement therapy, or other maintenance therapy should continue their use.  
Concomitant use of hematopoietic growth factors is allowed in accordance with 
instructions provided in the package inserts. 
Patients who experience infusion-related temperature elevations of > 38.5°C (> 101.3°F) 
or other minor infusion-related symptoms may be treated symptomatically with 
acetaminophen/paracetamol (≥ 500 mg) and/or H1 and H2 histamine-receptor 
antagonists (e.g., diphenhydramine, ranitidine).  Serious infusion-related events 
manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced 
oxygen saturation, or respiratory distress should be managed with additional supportive 
therapies (e.g., supplemental oxygen, β2-agonists, and/or corticosteroids) as clinically 
indicated according to standard clinical practice (see Table 1).   


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For patients enrolled in obinutuzumab-containing regimens, it is recommended that 
corticosteroids (e.g., 100 mg of IV prednisolone or equivalent) be given as premedication 
within 12 hours of, but at least 60 minutes prior to, the obinutuzumab infusion on Cycle 1 
Day 1.  After the first obinutuzumab infusion, additional glucocorticoids are allowed at 
the investigator’s discretion.  For patients who did not experience infusion-related 
symptoms with their previous infusion, premedication at subsequent infusions may be 
omitted at the investigator’s discretion.
Infusion reaction prophylaxis with medications (e.g., acetaminophen/paracetamol, 
antihistamines, and/or corticosteroids) may be instituted at any point in the study if it is 
determined to be in the best interest of the patient on the basis of the observation of 
IRRs in patients already enrolled in the study.  Patients with Grade 3 hypotension or 
fever must be premedicated prior to retreatment (see Section 4.3.1.5).  Patients with 
hypotension requiring vasopressor support or with Grade 3 wheezing, hypoxia, or 
generalized urticaria must be permanently discontinued from study treatment.
4.4.2
Excluded Therapy
Use of the following therapies is prohibited during the study:

Cytotoxic chemotherapy

Radiotherapy

Immunotherapy including immunosuppressive therapy

Radioimmunotherapy

Hormone therapy (other than contraceptives, hormone-replacement therapy, or 
megestrol acetate)

Biologic agents (other than hematopoietic growth factors, which are allowed 
if clinically indicated and used in accordance with instructions provided in the 
package inserts); guidelines for the use of G-CSF are detailed in Section 4.3.1.6
and Appendix F.

Any therapies intended for the treatment of lymphoma or leukemia, whether
approved by local regulatory authorities or investigational
Patients who require the use of any of these agents will be discontinued from all study 
treatment.  Patients who are discontinued from study treatment will be followed for safety 
outcomes for 30 days following the patient’s last dose of DCDT2980S or DCDS4501A or 
rituximab or obinutuzumab, whichever is later, or until the patient receives another 
anti-cancer therapy, whichever occurs first.


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4.5
STUDY ASSESSMENTS 
4.5.1
Definitions of Study Assessments
4.5.1.1
Medical History and Demographics
Medical history includes all clinically significant diseases, prior cancer history, prior 
cancer therapies and procedures, and all medications used by the patient within 7 days 
preceding the screening visit.
4.5.1.2
Vital Signs
Vital signs will include measurements of systolic and diastolic blood pressure while the 
patient is in a sitting or semi-supine position, pulse oximetry, pulse rate, and body 
temperature.  Every effort will be made to ensure that vital signs are obtained from 
patients in a consistent manner and position.  The timing of vital sign collection on the
days of study treatment administration is as follows:

For the administration of rituximab or obinutuzumab, vital signs should be assessed 
prior to the start of the infusion, every 15 (5) minutes during the first hour of the 
infusion, as clinically indicated during the remainder of the infusion, and following 
the completion of the infusion. 

For the administration of DCDT2980S or DCDS4501A, vital signs should be assessed 
prior to the start of the infusion, every 15 (5) minutes during the infusion, at the end 
of the infusion, and every 30 (10) minutes for 90 minutes post-infusion following 
dosing at Cycle 1 and 30 (10) minutes following dosing in subsequent cycles. 
Additional monitoring of vital signs should be performed if clinically indicated.
4.5.1.3
Physical Examination
A complete physical examination should include the evaluation of the head, eyes, ears,
nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory,
gastrointestinal, and neurological systems.  
Targeted physical examinations should be limited to systems of clinical relevance 
(i.e., cardiovascular, respiratory, and any system that might be associated with tumor 
assessment, such as lymph nodes, liver, and spleen) and those systems associated with 
symptoms.
Changes from baseline should be recorded at each subsequent physical examination.  
New or worsened abnormalities should be recorded as adverse events if appropriate.
Resolution or any change in grade of peripheral neuropathy AEs and SAEs (with dates) 
should be documented on the Adverse Event eCRF and in the patient’s medical record 
to facilitate source data verification (SDV).  This also applies to AEs for which study drug 
was discontinued or for patients in the follow-up phase after last dose of study treatment 
with either ongoing AEs or new onset of an AE.  For the AEs referring to the follow-up 
phase newly initiated, relevant treatments need to be documented with treatment dates. 


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4.5.1.4
Laboratory Assessments
On days of study drug administration, pre-infusion laboratory samples should be drawn 
within 4 hours prior to the start of infusion, unless otherwise specified.  Local laboratory 
assessments may be obtained up to 72 hours prior to the start of study treatment 
administration (see below and Section 4.5.3).  Instruction manuals and supply kits will be 
provided for all central laboratory assessments.
Central Laboratory Assessments
Samples for flow cytometry, PK, bone marrow, and anti-DCDT2980S, anti-DCDS4501A,
or anti-obinutuzumab antibody assessments will be sent to one or several laboratories or 
to Genentech for analyses (see Section 3.6).  The following assessments will be 
conducted:

Leukocyte immunophenotyping/flow cytometry (fluorescence-activated cell sorting 
[FACS] lymphocyte subsets)
Whole-blood samples will be collected to analyze B-cell subsets (CD19+), T-cell 
counts (CD3+, CD4+, CD8+), and NK cell counts (CD16+, CD56+), by flow 
cytometry.

ATA assays
ATAs to DCDT2980S, DCDS4501A, or obinutuzumab will be determined using 
validated ELISAs (see Section 4.9). 

PK and PD assays (see Section 4.5.1.6)

A plasma sample and blood samples will be collected from patients for exploratory 
research as indicated in Section 4.5.1.9. 

For patients who sign the optional consent, a blood sample will be collected prior to 
the first dose of study treatment for exploratory research.

Tumor tissue sample (archival or fresh) will be collected from patients for central 
pathologic review as described in Section 4.1.1 and Section 4.5.1.9.
Local Laboratory Assessments
Samples for hematology, serum chemistry, liver function, and pregnancy will be 
analyzed at the study site’s local laboratory.  Local laboratory assessments may be 
obtained up to 72 hours prior to start of study treatment administration on Day 1 of the 
treatment cycle.  

Hematology:  includes complete blood count (hemoglobin, hematocrit, red blood cell 
count, white blood cell count, platelet count, absolute neutrophil count, and percent 
or absolute differential counts [e.g., segmented neutrophils, bands, lymphocytes, 
eosinophils, monocytes, basophils, and other cells)

Coagulation:  aPTT, PT, and INR

Quantitative immunoglobulins (IgA, IgG, and IgM)


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
Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen (BUN or local equivalent), creatinine, calcium, magnesium, phosphorus, 
total and direct bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, 
LDH, and uric acid, amylase, and lipase

Serum -glutamyl transpeptidase (GGT) levels will be required at screening only

Hemoglobin A1c

Viral serology and detection (screening assessment only and if clinically indicated)
Hepatitis B (HBsAg and HBcAb; also HBV DNA by PCR if the patient is HBcAb 
positive)
HCV antibody

Pregnancy test
For women of childbearing potential (see Section 4.1.2), a serum pregnancy test 
must be performed within 14 days prior to Cycle 1 Day 1.  
Urine pregnancy tests will be performed during the study treatment period.  If any 
urine test result is positive, patient dosing will be postponed until the result is 
confirmed by a serum pregnancy test.  Any patient with a positive serum test will 
not be allowed to receive any study treatment.
4.5.1.5
Electrocardiogram Assessments
Twelve-lead digital ECG measurements will be obtained in triplicate, with immediately 
consecutive ECGs obtained until three evaluable ECGs are recorded, at the following 
timepoints:

Screening

3060 minutes before the start of DCDT2980S or DCDS4501A infusion in Cycle 1

3060 minutes after the completion of DCDT2980S or DCDS4501A infusion in 
Cycle 1

3060 minutes after the completion of DCDT2980S or DCDS4501A infusion in 
Cycle 3

Day 8 (1 day) of Cycle 3 time matched (i.e., obtained at the same time of day) with 
post-DCDT2980s/DCDS4501A infusion ECGs for Cycle 3

Treatment completion/early termination visit
Non-triplicate ECGs should also be performed when clinically indicated in any patient 
with evidence of or suspicion for clinically significant signs or symptoms of cardiac 
dysfunction. 
All ECGs as described above will be submitted to a Sponsor-designated ECG central 
laboratory for storage and potential analysis.  Detailed instructions on ECG acquisitions 
and transmissions to the ECG central laboratory will be provided in the ECG manual 
provided for this study.


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Representative ECGs at each timepoint should be reviewed by the investigator or a 
qualified designee.  Post-screening ECG measurements should be obtained as close as 
possible to scheduled serum and plasma PK samples (see Appendices B-1 and B-2) 
and should be no more than 30 minutes apart.  If QTc prolongation (500 ms and 
60 ms longer than the pre-dose baseline value) is noted, ECGs should be repeated 
until the prolongation is reversed or stabilized.  If a PK sample is not scheduled at the 
timepoint where QTc prolongation is first observed, then an unscheduled sample should 
be obtained.  An evaluation for potential causes of QT prolongationfor 
example, electrolyte imbalances or concomitant medicationsshould be performed, 
study treatment dosing held, and the Medical Monitor notified.  Management of QT/QTc 
prolongation should be performed in accordance with institutional standard of care at the 
discretion of the treating physician.
4.5.1.6
Pharmacokinetic and Pharmacodynamic Assessments
Pharmacokinetics of DCDT2980S and DCDS4501A will be characterized by measuring 
total antibody (conjugated and unconjugated antibody), acMMAE, and free MMAE 
concentrations using validated methods (see Section 4.9).  Plasma samples may also be 
analyzed for other potential MMAE-containing catabolites, per sponsor’s discretion.  
Pharmacokinetics of rituximab will be characterized by measuring rituximab 
concentrations using a validated method (see Section 4.9).  Pharmacokinetics of 
obinutuzumab will be characterized by measuring obinutuzumab concentrations with use 
of a validated method (see Section 4.9). These assessments will allow for further 
characterization of pharmacokinetics of DCDT2980S and DCDS4501A, the assessment 
of the drug interaction potential when they are given in combination with rituximab or 
obinutuzumab, and the investigation of potential correlations between PK parameters 
and safety and/or activity if data allow and at the sponsor’s discretion.  
Pharmacodynamics of obinutuzumab and DCS4501A may be assessed by monitoring 
the release of tumor associated DNA following treatment.
4.5.1.7
Immunogenicity Assessments
The immunogenicity evaluation will utilize a risk-based strategy and tiered approach 
(Rosenberg and Worobec 2004a, 2004b, 2005; Koren et al. 2008) designed to detect 
and characterize all ATA responses to DCDT2980S and DCDS4501A.  Patient samples 
will first be screened to detect all antibody responses toward DCDT2980S or 
DCDS4501A.  Samples that screen positive will be analyzed in a confirmatory assay 
(competitive binding with DCDT2980S or DCDS4501A) to assess the specificity of the 
positive response.  Titers will be determined for confirmed positive samples. Further 
characterization will be assessed by competitive binding with the MAb component of 
DCDT2980S or DCDS4501A to characterize whether the ATA responses are primarily to 
the mAb or the linker-drug regions of the ADC.  Positive ATA samples will be stored for 
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The schedule of sample collection for ATA assessment is outlined in Appendices B-1,
B-2, or B-3, depending on the schedule of study treatment administration.  Samples for 
ATA will not be collected during the crossover treatment period.
ATA responses to obinutuzumab will be detected and confirmed using a similar tiered 
approach.  Patient samples will first be screened to detect all antibody responses to 
obinutuzumab.  Samples that screen positive will be analyzed in a confirmatory assay 
(competitive binding with obinutuzumab) to assess the specificity of the positive 
response.  The relative levels of ATA in confirmed positive samples will be determined in 
a titering assay.  Positive ATA samples will be stored for further characterization of ATA 
responses, if necessary.
4.5.1.8
Tumor Response Assessments
All measurable disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Response assessments will be assessed by the 
investigator, on the basis of physical examinations, CT scans, PET/CT scans, and/or 
MRI scans, and bone marrow examinations, using standard response criteria for NHL 
(Cheson et al. 2007; Cheson et al. 2014) (see Appendix C-1 and C-2).  Specific response 
assessment criteria differ between the rituximab-containing arms/cohorts and the 
obinutuzumab-containing cohorts (see Section 4.5.1.8a. and 4.5.1.8b).
a.
Radiographic Assessments for Patients on Rituximab-Containing 
Arms/Cohorts
CT scans with contrast should include chest, abdomen, and pelvis scans; CT scans of 
the neck should be performed at screening and followed only if disease is present at 
screening.  Post-screening radiographic assessments may be limited to areas of prior 
involvement only if required by local health authorities.
MRI scans may be used instead of CT scans in patients for whom CT scans with IV 
contrast are contraindicated.  Details regarding imaging procedures in these cases will be 
provided in the Imaging Manual.
A PET/CT scan is required during screening for all patients with DLBCL.  An additional 
PET/CT scan in patients with DLBCL should be obtained at the 6-month tumor 
assessment to ensure consistency of response assessment methodology at this 
timepoint for all patients.  PET/CT scans should additionally be obtained to confirm 
disappearance of metabolically active disease during study treatment and to confirm a 
CR upon discontinuation of study treatment.  
For patients with FL, PET/CT scans are not required but may be obtained on the basis 
of physician preference and if permitted by local health authorities.  Similarly, for patients 
with DLBCL, PET/CT scans on patients with FL should be obtained during screening; 
for patients whose tumors are PET positive during screening, an additional PET/CT
scan should be obtained at the 6-month tumor assessment.  PET/CT scans should 


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additionally be obtained to confirm disappearance of metabolically active disease during 
study treatment and to confirm a CR upon discontinuation of study treatment. 
For all patients regardless of disease subtype, combined PET/CT scans may be used 
instead of CT alone if performed with contrast and if collected with resolution sufficient to 
allow accurate and consistent comparison of target lesion measurements with 
subsequent PET/CT scans.  If a PET/CT scan is to be used during screening, then 
PET/CT scans should be performed for all subsequent tumor assessments in order to 
ensure their consistency across different timepoints.
All tumor assessments will be submitted to an IRF for storage and possible independent 
centralized review.  Details related to submission of data to the IRF will be defined in a 
separate Imaging Manual.
b.
Radiographic Assessments for Patients on Obinutuzumab-Containing 
Cohorts
PET/CT scans should minimally extend from skull-base to mid-thigh.  Full-body PET 
scan should be performed when clinically appropriate.
CT scans with oral and IV contrast should include chest, abdomen, and pelvic scans; CT 
scans of the neck should be included if clinically indicated.  CT scans for response 
assessment may be limited to areas of prior involvement only if required by local health
authorities.  At the investigator’s discretion, CT scans may be repeated at any time if 
progressive disease is suspected.
In patients for whom contrast is contraindicatedfor example, patients with contrast 
allergy or impaired renal CLCT or combined PET/CT scans without contrast are 
permitted so long as they permit consistent and precise measurement of target lesions 
during the study treatment period.  
PET/CT scans are required for patients with follicular NHL and DLBCL at screening, 
after Cycle 4 of study treatment (i.e., between Cycle 4 Day 15 and Cycle 5 Day 1), and
at EOT.  The EOT response assessment should be performed 68 weeks after Cycle 8 
Day 1 or last study treatment. CT scans without PET scans will be obtained every 
6 months for 2 years, with use of Lugano 2014 Response Criteria for NHL
(see Appendix C-2).  
c.
Bone Marrow Assessments
A bone marrow biopsy for morphology is required at screening and should reflect 
disease status in the bone marrow following documented relapse on the last prior 
therapy or within 3 months of Day 1, whichever occurs later. For 
obinutuzumab-containing cohorts, only follicular NHL patients are required to undergo a 
bone marrow biopsy at screening. If the bone marrow biopsy at screening demonstrates 
presence of tumor cells, a subsequent bone marrow examination is required only to 


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confirm a CR or if clinically indicated.  If the bone marrow biopsy at screening does not 
demonstrate presence of tumor cells, then subsequent bone marrow examination is 
required only if clinically indicated.
d.
Schedule of Tumor Response Assessments for Rituximab-Containing 
Arms/Cohorts
Tumor response assessments will be performed every 3 months (1 week) from the 
initiation of study treatment until study treatment completion or early termination
(e.g., between Days 14 and 21 of Cycles 4 and 8 for those patients receiving at least 
eight 21-day cycles of treatment).  The schedule of tumor assessments is independent 
of the study treatment dose schedule.  For patients enrolled in rituximab-containing 
arms/cohorts, the schedule of tumor response assessments is detailed in Appendix A-1.  
As stated above, for all patients with DLBCL enrolled in a rituximab-containing 
arm/cohort, PET/CT scans are required during the screening period and at the 6-month 
tumor assessment timepoint.
The schedule for tumor response assessments for patients who proceed to crossover 
treatment is detailed in Appendix A-2.  
Additional response assessments, after the final dose of study treatment, for patients 
who discontinue from study treatment (either initial or crossover treatment) for reasons 
other than progressive disease, will be performed as described in Appendix A-4. 
Tumor assessments should also be performed within 30 days after the last study drug 
infusion (both initial and crossover treatment) at the treatment completion/early 
termination visit.  Imaging scans are not required at the treatment completion/early 
termination visit if scans have been performed within the previous 8 weeks or if disease 
progression while receiving study treatment is documented.
If, at any time during the study, disease progression is suspected, a tumor assessment 
must be performed.  
e.
Schedule of Tumor Response Assessments for 
Obinutuzumab-Containing Cohorts
All patients with follicular NHL and DLBCL enrolled in obinutuzumab-containing cohorts 
are required to have a combined PET/CT scan at screening, after Cycle 4 of treatment, 
and at EOT.  The schedule for tumor response assessments for patients enrolled in 
obinutuzumab-containing cohorts is detailed in Appendix A-3.


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4.5.1.9
Exploratory Research
a.
Tumor Tissue Samples
Required Tumor Tissue Samples
Tumor tissue samples will be used for central pathologic laboratory review of CD20, 
CD22, and CD79b expression.  Additional studies to fulfill the exploratory objectives in 
Section 3.3.4 will be performed, including, but not limited, to the following:

Messenger RNA (mRNA) expression profiling for signatures of NHL biology, 
including prognostic subpopulations (Alizadeh et al. 2000; Wright et al. 2003), target 
expression (CD20, CD22 and CD79b), and apoptotic response 

Tissue microarrays (TMAs) from cores taken from provided blocks for 
immunohistochemistry (IHC) and in situ hybridization (ISH) assessments
for biomarker endpoints involved in response to chemotherapy including quantitation 
of Bcl-2 protein and genetic alterations of bcl-2 including gene rearrangements, 
amplifications, and t(14;18) translocations. Additional IHC markers may include 
those related to the tumor microenvironment.

Tumor DNA to assess mutations that have been shown to be associated with NHL 
biology and activation of the B-cell receptor, including mutations in CD79b 
(Pasqualucci et al. 2011)
For patients who develop progressive disease and are eligible to receive crossover 
treatment (see Section 3.1.8), a biopsy of a safely accessible site of disease will be 
performed.  Tumor tissue samples obtained at this timepoint will be used to assess 
changes in biology, target expression, and regulators of apoptosis as described above, 
which have occurred and may be linked to progression on initial study treatment.
Optional Tumor Tissue Samples (Requires Optional Research Informed 
Consent
For patients who provide informed consent, an optional tumor biopsy will be collected at 
time of progression from the following patients:

Patients who develop disease progression following initial study treatment and do 
not proceed to receive crossover treatment

Patients who develop disease progression on crossover treatment
Tumor tissue samples obtained at these timepoints will be used to assess changes in 
biology, target expression, and regulators of apoptosis, as described above, that have 
occurred and may be linked to progression on treatment.
b.
Blood and Plasma Samples
A plasma sample will be collected prior to treatment.
Blood samples will be taken aligned with PK sampling to assess the pharmacodynamics 
response by monitoring circulating tumor DNA.


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For patients who sign the Optional Research Informed Consent, an additional blood 
sample will also be taken prior to treatment.
The plasma and blood samples may be used for the assessment of specific tumor 
biologic markers, including proteins, circulating DNA, and microRNAs.  The information 
obtained from these samples will enable a better understanding of the biology of NHL 
and disease prognosis, identify potential predictors of response to treatment with 
DCDT2980S, DCDS4501A, rituximab, and/or obinutuzumab, improve diagnostic 
assessments, and identify and characterize mechanisms of resistance to DCDT2980S or 
DCDS4501A and rituximab or obinutuzumab activity.  
Because tumorigenesis is a multiple-step process linked to somatic events, any DNA 
analysis will focus on sporadic mutations specifically found in tumor tissue and not on 
inherited changes found in the whole body.  For this purpose, some tumor-containing 
sections may be taken from the tissue block and used for the DNA extraction process.  
Assays on stored tissue samples may be performed at Genentech or at a central 
specialty laboratory.
4.5.1.10
Patient-Reported Outcomes
The MDASI (Cleeland et al., 2000; Appendix E) is a multi-symptom self-report measure 
for clinical and research use. The MDASI’s 13 core-symptom items, plus an additional 
4 items, for a total of 17 symptom items, include those found to have the highest 
frequency and/or severity in patients with various cancers and treatment types.  These 
include pain, fatigue, nausea, disturbed sleep, emotional distress, shortness of breath, 
lack of appetite, drowsiness, dry mouth, sadness, vomiting, difficulty remembering, and 
numbness or tingling.  Six additional items focus on the degree of interference of the 
aforementioned symptoms for a total of 23 items in the questionnaire.
PRO data will be elicited from all patients in this study (with the exception of Cohorts E, 
G, and H) to more fully characterize the clinical profile of study treatment.  The MDASI 
PRO instrument will be supplied in the local language of each participating country.  
Electronic (handheld computers) will be used for the daily collection of symptoms 
derived from the MDASI.  
4.5.2
Screening and Pretreatment Assessments
All screening evaluations must be completed and reviewed by the Genentech Medical 
Monitor or designated CRO Medical Monitor to confirm that patients meet all eligibility 
criteria and are approved for enrollment before the first infusion of study treatment.  
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for patients who are not subsequently enrolled will be maintained at the study site.
Screening and pretreatment tests and evaluations will be performed within 28 days 
preceding the day of the first dose of study treatment on Cycle 1 Day 1.  Results of 


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standard-of-care tests or examinations performed prior to obtaining informed consent 
and within 28 days prior to Cycle 1 Day 1 may be used; such tests do not need to be 
repeated for screening.
The availability of a patient’s tumor tissue sample for studies (see Section 4.1.1 and 
Section 4.5.1.9) should be confirmed prior to Cycle 1 Day 1.  Such specimens should 
consist of representative core biopsy in a paraffin block, which is the preferred method, 
or at least 15 unstained slides.  Tumor specimens should be submitted with an 
accompanying pathology report and may be obtained at any time prior to entry to study.  
Bone marrow biopsy and aspirate specimens are required at screening (see 
Section 4.5.1.8).  For obinutuzumab-containing cohorts, bone marrow biopsy and 
aspirate are only required for follicular NHL patients.  Unsuccessful attempts at obtaining 
marrow aspirates will not be considered a protocol deviation or violation.
Refer to the Study Flowchart provided in Appendix A-1 and A-3 for the schedule of 
screening and pretreatment assessments.
4.5.3
Assessments During Treatment
Study drug infusions (rituximab, obinutuzumab, DCDT2980S, or DCDS4501A) should 
occur on the scheduled 21-day (or 28-day) cycle but may be given up to 2 days from 
the date scheduled (i.e., with a minimum of 19 days between doses) if required for 
logistical/scheduling reasons.  All other study visits during Cycles 1 and 2 must occur 
within 1 day from the scheduled date, unless otherwise noted.  Study visits starting in 
Cycle 3 should occur within 2 days from the scheduled date, unless otherwise noted.  
All assessments will be performed on the day of the specified visit unless a time window 
is specified.  Assessments scheduled on the day of study drug administration (Day 1) of 
each cycle should be performed prior to study drug infusion unless otherwise noted.  
Local laboratory assessments may be performed within 72 hours preceding study drug 
administration on Day 1 of each cycle.  Otherwise, laboratory samples should be drawn 
04 hours before infusion.  Results must be reviewed and the review documented prior 
to study drug administration.
Refer to the Study Flowchart provided in Appendix A-1 for the schedule of treatment 
period assessments.  For patients enrolled in the obinutuzumab-containing cohorts, refer 
to the Study Flowchart provided in Appendix A-3.
4.5.4
Study Treatment Completion Visit
Patients who complete study treatment or discontinue from study treatment early will be 
asked to return to the clinic within 30 days after the last DCDT2980S, DCDS4501A,
rituximab, or obinutuzumab infusion (whichever is later) for a study treatment completion 
visit.  The visit at which response assessment shows progressive disease may be used 
as the early termination visit.


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Refer to the Study Flowchart provided in Appendix A-1 for assessments to be performed 
at the treatment completion/early termination visit.  For patients enrolled in the 
obinutuzumab-containing cohorts, refer to the Study Flowchart provided in 
Appendix A-3.
Assessments conducted at the treatment completion/early termination visit may be used 
for the purposes of re-screening to determine eligibility to receive crossover treatment 
(see Section 3.1.3 and Section 4.5.5).
4.5.5
Crossover Treatment Completion Visit
Patients who fulfill the criteria to receive crossover treatment (see Section 3.1.6) will 
have assessments during the crossover treatment period as described in Appendix A-2.  
The same guidelines regarding scheduling of assessments for treatment with initial study 
treatment as detailed in Section 4.5.3 will apply to crossover treatment.  
Patients who proceed to receive crossover treatment will have on-treatment 
assessments as described in Appendix A-2.
Patients who complete the crossover treatment (approximately 1 year/17 cycles) or 
discontinue from crossover treatment early will be asked to return to the clinic within 
30 days after the last DCDT2980S, DCDS4501A, or rituximab infusion (whichever is 
later) for a crossover treatment completion/early termination visit.  The visit at which 
response assessment shows disease progression on crossover treatment may be used 
as the early termination visit.
Refer to Appendix A-2 for assessments to be performed at the treatment 
completion/early termination visit.
4.5.6
Follow-Up Assessments
Ongoing adverse events thought to be related to DCDT2980S, DCS4501A, rituximab, or 
obinutuzumab will be followed until the event has resolved to baseline (pre-treatment) 
grade, the event is assessed by the investigator as stable, new anti-tumor treatment is 
initiated, the patient is lost to follow-up, the patient withdraws consent, or when it has 
been determined that the study treatment or participation is not the cause of the adverse 
event.
Patients will be followed after the last dose of study treatment (either initial study 
treatment or crossover treatment) for safety outcomes.  Such follow-up will require an 
assessment (per verbal report, at minimum) of any adverse events and serious adverse 
events for 30 days after the last dose of study drug or until the patient receives another 
anti-cancer therapy, whichever occurs first.


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4.5.6.1
Follow-Up Assessments for Rituximab-Containing Regimens
Patients who discontinue from study treatment (either initial study treatment or crossover 
treatment) for reasons other than progressive disease will be followed for response for 
up to 1 year after the last infusion of study treatment or until disease progression or 
initiation of another anti-lymphoma/leukemia therapy, whichever occurs first.  Response
assessments should occur approximately every 23 months following the last infusions 
of DCDT2980S, DCDS4501A, or rituximab.  Post-treatment assessments are described 
in Appendix A-4.
Following discontinuation of study treatment, patients will be followed for survival 
approximately every 3 months until death, loss to follow-up, withdrawal of consent, or 
study termination.
4.5.6.2
Follow-Up Assessments for Obinutuzumab-Containing 
Regimens
Patients who discontinue from study treatment for reasons other than progressive 
disease will be followed for response for up to 2 years after the last infusion of study 
treatment or until disease progression or initiation of another anti-lymphoma/leukemia 
therapy, whichever occurs first.  Response assessments should occur approximately 
every 23 months following the last infusions of DCDS4501A or obinutuzumab for the 
first year after completion of treatment, then every 6 months for the second year after 
completion of treatment.  Post-treatment assessments are described in Appendix A-5. 
Following discontinuation of study treatment, patients will be followed for survival 
approximately every 6 months until death, loss to follow-up, withdrawal of consent, or 
study termination.
4.6
PATIENT DISCONTINUATION
4.6.1
Discontinuation from Treatment
Patients may discontinue study treatment early for reasons other than disease 
progression, such as patient/investigator choice or unacceptable toxicity.  The reasons 
for early discontinuation of treatment must be documented on the appropriate eCRF.  
Patients may continue treatment with either DCDT2980S/DCDS4501A or rituximab 
alone following a careful assessment and discussion of risk versus benefit with the 
patient by the investigator and approval from the Medical Monitor.
Patients who discontinue study treatment early due to toxicity should continue to be 
followed until resolution of toxicity as scheduled.
Refer to Section 4.5.4 and Section 4.5.5 for assessments that are to be performed for 
patients who discontinue from the study during the study treatment period.


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4.6.2
Discontinuation from Study
Patients must be discontinued from the study if they experience disease progression as 
defined using response and progression criteria in Appendix C.  Patients can continue 
crossover treatment following documentation of the first progressive disease event but 
must be discontinued from the study if they experience a second progressive disease 
event on the crossover treatment.
The investigator has the right to discontinue a patient from the study for any medical 
condition that the investigator determines may jeopardize the patient’s safety if he or she 
continues in the study, for reasons of noncompliance (e.g., missed doses or missed
visits) or pregnancy or if the investigator determines it is in the best interest of the 
patient.
Refer to Section 4.5.4 and Section 4.5.5 for assessments that are to be performed for 
patients who prematurely discontinue from the study during the treatment period.
4.7
STUDY DISCONTINUATION
Genentech has the right to terminate this study at any time.  Reasons for terminating the 
study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.

Data recording is inaccurate or incomplete.
4.8
POST-TRIAL ACCESS
Genentech does not have any plans to provide DCDT2980S, DCDS4501A, rituximab, 
obinutuzumab, or other study interventions to patients after the conclusion of the study 
or if the study is terminated or for patients who withdraw early from the study or 
complete their study treatment.  Genentech will evaluate the appropriateness of 
continuing to provide DCDT2980S, DCDS4501A, rituximab, or obinutuzumab to study 
patients after evaluating the safety and activity data from the study.  
4.9
ASSAY METHODS 
4.9.1
Total DCDT2980S/DCDS4501A Antibody ELISA
Total DCDT2980S or DCDS4501A antibody (conjugated and unconjugated antibody) will 
be measured in serum samples using validated ELISAs.
4.9.2
Antibody-Conjugated MMAE (MMAE Affinity Capture 
Enzyme-Release LC/MS-MS)
acMMAE (a measure of MMAE conjugated to DCDT2980S/DCDS4501A) will be 
measured in plasma samples using validated affinity capture enzyme-release liquid 
chromatographytandem mass spectrometry (LC-MS/MS) assays.


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4.9.3
Free MMAE LC-MS/MS
Free MMAE will be measured in plasma samples using a validated electrospray 
LC-MS/MS method.
4.9.4
Rituximab ELISA
Rituximab will be measured in serum samples using a validated ELISA.
4.9.5
Obinutuzumab ELISA
Obinutuzumab will be measured in serum samples using a validated ELISA.  
4.9.6
Anti-Therapeutic Antibody
ATAs against DCDT2980S and DCDS4501A in serum samples will be measured using 
validated bridging antibody ELISAs and characterized by competitive binding assays.
ATAs against obinutuzumab in serum samples will be measured using a validated 
bridging antibody ELISA and characterized by a competitive binding assay.
4.9.7
Biomarker Assays
Tumor tissue assessment of biomarkers will be assayed using IHC, ISH, qPCR gene 
expression profiling using microarray and mutation detection assays.  Circulating Tumor 
DNA (ctDNA) in plasma samples may be assessed using a next generation sequencing 
approach (CAPP-Seq) to detect and quantitate lymphoma specific markers.
4.10
STATISTICAL METHODS
The final analysis will be based on patient data collected until all patients discontinue
from the study or the study is terminated by the Sponsor, whichever occurs first.  The 
analyses will be based on the safety evaluable population, defined as patients who 
received at least one dose of study treatment.  All summaries will be presented 
according to the disease-specific cohort, treatment group, and assigned dose level.
4.10.1
Analysis of the Conduct of the Study
Enrollment, major protocol violations, and reasons for discontinuations from the study 
will be summarized.
Demographic and baseline characteristics, such as age, sex, race/ethnicity, weight, 
duration of malignancy, and baseline ECOG Performance Status, will be summarized 
using means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables.  All summaries will be presented overall and by 
treatment group, assigned dose level, and disease-specific cohort.
Study drug administration data will be listed by the disease-specific cohorts described in 
Section 3.1.1 and Section 3.1.2.  Any dose modifications will be flagged.  Means and 
standard deviations will be used to summarize the total doses of DCDT2980S, 


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DCDS4501A, rituximab, and obinutuzumab received.  All summaries will be presented 
by treatment group, assigned dose level, and disease-specific cohort.
4.10.2
Safety Analysis
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in physical findings on physical examinations, and changes in vital 
signs.  All patients who receive any amount of DCDT2980S, DCDS4501A, rituximab, or 
obinutuzumab will be included in the safety analysis and will be assigned to the 
treatment group on the basis of the study treatment received.  Patients who have dose 
level changes from the initial assigned dose level will be summarized by the initial 
assigned dose level of DCDT2980S or DCDS4501A.
All adverse event data will be listed by study site, patient number, treatment group, 
disease-specific cohort, and cycle.  All adverse events occurring on or after treatment on 
Day 1 of Cycle 1 will be summarized by mapped terms, appropriate thesaurus levels, 
and NCI CTCAE v4.0 toxicity grade.  In addition, all serious adverse events, including 
deaths will be listed separately and summarized.  
Selected laboratory data will be listed, with values outside of normal ranges identified.  
The incidence of antibodies to DCDT2980S and DCDS4501A will be summarized.
4.10.3
Pharmacokinetic and Pharmacodynamic Analyses
Individual and mean serum concentrations of total DCDT2980S or DCDS4501A antibody 
(conjugated and unconjugated antibody) and rituximab or obinutuzumab and plasma 
concentrations of acMMAE and free MMAE versus time data will be tabulated and 
plotted by NHL disease subtype (relapsed or refractory follicular NHL or DLBCL).  The 
pharmacokinetics of the above analytes will be summarized by estimating the 
appropriate PK parameters (e.g., AUC, Cmax, CL, Vss, and t1/2).  Estimates for these 
parameters will be tabulated and summarized (mean, standard deviation, and range).  
Non-compartmental, compartmental, and/or population methods will be used, as data 
allow. 
Exposure-response (safety and efficacy) analysis may be conducted with use of PK data 
and available drug effect (e.g., imaging, measures of tumor burden) and toxicity 
(e.g., clinical pathology) data, at the sponsor’s discretion.
In addition, population PK methods may be employed to manage sparse data and to 
investigate the effects of certain covariates on the pharmacokinetics of DCDT2980S and 
DCDS4501A, as data allow, and at the sponsor’s discretion.


 
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4.10.4 
Activity Analyses 
Best overall response, duration of response, and PFS will be listed for all patients. 
ORR from the initial study treatment will be calculated on the basis of data from patients 
who received study treatment.  Objective response is defined as CR or PR as 
determined by the investigator, on the basis of physical examinations, radiographic 
scans, and bone marrow examinations, using modified response criteria for NHL 
(Cheson et al. 2007; see Appendix C) and confirmed by repeat assessments ≥ 4 weeks 
after initial documentation.  Any patient with insufficient data to determine response will 
be classified as a non-responder. 
For patients in the rituximab-containing arms/cohorts with DLBCL, primary assessment 
of tumor response will be based on diagnostic imaging scansfor example, CT and/or 
MRI scans and PET/CT scans.  For patients with FL enrolled in the rituximab-containing 
arms/cohorts, primary assessment of response will be based on CT scans only; the 
assessment of response in patients with FL based on PET/CT scans will be performed 
for exploratory purposes only. 
For patients in the obinutuzumab-containing cohorts, primary response assessment for 
patients with DLBCL or FL will be based on PET/CT scans using the updated 2014 
Lugano Response Criteria as determined by an IRC.  Patients in Cohorts E, G, and H 
will be evaluated with a PET/CT scan at screening, between Cycle 4 Day 15 and 
Cycle 5 Day 1, and at EOT (6−8 weeks after completing treatment).  The efficacy 
analysis for these cohorts will, therefore, be different from the analysis for Arms A−B and 
Cohorts C−D (Cheson, et al 2014) (see Appendix C-2).  Subsequent imaging can be CT 
only.  Responses to study treatment will also be based on investigator assessments. 
Among patients with an objective response, duration of response will be defined as the 
time from the initial documentation of a CR or PR to the time of disease progression or 
death.  If a patient does not experience death or disease progression before the end of 
the study, duration of response will be censored at the day of the last tumor assessment. 
For the randomized portion of the study (Arms A and B), PFS is defined as the time from 
the date of randomization to the date of disease progression or death from any cause, 
whichever occurs first.  If a patient has not experienced progressive disease or death, 
PFS will be censored at the date of the last tumor assessment.  Patients with no 
post-baseline tumor assessment will be censored on the date of randomization.  For the 
non-randomized portion of the study (Cohorts C through H), PFS is defined as the time 
from the date of study enrollment to the date of disease progression or death from any 
cause, whichever occurs first. 


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For the randomized portion of the study (Arms A and B), OS is defined as the time from 
the date of randomization to the date of death from any cause.  For the non-randomized 
portion of the study (Cohorts C through H), OS is defined as the time from the date of 
study enrollment to date of death from any cause.
4.10.5
Exploratory Analyses 
Assay results of possible predictive markers will be listed by treatment group and 
response status.
Frequencies and percentages of missing data for the PRO endpoints will be reported.  
Dropouts (defined as patients withdrawing from treatment for reasons other than 
documented disease progression or death) will be summarized
Summary statistics of the MDASI items, scales, and their changes from baseline will be 
calculated at each assessment timepoint.  The mean, standard error, and median of the 
absolute scores and the mean changes from baseline (and 95% CI) within and between 
study arms will be reported for the MDASI scales and single items, as well as the weekly 
averages of the worst symptom rating.  For change scores in the MDASI from baseline, 
patients without baseline scores will not be included in the analyses.  Line charts 
depicting the means and mean changes of subscales over time will be also provided.  
Repeated measures mixed-effects models will explore MDASI subscale scores with a 
baseline score and appropriate covariates added, as appropriate.
4.10.6
Handling of Missing Data
For the endpoint of objective response, patients without a post-baseline tumor 
assessment will be considered non-responders in the all-treated population analysis. 
For duration of response and PFS, data from patients who are lost to follow-up will be 
included in the analysis as censored observations on the last date that the patient is 
known to be progression free, defined as the date of the last tumor assessment, or, if no 
tumor assessments were performed, as the date of last study treatment plus 1 day.
Compliance to PRO data collection will be reported with summary statistics, including 
frequencies of reasons for non-compliance such as patient refusal to complete PRO 
data collection.  
4.10.7
Determination of Sample Size
For the randomized portion of the study (Arms A and B), a target of 120 patients will be 
enrolled in two separate cohorts of patients (40 in the follicular NHL cohort and 80 in the 
DLBCL cohort).  The randomized portion of this study is non-comparative in nature. No 
formal hypothesis testing is planned to compare the treatment arms.  Moreover, there is 
insufficient power to detect minimum clinically meaningful differences between the two 
treatment arms.  Genentech has judged the proposed sample size to provide sufficient 


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precision in estimating the anti-tumor activity of DCDT2980S combined with rituximab or 
DCDS4501A combined with rituximab as measured by objective response.  For example, 
with the assumption of an observed response rate of 40%, a 90% confidence interval for 
the response rate would be approximately 22%58% (i.e., 40% 18%) for the follicular 
NHL cohort and approximately 27%53% (i.e., 40% 13%) for the DLBCL cohort.  With 
40 patients, there is an 87% chance of observing at least one adverse event with a true 
incidence of 5%.
For the non-randomized portions of the study (Cohorts C and D), approximately 
20 patients will be enrolled into each arm, for a total of 40 patients.  With 20 patients 
under an observed response rate of 40%, the exact Clopper-Pearson 90% confidence 
interval for the response rate would be 22%61%.  With respect to the assessment of 
safety based upon a sample size of 20 patients, the chance of observing at least one 
adverse event with a true incidence of 10% is 88%.
For the obinutuzumab safety run-in cohort (Cohort E), 6 patients will be enrolled.  For the 
obinutuzumab expansion cohorts (Cohorts G and H), 40 patients with follicular NHL, and 
40 patients with DLBCL will be enrolled at the RP2D to further evaluate safety and 
efficacy of the combination.  Table 3 provides asymptotic 90% confidence intervals for 
the true probability of response for a range of observed proportions based upon a 
sample of 40 patients. A sample size of 40 patients is deemed sufficient to provide 
adequate precision on the point estimate and for the lower end of the 90% CI to rule out 
a clinically uninteresting rate of 45% assuming observed response rates of 
approximately 60% or higher (~24 responders observed among 40 patients).
Table 3
Potential 90% Interval Estimates for the True Response Probability
Observed Proportion
of Responders
90% Confidence Interval 
for
True Probability of 
Response
0.50
(0.37, 0.63)
0.60
(0.47, 0.73)
0.65
(0.53, 0.77)
0.70
(0.58, 0.82)
0.75
(0.64, 0.86)
Therefore, up to 246 patients may be enrolled in this study. 


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4.11
DATA QUALITY ASSURANCE
The data will be collected via EDC using eCRFs.  The site will be responsible for data 
entry into the EDC system.  In the event of discrepant data, the CRO will request data 
clarification from the sites, which the sites will resolve electronically in the EDC system.  
The CRO will be responsible for the data management of this trial, including quality 
checking of the data.  
Genentech will perform oversight of the data management of this trial.  Genentech will 
produce an EDC Study Specification document that describes the quality checking to be 
performed on the data.  Central Laboratory data and other electronic data will be sent 
directly to Genentech, using Genentech’s standard procedures to handle and process 
the electronic transfer of these data.  eCRFs and correction documentation will be 
maintained in the EDC system’s audit trail.  System backups for data stored at 
Genentech and records retention for the study data will be consistent with Genentech’s 
standard procedures.
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording protocol-defined adverse 
events (AEs) and serious adverse events (SAEs); measurement of protocol-specified 
hematology, clinical chemistry, and urinalysis variables; measurement of 
protocol-specified vital signs; and physical examinations and other protocol-specified 
tests that are deemed critical to the safety evaluation of the study drug(s).
Genentech or its designee is responsible for reporting relevant SAEs to the Competent 
Authority, other applicable regulatory authorities, and participating investigators, in 
accordance with ICH guidelines, FDA regulations, European Clinical Trials Directive 
(Directive 2001/20/EC), and/or local regulatory requirements.
Genentech or its designee is responsible for reporting unexpected fatal or 
life-threatening events associated with the use of the study drug to the regulatory 
agencies and competent authorities by telephone or fax within 7 calendar days after 
being notified of the event.  Genentech or its designee will report other relevant SAEs 
associated with the use of the study medication to the appropriate competent authorities 
(according to local guidelines), investigators, and central Institutional Review 
Board/ethics committee (IRBs/ECs, except in the United States where investigators are 
responsible for reporting to their IRBs per local requirements) by a written safety report 
within 15 calendar days of notification.  
5.1.1
Adverse Event
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an IMP or other protocol-imposed intervention, regardless of 
attribution.


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This includes the following:

AEs not previously observed in the patient that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with the baseline 
hematologic malignancy (i.e., leukemia or lymphoma) that were not present prior to 
the AE reporting period (see Section 5.2.1)

Complications that occur as a result of protocol-mandated interventions 
(e.g., invasive procedures such as biopsies)

AEs that occur prior to assignment of study treatment that are related to a 
protocol-mandated intervention (e.g., medication washout, no treatment run-in, or 
invasive procedures such as biopsies)

Preexisting medical conditions other than the disease under study that are judged 
by the investigator to have worsened in severity or frequency or changed in 
character during the protocol-specified AE reporting period
5.1.2
Serious Adverse Event
An SAE is any AE that is any of the following:

Fatal (i.e., the AE actually causes or leads to death)

Life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death)

Requires or prolongs inpatient hospitalization

Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions)

A congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
the investigational product(s)

Considered a significant medical event by the investigator (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
All AEs that do not meet any of the criteria for serious should be regarded as 
non-serious AEs.
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an AE (as in mild, moderate, or severe pain); the event itself may be of relatively minor 
medical significance (such as severe headache).  “Serious” is a regulatory definition and 
is based on patient or event outcome or action criteria usually associated with events 
that pose a threat to a patient’s life or vital functions.  Seriousness (not severity) serves 
as the guide for defining regulatory reporting obligations.
Severity and seriousness should be independently assessed when recording AEs and 
SAEs on the eCRF. 


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5.1.3
Protocol-Defined Adverse Events of Special Interest/Non-
Serious Expedited Adverse Events
Non-serious adverse events of special interest are required to be reported by the 
investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2 for reporting instructions), irrespective of regulatory seriousness 
criteria.  Adverse events of special interest for this study include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s Law (see Section 5.3.1.6; treatment-emergent ALT or AST 3 baseline value 
in combination with total bilirubin 2 ULN [of which 35% is direct bilirubin])

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Tumor lysis syndrome (TLS) of any grade, irrespective of causality

Secondary malignancies 
5.2
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all AEs and SAEs (as defined in 
Section 5.1) are recorded on the eCRF and reported to the Sponsor in accordance with 
protocol instructions. 
5.2.1
Adverse Event Reporting Period
After informed consent, but prior to initiation of study drug, only SAEs caused by a 
protocol-mandated intervention will be collected (e.g., SAEs related to invasive 
procedures such as biopsies, medication washout, or no treatment run-in).
After initiation of study drug (the Genentech product[s] or other IMP), all new AEs and 
SAEs regardless of attribution will be collected until 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is later.  
After this period, investigators should report only SAEs that are felt to be related to prior 
study treatment with the exception of second malignancies (see Section 5.6).  Second 
malignancies will be recorded indefinitely (even if the study has ended) and irrespective 
of new anti-lymphoma treatment (NALT).


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5.2.2
Eliciting Adverse Events
A consistent methodology of non-directive questioning for eliciting AEs at all patient 
evaluation timepoints should be adopted.  Examples of non-directive questions include:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?” 
5.2.3
Assessment of Severity and Causality of Adverse Events
Investigators will seek information on AEs and SAEs at each patient contact.  All AEs 
and SAEs, whether reported by the patient or noted by authorized study personnel, will 
be recorded in the patient’s medical record and on the Adverse Event eCRF.
For each AE and SAE recorded on the applicable eCRF, the investigator will make an 
assessment of seriousness (see Section 5.1.2 for seriousness criteria), severity, and 
causality.  
Table 4 provides guidance for grading AE severity, and Table 5 provides guidance for 
assessing the causal relationship to the investigational product(s). 
The AE grading (severity) scale found in the NCI CTCAE v4.0 will be used for AE 
reporting


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Table 4
Adverse Event Grading (Severity) Scale
Grade
Severity
Alternate Description a
1
Mild (apply event-specific 
NCI CTCAE grading criteria)
Transient or mild discomfort (48 hours); 
no interference with the patient’s daily 
activities; no medical intervention/therapy 
required
2
Moderate (apply event-specific 
NCI CTCAE grading criteria)
Mild to moderate interference with the 
patient’s daily activities; no or minimal 
medical intervention/therapy required
3
Severe (apply event-specific 
NCI CTCAE grading criteria)
Considerable interference with the 
patient’s daily activities; medical 
intervention/therapy required; 
hospitalization possible
4
Very severe, life threatening, 
or disabling (apply event-specific 
NCI CTCAE grading criteria)
Extreme limitation in activity; significant 
medical intervention/therapy required, 
hospitalization probable
5
Death related to AE
AE=adverse event; NCI CTCAE= National Cancer Institute Common Terminology Criteria 
for Adverse Events; SAE=serious adverse event.
The NCI CTCAE v4.0 can be found at
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.
Note:  Regardless of severity, some events may also meet regulatory serious criteria.  
Refer to definitions of an SAE (see Section 5.1.2).
a Use these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or 
reported AE is not in the NCI CTCAE listing.
To ensure consistency of causality assessments, investigators should apply the 
following general guidelines:
Table 5
Causal Attribution Guidance
Is the AE/SAE suspected to be caused by the investigational product based on facts, 
evidence, science-based rationales, and clinical judgment?
YES
The temporal relationship of the AE/SAE to investigational product administration 
makes a causal relationship possible, AND other drugs, therapeutic interventions 
or underlying conditions do not provide sufficient explanation for the AE/SAE.  
NO
The temporal relationship of the AE/SAE to investigational product administration 
makes a causal relationship unlikely, OR other drugs, therapeutic interventions or 
underlying conditions provide a sufficient explanation for the AE/SAE.  
AE=adverse event; SAE=serious adverse event.
The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the “Yes” or “No” causality assessment for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities.  


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5.3
PROCEDURES FOR RECORDING ADVERSE EVENTS
5.3.1
Recording Adverse Events on the eCRF
Investigators should use correct medical terminology/concepts when recording AEs or 
SAEs on the eCRF.  Avoid colloquialisms and abbreviations.
There is one eCRF page for recording AEs or SAEs.
Only one medical concept should be recorded in the event field on the Adverse Event 
eCRF.
5.3.1.1
Diagnosis versus Signs and Symptoms
If known, a diagnosis should be recorded on the eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded as an AE or SAE on the eCRF.  If a diagnosis 
is subsequently established, it should be reported as follow-up information.
5.3.1.2
Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause.  For example, if severe diarrhea is 
known to have resulted in dehydration, it is sufficient to record only diarrhea as an AE or 
SAE on the eCRF. 
However, medically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the eCRF.  For 
example, if a severe gastrointestinal hemorrhage leads to renal failure, both events 
should be recorded separately on the eCRF.
5.3.1.3
Persistent or Recurrent Adverse Events
A persistent AE is one that extends continuously, without resolution between patient 
evaluation timepoints.  Such events should only be recorded once in the eCRF unless 
their severity increases.  If a persistent AE becomes more severe, it should be recorded 
again on the Adverse Event eCRF.  
A recurrent AE is one that occurs and resolves between patient evaluation timepoints 
and subsequently recurs.  All recurrent AEs should be recorded on Adverse Event 
eCRF.


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5.3.1.4
Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management, 
e.g., concomitant medication, will be recorded as AEs or SAEs on the eCRF 
(e.g., abnormalities that require study drug dose modification, discontinuation of study 
treatment, more frequent follow-up assessments, further diagnostic investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholecystitis), only the 
diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event eCRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded as an AE or SAE on the eCRF.  If the 
laboratory abnormality can be characterized by a precise clinical term, the clinical term 
should be recorded as the AE or SAE.  For example, an elevated serum potassium level 
of 7.0 mEq/L should be recorded as “hyperkalemia.”
Specific to this study, lymphopenia and leukopenia due to lymphopenia of any grade are 
expected PD effects of study drug and therefore are not considered to be AEs.  
However, complications of lymphopenia (e.g., infections) will need to be reported as 
AEs.  In addition, because monocytopenia is not reportable and neutropenia is already 
being monitored and reported as an AE, leukopenia does not need to be reported as a 
distinct AE.
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded as AEs or SAEs on the eCRF, unless their severity, 
seriousness, or etiology changes. 
5.3.1.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported 
as an AE if it meets any of the following criteria:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (including a diagnostic evaluation not mandated in 
this protocol) or a change in concomitant therapy

Clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an AE.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.


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Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.1.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an AE the occurrence of either of the following:

Treatment-emergent ALT or AST 3 baseline value in combination with total 
bilirubin 2 ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3 baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as an SAE or a non-serious adverse event of special interest (see 
Section 5.4.2)
5.3.1.7
Deaths
Deaths that occur during the protocol-specified AE reporting period (see Section 5.2.1 ) 
that are attributed by the investigator solely to progression of lymphoma will be recorded 
only on the Study Discontinuation eCRF.  All other on-study deaths, regardless of 
attribution, will be recorded on the Adverse Event eCRF and expeditiously reported to 
the Sponsor.
When recording a death on an eCRF, the event or condition that caused or contributed 
to the fatal outcome should be recorded as the single medical concept on the eCRF.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
record “Unexplained Death” on the Adverse Event eCRF.
5.3.1.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the start of the study.  Such 
conditions should be recorded on the Medical and Surgical History eCRF.
A preexisting medical condition should be recorded as an AE or SAE only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”).


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5.3.1.9
Worsening of Baseline Hematologic Malignancy
Worsening and/or progression of the baseline hematologic malignancy (e.g. leukemia or 
lymphoma) should not be recorded as an AE or SAE.  These data will be captured as 
efficacy assessment data only.  
5.3.1.10
Hospitalization, Prolonged Hospitalization or Surgery
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol.  
There are some hospitalization scenarios that do not require reporting as an SAE when 
there is no occurrence of an AE.  These scenarios include a planned hospitalization or 
prolonged hospitalization to:

Perform an efficacy measurement for the study

Undergo a diagnostic or elective surgical procedure for a preexisting medical 
condition that has not changed

Receive scheduled therapy for the target disease of the study
5.3.1.11
Pregnancy
If a female patient becomes pregnant while receiving the study drug or within 12 months 
after the last dose of study treatment, a Pregnancy Report eCRF should be completed 
within 24 hours of learning of the pregnancy.  A pregnancy report will automatically be 
generated and sent to Genentech’s Drug Safety Department or its designee.  Pregnancy 
should not be recorded on the Adverse Event eCRF.
Male patients must also be instructed to immediately inform the investigator if their 
partner becomes pregnant during the study or within 5 months after the last dose of 
study drug.  If such an event occurs, it should be reported as described below.
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE 
(as the Sponsor considers these medically significant), recorded on an Adverse Event 
eCRF, and expeditiously reported to the Sponsor (see Section 5.4.2).
Any congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to study drug should be classified as an SAE, recorded on the Adverse Event eCRF, and 
expeditiously reported to the Sponsor (see Section 5.4.2).
After the study period, abortions, congenital anomalies/birth defects, and pregnancy 
outcomes should still be reported expeditiously to the Sponsor.  
In the event the EDC system is unavailable, a paper Pregnancy Report form and 
Pregnancy Fax Coversheet should be completed and faxed to Genentech’s Drug Safety 
Department or its designee within 24 hours of learning of the pregnancy, at the fax 
numbers listed in Section 5.4.2.


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a.
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
5 months after the last dose of study drug.  A Pregnancy Report eCRF should be 
completed by the investigator within 1 working day after learning of the pregnancy and 
submitted via the EDC system.  Attempts should be made to collect and report details of 
the course and outcome of any pregnancy in the partner of a male patient exposed to 
study drug.  The pregnant partner will need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
Once the authorization has been signed, the investigator will update the Pregnancy 
Report eCRF with additional information on the course and outcome of the pregnancy.  
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician.
In the event that the EDC system is unavailable, a paper Pregnancy Report form and 
Pregnancy Fax Coversheet should be completed and faxed to Genentech’s Drug Safety 
Department or its designee within 24 hours of learning of the pregnancy, at the fax 
numbers listed in Section 5.4.2.
5.4
EXPEDITED REPORTING REQUIREMENTS FOR SERIOUS 
ADVERSE EVENTS 
5.4.1
Reporting Requirements for Fatal/Life-Threatening SAEs 
Related to Investigational Product
Any life-threatening (i.e., imminent risk of death) or fatal AE that is attributed by the 
investigator to the investigational product will be telephoned to the Medical Monitor 
immediately, followed by submission of written case details on an eCRF within 24 hours
as described in Section 5.4.2.
Medical Monitor Contact Information for sites in North America:
Medical Monitor:
, M.D.
Telephone No.:
Mobile Telephone No.:
For sites outside of North America, local contact details and numbers for safety issues 
and safety reporting will be provided in the study reference binder.
5.4.2
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest
For reports of SAEs and non-serious adverse events of special interest, investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours) on 
the Adverse Event eCRF and submit the report via the EDC system.  A report will be 


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generated and sent to the Sponsor’s Safety Risk Management department by the EDC 
system.
In the event that the EDC system is unavailable, a paper Serious Adverse 
Event/Non-Serious Adverse Event of Special Interest CRF and Fax Coversheet should 
be completed and faxed to Safety Risk Management or its designee immediately (i.e., no 
more than 24 hours after learning of the event), using the fax numbers provided below.  
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.  
Sites in North America:
Fax No.:
Sites in Europe:
Fax No.: 
Relevant follow-up information should be submitted to Genentech’s Drug Safety 
Department or its designee as soon as it becomes available and/or upon request.
5.5
TYPE AND DURATION OF FOLLOW-UP OF PATIENTS AFTER
ADVERSE EVENTS
The investigator should follow all unresolved AEs and SAEs until the events are resolved 
or stabilized, the patient is lost to follow up, or it has been determined that the study 
treatment or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs 
(with dates) should be documented on the Adverse Event eCRF and in the patient’s 
medical record to facilitate source data verification (SDV).
For some SAEs, the Sponsor or its designee may follow up by telephone, fax, electronic 
mail, and/or a monitoring visit to obtain additional case details deemed necessary to 
appropriately evaluate the SAE report (e.g., hospital discharge summary, consultant 
report, or autopsy report).
5.6
POST-STUDY ADVERSE EVENTS
At the last scheduled visit, the investigator should instruct each patient to report to the 
investigator any subsequent SAEs that the patient’s personal physician believes could 
be related to prior study treatment.  
The investigator should notify the study Sponsor of any death or other SAE occurring at 
any time after a patient has discontinued or terminated study participation if felt to be 
related to prior study treatment.  Second malignancies will be recorded indefinitely (even 
if the study has been closed) and irrespective of NALT.  The Sponsor should also be 
notified if the investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a patient that participated in
this study.  The investigator should report these events to Genentech Drug Safety on the 


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study eCRF.  If the study eCRF is no longer available, the investigator should report the 
event directly to Genentech Drug Safety either by faxing or by scanning and emailing the 
Serious Adverse Event/Adverse Event of Special Interest Reporting Form with use of the 
fax number or email address provided below.
Canada:
Fax No.:  (905) 5425864
Email:  mississauga.drug_safety@roche.com
France:
Fax No:  33 147617777
Email:  neuilly.drug_safety@roche.com
Germany:
Fax No.:
Email: grenzach.drug_safety@roche.com
Italy:
Fax No.:  
Email:  monza.drug_safety@roche.com
Netherlands:
Fax No.:  
Email:   woerden.drug_safety@roche.com
United States:
Fax No.: 
Email: us_drug.safety@gene.com
6.
INVESTIGATOR REQUIREMENTS
6.1
STUDY INITIATION
Before the start of this study and any study-related procedures at a specific site, the 
following documents must be on file with Genentech or a Genentech representative:

FDA Form 1572 for each site (for all studies conducted under U.S. Investigational 
New Drug [IND] regulations), signed by the Principal Investigator
The names of any subinvestigators must appear on this form.  Investigators 
must also complete all regulatory documentation as required by local and 
national regulations.

Current curricula vitae and evidence of licensure of the Principal Investigator and all 
subinvestigators


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
Complete financial disclosure forms for the Principal Investigator and all 
subinvestigators listed on the FDA Form 1572 

Federalwide Assurance number or IRB statement of compliance

Written documentation of IRB/EC approval of the protocol (identified by protocol 
number or title and date of approval) and Informed Consent Form (identified by 
protocol number or title and date of approval)

A copy of the IRB/EC-approved Informed Consent Form
Genentech or its designee must review any proposed deviations from the sample 
Informed Consent Form.

Current laboratory certification of the laboratory performing the analysis (if other 
than a Genentech-approved central laboratory), as well as current references 
ranges for all laboratory tests

A Clinical Research Agreement signed and dated by the study site

Investigator Brochure Receipt signed and dated by the Principal Investigator

Certified translations of an approved Informed Consent Form, and any other written 
information to be given to the patient (when applicable) , IRB/EC approval letters, 
and pertinent correspondence

A Protocol Acceptance Form signed and dated by the Principal Investigator

Canada only when applicable:  original Qualified Investigator Undertaking Form, 
signed by each Canadian investigator involved in the study

For global studies, list documents as appropriate for additional countries.
6.2
STUDY COMPLETION
The following data and materials are required by Genentech before a study can be 
considered complete or terminated:

Laboratory findings, clinical data, and all special test results from screening through 
the end of the study follow-up period

All laboratory certifications for laboratories performing the analysis (is other than 
Genentech-approved central laboratory), as well as current normal laboratory 
ranges for all laboratory tests

eCRFs (including queries) properly completed by appropriate study personnel and 
electronically signed and dated by the investigator

Completed Drug Accountability Records (Retrieval Record, Drug Inventory Log, and 
Inventory of Returned Clinical Material forms)

Copies of protocol amendments and IRB/EC approval/notification, if appropriate

A summary of the study prepared by the Principal Investigator (IRB summary close 
letter is acceptable)

All essential documents (e.g., curriculum vitae for each Principal Investigator and 
subinvestigator, FDA Form 1572 for each site)


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
A signed and dated Protocol Amendment Acceptance Form(s) [if applicable]

Updated financial disclosure forms for the Principal Investigator and all 
subinvestigators listed on the FDA Form 1572 (applicable for 1 year after the last 
patient has completed the study)
6.3
INFORMED CONSENT FORM
Genentech’s Sample Informed Consent Form will be provided to each site.  Genentech 
or its designee must review and approve any proposed deviations from the Sample 
Informed Consent Form or any alternate consent forms proposed by the site 
(collectively, the “Consent Forms”) before IRB/EC submission.  Patients must be 
re-consented to the most current version of the Consent Forms during their participation 
in the study.  The final IRB/EC-approved Consent Forms must be provided to Genentech 
for regulatory purposes.
The Consent Forms must be signed by the patient or the patient’s legally authorized 
representative before his or her participation in the study.  The case history for each 
patient shall document the informed consent process and that written informed consent 
was obtained prior to participation in the study.  A copy of each signed Consent Form 
must be provided to the patient or the patient’s legally authorized representative.  
If applicable, it will be provided in a certified translation of the local language.
All signed and dated Consent Forms must remain in each patient’s study file and must 
be available for verification by study monitors at any time.
The Informed Consent Form should be revised whenever there are changes to 
procedures outlined in the informed consent or when new information becomes available 
that may affect the willingness of the patient to participate.
For any updated or revised Consent Forms, the case history for each patient shall 
document the informed consent process and that written informed consent was obtained 
for the updated/revised Consent Form for continued participation in the study.  The final 
revised IRB/EC-approved Informed Consent Form must be provided to Genentech for 
regulatory purposes.
If the site utilizes a separate Authorization Form for patient authorization to use and 
disclose personal health information under the U.S. Health Insurance Portability and 
Accountability Act (HIPAA) regulations, the review, approval, and other processes 
outlined above apply except that IRB/IEC review and approval may not be required per 
study site policies.
Optional Research Informed Consent
Informed consent for the collection and use of fresh tumor tissue at time of progression 
for optional research described in Section 4.5.1.10 will be documented in a section of the 
main Informed Consent Form.  This section provides patients with the option to authorize 


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the collection and use of these samples and personal health information for additional 
research purposes.  Agreement to participate in the optional research (by checking the 
appropriate box in this section of the main Informed Consent Form) is not required for 
enrollment in the trial but is required prior to any optional research sample collection.  
Optional consent may be withdrawn at any time by the patient.
6.4
COMMUNICATION WITH THE INSTITUTIONAL REVIEW BOARD 
OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator for review and approval before the study is initiated.  In addition, any patient 
recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the regulatory 
requirements and policies and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol changes or 
amendments and of any unanticipated problems involving risk to human patients 
or others.
In addition to the requirements to report protocol-defined AEs to the Sponsor, 
investigators are required to promptly report to their respective IRB/EC all unanticipated 
problems involving risk to human patients.  Some IRBs/ECs may want prompt 
notification of all SAEs, whereas others require notification only about events that are 
serious, assessed to be related to study treatment, and are unexpected.  Investigators 
may receive written IND safety reports or other safety-related communications from 
Genentech.  Investigators are responsible for ensuring that such reports are reviewed 
and processed in accordance with regulatory requirements and with the policies and 
procedures established by their IRB/EC and archived in the site’s Study File. 
6.5
STUDY MONITORING REQUIREMENTS
Site visits will be conducted by an authorized Genentech representative to inspect site 
facilities and equipment, study source data, patients’ medical records, and eCRFs.  The 
Principal Investigator will oversee all aspects of the conduct of this protocol and permit 
Genentech monitors/representatives and collaborators, the FDA, other regulatory 
agencies, Institutional Review Boards, and the respective national or local health 
authorities to inspect facilities and records relevant to this study.
6.6
ELECTRONIC CASE REPORT FORMS
eCRFS are to be completed using the 
EDC 
system.  Sites will receive training for appropriate eCRF completion.  eCRFs will be 
submitted electronically to Genentech and should be handled in accordance with 
instructions from Genentech.


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All eCRFs should be completed by designated, trained personnel or the study 
coordinator as appropriate.  The eCRF should be reviewed and electronically signed and 
dated by the investigator.
In addition, at the end of the study, the investigator will receive patient data for his or her 
site in a readable format on a compact disc that must be kept with the study records.
6.7
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing SDV to confirm that critical protocol data 
(i.e., source data) entered into the eCRFs by authorized site personnel are accurate, 
complete, and verifiable from source documents. 
Source documents are where original patient data are recorded and documented for the 
first time.  They include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, patient diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, certified accurate and 
complete copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at the pharmacy, laboratories, and medico-technical 
departments involved in a clinical trial.
Original source documents that are required to verify the validity and completeness of 
data entered into the eCRFs must never be obliterated or destroyed.
To facilitate SDV, the investigator(s) and institution(s) must provide the Sponsor direct 
access to all applicable source documents and reports for trial-related monitoring, 
Sponsor audits, and IRB/EC review.  The investigational site must also allow inspection 
by applicable regulatory authorities.
6.8
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), 
the electronic record can serve as the source document if the system has been validated 
in accordance with FDA requirements pertaining to computerized systems used in 
clinical research.  An acceptable computerized data collection system (for clinical 
research purposes) would be one that (1) allows data entry only by authorized 
individuals; (2) prevents the deletion or alteration of previously entered data and 
provides an audit trail for such data changes (e.g., modification of file); (3) protects the 
database from tampering; and (4) ensures data preservation.
In collaboration with the study monitor, Genentech’s Quality Assurance group may assist 
in assessing whether electronic records generated from computerized medical record 
systems used at investigational sites can serve as source documents for the purposes of 
this protocol.


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If a site’s computerized medical record system is not adequately validated for the 
purposes of clinical research (as opposed to general clinical practice), applicable 
hardcopy source documents must be maintained to ensure that critical protocol data 
entered into the eCRFs can be verified.
6.9
STUDY MEDICATION ACCOUNTABILITY
All study drug required for completion of this study will be provided by Genentech.  
The recipient will acknowledge receipt of the drug by returning the appropriate 
documentation form indicating shipment content and condition.  Damaged supplies will 
be replaced.
Accurate records of all study drug received at, dispensed from, returned to and disposed 
of by the study site should be recorded by using the Drug Inventory Log.
Study drug will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or returned to Genentech with the appropriate 
documentation, as determined by the study site.  If the study site chooses to destroy 
study drug, the method of destruction must be documented.
Genentech must evaluate and approve the study site’s drug destruction standard 
operating procedure prior to the initiation of drug destruction by the study site.
6.10
DISCLOSURE OF DATA
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization to use and disclose personal health information) signed by the patient or 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other regulatory agencies, national and local health 
authorities, Genentech monitors/representatives and collaborators, and the IRB/EC for 
each study site, if appropriate.
6.11
RETENTION OF RECORDS
FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see Section 4.9 of 
the guideline) require that records and documents pertaining to the conduct of this study 
and the distribution of investigational drug, including eCRFs, consent forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for 2 years after the last marketing application approval in an ICH region or 
after at least 2 years have elapsed since formal discontinuation of clinical development 
of the investigational product.  All state and local laws for retention of records also apply. 


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No records should be disposed of without the written approval of Genentech.  Written 
notification should be provided to Genentech prior to transferring any records to another 
party or moving them to another location.
For studies conducted outside the United States under a U.S. IND, the Principal 
Investigator must comply with the record retention requirements set forth in the FDA IND 
regulations and the relevant national and local health authorities, whichever is longer.


 
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Appendix A1
Study Flowchart:  Initial Study Treatment (Arms AB, Cohorts CD)
Screening
Treatment Period
Treatment 
Completion/Early 
Termination Visit c
Safety and 
Survival 
Follow-Up d
Cycle
Cycle 1
Cycles 24
Cycles 517
Day(s)a
Assessment
28 to 1
1 b
2
8
15
1 b
2
8
15
1 b
2
15
Written informed consent e
x
Review inclusion/exclusion criteria
x
Medical history and demographics
x
Height (screening only) and weight
x
x
x
x
Vital signs 
x
x f
x f
x
x
x f
(x) f
x
x
x f
(x) f
x
x
ECOG Performance Status
x
x
x
x
x
x
x
x
x
B symptoms g
x
x
x
x
x
Complete physical examination h
x
Targeted physical examination i
x
x
x
x
(x)
x
(x)
x
Concomitant medications
x
x
x
x
x
x
(x)
x
x
x
(x)
x
x
Adverse events j
x
x
x
x
x
x
(x)
x
x
x
(x)
x
x
x
MDASI PRO k
Day 1–8 of Cycles 1–8
12-lead electrocardiogram l
x
Refer to Footnote “l”
x
Tumor assessments m
x
Every 3 months
x
PET/CT scan (required for DLBCL; 
optional for FL) m
x
6-month tumor assessment and as clinically indicated
Rituximab infusion
x
x
x
DCDT2980S or DCDS4501A infusion n
x
x
(x)
x
(x)


Appendix A1 (cont.)
Study Flowchart:  Initial Study Treatment (Arms AB, Cohorts CD)
DCDT2980S and DCDS4501A—Genentech, Inc.
140/Protocol GO27834, Version A4
Screening
Treatment Period
Treatment 
Completion/Early 
Termination Visit c
Safety and 
Survival 
Follow-Up d
Cycle
Cycle 1
Cycles 24
Cycles 517
Day(s)a
Assessment
28 to 1
1 b
2
8
15
1 b
2
8
15
1 b
2
15
Local Laboratory Assessments
HBV and HCV screening o
x
Hematology p
x
x
x
x
x
x
x
x
x
x
Serum chemistry q
x
x
x
x
x
x
x
x
x
x
Hemoglobin A1c
x
Cycle 5 Day 1
Total IgA, IgG, IgM
x
Cycle 8 Day 1
x
Coagulation (aPTT, PT, and INR)
x
Pregnancy test r
x
Within 10 days of Day 1 of Cycles 3, 6, 9, 12, and 15
x
Bone marrow biopsy s
x
Perform to confirm CR if positive for disease at screening or if clinically 
indicated
Central Laboratory Assessments
Leukocyte immunophenotyping (FACS) t
Day 1 of Cycle1, Cycle 4, Cycle 8 and Cycle12
x
Tumor tissue sample u
x
x
Exploratory plasma (required) and blood 
(optional) sample v
x
DCDT2980S or DCDS4501A and 
rituximab pharmacokinetic sampling w
Refer to Appendix B-1 and Appendix B-2
Serum sample for anti-DCDT2980S or 
anti-DCDS4501A antibody x


Appendix A1 (cont.)
Study Flowchart:  Initial Study Treatment (Arms AB, Cohorts CD)
DCDT2980S and DCDS4501A—Genentech, Inc.
141/Protocol GO27834, Version A4
AEadverse event; ALT alanine aminotransferase; aPTT activated partial thromboplastin time; AST aspartate aminotransferase; CRcompleted 
response; CT computed tomography; DLBCLECGelectrocardiogram; ECOG Eastern Cooperative Oncology Group; FACSfluorescent-activated cell 
sorting; FLfollicular lymphoma; GGT-glutamyl transpeptidase; HBVhepatitis B virus; HCVhepatitis C virus; Igimmunoglobulin; INRinternational 
normalized ratio; LDHlactate dehydrogenase; MDASIMD Anderson Symptom Inventory; MRImagnetic resonance imaging; NHLnon-Hodgkin’s 
lymphoma; PET positron emission tomography; PCR polymerase chain reaction; PT prothrombin time; QLQQuality of Life Questionnaire; 
SAEserious adverse event; (x) Assessment or action to be performed only if study treatment is administered on Day 2 of the Cycle —refer to footnote ‘n’ 
for details.
a Study drug infusions should occur on the scheduled 21-day cycle up to a maximum of 1 year (approximately 17 cycles on an every-21-day schedule) and 
may be given up to 2 days from the date scheduled (i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  
All other study visits during Cycles 1 and 2 must occur within 1 day from the scheduled date unless otherwise noted.  Study visits starting in Cycle 3 
should occur within 2 days from the scheduled date unless otherwise noted.  Treatment cycles may be extended to 28 days if needed to provide 
sufficient time for recovery from a transient and reversible toxicity (e.g., cytopenia) without reducing the dose of DCDT2980S or DSDA4501A.  Patients 
receiving study treatment on 28-day cycles should also follow the assessment schedule above up to a maximum of 1 year of total study treatment 
(approximately 13 cycles).
b Local laboratory assessments and targeted physical examination may be performed within 72 hours preceding rituximab administration unless otherwise 
specified; pre-infusion laboratory samples should be drawn 04 hours prior to infusion.
c Perform within 30 days after the last infusion of DCDT2980S, DCDS4501A, or rituximab.  The visit at which response assessment shows progressive 
disease may be used as the early termination visit.  Assessments during the treatment completion/early termination visit may be applied to assessments 
required to determine eligibility to receive crossover treatment.  Patients enrolled into Cohorts C and D are not eligible to receive crossover treatment.
d Patients will be followed for safety for 30 days after the last infusions of DCDT2980S, DCDS4501A, or rituximab.  Such follow-up will require an 
assessment (per verbal report from the patient, at minimum) of any AEs and/or SAEs through 30 days after the last dose of study drug or until the patient 
receives another anti-cancer therapy including crossover treatment, whichever occurs first.  Patients who discontinue study treatment for reasons other 
than progressive disease will continue to be followed for response for up to 1 year after the last infusions of DCDT2980S or DCDS4501A and rituximab, 
or until disease progression or initiation of another anti-lymphoma/leukemia therapy, whichever occurs first.  Refer to Appendix A-4 for schedule of 
assessments during the post-treatment period.  Patients will also be followed for survival following study treatment discontinuation approximately every 
three months until death, loss to follow-up, withdrawal of consent, or study termination.
e Informed consent form(s) must be signed by the patient before any study-specific procedures are performed.
f
Vital signs on days of study treatment administration should be recorded according to Section 4.5.1.2 of the protocol.
g Defined as unexplained weight loss 10% over previous 6 months, fever (38C/100.4F), and/or drenching night sweats.
h Complete physical examination includes all systems described in Section 4.5.1.3.  
i
Targeted physical examinations should be limited to systems of clinical relevance (see Section 4.5.1.3) and those systems associated with clinical 
signs/symptoms.  A targeted symptom directed examination is required prior to DCDT2980S or DCDS4501A dosing on Day 2 of each cycle if given on 
separate days from rituximab only if clinically indicatedfor example, to follow- up on signs or symptoms observed from the examinations performed on 
Day 1.


Appendix A1 (cont.)
Study Flowchart:  Initial Study Treatment (Arms AB, Cohorts CD)
DCDT2980S and DCDS4501A—Genentech, Inc.
142/Protocol GO27834, Version A4
j
After informed consent is obtained but prior to initiation of study treatment, only SAEs caused by a protocol-mandated intervention should be reported.  
After initiation of study drug, all AEs and SAEs, regardless of attribution, must be reported until 30 days following the last administration of study drug or 
until the patient receives another anti-cancer therapy, whichever occurs first.  After this period, investigators should report only SAEs considered related 
to prior study treatment with the exception of second malignancies.  Second malignancies will be recorded indefinitely (even if the study has ended) 
and irrespective of NALT.
k Treatment and disease associated symptoms using the MDASI questionnaire will be collected on hand-held computer devices (see Section 4.5.1.10).  
l
Twelve-lead digital electrocardiogram (ECG) measurements must be obtained in triplicate (with immediately consecutive ECGs obtained until 
three evaluable ECGs are recorded) at the timepoints specified in Section 4.5.1.5.  Non-triplicate ECGs should also be performed when clinically 
indicated in any patient with evidence of, or suspicion for, clinically significant signs or symptoms of cardiac dysfunction.  The evaluating physician should 
determine the clinical significance of any abnormal ECGs.
m Tumor assessments should be performed at screening and every 3 months while receiving study treatment regardless of study treatment dose schedule.  
Tumor assessments should also be performed within 30 days after the last study drug infusion as part of the treatment completion/early termination visit.  
Response should be assessed based on physical examination and imaged-based evaluation, using standard NHL criteria (Appendix C-1).  For DLBCL 
patients, a PET scan is required during screening, at the 6-month tumor assessment timepoint and as clinically indicated.  For patients with FL, a PET 
scan is not required but may be obtained based on physician preference and if permitted by local health authorities.  Refer to Section 4.5.1.8 for 
complete details.
n Administer DCDT2980S or DCDS4501A over 90 minutes for Cycle 1 and over 30 minutes in subsequent cycles if there are no infusion-related AEs.  For 
Cycle 1 and Cycle 2, DCDT2980S or DCDS4501A should be administered on the day after rituximab is administeredfor example, Day 2 if rituximab is 
given on Day 1, or Day 3 if rituximab is given as a split dose on Days 1 and 2.  In the absence of any infusion-related AEs, rituximab followed by 
DCDT2980S or DCDS4501A may be administered on the same day in each cycle starting with Cycle 3.  Study drug infusions should occur on the 
scheduled 21-day (or 28-day) cycle but may be given up to 2 days from the date scheduled (i.e., with a minimum of 19 days between doses) if required 
for logistical/scheduling reasons.  Doses may also be delayed up to 2 weeks for recovery from reversible toxicity.
o HBsAg, HBcAb, and Hep C Ab serology required.  If HBcAb or HCV antibody is positive, HBV/HCV DNA by PCR is required.
p Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, absolute neutrophil count, and 
percent or absolute differential counts [e.g., segmented neutrophils, bands, lymphocytes, eosinophils, monocytes, basophils, and other cells]).
q Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), creatinine, calcium, magnesium, phosphorus, total 
and direct bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, LDH, and uric acid.  Serum GGT levels will be required at screening only.
r
A serum pregnancy test should be performed for women of childbearing potential within 14 days prior to receiving first study treatment.  In addition, a 
urine pregnancy test must also be performed within 10 days prior to Day 1 of Cycles 3, 6, 9, 12, and 15, and at the treatment completion/early 
termination visit unless patient receives crossover treatment, in which case follow the schedule of pregnancy testing outlined in Appendix A-2.  If any 
urine test result is positive, patient dosing will be postponed until the patient’s status is confirmed by a serum pregnancy test.


Appendix A1 (cont.)
Study Flowchart:  Initial Study Treatment (Arms AB, Cohorts CD)
DCDT2980S and DCDS4501A—Genentech, Inc.
143/Protocol GO27834, Version A4
s Bone marrow biopsy for morphology (aspirates for morphology and/or flow studies are optional) is required at screening.  Bone marrow biopsy 
for morphology is required at screening and should reflect disease status in the bone marrow following documented relapse on the last prior therapy 
or within 3 months of Day 1, whichever occurs later.  If the bone marrow biopsy at screening demonstrates presence of tumor cells, a subsequent 
bone marrow examination is required only to confirm a CR or if clinically indicated.  If the bone marrow biopsy at screening does not demonstrate 
presence of tumor cells, then subsequent bone marrow examination is required only if clinically indicated.  Unsuccessful attempts at marrow aspiration 
will not be considered a protocol violation.
t
A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.  
u Availability of archival or freshly biopsied tumor tissue samples should be confirmed at screening.  Tumor tissue samples should consist of representative 
tumor specimens in paraffin blocks (preferred) or at least 15 unstained slides, with an associated pathology report, obtained at any time prior to entry to 
study.  A biopsy of a safely accessible site of disease, defined as requiring only local anesthesia and in general excluding brain, lungs or any internal 
organs that may subject patients to significant risk, is required for patients who proceed to crossover treatment; if no such lesion exists, then a biopsy is 
not required.
v All patients who have successfully passed screening and are fully eligible for the study will have a 10-mL plasma sample taken for exploratory research.  
w Pharmacokinetic serum and plasma samples should be drawn according to the schedule provided in Appendices B-1 and B-2.
x Whole blood samples for assessment of anti-DCDT2980S or anti-DCDS4501A antibodies in serum will be drawn according to the schedule provided in 
Appendices B-1 and B-2.


DCDT2980S and DCDS4501A—Genentech, Inc.
144/Protocol GO27834, Version A4
Appendix A2
Study Flowchart: Crossover Treatment (Patients Randomized to Arms A or B Only)
Treatment Period
Crossover 
Treatment 
Completion/Early 
Termination Visit c
Safety and 
Survival 
Follow-Up d
Cycle
Cycle 1b
Cycles 2b4b
Cycles 5b17b
Day(s) a
Assessment
1 b
2
8
15
1 b
2
8
15
1 b
2
15
Weight
x
x
x
Vital signs
x e
(x) e
x
x
x e
(x) e
x
x
x e
(x) e
x
x
ECOG Performance Status
x
x
x
x
x
x
x
x
B symptoms f
x
x
x
x
Targeted physical examination g
x
(x)
x
x
(x)
x
(x)
x
Concomitant medications
x
(x)
x
x
x
(x)
x
x
x
(x)
x
x
Adverse events h
x
(x)
x
x
x
(x)
x
x
x
(x)
x
x
x
Tumor assessments i
Every 3 months
x
Rituximab infusion
x
x
x
DCDT2980S or DCDS4501A infusion j
x
(x)
x
(x)
x
(x)
Local Laboratory Assessments
Hematology k
x
x
x
x
x
x
x
x
x
Serum chemistry l
x
x
x
x
x
x
x
x
x
Total IgA, IgG, IgM
Cycle 8b Day 1
x
Pregnancy test m
Day 1 of Cycles 3b, 6b, 9b, 12b, and 15b
x
Bone marrow biopsy n
Perform to confirm CR if positive for disease at screening or if clinically indicated
Central Laboratory Assessments
Leukocyte immunophenotyping (FACS)o
Day 1 of Cycle 4, 8, and 12
x
Tumor biopsy/sample
x p


Appendix A2 (cont.)
Study Flowchart: Crossover Treatment (Patients Randomized to Arms A or B Only)
DCDT2980S and DCDS4501A—Genentech, Inc.
145/Protocol GO27834, Version A4
AEadverse event; ALalanine aminotransferase; AST aspartate aminotransferase; CRcomplete response; LDHlactate dehydrogenase; 
SAEserious adverse event; (x)Assessment or action to be performed only if study treatment is administered on Day 2 of the Cycle—refer to footnote 
‘j’ for details.
a Study drug infusions should occur on the scheduled 21-day cycle up to a maximum of 1 year (approximately 17 cycles) and may be given up to 
2 days from the date scheduled (i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  All other study visits 
during Cycles 1 and 2 must occur within 1 day from the scheduled date unless otherwise noted.  Study visits starting in Cycle 3 should occur within 
2 days from the scheduled date unless otherwise noted.  Treatment cycles may be extended to 28 days if needed to provide sufficient time for 
recovery from a transient and reversible toxicity (e.g., cytopenia) without reducing the dose of DCDT2980S or DSDA4501A.  Patients receiving study 
treatment on 28-day cycles should also follow the assessment schedule above up to a maximum of 1 year of total study treatment (approximately 
13 cycles).
b Local laboratory assessments and targeted physical examination may be performed within 72 hours preceding rituximab administration unless 
otherwise specified; pre-infusion laboratory samples should be drawn 04 hours prior to infusion.
c Perform within 30 days after the last infusion of DCDT2980S, DCDS4501A or rituximab. The visit at which response assessment shows progressive 
disease may be used as the early termination visit.
d Patients will be followed for safety for 30 days after the last infusions of DCDT2980S, DCDS4501A, or rituximab.  Such follow-up will require an 
assessment (per verbal report, at minimum) of any AEs and/or SAEs through 30 days after the last dose of study drug or until the patient receives 
another anti-cancer therapy including crossover treatment, whichever occurs first.  Patients who discontinue study treatment for reasons other than 
progressive disease will continue to be followed for response for up to 1 year after the last infusions of DCDT2980S or DCDS4501A and rituximab, or 
until disease progression or initiation of another anti-lymphoma/leukemia therapy, whichever occurs first.  Refer to Appendix A-4 for schedule of 
assessments during the post-treatment period.  Patients will also be followed for survival following study treatment discontinuation approximately 
every three months until death, loss to follow-up, withdrawal of consent, or study termination.
e Vital signs on days of study treatment administration should be recorded according to Section 4.5.1.2 of the protocol.
f
Defined as unexplained weight loss 10% over previous 6 months, fever (38C/100.4F), and/or drenching night sweats.
g Targeted physical examinations should be limited to systems of clinical relevance and those systems associated with clinical signs/symptoms. 
A targeted symptom directed examination is required prior to DCDT2980S or DCDS4501A dosing on Day 2 of each cycle if given on separate days 
from rituximab only if clinically indicated, e.g. to follow -up on signs or symptoms observed from the examinations performed on Day 1.
h Patients will be followed for safety for 30 days after the last infusions of DCDT2980S, DCDS4501A, or rituximab.  Such follow-up will require an 
assessment (per verbal report, at minimum) of any AEs and/or SAEs through 30 days after the last dose of study drug or until the patient receives 
another anti-cancer therapy including crossover treatment, whichever occurs first.  Investigators should report second malignancies indefinitely 
(even if the study has ended) and irrespective of NALT.  Patients who discontinue study treatment for reasons other than progressive disease will 
continue to be followed for response for up to 1 year after the last infusions of DCDT2980S or DCDS4501A and rituximab, or until disease 
progression or initiation of another anti-lymphoma/leukemia therapy, whichever occurs first.  Refer to Appendix A-4 for schedule of assessments 


Appendix A2 (cont.)
Study Flowchart: Crossover Treatment (Patients Randomized to Arms A or B Only)
DCDT2980S and DCDS4501A—Genentech, Inc.
146/Protocol GO27834, Version A4
during the post-treatment period.
i
Tumor assessments should be performed at screening and every 3 months while receiving study treatment.  Tumor assessments should also be 
performed 2856 days after the last study drug infusion as part of the crossover treatment completion/early termination visit.  Response should be 
assessed based on physical examination and imaged-based evaluation, using standard NHL criteria (Appendix C-1).
j
Administer DCDT2980S or DCDS4501A over 90 minutes for Cycle 1 and over 30 minutes in subsequent cycles if there are no infusion-related 
adverse events.  For Cycle 1b and Cycle 2b, DCDT2980S or DCDS4501A should be administered on the day after rituximab is administered, 
e.g., Day 2 if rituximab is given on Day 1, or Day 3 if rituximab is given as a split dose on Days 1 and 2.  In the absence of any infusion-related 
adverse events, rituximab followed by DCDT2980S or DCDS4501A may be administered on the same day in subsequent cycles starting with 
Cycle 3b.  Study drug infusions should occur on the scheduled 21-day (or 28-day) cycle, but may be given up to 2 days from the date scheduled 
(i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  Doses may also be delayed up to 2 weeks for recovery 
from reversible toxicity.
k Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, absolute neutrophil count, and 
percent or absolute differential counts [e.g., segmented neutrophils bands, lymphocytes, eosinophils, monocytes, basophils, and other cells]).
l
Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), creatinine, calcium, magnesium, phosphorus, 
total and direct bilirubin, total protein, albumin, ALT), AST, alkaline phosphatase, LDH, and uric acid.
m A serum pregnancy test should be performed for women of childbearing potential within 14 days prior to receiving first study treatment.  In addition, a 
serum or urine pregnancy test must be performed within 10 days prior to Day 1 of Cycles 3, 6, 9, 12, and 15 and at the crossover treatment 
completion/early termination visit.  If any urine test result is positive, patient dosing will be postponed until the patient’s status is confirmed by a serum 
pregnancy test.
n Bone marrow biopsy for morphology (aspirate for morphology and/or flow studies are optional) should be repeated only to confirm a CR where 
presence of tumor was documented at the screening bone marrow examination.
o A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.  
p Optional tumor biopsy of a safely accessible site of disease, defined as requiring only local anesthesia and in general excluding brain, lungs or any 
internal organs that may subject patients to significant risk.  Tumor samples will be used for research purposes.


DCDT2980S and DCDS4501A—Genentech, Inc.
147/Protocol GO27834, Version A4
Appendix A3
Study Flowchart for Obinutuzumab-Containing Cohorts (E, GH):  Initial Study Treatment
Cycle
Screening
Treatment Period
Treatment 
Completion/ Early 
Termination Visitc
End of Treatment Response 
Assessment (after Cycle 8
Day 1 or last study treatment 
68 weeks)
Safety and 
Survival 
Follow-Up d
Cycle 1
Cycles 24
Cycle 4
Cycles 58
Day(s)a
Assessment
28 to 1
1
b
2
8
15
1b
2
15c
1b
2
Written informed consent 
e
x
Review 
inclusion/exclusion criteria
x
Medical history and 
demographics
x
Height (screening only) 
and weight
x
x
x
x
Vital signs 
x
x
f
xf
xf
xf
x f
(x) f
x f
(x) f
x
ECOG Performance 
Status
x
x
x
x
x
x
x
Complete physical 
examination g
x
Targeted physical 
examination h
x
x
x
x
(x)
x
(x)
x
Concomitant medications
x
x
x
x
x
x
(x)
x
(x)
x
Adverse events i
x
x
x
x
x
x
(x)
x
(x)
x
x
12-lead 
electrocardiogramj
x
Refer to Footnote “j”
x
Tumor/Assessment 
(PET/CT scan (required 
for DLBCL and FL) k
x
xm
x m


Appendix A-3 (cont.)
Study Flowchart for Obinutuzumab-Containing Cohorts (E, GH):  Initial Study Treatment
DCDT2980S and DCDS4501A—Genentech, Inc.
148/Protocol GO27834, Version A4
Obinutuzumab infusion
x
x
x
x
x
DCDS4501A infusion l
x
x
(x)
x
(x)
Local Laboratory Assessments
HBV and HCV 
screening m
x
Hematology n
x
x
x
x
x
x
x
Serum chemistry p
x
x
x
x
x
x
x
Hemoglobin A1c
x
Cycle 5 
Day 1
Total IgA, IgG, IgM
x
Cycle 8 
Day 1
x
Coagulation (aPTT, PT, 
and INR)
x
Pregnancy test p
x
Within 10 days of Day 1 of Cycles 3, 6
x
Bone marrow biopsy q
xq
Perform to confirm CR if positive for disease at screening or 
if clinically indicated
Central Laboratory Assessments
Leukocyte 
immunophenotyping 
(FACS) t
Day 1 of Cycle1, Cycle 4, and Cycle 8 
x
Tumor tissue sample u
x
x
Exploratory plasma 
sample v
x
DCDS4501A and 
obinutuzumab 
pharmacokinetic
samplingw
Refer to Appendix B-3
Serum sample for 
anti-DCDS4501A 
antibodyx
Refer to Appendix B-3


Appendix A-3 (cont.)
Study Flowchart for Obinutuzumab-Containing Cohorts (E, GH):  Initial Study Treatment
DCDT2980S and DCDS4501A—Genentech, Inc.
149/Protocol GO27834, Version A4
AEadverse event; ALPalanine aminotransferase; aPTT activated partial thromboplastin time; AST aspartate aminotransferase; CRcompleted response; 
CTcomputed tomography; DLBCLdiffuse large B-cell lymphoma; ECGelectrocardiogram; ECOG Eastern Cooperative Oncology Group; EOT end of treatment; 
FACSfluorescent-activated cell sorting; FLLfollicular lymphoma; GGT -glutamyl transpeptidase; HBVhepatitis B virus; HCVhepatitis C virus; Igimmunoglobulin; 
INRinternational normalized ratio; LDHlactase dehydrogenase; MRImagnetic resonance imaging; NALTnew anti-lymphoma treatment; NHLnon-Hodgkin’s 
lymphoma; PET positron emission tomography; PT prothrombin time; SAEserious adverse event; (x) Assessment or action to be performed only if study treatment is 
administered on Day 2 of the Cycle—refer to footnote ‘n’ for details. 
a Study drug infusions should occur on the scheduled 21-day cycle up to a maximum of 6 months (8 cycles on an every-21-day schedule) and may be given up to 
2 days from the date scheduled (i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  All other study visits during Cycle 1 
must occur within 1 day from the scheduled date unless otherwise noted.  Study visits starting in Cycle 2 should occur within 2 days from the scheduled date unless 
otherwise noted.  Treatment cycles may be extended to 28 days if needed to provide sufficient time for recovery from a transient and reversible toxicity (e.g., cytopenia) 
without reducing the dose of DCDA4501A.  Patients receiving study treatment on 28-day cycles should also follow the assessment schedule above up to a maximum of 
6 months of total study treatment (6 cycles on an every-28-day schedule).
b Local laboratory assessments and targeted physical examination may be performed within 72 hours preceding obinutuzumab administration unless otherwise specified; 
pre-infusion laboratory samples should be drawn 04 hours prior to infusion.
c Cycle 4 Day 15 assessment should be performed between Cycle 4 Day 15 and Cycle 5 Day 1.  The Treatment Completion/Early Termination Visit should be performed 
within 30 days after the last infusion of DCDS4501A or obinutuzumab.  The visit at which response assessment shows progressive disease may be used as the early 
termination visit.
d Patients will be followed for safety for 30 days after the last infusions of DCDS4501A or obinutuzumab.  Such follow-up will require an assessment (per verbal report 
from the patient, at minimum) of any AEs and/or SAEs through 30 days after the last dose of study drug or until the patient receives another anti-cancer therapy 
including crossover treatment, whichever occurs first.  Patients who discontinue study treatment for reasons other than progressive disease will continue to be followed 
for response for up to 2 years after the last infusions of DCDS4501A or obinutuzumab, or until disease progression or initiation of another anti-lymphoma/leukemia 
therapy, whichever occurs first.  Refer to Appendix A-5 for schedule of assessments during the post-treatment period.  Patients will also be followed for survival 
following study treatment discontinuation approximately every three months until death, loss to follow-up, withdrawal of consent, or study termination.
e Informed consent form(s) must be signed by the patient before any study-specific procedures are performed.
f
Vital signs on days of study treatment administration should be recorded according to Section 4.5.1.2of the protocol.
g Complete physical examination includes all systems described in Section 4.5.1.3.  
h Targeted physical examinations should be limited to systems of clinical relevance (see Section 4.5.1.3) and those systems associated with clinical signs/symptoms.  A 
targeted symptom directed examination is required prior to DCDS4501A dosing on Day 2 of each cycle if given on separate days from obinutuzumab only if clinically 
indicated (e.g., to follow up on signs or symptoms observed from the examinations performed on Day 1).
i
After informed consent is obtained but prior to initiation of study treatment, only SAEs caused by a protocol-mandated intervention should be reported.  After initiation of 
study drug, all AEs and SAEs, regardless of attribution, must be reported until 30 days following the last administration of study drug or until the patient receives another 
anti-cancer therapy, whichever occurs first.  After this period, investigators should report only SAEs considered related to prior study treatment with the exception of 
second malignancies.  Second malignancies will be recorded indefinitely (even if the study has ended) and irrespective of NALT.
j
Twelve-lead digital electrocardiogram (ECG) measurements must be obtained in triplicate (with immediately consecutive ECGs obtained until three evaluable ECGs are 
recorded) at the timepoints specified in Section 4.5.1.5.  Non-triplicate ECGs should also be performed when clinically indicated in any patient with evidence of, or 
suspicion for, clinically significant signs or symptoms of cardiac dysfunction.  The evaluating physician should determine the clinical significance of any abnormal ECGs.


Appendix A-3 (cont.)
Study Flowchart for Obinutuzumab-Containing Cohorts (E, GH):  Initial Study Treatment
DCDT2980S and DCDS4501A—Genentech, Inc.
150/Protocol GO27834, Version A4
k Response assessment should be performed using Lugano Response Criteria (Appendix C-2).  For patients with DLBCL or FL, a combined PET/CT scan is required 
during screening, between Cycle 4 Day 15 and Cycle 5 Day 1, EOT assessment, and as clinically indicated.   The EOT assessment should be performed 68 weeks 
after Cycle 8 Day 1 or last study treatment. During the follow-up period, scans (CT or PET/CT) should be performed every 6 months for 2 years or until study end or at 
any time that progression is suspected. Refer to Appendix A-5 for imaging assessment during post-treatment follow-up.  Refer to Section 4.5.1.8 for complete details 
for radiographic assessments.  
l
Administer DCDS4501A over 90 minutes for Cycle 1 and over 30 minutes in subsequent cycles if there are no infusion-related adverse events.  For Cycle 1, 
DCDS4501A should be administered on the day after obinutuzumab is administered (e.g., Day 2 if obinutuzumab is given on Day 1, or Day 3 if obinutuzumab is given 
as a split dose on Days 1 and 2).  In the absence of any infusion-related adverse events, obinutuzumab followed by DCDS4501A may be administered on the same day 
in each cycle starting with Cycle 2.  Study drug infusions should occur on the scheduled 21-day (or 28-day) cycle but may be given up to 2 days from the date 
scheduled (i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  Doses may also be delayed up to 2 weeks for recovery from 
reversible toxicity.
m HBsAg, HBcAb, and Hep C Ab serology required.  If HBcAb or HCV antibody is positive, HBV/HCV DNA by PCR is required.
n Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, absolute neutrophil count, and percent or absolute 
differential counts [e.g., segmented neutrophils, bands, lymphocytes, eosinophils, monocytes, basophils, and other cells]).
o Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), creatinine, calcium, magnesium, phosphorus, total and direct 
bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, LDH, and uric acid., amylase, and lipase  Serum GGT levels will be required at screening only.
p A serum pregnancy test should be performed for women of childbearing potential within 14 days prior to receiving first study treatment.  In addition, a urine pregnancy 
test must also be performed within 10 days prior to Day 1 of Cycles 3, and 6 and at the treatment completion/early termination visit.  If any urine test result is positive, 
patient dosing will be postponed until the patient’s status is confirmed by a serum pregnancy test.
q Bone marrow biopsy for morphology (aspirates for morphology and/or flow studies are optional) is required at screening for follicular NHL patients only and should 
reflect disease status in the bone marrow following documented relapse on the last prior therapy or within 3 months of Day 1, whichever occurs later.  If the bone 
marrow biopsy at screening demonstrates presence of tumor cells, a subsequent bone marrow examination is required only to confirm a CR or if clinically indicated.  If 
the bone marrow biopsy at screening does not demonstrate presence of tumor cells, then subsequent bone marrow examination is required only if clinically indicated.  
Unsuccessful attempts at marrow aspiration will not be considered a protocol violation.
r
A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.  
s Availability of archival or freshly biopsied tumor tissue samples should be confirmed at screening.  Tumor tissue samples should consist of representative tumor 
specimens in paraffin blocks (preferred) or at least 15 unstained slides, with an associated pathology report, obtained at any time prior to entry to study.  
t
All patients who have successfully passed screening and are fully eligible for the study will have a 10-mL plasma sample taken for exploratory research prior to 
receiving study treatment.  
u Pharmacokinetic serum and plasma samples and pharmacodynamics blood samples should be drawn according to the schedule provided in Appendix B-3.
v Whole blood samples for assessment of anti-DCDS4501A or anti-obinutuzumab antibodies in serum will be drawn according to the schedule provided in Appendix B-3.


 
DCDT2980S and DCDS4501A—Genentech, Inc. 
151/Protocol GO27834, Version A4 
Appendix A-4 
 
Study Flowchart: Post-Treatment Follow-Up for Rituximab-Containing Regimens 
(Arms A-B, Cohorts C−D) 
Assessments/Procedures 
Post-treatment Follow-up 
Months after treatment completion visit 
2 Months 
4 Months 
6 Months 
9 Months 
12 Months 
Targeted physical examination a 
x 
x 
x 
x 
x 
Vital signs (blood pressure, pulse rate, and 
body temperature) 
x 
x 
x 
x 
x 
ECOG Performance Status 
x 
x 
x 
x 
x 
B symptoms b 
x 
x 
x 
x 
x 
Tumor assessments c 
x 
x 
x 
x 
x 
Total IgA, IgG, IgM 
x 
x 
x 
x 
x 
Hematology d 
x 
x 
x 
x 
x 
Serum chemistry e 
x 
x 
x 
x 
x 
Bone marrow f 
Perform to confirm CR if positive for disease at screening or if 
clinically indicated 
Central Lab Assessments 
 
 
 
 
 
Leukocyte immunophenotyping (FACS) g 
x 
x 
x 
x 
x 
Pharmacokinetic sampling h 
x 
x 
x 
 
 
Serum sample for anti-DCDT2980S / 
anti-DCDS4501A ATA assay h 
x 
x 
x 
 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ATA = anti-therapeutic antibody; 
CR = completed response; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; 
FACS = fluorescent-activated cell sorting; Ig = immunoglobulin; MRI = magnetic resonance imaging; 
NHL = non-Hodgkin’s lymphoma; PET = positron emission tomography. 
 


 
Appendix A-4 (cont.) 
Study Flowchart: Post-Treatment Follow-Up for Rituximab-Containing Regimens 
(Arms A-B, Cohorts C−D) 
DCDT2980S and DCDS4501A—Genentech, Inc. 
152/Protocol GO27834, Version A4 
NOTE: Post-treatment assessments apply to patients who discontinue from study treatment (initial or crossover 
treatment) for reasons other than disease progression.  The schedule corresponds to visits timed from 
treatment completion/early termination visit or crossover treatment completion/early termination visit until the 
time of disease progression, start of new anti-cancer therapy, or withdrawal from study participation.  
Two-month and 4-month follow-up visits should occur within ± 7 days from the scheduled date, while 
subsequent visits should occur within ± 14 days from the scheduled date. 
a Targeted physical examinations should be limited to systems of clinical relevance (see Section 4.5.1.3) and 
those systems associated with clinical signs/symptoms. 
b Defined as unexplained weight loss > 10% over previous 6 months, fever (> 38°C/100.4°F), and/or drenching 
night sweats. 
c Response should be assessed based on physical examination and imaged-based evaluation, using standard 
NHL criteria (Appendix C).   
d Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, 
platelet count, absolute neutrophil count, and percent or absolute differential counts [e.g., segmented 
neutrophils bands, lymphocytes, eosinophils, monocytes, basophils, and other cells]). 
e Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), 
creatinine, calcium, magnesium, phosphorus, total and direct bilirubin, total protein, albumin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase 
(LDH), and uric acid.  
f Bone marrow biopsy for morphology (aspirate for morphology and/or flow studies are optional) should be 
repeated only to confirm a CR where presence of tumor was documented at the screening bone marrow 
examination. 
g A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.   
h Refer to Appendix B1 or B-2. 
 


 
DCDT2980S and DCDS4501A—Genentech, Inc. 
153/Protocol GO27834, Version A4 
Appendix A-5 
 
Study Flowchart:  Post-Treatment Follow-Up for Obinutuzumab-Containing Regimens 
(Cohorts E, G-H) 
Assessments/Procedures 
Post-Treatment Follow-Up 
Months after treatment completion visit 
3 Months 
6 Months 
9 Months 12 Months 18 Months 
24 Months 
Targeted physical examination a 
x 
x 
x 
x 
x 
x 
Vital signs (blood pressure, pulse rate, and 
body temperature) 
x 
x 
x 
x 
x 
x 
ECOG Performance Status 
x 
x 
x 
x 
x 
x 
Tumor Assessment (Imaging [PET/CT or C]) 
b 
 
x 
 
x 
x 
x 
Total IgA, IgG, IgM 
x 
x 
x 
x 
x 
x 
Hematology c 
x 
x 
x 
x 
x 
x 
Serum chemistry d 
x 
x 
x 
x 
x 
x 
Bone marrow e 
Perform to confirm CR if positive for disease at screening or if clinically 
indicated 
Central Lab Assessments 
 
 
 
 
 
Leukocyte immunophenotyping (FACS) f 
x 
x 
x 
x 
x 
x 
Pharmacokinetic sampling g 
x 
x 
 
x 
x 
x 
Serum sample for 
anti-DCDT2980S/anti-DCDS4501A, 
anti-obinutuzumab ATA assay g 
x 
x 
 
x g 
x g 
x g 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ATA = anti-therapeutic antibody; CR = completed 
response; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; FACS = fluorescent-activated cell 
sorting; Ig = immunoglobulin; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; NHL = non-Hodgkin’s 
lymphoma; PET = positron emission tomography. 
 


 
Appendix A-5 (cont.) 
Study Flowchart: Post-Treatment Follow-Up for Obinutuzumab-Containing Regimens 
(Cohorts E, G-H) 
DCDT2980S and DCDS4501A—Genentech, Inc. 
154/Protocol GO27834, Version A4 
NOTE: Post-treatment assessments apply to patients who discontinue from study treatment (initial or crossover treatment) 
for reasons other than disease progression.  The schedule corresponds to visits timed from treatment completion/early 
termination visit or crossover treatment completion/early termination visit until the time of disease progression, start of new 
anti-cancer therapy, or withdrawal from study participation.  Three-month and 6-month follow-up visits should occur within 
± 7 days from the scheduled date, while subsequent visits should occur within ± 14 days from the scheduled date. 
a Targeted physical examinations should be limited to systems of clinical relevance (see Section 4.5.1.3 ) and those 
systems associated with clinical signs/symptoms. 
b Response should be assessed using Lugano Response Criteria (Appendix C-2).  CT or combined PET/CT scan should be 
obtained during the post-treatment follow-up up every 6 months for 2 years or until study end or at any time that 
progression is suspected.  
c Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, 
absolute neutrophil count, and percent or absolute differential counts [e.g., segmented neutrophils bands, lymphocytes, 
eosinophils, monocytes, basophils, and other cells]). 
d Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), creatinine, calcium, 
magnesium, phosphorus, total and direct bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, LDH, and uric 
acid. 
e Bone marrow biopsy for morphology (aspirate for morphology and/or flow studies are optional) should be repeated only to 
confirm a CR where presence of tumor was documented at the screening bone marrow examination. 
f A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.   
g Refer to Appendix B-3. 
 


 
DCDT2980S and DCDS4501A—Genentech, Inc. 
155/Protocol GO27834, Version A4 
Appendix B-1 
 
Serum and Plasma Pharmacokinetic Schedule for 
DCDT2980S/DCDS4501A and Rituximab, and ATA Schedule for 
DCDT2980S/DCDS4501A (For Patients Receiving Rituximab on 
Day 1 and DCDT2980S/DCDS4501A on Day 2 of Every Cycle) 
(Arms A-B, Cohorts C-D) 
Study Visit 
Sample Timepoint(s) a 
Samples b 
Cycle 1, Day 1 
Pre-rituximab infusion 
• 
Rituximab PK 
 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Cycle 1, Day 2 
Pre-DCDT2980S/DCDS4501A 
infusion 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
DCDT2980S/DCDS4501A PK b 
30 minutes (± 15 minutes)  
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK 
Cycle 1, Day 8 (± 1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
Cycle 1, Day 15 (± 1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK  
Cycles 2−3, Day 1 
Pre-rituximab dose 
• 
Rituximab PK 
 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Cycles 2−3, Day 2 
Pre-DCDT2980S/DCDS4501A 
infusion 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody c 
• 
DCDT2980S/DCDS4501A PK 
30 minutes (± 15 minutes) 
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK 
Cycle 3, Day 8 (± 1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK  
Cycle 3, Day 15 (±1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
Cycles 4, and 
every 4th cycle 
thereafter), Day 1 
Pre-rituximab infusion 
• 
Rituximab PK 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Cycles 4, and 
every 4th cycle 
thereafter), Day 2 
Pre-DCDT2980S/DCDS4501A 
infusion 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody c 
• 
DCDT2980S/DCDS4501A PK 
30 minutes (± 15 minutes) 
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK 


 
Appendix B-1 (cont.) 
Serum and Plasma Pharmacokinetic Schedule for 
DCDT2980S/DCDS4501A and Rituximab, and ATA Schedule for 
DCDT2980S/DCDS4501A (For Patients Receiving Rituximab on 
Day 1 and DCDT2980S/DCDS4501A on Day 2 of Every Cycle) 
(Arms A-B, Cohorts C-D) 
DCDT2980S and DCDS4501A—Genentech, Inc. 
156/Protocol GO27834, Version A4 
Study Visit 
Sample Timepoint(s) a 
Samples b 
Treatment 
Completion/ 
Early Termination 
Visit 
Approximately 15−30 days 
after last infusion  
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK e 
Post-treatment 
Follow-Up Visits d 
2, 4, and 6 months after 
treatment completion visit 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
ATA = Anti-therapeutic antibody; MMAE = monomethyl auristatin E; PK = pharmacokinetic. 
Note:  “Pre-infusion” means prior to the start of infusion; “Post-infusion” means after the infusion is 
completed. 
a A 3-mL whole-blood sample will be taken for each of the following at each specified timepoint: 
anti-DCDT2980S or anti-DCDS4501A antibody; rituximab PK; and/or DCDT2980S/DCDS4501A 
PK.  If rituximab dosing is split over two days, then PK will be obtained prior to the rituximab 
dose on the first day and 30 minutes (± 15 minutes) post-rituximab infusion on the second day. 
b PK sampling will not be obtained from patients who cross-over to another treatment arm. 
c Cycles 2 and 4 only for anti-DCDT2980S or anti-DCDS4501A antibody.  
d Post-treatment follow-up PK and ATA assessments only apply to patients who did not receive 
crossover treatment. 
e DCDT2980S/DCDS4501A PK including serum PK samples for total DCDT2980S and 
DCDS4501A antibody and plasma PK samples for antibody-conjugated MMAE and free MMAE. 


 
DCDT2980S and DCDS4501A—Genentech, Inc. 
157/Protocol GO27834, Version A4 
Appendix B-2 
 
Serum and Plasma Pharmacokinetic Schedule for Rituximab and 
DCDT2980S/DCDS4501A, and ATA Schedule for 
DCDT2980S/DCDS4501A for Patients Receiving Rituximab and 
DCDT29808S/DCDS4501A on Day 1 of Every Cycle Beginning 
Cycle 3 (Arms A-B, Cohorts C-D) 
Study Visit 
Sample Timepoint(s) a 
Samples b 
For Cycle 1 and Cycle 2 PK assessments, refer to Appendix B-1 
Cycle 3, Day 1 
 
Pre-rituximab infusion 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK e 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
30 minutes (± 15 minutes) 
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK  
Cycle 3, Day 8 (± 1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK  
Cycle 3, Day 15 (±1 day) 
• 
Rituximab  
• 
DCDT2980S/DCDS4501A PK 
Cycles 4, and 
every 4th cycle 
thereafter), Day 1 
Pre-rituximab infusion 
• 
Rituximab PK 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody c 
• 
DCDT2980S/DCDS4501A PK 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
30 minutes (± 15 minutes) 
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK 
Treatment 
Completion/ 
Early Termination 
Visit 
Approximately 15−30 days 
after last infusion  
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
Post-treatment 
Follow-Up Visits d 
2, 4, and 6 months after 
treatment completion visit 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 


 
Appendix B−2 (cont.) 
Serum and Plasma Pharmacokinetic Schedule for Rituximab and 
DCDT2980S/DCDS4501A, and ATA Schedule for 
DCDT2980S/DCDS4501A for Patients Receiving Rituximab and 
DCDT29808S/DCDS4501A on Day 1 of Every Cycle Beginning 
Cycle 3 (Arms A-B, Cohorts C-D) 
DCDT2980S and DCDS4501A—Genentech, Inc. 
158/Protocol GO27834, Version A4 
ATA = Anti-therapeutic antibody; MMAE = monomethyl auristatin E; PK = pharmacokinetic. 
Note:  “Pre-infusion” means prior to the start of infusion; “Post-infusion” means after the infusion is 
completed. 
a A 3-mL whole-blood sample will be taken for each of the following at each specified timepoint: 
anti-DCDT2980S or anti-DCDS4501A antibody, rituximab PK, and/or DCDT2980S/DCDS4501A 
PK.  If rituximab dosing is split over two days, then PK will be obtained prior to the rituximab 
dose on the first day and 30 minutes (± 15 minutes) post-rituximab infusion on the second day. 
b PK sampling will not be obtained from patients who cross-over to another treatment arm. 
c Cycles 4 only for anti-DCDT2980S or anti-DCDS4501A antibody.  
d Post-treatment follow-up PK and ATA assessments only apply to patients who did not receive 
crossover treatment. 
e DCDT2980S/DCDS4501A PK including serum PK samples for total DCDT2980S and 
DCDS4501A antibody and plasma PK samples for antibody-conjugated MMAE and free MMAE. 
 


 
DCDT2980S and DCDS4501A—Genentech, Inc. 
159/Protocol GO27834, Version A4 
Appendix B−3  
Serum and Plasma Pharmacokinetic, Blood Pharmacodynamic, 
and ATA Schedule for Obinutuzumab and DCDS4501A 
(Cohorts E, G−H) 
Study Visit 
Sample Timepoint(s) a 
Samples a 
Cycle 1, Day 1 
Pre-obinutuzumab infusion 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
PD Blood c 
 
End of obinutuzumab infusion 
• 
Obinutuzumab PK (serum) 
• 
PD Blood c 
Cycle 1, Day 2 
Pre-DCDS4501A infusion 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
End of DCDS4501A infusion 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
Cycle 1, Day 8 
6 days (± 1 day) after Day 2 
infusion 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
Cycle 1, Day 15 
13 days (± 1 day) after Day 2 
infusion 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
Cycle 2, Day 1 
Pre-obinutuzumab infusion 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
PD Blood c 
 
End of obinutuzumab infusion 
• 
PD Bloodc 
 
Pre-DCDS4501A infusion 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
 
End of DCDS4501A infusion 
• 
PD Blood 
Cycle 4, Day 1 
Pre-obinutuzumab infusion 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
End of obinutuzumab infusion 
• 
Obinutuzumab PK (serum) 
 
Pre-DCDS4501A infusion 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 
 
End of DCDS4501A infusion 
• 
DCDS4501A PK (serum and plasma)b 
Cycle 4  Day 15 
Aligned with PET imaging 
• 
PD Blood c 
Treatment Completion/ 
Early Termination Visit 
Approximately 15−30 days 
after last infusion  
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 
End of Treatment 
Assessment Visit 
6−8 weeks after last study 
dose 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 


 
Appendix B−3 (cont.) 
Serum and Plasma Pharmacokinetic and ATA Schedule for 
Obinutuzumab and DCDS4501A (Cohorts E, G-H) 
DCDT2980S and DCDS4501A—Genentech, Inc. 
160/Protocol GO27834, Version A4 
Study Visit 
Sample Timepoint(s) a 
Samples a 
• 
PD Blood c 
Post-treatment 
Follow-Up Visits  
3 and 6 months after treatment 
completion visit 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
 
9 months after treatment 
completion visit 
• 
PD Blood c 
 
12 and 18 months after 
treatment completion visit 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
PD Blood c 
 
24 months after treatment 
completion visit 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
PD Blood c 
ATA = Anti-therapeutic antibody; MMAE = monomethyl auristatin E; PK = pharmacokinetic. 
Note:  “Pre-infusion” means prior to the start of infusion; “End-of-infusion” samples should be drawn 30 
minutes (± 15 minutes) unless otherwise specified. 
a Up to 10-mL whole-blood samples will be taken for obinutuzumab PK, obinutuzumab ATA, obinutuzumab 
concentration, DCDS4501A PK (DCDS4501A total antibody, unconjugated MMAE and conjugate 
[evaluated as antibody-conjugated MMAE]), DCDS4501A ATA, DCDS4501A concentration, and for 
exploratory studies at each specified point with separate tubes for plasma or serum samples.  If 
obinutuzumab dosing is split over two days, then PK will be obtained prior to the obinutuzumab dose on 
the first day and 30 minutes (± 15 minutes) post-obinutuzumab infusion on the second day. 
b DCDS4501A PK including serum PK samples for total DCDS4501A antibody and plasma PK samples for 
antibody-conjugated MMAE and free MMAE. 
c Up to 10-mL whole-blood samples will be taken for exploratory studies at each specified timepoint with 
separate tubes. 
 


 
DCDT2980S and DCDS4501A—Genentech, Inc. 
161/Protocol GO27834, Version A4 
Appendix C-1 
 
Modified Response and Progression Criteria for NHL 
Adapted from:  Cheson BD, Pfistner B, Juweid ME, et al. Revised Response Criteria for 
Malignant Lymphoma. J Clin Oncol 2007;25:579–86. 
Selection of Indicator (Target) Lesions 
Up to six of the largest dominant nodes or tumor masses selected according to all of the 
following: 
• 
Clearly measurable in at least two perpendicular dimensions 
Abnormal lymph nodes are those that are either 
> 15 mm in the greatest transverse diameter (GTD) regardless of the short axis 
diameter, or 
> 10 mm in short axis diameter regardless of long axis 
• 
If possible, they should be from disparate regions of the body. 
• 
Should include mediastinal and retroperitoneal areas of disease whenever these 
sites are involved 
• 
Extranodal lesions within the liver or spleen must be at least 1.0 cm in 
two perpendicular dimensions. 
 
PET Scans--Definition of a Positive PET scan 
Visual assessment currently is considered adequate for determining whether a PET 
scan is positive, and use of the standardized uptake value is not necessary.  In brief, a 
positive scan is defined as focal or diffuse FDG uptake above background in a location 
incompatible with normal anatomy or physiology, without a specific standardized uptake 
value cutoff.  Other causes of false-positive scans should be ruled out.  Exceptions 
include mild and diffusely increased FDG uptake at the site of moderate or large-sized 
masses with an intensity that is lower than or equal to the mediastinal blood pool, 
hepatic or splenic nodules 1.5 cm with FDG uptake lower than the surrounding 
liver/spleen uptake, and diffusely increased bone marrow uptake within weeks after 
treatment. 
Complete Remission (CR) 
1. Complete disappearance of all detectable clinical evidence of disease 
and disease-related symptoms if present prior to therapy.  
Typically FDG-avid lymphoma: in patients with no pre-treatment PET scan or 
when the PET scan was positive before therapy, a post-treatment residual mass 
of any size is permitted as long as it is PET negative. 


 
Appendix C−1 (cont.) 
Modified Response and Progression Criteria for NHL 
DCDT2980S and DCDS4501A—Genentech, Inc. 
162/Protocol GO27834, Version A4 
Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, the 
designation of CR requires all nodal indicator lesions to regress to the size of 
normal lymph nodes.  Lymph nodes that were > 15 mm in GTD regardless of the 
short axis diameter at the screening tumor assessment must regress to ≤ 15 mm 
in GTD regardless of the short axis diameter.  Lymph nodes that were 11 to 
15 mm in GTD and > 10 mm in the short axis diameter at the screening tumor 
assessment must regress to ≤ 10 mm in the short axis diameter. 
2. The spleen and/or liver, if considered enlarged prior to therapy on the basis of 
a physical examination or CT scan, should not be palpable on physical examination 
and should be considered normal size by imaging studies, and nodules related to 
lymphoma should disappear.  However, determination of splenic involvement is not 
always reliable because a spleen considered normal in size may still contain 
lymphoma, whereas an enlarged spleen may reflect variations in anatomy, blood 
volume, the use of hematopoietic growth factors, or causes other than lymphoma. 
3. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must 
have cleared on repeat bone marrow biopsy.  The biopsy sample on which this 
determination is made must be adequate (> 20 mm unilateral core).  If the sample is 
indeterminate by morphology, it should be negative by immunohistochemistry.  A 
sample that is negative by immunohistochemistry but demonstrating a small 
population of clonal lymphocytes by flow cytometry will be considered a CR until data 
become available demonstrating a clear difference in patient outcome.  
Partial Remission (PR) 
1. ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of 
the largest dominant nodes or nodal masses.  These nodes or masses should 
be selected according to the following: (a) they should be clearly measurable in 
at least 2 perpendicular dimensions; (b) if possible they should be from disparate 
regions of the body; (c) they should include mediastinal and retroperitoneal areas of 
disease whenever these sites are involved. 
2. No increase in the size of the other nodes, liver, or spleen. 
3. Splenic and hepatic nodules must regress by ≥ 50% in their SPD or, 
for single nodules, in the greatest transverse diameter. 
4. With the exception of splenic and hepatic nodules, involvement of other organs 
is usually assessable and no measurable disease should be present. 


 
Appendix C−1 (cont.) 
Modified Response and Progression Criteria for NHL 
DCDT2980S and DCDS4501A—Genentech, Inc. 
163/Protocol GO27834, Version A4 
5. Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive prior to treatment.  However, if positive, the cell type should be specified 
(e.g., large-cell lymphoma or small neoplastic B cells).  Patients who achieve a 
complete remission by the above criteria, but who have persistent morphologic bone 
marrow involvement will be considered partial responders. 
6. No new sites of disease should be observed (e.g., nodes > 1.5 cm in any axis). 
7. Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the 
PET scan was positive before therapy, the post-treatment PET should be positive in 
at least one previously involved site. 
8. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET/CT scan, or if a pretreatment PET/CT scan was negative, CT 
criteria should be used. 
9. 
In patients with follicular lymphoma, a PET scan is only indicated with one or at 
most two residual masses that have regressed by more than 50% on CT; those with 
more than two residual lesions are unlikely to be PET negative and should be 
considered partial responders. 
Stable Disease (SD) 
1. Failing to attain the criteria needed for a CR or PR, but not fulfilling those 
for progressive disease (see below). 
2. Typically FDG-avid lymphomas: the PET should be positive at prior sites of disease 
with no new areas of involvement on the post- treatment CT or PET. 
3. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan or if the pretreatment PET was negative, there must be no 
change in the size of the previous lesions on the post-treatment CT scan. 
Relapsed Disease (RD; after CR) or Progressive Disease (PD; for Patients 
with PR or SD) 
1. Lymph nodes should be considered abnormal if the long axis is > 1.5 cm, regardless 
of the short axis.  If a lymph node has a long axis of 1.1−1.5 cm, it should only be 
considered abnormal if its short axis is > 1.0.  Lymph nodes ≤ 1.0 cm by ≤ 1.0 cm will 
not be considered as abnormal for relapse or progressive disease. 
2. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size.  Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive disease 
after confirmation with other modalities. 


 
Appendix C−1 (cont.) 
Modified Response and Progression Criteria for NHL 
DCDT2980S and DCDS4501A—Genentech, Inc. 
164/Protocol GO27834, Version A4 
3. At least a 50% increase from nadir in the SPD of any previously involved nodes, or in 
a single involved node, or the size of other lesions (e.g., splenic or hepatic nodules).  
To be considered progressive disease, a lymph node with a diameter of the short 
axis of less than 1.0 cm must increase by ≥ 50% and to a size of 1.5 × 1.5 cm or 
more than 1.5 cm in the long axis. 
4. At least a 50% increase in the longest diameter of any single previously identified 
node more than 1 cm in its short axis. 
5. Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected 
with current PET systems (< 15 mm in its long axis by CT). 
6. Measurable extranodal disease should be assessed in a manner similar to that 
for nodal disease.  For these recommendations, the spleen is considered nodal 
disease. 
 


 
DCDT2980S and DCDS4501A—Genentech, Inc. 
165/Protocol GO27834, Version A4 
Appendix C−2  
Revised Criteria for Response Assessment: The Lugano Classification (Cohorts E, G−H) 
Response should be determined on the basis of radiographic and clinical evidence of disease.  For the end-of-treatment response 
assessment, an 18F-fluorodeoxyglucose−positron emission tomography (FDG-PET)/computed tomography (CT) scan will be 
performed 6−8 weeks after Cycle 8 Day 1 or last study treatment as assessed by the Independent Review Committee and by the 
investigator.  Assessment of PET/CT scan should follow the criteria described by Cheson (2014) presented below.  
Selection of measured dominant (indicator) lesions: 
• 
Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected should be clearly measurable in two 
diameters: 
A measurable node must have a longest transverse diameter of a lesion (LDi)  > 1.5 cm. 
A measurable extranodal lesion should have an LDi  > 1.0 cm. 
• 
Nodes should preferably be from disparate regions of the body and should include, where applicable, mediastinal and 
retroperitoneal areas.  
• 
Non-nodal lesions should include those in solid organs (e.g., liver, spleen, kidneys, and lungs), gastrointestinal involvement, 
cutaneous lesions, or those noted on palpation.  
• 
If possible, they should be from disparate regions of the body. 
• 
They should include mediastinal and retroperitoneal areas of disease whenever these sites are involved. 
 
Selection of non-measured (non-indicator) lesions: 
• 
Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured.   
These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not 
meet the requirements for measurability but are still considered abnormal, as well as truly assessable disease, which is any 
site of suspected disease that would be difficult to follow quantitatively with measurement, including pleural effusions, 
ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed 
by imaging.  


 
Appendix C−2 (cont.) 
Revised Criteria for Response Assessment: The Lugano Classification (Cohorts E, G-H) 
DCDT2980S and DCDS4501A—Genentech, Inc. 
166/Protocol GO27834, Version A4 
In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, and bone marrow), FDG uptake may be greater than in the 
mediastinum with complete metabolic response, but it should be no higher than surrounding normal physiologic uptake (e.g., 
with marrow activation as a result of chemotherapy or myeloid growth factors). 
 
Response 
Site 
PET/CT−Based Response 
CT-Based Response 
Complete 
 
Complete metabolic response 
Complete radiologic response (all of the following) 
Lymph nodes and 
extralymphatic sites 
• Score 1, 2, or 3 a with or without a residual mass on 5-PS b 
• It is recognized that in Waldeyer’s ring or extranodal sites 
with high physiologic uptake or with activation within spleen 
or marrow (e.g., with chemotherapy or myeloid colony-
stimulating factors), uptake may be greater than normal 
mediastinum and/or liver.  In this circumstance, complete 
metabolic response may be inferred if uptake at sites of 
initial involvement is no greater than surrounding normal 
tissue even if the tissue has high physiologic uptake. 
• Target nodes/nodal masses must regress to ≤ 1.5 cm 
in LDi 
• No extralymphatic sites of disease 
Nonmeasured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
• No evidence of FDG-avid disease in marrow 
• Normal by morphology, if indeterminate, IHC negative 
Normal by morphology; if indeterminate, IHC negative 
 
 


 
Appendix C−2 (cont.) 
Revised Criteria for Response Assessment: The Lugano Classification (Cohorts E, G-H) 
DCDT2980S and DCDS4501A—Genentech, Inc. 
167/Protocol GO27834, Version A4 
Response 
Site 
PET/CT−Based Response 
CT-Based Response 
Partial 
 
Partial metabolic response 
Partial remission (all of the following) 
Lymph nodes and 
extralymphatic sites 
• Score of 4 or 5 b with reduced uptake compared with 
baseline and residual mass(es) of any size 
At interim, these findings suggest responding disease. 
• At end of treatment, these findings indicate residual disease. 
• ≥ 50% decrease in SPD of up to 6 target 
measureable nodes and extranodal sites 
• When a lesion is too small to measure on CT, assign 
5 mm × 5 mm as the default value 
• When no longer visible, 0 × 0 mm 
• For a node > 5 mm × 5 mm, but smaller than normal, 
use actual measurement for calculation 
Nonmeasured 
lesions 
Not applicable 
Absent/normal, regressed, but no increase 
Organ enlargement 
Not applicable 
Spleen must have regressed by > 50% in length beyond 
normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake compatible 
with reactive changes from chemotherapy allowed).  If there 
are persistent focal changes in the marrow in the context of a 
nodal response, consideration should be given to further 
evaluation with MRI or biopsy or an interval scan. 
Not applicable 
No response or 
stable disease 
 
No metabolic response 
Stable disease 
Target nodes/nodal 
masses, extranodal 
lesions 
Score 4 or 5 b with no significant change in FDG uptake from 
baseline at interim or end of treatment 
< 50% decrease from baseline in SPD for up to 6 
dominant, measurable nodes and extranodal sites; 
no criteria for progressive disease are met 
Nonmeasured 
lesions 
Not applicable 
No increase consistent with progression 
Organ enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 


 
Appendix C−2 (cont.) 
Revised Criteria for Response Assessment: The Lugano Classification (Cohorts E, G-H) 
DCDT2980S and DCDS4501A—Genentech, Inc. 
168/Protocol GO27834, Version A4 
Response 
Site 
PET/CT−Based Response 
CT-Based Response 
Progressive 
disease  
 
Progressive metabolic disease 
Progressive disease  
(requires at least one of the following) 
Individual target 
nodes/nodal lesions 
and extranodal 
lesions 
• Score 4 or 5 b with an increase in intensity of uptake from 
baseline and/or 
• New FDG-avid foci consistent with lymphoma at interim or 
end-of-treatment assessment 
PPD progression: 
An individual node/lesion must be abnormal with:  
• 
LDi > 1.5 cm AND  
• 
Increase by ≥ 50% from PPD nadir AND  
An increase in LDi or SDi from nadir 
• 
0.5 cm for lesions ≤ 2 cm 
• 
1.0 cm for lesions > 2 cm 
Nonmeasured 
lesions 
None 
New or clear progression of preexisting nonmeasured 
lesions 
Organ enlargement 
 
• In the setting of splenomegaly, the splenic length 
must increase by > 50% of the extent of its prior 
increase beyond baseline (e.g., 15-cm spleen must 
increase to > 16 cm).  If no prior splenomegaly, must 
increase by at least 2 cm from baseline. 
• New or recurrent splenomegaly 
New lesions 
New FDG-avid foci consistent with lymphoma rather than 
another etiology (e.g., infection, inflammation).  If uncertain 
regarding etiology of new lesions, biopsy or interval scan may 
be considered. 
• Regrowth of previously resolved lesions 
A new node > 1.5 cm in any axis 
• A new extranodal site > 1.0 cm in any axis; if < 1.0 
cm in any axis, its presence must be unequivocal and 
must be attributable to lymphoma 
• Assessable disease of any size unequivocally 
attributable to lymphoma 
Bone marrow 
New or recurrent FDG-acid foci 
New or recurrent involvement 


 
Appendix C−2 (cont.) 
Revised Criteria for Response Assessment: The Lugano Classification (Cohorts E, G-H) 
DCDT2980S and DCDS4501A—Genentech, Inc. 
169/Protocol GO27834, Version A4 
5-PS = 5-point scale; CT = computed tomography; FDG = fluorodeoxyglucose; IHC = immunohistochemistry; LDi = longest transverse diameter of a lesion; 
MRI = magnetic resonance imaging; PET = positron emission tomography; PPD = cross product of the LDi and perpendicular diameter; SDi = shortest axis 
perpendicular to the LDi; SPD = sum of the product of the perpendicular diameters for multiple lesions. 
a A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan.   However, in trials involving PET 
where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid under treatment). 
b PET 5-PS:  1, no uptake above background; 2, uptake  ≤  mediastinum; 3, uptake < mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly 
higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma. 
 
REFERENCE 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin 
and non-Hodgkin lymphoma:  the Lugano classification. J Clin Oncol 2014;32:3059−68. 


 
DCDT2980S and DCDS4501A—Genentech, Inc. 
170/Protocol GO27834, Version A4 
Appendix D  
Anaphylaxis Management 
The following equipment is needed in the event of a suspected anaphylactic 
reaction during study drug infusion: 
• 
Appropriate monitors (electrocardiogram, blood pressure, pulse oximetry 
• 
Oxygen 
• 
Epinephrine for intravenous, intramuscular, and/or endotracheal administration 
in accordance with institutional guidelines.   
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
 
The following are the procedures to follow in the event of a suspected 
anaphylactic reaction during study drug infusion: 
• 
Stop the study drug infusion. 
• 
Call for additional assistance! 
• 
Maintain an adequate airway. 
• 
Provide oxygen as needed. 
• 
Ensure that appropriate monitoring is in place, with continuous electrocardiogram 
and pulse oximetry monitoring, if possible. 
• 
Administer antihistamines, epinephrine, inhaled bronchodilators, or other 
medications as required by patient status and directed by the physician in charge. 
• 
Continue to observe the patient and document observations. 
 






 
DCDT2980S and DCDS4501A—Genentech, Inc. 
173/Protocol GO27834, Version A4 
Appendix F  
Recommendations for the Use of White Blood Cell Growth 
Factors 
Primary Prophylactic G-CSF Administration (First and Subsequent-Cycle Use) 
Primary prophylaxis with G-CSF is recommended if any of the following clinical factors 
are present: 
• 
Age >65 years 
• 
Poor performance status 
• 
Previous history of febrile neutropenia 
• 
Open wounds or active infections 
• 
More advanced cancer 
• 
Extensive prior treatment, including large radiation therapy ports 
• 
Cytopenias due to bone marrow involvement by tumor 
• 
Other serious comorbidities 
 
Secondary Prophylactic G-CSF Administration 
Prophylactic G-CSF administration is recommended for patients who fulfill each of the 
following circumstances: 
• 
Experienced a neutropenic complication from a prior cycle of study treatment 
• 
Primary prophylactic G-CSF was not received; and 
• 
The intent is to avoid dose reduction of the antibody−drug conjugate (ADC), where 
the effect of the reduced dose on disease-free, overall survival or treatment 
outcome is not known 
 
Therapeutic Use of G-CSF 
G-CSF administration should be considered for the following patients: 
• 
Patients with febrile neutropenia who are at high risk for infection-associated 
complications; or 
• 
Patients who have prognostic factors that are predictive of poor clinical outcome, 
e.g., prolonged (>10 days) and profound (<100/µL) neutropenia, age >65 years, 
uncontrolled primary disease, pneumonia, hypotension and multi-organ dysfunction 
(sepsis), invasive fungal infection, being hospitalized at the time of fever 
development 
 
Source:  Smith TJ et al. 2006 Update of Recommendations for the use of White Blood Cell 
Growth Factors: An Evidence-Based Clinical Practice Guideline. JCO 24:3187-3205. 2006. 
 
 
 
 


 
Title
30-Apr-2015 15:38:20
Date and Time (UTC)
Clinical Science Leader
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
This is a Genentech, Inc., document that contains confidential information.   
It is intended solely for the recipient clinical investigator(s) and must not be disclosed to any other 
party.  This material may be used only for evaluating or conducting clinical investigations; any 
other proposed use requires written consent from Genentech, Inc. 
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
P GO27834-A3 
PROTOCOL
TITLE: 
A RANDOMIZED, OPEN-LABEL, MULTICENTER, 
PHASE II TRIAL EVALUATING THE SAFETY 
AND ACTIVITY OF PINATUZUMAB VEDOTIN 
(DCDT2980S) IN COMBINATION WITH 
RITUXIMAB OR POLATUZUMAB VEDOTIN 
(DCDS4501A) IN COMBINATION WITH 
RITUXIMAB AND A NON-RANDOMIZED PHASE 
IB/II EVALUATION OF POLATUZUMAB 
VEDOTIN IN COMBINATION WITH 
OBINUTUZUMAB IN PATIENTS WITH 
RELAPSED OR REFRACTORY B-CELL 
NON-HODGKIN’S LYMPHOMA 
PROTOCOL NUMBER: 
GO27834 
EUDRACT NUMBER: 
2011-004377-84 
STUDY DRUG: 
Pinatuzumab Vedotin (DCDT2980S);  
Polatuzumab Vedotin (DCDS4501A) 
IND: 
107713 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc.  
1 DNA Way 
South San Francisco, CA  94080-4990 U.S.A. 
DATE FINAL: 
27 July 2012 
DATE AMENDED: 
Version A1:  
24 June 2013 
Version A2:  
6 November 2014. 
Version A3:  
See electronic date stamp below. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
2/P GO27834-A3   
PROTOCOL AMENDMENT, VERSION A3: 
RATIONALE 
Protocol GO27834 has been amended to enable the following changes: 
• 
In addition to sites in the United States, sites worldwide will now participate in the 
enrollment of patients into the non-randomized expansion cohorts (G and H) of the 
obinutuzumab portion of the study.  Cohorts G and H will each contain 40 patients 
with a diagnosis of either follicular NHL (Cohort G) or DLBCL (Cohort H) and will 
receive DCDS4501A at 1.8mg/kg in combination with obinutuzumab. 
• 
In Section 1.2.3, the reference for Rituximab was updated from Product 
Insert/Summary of Product Characteristics to Investigator’s Brochure because 
Rituximab is an IMP in the protocol. 
• 
The criteria for opening enrollment to the expansion portion of the study have been 
modified.  Six patients will complete the safety observation period in the safety run-
in phase of the study before the expansion portion of the study can begin, because 
sufficient safety data will be collected to determine whether the 1.8 mg/kg dose of 
DCDS4501A (polatuzumab vedotin) is safe in combination with obinutuzumab. 
• 
Guidelines for dose modification of DCDS4501A (polatuzumab vedotin) have been 
updated to allow for dose reductions to 1.4 mg/kg of polatuzumab vedotin for Grade 
2 or Grade 3 peripheral neuropathy.  Dose reductions below 1.8 mg/kg of 
polatuzumab vedotin for neutropenia will not be allowed.  
• 
ePRO MDASI assessments have been removed for the obinutuzumab cohorts, as 
no comparison will be made for ePRO between the obinutuzumab and rituximab 
cohorts.  Only the rituximab cohorts will be assessed for ePRO. 
• 
Non-serious adverse events of special interest for this study have been updated as 
described below.  The proposed update does not impact the routine collection and 
regulatory reporting of the adverse events that are removed from the AESI list. 
Peripheral neuropathy (sensory and/or motor) is already classified as an adverse 
drug reaction for polatuzumab vedotin.  Therefore, non-serious adverse events 
suggestive of the diagnosis or signs/symptoms of peripheral neuropathy no 
longer need to be reported immediately by the investigator to the Sponsor.  This 
administrative amendment does not change the Sponsor’s approach in close 
monitoring of data suggestive of peripheral neuropathy.  Comprehensive adverse 
event documentation of actions taken on occurrence of the diagnosis or 
signs/symptoms suggestive of sensory and/or motor neuropathy and the adverse 
event outcome will continue.  
In addition, revision was made to include tumor lysis syndrome, a program-wide 
AESI for obinutuzumab. 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
3/P GO27834-A3 
PROTOCOL AMENDMENT, VERSION A3: 
SUMMARY OF CHANGES 
COVER PAGE 
The Medical Monitor has been changed from 
, M.D. to 
 
M.D. 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.2.3:  Rituximab 
Refer to the Rituximab Product Insert/Summary of Product Characteristics Investigator’s 
Brochure for complete details regarding clinical data related to approved indications.   
SECTION 1.3.1:  Rationale for Assessing ADC Dose of 1.8 mg/kg Combined 
with Rituximab in iNHL 
In contrast to iNHL, treatment paradigms in relapsed or refractory aggressive 
lymphomas such as DLBCL continue to place a premium on anti-tumor activity and 
higher tolerance for treatment-related toxicity, given that the durations of disease control 
and survival are substantially shorter and that treatment options are extremely limited.  
Early Phase I data suggest lower rates of study treatment discontinuation for adverse 
events among patients with DLBCL compared with patients with iNHL.  Taken together 
with anti-tumor activity observed to date, the benefit-risk profile of the currently tested 
ADC dose of 1.82.4 mg/kg is considered acceptable to combine with rituxminab in the 
treatment of patients with iNHL.  
SECTION 2.1:  PRIMARY OBJECTIVES 
• 
To assess the anti-tumor activity of the combination of DCDS4501A and 
obinutuzumab in patients with relapsed or refractory follicular NHL and DLBCL based 
on PET-CR at the end of treatment according to IRC per Lugano 2014 response criteria 
 
SECTION 2.2.2:  Activity Objectives 
The secondary activity objective for rituximab-containing arms of the study is the 
following: 
• 
To compare the anti-tumor activity of the combination of DCT2980S and rituximab 
and DCDS4501A and rituximab or obinutuzumab 
The secondary activity objectives for obinutuzumab-containing arms of the study are the 
following: 
• 
CR at end of treatment based on PET alone, as determined by the investigator 
• 
Objective response (OR; CR or PR) at end of treatment based on PET alone as determined by 
investigator and IRC  
• 
CR at end of treatment based on CT only as determined by the investigator and IRC 
• 
OR at end of treatment based on CT only as determined by the investigator and IRC 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
4/P GO27834-A3 
• 
Best objective response (BOR, CR or PR) while on study based on PET alone or CT only, as 
determined by the investigator 
 
SECTION 2.3.1:  Efficacy Objectives 
The exploratory efficacy objectives for this study are to evaluate the long-term outcome of 
obinutuzumab-treated patients according to Lugano 2014 response criteria, as measured by the 
following: 
• 
Duration of response based on PET and/or CT scans 
• 
Progression-free survival (PFS) based on PET and/or CT scans  
• 
Event-free survival (EFS) based on PET and/or CT scans 
• 
Overall survival 
 
SECTION 2.3.3:  Patient-Reported Outcomes Objective 
• 
To assess patient-reported tolerability to study treatment and the impact of study 
treatment on patient functioning on the basis of PRO in Rituximab cohorts only 
 
SECTION 3.1:  DESCRIPTION OF THE STUDY 
This is a Phase Ib/II, multicenter, open-label study.  Up to approximately 24652 patients 
with relapsed or refractory FL and DLBCL will be enrolled at approximately 
30−40 investigative sites worldwide.   
Only investigational sites in the United States will enroll patients into Cohort E.  
Investigational sites in the United States, and Canada and worldwide will participate in 
Cohorts G and H).   
SECTION 3.1.1.1:  Randomized Portion of the Study (Arms A 
and B) − Closed to Enrollment 
 
SECTION 3.1.1.2:  Randomized Portion of the Study with Rituximab 
(Cohorts C and D) − Closed to Enrollment 
 
SECTION 3.1.3.1:  Obinutuzumab-Containing Regiment in Phase Ib:  Safety 
Run-In (Cohort E) 
This portion of the study will consist of a safety run-in that will evaluate the safety of 
DCDS4501A at 1.8 mg/kg in combination with obinutuzumab in 6 patients (Cohort E).  
The safety run-in is described in detail in Section 3.4.  In case an amendment to the 
protocol allows to study higher doses of DCDS4501A, the safety run in for the 1.8 mg/kg 
may be shortened to 3 patients. 
SECTION 3.2:  RATIONALE FOR STUDY DESIGN 
DCDT2980S and DCDS4501A arewere both being evaluated as single agents and in 
combination with rituximab in the ongoing Phase I studies Study DCT4862g and 
Study DCS4968g, respectively.   


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
5/P GO27834-A3 
Study GO27834 will continue to assess the cumulative safety and longer-term tolerability 
of ADC-rituximab combination therapy.  Due to additional information about the benefit-risk 
profile of DCDS4501A at the 2.4 mg/kg dose, the Sponsor is no longer pursuing the 2.4 mg/kg 
dose of DCDS4501A in the obinutuzumab-containing cohorts. 
SECTION 3.3.3:  Activity Outcome Measures 
The following activity outcome measures will be assessed for rituximab-containing 
arms/cohorts (Arms A and B, Cohort C): 
The following activity outcome measures will be assessed for obinutuzumab-containing 
cohorts (Cohorts E, G, and H) according to Lugano 2014 Response Criteria (Cheson et al. 
2014): 
The primary activity outcome measure will be assessed by:  
• 
CR at end of treatment (6−8 weeks after Cycle 6 Day 1 or last dose of study medication) 
based on PET alone, as determined by the IRC  
The following secondary efficacy outcome measures will be assessed: 
• 
OR (CR or PR) at end of treatment based on PET alone as determined by the investigator 
and IRC  
• 
CR at end of treatment based on CT only, as determined by the investigator and IRC  
• 
OR (CR or PR) at end of treatment based on CT only as determined by the investigator and 
IRC  
• 
BOR (CR or PR) while on study based on PET alone or CT only, as determined by the 
investigator  
 
SECTION 3.3.4:  Exploratory Outcome Measures 
• 
Treatment and disease symptom assessments using the M.D. Anderson Symptom 
Inventory (MDASI) in rituximab-containing cohorts only 
 
The following exploratory efficacy outcome measures will be assessed: 
• 
DOR, defined as the time from the date of the first occurrence of a documented CR or PR to 
the date of disease progression, relapse, or death from any cause, for the subgroup of patients 
with a best overall response of CR or PR, based on PET and/or CT scans as determined by 
the investigator assessment.  For patients achieving a response who have not experienced 
disease progression, relapse, or died prior to the time of the analysis, the DOR will be 
censored on the date of last disease assessment. 
• 
PFS, defined as the time from date of randomization or first treatment (for G-containing 
arms) to the first occurrence of progression or relapse, or death from any cause , based on 
PET and/or CT scans as determined by the investigator assessment. 
• 
EFS, defined as the time from date of randomization or first treatment (for G-containing 
arms) to any treatment failure including disease progression relapse, initiation of new 
anti-lymphoma therapy, or death from any cause, whichever occurs first, based on PET 
and/or CT scans as determined by the investigator assessment  
• 
OS, defined as the time from the date of first treatment to the date of death from any cause 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
6/P GO27834-A3 
SECTION 3.4.1:  Safety Run-In Analysis 
As outlined in Figure 3b and Section 3.1.3.1, a safety run-in analysis (Cohort E) will be 
conducted by the Internal Monitoring Committee (IMC) to evaluate the combination of 
DCDS4501A at a dose of 1.8 mg/kg with obinutuzumab.  This analysis will include data 
from the first 6 patients treated through the safety observation period, from Cycle 1 Day 1 to 
Day 21 of Cycle 1Cycle 2 Day 1 for a minimum of 21days.  Three patients will initially be 
enrolled, and then an additional 3 patients will be enrolled after the first 3 patients have 
safely completed the first cycle.  The decision to enroll an additional 3 patients will be 
made by the Sponsor’s Medical Monitor in consultation with the safety science leader, 
biostatistician, and participating investigators.  At the IMC’s discretion, and at any 
point during enrollment of the safety run-in, a decision could be made that more than 
6 patients are needed to evaluate safety.  Additional patients may also be enrolled at dose 
levels below 1.8 mg/kg of DCDS4501A (i.e., 1.4 mg/kg) based upon review of all safety data.  In 
this case, the protocol will be amended to allow for more than 6 patients in the safety 
run in.  In case the study is amended to test additional doses the safety run in for 1.8 
mg/kg may be shortened to three patients. 
Before the expansion portion of the study can begin (enrollment of 
Cohorts G and H), the following criteria must be met: 
sSix patients must have completed enrollment the safety observation period 
(Cycle 1 Day 1 to Cycle 2 Day 1 for a minimum of 21 days) in the safety run-in 
(Cohort E). 
1. 
Three patients must have completed at least 4 cycles of treatment. 
SECTION 3.4.2:  Internal Monitoring Committee 
The IMC will include the Roche/Genentech Medical Monitor, at least one other Clinical Science 
representative who is not directly involved in the study,a sponsor Medical Monitor not 
affiliated with the study, a Drug Safety Scientist, a biostatistician, and a statistical 
programmer.   
Throughout the course of the study, the IMC will meet, at regular intervals during the 
study and as needed, at the request of the Medical Monitor (e.g., on the basis of 
unexpected safety signals).   
 
Specific operational details such as the committee’s composition, frequency and timing 
of meetings and members’ roles and responsibilities will be detailed Complete details 
of the IMC will be described in the IMC charter. 
SECTION 3.4.5.7:  Immunization 
The safety of immunization with live viral vaccines following rituximab therapy has not 
been studied.  Patients who participate in this study may not receive either primary or 
booster vaccination with live virus vaccines for at least 28 days 6 months prior to initiation 
of rituximab or at any time during study treatment.  Investigators should review the 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
7/P GO27834-A3 
vaccination status of potential study patients being considered for this study and follow 
the U.S. Centers for Disease Control and Prevention guidelines for adult vaccination with 
non-live vaccines intended to prevent infectious diseases prior to study therapy. 
SECTION 3.4.6.2:  Tumor Lysis Syndrome 
TLS has been reported with obinutuzumab administration.  Patients with a high tumor 
burden, including patients with a lymphocyte count ≥ 25 × 109/L, particularly patients with 
B-cell CLL and MCL, are at increased risk for TLS and severe IRRs.  All patients with 
peripheral blood lymphocyte counts of ≥ 25 × 109/L or bulky adenopathy must receive 
prophylaxis for TLS prior to the initiation of study treatment.  This includes appropriate 
hydration, consisting of fluid intake of approximately 3 L/day, starting 1−2 days prior to 
the first dose of obinutuzumab, and administration of allopurinol (300 mg/day orally) or a 
suitable alternative (i.e., rasburicase) treatment, starting at least 12 − 2472 hours prior to 
the first infusion of obinutuzumab (Cycle 1, Day 1).  All patients should then be carefully 
monitored during the initial weeks of treatment.  Patients still considered at risk for TLS 
because of persistently high tumor burden (i.e., peripheral blood lymphocyte counts 
≥ 25 × 109/L) before the second and subsequent infusions of obinutuzumab should 
receive continuous TLS prophylaxis with allopurinol or a suitable alternative (i.e., 
rasburicase) and adequate hydration until the risk is abated, as determined by the 
investigator.  For treatment of TLS, correct electrolyte abnormalities, monitor renal function and 
fluid balance, and administer supportive care, including dialysis as indicated. 
SECTION 3.4.6.6:  Immunization 
The safety of immunization with live virus vaccines following obinutuzumab therapy has not 
been studied.  Thus, vaccination with live virus vaccines is not recommended during treatment 
and until B-cell recovery. 
SECTION 3.4.6.7:  Worsening of Preexisting Cardiac Condition 
In patients with underlying cardiac disease and treated with obinutuzumab, adverse events such 
as angina pectoris, acute coronary syndrome, myocardial infarction, heart failure, and 
arrhythmias, including atrial fibrillation and tachyarrhythmia, have been observed.  These events 
may occur as part of an IRR and can be fatal.  Therefore, patients with a history of cardiac disease 
should be monitored closely.  In addition, these patients should be hydrated with caution to 
prevent a potential fluid overload. 
SECTION 4.1.2:  Exclusion Criteria 
• 
Vaccination with a live vaccine within 28 days prior to treatment 
  
SECTION 4.2:  METHOD OF TREATMENT ASSIGNMENT 
For obinutuzumab-containing cohorts (Cohorts E, G, and H), patients with either 
relapsed or refractory follicular NHL or relapsed or refractory DLBCL will be enrolled.  
After the safety run-in stage for DCDS4501A at 1.8 mg/kg in combination with 
obinutuzumab, the non-randomized dose-expansion portion of the study will enroll 40 
relapsed or refractory FL patients into Cohort G and 40 relapsed or refractory DLBCL 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
8/P GO27834-A3 
patients into Cohort H. will be enrolled into the dose expansion portion with 
40 patients in each histology group. 
SECTION 4.3.1.2:  Dosage and Administration 
c. 
General Information 
The total dose of DCDT2980S and DCDS4501A for each patient will depend on the 
patient’s weight within 96 hours prior to Day 1 of each cycle.  The patient weight 
obtained during screening may be used for dose determination at all treatment cycles; if 
the patient’s weight within 96 hours prior to Day 1 of a given treatment cycle differs by 
>10% from the weight obtained during screening, then the new weight should be used to 
calculate the dose.   
SECTION 4.3.1.3:  Dosage Modification 
Specific guidelines around dosage modifications for neutropenia and peripheral 
neuropathy are detailed below in Sections 4.3.1.6 and 4.3.1.7.  Patients who experience 
other treatment-related Grade 3 or 4 toxicity or laboratory abnormalities will be allowed 
to delay dosing of study treatment (both ADC and rituximab or obinutuzumab) for up to 
2 weeks to allow for recovery.  Patients may continue to receive additional infusions of 
DCDT2980S or DCDS4501A per their treatment assignment provided that the toxicity 
has resolved to Grade ≤ 2 or ≥ 80% of the baseline value, whichever is lower, within the 
2−week delay period.  Upon resolution, the dose for subsequent infusions may be 
reduced to 1.8 mg/kg (in Cohorts C and D).  If the toxicity that resulted in the dose 
reduction persists or recurs at the reduced dose, then the patient should be discontinued 
from study treatment.  The decision for dose modification will be made on the basis of 
the investigator’s assessment of ongoing clinical benefit with continued study treatment 
and in consultation with the Medical Monitor.   
Once dose reductions of DCDT2980S or DCDS4501A are made for toxicity, dose 
re-escalation will not be allowed.  Patients who are enrolled in the non randomized 
portion of the study (Cohorts C and D), are dosed at an ADC dose of 1.8 mg/kg, and 
have progressive disease in the absence of any drug related toxicity may have their 
ADC dose increased to 2.4 mg/kg if it is felt that there is reasonable justification for 
ongoing clinical benefit.  The decision to increase the dose must be made in consultation 
with and approval of the Medical Monitor.  Patients in Cohorts E, G, and H 
(obinutuzumab containing cohorts) will not be eligible for dose escalation. 
SECTION 4.3.1.6:  Neutropenia 
• 
If prophylactic G-CSF was not administered prior to the cycle in which the 
Grade 3−4 neutropenia developed, then prophylactic G-CSF may be administered 
prior to subsequent cycles without DCDT2980S/DCDS4501A dose reduction.  The 
dose schedule may be changed from 21-day to 28-day cycles to provide sufficient 
time for neutrophil recovery in subsequent cycles.  In the absence of prophylactic 
G-CSF or dose schedule modification, the dose of DCDT2980S/DCDS4501A in 
subsequent cycles should be reduced to 1.8 mg/kg for Arms A and B.  For Cohorts 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
9/P GO27834-A3 
E, G, and H, patients will be given DCDS4501A at a dose of 1.8 mg/kg, and further 
dose reductions cannot be made.   
• 
If Grade 3−4 neutropenia recurs with prophylactic G-CSF, the dose for subsequent 
DCDT2980S/DCDS4501A should be reduced to 1.8 mg/kg for Arms A and B.  
Prophylactic G-CSF and dose schedule modifications as described above are 
permitted in order to maintain the reduced DCDT2980S/DCDS4501A dose level and 
schedule. 
• 
For patients enrolled into the non-randomized portion of the study (Cohorts C 
and D, as well as Cohorts E, G, and H), dose reductionsmodifications will not be 
allowed for neutropenia.  Administration of therapeutic/prophylactic G-CSF and 
dose-schedule modifications as described above are allowed.  Patients who have 
persistent or recurrent Grade 3−4 neutropenia as defined above should be 
discontinued from study treatment. 
SECTION 4.3.1.7:  Peripheral Neuropathy 
Peripheral neuropathy (sensory and/or motor) is a known risk of DCDT2980S and 
DCDS4501A (see Section 3.4.2.5).  For new or worsening drug-related Grade 2 or 3 
peripheral sensory and/or motor neuropathy, dosing should be held for up to 2 weeks 
until peripheral neuropathy (sensory or motor) improves to Grade 1 or baseline grade.  
Continuation of study treatment following dose delays beyond 2 weeks will require 
consultation with and approval of the Medical Monitor based on an assessment of the 
benefit-risk analysis of continuing to delay study treatment. 
For patients enrolled on arms A or B fFollowing resolution of peripheral neuropathy 
(sensory and/or motor), subsequent doses of DCDT2980S/DCDS4501A should be 
reduced to 1.8 mg/kg.  DCDS4501A should not be reduced to a dose lower than 
1.8 mg/kg.   If worsening Grade 2 or 3 peripheral neuropathy (sensory and/or motor) 
recurs following dose reduction, study treatment should be discontinued.  For Grade 43 
peripheral neuropathy (sensory and/or motor), study treatment should be discontinued.  
For patients enrolled into Cohorts C and D, the non randomized portion of the study 
(Cohorts C and D), dose modifications will not be allowed.  Patients who have Grade 2 
or 3 peripheral neuropathy (sensory and/or motor), as defined above, should be 
discontinued from study treatment.   
For patients enrolled on Cohorts E, G, or H, following resolution of Grade 2 or Grade 3 
peripheral neuropathy (sensory and/or motor), subsequent doses of DCDS4501A should 
be permanently reduced from 1.8 mg/kg to 1.4 mg/kg.  If worsening Grade 2 or Grade 3 
peripheral neuropathy (sensory and/or motor) recurs following dose reduction, study 
treatment should be discontinued.  For Grade 4 peripheral neuropathy (sensory and/or 
motor), study treatment should be discontinued. 
SECTION 4.3.3.4:  Schedule Modification 
Specific guidelines around schedule modifications for thrombocytopenia and febrile 
neutropenia are detailed below in Section 4.3.3.5 and Section 4.3.3.6. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
10/P GO27834-A3 
SECTION 4.3.3.5:  Thrombocytopenia 
In the event of severe thrombocytopenia (platelet count < 10,000/μL) and/or symptomatic 
bleeding (irrespective of platelet count) in patients who are not receiving concomitant 
anticoagulants or platelet inhibitors: 
• 
Hold obinutuzumab until thrombocytopenia or symptomatic bleeding resolves.  If 
Cycle 1 Day 8 is delayed, then skip Day 8 and administer Day 15 as previously scheduled 
(if thrombocytopenia or symptomatic bleeding has resolved).  If Cycle 1 Day 15 is delayed, 
then skip Day 15 dosing and administer Cycle 2 Day 1 of obinutuzumab and DCDS4501A 
as scheduled (if thrombocytopenia or symptomatic bleeding has resolved). but do not skip 
any doses of obinutuzumab for the sake of maintaining the study treatment 
schedule. 
 
In the event of thrombocytopenia with platelet count < 20,000/μL and/or symptomatic 
bleeding (irrespective of platelet count) in patients who are receiving concomitant 
anticoagulants or platelet inhibitors: 
• 
Hold obinutuzumab until thrombocytopenia or symptomatic bleeding resolves., but 
do not skip any doses of obinutuzumab for the sake of maintaining the study 
treatment schedule.  If Cycle 1 Day 8 is delayed, then skip Day 8 and administer Day 15 
as previously scheduled (if thrombocytopenia or symptomatic bleeding has resolved).  If 
Cycle 1 Day 15 is delayed, then skip Day 15 dosing and administer Cycle 2 Day 1 of 
obinutuzumab and DCDS4501A as scheduled (if thrombocytopenia or symptomatic 
bleeding has resolved). 
SECTION 4.3.3.6:  Febrile Neutropenia 
In the event of febrile neutropenia or neutropenia with infection, hold obinutuzumab until febrile 
neutropenia or neutropenia with infection resolves.   
• 
If Cycle 1 Day 8 is delayed long enough that the patient is approaching Day 15, then skip 
Day 8 and administer Day 15 as previously scheduled (if infection or fever has resolved) 
• 
If Cycle 1 Day 15 is delayed long enough that the patient approaching Cycle 2, then skip 
Day 15 dosing and administer Cycle 2 Day 1 of DCDS4501 as scheduled (if infection or 
fever has resolved) 
• 
Note:  Obinutuzumab Patients will receive DCDT2980S or DCDS4501A at 1.8 mg/kg 
or 2.4 mg/kg by IV infusion on Day 1 or Day  should not be held for neutropenia without 
fever or infection 
 
SECTION 4.4.1:  Concomitant Therapy 
For patients enrolled on obinutuzumab-containing regimens, it is recommended that 
corticosteroids (e.g., 100 mg of IV prednisolone or equivalent)  oral prednisone, prednisolone, 
or methylprednisolone be given as premedication within 12 hours of, but at least 
60 minutes prior to, the obinutuzumab infusion on Cycle 1 Day 1.   
SECTION 4.5.1.4:  Laboratory Assessments 
Central Laboratory Assesssments 
• 
ATA assays 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
11/P GO27834-A3 
ATAs to DCDT2980S, DCDS4501A, or obinutuzumab will be determined at 
Genentech using a validated ELISAs (see Section 4.9).  
Local Laboratory Assesssments 
• 
Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen (BUN or local equivalent), creatinine, calcium, magnesium, phosphorus, 
total and direct bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, 
LDH, and uric acid, amylase, and lipase 
 
SECTION 4.5.1.5:  Electrocardiogram Assessments 
• 
Day 8 (± 1 day) of Cycle 3 time matched (i.e., obtained at the same time of day) with 
post-DCDT2980s/DCDS4501A infusion ECGs for Cycle 3 only for 
rituximab containing arms/cohorts 
SECTION 4.5.1.8:  Tumor Response Assessments 
All measurable disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Response assessments will be assessed by the 
investigator, on the basis of physical examinations, CT scans, PET scans, and/or MRI 
scans, and bone marrow examinations, using standard response criteria for NHL 
(Cheson et al. 2007; Cheson et al. 2014) (see Appendix C-1 and C-2). 
b. Radiographic Assessments for Patients on Obinutuzumab-Containing 
Cohorts 
PET and CT scans are required for follicular NHL and DLBCL patients at screening, after 
Cycle 4 of study treatment (i.e., between Cycle 4 Day 15 and Cycle 5 Day 1), and at 
EOT.  The EOT response assessment should be performed 6−8 weeks after Cycle 8 
Day 1 or last study treatment.  CT scans without PET scans will be obtained every 
63 months for 21 years, then every 6 months for 1 year, for a total of approximately 
2 years after the treatment completion visit, with use of Lugano 2014standard Rresponse 
Ccriteria for NHL (see Appendix C-2).   
c. Bone Marrow Assessments 
A bone marrow biopsy for morphology is required at screening and should reflect 
disease status in the bone marrow following documented relapse on the last prior 
therapy or within 3 months of Day 1, whichever occurs later.  For obinutuzumab-containing 
cohorts, only follicular NHL patients are required to undergo a bone marrow biopsy at screening.   
SECTION 4.5.1.10:  Patient-Reported Outcomes 
PRO data will be elicited from all patients in this study (with the exception of Cohorts E, 
G, and H) to more fully characterize the clinical profile of study treatment.  The MDASI 
PRO instrument will be supplied in the local language of each participating country.  
Electronic (handheld computers) will be used for the daily collection of symptoms 
derived from the MDASI.   


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
12/P GO27834-A3 
SECTION 4.5.2:  Screening and Pretreatment Assessments 
Bone marrow biopsy and aspirate specimens are required at screening (see 
Section 4.5.1.8).  For obinutuzumab-containing cohorts, bone marrow biopsy and aspirate are 
only required for follicular NHL patients.  Unsuccessful attempts at obtaining marrow 
aspirates will not be considered a protocol deviation or violation. 
SECTION 4.9.6:  Anti-Therapeutic Antibody 
ATAs against obinutuzumab in serum samples will be measured using a validated 
bridging antibody ELISA and characterized by a competitive binding assay. 
SECTION 4.9.7:  Biomarker Assays 
Tumor tissue assessment of biomarkers will be assayed using IHC, ISH, qPCR gene 
expression profiling using microarray and mutation detection assays.  Circulating Tumor 
DNA (ctDNA) in plasma samples maywill be assessed using a next generation 
sequencing approach (CAPP-Seq) to detect and quantitate lymphoma specific markers 
(Newman et al. 2014). 
SECTION 4.10.4:  Activity Analyses 
For patients with DLBCL or FL on obinutuzumab-containing cohorts, primary response 
assessment for both DLBCL and FL will be primary assessment of tumor response will 
be based on PET/CT scans using the updated 2014 Lugano Response Criteria.  Given 
the new Lugano Classification, 2014, criteria which recommend that complete response 
(PET CR) be determined by PET CT scan,scanResponse Criteria as determined by an 
Independent Review CommitteeFacility (IRCF).   Ppatients in Cohorts E, G, and H will be 
evaluated with a PET- CT scan at screening, between Cycle 4 Day 15 and Cycle 5 Day 
1, and at the end of treatment (6-8 weeks after completing treatment).  The efficacy 
analysis for these cohorts will, therefore, be different from the analysis for Arms A-B and 
Cohorts C-D (Cheson, et al 2014) (see Appendix C-2).  Subsequent imaging can be CT 
only.  Responses to study treatment will also be based on investigator assessments. 
SECTION 4.10.5:  Exploratory Analyses 
Frequencies and percentages of missing data for the PRO endpoints will be reported.  Dropouts 
(defined as patients withdrawing from treatment for reasons other than documented disease 
progression or death) will be summarized 
Frequencies and percentages of missing data for the PRO endpoints will be reported.  
Dropouts (defined as patients withdrawing from treatment for reasons other than 
documented disease progression or death) will be summarized. 
SECTION 4.10.7:  Determination of Sample Size 
Therefore, up to 24652 patients may be enrolled in this study.  
SECTION 5.1.3:  Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor 
• 
Suspected transmission of an infectious agent by the study drug, as defined below: 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
13/P GO27834-A3 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
• 
Tumor lysis syndrome (TLS) of any grade, irrespective of causality 
• 
Grade ≥2 motor neuropathy 
• 
Grade ≥2 infusion reactions 
 
SECTION 5.3.1.11:  Pregnancy 
If a female patient becomes pregnant while receiving the study drug or within 
126 months after the last dose of study treatmentinvestigational product, a Pregnancy 
Report eCRF should be completed within 24 hours of learning of the pregnancy.  
A pregnancy report will automatically be generated and sent to Genentech’s Drug Safety 
Department or its designee.  Pregnancy should not be recorded on the Adverse Event 
eCRF. 
Male patients must also be instructed to immediately inform the investigator if their 
partner becomes pregnant during the study or within 56 months after the last dose of 
study drug.  If such an event occurs, it should be reported as described below. 
SECTION 5.4.1:  Reporting Requirements for Fatal/Life-Threatening SAEs 
Related to Investigational Product 
Medical Monitor Contact Information for sites in North America: 
Medical Monitor: 
 M.D. 
Telephone No.: 
 
 
Mobile Telephone No.: 
 
Alternate Telephone No.:  (888) 835 2555 (U.S. sites only) 
SECTION 5.4.2:  Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
Sites in Europe: 
Fax No.:  
 
SECTION 5.6:  Post-Study Adverse Events 
France: 
Fax No:  33 147617777 
Email:  neuilly.drug_safety@roche.com 
 
Germany: 
Fax No.:  
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
14/P GO27834-A3 
Email:  grenzach.drug_safety@roche.com 
 
Italy: 
Fax No.:  
 
Email:  monza.drug_safety@roche.com 
 
Netherlands: 
Fax No.:  
 
Email:   woerden.drug_safety@roche.com 
FIGURE 3a:  Study Schema for Rituximab-Containing Arms/Cohorts 
(Closed to Enrollment) 
FIGURE 3b:  Study Schema for Obinutuzumab-Containing Arms/Cohorts 
Figure 3b has been updated to reflect changes to the protocol. 
REFERENCES 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and Non-Hodgkin lymphoma:  The 
Lugano Classification. J Clin Oncol. 2014;32:3059−68. Aug [cited 2014 Aug 29]. 
Available from: 
http://jco.ascopubs.org/content/early/2014/08/11/JCO.2013.54.8800.long. 
APPENDIX A-3:  Study Flowchart for Obinutuzumab-Containing Cohorts 
(E, G-H):  Initial Study Treatment 
Appendix A-3 has been updated to reflect changes to the protocol. 
APPENDIX A-5:  Study Flowchart: Post-Treatment Follow-Up for 
Obinutuzumab-Containing Regimens (Cohorts E, G-H) 
Appendix A-5 has been updated to reflect changes to the protocol. 
APPENDIX B-3:  Serum and Plasma Pharmacokinetic, Blood 
Pharmacodynamic, and ATA Schedule for Obinutuzumab and DCDS4501A 
(Cohorts E, G-H) 
Appendix A-5 has been updated to reflect changes to the protocol


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
15/P GO27834-A3 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 24 
1. 
BACKGROUND .......................................................................................... 42 
1.1 
Background on Disease......................................................... 42 
1.2 
Background on the Molecules ............................................... 42 
1.2.1 
DCDT2980S .......................................................................... 42 
1.2.1.1 
Background and Preclinical Data........................................... 42 
1.2.1.2 
DCDT2980S Clinical Data ..................................................... 44 
1.2.2 
DCDS4501A.......................................................................... 47 
1.2.2.1 
Background and Preclinical Data........................................... 47 
1.2.2.2 
DCDS4501A Clinical Data..................................................... 50 
1.2.3 
Rituximab............................................................................... 53 
1.2.4 
Obinutuzumab ....................................................................... 54 
1.2.4.1 
Obinutuzumab Mechanism of Action ..................................... 54 
1.2.4.2 
Obinutuzumab Nonclinical Toxicology................................... 54 
1.2.4.3 
Obinutuzumab Nonclinical Efficacy ....................................... 55 
1.2.4.4 
Obinutuzumab Clinical Experience........................................ 56 
1.2.4.5 
Obinutuzumab Pharmacokinetics and 
Pharmacodynamics ............................................................... 57 
1.3 
Rationale for Doing this Study ............................................... 58 
1.3.1 
Rationale for Assessing ADC Dose of 1.8 mg/kg 
Combined with Rituximab in iNHL ......................................... 59 
1.3.2 
Rationale for Assessing DCDS4501A in 
Combination with Obinutuzumab in Relapsed or 
Refractory NHL...................................................................... 59 
2. 
OBJECTIVES.............................................................................................. 60 
2.1 
Primary Objectives ................................................................ 60 
2.2 
Secondary Objectives............................................................ 60 
2.2.1 
Safety Objectives................................................................... 60 
2.2.2 
Activity Objective ................................................................... 60 
2.2.3 
Pharmacokinetic Objectives .................................................. 61 
2.3 
Exploratory Objectives........................................................... 61 
2.3.1 
Efficacy Objectives ................................................................ 61 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
16/P GO27834-A3 
2.3.2 
Biomarker Objectives ............................................................ 61 
2.3.3 
Patient-Reported Outcomes Objective .................................. 62 
2.3.4 
Crossover Treatment Objective............................................. 62 
3. 
STUDY DESIGN ......................................................................................... 62 
3.1 
Description of the Study......................................................... 62 
3.1.1 
Rituximab-Containing Regimens with 
DCDT2980S or DCDS4501A................................................. 64 
3.1.1.1 
Randomized Portion of the Study (Arms A 
and B) − Closed to Enrollment............................................... 64 
3.1.1.2 
Non-Randomized Portion of the Study with 
Rituximab (Cohorts C and D) − Closed to 
Enrollment ............................................................................. 64 
3.1.2 
All Patients on Rituximab-Containing 
Arms/Cohorts......................................................................... 65 
3.1.3 
Obinutuzumab-Containing Regimen with 
DCDS4501A (Cohorts E, G, and H) ...................................... 65 
3.1.3.1 
Obinutuzumab-Containing Regimen in Phase Ib: 
Safety Run-In (Cohort E) ....................................................... 66 
3.1.4 
Follicular NHL Patients for Rituximab-Containing 
Arms/Cohorts......................................................................... 66 
3.1.5 
Follicular NHL Patients for 
Obinutuzumab-Containing Cohorts ....................................... 67 
3.1.6 
DLBCL Patients for Rituximab-Containing 
Arms/Cohorts......................................................................... 67 
3.1.7 
DLBCL Patients for Obinutuzumab-Containing 
Cohorts.................................................................................. 68 
3.1.8 
Crossover Treatment (Randomized Patients in 
Arms A and B Only)............................................................... 68 
3.2 
Rationale for Study Design.................................................... 70 
3.2.1 
Rationale for the PK Sample Schedule ................................. 71 
3.3 
Outcome Measures ............................................................... 72 
3.3.1 
Safety Outcome Measures .................................................... 72 
3.3.2 
Pharmacokinetic/Pharmacodynamic Outcome 
Measures............................................................................... 72 
3.3.3 
Activity Outcome Measures................................................... 73 
3.3.4 
Exploratory Outcome Measures ............................................ 74 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
17/P GO27834-A3 
3.4 
Safety Plan ............................................................................ 74 
3.4.1 
Safety Run-In Analysis .......................................................... 75 
3.4.2 
Internal Monitoring Committee............................................... 76 
3.4.3 
Risks Associated with DCDT2980S and 
DCDS4501A.......................................................................... 77 
3.4.3.1 
Infusion-Related Events......................................................... 77 
3.4.3.2 
Tumor Lysis Syndrome.......................................................... 78 
3.4.3.3 
Bone Marrow Toxicity/Neutropenia........................................ 78 
3.4.3.4 
Immunogenicity ..................................................................... 78 
3.4.3.5 
Peripheral Neuropathy........................................................... 79 
3.4.3.6 
Reproductive Toxicity ............................................................ 79 
3.4.3.7 
Hyperglycemia....................................................................... 79 
3.4.3.8 
Hepatotoxicity........................................................................ 79 
3.4.3.9 
Commonly Reported Side Effects.......................................... 79 
3.4.4 
Risks Associated with ADCETRIS® 
(Brentuximab Vedotin)........................................................... 80 
3.4.5 
Risks Associated with Rituximab Therapy and 
Their Management ................................................................ 80 
3.4.5.1 
Infusion Reactions ................................................................. 80 
3.4.5.2 
Management of Severe Infusion Reactions........................... 81 
3.4.5.3 
Tumor Lysis Syndrome.......................................................... 81 
3.4.5.4 
Hepatitis B Reactivation with Related Fulminant 
Hepatitis and Other Viral Infections ....................................... 81 
3.4.5.5 
Cardiovascular Events........................................................... 82 
3.4.5.6 
Bowel Obstruction and Perforation........................................ 82 
3.4.5.7 
Immunization ......................................................................... 83 
3.4.6 
Risks Associated with Obinutuzumab Therapy...................... 83 
3.4.6.1 
Infusion-Related Reactions and Hypersensitivity 
Reactions (including Anaphylaxis)......................................... 83 
3.4.6.2 
Tumor Lysis Syndrome.......................................................... 83 
3.4.6.3 
Neutropenia........................................................................... 84 
3.4.6.4 
Thrombocytopenia................................................................. 84 
3.4.6.5 
Infection................................................................................. 84 
3.4.6.6 
Immunization ......................................................................... 85 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
18/P GO27834-A3 
3.4.6.7 
Worsening of Preexisting Cardiac Condition ......................... 85 
3.5 
Minimization of Bias............................................................... 86 
3.6 
Administrative Structure......................................................... 86 
3.7 
Compliance with Laws and Regulations ................................ 86 
4. 
MATERIALS AND METHODS .................................................................... 86 
4.1 
Patients.................................................................................. 86 
4.1.1 
Inclusion Criteria.................................................................... 86 
4.1.2 
Exclusion Criteria................................................................... 88 
4.2 
Method of Treatment Assignment.......................................... 89 
4.3 
Study Treatment.................................................................... 89 
4.3.1 
DCDT2980S and DCDS4501A.............................................. 89 
4.3.1.1 
Formulation and Storage ....................................................... 89 
4.3.1.2 
Dosage and Administration.................................................... 91 
4.3.1.3 
Dosage Modification .............................................................. 92 
4.3.1.4 
Schedule Modification ........................................................... 92 
4.3.1.5 
Infusion Reaction................................................................... 93 
4.3.1.6 
Neutropenia........................................................................... 94 
4.3.1.7 
Peripheral Neuropathy........................................................... 95 
4.3.1.8 
Hyperglycemia....................................................................... 96 
4.3.2 
Rituximab............................................................................... 96 
4.3.2.1 
Formulation............................................................................ 96 
4.3.2.2 
Dosage, Administration, and Storage .................................... 97 
4.3.2.3 
Dosage Modification .............................................................. 98 
4.3.2.4 
Schedule Modification ........................................................... 98 
4.3.2.5 
Infusion Reaction................................................................... 99 
4.3.3 
Obinutuzumab ....................................................................... 99 
4.3.3.1 
Formulation............................................................................ 99 
4.3.3.2 
Dosage, Administration, and Storage .................................... 99 
4.3.3.3 
Dosage Modification ............................................................ 100 
4.3.3.4 
Schedule Modification ......................................................... 101 
4.3.3.5 
Thrombocytopenia............................................................... 101 
4.3.3.6 
Febrile Neutropenia ............................................................. 102 
4.3.4 
Investigational Medicinal Product Accountability ................. 102 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
19/P GO27834-A3 
4.4 
Concomitant and Excluded Therapies................................. 103 
4.4.1 
Concomitant Therapy .......................................................... 103 
4.4.2 
Excluded Therapy................................................................ 104 
4.5 
Study Assessments ............................................................. 104 
4.5.1 
Definitions of Study Assessments ....................................... 104 
4.5.1.1 
Medical History and Demographics..................................... 104 
4.5.1.2 
Vital Signs............................................................................ 104 
4.5.1.3 
Physical Examination .......................................................... 105 
4.5.1.4 
Laboratory Assessments ..................................................... 105 
4.5.1.5 
Electrocardiogram Assessments ......................................... 107 
4.5.1.6 
Pharmacokinetic and Pharmacodynamic 
Assessments ....................................................................... 107 
4.5.1.7 
Immunogenicity Assessments ............................................. 108 
4.5.1.8 
Tumor Response Assessments........................................... 108 
4.5.1.9 
Exploratory Research .......................................................... 111 
4.5.1.10 
Patient-Reported Outcomes ................................................ 112 
4.5.2 
Screening and Pretreatment Assessments.......................... 113 
4.5.3 
Assessments During Treatment .......................................... 113 
4.5.4 
Study Treatment Completion Visit ....................................... 114 
4.5.5 
Crossover Treatment Completion Visit ................................ 114 
4.5.6 
Follow-Up Assessments ...................................................... 115 
4.5.6.1 
Follow-Up Assessments for Rituximab-
Containing Regimens .......................................................... 115 
4.5.6.2 
Follow-Up Assessments for Obinutuzumab-
Containing Regimens .......................................................... 115 
4.6 
Patient Discontinuation........................................................ 116 
4.6.1 
Discontinuation from Treatment........................................... 116 
4.6.2 
Discontinuation from Study.................................................. 116 
4.7 
Study Discontinuation.......................................................... 116 
4.8 
Post-Trial Access................................................................. 116 
4.9 
Assay Methods.................................................................... 117 
4.9.1 
Total DCDT2980S/DCDS4501A Antibody ELISA................ 117 
4.9.2 
Antibody-Conjugated MMAE (MMAE Affinity 
Capture Enzyme-Release LC/MS-MS)................................ 117 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
20/P GO27834-A3 
4.9.3 
Free MMAE LC-MS/MS....................................................... 117 
4.9.4 
Rituximab ELISA ................................................................. 117 
4.9.5 
Obinutuzumab ELISA .......................................................... 117 
4.9.6 
Anti-Therapeutic Antibody ................................................... 117 
4.9.7 
Biomarker Assays................................................................ 117 
4.10 
Statistical Methods .............................................................. 117 
4.10.1 
Analysis of the Conduct of the Study................................... 118 
4.10.2 
Safety Analysis.................................................................... 118 
4.10.3 
Pharmacokinetic and Pharmacodynamic 
Analyses.............................................................................. 118 
4.10.4 
Activity Analyses.................................................................. 119 
4.10.5 
Exploratory Analyses........................................................... 120 
4.10.6 
Handling of Missing Data..................................................... 120 
4.10.7 
Determination of Sample Size ............................................. 121 
4.11 
Data Quality Assurance....................................................... 122 
5. 
ASSESSMENT OF SAFETY..................................................................... 122 
5.1 
Safety Parameters and Definitions ...................................... 122 
5.1.1 
Adverse Event ..................................................................... 123 
5.1.2 
Serious Adverse Event ........................................................ 123 
5.1.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) ............................ 124 
5.2 
Methods and Timing for capturing and Assessing 
Safety Parameters............................................................... 124 
5.2.1 
Adverse Event Reporting Period ......................................... 124 
5.2.2 
Eliciting Adverse Events ...................................................... 125 
5.2.3 
Assessment of Severity and Causality of Adverse 
Events.................................................................................. 125 
5.3 
Procedures for Recording Adverse Events.......................... 127 
5.3.1 
Recording Adverse Events on the eCRF............................. 127 
5.3.1.1 
Diagnosis versus Signs and Symptoms............................... 127 
5.3.1.2 
Adverse Events Occurring Secondary to Other 
Events.................................................................................. 127 
5.3.1.3 
Persistent or Recurrent Adverse Events.............................. 127 
5.3.1.4 
Abnormal Laboratory Values ............................................... 128 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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5.3.1.5 
Abnormal Vital Sign Values ................................................. 128 
5.3.1.6 
Abnormal Liver Function Tests............................................ 129 
5.3.1.7 
Deaths ................................................................................. 129 
5.3.1.8 
Preexisting Medical Conditions............................................ 129 
5.3.1.9 
Worsening of Baseline Hematologic Malignancy................. 130 
5.3.1.10 
Hospitalization, Prolonged Hospitalization or 
Surgery................................................................................ 130 
5.3.1.11 
Pregnancy ........................................................................... 130 
5.4 
Expedited Reporting Requirements for Serious 
Adverse Events ................................................................... 131 
5.4.1 
Reporting Requirements for 
Fatal/Life-Threatening SAEs Related to 
Investigational Product ........................................................ 131 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest.................................................................... 131 
5.5 
Type and Duration of Follow-Up of Patients after 
Adverse Events ................................................................... 132 
5.6 
Post-Study Adverse Events................................................. 132 
6. 
INVESTIGATOR REQUIREMENTS.......................................................... 133 
6.1 
Study Initiation..................................................................... 133 
6.2 
Study Completion ................................................................ 134 
6.3 
Informed Consent Form....................................................... 135 
6.4 
Communication with the Institutional Review 
Board or Ethics Committee.................................................. 136 
6.5 
Study Monitoring Requirements .......................................... 136 
6.6 
Electronic Case Report Forms............................................. 136 
6.7 
Source Data Documentation................................................ 137 
6.8 
Use of Computerized Systems ............................................ 137 
6.9 
Study Medication Accountability.......................................... 138 
6.10 
Disclosure of Data ............................................................... 138 
6.11 
Retention of Records........................................................... 138 
7. 
REFERENCES ......................................................................................... 140 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
22/P GO27834-A3 
 
 
LIST OF TABLES 
Table 1 
Management of Infusion-Related Symptoms for All Study 
Drugs .......................................................................................... 94 
Table 2 
Administration of First and Subsequent Infusions of 
Obinutuzumab........................................................................... 100 
Table 3 
Potential 90% Interval Estimates for the True Response 
Probability ................................................................................. 122 
Table 4 
Adverse Event Grading (Severity) Scale................................... 126 
Table 5 
Causal Attribution Guidance ..................................................... 126 
 
LIST OF FIGURES 
Figure 1 
CD22 Expression Levels on B-Cell Tumor Cells......................... 43 
Figure 2 
CD79b Expression Levels on B-Cell Tumor Cells....................... 48 
Figure 3a 
Study Schema for Rituximab-Containing Arms/Cohorts 
(Closed to Enrollment) ................................................................ 63 
Figure 3b 
Study Schema for Obinutuzumab-Containing Arms/Cohorts ...... 63 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
23/P GO27834-A3 
 
 
LIST OF APPENDICES 
Appendix A-1  Study Flowchart:  Initial Study Treatment (Arms A-B, Cohorts 
C-D) .......................................................................................... 143 
Appendix A-2 Study Flowchart:  Crossover Treatment (Patients 
Randomized to Arms A or B Only)............................................ 148 
Appendix A-3 Study Flowchart for Obinutuzumab-Containing Cohorts (E, G-
H):  Initial Study Treatment ....................................................... 151 
Appendix A-4 Study Flowchart: Post-Treatment Follow-Up for 
Rituximab-Containing Regimens (Arms A-B, Cohorts C-D) ...... 155 
Appendix A-5 Study Flowchart: Post-Treatment Follow-Up for 
Obinutuzumab-Containing Regimens (Cohorts E, G-H) ........... 157 
Appendix B-1 Serum and Plasma Pharmacokinetic Schedule for 
DCDT2980S/DCDS4501A and Rituximab, and ATA 
Schedule for DCDT2980S/DCDS4501A (For Patients 
Receiving Rituximab on Day 1 and 
DCDT2980S/DCDS4501A on Day 2 of Every Cycle) 
(Arms A-B, Cohorts C-D) .......................................................... 159 
Appendix B-2 Serum and Plasma Pharmacokinetic Schedule for Rituximab 
and DCDT2980S/DCDS4501A, and ATA Schedule for 
DCDT2980S/DCDS4501A for Patients Receiving Rituximab 
and DCDT29808S/DCDS4501A on Day 1 of Every 
Cycle Beginning Cycle 3 (Arms A-B, Cohorts C-D)................... 161 
Appendix B-3 Serum and Plasma Pharmacokinetic, Blood 
Pharmacodynamic, and ATA Schedule for Obinutuzumab 
and DCDS4501A (Cohorts E, G-H)........................................... 163 
Appendix C-1  Modified Response and Progression Criteria for NHL .............. 165 
Appendix C-2 Revised Criteria for Response Assessment: The Lugano 
Classification (Cohort E, G-H)................................................... 169 
Appendix D  Anaphylaxis Management............................................................ 173 
Appendix E  M. D. Anderson Symptom Inventory (MDASI).............................. 174 
Appendix F  Recommendations for the Use of White Blood Cell Growth 
Factors...................................................................................... 176 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
24/P GO27834-A3 
 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A RANDOMIZED, OPEN-LABEL, MULTICENTER, 
PHASE II TRIAL EVALUATING THE SAFETY AND 
ACTIVITY OF PINATUZUMAB VEDOTIN 
(DCDT2980S) IN COMBINATION WITH RITUXIMAB 
OR POLATUZUMAB VEDOTIN (DCDS4501A) IN 
COMBINATION WITH RITUXIMAB AND A NON-
RANDOMIZED PHASE IB/II EVALUATION OF 
POLATUZUMAB VEDOTIN IN COMBINATION WITH 
OBINUTUZUMAB IN PATIENTS WITH RELAPSED 
OR REFRACTORY B-CELL NON-HODGKIN’S 
LYMPHOMA 
PROTOCOL NUMBER: GO27834 
EUDRACT NUMBER: 
2011−004377−84 
STUDY DRUG: 
Pinatuzumab Vedotin (DCDT2980S);  
Polatuzumab Vedotin (DCDS4501A) 
IND: 
107713 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA  94080-4990  U.S.A. 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return a copy of the form to the CRO Monitor at your site.  Please retain the 
original for your study files. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
25/P GO27834-A3   
PROTOCOL SYNOPSIS 
TITLE: 
A RANDOMIZED, OPEN-LABEL, MULTICENTER, PHASE II 
TRIAL EVALUATING THE SAFETY AND ACTIVITY OF 
PINATUZUMAB VEDOTIN (DCDT2980S) IN COMBINATION 
WITH RITUXIMAB OR POLATUZUMAB VEDOTIN 
(DCDS4501A) IN COMBINATION WITH RITUXIMAB AND A 
NON-RANDOMIZED PHASE Ib/II EVALUATION OF 
POLATUZUMAB VEDOTIN IN COMBINATION WITH 
OBINUTUZUMAB IN PATIENTS WITH RELAPSED OR 
REFRACTORY B-CELL NON-HODGKIN’S LYMPHOMA 
PROTOCOL NUMBER: 
GO27834 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2011-004377-84 
IND: 
107713 
STUDY DRUG: 
Pinatuzumab Vedotin (DCDT2980S);  
Polatuzumab Vedotin (DCDS4501A) 
PHASE: 
II 
INDICATION: 
Relapsed or refractory B-cell NHL 
SPONSOR: 
Genentech, Inc. 
Objectives 
Primary Objectives 
The primary objectives of this study are the following: 
• 
To assess the safety and tolerability of the combination of DCDT2980S and rituximab 
administered to patients with relapsed or refractory follicular non-Hodgkin’s lymphoma 
(NHL) and diffuse large B-cell lymphoma (DLBCL) 
• 
To assess the safety and tolerability of the combination of DCDS4501A and rituximab 
administered to patients with relapsed or refractory follicular NHL and DLBCL  
• 
To assess the safety and tolerability of the combination of DCDS4501A and obinutuzumab 
when administered to patients with relapsed or refractory follicular NHL or DLBCL 
• 
To assess the anti-tumor activity of the combination of DCDT2980S and rituximab in 
patients with relapsed or refractory follicular NHL and DLBCL 
• 
To assess the anti-tumor activity of the combination of DCDS4501A and rituximab in 
patients with relapsed or refractory follicular NHL and DLBCL 
• 
To assess the anti-tumor activity of the combination of DCDS4501A and obinutuzumab in 
patients with relapsed or refractory follicular NHL and DLBCL based on PET-CR at the end of 
treatment according to IRC per Lugano 2014 response criteria 
 
The secondary safety objectives of this study are the following: 
• 
To assess the incidence of antibody formation to DCDT2980S, DCDS4501A, and 
obinutuzumab as measured by the formation of anti-therapeutic antibodies (ATAs) 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
26/P GO27834-A3 
• 
To compare the safety and tolerability of the combination of DCT2980S and rituximab and 
DCDS4501A and rituximab or obinutuzumab 
 
Activity Objectives 
The secondary activity objective for rituximab-containing arms of the study is the following: 
• 
To compare the anti-tumor activity of the combination of DCT2980S and rituximab and 
DCDS4501A and rituximab or obinutuzumab 
The secondary activity objectives for obinutuzumab-containing arms of the study are the following: 
• 
CR at end of treatment based on PET alone, as determined by the investigator 
• 
Objective response (OR; CR or PR) at end of treatment based on PET alone as determined by 
investigator and IRC  
• 
CR at end of treatment based on CT only as determined by the investigator and IRC 
• 
OR at end of treatment based on CT only as determined by the investigator and IRC 
• 
Best objective response (BOR, CR or PR) while on study based on PET alone or CT only, as 
determined by the investigator 
 
Pharmacokinetic Objectives 
The pharmacokinetic (PK) objectives of this study are the following: 
• 
To characterize the pharmacokinetics of DCDT2980S and rituximab in patients with 
relapsed or refractory NHL when the two drugs are given in combination 
• 
To characterize the pharmacokinetics of DCDS4501A and rituximab or obinutuzumab in 
patients with relapsed or refractory NHL when the two drugs are given in combination 
 
Patient-Reported Outcome Objectives 
The objective of this study related to assessment of patient-reported outcomes (PRO) is the 
following: 
• 
To assess patient-reported tolerability to study treatment and the impact of study treatment 
on patient functioning, on the basis of PRO  in Rituximab cohorts only 
 
Biomarker Objectives 
The objectives of this study related to assessment of biologic markers are the following: 
• 
To make a preliminary assessment of biologic markers that might act as predictors of 
DCDT2980S + rituximab combination anti-tumor activity and allow assessment of response 
in different prognostic subgroups of DLBCL and follicular NHL 
• 
To make a preliminary assessment of biologic markers that might act as predictors of 
DCDS4501A + rituximab or obinutuzumab combination anti-tumor activity and allow 
assessment of response in different prognostic subgroups of DLBCL and follicular NHL 
 
Study Design 
Description of Study 
This is a Phase Ib/II, multicenter, open-label study.  Up to approximately 246 patients with 
relapsed or refractory FL and DLBCL will be enrolled at approximately 30−40 investigative sites 
worldwide.  Additional patients may be enrolled in order to obtain additional safety and/or 
efficacy data. Arms A and B and Cohort C are no longer enrolling patients. 
For Obinutuzumab Cohorts: 
Only investigational sites in the United States will enroll patients into Cohort E.  Investigational 
sites in the United States and worldwide will participate in Cohorts G and H). 
The study will be composed of a randomized portion and a non-randomized portion, as 
described in the protocol. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
27/P GO27834-A3 
Rituximab-Containing Regimens with DCDT2980S or DCDS4501A 
Randomized Portion of the Study (Arms A and B) − Closed to Enrollment 
Following determination of eligibility, patients within each disease group will be randomized in a 
1:1 ratio to receive one of two treatments: 
• 
Arm A:  Rituximab (375 mg/m2) followed by DCDT2980S (2.4 mg/kg) every 21 days; 
• 
Arm B:  Rituximab (375 mg/m2) followed by DCDS4501A (2.4 mg/kg) every 21 days 
 
The first day of treatment constitutes Day 1 of each cycle.  A typical cycle is 21 days in duration. 
A dynamic hierarchical randomization scheme will be employed with respect to the following 
stratification factors: 
• 
For patients with follicular lymphoma (FL) (see the protocol for definitions) 
Rituximab refractory disease (no response or disease relapse < 6 months from last 
rituximab treatment) versus rituximab relapsed disease (disease relapse after 
response ≥  6 months from last rituximab treatment) 
• 
For patients with DLBCL (see the protocol for definitions) 
Second-line versus third-line (or beyond) therapy 
For second-line patients, disease relapse or no objective response (complete response 
[CR], unconfirmed CR [CRu], or partial response [PR]) <12 months from the start of 
initial therapy versus disease relapse, after initial objective response (CR, unconfirmed 
response [CRu] or PR), ≥ 12 months from start of initial therapy  
For third-line patients, failure to achieve a CR or progression < 6 months from start of 
most recent therapy versus CR or progression ≥ 6 months from start of most recent 
therapy 
No formal testing comparing the two treatment arms in the randomized portion of the study is 
planned. 
Non-Randomized Portion of the Study with Rituximab (Cohorts C and D) − Closed to 
Enrollment 
Only select investigator sites that have agreed to participate in the non-randomized portion of 
the study will enroll patients into these cohorts. 
Patients with relapsed or refractory follicular NHL will be enrolled in Cohorts C and D to receive 
rituximab (375 mg/m2) combined with DCDT2980S or DCDS4501A at a dose of 1.8 mg/kg.  The 
first day of treatment constitutes Day 1 of each cycle.  A typical cycle will be 21 days in duration. 
The opening of either or both cohorts will be at the Sponsor’s discretion and only after the 
enrollment of patients with FL into the randomized portion of the study is completed.  Patients 
will not be randomized to receive one treatment or the other.  It is anticipated that Cohort C 
and D will be opened sequentially.   
All Patients on Rituximab-Containing Arms/Cohorts 
All patients on rituximab-containing regimens, regardless of assigned arm/cohort, will receive 
DCDT2980S or DCDS4501A and rituximab administered by intravenous (IV) infusion on a 
21-day cycle.  For the first two cycles, rituximab will be administered by IV infusion on Day 1 
and DCDT2980S or DCDS4501A will be administered by IV infusion on Day 2.  In the absence 
of any infusion-related adverse events, rituximab and DCDT2980S or DCDS4501A may be 
administered on the same day (Day 1) in subsequent cycles beginning with the third cycle.  In 
this instance, rituximab will be administered first, followed by DCDT2980S or DCDS4501A.  In 
certain circumstances⎯for example, infusion-related reactions (IRRs) requiring interruption or 
slowing of infusion rate⎯rituximab may be administered over 2 days (e.g., Day 1 and Day 2 of 
the cycle); in this case, DCDT2980S or DCDS4501A may be administered on Day 2 following 
completion of the rituximab infusion or on Day 3 of the cycle. 
Patients may receive treatments for up to 1 year (17 cycles on an every-21-day schedule) if not 
discontinued because of significant toxicity, disease progression, or withdrawal from study. 
Patients will be evaluated for safety and efficacy according to the Schedules of Assessments 
outlined in the protocol.  Initial response assessments in this study will be performed every 
3 months from the initiation of therapy until study treatment completion or early termination 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
28/P GO27834-A3 
(e.g., between Days 14 and 21 of Cycles 4 and 8 for those patients receiving at least 
eight 21-day cycles of treatment).  Additional response assessments for patients who proceed 
to crossover treatment will be performed as described in the protocol; response assessments 
for patients who discontinue study treatment (both initially assigned treatment and crossover 
treatment) for reasons other than disease progression will be performed as described in the 
protocol. 
Responses to study treatment will be based on investigator assessments.  In addition, tumor 
assessment data will be transmitted to an Independent Review Facility (IRF) for collection and 
possible independent review. 
Obinutuzumab-Containing Regimens with DCDS4501A (Cohorts E, G, and H) 
DCDS4501A at 1.8 mg/kg will be given in combination with obinutuzumab to patients with 
relapsed or refractory follicular NHL and DLBCL in two stages: (1) safety run-in and (2) 
expansion. 
Study treatment will be given in 21-day cycles for both follicular NHL and DLBCL.  Patients will 
be treated for up to a total of 8 cycles.  For the first cycle, obinutuzumab will be administered by 
IV infusion on Days 1, 8, and 15.  DCDS4501A will be given on Day 2 for Cycle 1.  In the 
absence of any infusion-related adverse events, obinutuzumab and DCDS4501A may be 
administered on the same day (Day 1) in subsequent cycles beginning with the second cycle.  If 
obinutuzumab and DCDS4501A are administered on the same day, the study drugs will be 
given sequentially.  Obinutuzumab will be administered first, followed by DCDS4501A.  In 
certain circumstances⎯for example, IRRs requiring interruption or slowing of infusion 
rate⎯obinutuzumab may be administered over 2 days (e.g., Day 1 and Day 2 of the cycle); in 
this case, DCDS4501A may be administered on Day 2 following completion of the 
obinutuzumab infusion. 
Obinutuzumab-Containing Regimen in Phase Ib: Safety Run-In (Cohort E) 
This portion of the study will consist of a safety run-in that will evaluate the safety of 
DCDS4501A at 1.8 mg/kg in combination with obinutuzumab in 6 patients (Cohort E).  The 
safety run-in is described in detail in the protocol.   
Obinutuzumab-Containing Regimens in Phase II:  Expansion Stage (Cohorts G and H) 
After the safety run-in has demonstrated that DCDS4501A at 1.8 mg/kg in combination with 
obinutuzumab is safe to administer, patients will be enrolled into two expansion cohorts based 
on histology of follicular NHL or DLBCL (Cohorts G and H respectively).  Forty patients will be 
enrolled into each expansion cohort.  An additional cohort(s) may be added in the future. 
Follicular NHL Patients for Rituximab-Containing Arms/Cohorts 
Patients with relapsed or refractory follicular NHL will be enrolled into the study as defined by 
the following: 
• 
Relapsed to regimens containing rituximab, defined as documented history of response 
(CR, CRu, or PR) of ≥ 6 months in duration from completion of all prior rituximab-containing 
regimens.  A rituximab-containing regimen is defined as rituximab as a single agent during 
induction and/or maintenance or in combination with other agents during induction and/or 
maintenance. 
• 
Refractory to any prior regimen containing rituximab, defined as no response to or 
progression within 6 months of completion of the last dose of rituximab therapy (either as 
monotherapy or in combination with chemotherapy), including: 
Patients with progressive disease while receiving rituximab monotherapy, 
rituximab combined with chemotherapy, or rituximab maintenance therapy; patients 
must have received at least one full dose (375 mg/m2) of rituximab. 
Patients with no objective response (PR or CR) to a rituximab-containing regimen 
consisting of at least 4 weekly doses of rituximab monotherapy or at least 4 cycles of 
rituximab combined with chemotherapy 
Patients with disease relapse, after having achieved an objective response, within 
6 months of completion of the last dose of rituximab therapy in a regimen consisting of 
at least four weekly doses of rituximab monotherapy or at least 4 cycles of rituximab 
combined with chemotherapy 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
29/P GO27834-A3 
 
Enrollment of patients with refractory disease as defined above may be limited to no greater 
than 60% of the total follicular NHL cohort, in order to avoid overrepresentation of the refractory 
disease population. 
Follicular NHL Patients for Obinutuzumab-Containing Cohorts 
Patients with relapsed or refractory follicular NHL will be enrolled into the study as defined by 
the following: 
• 
Relapsed to prior regimen(s) after having a documented history of response (CR, CRu, or 
PR) of ≥ 6 months in duration from completion of regimen(s)   
• 
Refractory to any prior regimen, defined as no response to the prior therapy, or progression 
within 6 months of completion of the last dose of therapy 
DLBCL Patients for Rituximab-Containing Arms/Cohorts 
Patients with relapsed or refractory DLBCL who are determined by the investigator to be 
ineligible for high-dose therapy with autologous stem cell rescue/stem cell transplant (SCT) will 
be enrolled into the study as defined by the following: 
• 
Second-line SCT-ineligible patients with progressive disease or no response 
(SD) < 12 months from start of initial therapy (second-line refractory) 
• 
Second-line SCT-ineligible patients with disease relapse after initial response ≥ 12 months 
from start of initial therapy (second-line relapsed) 
• 
Third-line (or beyond) SCT-ineligible patients with progressive disease or no response 
(SD) < 6 months from start of prior therapy (third-line + refractory) 
• 
Third-line (or beyond) SCT-ineligible patients with disease relapse after initial response 
≥ 6 months from start of prior therapy (third-line + relapsed) 
 
Enrollment into any of the above four categories may be limited to no greater than 40% of the 
DLBCL cohort—and to no more than 60% of the two refractory categories combined—in order 
to avoid overrepresentation of any specific subpopulation, refractory patients in particular. 
DLBCL Patients for Obinutuzumab-Containing Cohorts 
Patients with relapsed or refractory DLBCL who are determined by the investigator to be 
ineligible for high-dose therapy with autologous stem cell rescue/SCT as determined by the 
investigator will be enrolled into the study as defined by the following: 
• 
Second-line SCT-ineligible patients with progressive disease or no response 
(SD) < 12 months from start of initial therapy (second-line refractory) 
• 
Second-line SCT-ineligible patients with disease relapse after initial response ≥ 12 months 
from start of initial therapy (second-line relapsed) 
• 
Third-line (or beyond) SCT-ineligible patients with progressive disease or no response 
(SD) < 6 months from start of prior therapy (third-line + refractory) 
• 
Third-line (or beyond) SCT-ineligible patients with disease relapse after initial response 
≥ 6 months from start of prior therapy (third-line + relapsed) 
 
Crossover Treatment (Randomized Patients in Arms A and B Only) 
Patients randomized to Arm A or Arm B who develop progressive disease may be eligible to 
receive crossover treatment consisting of rituximab and the other antibody-drug conjugate 
(ADC) or the other ADC alone⎯for example, Arm B treatment for patients who have disease 
progression while receiving Arm A treatment, and vice versa⎯provided the following conditions 
are met: 
• 
Patients must not have experienced a toxicity requiring the discontinuation of 
DCDT2980S/DCDS4501A treatment OR experienced toxicity during the last dose of study 
treatment that would preclude treatment with the crossover regimen. 
Patients who had modifications to dosing and/or schedule on the initial study treatment 
will be permitted to receive crossover treatment in the absence of toxicities on the 
modified dose and/or schedule.  The dose and schedule of crossover treatment will be 
determined by the investigator and the Medical Monitor. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
30/P GO27834-A3 
Patients who had rituximab discontinued and continued on single-agent 
DCDT2980S/DCDS4501A treatment may receive crossover treatment of single-agent 
DCDS4501A/ DCDT2980S. 
• 
Patients must have radiographically documented disease progression. 
• 
Patients must meet all inclusion and exclusion criteria described in the Inclusion Criteria 
and Exclusion Criteria sections below, except for those related to prior rituximab treatment. 
• 
Acceptable toxicity:  All study drug–related adverse events from the initial study treatment 
must have decreased to Grade 1 or baseline grade on or before the first day of treatment 
on the crossover regimen.  Exceptions may be allowed after a careful assessment and 
discussion of the benefit-risk balance with the patient by the investigator and approval from 
the Medical Monitor. 
• 
Administration of crossover treatment must be in the best interests of the patient as 
determined after a careful assessment and discussion of benefit-risk balance with the 
patient by the investigator and approval from the Medical Monitor. 
• 
A tumor biopsy (described in the protocol) will be required for patients with safely accessible 
site of disease, defined as requiring only local anesthesia and, in general, excluding the 
brain, lungs or any internal organs that may subject patients to significant risk.  
Patients for whom a safely accessible site of disease is not present may still receive 
crossover treatment without undergoing a biopsy.  Eligibility to receive crossover 
treatment should be discussed with and approved by the Medical Monitor. 
A tumor biopsy of a safely accessible site of disease is optional for patients who are 
not eligible for study cross over.  
 Patients who are determined to be eligible for study cross over will be treated as follows: 
• 
Assessments obtained at the initial study treatment discontinuation visit (described in the 
protocol) may be used as screening assessments for crossover treatment.  The following 
re-screening assessments must be repeated/obtained within 1 week prior to starting 
treatment on the crossover regimen, in order to re-establish baseline pretreatment clinical 
and disease status:  targeted physical exam, Eastern Cooperative Oncology Group (ECOG) 
status, and hematology and serum chemistry laboratory tests. 
Re-screening tests for hepatitis B and C do not need to be performed unless there is 
clinical suspicion of hepatitis B and/or C positivity. 
A radiographic tumor assessment must also be performed, unless already done to 
document disease progression, within 6 weeks prior to starting crossover treatment. 
• 
Crossover treatment will begin no later than 42 days after the last dose of the prior study 
treatment. 
 
Patients will be treated with the crossover treatment until a second disease progression event 
relative to the tumor assessment, documenting progressive disease on the initial study 
treatment, clinical deterioration, and/or intolerance to the crossover treatment for up to a 
maximum of 1 year (17 cycles on an every-21-day schedule).  Patients will be evaluated for 
safety and efficacy according to the schedules of assessments outlined in the protocol.  
Response assessments for patients who discontinue study treatment for reasons other than 
disease progression will be performed as described in the protocol.  
Clinical data and exploratory data derived from tumor biopsies obtained prior to crossover 
treatment will be monitored on an ongoing basis.  Genentech has the right to restrict or suspend 
enrollment into crossover treatment at any time.  Reasons for this may include, but are not 
limited to, the following: 
• 
The incidence or severity of adverse events during crossover treatment indicates a potential 
safety hazard to patients. 
• 
Patient enrollment into crossover treatment is unsatisfactory. 
• 
Data recording is inaccurate or incomplete.  
• 
Patients who are enrolled into the non-randomized portion of the study (Cohorts C, D, E, G, 
and H) will not have the option to receive crossover treatment upon disease progression. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
31/P GO27834-A3 
 
Number of Patients 
Up to approximately 246 patients with relapsed or refractory FL and DLBCL will be enrolled at 
approximately 30−40 investigative sites worldwide.  Additional patients may be enrolled in order 
to obtain additional safety and/or efficacy data.  
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form(s) 
• 
Age ≥ 18 years  
• 
ECOG Performance Status of 0, 1, or 2 
• 
Life expectancy of at least 12 weeks 
• 
History of histologically documented relapsed or refractory Grades 1−3a FL or relapsed or 
refractory DLBCL 
• 
Availability of an archival or freshly biopsied tumor tissue sample must be confirmed for 
study enrollment. 
• 
Have a clinical indication for treatment as determined by the investigator 
• 
Must have at least one bidimensionally measurable lesion (> 1.5 cm in its largest dimension 
by computed tomography [CT] scan or magnetic resonance imaging [MRI]) 
• 
Laboratory values (including patients with hepatic or renal involvement), as follows: 
AST and ALT ≤ 2.5 × ULN 
Total bilirubin ≤ 1.5 × ULN 
Platelet count ≥ 75,000/mm3 (unless thrombocytopenia clearly due to marrow 
involvement of NHL and/or disease-related immune thrombocytopenia) 
Absolute neutrophil count ≥ 1000/mm3 (without growth factor support, unless 
neutropenia clearly due to marrow involvement of NHL) 
Total hemoglobin ≥ 9 g/dL (without transfusion support > 14 days prior to screening, 
unless anemia clearly due to marrow involvement of NHL) 
Serum creatinine ≤ 2.0 mg/dL or measured creatinine CL ≥ 50 mL/min 
• 
For female patients of childbearing potential and male patients with female partners of 
childbearing potential, agreement to use one highly effective form of nonhormonal 
contraception or two effective forms of nonhormonal contraception, including at least one 
method with a failure rate of < 1% per year, through the course of study treatment and for 
≥ 12 months after the last dose of DCDT2980S, DCDS4501A, rituximab, or obinutuzumab 
(whichever is later) in women and at least 5 months after the last dose of DCDT2980S, 
DCDS4501A, rituximab, or obinutuzumab (whichever is later) in men 
A woman is considered not to be of childbearing potential if she is postmenopausal, 
defined by amenorrhea of ≥ 12 months duration and age ≥ 45 years, or has undergone 
hysterectomy and/or bilateral oophorectomy. 
The following are considered highly effective forms of contraception:  1) true 
abstinence; 2) male sterilization (with post-procedure documentation of absence of 
sperm in the ejaculate).  For female patients, the sterilized male partner should be the 
sole partner. 
The following are considered effective forms of contraception:  1) intrauterine device 
(IUD; copper IUD or hormonal IUDs only) or intrauterine system; 2) condom with 
spermicidal foam/gel/film/cream/suppository; 3) occlusive cap (diaphragm or 
cervical/vault cap) with spermicidal foam/gel/film/cream/suppository. 
Males must agree to abstain from sperm donation for at least 5 months after the last 
dose of DCDT2980S or, DCDS4501A or, rituximab, or obinutuzumab (whichever is 
later). 
 
Exclusion Criteria 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
32/P GO27834-A3 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Prior use of any MAb, radioimmunoconjugate or ADC within 4 weeks before Cycle 1, Day 1 
• 
Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, 
or any investigational anti-cancer agent within 2 weeks prior to Cycle 1, Day 1 
Adverse events except for sensory neuropathy from any previous treatments must be 
resolved or stabilized to Grade ≤ 2 prior to Cycle 1, Day 1. 
• 
Completion of autologous stem cell transplant within 100 days prior to Cycle 1, Day 1 
• 
Prior allogeneic stem cell transplant 
• 
Eligibility for autologous SCT (patients with relapsed or refractory DLBCL) 
• 
History of transformation of indolent disease to DLBCL 
• 
History of severe allergic or anaphylactic reactions to MAb therapy (or recombinant 
antibody-related fusion proteins) 
• 
History of other malignancy that could affect compliance with the protocol or interpretation 
of results 
Patients with a history of curatively treated basal or squamous cell carcinoma of the 
skin or in situ carcinoma (e.g., of the cervix or breast) are allowed.  Patients with a 
malignancy that has been treated with curative intent will also be allowed if the 
malignancy has been in remission without treatment for ≥ 2 years prior to Cycle 1, 
Day 1. 
• 
Current or past history of CNS lymphoma 
• 
Current Grade > 1 peripheral neuropathy 
• 
Evidence of significant, uncontrolled, concomitant diseases that could affect compliance 
with the protocol or interpretation of results, including significant cardiovascular disease 
(such as New York Heart Association Class III or IV cardiac disease, myocardial infarction 
within the last 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary 
disease (including obstructive pulmonary disease and history of bronchospasm) 
• 
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding 
fungal infections of nail beds) at study enrollment or any major episode of infection requiring 
treatment with IV antibiotics or hospitalization (relating to the completion of the course of 
antibiotics) within 4 weeks prior to Cycle 1, Day 1 
• 
Recent major surgery within 6 weeks prior to Cycle 1, Day 1, other than for diagnosis 
• 
Presence of positive test results for hepatitis B (HBsAg and/or total anti-HBc) or hepatitis C 
(HCV antibody) 
Patients who are positive for anti-HBc are eligible only if polymerase chain reaction 
(PCR) is negative for HBV DNA and it is believed by both the investigator and Medical 
Monitor that it is in the patient’s best interest to participate.  
Patients who are positive for HCV antibody must be negative for HCV by PCR to be 
eligible for study participation. 
• 
Vaccination with a live vaccine within 28 days prior to treatment 
• 
Known history of HIV seropositive status 
• 
Women who are pregnant or lactating 
• 
Ongoing corticosteroid use > 30 mg/day prednisone or equivalent 
Patients receiving corticosteroid treatment ≤ 30 mg/day prednisone or equivalent must 
be documented to be on a stable dose prior to study enrollment and initiation of 
therapy 
 
Length of Study 
The length of study will be the time from screening of the first enrolled patient through 2 years 
after the Treatment Completion Visit for the last enrolled patient on an obinutuzumab-containing 
regimen.  The length of the study for the obinutuzumab-containing cohorts is expected to be 
approximately 48 months. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
33/P GO27834-A3 
End of Study 
The end of study is defined as the timepoint at which patients enrolled in the 
obinutuzumab-containing regimens in the study have had at least 2 years of follow-up from the 
time of the Treatment Completion Visit or have discontinued from the study. 
Outcome Measures 
Safety Outcome Measures 
The safety and tolerability of the combination of DCDT2980S and rituximab and DCDS4501A 
and rituximab or obinutuzumab will be assessed using the following safety outcome measures: 
• 
Incidence, nature, and severity of adverse events 
• 
Incidence of anti-DCDT2980S, anti-DCDS4501A, or anti-obinutuzumab antibodies 
• 
Changes in vital signs 
• 
Changes in laboratory values 
 
The determination of the DCDS4501A RP2D in combination with obinutuzumab will be 
assessed using the following primary safety outcome measures for the Phase Ib portion of the 
study: 
• 
Incidence and nature of DLTs 
• 
Incidence, nature, and severity of adverse events and serious adverse events 
• 
Changes in vital signs, physical findings, ECGs, and clinical laboratory values during and 
following study treatment administration 
 
Pharmacokinetic/Pharmacodynamic Outcome Measures 
The following PK parameters will be derived from the serum concentration–time profiles of total 
antibody (the sum of conjugated and unconjugated antibody), including rituximab or 
obinutuzumab, and plasma concentration-time profiles of antibody-conjugated monomethyl 
auristatin E (acMMAE) and free MMAE following administration of DCDT2980S or DCDS4501A, 
when appropriate, as data allow: 
• 
Total exposure (area under the concentration-time curve [AUC]) 
• 
Maximum plasma and serum concentration (Cmax) 
• 
Clearance (CL) 
• 
Terminal half-life (t1/2) 
• 
Steady-state volume of distribution (Vss) 
 
Compartmental, non-compartmental, and/or population methods may be used.  Other 
parameters, such as accumulation ratio and trough plasma and serum concentration (Cmin), may 
also be calculated. 
The following PD outcome measures will be assessed when appropriate, as data allow: 
• 
Peripheral blood B-cell depletion and recovery.  For each visit at which CD19+ B-cell 
measurements are taken, B-cell data will be listed for each patient by dose level as follows: 
Absolute blood cell counts 
Percent change relative to the baseline blood counts 
CD19+ B-cell recovery, defined as the timepoint when the values return to baseline 
levels or ≥ 50% of baseline levels 
 
Activity Outcome Measures 
The following activity outcome measures will be assessed for rituximab-containing 
arms/cohorts (Arms A and B, Cohort C): 
• 
Objective response, defined as a PR or CR 
• 
Duration of objective response, defined as the duration of time from the first occurrence of a 
documented objective response to time of relapse or death from any cause 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
34/P GO27834-A3 
• 
Progression-free survival (PFS), defined as the duration from initial randomization to the 
first occurrence of progression or death within 30 days of the last administration of study 
drug, whichever occurs first 
• 
Overall survival (OS), defined as the duration from the date of randomization/enrollment to 
the date of death from any cause 
 
Objective response and disease progression will be determined using standard criteria for NHL. 
The following activity outcome measures will be assessed for obinutuzumab-containing cohorts (Cohorts 
E, G, and H) according to Lugano 2014 Response Criteria (Cheson et al. 2014): 
The primary activity outcome measure will be assessed by:  
• 
CR at end of treatment (6−8 weeks after Cycle 6 Day 1 or last dose of study medication) based on 
PET alone, as determined by the IRC  
The following secondary efficacy outcome measures will be assessed: 
• 
OR (CR or PR) at end of treatment based on PET alone as determined by the investigator and IRC  
• 
CR at end of treatment based on CT only, as determined by the investigator and IRC  
• 
OR (CR or PR) at end of treatment based on CT only as determined by the investigator and IRC  
• 
BOR (CR or PR) while on study based on PET alone or CT only, as determined by the investigator 
Exploratory Outcome Measures 
The exploratory outcome measures will include, but will not be limited to, the following:  
• 
Confirmation and quantitation of CD22, CD79b, and CD20 expression levels in either 
archival or freshly obtained (when available) tumor specimens (tumor biopsies, 
bone marrow biopsies, peripheral blood) by immunohistochemistry/flow 
cytometry/quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) 
• 
Additional assessments related to the understanding of the mechanism of action of 
DCDT2980S, DCDS4501A, rituximab, and obinutuzumab, mechanisms of resistance to 
DCDT2980S, DCDS4501A, rituximab, and obinutuzumab, and/or NHL pathogenesis may 
be included. 
• 
Treatment and disease symptom assessments using the M.D. Anderson Symptom 
Inventory (MDASI) in rituximab-containing cohorts only 
The following exploratory efficacy outcome measures will be assessed: 
• 
DOR, defined as the time from the date of the first occurrence of a documented CR or PR to the date 
of disease progression, relapse, or death from any cause, for the subgroup of patients with a best 
overall response of CR or PR, based on PET and/or CT scans as determined by the investigator 
assessment.  For patients achieving a response who have not experienced disease progression, relapse, 
or died prior to the time of the analysis, the DOR will be censored on the date of last disease 
assessment. 
• 
PFS, defined as the time from date of randomization or first treatment (for G-containing arms) to the 
first occurrence of progression or relapse, or death from any cause , based on PET and/or CT scans as 
determined by the investigator assessment. 
• 
EFS, defined as the time from date of randomization or first treatment (for G-containing arms) to 
any treatment failure including disease progression relapse, initiation of new anti-lymphoma 
therapy, or death from any cause, whichever occurs first, based on PET and/or CT scans as 
determined by the investigator assessment  
• 
OS, defined as the time from the date of first treatment to the date of death from any cause 
 
Investigational Medicinal Products 
Test Product 
Pinatuzumab Vedotin (DCDT2980S) and Polatuzumab Vedotin (DCDS4501A) 
Patients will receive DCDT2980S or DCDS4501A at 1.8 mg/kg or 2.4 mg/kg by IV infusion on 
Day 1 or Day 2 for each cycle.  The total dose of DCDT2980S or DCDS4501A for each patient 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
35/P GO27834-A3 
will be determined by the dose cohort to which the patient is assigned and depend on the 
patient’s weight within 96 hours prior to Day 1 of each cycle. 
Rituximab 
All patients in rituximab-containing arms/cohorts will receive DCDT2980S or DCDS4501A and 
rituximab administered by IV infusion on a 21-day cycle.  For the first two cycles, patients will 
receive rituximab 375 mg/m2 by IV infusion on Day 1 and DCDT2980S or DCDS4501A by IV 
infusion on Day 2.  In the absence of any infusion-related adverse events, rituximab 375 mg/m2 
and DCDT2980S or DCDS4501A may be administered on the same day (Day 1) in subsequent 
cycles beginning with the third cycle.  In this case, rituximab will be administered first, followed 
by DCDT2980S or DCDS4501A. 
Obinutuzumab 
Patients in obinutuzumab-containing cohorts will receive DCDS4501A and obinutuzumab 
administered by IV infusion on a 21-day cycle.  For the first cycle, patients will receive 
obinutuzumab 1000 mg by IV infusion on Days 1, 8, and 15.  DCDS4501A will be given on 
Day 2 for Cycle 1.  In the absence of any infusion-related adverse events, obinutuzumab and 
DCDS4501A may be administered on the same day (Day 1) in subsequent cycles beginning 
with the second cycle. 
Non-Investigational Medicinal Products 
Not applicable. 
Statistical Methods 
The final analysis will be based on patient data collected until all patients discontinue from the 
study or the study is terminated by the Sponsor, whichever occurs first.  The analyses will be 
based on the safety evaluable population, defined as patients who received at least one dose of 
study treatment.  All summaries will be presented according to the disease-specific cohort, 
treatment group, and assigned dose level. 
Analysis of the Conduct of the Study 
Enrollment, major protocol violations, and reasons for discontinuations from the study will be 
summarized. 
Demographic and baseline characteristics, such as age, sex, race/ethnicity, weight, duration of 
malignancy, and baseline ECOG Performance Status, will be summarized using means, 
standard deviations, medians, and ranges for continuous variables and proportions for 
categorical variables.  All summaries will be presented overall and by treatment group, assigned 
dose level, and disease-specific cohort. 
Study drug administration data will be listed by the disease-specific cohorts described in the 
protocol.  Any dose modifications will be flagged.  Means and standard deviations will be used 
to summarize the total doses of DCDT2980S, DCDS4501A, rituximab, and obinutuzumab 
received.  All summaries will be presented by treatment group, assigned dose level, and 
disease-specific cohort. 
Safety Analysis 
Safety will be assessed through summaries of adverse events, changes in laboratory test 
results, changes in physical findings on physical examinations, and changes in vital signs.  All 
patients who receive any amount of DCDT2980S, DCDS4501A, rituximab, or obinutuzumab will 
be included in the safety analysis and will be assigned to the treatment group on the basis of 
the study treatment received.  Patients who have dose level changes from the initial assigned 
dose level will be summarized by the initial assigned dose level of DCDT2980S or DCDS4501A. 
All adverse event data will be listed by study site, patient number, treatment group, 
disease-specific cohort, and cycle.  All adverse events occurring on or after treatment on Day 1 
of Cycle 1 will be summarized by mapped terms, appropriate thesaurus levels, and 
NCI CTCAE v4.0 toxicity grade.  In addition, all serious adverse events, including deaths will be 
listed separately and summarized.   
Selected laboratory data will be listed, with values outside of normal ranges identified.  The 
incidence of antibodies to DCDT2980S and DCDS4501A will be summarized. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
36/P GO27834-A3 
Pharmacokinetic and Pharmacodynamic Analyses 
Individual and mean serum concentrations of total DCDT2980S or DCDS4501A antibody 
(conjugated and unconjugated antibody) and rituximab or obinutuzumab and plasma 
concentrations of acMMAE and free MMAE versus time data will be tabulated and plotted by 
NHL disease subtype (relapsed or refractory follicular NHL or DLBCL).  The pharmacokinetics 
of the above analytes will be summarized by estimating the appropriate PK parameters 
(e.g., AUC, Cmax, CL, Vss, and t1/2).  Estimates for these parameters will be tabulated and 
summarized (mean, standard deviation, and range).  Non-compartmental, compartmental, 
and/or population methods will be used, as data allow.  
Exposure-response (safety and efficacy) analysis may be conducted with use of PK data and 
available drug effect (e.g., imaging, measures of tumor burden) and toxicity (e.g., clinical 
pathology) data, at the sponsor’s discretion. 
In addition, population PK methods may be employed to manage sparse data and to investigate 
the effects of certain covariates on the pharmacokinetics of DCDT2980S and DCDS4501A, as 
data allow, and at the sponsor’s discretion. 
Activity Analyses 
Best overall response, duration of response, and PFS will be listed for all patients. 
Overall response rate (ORR) from the initial study treatment will be calculated on the basis of 
data from patients who received study treatment.  Objective response is defined as CR or PR 
as determined by the investigator, on the basis of physical examinations, radiographic scans, 
and bone marrow examinations, using modified response criteria for NHL and confirmed by 
repeat assessments ≥ 4 weeks after initial documentation.  Any patient with insufficient data to 
determine response will be classified as a non-responder. 
For patients with DLBCL, primary assessment of tumor response will be based on diagnostic 
imaging scans⎯for example, CT and/or MRI scans and positron emission tomography (PET) 
scans.  For patients with FL enrolled on rituximab-containing arms/cohorts, primary assessment 
of response will be based on CT scans only; the assessment of response in FL based on PET 
scans will be performed for exploratory purposes only. 
For patients on obinutuzumab-containing cohorts, primary response assessment for both 
DLBCL and FL will be based on PET/CT scans using the updated 2014 Lugano Response 
Criteria.  Patients in Cohorts E, G, and H will be evaluated with a PET-CT scan at screening, 
between Cycle 4 Day 15 and Cycle 5 Day 1, and at the end of treatment (6-8 weeks after 
completing treatment).  The efficacy analysis for these cohorts will, therefore, be different from 
the analysis for Arms A-B and Cohorts C-D. (Cheson, et al 2014) (see Appendix C-2).  
Subsequent imaging can be CT only.  Responses to study treatment will also be based on 
investigator assessments. 
Among patients with an objective response, duration of response will be defined as the time 
from the initial documentation of a CR or PR to the time of disease progression or death.  If a 
patient does not experience death or disease progression before the end of the study, duration 
of response will be censored at the day of the last tumor assessment. 
For the randomized portion of the study (Arms A and B), PFS is defined as the time from the 
date of randomization to the date of disease progression or death from any cause, whichever 
occurs first.  If a patient has not experienced progressive disease or death, PFS will be 
censored at the date of the last tumor assessment.  Patients with no post-baseline tumor 
assessment will be censored on the date of randomization.  For the non-randomized portion of 
the study (Cohorts C through H), PFS is defined as the time from the date of study enrollment to 
the date of disease progression or death from any cause, whichever occurs first. 
For the randomized portion of the study (Arms A and B), OS is defined as the time from the date 
of randomization to the date of death from any cause.  For the non-randomized portion of the 
study (Cohorts C through H), OS is defined as the time from the date of study enrollment to date 
of death from any cause. 
Exploratory Analyses 
Assay results of possible predictive markers will be listed by treatment group and response 
status. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
37/P GO27834-A3 
Frequencies and percentages of missing data for the PRO endpoints will be reported.  Dropouts (defined 
as patients withdrawing from treatment for reasons other than documented disease progression or death) 
will be summarized. 
Summary statistics of the MDASI items, scales, and their changes from baseline will be 
calculated at each assessment timepoint.  The mean, standard error, and median of the 
absolute scores and the mean changes from baseline (and 95% CI) within and between study 
arms will be reported for the MDASI scales and single items, as well as the weekly averages of 
the worst symptom rating.  For change scores in the MDASI from baseline, patients without 
baseline scores will not be included in the analyses.  Line charts depicting the means and mean 
changes of subscales over time will be also provided.   
Repeated measures mixed-effects models will explore MDASI subscale scores with a baseline 
score and appropriate covariates added, as appropriate. 
Handling of Missing Data 
For the endpoint of objective response, patients without a post-baseline tumor assessment will 
be considered non-responders in the all-treated population analysis.  
For duration of response and PFS, data from patients who are lost to follow-up will be included 
in the analysis as censored observations on the last date that the patient is known to be 
progression free, defined as the date of the last tumor assessment, or, if no tumor assessments 
were performed, as the date of last study treatment plus 1 day. 
Compliance to PRO data collection will be reported with summary statistics, including 
frequencies of reasons for non-compliance such as patient refusal to complete PRO data 
collection.   
Determination of Sample Size 
For the randomized portion of the study (Arms A and B), a target of 120 patients will be enrolled 
in two separate cohorts of patients (40 in the follicular NHL cohort and 80 in the DLBCL cohort).  
The randomized portion of this study is non-comparative in nature.  No formal hypothesis 
testing is planned to compare the treatment arms.  Moreover, there is insufficient power to 
detect minimum clinically meaningful differences between the two treatment arms.  Genentech 
has judged the proposed sample size to provide sufficient precision in estimating the anti-tumor 
activity of DCDT2980S combined with rituximab or DCDS4501A combined with rituximab as 
measured by objective response.  For example, with the assumption of an observed response 
rate of 40%, a 90% confidence interval for the response rate would be approximately 22%−58% 
(i.e., 40% ± 18%) for the follicular NHL cohort and approximately 27%−53% (i.e., 40% ± 13%) 
for the DLBCL cohort.  With 40 patients, there is an 87% chance of observing at least one 
adverse event with a true incidence of 5%. 
For the non-randomized portions of the study (Cohorts C and D), approximately 20 patients will 
be enrolled into each arm, for a total of 40 patients.   With 20 patients under an observed 
response rate of 40%, the exact Clopper-Pearson 90% confidence interval for the response rate 
would be 22%−61%.  With respect to the assessment of safety based upon a sample size of 
20 patients, the chance of observing at least one adverse event with a true incidence of 10% is 
88%. 
For the obinutuzumab safety run-in cohort (Cohort E), 6 patients will be enrolled.  For the 
obinutuzumab expansion cohorts (Cohorts G and H), 40 patients with follicular NHL and 
40 patients with DLBCL will be enrolled at the RP2D to further evaluate safety and efficacy of 
the combination.  Table 3 in the protocol provides asymptotic 90% confidence intervals for the 
true probability of response for a range of observed proportions based upon a sample of 
40 patients.  A sample size of 40 patients is deemed sufficient to provide adequate precision on 
the point estimate and for the lower end of the 90% CI to rule out a clinically uninteresting rate 
of 45% assuming observed response rates of approximately 60% or higher (~24 responders 
observed among 40 patients). 
Therefore, up to 252 patients may be enrolled in this study.  
 


 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ac 
antibody-conjugated 
ADC 
antibody−drug conjugate  
ADCC 
antibody-dependent cellular cytotoxicity 
ADCP 
antibody-dependent cell-mediated phagocytosis 
AE 
adverse event 
anti-HBc 
hepatitis B core antibody 
ASCO 
American Society of Clinical Oncology 
ATA 
anti-therapeutic antibody 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from 0 to 24 hours 
AUCinf 
area under the concentration-time curve from 0 to infinity 
CDC 
complement-dependent cytotoxicity  
CHOP 
cyclophosphamide, doxorubicin, vincristine, and prednisone 
CL 
clearance  
CLL 
chronic lymphocytic leukemia  
Cmax 
maximum plasma and serum concentration 
Cmin 
trough plasma and serum concentration 
CR 
complete response 
CRu 
unconfirmed response 
CT 
computed tomography (scan) 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVP 
cyclophosphamide, vincristine, and prednisone 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EC 
ethics committee 
eCRF 
electronic Case Report Form  
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture  
EFS 
event-free survival 
EMA 
European Medicines Agency 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
EOT 
end of treatment 
FACS 
fluorescence-activated cell sorting 


 
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Abbreviation 
Definition 
FBS 
fasting blood sugar 
FDA 
U.S. Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FL 
follicular lymphoma 
G 
GA101 or obinutuzumab 
G-CHOP 
obinutuzumab, cyclophosphamide, doxorubicin, vincristine, 
and prednisone 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
HbsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HNSTD 
highest non-severely toxic dose 
HPW 
highly purified water 
ICH 
International Conference on Harmonisation 
IgG1 
immunoglobulin-G1  
IHC 
immunohistochemistry 
IL 
interleukin 
IMC 
Internal Monitoring Committee 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
iNHL 
indolent non-Hodgkin’s lymphoma 
IP 
interferon-inducible protein 
IRB 
Institutional Review Board 
IRF 
Independent Review Facility 
IRR 
infusion-related reaction 
ISH 
in situ hybridization 
IV 
intravenous 
IXRS 
Interactive Voice and Web Response System 
JC 
John Cunningham 
Kd 
equilibrium dissociation constant 
LC-MS/MS 
liquid chromatography–tandem mass spectrometry 
LMWH 
low-molecular weight heparin 
MCL 
mantle cell lymphoma 
MC-VC-PABC 
maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl 
MDASI 
M.D. Anderson Symptom Inventory 
MMAE 
monomethyl auristatin E  


 
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Abbreviation 
Definition 
MAb 
monoclonal antibody 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose  
MZL 
marginal zone lymphoma 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphoma 
NK 
natural killer 
NOAC 
new oral anticoagulant 
ORR 
overall response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PE 
polyethylene 
PET 
positron emission topography 
PD 
pharmacodynamic 
PFS 
progression-free survival 
PK 
pharmacokinetic  
PML 
progressive multifocal leukoencephalopathy 
PP 
polypropylene 
PR 
partial response 
PRO 
patient-reported outcomes 
PVC 
polyvinyl chloride 
PUR 
polyurethane 
qRT-PCR 
quantitative reverse transcriptase polymerase chain reaction 
q3w 
every 3 weeks 
R 
rituximab 
R-CHOP 
rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone 
RP2D 
recommended Phase II dose 
SAE 
serious adverse event 
SC 
subcutaneous 
SCID 
severe combined immunodeficiency 
SCT 
stem cell transplant 
SD 
stable disease 
SDV 
source data verification 
SmPC 
Summary of Product Characteristics 


 
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Abbreviation 
Definition 
STD10 
severely toxic dose to 10% 
SWFI 
Sterile Water for Injection 
t1/2 
terminal half-life 
TLS 
tumor lysis syndrome  
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
Vss 
steady-state volume of distribution 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON DISEASE  
B-cell lymphoproliferative disorders are a heterogeneous group of malignancies, ranging 
from slow-growing indolent and incurable diseases with a median survival of 8−10 years 
(such as follicular non-Hodgkin’s lymphoma [NHL]) to more aggressive intermediate- to 
high-grade lymphomas (such as diffuse large-cell lymphoma), which can have a median 
survival of 6 months if left untreated or long-term remission in more than 50% of patients 
with appropriate treatment.  Diffuse large B-cell lymphoma (DLBCL) is the most common 
type of NHL accounting for approximately 30%−40% of all new patients, whereas 
follicular lymphoma (FL) accounts for approximately 20%−25% of new lymphomas.   
Despite advances in the clinical outcomes of patients with NHL using treatments such as 
the CD20-specific monoclonal antibody (MAb) rituximab (Rituxan®, MabThera®) in 
combination with chemotherapy, indolent B-cell malignancies remain incurable, as do 
approximately half of aggressive NHL patients.  Thus, there is still a need for treatments 
that can be combined with chemoimmunotherapy and can significantly extend 
disease-free and overall survival (OS) in these patients, with at least acceptable, if not 
superior, safety profiles. 
1.2 
BACKGROUND ON THE MOLECULES 
1.2.1 
DCDT2980S 
1.2.1.1 
Background and Preclinical Data 
CD22 is a cell-surface antigen whose expression is restricted to all mature B cells except 
plasma cells.  It is expressed in a majority of the B cell−derived malignancies, including 
nearly all NHL and chronic lymphocytic leukemia (CLL) samples tested (see Figure 1).  
Antibodies bound to CD22 are rapidly internalized, making CD22 ideally suited for 
targeted delivery of cytotoxic agents (Shan and Press 1995).   
DCDT2980S is an antibody−drug conjugate (ADC) that consists of a potent anti-mitotic 
agent, monomethyl auristatin E (MMAE) conjugated to a humanized immunoglobulin-G1 
(IgG1) anti-CD22 MAb, MCDT2219A, via a protease-labile linker, 
maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-VC-PABC).  
MMAE has a mode of action similar to vincristine, which is a component of standard 
chemotherapy used in lymphoma therapy.  This therapeutic approach takes advantage 
of the specific targeting capability of the antibody and the cytotoxic activity of MMAE.  
Following internalization, the MMAE is deconjugated from DCDT2980S by lysosomal 
enzymes, binds to tubulin, and disrupts the microtubule network, resulting in inhibition of 
cell division and cell growth and induction of apoptosis (Doronina et al. 2003).  


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Figure 1 CD22 Expression Levels on B-Cell Tumor Cells 
0
1000
2000
3000
CLL
DLBCL
FL
MCL
MZL
0
1000
2000
3000
CLL
DLBCL
FL
MCL
MZL
 
CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; FL = follicular 
lymphoma; MCL = mantle cell lymphoma; MFI = mean fluorescence intensity; MZL =  marginal 
zone lymphoma. 
CD22 expression levels (MFI) on B-cell tumor cells were assessed by flow cytometry in patients 
diagnosed with the following B-cell lymphomas:  CLL (n = 49), DLBCL (n = 59), FL (n = 58), 
MCL (n = 20), and MZL (n = 60).  
 
Comprehensive pharmacologic, pharmacokinetic (PK), pharmacodynamic (PD), and 
toxicology evaluations were conducted to support the use of DCDT2980S in clinical 
trials.  DCDT2980S binds human CD22 with a high affinity (equilibrium dissociation 
constant [Kd] = 1.7 ± 0.2 nM) and showed similar binding affinity to cynomolgus monkey 
CD22.  No binding activity was observed with mouse and rat peripheral blood 
mononuclear cells (PBMCs).   
The unconjugated antibody MCDT2219A did not appear to induce antibody-dependent 
cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) in vitro.  
In contrast, DCDT2980S displayed potent and selective inhibition of cell proliferation in 
vitro (50% of the maximal inhibitory concentration [IC50] = 0.33 nM) by cell viability 
assays.  Efficacy studies conducted in murine xenograft models of human lymphoma 
(CD22-positive WSU-DLCL2 and BJAB cell lines) showed that a single dose of 
DCDT2980S resulted in regression of tumor growth at doses ranging from 1 to 4 mg/kg.  
PD studies with DCDT2980S showed that a single dose of 1−6 mg/kg resulted in partial 
depletion of peripheral blood B cells in cynomolgus monkeys with a corresponding 
depletion in germinal center B cells in lymphoid tissue. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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The PK profiles of DCDT2980S were observed to be linear in rodents and moderately 
non-linear in cynomolgus monkeys over the tested dose range.  The non-linear 
clearance (CL) observed in cynomolgus monkeys with DCDT2980S is likely due to the 
contribution of B cell-mediated CL to the total CL.  The free MMAE concentrations in 
cynomolgus monkeys following DCDT2980S administration were generally 10,000 times 
lower than the concentration of DCDT2980S.   
Cynomolgus monkeys were selected as the most relevant nonclinical species for the 
toxicology and PK/PD studies of DCDT2980S, given the comparable sequence 
homology of human and cynomolgus monkey CD22, similar binding affinity of 
DCDT2980S to human and cynomolgus monkey CD22, and comparable tissue 
cross-reactivity in both human and cynomolgus monkey tissues.  DCDT2980S was well 
tolerated at doses of up to 3 mg/kg (highest non-severely toxic dose [HNSTD]) in 
monkeys and up to or greater than 10 mg/kg in rats (severely toxic dose to 10% [STD10] 
of rats ≥ 10 mg/kg).  Reversible bone marrow toxicity and associated hematopoietic 
changes were observed in both rats and monkeys treated with DCDT2980S or MMAE, 
suggesting that the toxicity of DCDT2980S is related to MMAE.  Additional effects on 
liver and lung in rats were minimal in severity and reversible and did not occur in 
cynomolgus monkeys, which may be due to differences in species sensitivity, exposure, 
and/or pharmacokinetics.   
Complete details of preclinical studies of DCDT2980S can be found in the DCDT2980S 
Investigator’s Brochure. 
1.2.1.2 
DCDT2980S Clinical Data 
a. Patient Enrollment 
Both DCDT2980S monotherapy and combination therapy with rituximab have been 
studied in a Phase I study (Study DCT4862g) of patients with relapsed or refractory 
B-cell malignancies expected to express CD22, including indolent NHL, DLBCL, mantle 
cell lymphoma (MCL), and CLL. 
All data presented herein is based on a data entry cutoff of 22 February 2013, with 
clinical data available from 65 patients with NHL (excluding patients with CLL) enrolled in 
dose-escalation and expansion cohorts.  These include 49 patients who were treated 
with single-agent DCDT2980S at doses ranging from 0.1 to 3.2 mg/kg administered 
intravenously every 21 days and 16 patients who were enrolled into two Phase Ib 
cohorts with DCDT2980S administered at doses of 1.8 mg/kg (5 patients) and 2.4 mg/kg 
(11 patients) in combination with 375 mg/m2 rituximab. 
Enrollment into CLL dose escalation cohorts was closed on 31 May 2013.  Refer to the 
DCDT2980S Investigator Brochure for details regarding clinical data in CLL patients. 


 
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b. Pharmacokinetics 
The pharmacokinetics of DCDT2980S have been characterized in the Phase I 
Study DCT4862g.  DCDT2980S was administered to patients with NHL at dose levels 
ranging from 0.1 to 3.2 mg/kg every 3 weeks (q3w).  Three analytes were quantified:  
antibody-conjugated MMAE (acMMAE), total antibody, and free MMAE.  
Preliminary PK analysis based on available data as of 22 June 2012 is summarized 
below.   
The mean value of CL estimates of acMMAE and total antibody of each dose level for 
doses of ≥ 1.0 mg/kg ranged from 17.6 to 21.3 mL/day/kg and from 10.5 to 
16.2 mL/day/kg, respectively.  Similar CL estimates for doses ≥ 1.0 mg/kg suggested 
dose-proportional increase of acMMAE and total antibody exposure.  CL estimates 
appeared to be slightly higher at doses < 1.0 mg/kg (0.1, 0.25, and 0.5 mg/kg), although 
data from these dose levels are limited.  The CL of acMMAE was faster than that of total 
antibody at each dose level.   
In patients with NHL, the mean value of the steady-state volume of distribution (Vss) of 
acMMAE and total antibody of each dose level ranged from 69.2 to 130 mL/kg and from 
97.4 to 154 mL/kg, respectively, across the dose levels tested, approximating human 
serum volume.  Vss values did not appear to change substantially with dose.  The half-life 
for acMMAE and total antibody ranged from 2.9 to 7.0 days and from 4.4 to 13 days, 
respectively.   
For acMMAE and total antibody, the time to maximum concentration occurred 
immediately after infusion.  For free MMAE, the time to maximum concentration was 
approximately 2 to 3 days after infusion.  Maximum plasma and serum concentration 
(Cmax) and area under the concentration-time curve from Time 0 to infinity (AUCinf) of free 
MMAE appeared to increase with dose across the dose levels tested.  A half-life of 
3-4 days for free MMAE was observed, which is relatively long and similar to that of its 
parent conjugate, suggesting formation rate−limited kinetics of free MMAE.  No 
accumulation of free MMAE is expected for the q3w regimen.  The Cmax values of free 
MMAE in NHL patients were at least 100-fold lower than acMMAE concentrations at 
each dose level, suggesting a slow release of free MMAE from acMMAE and potentially 
fast elimination once it is formed.  
Preliminary comparisons of pharmacokinetics between patients with NHL and CLL (for 
which patients are enrolled into separate dose-escalation cohorts) treated with identical 
doses of DCDT2980S provide some insight into the factors that affect pharmacokinetics.  
Both acMMAE and total antibody were cleared faster in CLL patients than in NHL 
patients.  This observation is likely to be related to the high number of circulating B cells 
generally observed in CLL patients, which may result in significant target-mediated CL of 
DCDT2980S.  The free MMAE exposure in CLL patients was relatively low compared to 
that of its parent conjugate.   


 
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The exposure parameters (Cmax and AUCinf) of total antibody, acMMAE, and free MMAE 
were similar between DCDT2980S and DCDT2980S + rituximab at doses of 1.8 and 
2.4 mg/kg, based on preliminary data.  This observation suggests that when given in 
combination, rituximab does not impact the pharmacokinetics of DCDT2980S; the effect 
of DCDT2980S on rituximab pharmacokinetics will be assessed. 
All observations will be verified with additional data from the ongoing Phase I study as 
well as this study.  
Refer to the DCDT2980S Investigator Brochure for complete and updated details. 
c. Safety 
Dose Limiting Toxicity 
Study DCT4862g utilizes a standard 3 + 3 dose-escalation cohort enrollment scheme.  
Patients enrolled into each dose-escalation cohort in Study DCT4862g have been 
observed for dose-limiting toxicities (DLT) for a minimum of 21 days after their first dose 
of DCDT2980S.  Any patient who did not complete the DLT observation period for any 
reason other than a DLT was replaced. 
Separate dose-escalation cohorts enrolled patients with B-cell NHL and CLL.  For the 
NHL dose escalation, DLTs of Grade 4 neutropenia occurred in 1 patient out of 
3 DLT-evaluable patients in the 3.2 mg/kg single-agent cohort and 1 patient out of 
11 DLT-evaluable patients in the 2.4 mg/kg + rituximab cohort.  Consequently, 
DCDT2980S at 2.4 mg/kg was determined to be the recommended Phase II dose 
(RP2D) as both monotherapy and in combination with rituximab.   
For the CLL dose-escalation cohorts, one DLT was reported to date.  This Grade 5 event 
of febrile neutropenia resulted in the patient’s death.  Whereas the contribution of the 
study drug to the neutropenia could not be completely ruled out, other factors, including 
bone marrow involvement of disease that resulted in baseline anemia, thrombocytopenia 
and neutropenia, and clinical evidence of disease progression may have also played a 
contributory role. 
Single-Agent DCDT2980S and DCDT2980S Combined with Rituximab in 
NHL 
Forty-nine patients received single-agent DCDT2980S at a starting dose of  ≥ 1.8 mg/kg 
(7 at 1.8 mg/kg, 42 at 2.4 mg/kg); 16 patients received DCDT2980S at a starting dose 
of ≥ 1.8 mg/kg in combination with rituximab (5 at 1.8 mg/kg, 11 at 2.4 mg/kg).  Overall 
the safety profile of DCDT2980S combined with rituximab did not differ from that of 
single-agent DCDT2980S. 
Treatment-emergent hematologic and commonly reported nonhematologic adverse 
events for all grades in patients treated with single-agent DCDT2980S and DCDT2980S 
plus rituximab included neutropenia (29%), febrile neutropenia (3%), infection (system 
organ class; 43%), anemia (25%), thrombocytopenia (12%), peripheral neuropathy 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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(28%), diarrhea (40%), pyrexia (14%), nausea (34%), and fatigue (55%).  
Treatment-emergent Grade ≥ 3 adverse events included neutropenia (25%), febrile 
neutropenia (3%), infection (system organ class; 11%), anemia (5%), peripheral 
neuropathy (3%), diarrhea (5%), pyrexia (2%), and fatigue (3%).  Serious adverse 
events assessed by the treating investigator to be related to DCDT2980S were reported 
in 21% of patients.   Dose discontinuations for adverse events were reported in 20% of 
patients. 
Refer to the DCDT2980S Investigator’s Brochure for complete and updated details 
related to safety.  
d. Efficacy in Non-Hodgkin’s Lymphoma 
Investigator-based objective responses were observed in 17 of 43 (40%) patients treated 
with single-agent DCDT2980S and 5 of 15 (33%) patients treated with DCDT2980S 
combined with rituximab.  Among patients with relapsed or refractory DLBCL, 11 of 28 
(39%) objective responses (5 complete responses [CR] and 6 partial responses [PR]) 
were observed with single-agent DCDT2980S and 3 of 7 (43%; 2 CR, 1 PR) with 
DCDT2980S combined with rituximab.  Among patients with relapsed or refractory 
indolent NHL (iNHL), 6 of 13 (46%) objective responses (2 CR, 4 PR) were observed 
with single-agent DCDT2980S and 1 of 4 (PR) with DCDT2980S combined with 
rituximab.   
Refer to the DCDT2980S Investigator Brochure for complete and updated details related 
to anti-tumor activity. 
1.2.2 
DCDS4501A 
1.2.2.1 
Background and Preclinical Data 
CD79b is a cell-surface antigen whose expression is restricted to all mature 
B cells except plasma cells.  It is expressed in a majority of B cell−derived malignancies, 
including nearly all NHL and CLL samples tested (see Figure 2) (Dornan et al. 2009).  
Antibodies bound to CD79b are rapidly internalized, making CD79b ideally suited 
for targeted delivery of cytotoxic agents (Polson et al. 2007, 2009).   
Similar to DCDT2980S, DCDS4501A is an ADC that contains a humanized 
immunoglobulin-G1 (IgG1) anti−human CD79b MAb (MCDS4409A) and MMAE linked 
through MC-VC-PABC.   
Comprehensive pharmacologic, PK, PD, and toxicological evaluations were undertaken to 
support the entry of DCDS4501A into clinical trials.  Because DCDS4501A specifically 
recognizes CD79b on B cells of human but not on those of cynomolgus monkey, rat, or 
mouse, a surrogate ADC (DCDS5017A) that binds to cynomolgus monkey CD79b was 
generated to assess the antigen-dependent pharmacological, toxicological, and PK/PD 
activities in cynomolgus monkeys.  The structure, binding epitope, and binding affinity of 
the surrogate ADC are similar to those of DCDS4501A. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Figure 2 CD79b Expression Levels on B-Cell Tumor Cells 
 
CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; 
FL = follicular lymphoma; MCL = mantle cell lymphoma; MFI = mean fluorescence intensity; 
MZL = marginal zone lymphoma.  
CD79b expression levels (MFI) on B-cell tumor cells were assessed by flow cytometry in patients 
diagnosed with the following B-cell lymphomas:  CLL (n = 49), DLBCL (n = 59), FL (n = 58), 
MCL (n = 20), and MZL (n = 60). 
 
DCDS4501A bound human CD79b with high affinity (Kd = 1.83± 0.26 nM); the surrogate 
ADC also showed similar high binding affinity to cynomolgus monkey CD79b.  
DCDS4501A displayed potent and selective inhibition of tumor cell proliferation in vitro 
(IC50 = 0.071 nM ± 0.01 nM) in cell viability assays.  Moderate ADCC but no CDC activity 
was observed with the unconjugated clinical candidate antibody MCDS4409A.  Both 
clinical and surrogate unconjugated antibodies showed no appreciable cytokine release 
when evaluated in in vitro cytokine release assays with PBMCs.  Moderate elevations 
in interleukin (IL)-1α and interferon-inducible protein (IP)-10 were observed only with the 
unconjugated clinical antibody, however the clinical significance of these observations 
are not known because IL-1α and IP-10 are not produced by B cells, are not involved in 
B-cell signaling through CD79b, and are not associated with cytokine-release syndromes 
in vivo. 
Single intravenous (IV) doses of DCDS4501A resulted in inhibition of tumor growth in 
murine xenograft models of lymphoma.  Tumor regression was observed at doses 
ranging from 0.5 to 3 mg/kg.  In contrast, MCDS4409A showed no activity.  DCDS4501A 
administered at 5 mg/kg demonstrated better anti-tumor activity compared to a current 
standard-of-care regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, 
and prednisone [R-CHOP]) in xenograft models of NHL.  PD studies demonstrated that 
doses of the surrogate ADC ranging from 0.3 to 5 mg/kg resulted in a decrease of 


 
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peripheral blood B cells in cynomolgus monkeys.  A preferential decrease of proliferating 
B cells (CD20+ Ki67+) compared to the resting B cells (CD20+ Ki67−) ) by the surrogate 
ADC was demonstrated in cynomolgus monkeys, in line with the expected mechanism of 
action of an anti-mitotic agent, MMAE. 
Due to B cell−mediated CL, non-linear pharmacokinetics were observed with the 
surrogate ADC in cynomolgus monkeys following single IV doses of 0.3−3 mg/kg or four 
doses of 3 and 5 mg/kg given q3w.  The total antibody exposure after the fourth dose 
increased approximately 1.2- to 1.5-fold compared to the first dose.  As expected, the 
toxicokinetic profile of the clinical ADC in rats and cynomolgus monkeys was linear in the 
tested dose range.  Consistent with the half-life of the clinical ADC, minimal 
accumulation was observed following weekly dosing in rats and no accumulation was 
observed following q3w dosing in cynomolgus monkeys.  The free MMAE concentrations 
in plasma following administration of the clinical or surrogate ADCs were generally low 
and overall did not exceed 2 ng/mL, regardless of dose.  The overall incidence of 
anti-therapeutic antibodies (ATAs) was 20%−67% following administration of the clinical 
or surrogate ADCs in cynomolgus monkeys; however, the ATAs did not appear to impact 
the toxicokinetic/PK parameter estimates. 
In repeat-dose toxicity studies in rats and cynomolgus monkeys, DCDS4501A and 
the surrogate ADC were well tolerated in monkeys up to doses of 5 mg/kg and 3 mg/kg 
respectively, with 3 mg/kg considered the HNSTD.  In rats, DCDS4501A was well 
tolerated up to 6 mg/kg (STD10 = 10 mg/kg).  The predominant antigen-independent 
findings associated with DCDS4501A or surrogate ADC exposure were reversible bone 
marrow toxicity and associated peripheral blood cell effects in both monkeys and rats.  
Administration of the surrogate ADC to monkeys also resulted in expected 
antigen-dependent reversible decreases in peripheral blood B cells and the 
disappearance of B-cell germinal centers in splenic lymphoid follicles at doses ≥ 3 mg/kg.  
Additional findings observed in rats but not in monkeys included thymic lymphoid 
depletion at ≥ 6 mg/kg, minimal to mild liver toxicities (at ≥ 6 mg/kg), lung toxicities at 
10 mg/kg in male animals only, and a slight increase in apoptosis and mitoses in multiple 
tissues, including skin and adnexa.  Hepatobiliary toxicity consisted of transient 
dose-dependent liver enzyme elevations accompanied by minimal to slight 
dose-dependent increases in mitotic figures/apoptosis in hepatocytes, sinusoidal cells, 
and bile duct epithelium as well as minimal to slight dose-dependent random focal 
hepatic necrosis.  Pulmonary toxicity was characterized by minimal to slight 
dose-dependent alveolar macrophage infiltration, sometimes accompanied by minimal to 
slight type II pneumocyte hyperplasia/hypertrophy.  These findings were consistent with 
the expected pharmacologic effect of MMAE on inducing mitotic arrest due to inhibition 
of tubulin polymerization.  Except for two individual instances (one female given 
10 mg/kg in the liver and one male given 10 mg/kg in the lung), these findings were 
completely reversible after a 6-week recovery period.  Non-reversible male reproductive 


 
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toxicity, characterized by degeneration of testicular seminiferous tubules, was observed 
in rats at all doses.  
Complete details of preclinical studies of DCDS4501A can be found in the DCDS4501A 
Investigator’s Brochure. 
1.2.2.2 
DCDS4501A Clinical Data 
a. Patient Enrollment 
Both DCDS4501A monotherapy and combination therapy with rituximab are being 
studied in a Phase I study (Study DCS4968g) of patients with relapsed or refractory 
B-cell malignancies expected to express CD79b, including indolent NHL, DLBCL, MCL, 
and CLL.   
All data presented herein is based on a data entry cutoff of 28 February 2013, with 
clinical data available from 60 patients with NHL (excluding patients with CLL) enrolled in 
dose-escalation and expansion cohorts.  These include 51 patients who were treated 
with single-agent DCDS4501A ranging from 0.1 to 2.4 mg/kg administered intravenously 
every 21 days and 9 patients who were enrolled into a single Phase Ib cohort with 
DCDS4501A administered at a dose of 2.4 mg/kg in combination with 375 mg/m2 
rituximab. 
In the CLL dose-escalation cohorts, two DLTs were reported at the single-agent dose of 
1.8 mg/kg.   Enrollment into the CLL cohorts was stopped on 7 January 2013.  Refer to 
the DCDS4501A Investigator Brochure for details regarding clinical data in CLL patients.   
b. Pharmacokinetics 
The pharmacokinetics of DCDS4501A were characterized in the Phase I Study 
DCDS4501A.  DCDS4501A was administered in patients with NHL at escalating doses 
of 0.1 to 2.4 mg/kg q3w as monotherapy and following administration of rituximab in the 
Phase Ib cohort.  Three analytes were quantified:  acMMAE, total antibody, and free 
MMAE.  
Preliminary PK analysis based on available data as of 22 June 2012 is summarized 
below.  The CL estimates of acMMAE and total antibody of each dose level is in the 
range of 14.9–21.2 mL/day/kg and 7.12–27.9 mL/day/kg, respectively.  CL estimates 
were similar across doses of 0.1–2.4 mg/kg tested, suggesting dose-proportional 
increase of acMMAE and total antibody exposure.  The CL of acMMAE was faster than 
that of total antibody at each dose level.   
The mean value of Vss of acMMAE and total antibody of each dose level ranged from 
61 to 80.8 mL/kg and from 59.4 to 114.3 mL/kg, respectively, across the dose levels 
tested, which approximated human serum volume.  Vss values did not appear to change 
substantially with dose.  The half-lives for acMMAE and total antibody are from 2.4 to 
5.5 days and 2.9 to 7 days, respectively.  


 
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In a single-agent dose-escalation study, for acMMAE and total antibody, the time to 
maximum concentration occurred immediately after infusion.  For free MMAE, the time to 
maximum concentration was approximately 2 to 3 days after infusion.  Cmax and AUCinf of 
free MMAE appear increased with dose across the dose levels.  A half-life of 3–4 days 
for free MMAE was observed, which is relatively long and similar to acMMAE and 
suggests formation rate−limited kinetics for free MMAE.  No accumulation of free MMAE 
is expected for the q3w regimen.  The Cmax values of free MMAE in NHL patients were at 
least 100-fold lower compared with acMMAE concentrations at each dose level, 
suggesting a slow release of free MMAE from acMMAE and potentially fast elimination 
once it is formed.   
Preliminary comparisons of pharmacokinetics between patients with NHL and CLL (for 
which patients are enrolled into separate dose-escalation cohorts) treated with identical 
doses of DCDS4501A provide some insight into the factors that affect pharmacokinetics.  
Both acMMAE and total antibody were cleared faster in CLL patients than in NHL 
patients.  This observation is likely to be related to the high number of circulating B cells 
generally observed in CLL patients, which may result in significant target-mediated CL of 
DCDS4501A.  The free MMAE exposure in CLL patients was relatively low compared 
with that of its parent conjugate. 
To date, PK data for patients treated with DCDS4501A in combination with rituximab is 
limited.  Consequently, full comparison with single-agent DCDS4501A pharmacokinetics 
is not possible.  On the basis of very limited data from 3 patients, total antibody 
pharmacokinetics was comparable between 2.4 mg/kg of DCDS4501A administered as 
a single agent and following rituximab administration, suggesting that when given in 
combination, rituximab does not affect the pharmacokinetics of DCDS4501A; the effect 
of DCDS4501A on rituximab pharmacokinetics will be assessed.   
All observations will be verified with additional data from the ongoing Phase I study as 
well as this study. 
Refer to the DCDS4501A Investigator Brochure for complete and updated details. 
c. Safety 
Dose-Limiting Toxicities 
Study DCS4968g utilizes a standard 3 + 3 dose escalation cohort enrollment scheme.  
Patients enrolled into each dose-escalation cohort in Study DCS4968g have been 
observed for DLTs for a minimum of 21 days after their first dose of DCDS4501A.  
Any patient who did not complete the DLT observation period for any reason other than 
a DLT was replaced. 
DLT of Grade 4 neutropenia occurred in 1 patient out of 10 DLT-evaluable patients in the 
2.4 mg/kg single-agent cohort and 1 patient out of 9 DLT-evaluable patients in the 
2.4 mg/kg + rituximab cohort.  Doses of DCDS4501A greater than 2.4 mg/kg as 


 
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monotherapy or in combination with rituximab were not assessed.  Consequently, 
DCDS4501A at 2.4 mg/kg was therefore determined to be the RP2D as both 
monotherapy and in combination with rituximab.   
In the CLL dose-escalation cohorts, two DLTs were reported at the single-agent dose of 
1.8 mg/kg.  One patient had a Grade 4 neutropenia, and 1 patient had a Grade 4 
invasive fungal infection.   
Single-Agent DCDS4501A and DCDS4501A Combined with Rituximab 
Fifty-two patients received single-agent DCDS4501A at a starting dose of ≥ 1.8 mg/kg 
(6 at 1.8 mg/kg, 45 at 2.4 mg/kg); an additional 9 patients received DCDS4501A at a 
dose of 2.4 mg/kg in combination with rituximab.  Overall, the safety profile of 
DCDS4501A combined with rituximab did not differ from that of single-agent 
DCDS4501A. 
Treatment-emergent hematologic and commonly reported non-hematologic adverse 
events of all grades in patients treated with single-agent DCDS4501A and DCDS4501A 
plus rituximab included neutropenia (50%), febrile neutropenia (5%), infection (system 
organ class; 35%), anemia (13%), thrombocytopenia (18%), peripheral neuropathy 
(32%), diarrhea (43%), pyrexia (37%), nausea (35%), and fatigue (18%).  
Treatment-emergent Grade ≥ 3 adverse events included neutropenia (43%), febrile 
neutropenia (5%), infection (system organ class; 10%), anemia (8%), peripheral 
neuropathy (7%), diarrhea (3%), pyrexia (2%), and fatigue (5%).   Serious adverse 
events assessed by the treating investigator to be related to DCDS4501A were reported 
in 20% of patients.   Dose discontinuations for adverse events were reported in 33% of 
patients. 
Refer to the DCDS4501A Investigator’s Brochure for complete and updated details 
related to safety.   
d. Efficacy 
Investigator-based objective responses were observed in 28 of 49 (57%) patients treated 
with single-agent DCDS4501A and 7 of 9 patients (78%) treated with DCDS4501A 
combined with rituximab.  Among patients with relapsed or refractory DLBCL, objective 
responses were observed in 16 of 30 (53%; 4 CR, 12 PR) patients treated with 
DCDS4501A; 1 patient with DLBCL was treated with DCDS4501A combined with 
rituximab and achieved a PR.  Among patients with relapsed or refractory iNHL, 
objective responses were observed in 7 of 14 (50%; 2 CR, 5 PR) patients treated with 
single-agent DCDS4501A and 5 of 5 (100%; 2 CR, 3 PR) patients treated with 
DCDS4501A plus rituximab.  
Refer to the DCDS4501A Investigator’s Brochure for complete and updated details 
regarding anti-tumor activity. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
53/P GO27834-A3 
1.2.3 
Rituximab 
Rituximab has been shown to be an effective treatment for CD20-positive B-cell 
malignancies and is commonly used both as a single agent and in combination with 
cytotoxic chemotherapy.  Rituximab binds to CD20, a hydrophobic, transmembrane 
protein that is present on pre–B cells and mature B cells and in ≥ 90% of B-cell NHLs.  
It exerts its cytotoxic effects via complement-mediated B-cell lysis, ADCC, and induction 
of apoptosis (Cartron et al. 2004). 
In the United States, rituximab has been approved by the U.S. Food and Drug 
Administration (FDA) for the following indications in NHL:  as a single agent for the 
treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive 
B-cell NHL; for the treatment of relapsed or refractory, low-grade or follicular, 
CD20-positive B-cell NHL, including initial treatment weekly for eight doses and 
re-treatment (weekly for four doses) in patients who responded to an initial course of 
rituximab; for the treatment of low-grade, CD20-positive B-cell NHL, in combination with 
cyclophosphamide, vincristine, and prednisone (CVP) induction chemotherapy in 
previously untreated patients with follicular, CD20-positive NHL; as treatment in 
previously untreated patients with low-grade, CD20-positive NHL who achieve an 
objective response or stable disease (SD) following CVP induction; and as maintenance 
therapy for previously untreated follicular CD20-positive B-cell NHL after achieving a 
response to a regimen including chemotherapy and rituximab. 
In the European Union, rituximab (MabThera®) is approved for the treatment of the 
following indications in NHL:  treatment of patients with Stage III–IV follicular NHL who 
are chemotherapy-resistant or in their second or subsequent relapse after 
chemotherapy; treatment of patients with CD20-positive DLBCL in combination with 
cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy; as 
front-line therapy in Stage III–IV follicular NHL in combination with CVP chemotherapy; 
as maintenance therapy in patients with relapsed or refractory, follicular NHL responding 
to induction treatment with CHOP or R-CHOP; and as maintenance treatment for 
patients with FL who have responded to initial treatment with rituximab plus 
chemotherapy. 
Rituximab has also been approved for the treatment of CLL.  The European Medicines 
Agency (EMA) granted an approval for the use of rituximab in combination with 
chemotherapy for previously untreated CLL.  The FDA approved the use of rituximab in 
combination with fludarabine and cyclophosphamide for patients with previously 
untreated and previously treated CD20-positive CLL.   
Refer to the Rituximab Investigator’s Brochure for complete details regarding clinical data 
related to approved indications.  For rituximab safety information, refer to local rituximab 
prescribing information. 


 
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1.2.4 
Obinutuzumab 
1.2.4.1 
Obinutuzumab Mechanism of Action 
Obinutuzumab ([G], also known as RO5072759, GA101, Gazyva™, and Gazyvaro™) is a 
humanized type II and glycoengineered anti-CD20 MAb, derived by humanization of the 
parental B-Ly1 mouse antibody and subsequent glycoengineering leading to the 
following characteristics (Mössner et al. 2010; Golay et al. 2013): 
• 
High-affinity binding to CD20 antigen on B cells 
• 
Type II binding mode to the CD20 antigen, leading to a more even distribution of 
bound antibody to the surface membrane of the B cell due to lack of CD20 
translocation into lipid rafts after antibody binding and low complement activation 
and low complement-dependent cytotoxicity related to the recognition of the CD20 
epitope  
• 
Compared with the type I anti-CD20 antibodies rituximab or ofatumumab, increased 
ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) related to an 
improved binding of obinutuzumab to the different allotypes of FcγRIIIa and FcγRIIIb  
expressed by natural killer (NK) cells , monocytes/macrophages and neutrophils 
• 
Compared with rituximab, increased direct cell-death induction related to an elbow 
hinge amino exchange of the Fab region and type II binding of the CD20 epitope 
 
Obinutuzumab received FDA approval in November 2013 and EMA approval in 
July 2014 on the basis of the CLL-11 Study BO21004 for patients with relapsed Chronic 
Lymphocytic Leukemia.  Obinutuzumab plus chlorambucil showed superiority over 
rituximab plus chlorambucil in all efficacy parameters such as overall response rate 
(ORR), complete remission rate (CRR), minimal residual disease (MRD), 
progression-free survival (PFS), event-free survival (EFS), and duration of response 
(DOR) (Goede et al. 2014). 
Obinutuzumab is currently being explored in the treatment of lymphoid malignancies 
such as aggressive and indolent lymphomas (DLBCL, FL, and marginal zone lymphoma 
[MZL]).  Preliminary data suggest possible increased anti-lymphoma efficacy over 
rituximab, a hypothesis that is currently being explored in several randomized trials, 
including a Phase III study of R-CHOP versus G-CHOP in first-line treatment of DLBCL, 
a Phase III study of R-chemotherapy (CHOP, CVP, or bendamustine) followed by 
rituximab maintenance compared with G-chemotherapy (CHOP, CVP, or bendamustine) 
followed by obinutuzumab maintenance in first-line treatment of FL and MZL, and a 
Phase III study of obinutuzumab combined with bendamustine compared with 
bendamustine in patients with rituximab-refractory indolent NHL. 
1.2.4.2 
Obinutuzumab Nonclinical Toxicology 
The nonclinical toxicology of obinutuzumab has been evaluated in repeat-dose studies in 
cynomolgus monkeys given weekly IV (30-minute infusion) up to 26 weeks in duration 
and weekly SC injections for 4 weeks in duration.  The high dose of 50 mg/kg in the 26-
week study resulted in a steady-state area under the concentration-time curve from 0 to 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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24 hours (AUC0−24) exposure of 341,000 μg•hr/mL, which is approximately 61-fold above 
that of the clinical exposure of 5584 μg•hr/mL. 
Consistent with expected pharmacologic activity, obinutuzumab caused marked 
decreases in B cells, with corresponding lymphoid depletion in spleen and lymph nodes.  
Circulating CD40-positive mature B cells began to reverse after several months without 
treatment and maximally reversed to 7%−152% of baseline by 37 weeks.  In addition, 
transient decreases in NK cells were observed; this finding is consistent with the 
pharmacologic effect of FcγRIIIa binding.  Suspected opportunistic infections in as many 
as three unscheduled deaths were considered a possible secondary result of B-cell 
depletion. 
Obinutuzumab was immunogenic in the cynomolgus monkey, which led to reduced 
systemic exposures in several animals and abrogation of the pharmacologic activity.  
Hypersensitivity reactions were noted that included systemic inflammation and infiltrates 
consistent with immune complex−mediated hypersensitivity reactions such as 
arteritis/periarteritis, glomerulonephritis, and serosal/adventitial inflammation and led to 
unscheduled termination in six animals. 
Both the clinical IV formulation and the SC formulation of obinutuzumab were locally well 
tolerated across studies.  No effects were present in male and female reproductive 
parameters included in the 26-week IV dose study.  No obinutuzumab-related effects 
were observed on CNS, respiratory, or cardiovascular function. 
In vitro assays using undiluted human whole blood measured significant increases in 
cytokine secretion caused by obinutuzumab, indicating that obinutuzumab has an 
increased propensity to trigger first infusion−related cytokine release in patients. 
See the Obinutuzumab Investigator’s Brochure for details on the nonclinical studies. 
1.2.4.3 
Obinutuzumab Nonclinical Efficacy 
Obinutuzumab has in vivo efficacy superior to rituximab in various human lymphoma 
xenograft models.  Both antibodies were tested in human SUDHL-4 cells (DLBCL model) 
injected subcutaneously in severe combined immunodeficient (SCID) beige mice.  
Rituximab administration was started when tumors were established and rapidly 
growing.  Results showed that rituximab at 10 mg/kg inhibited tumor growth compared 
with rituximab at 1 mg/kg; however, increasing the rituximab dose to 30 mg/kg did not 
result in increased efficacy and rituximab was not able to achieve complete tumor 
regression.  In contrast, obinutuzumab showed a dose-dependent increase in efficacy in 
the range of 1−30 mg/kg.  Results showed complete tumor regression in all animals and 
lasting tumor eradication in 9 of 10 animals at the highest dose of 30 mg/kg and in 
1 of 10 animals at a dose of 10 mg/kg. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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In another experiment, SUDHL4 xenografts in SCID mice were first treated with weekly 
rituximab 30 mg/kg.  When the tumors became refractory to rituximab (Day 35), 
rituximab treatment was continued or changed to either weekly vehicle control or 
obinutuzumab 30 mg/kg.  While tumors in control- and rituximab-treated mice continued 
to grow, obinutuzumab-treated mice showed control of tumor growth and lived until 
Day 61 when control or rituximab-treated mice had already been sacrificed.   
Additional studies have also shown similar results, with obinutuzumab treatment 
controlling tumor growth, whereas vehicle- and rituximab-treated tumors were not 
controlled (Mössner et al. 2010). 
See the Obinutuzumab Investigator’s Brochure for details on the nonclinical studies. 
1.2.4.4 
Obinutuzumab Clinical Experience 
As of July 2013, more than 1900 patients with CD20-positive malignant disease have 
been treated with obinutuzumab in clinical trials.  Clinical data for obinutuzumab are 
available from six clinical trials, including three Phase I and Phase II studies of 
obinutuzumab monotherapy, a Phase Ib chemotherapy combination study in NHL 
(Study BO21000), and two Phase III studies (Study BO21004 in CLL and 
Study GAO4753g in NHL). 
Infusion-related reactions (IRRs), mostly Grades 1 and 2, are the most common adverse 
events observed during therapy.  IRRs have been associated predominantly with the first 
infusion, generally occurring early during the infusion, shortly after the infusion, or, in 
some cases, up to 24 hours after the completion of the infusion.  In a few patients, 
concurrent signs of laboratory tumor lysis syndrome (TLS) were observed.  The 
incidence and intensity of IRRs decreased strongly with subsequent infusions of 
obinutuzumab.  On the basis of preliminary observations, extensive tumor burden, tumor 
factors, and host factors may be predisposing factors for the occurrence of IRRs.  The 
frequency and severity of IRRs is also reduced in lymphomas compared with CLL. 
Other frequently observed adverse events include infections and neutropenia.  
Grade 3−4 thrombocytopenia and neutropenia, including febrile neutropenia, have been 
reported with obinutuzumab, associated predominantly with treatment of CLL rather than 
NHL.  Given its anticipated mode of action, which results in profound B-cell depletion, 
obinutuzumab may be associated with an increased risk of infections during and after 
treatment. 
Data from Study BO20999 (obinutuzumab monotherapy) showed safety and efficacy of 
single-agent obinutuzumab in patients with relapsed indolent and aggressive 
lymphomas.  Responses were seen at both lower (400 mg) and higher (1600/800 mg) 
doses, although responses increased at the higher dose, with 54% of patients with 
indolent lymphoma and 32% of patients with aggressive lymphomas showing PR or CR 
at the end of treatment (EOT) (Morschhauser et al. 2013; Salles et al. 2013).   


 
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Study BO21000 (Phase Ib) evaluated obinutuzumab in combination with chemotherapy:  
obinutuzumab with fludarabine and cyclophosphamide and obinutuzumab with CHOP 
(Radford et al. 2013).  Both chemotherapy combinations were shown to be feasible in 
patients with previously untreated or relapsed or refractory FL, with response rates of 
> 90% for both regimens.  Safety was acceptable, with no new or unexpected adverse 
events observed.  The most common adverse event was neutropenia. 
Data from obinutuzumab in combination with chlorambucil in CLL (Phase III 
Study BO21004) showed increased efficacy of this combination over 
rituximab-chlorambucil, with a hazard ratio of 0.39 for PFS.  IRRs were common (65% all 
grades, 20% Grade 3−4, no fatal IRRs) and neutropenia occurred at increased 
frequency with the combination therapy (33% Grade 3−5), but there was no increase in 
infections or treatment-related deaths (Goede et al. 2014). 
See the Obinutuzumab Investigator’s Brochure for additional details on the clinical 
studies. 
1.2.4.5 
Obinutuzumab Pharmacokinetics and Pharmacodynamics 
A two-compartment model comprising a time-varying CL pathway and a linear CL 
pathway provides an adequate description of the pharmacokinetics of obinutuzumab 
following IV administration in Study BO20999 and Study BO21003.  Following the 
infusion of obinutuzumab, the elimination appears to be characterized by a linear CL 
pathway that is dependent on time (i.e., starting at a typical value of 630 mL/day and 
then gradually decreasing to an asymptote of 60 mL/day at steady state).  Tumor burden 
may potentially contribute significantly to the CL of obinutuzumab, especially at the 
beginning of treatment when CD20-positive tumor cells are most abundant.  As tumor 
burden decreases, the CL reaches an asymptote, which is considered to be primarily a 
function of the proteolytic metabolic CL.  Some patients with a high tumor burden may 
appear to clear the drug from the plasma faster than patients with a low tumor burden 
because obinutuzumab binds to the CD20-positive tumor cells and is effectively 
removed from the plasma.  The CL of the drug will vary with time because repeated 
treatments with obinutuzumab will reduce the quantity of CD20-positive tumor cells.  The 
number of times obinutuzumab is administered during the first cycle of treatment may be 
expected to reduce the number of CD20-positive tumor cells, thus minimizing the impact 
of the time-varying CL pathway on obinutuzumab exposure. 
Treatment with obinutuzumab resulted in extensive B-cell depletion, with all patients 
showing a reduction in B-cell counts to absolute zero at some stage of their treatment 
cycle.  Overall, there has been no notable increase in complement levels before and 
after infusion, but transient increases occurring during the administration of 
obinutuzumab have been observed in the levels of tumor necrosis factor (TNF)-α, 
interleukin (IL)-6, IL-8, IL-10, and interferon (IFN)-γ. 


 
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1.3 
RATIONALE FOR DOING THIS STUDY 
The goals of this study are to continue to assess the safety, tolerability, and biologic and 
clinical activity of the combinations of DCDT2980S and rituximab and DCDS4501A and 
rituximab in two specific NHL patient populations:  patients with relapsed or refractory 
follicular NHL and patients with relapsed or refractory DLBCL.  An additional goal of this 
study is to assess the safety, tolerability, and potential biologic and clinical activity of 
DCDS4501A in combination with obinutuzumab, an anti-CD20 antibody, in the 
aforementioned NHL patient populations.  These patients continue to have an extremely 
poor prognosis with no curative options available.  Consequently, new therapeutic 
options are needed.   
DCDT2980S, DCDS4501A, rituximab, and obinutuzumab each target antigens specific 
to B-cell malignancies including follicular NHL and DLBCL (see Figures 1 and 2).  
The randomized component of the Phase II study design permits an assessment of the 
clinical benefit provided by each of these molecules in combination with rituximab, which 
has established clinical activity in B-cell malignancies both as monotherapy and in 
combination with chemotherapy.  Data from this study will help inform the feasibility of 
the combination regimens in earlier lines of therapy (e.g., as first-line therapy in newly 
diagnosed patients).   
The non-randomized component of the study will further evaluate the safety and 
tolerability and clinical activity of DCDS4501A in combination with obinutuzumab in 
patients with relapsed or refractory follicular lymphoma or DLBCL and will also provide 
preliminary evidence as to which anti-CD20 agent, rituximab or obinutuzumab, in 
combination with DCDS4501A, provides a better benefit-risk profile in the target 
population being studied.  
The feasibility of combining an ADC with rituximab has previously been tested clinically 
with the combination of another, different CD22-specific ADC, inotuzumab ozogamicin 
(CMC-544), with results suggesting that the addition of rituximab may have increased 
clinical activity without significant increase in toxicity over the ADC alone in patients with 
aggressive NHL (Fayad et al. 2006; Nam et al. 2009; Nina et al. 2010).  As noted in 
Section 1.2.1 and Section 1.2.2, the combinations of DCDT2980S and rituximab, and 
DCDS4501A and rituximab have been shown to have acceptable safety in patients with 
relapsed or refractory NHL in the Phase I studies (Studies DCT4862g and DCS4968g).   
Given the relatively poor prognosis of patients with relapsed or refractory hematologic 
malignancies that have failed standard therapies, the nonclinical toxicity profile 
associated with DCDT2980S and DCDS4501A treatment, and the clinical safety profile 
observed to date for both ADCs, the benefit-risk ratio of a clinical study of DCDT2980S 
and DCDS4501A, each combined with rituximab or obinutuzumab, is considered 
acceptable.  


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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1.3.1 
Rationale for Assessing ADC Dose of 1.8 mg/kg Combined with 
Rituximab in iNHL 
On the basis of available Phase I data (see Section 1.2.1 and Section 1.2.2), both 
DCDT2980S and DCDS4501A as single agents and combined with rituximab have 
shown early signs of clinical activity in heavily pretreated patients with relapsed or 
refractory NHL.  However, early evidence in the Phase I studies indicate that duration of 
study treatment may be limited by tolerability to ADC.  Specifically, for both ADCs, 
peripheral sensory neuropathy has been identified as a known risk (see Section 3.4.3.5).  
Notably, 4 of 7 and 5 of 11 discontinuations for adverse events in Studies DCT4862g 
and DCS4968g, respectively, were the result of peripheral neuropathy.   
Because of the chronic course and incurability of iNHL, treatment paradigms are 
increasingly emphasizing tolerability to treatment in addition to efficacy.  As both 
DCDT2980S and DCDS4501A have shown single-agent activity at the 1.8 mg/kg dose 
level (Advani et al. 2012; Palanca-Wessels et al. 2012), the purpose of enrolling 
additional cohorts of patients with FL is to determine whether lower doses of ADC in 
combination with standard doses of rituximab result in improved tolerability while 
maintaining efficacy in FL.   
In contrast to iNHL, treatment paradigms in relapsed or refractory aggressive 
lymphomas such as DLBCL continue to place a premium on anti-tumor activity and 
higher tolerance for treatment-related toxicity, given that the duration of disease control 
and survival are substantially shorter and that treatment options are extremely limited.  
Early Phase I data suggest lower rates of study treatment discontinuation for adverse 
events among patients with DLBCL compared with patients with iNHL.  Taken together 
with anti-tumor activity observed to date, the benefit-risk profile of the currently tested 
ADC dose of 1.8 mg/kg is considered acceptable to combine with rituxminab in the 
treatment of patients with iNHL.  
1.3.2 
Rationale for Assessing DCDS4501A in Combination with 
Obinutuzumab in Relapsed or Refractory NHL 
The development of next-generation anti-CD20−directed therapy may further enhance 
the efficacy of current standard regimens for NHL.  Obinutuzumab, also known as 
RO5072759, GA101, and Gazyva™/Gazyvaro™, a novel type II and glycoengineered 
anti-CD20 antibody, has shown superiority over rituximab in a Phase III trial in first-line 
CLL (Goede et al. 2014).  Obinutuzumab is currently being compared with rituximab in 
two large Phase III studies in patients with newly diagnosed DLBCL (Study BO21005) 
and with previously untreated iNHL, including FL (Study BO21223).  Assuming these 
studies demonstrate greater clinical benefit with obinutuzumab- vs. rituximab-containing 
regimens, potentially altering the standard of care in NHL, it will be important to also 
assess the safety and efficacy of combining DCDS4501A with obinutuzumab-containing 
regimens. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
60/P GO27834-A3 
The goals of the non-randomized portion of the Phase Ib study are to assess the safety, 
tolerability, and potential biologic and clinical activity of DCDS4501A at 1.8 mg/kg in 
combination with obinutuzumab in patients with relapsed or refractory follicular NHL or 
DLBCL.  The RP2D, the Phase II dose-expansion portion of the study, will further 
evaluate the safety and tolerability and clinical activity of DCDS4501A at 1.8 mg/kg in 
combination with obinutuzumab in patients with relapsed or refractory follicular NHL or 
DLBCL.   
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
The primary objectives of this study are the following: 
• 
To assess the safety and tolerability of the combination of DCDT2980S and 
rituximab administered to patients with relapsed or refractory follicular NHL and 
DLBCL 
• 
To assess the safety and tolerability of the combination of DCDS4501A and 
rituximab administered to patients with relapsed or refractory follicular NHL and 
DLBCL  
• 
To assess the safety and tolerability of the combination of DCDS4501A and 
obinutuzumab when administered to patients with relapsed or refractory follicular 
NHL or DLBCL 
• 
To assess the anti-tumor activity of the combination of DCDT2980S and rituximab in 
patients with relapsed or refractory follicular NHL and DLBCL 
• 
To assess the anti-tumor activity of the combination of DCDS4501A and rituximab in 
patients with relapsed or refractory follicular NHL and DLBCL 
• 
To assess the anti-tumor activity of the combination of DCDS4501A and 
obinutuzumab in patients with relapsed or refractory follicular NHL and DLBCL based 
on PET-CR at the end of treatment according to IRC per Lugano 2014 response criteria 
 
2.2 
SECONDARY OBJECTIVES 
2.2.1 
Safety Objectives 
The secondary safety objectives of this study are the following: 
• 
To assess the incidence of antibody formation to DCDT2980S, DCDS4501A, and 
obinutuzumab as measured by the formation of ATAs 
• 
To compare the safety and tolerability of the combination of DCT2980S and 
rituximab and DCDS4501A and rituximab or obinutuzumab 
 
2.2.2 
Activity Objective 
The secondary activity objective for rituximab-containing arms of the study is the 
following: 
• 
To compare the anti-tumor activity of the combination of DCT2980S and rituximab 
and DCDS4501A and rituximab or obinutuzumab 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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The secondary activity objectives for obinutuzumab-containing arms of the study are the 
following: 
• 
CR at end of treatment based on PET alone, as determined by the investigator 
• 
Objective response (OR; CR or PR) at end of treatment based on PET alone as determined by 
investigator and IRC  
• 
CR at end of treatment based on CT only as determined by the investigator and IRC 
• 
OR at end of treatment based on CT only as determined by the investigator and IRC 
• 
Best objective response (BOR, CR or PR) while on study based on PET alone or CT only, as 
determined by the investigator 
 
2.2.3 
Pharmacokinetic Objectives 
The PK objectives of this study are the following: 
• 
To characterize the pharmacokinetics of DCDT2980S and rituximab in patients with 
relapsed or refractory NHL when the two drugs are given in combination 
• 
To characterize the pharmacokinetics of DCDS4501A and rituximab or 
obinutuzumab in patients with relapsed or refractory NHL when the two drugs are 
given in combination 
 
2.3 
EXPLORATORY OBJECTIVES 
2.3.1 
Efficacy Objectives 
The exploratory efficacy objectives for this study are to evaluate the long-term outcome of 
obinutuzumab-treated patients according to Lugano 2014 response criteria, as measured by the 
following: 
• 
Duration of response based on PET and/or CT scans 
• 
Progression-free survival (PFS) based on PET and/or CT scans  
• 
Event-free survival (EFS) based on PET and/or CT scans 
• 
Overall survival  
 
2.3.2 
Biomarker Objectives 
The objectives of this study related to assessment of biologic markers are the following: 
• 
To make a preliminary assessment of biologic markers that might act as predictors 
of DCDT2980S + rituximab combination anti-tumor activity and allow assessment of 
response in different prognostic subgroups of DLBCL and follicular NHL 
• 
To make a preliminary assessment of biologic markers that might act as predictors 
of DCDS4501A + rituximab or obinutuzumab combination anti-tumor activity and 
allow assessment of response in different prognostic subgroups of DLBCL and 
follicular NHL 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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2.3.3 
Patient-Reported Outcomes Objective 
The objective of this study related to assessment of patient-reported outcomes (PRO) is 
the following: 
• 
To assess patient-reported tolerability to study treatment and the impact of study 
treatment on patient functioning on the basis of PRO in Rituximab cohorts only 
 
2.3.4 
Crossover Treatment Objective 
The objective of this study related to assessment of crossover treatment is the following: 
• 
To preliminarily assess the safety, tolerability, and anti-tumor activity of DCDT2980S 
and DCDS4501A, either as a single-agent or in combination with rituximab, as 
crossover treatment following disease progression on initial study treatment. (Note:  
This objective applies only to patients enrolled in Arms A and B [see Section 3.1]) 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a Phase Ib/II, multicenter, open-label study.  Up to approximately 246 patients 
with relapsed or refractory FL and DLBCL will be enrolled at approximately 
30−40 investigative sites worldwide.  Additional patients may be enrolled in order to 
obtain additional safety and/or efficacy data.  Arms A and B and Cohort C are no longer 
enrolling patients. 
For Obinutuzumab Cohorts: 
Only investigational sites in the United States will enroll patients into Cohort E.  
Investigational sites in the United States and worldwide will participate in Cohorts G 
and H.   
The study will be composed of a randomized portion and a non-randomized portion, as 
illustrated in Figure 3 . 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Figure 3a Study Schema for Rituximab-Containing Arms/Cohorts (Closed 
to Enrollment) 
Arms A and B:  RTX (375 mg/m2) + ADC (2.4 mg/kg) administered in every-21-day cycles.
Cohorts C and D: RTX (375 mg/m2) + ADC (1.8 mg/kg) administered in every-21-day cycles.
RTX + DCDT2980S ADC
RTX + DCDS4501A ADC
Randomize
1:1
PD
PD
RTX + DCDS4501A ADC
RTX + DCDT2980S ADC
Arm A
Arm B
RTX + DCDS4501A ADC
Cohort C
r/r FL=40
r/r DLBCL=80
r/r FL=20
Total N = 140−160
RTX + DCDT2980S ADC
Cohort D
r/r FL=20
• No crossover
• No randomization
• Cohorts open at Sponsor 
discretion
• Cohorts open after FL cohorts 
in Arms A and B are filled
  
 
Figure 3b  Study Schema for Obinutuzumab-Containing Arms/Cohorts 
 
  
ADC = antibody-drug conjugate; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; 
G = GA101/obinutuzumab; PD = progressive disease; r/r = relapsed or refractory; 
RTX = rituximab.  
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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3.1.1 
Rituximab-Containing Regimens with DCDT2980S or 
DCDS4501A 
3.1.1.1 
Randomized Portion of the Study (Arms A and B) − Closed to 
Enrollment 
Following determination of eligibility, patients within each disease group will be 
randomized in a 1:1 ratio to receive one of two treatments: 
• 
Arm A:  Rituximab (375 mg/m2) followed by DCDT2980S (2.4 mg/kg) every 21 days; 
• 
Arm B:  Rituximab (375 mg/m2) followed by DCDS4501A (2.4 mg/kg) every 21 days 
 
The first day of treatment constitutes Day 1 of each cycle.  A typical cycle is 21 days in 
duration. 
A dynamic hierarchical randomization scheme will be employed with respect to the 
following stratification factors: 
• 
For patients with FL (see Section 3.1.4 for definitions) 
Rituximab refractory disease (no response or disease relapse < 6 months from 
last rituximab treatment) versus rituximab relapsed disease (disease relapse 
after response ≥  6 months from last rituximab treatment) 
• 
For patients with DLBCL (see Section 3.1.5 for definitions) 
Second-line versus third-line (or beyond) therapy 
For second-line patients, disease relapse or no objective response (CR, 
unconfirmed CR [CRu], or PR) <12 months from the start of initial therapy versus 
disease relapse, after initial objective response (CR, unconfirmed response 
[CRu] or PR), ≥ 12 months from start of initial therapy  
For third-line patients, failure to achieve a CR or progression < 6 months from 
start of most recent therapy versus CR or progression ≥ 6 months from start of 
most recent therapy 
No formal testing comparing the two treatment arms in the randomized portion of the 
study is planned. 
3.1.1.2 
Non-Randomized Portion of the Study with Rituximab 
(Cohorts C and D) − Closed to Enrollment 
Only select investigator sites that have agreed to participate in the non-randomized 
portion of the study will enroll patients into these cohorts. 
Patients with relapsed or refractory follicular NHL will be enrolled in Cohorts C and D to 
receive rituximab (375 mg/m2) combined with DCDT2980S or DCDS4501A at a dose of 
1.8 mg/kg.  The first day of treatment constitutes Day 1 of each cycle.  A typical cycle will 
be 21 days in duration. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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The opening of either or both cohorts will be at the Sponsor’s discretion and only after 
the enrollment of patients with FL into the randomized portion of the study is completed.  
Patients will not be randomized to receive one treatment or the other.  It is anticipated 
that Cohort C and D will be opened sequentially.   
3.1.2 
All Patients on Rituximab-Containing Arms/Cohorts  
All patients on rituximab-containing regimens, regardless of assigned arm/cohort, will 
receive DCDT2980S or DCDS4501A and rituximab administered by IV infusion on a 
21-day cycle.  For the first two cycles, rituximab will be administered by IV infusion on 
Day 1 and DCDT2980S or DCDS4501A will be administered by IV infusion on Day 2.  In 
the absence of any infusion-related adverse events, rituximab and DCDT2980S or 
DCDS4501A may be administered on the same day (Day 1) in subsequent cycles 
beginning with the third cycle.  In this instance, rituximab will be administered first, 
followed by DCDT2980S or DCDS4501A.  In certain circumstances⎯for example, IRRs 
requiring interruption or slowing of infusion rate⎯rituximab may be administered over 
2 days (e.g., Day 1 and Day 2 of the cycle); in this case, DCDT2980S or DCDS4501A 
may be administered on Day 2 following completion of the rituximab infusion or on Day 3 
of the cycle. 
Patients may receive treatments for up to 1 year (17 cycles on an every-21-day 
schedule) if not discontinued because of significant toxicity, disease progression, or 
withdrawal from study. 
Patients will be evaluated for safety and efficacy according to the Schedules 
of Assessments outlined in Appendices A-1, A-2, and A-4.  Initial response assessments 
in this study will be performed every 3 months from the initiation of therapy until study 
treatment completion or early termination (e.g., between Days 14 and 21 of Cycles 4 
and 8 for those patients receiving at least eight 21-day cycles of treatment).  Additional 
response assessments for patients who proceed to crossover treatment 
(see Section 3.1.6) will be performed as described in Appendix A-2; response 
assessments for patients who discontinue study treatment (both initially assigned 
treatment and crossover treatment) for reasons other than disease progression will be 
performed as described in Appendix A-4. 
Responses to study treatment will be based on investigator assessments.  In addition, 
tumor assessment data will be transmitted to an Independent Review Facility (IRF) for 
collection and possible independent review. 
3.1.3 
Obinutuzumab-Containing Regimen with DCDS4501A 
(Cohorts E, G, and H) 
DCDS4501A at 1.8 mg/kg will be given in combination with obinutuzumab to patients 
with relapsed or refractory follicular NHL and DLBCL in two stages:  (1) safety run-in and 
(2) expansion. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Study treatment will be given in 21-day cycles for both follicular NHL and DLBCL.  
Patients will be treated for up to a total of 8 cycles.  For the first cycle, obinutuzumab will 
be administered by IV infusion on Days 1, 8, and 15.  DCDS4501A will be given on Day 
2 for Cycle 1.  In the absence of any infusion-related adverse events, obinutuzumab and 
DCDS4501A may be administered on the same day (Day 1) in subsequent cycles 
beginning with the second cycle.  If obinutuzumab and DCDS4501A are administered on 
the same day, the study drugs will be given sequentially.  Obinutuzumab will be 
administered first, followed by DCDS4501A.  In certain circumstances⎯for example, 
IRRs requiring interruption or slowing of infusion rate⎯obinutuzumab may be 
administered over 2 days (e.g., Day 1 and Day 2 of the cycle); in this case, DCDS4501A 
may be administered on Day 2 following completion of the obinutuzumab infusion. 
3.1.3.1 
Obinutuzumab-Containing Regimen in Phase Ib: Safety Run-In 
(Cohort E) 
This portion of the study will consist of a safety run-in that will evaluate the safety of 
DCDS4501A at 1.8 mg/kg in combination with obinutuzumab in 6 patients (Cohort E).  
The safety run-in is described in detail in Section 3.4.   
Obinutuzumab-Containing Regimens in Phase II:  Expansion Stage 
(Cohorts G and H) 
After the safety run-in has demonstrated that DCDS4501A at 1.8 mg/kg in combination 
with obinutuzumab is safe to administer, patients will be enrolled into two expansion 
cohorts based on histology of follicular NHL or DLBCL (Cohorts G and H, respectively).  
Forty patients will be enrolled into each expansion cohort.  An additional cohort(s) 
may be added in the future. 
3.1.4 
Follicular NHL Patients for Rituximab-Containing 
Arms/Cohorts 
Patients with relapsed or refractory follicular NHL will be enrolled into the study as 
defined by the following: 
• 
Relapsed as documented history of response (CR, CRu, or PR) of ≥ 6 months in 
duration from completion of all prior rituximab-containing regimens.  A 
rituximab-containing regimen is defined as rituximab as a single agent during 
induction and/or maintenance or in combination with other agents during induction 
and/or maintenance. 
• 
Refractory to any prior regimen containing rituximab, defined as no response to or 
progression within 6 months of completion of the last dose of rituximab therapy 
(either as monotherapy or in combination with chemotherapy), including: 
Patients with progressive disease while receiving rituximab monotherapy, 
rituximab combined with chemotherapy, or rituximab maintenance therapy; 
patients must have received at least one full dose (375 mg/m2) of rituximab. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Patients with no objective response (PR or CR) to a rituximab-containing regimen 
consisting of at least 4 weekly doses of rituximab monotherapy or at least 
4 cycles of rituximab combined with chemotherapy 
Patients with disease relapse, after having achieved an objective response, 
within 6 months of completion of the last dose of rituximab therapy in a regimen 
consisting of at least four weekly doses of rituximab monotherapy or at least 
4 cycles of rituximab combined with chemotherapy 
 
Enrollment of patients with refractory disease as defined above may be limited to no 
greater than 60% of the total follicular NHL cohort, in order to avoid overrepresentation 
of the refractory disease population. 
3.1.5 
Follicular NHL Patients for Obinutuzumab-Containing Cohorts 
Patients with relapsed or refractory follicular NHL will be enrolled into the study as 
defined by the following: 
• 
Relapsed to prior regimen(s) after having a documented history of response (CR, 
CRu, or PR) of ≥ 6 months in duration from completion of regimen(s)   
• 
Refractory to any prior regimen, defined as no response to the prior therapy, or 
progression within 6 months of completion of the last dose of therapy 
 
3.1.6 
DLBCL Patients for Rituximab-Containing Arms/Cohorts 
Patients with relapsed or refractory DLBCL who are determined by the investigator to be 
ineligible for high-dose therapy with autologous stem cell rescue/stem cell transplant 
(SCT) will be enrolled into the study as defined by the following: 
• 
Second-line SCT-ineligible patients with progressive disease or no response 
(SD) < 12 months from start of initial therapy (second-line refractory) 
• 
Second-line SCT-ineligible patients with disease relapse after initial response 
≥ 12 months from start of initial therapy (second-line relapsed) 
• 
Third-line (or beyond) SCT-ineligible patients with progressive disease or no 
response (SD) < 6 months from start of prior therapy (third-line + refractory) 
• 
Third-line (or beyond) SCT-ineligible patients with disease relapse after initial 
response ≥ 6 months from start of prior therapy (third-line + relapsed) 
 
Enrollment into any of the above four categories may be limited to no greater than 40% 
of the DLBCL cohort—and to no more than 60% of the two refractory categories 
combined—in order to avoid overrepresentation of any specific subpopulation, refractory 
patients in particular. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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3.1.7 
DLBCL Patients for Obinutuzumab-Containing Cohorts 
Patients with relapsed or refractory DLBCL who are determined by the investigator to be 
ineligible for high-dose therapy with autologous stem cell rescue/SCT will be enrolled 
into the study as defined by the following: 
• 
Second-line SCT-ineligible patients with progressive disease or no response 
(SD) < 12 months from start of initial therapy (second-line refractory) 
• 
Second-line SCT-ineligible patients with disease relapse after initial response 
≥ 12 months from start of initial therapy (second-line relapsed) 
• 
Third-line (or beyond) SCT-ineligible patients with progressive disease or no 
response (SD) < 6 months from start of prior therapy (third-line + refractory) 
• 
Third-line (or beyond) SCT-ineligible patients with disease relapse after initial 
response ≥ 6 months from start of prior therapy (third-line + relapsed) 
 
3.1.8 
Crossover Treatment (Randomized Patients in Arms A and B 
Only) 
Patients randomized to Arm A or Arm B who develop progressive disease may be 
eligible to receive crossover treatment consisting of rituximab and the other ADC or the 
other ADC alone⎯for example, Arm B treatment for patients who have disease 
progression while receiving Arm A treatment, and vice versa⎯provided the following 
conditions are met: 
• 
Patients must not have experienced a toxicity requiring the discontinuation of 
DCDT2980S/DCDS4501A treatment OR experienced toxicity during the last dose of 
study treatment that would preclude treatment with the crossover regimen. 
Patients who had modifications to dosing and/or schedule on the initial study 
treatment will be permitted to receive crossover treatment in the absence of 
toxicities on the modified dose and/or schedule.  The dose and schedule of 
crossover treatment will be determined by the investigator and the Medical 
Monitor. 
Patients who had rituximab discontinued and continued on single-agent 
DCDT2980S/DCDS4501A treatment may receive crossover treatment of 
single-agent DCDS4501A/ DCDT2980S. 
• 
Patients must have radiographically documented disease progression. 
• 
Patients must meet all inclusion and exclusion criteria described in Section 4.1.1 
and Section 4.1.2, except for those related to prior rituximab treatment. 
• 
Acceptable toxicity:  All study drug–related adverse events from the initial study 
treatment must have decreased to Grade 1 or baseline grade on or before the first 
day of treatment on the crossover regimen.  Exceptions may be allowed after a 
careful assessment and discussion of the benefit-risk balance with the patient by the 
investigator and approval from the Medical Monitor. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
69/P GO27834-A3 
• 
Administration of crossover treatment must be in the best interests of the patient as 
determined after a careful assessment and discussion of benefit-risk balance with 
the patient by the investigator and approval from the Medical Monitor. 
• 
A tumor biopsy (see Section 4.5.1.9) will be required for patients with safely 
accessible site of disease, defined as requiring only local anesthesia and, in 
general, excluding the brain, lungs or any internal organs that may subject patients 
to significant risk.  
Patients for whom a safely accessible site of disease is not present may still 
receive crossover treatment without undergoing a biopsy.  Eligibility to receive 
crossover treatment should be discussed with and approved by the Medical 
Monitor. 
A tumor biopsy of a safely accessible site of disease is optional for patients who 
are not eligible for study cross over.  
 
Patients who are determined to be eligible for study cross over will be treated as follows: 
• 
Assessments obtained at the initial study treatment discontinuation visit 
(see Section 4.5.4) may be used as screening assessments for crossover treatment.  
The following re-screening assessments must be repeated/obtained within 1 week 
prior to starting treatment on the crossover regimen, in order to re-establish baseline 
pretreatment clinical and disease status:  targeted physical exam, Eastern 
Cooperative Oncology Group (ECOG) status, and hematology and serum chemistry 
laboratory tests. 
Re-screening tests for hepatitis B and C do not need to be performed unless 
there is clinical suspicion of hepatitis B and/or C positivity. 
A radiographic tumor assessment must also be performed, unless already done 
to document disease progression, within 6 weeks prior to starting crossover 
treatment. 
• 
Crossover treatment will begin no later than 42 days after the last dose of the prior 
study treatment. 
 
Patients will be treated with the crossover treatment until a second disease progression 
event relative to the tumor assessment, documenting progressive disease on the initial 
study treatment, clinical deterioration, and/or intolerance to the crossover treatment for 
up to a maximum of 1 year (17 cycles on an every-21-day schedule).  Patients will be 
evaluated for safety and efficacy according to the schedules of assessments outlined in 
Appendices A-2.  Response assessments for patients who discontinue study treatment 
for reasons other than disease progression will be performed as described in 
Appendix A-4.  


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Clinical data and exploratory data derived from tumor biopsies obtained prior to 
crossover treatment will be monitored on an ongoing basis.  Genentech has the right to 
restrict or suspend enrollment into crossover treatment at any time.  Reasons for this 
may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events during crossover treatment indicates a 
potential safety hazard to patients. 
• 
Patient enrollment into crossover treatment is unsatisfactory. 
• 
Data recording is inaccurate or incomplete.  
• 
Patients who are enrolled into the non-randomized portion of the study (Cohorts C, 
D, E, G, and H) will not have the option to receive crossover treatment upon 
disease progression (see Section 3.2 for rationale). 
 
3.2 
RATIONALE FOR STUDY DESIGN 
The primary rationale for the randomized non-comparative portion of the study is to 
assess clinical activity for the ADCs DCDT2980S and DCDS4501A in patients with 
relapsed or refractory NHL.  The study design ensures that the patient populations under 
study are balanced with respect to critical variables such as prior therapy and ensures 
consistent clinical assessment of safety and efficacy.  The collection and assessment of 
tumor tissue obtained prior to first study treatment and following progressive disease will 
provide further understanding of disease biology, possible mechanisms of resistance to 
the study treatment, and initial insights into tumor subtypes based on tumor biomarkers 
that are sensitive to study treatment.  Finally, the inclusion of study treatment crossover 
(see Section 3.1.8) will address important questions regarding efficacy and tolerability of 
a second ADC-rituximab combination following disease progression on the initial 
ADC-rituximab combination.  
The primary rationale for the non-randomized portion of the study (Cohorts C and D) is 
to assess the therapeutic index (i.e., the balance of efficacy and tolerability of 
DCDT2980S and DCDS4501A at a dose of 1.8 mg/kg in patients with relapsed or 
refractory follicular NHL).  An informal comparison between patients with follicular NHL 
treated at the two doses of the ADC will help determine if tolerability is improved at the 
lower ADC dose without substantial compromise of efficacy.  
The clinical feasibility of an ADC-rituximab combination regimen in patients with relapsed 
or refractory NHL has been previously studied.  Results from studies of rituximab in 
combination with a different CD22-specific ADC, inotuzumab ozogamicin, demonstrated 
that when combined with rituximab, the ADC was able to be given at the single-agent 
MTD without the need for dose reduction of the ADC because of the lack of significant 
overlapping toxicity (Fayad et al. 2006; Nam et al. 2009; Nina et al. 2010). 
DCDT2980S and DCDS4501A were both evaluated as single agents and in combination 
with rituximab in the Phase I studies Study DCT4862g and Study DCS4968g, 
respectively.  Results from these trials have determined an MTD of 2.4 mg/kg for 
single-agent DCDT2980S and an RP2D of 2.4 mg/kg for single-agent DCDS4501A in 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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patients with mixed NHL.  In addition, the RP2D of DCT2980S and DCDS4501 each in 
combination with rituximab (375 mg/m2) on an every-21-day schedule was determined to 
be 2.4 mg/kg.   
Study GO27834 will continue to assess the cumulative safety and longer-term tolerability 
of ADC-rituximab combination therapy.  Due to additional information about the benefit-risk 
profile of DCDS4501A at the 2.4 mg/kg dose, the Sponsor is no longer pursuing the 2.4 mg/kg 
dose of DCDS4501A in the obinutuzumab-containing cohorts. 
The primary rationale for the non-randomized Phase Ib/II obinutuzumab-containing 
cohorts (Cohorts E−H) is to assess safety and clinical activity for the combination of 
obinutuzumab and DCDS4501A in patients with relapsed/refractory NHL (Cohorts E, G, 
and H).  Obinutuzumab (also known as RO5072759, GA101 and Gazyva™/Gazyvaro™), 
a novel type II and glycoengineered anti-CD20 antibody, has shown superiority over 
rituximab in a Phase III trial in first-line CLL (Goede et al. 2014).  Obinutuzumab is 
currently being compared with rituximab in two large Phase III studies in patients with 
newly diagnosed DLBCL (Study BO21005) and previously untreated iNHL, including FL 
(Study BO21223).  Assuming these studies demonstrate greater clinical benefit with 
obinutuzumab- vs. rituximab-containing regimens, potentially altering the standard of 
care in NHL, it will be important to also assess the safety and efficacy of combining 
DCDS4501A with obinutuzumab-containing regimens. 
Study drug dosing will occur on Days 1 or 2 of each 21-day (or 28-day) cycle to allow for 
recovery from potential bone marrow toxicity. 
3.2.1 
Rationale for the PK Sample Schedule 
PK data obtained in this study will be important in informing potential future trials with 
this combination.  Given the likely changing effect of peripheral B-cell counts, tumor 
burden, and target antigen expression on target-mediated drug CL over multiple doses 
of DCDT2980S or DCDS4501A plus rituximab or obinutuzumab when the two drugs are 
given in combination, the drug levels of DCDT2980S or DCDS4501A-related analytes 
and rituximab or obinutuzumab will be assessed in this combination study.   
In Studies DCT4862g and DCS4968g, single-agent DCDT2980S and DCDS4501A 
administered by IV infusion every 21 days were evaluated at doses ranging from 0.1 to 
3.2 mg/kg for DCDT2980S and 0.1 mg/kg to 2.4 mg/kg for DCDS4501A in patients with 
NHL.  Intensive PK sampling of all patients in the ongoing Phase I studies will provide 
sufficient data to allow complete profiling of the distribution and elimination phases for 
DCDT2980S and DCDS4501A and the investigation of potential correlations between 
various PK parameters and efficacy and/or toxicity.  Consequently a reduced PK 
sampling scheme of DCDT2980S and DCDS4501A will be used in this study.  
The PK data collected in this study will allow further characterization of the PK properties 
of DCDT2980S and DCDS4501A.  In addition, the DCDT2980S and DCDS4501A 
concentration results from this study will be compared with available data from the 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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single-agent clinical studies to evaluate whether concurrent administration of rituximab 
affects the exposure of DCDT2980S and/or DCDS4501A.   
Rituximab serum concentration measurements from this study will be compared with 
PK data from historical rituximab clinical studies to evaluate whether the combination 
with DCDT2980S and/or DCDS4501A affects the pharmacokinetics of rituximab.  
Limited sampling of serum concentrations of obinutuzumab will be assessed and 
compared with historical data to evaluate potential PK interactions with 
DCDS4501A. 
3.3 
OUTCOME MEASURES 
3.3.1 
Safety Outcome Measures 
The safety and tolerability of the combination of DCDT2980S and rituximab and 
DCDS4501A and rituximab or obinutuzumab will be assessed using the following safety 
outcome measures: 
• 
Incidence, nature, and severity of adverse events 
• 
Incidence of anti-DCDT2980S, anti-DCDS4501A, or anti-obinutuzumab 
antibodies 
• 
Changes in vital signs 
• 
Changes in laboratory values 
  
3.3.2 
Pharmacokinetic/Pharmacodynamic Outcome Measures 
The following PK parameters will be derived from the serum concentration–time profiles 
of total antibody (the sum of conjugated and unconjugated antibody), including rituximab 
or obinutuzumab, and plasma concentration-time profiles of acMMAE and free MMAE 
following administration of DCDT2980S or DCDS4501A, when appropriate, as data 
allow: 
• 
Total exposure (area under the concentration-time curve [AUC]) 
• 
Maximum plasma and serum concentration (Cmax) 
• 
CL 
• 
Terminal half-life (t1/2) 
• 
Vss 
 
Compartmental, non-compartmental, and/or population methods may be used.  Other 
parameters, such as accumulation ratio and trough plasma and serum concentration 
(Cmin), may also be calculated. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
73/P GO27834-A3 
The following PD outcome measures will be assessed when appropriate, as data allow: 
• 
Peripheral blood B-cell depletion and recovery.  For each visit at which CD19+ B-cell 
measurements are taken, B-cell data will be listed for each patient by dose level as 
follows: 
Absolute blood cell counts 
Percent change relative to the baseline blood counts 
CD19+ B-cell recovery, defined as the timepoint when the values return to 
baseline levels or ≥ 50% of baseline levels 
• 
Assessment of the kinetics of circulating tumor DNA 
 
3.3.3 
Activity Outcome Measures 
The following activity outcome measures will be assessed for rituximab-containing 
arms/cohorts (Arms A and B, Cohort C): 
• 
Objective response, defined as a PR or CR 
• 
Duration of objective response, defined as the duration of time from the first 
occurrence of a documented objective response to time of relapse or death from 
any cause 
• 
PFS, defined as the duration from randomization to the first occurrence of 
progression or death within 30 days of the last administration of study drug, 
whichever occurs first 
• 
OS, defined as the duration from the date of randomization/enrollment to the date 
of death from any cause 
 
Objective response and disease progression will be determined using standard criteria 
for NHL (Cheson et al. 2007, 2014; see Appendix C-1 and Appendix C-2). 
The following activity outcome measures will be assessed for obinutuzumab-containing 
cohorts (Cohorts E, G, and H) according to Lugano 2014 Response Criteria (Cheson et al. 
2014): 
The primary activity outcome measure will be assessed by:  
• 
CR at end of treatment (6−8 weeks after Cycle 6 Day 1 or last dose of study medication) 
based on PET alone, as determined by the IRC  
The following secondary efficacy outcome measures will be assessed: 
• 
OR (CR or PR) at end of treatment based on PET alone as determined by the investigator 
and IRC  
• 
CR at end of treatment based on CT only, as determined by the investigator and IRC  
• 
OR (CR or PR) at end of treatment based on CT only as determined by the investigator and 
IRC  
• 
BOR (CR or PR) while on study based on PET alone or CT only, as determined by the 
investigator  


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
74/P GO27834-A3 
 
3.3.4 
Exploratory Outcome Measures  
The exploratory outcome measures will include, but will not be limited to, the following:  
• 
Confirmation and quantitation of CD22, CD79b, and CD20 expression levels in 
either archival or freshly obtained (when available) tumor specimens (tumor 
biopsies, bone marrow biopsies, peripheral blood) by immunohistochemistry/flow 
cytometry/quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) 
• 
Additional assessments related to the understanding of the mechanism of action of 
DCDT2980S, DCDS4501A, rituximab, and obinutuzumab, e.g., assessment of 
circulating tumor DNA(ctDNA) to monitor response, mechanisms of resistance to 
DCDT2980S, DCDS4501A, rituximab, and obinutuzumab, and/or NHL pathogenesis 
may be included. 
• 
Treatment and disease symptom assessments using the M.D. Anderson Symptom 
Inventory (MDASI) in rituximab-containing cohorts only 
 
The following exploratory efficacy outcome measures will be assessed: 
• 
DOR, defined as the time from the date of the first occurrence of a documented CR or PR to 
the date of disease progression, relapse, or death from any cause, for the subgroup of patients 
with a best overall response of CR or PR, based on PET and/or CT scans as determined by 
the investigator assessment.  For patients achieving a response who have not experienced 
disease progression, relapse, or died prior to the time of the analysis, the DOR will be 
censored on the date of last disease assessment. 
• 
PFS, defined as the time from date of randomization or first treatment (for G-containing 
arms) to the first occurrence of progression or relapse, or death from any cause , based on 
PET and/or CT scans as determined by the investigator assessment. 
• 
EFS, defined as the time from date of randomization or first treatment (for G-containing 
arms) to any treatment failure including disease progression relapse, initiation of new 
anti-lymphoma therapy, or death from any cause, whichever occurs first, based on PET 
and/or CT scans as determined by the investigator assessment  
• 
OS, defined as the time from the date of first treatment to the date of death from any cause 
 
3.4 
SAFETY PLAN  
See Section 5 (Assessment of Safety) for complete details of the safety evaluation for 
this study. 
Safety will be evaluated through the monitoring of the following: 
• 
Serious adverse events that are attributed to protocol-mandated interventions from 
the time of signing of the Informed Consent Form until the first dose of study 
treatment on Cycle 1, Day 1 
• 
All adverse events from Cycle 1, Day 1 until 30 days after the last dose of 
DCDT2980S, DCDS4501A, rituximab, or obinutuzumab, whichever is later, 
including doses that were administered as part of crossover treatment 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
75/P GO27834-A3 
• 
All serious adverse events from Cycle 1, Day 1 until 30 days after the last dose of 
DCDT2980S, DCDS4501A, rituximab, or obinutuzumab, whichever is later, 
including doses that were administered as part of crossover treatment 
• 
All serious adverse events from the last dose of DCDT2980S, DCDS4501A, 
rituximab, or obinutuzumab, whichever is later, including doses that were 
administered as part of crossover treatment, and which are judged to be caused by 
DCDT2980S, DCDS4501A, rituximab, or obinutuzumab, regardless of time of 
onset 
• 
Measurements of protocol-specified hematology and clinical chemistry laboratory 
values 
• 
Measurements of protocol-specified vital signs 
• 
Assessment of ECGs 
• 
Assessment of physical findings on clinical physical examinations 
 
Patients who have an ongoing study drug−related adverse event will be followed until 
the event has resolved to baseline grade, the event is assessed by the investigator as 
stable, new anti-tumor treatment is initiated, the patient is lost to follow-up, the patient 
withdraws consent, it is determined that the study treatment or participation is not the 
cause of the adverse event, or the study is terminated. 
See Section 5.2.3 for assessment of causality for adverse events. 
3.4.1 
Safety Run-In Analysis 
As outlined in Figure 3b and Section 3.1.3.1, a safety run-in analysis (Cohort E) will be 
conducted by the Internal Monitoring Committee (IMC) to evaluate the combination of 
DCDS4501A at a dose of 1.8 mg/kg with obinutuzumab.  This analysis will include data 
from the first 6 patients treated through the safety observation period, from Cycle 1 Day 1 to 
Cycle 2 Day 1 for a minimum of 21days.  Three patients will initially be enrolled, and then 
an additional 3 patients will be enrolled after the first 3 patients have safely completed 
the first cycle.  The decision to enroll an additional 3 patients will be made by the 
Sponsor’s Medical Monitor in consultation with the safety science leader, 
biostatistician, and participating investigators.  At the IMC’s discretion, and at any 
point during enrollment of the safety run-in, a decision could be made that more than 
6 patients are needed to evaluate safety.  Additional patients may also be enrolled at dose 
levels below 1.8 mg/kg of DCDS4501A (i.e., 1.4 mg/kg) based upon review of all safety data.   
Safety summaries will be assessed at the safety run-in for SAEs; Grade 3-5 treatment-
related AEs; all AEs; all Grade 3-5 AEs; and AEs leading to treatment discontinuation or 
dose modification/interruption. 
• 
During the 6-patient safety run-in, if any patient experiences a treatment-related 
death, then the obinutuzumab-containing portion of the study will be closed to 
further recruitment. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
76/P GO27834-A3 
• 
During the 6-patient safety run-in: 
If 2 or more of the first 3 patients enrolled experience Grade 4 febrile neutropenia 
or serious (i.e., SAE) documented infection requiring IV antibiotics in the 
presence of Grade 3−4 neutropenia, then the obinutuzumab-containing portion of 
the study will be closed to further recruitment 
If 1 of the first 3 patients enrolled experiences Grade 4 febrile neutropenia or 
serious (i.e., SAE) documented infection requiring IV antibiotics in the presence 
of Grade 3−4 neutropenia, then an additional 3 patients will be recruited.  If 2 or 
more of these first 3 patients experience Grade 4 febrile neutropenia or serious 
(i.e., SAE) infection with Grade 3−4 neutropenia, then the 
obinutuzumab-containing portion of the study will be closed to further 
recruitment. 
If 2 or more of the first 6 patients to be enrolled experiences Grade 4 febrile 
neutropenia or serious (i.e., SAE) documented infection requiring IV antibiotics in 
the presence of Grade 3−4 neutropenia, then the obinutuzumab-containing 
portion of the study will be closed to further recruitment. 
Before the expansion portion of the study can begin (enrollment of 
Cohorts G and H), six patients must have completed the safety observation period 
(Cycle 1 Day 1 to Cycle 2 Day 1 for a minimum of 21 days) in the safety run-in 
(Cohort E). 
 
3.4.2 
Internal Monitoring Committee 
This study will employ an Internal Monitoring Committee (IMC).  The purpose of the IMC 
will be to make recommendations regarding study conduct on the basis of trial safety 
data to ensure patient safety while receiving study treatment. 
The IMC will include the Roche/Genentech Medical Monitor, at least one other Clinical Science 
representative who is not directly involved in the study, a Drug Safety Scientist, a 
biostatistician, and a statistical programmer.  Representatives from other Sponsor 
functional areas may be included as additional ad hoc members. In addition to the 
ongoing assessment of the incidence and nature of adverse events, serious adverse 
events, and laboratory abnormalities by the Investigator and the Medical Monitor, the 
IMC will review the aforementioned data at least twice during the study.  
Throughout the course of the study, the IMC will meet at regular intervals during the 
study and at the request of the Medical Monitor (e.g., on the basis of unexpected safety 
signals).  The IMC may make recommendations regarding study conduct, including, but 
not limited to, performing additional safety analyses, amending the study protocol, 
holding patient enrollment to one or both treatment arms pending further safety 
evaluations, holding/discontinuing study treatment, or terminating the study. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
77/P GO27834-A3 
Specific operational details such as the committee’s composition, frequency and timing 
of meetings and members’ roles and responsibilities will be detailed in the IMC 
charter. 
For Arms A and B:  The first planned review will occur after approximately 10 patients 
are randomized and have at least 6 weeks follow-up, and the next formal review will 
occur when approximately 60 patients are randomized and have at least 6 weeks 
follow-up.   
3.4.3 
Risks Associated with DCDT2980S and DCDS4501A 
The clinical safety profile of DCDT2980S and DCDS4501A based on clinical data 
obtained in the ongoing Phase I studies are summarized in Section 1.2.1.2 and 
Section 1.2.2.2.  Known and suspected risks, based on clinical data to date, are 
described below.  Guidelines regarding the management of these risks through dose 
and schedule modifications are described in Section 4.3.1.3 and Section 4.3.1.4.   
Refer also to the Investigator’s Brochure for complete and updated details. 
3.4.3.1 
Infusion-Related Events 
Some MAbs may be associated with the development of allergic or anaphylactic 
reactions, to either the active protein or excipients.  True allergic or anaphylactic 
reactions are rare after the first dose of a product, as they require prior sensitization.  
Patients with true allergic or anaphylactic reactions should not receive further doses of 
the product. 
MAbs may also be associated with reactions that are clinically indistinguishable from 
true allergic or anaphylactic reactions but are mediated through direct release of 
cytokines or other pro-inflammatory mediators.  Such reactions are often termed IRRs.  
IRRs typically occur with the first infusion of a MAb product and are generally less 
frequent and/or less severe with subsequent infusions.  They can often be managed by 
slowing the infusion rate and/or pre-treatment with various medications. 
Allergic or anaphylactic reactions and IRRs typically begin during or within several hours 
of completing the infusion.  The onset of symptoms may be rapid, and some reactions 
may be life threatening. 
Patients should be monitored for these types of reactions during and after receiving 
DCDT2908S and DCDS4501A.  DCDT2980S and DCDS4501A should be administered 
in an environment under close supervision of a physician and where full resuscitation 
facilities are immediately available.  Specific guidelines for additional precautions to be 
taken during and following DCDT2980S and DCDS4501A administration are provided in 
Section 4.3.1.5. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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3.4.3.2 
Tumor Lysis Syndrome 
There is a potential risk of TLS if treatment with DCDT2980S or DCDS4501A results in 
the rapid destruction of a large number of tumor cells.  If any evidence of this occurs 
during the study, TLS prophylaxis measures will be instituted.  Patients who are 
considered to have a high tumor burden (e.g., lymphocyte count ≥ 25 × 109/L) or bulky 
lymphadenopathy and who are considered to be at risk for TLS by the investigator will 
receive TLS prophylaxis (e.g., allopurinol ≥ 300 mg/day orally or a suitable alternative 
treatment according to institutional practice starting 12−24 hours prior to study 
treatment) and must be well hydrated prior to the initiation of study treatment at Cycle 1, 
Day 1.  These patients should continue to receive repeated prophylaxis with allopurinol 
and adequate hydration prior to each subsequent infusion as deemed appropriate by the 
investigator. 
3.4.3.3 
Bone Marrow Toxicity/Neutropenia 
Based on preclinical toxicity studies in rats and cynomolgus monkeys and clinical data 
from the ongoing Phase I Studies DCT4862g and DCS4968g, neutropenia has been 
identified as a known risk (adverse drug reaction) of both DCDT2908S and 
DCDS4501A.  Neutropenia and neutropenia-associated events were reversible but in 
some cases resulted in protocol-mandated dose reductions and/or delays.   
Adequate hematologic function should be confirmed before initiation of study treatment.  
Patients receiving study treatment will be regularly monitored for evidence of marrow 
toxicity with complete blood counts.  Study treatment may be delayed or modified due to 
hematologic toxicities, as described in Section 4.3.1.  
The use of G-CSF for neutropenia is described in Section 4.3.1.6.  Transfusion support 
for anemia and thrombocytopenia is also permitted at the discretion of the treating 
physician. 
Febrile neutropenia is commonly associated with myelotoxicity, which is considered a 
class effect of MMAE because it is commonly reported with ADCETRIS®, other similar 
ADCs, and vincristine sulfate. 
Clinical data show that among the most common SAEs reported in both DCS4968g and 
DCT4862g studies were febrile neutropenia and pyrexia. 
3.4.3.4 
Immunogenicity 
As expected with any recombinant antibody, DCDT2980S, DCDS4501A, and 
obinutuzumab may elicit an immune response and patients may develop antibodies 
against DCDT2980S, DCDS4501A, or obinutuzumab.  Patients will be closely monitored 
for any potential immune response to DCDT2980S, DCDS4501A, and obinutuzumab.  
Appropriate screening and confirmatory assays will be employed to detect ATAs at 
multiple timepoints before, during, and after treatment with DCDT2980S, DCDS4501A, 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
79/P GO27834-A3 
and obinutuzumab.  Considering the historically low immunogenicity rate of rituximab in 
NHL patients, ATAs against rituximab will not be monitored in this study. 
3.4.3.5 
Peripheral Neuropathy 
On the basis of clinical data from the ongoing Phase I Studies DCT4862g and 
DCS4968g and data from brentuximab vedotin studies, an anti-CD30-vc-MMAE ADC 
(see Section 3.4.2), peripheral neuropathy (sensory and motor) has been identified as 
a known risk (adverse drug reaction) for both DCDT2980S and DCDS4501A. 
Careful clinical evaluation of patients for neuropathy should be conducted prior to 
initiation of study drug.  Patients should be monitored for signs of peripheral neuropathy 
or worsening neuropathy and appropriate action taken per protocol guidelines.  Study 
treatment dose and schedule modifications for significant and prolonged neuropathic 
toxicity and dose-reduction are described in Section 4.3.1.7.   
3.4.3.6 
Reproductive Toxicity 
Adverse effects on human reproduction and fertility are anticipated with the 
administration of DCDT2980S and DCDS4501A, given the mechanism of action of 
MMAE.  Standard exclusion criteria will be used to ensure that patients of childbearing 
potential (male or female) are using adequate contraceptive methods.  
3.4.3.7 
Hyperglycemia 
Hyperglycemia has been observed in patients treated with DCDT2980S and 
DCDS4501A as well as with other ADCs using the same vc-MMAE platform.  Several 
patients given both DCDT2980S and DCDS4501A had abnormal fasting blood sugar 
(FBS)  at screening with elevations of glucose following steroid administration prior to 
rituximab dose.  Hyperglycemia has been reversible upon holding or discontinuing 
treatment of the ADCs and/or initiation or adjustment of anti-hyperglycemic medications.  
Emerging data suggest that hyperglycemia may occur more commonly in individuals 
with abnormal FBS values or known diabetes.  This is also reported for ADCETRIS® 
(2013 SmPC and 2013 USPI).  
3.4.3.8 
Hepatotoxicity 
Elevations in transaminase and/or bilirubin levels requiring dose modifications and 
treatment discontinuations have been reported in the ongoing clinical studies.   
3.4.3.9 
Commonly Reported Side Effects 
Other commonly reported side effects of both DCDT2980S or DCDS4501A in the 
Phase I clinical trials and within this study include fatigue, nausea, decreased appetite, 
vomiting, hair thinning or loss, joint pains, loss of appetite, diarrhea, muscle aches, 
constipation, increases in blood glucose, and headaches. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
80/P GO27834-A3 
3.4.4 
Risks Associated with ADCETRIS® (Brentuximab Vedotin) 
An ADC using the same MMAE drug and linker as that used in DCDT2980S and 
DCDS4501A, but coupled to an antibody targeting the CD30 antigen (brentuximab 
vedotin, ADCETRIS®, Seattle Genetics), was recently approved by the FDA for use in 
the treatment of specific subsets of patients with relapsed Hodgkin lymphoma and 
systemic anaplastic large-cell lymphoma.   
The most common adverse reactions observed in studies with brentuximab vedotin 
(occurring in at least 20% of patients) were neutropenia, peripheral sensory neuropathy, 
fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, 
thrombocytopenia, cough, and vomiting.   
Serious adverse reactions were reported in 31% of patients receiving ADCETRIS®.  The 
most common occurring in > 2% of patients included peripheral motor neuropathy, 
abdominal pain, septic shock, supraventricular arrhythmia, pain in extremity, and urinary 
tract infection.  In addition, John Cunningham (JC) virus infection resulting in progressive 
multifocal leukoencephalopathy (PML) and death has been reported.   
Because of the use of the same MMAE drug, it is possible that the adverse events 
observed with the use of brentuximab vedotin can also be observed with the use of 
DCDT2980S and DCDS4501A.   
Refer to the current version of the ADCETRIS® Prescribing Information for full and 
updated details. 
3.4.5 
Risks Associated with Rituximab Therapy and Their 
Management 
3.4.5.1 
Infusion Reactions 
In single-agent clinical trials of rituximab and in post-marketing surveillance studies, mild 
to moderate infusion reactions consisting of fever and chills/rigors occurred in the 
majority of patients during the first rituximab infusion.  Other frequent infusion reaction 
signs and symptoms included nausea, pruritus, angioedema, asthenia, hypotension, 
headache, bronchospasm, throat irritation, rhinitis, urticaria, rash, vomiting, myalgia, 
dizziness, and hypertension.  These reactions generally occurred within 30−120 minutes 
of beginning the first infusion, and they resolved with slowing or interruption of the 
rituximab infusion and with supportive care (diphenhydramine, 
acetaminophen/paracetamol, IV saline, meperidine, and vasopressors).  The incidence 
of infusion reactions was highest during the first infusion and decreased with each 
subsequent infusion. 
Rituximab has caused severe infusion reactions.  In some cases, these reactions were 
fatal.  These severe reactions typically occurred during the first infusion with a time to 
onset of 30−120 minutes.  Signs and symptoms of severe infusion reactions may include 
urticaria, hypotension, angioedema, hypoxia, or bronchospasm and may require 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
81/P GO27834-A3 
interruption of rituximab administration.  The most severe manifestations and sequelae 
include pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, 
ventricular fibrillation, cardiogenic shock, and anaphylactic and anaphylactoid events 
(see Appendix D).  Approximately 80% of fatal infusion reactions occurred in association 
with the first infusion of rituximab.  Because of this, patients should receive 
premedication with acetaminophen/paracetamol, antihistamines, or corticosteroids, in 
accordance with standard clinical practice, prior to rituximab infusions. 
3.4.5.2 
Management of Severe Infusion Reactions 
Administration of rituximab will occur in a setting with emergency equipment and staff 
who are trained to monitor for and respond to medical emergencies.  The rituximab 
infusion should be interrupted for severe reactions on the basis of clinical judgment.   
Medications and supportive care measures⎯including, but not limited to, epinephrine, 
antihistamines, glucocorticoids, IV fluids, vasopressors, oxygen, bronchodilators and 
acetaminophen/paracetamol⎯should be available for immediate use and instituted as 
medically indicated for use in the event of a reaction during administration.   
In most cases, the infusion can be resumed at a 50% reduction in rate (e.g., from 
100 mg/hr to 50 mg/hr) when symptoms have completely resolved.  Patients requiring 
close monitoring during all rituximab infusions include those with preexisting cardiac and 
pulmonary conditions, those with prior clinically significant cardiopulmonary adverse 
events, and those with high numbers of circulating malignant cells (≥ 25,000/μL) with or 
without evidence of high tumor burden. 
3.4.5.3 
Tumor Lysis Syndrome 
Rapid reductions in tumor volume followed by acute renal failure, hyperkalemia, 
hypocalcemia, hyperuricemia, or hyperphosphatemia have been reported within 
12−24 hours after the first infusion of rituximab.  Rare instances of fatal outcome have 
been reported in the setting of TLS following treatment with rituximab.  The risks of TLS 
appear to be greater in patients with high tumor burden.  Patients deemed to be at high 
risk for TLS complications may, at the investigator’s discretion, receive their initial dose 
of rituximab over 2 consecutive days (see Section 4.3.2.3).  Correction of electrolyte 
abnormalities, monitoring of renal function and fluid balance, and administration of 
supportive care, including dialysis, should be initiated as indicated.  Following complete 
resolution of TLS complications, rituximab has been tolerated when re-administered in 
conjunction with prophylactic therapy for TLS in a limited number of cases. 
3.4.5.4 
Hepatitis B Reactivation with Related Fulminant Hepatitis and 
Other Viral Infections 
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death 
has been reported for some patients with hematologic malignancies treated with 
rituximab.  The majority of these patients received rituximab in combination with 
chemotherapy.  The median time to the diagnosis of hepatitis was approximately 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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4 months after the initiation of rituximab and approximately 1 month after the last dose of 
rituximab.  Patients with serologic findings consistent with chronic HBV (hepatitis B 
surface antigen [HBsAg] positivity) or hepatitis C virus (HCV) infection (HCV RNA or 
antibody positivity) are ineligible for this study.  Patients who are not chronically infected 
with HBV but have serologic evidence of prior infection at baseline (IgG hepatitis B core 
antibody[anti-HBc] positive but HBV DNA negative) may be eligible (if believed to be in 
the patient’s best interest by the investigator and Medical Monitor) and would be 
monitored closely for perturbations in liver function during the period of rituximab 
treatment and every 2−4 weeks thereafter.  Such patients would also be required to 
receive prophylactic anti-viral therapy with lamivudine for at least 6 months after 
completion of rituximab therapy (Yeo et al. 2009). 
Additional serious viral infections, new, reactivated, or exacerbated (e.g., infections 
caused by cytomegalovirus, varicella zoster virus, herpes simplex virus, West Nile virus, 
parvovirus B19, JC virus, and HCV) have been reported with rituximab, mainly in 
patients who had received rituximab in combination with chemotherapy or as part of a 
hematopoietic stem cell transplant.  Particular attention should be given to patients who 
have had significant prior immunosuppressive treatment such as high-dose 
chemotherapy and stem cell transplant.  JC virus infection resulting in PML and death 
has been observed in rituximab-treated patients with hematologic malignancies or with 
autoimmune diseases.  Most cases of PML were diagnosed within 12 months of the 
patient’s last infusion of rituximab.  Physicians should consider the diagnosis of PML in 
any patient presenting with new-onset neurologic manifestations.  Evaluation of PML 
includes, but is not limited to, consultation with a neurologist, brain magnetic resonance 
imaging (MRI), and lumbar puncture.  Physicians should discontinue rituximab (and 
DCDT2980S and/or DCDS4501A) and consider discontinuation or reduction of any 
immunosuppressive therapy in patients who develop PML. 
3.4.5.5 
Cardiovascular Events 
Infusions should be discontinued in the event of serious or life-threatening cardiac 
arrhythmias.  Patients who develop clinically significant arrhythmias should undergo 
cardiac monitoring during and after subsequent infusions of rituximab.  Patients with 
preexisting cardiac conditions, including arrhythmias and angina, who have had 
recurrences of these events during rituximab therapy should be monitored throughout 
the infusion and the immediate post-infusion period. 
3.4.5.6 
Bowel Obstruction and Perforation 
Abdominal pain, bowel obstruction, and perforation, in some cases leading to death, 
were observed in patients receiving rituximab in combination with chemotherapy for 
DLBCL.  In post-marketing reports, which include patients with low-grade or follicular 
NHL and patients with DLBCL, the mean time to onset of symptoms was 6 days 
(range, 1−77 days) in patients with documented gastrointestinal perforation.  Complaints 
of abdominal pain, especially early in the course of treatment, should prompt a thorough 
diagnostic evaluation and appropriate treatment.   


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
83/P GO27834-A3 
3.4.5.7 
Immunization 
The safety of immunization with live viral vaccines following rituximab therapy has not 
been studied.  Patients who participate in this study may not receive either primary or 
booster with live virus vaccines for at least 28 days prior to initiation of rituximab or at any 
time during study treatment.  Investigators should review the status of potential study 
patients being considered for this study and follow the U.S. Centers for Disease Control 
and Prevention guidelines for adult with non-live vaccines intended to prevent infectious 
diseases prior to study therapy. 
Refer to the Rituxan®/MabThera® (Rituximab) Package Insert/Summary of Product 
Characteristics (SmPC) for additional safety information. 
3.4.6 
Risks Associated with Obinutuzumab Therapy 
No evidence available at the time of the approval of this protocol indicates that special 
warnings or precautions are appropriate other than those noted in the Obinutuzumab 
Investigator’s Brochure and as described in the following sections. 
3.4.6.1 
Infusion-Related Reactions and Hypersensitivity Reactions 
(including Anaphylaxis) 
The commonly experienced IRRs have been characterized by fever, chills, flushing, 
nausea, vomiting, hypotension, hypertension, fatigue, and other symptoms. 
Respiratory infusion-related symptoms, such as hypoxia, dyspnea, bronchospasm, 
larynx and throat irritation, and laryngeal edema, have also been reported.  These IRRs 
were mostly mild or moderate (NCI CTCAE v4.0, Grade 1 and 2 events), and < 10% of 
the events were severe (Grade 3 events), occurring predominantly during the first hour 
of the infusion or shortly after the first infusion had finished.  The events resolved with 
the slowing or interruption of the infusion and supportive care.  The incidence and 
severity of IRRs decreased with subsequent infusions.  Extensive tumor burden 
predominantly localized in the blood circulation (e.g., high peripheral lymphocyte count in 
patients with CLL) may be a predisposing factor for the development of IRRs. 
IRRs may be clinically indistinguishable from IgE-mediated allergic or anaphylactic 
reactions. 
3.4.6.2 
Tumor Lysis Syndrome 
TLS has been reported with obinutuzumab administration.  Patients with a high tumor 
burden, including patients with a lymphocyte count ≥ 25 × 109/L, particularly patients with 
B-cell CLL and MCL, are at increased risk for TLS and severe IRRs.  All patients with 
peripheral blood lymphocyte counts of ≥ 25 × 109/L or bulky adenopathy must receive 
prophylaxis for TLS prior to the initiation of study treatment.  This includes appropriate 
hydration, consisting of fluid intake of approximately 3 L/day, starting 1−2 days prior to 
the first dose of obinutuzumab, and administration of allopurinol (300 mg/day orally) or a 
suitable alternative (i.e., rasburicase) treatment, starting at least 12 − 24 hours prior to the 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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first infusion of obinutuzumab (Cycle 1, Day 1).  All patients should then be carefully 
monitored during the initial weeks of treatment.  Patients still considered at risk for TLS 
because of persistently high tumor burden (i.e., peripheral blood lymphocyte counts 
≥ 25 × 109/L) before the second and subsequent infusions of obinutuzumab should 
receive continuous TLS prophylaxis with allopurinol or a suitable alternative (i.e., 
rasburicase) and adequate hydration until the risk is abated, as determined by the 
investigator.  For treatment of TLS, correct electrolyte abnormalities, monitor renal function and 
fluid balance, and administer supportive care, including dialysis as indicated. 
3.4.6.3 
Neutropenia 
Cases of Grade 3 or 4 neutropenia, including febrile neutropenia, have been reported 
with obinutuzumab administration.  Grade 3 or 4 neutropenia has predominantly been 
observed in patients with CLL.  Patients who experience Grade 3 or 4 neutropenia 
should be monitored until neutrophil values return to at least Grade 2.  Use of G-CSF 
has been found to result in a rapid normalization of neutrophils, similar to what has been 
observed in patients treated with rituximab.  The use of G-CSF is allowed for treatment 
of neutropenia in this study.  Primary prophylaxis with G-CSF is recommended 
according to the American Society of Clinical Oncology (ASCO), European Organisation 
for Research and Treatment of Cancer (EORTC), and European Society for Medical 
Oncology (ESMO) guidelines, namely for patients who are ≥ 60 years old and/or with co-
morbidities (Lyman et al. 2004).   
3.4.6.4 
Thrombocytopenia 
Severe and life-threatening thrombocytopenia, including acute thrombocytopenia 
(occurring within 24 hours after the infusion), has been observed during treatment with 
obinutuzumab.  Fatal hemorrhagic events have also been reported in patients treated 
with obinutuzumab.  It seems that the first cycle is the greatest risk of hemorrhage in 
patients treated with obinutuzumab.  A clear relationship between thrombocytopenia and 
hemorrhagic events has not been established.  Patients treated with concomitant 
medication, which could possibly worsen thrombocytopenia-related events (e.g., platelet 
inhibitors and anticoagulants), may be at greater risk of bleeding.  Patients should be 
closely monitored for thrombocytopenia, especially during the first cycle; regular 
laboratory tests should be performed until the event resolves, and dose delays should be 
considered in case of severe or life-threatening thrombocytopenia.  Transfusion of blood 
products (i.e., platelet transfusion) according to institutional practice is at the discretion 
of the treating physician.  
3.4.6.5 
Infection 
On the basis of its anticipated mode of action, resulting in profound B-cell depletion, 
obinutuzumab may be associated with an increased risk of infections.  Infections have 
been reported in patients receiving obinutuzumab.  Therefore, obinutuzumab should not 
be administered to patients with active severe infections. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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A “black-box” warning for obinutuzumab states that reactivation of hepatitis B as well as 
other serious viral infections (e.g., infections caused by cytomegalovirus, Varicella zoster 
virus, herpes simplex virus, JC virus, and HCV) that were new, reactivated, or 
exacerbated have been reported with the B cell−depleting antibody rituximab mainly in 
patients who had received the drug in combination with chemotherapy or as part of a 
hematopoietic SCT.  The risk of such infections with obinutuzumab is unknown.  
Particular attention should be given to patients who have previously received significant 
immunosuppressive treatment, such as high-dose chemotherapy and SCT. 
A “black-box” warning for obinutuzumab states that JC viral infection (including fatal) that 
resulted in PML with destructive infection of oligodendrocytes of the CNS white matte 
have been reported in patients treated with anti-CD20 therapies, including rituximab and 
obinutuzumab. 
The diagnosis of PML should be considered in any patient presenting with new-onset 
neurologic manifestations.  The symptoms of PML are unspecific and can vary 
depending on the affected region of the brain.  Motor involvement with corticospinal tract 
findings, sensory involvement, cerebellar deficits, and visual field defects are common.  
Some syndromes regarded as cortical (e.g., aphasia or visual-spatial disorientation) can 
occur. 
Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain 
MRI, and lumbar puncture (cerebrospinal fluid testing for JC viral DNA).  
Therapy with obinutuzumab should be withheld during the investigation of potential PML 
and permanently discontinued in case of confirmed PML.  Discontinuation or reduction of 
any concomitant chemotherapy or immunosuppressive therapy should also be 
considered.  The patient should be referred to a neurologist for the diagnosis and 
management of PML. 
3.4.6.6 
Immunization 
The safety of immunization with live virus vaccines following obinutuzumab therapy has not 
been studied.  Thus, vaccination with live virus vaccines is not recommended during treatment 
and until B-cell recovery. 
3.4.6.7 
Worsening of Preexisting Cardiac Condition 
In patients with underlying cardiac disease and treated with obinutuzumab, adverse events such 
as angina pectoris, acute coronary syndrome, myocardial infarction, heart failure, and 
arrhythmias, including atrial fibrillation and tachyarrhythmia, have been observed.  These events 
may occur as part of an IRR and can be fatal.  Therefore, patients with a history of cardiac disease 
should be monitored closely.  In addition, these patients should be hydrated with caution to 
prevent a potential fluid overload. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
86/P GO27834-A3 
3.5 
MINIMIZATION OF BIAS  
For the randomized, non-comparative, open-label portion of the study, patients were 
randomly allocated to two treatment arms in a 1:1 ratio through use of an Interactive 
Voice and Web Response System (IXRS).  A dynamic stratified randomization scheme 
was employed to ensure balance in the stratification factors as specified in Section 3.1.  
This portion of the study (Arms A and B) is now closed to enrollment. 
3.6 
ADMINISTRATIVE STRUCTURE  
Genentech, Inc., a member of the Roche group, will sponsor this study.  A Contract 
Research Organization (CRO) will be utilized to perform project management, study 
management, and clinical monitoring.  Genentech will conduct CRO oversight, approve 
patient eligibility, and perform dose escalation decision-making, medical monitoring, and 
statistical programming and analysis.  An IMC (see Section 3.4) will provide an 
additional level of safety monitoring for the study.  
Approximately 40 study centers in the United States, Canada, and Europe will 
participate in the study to enroll approximately 252 patients.  Additional patients may be 
enrolled in order to obtain additional safety and/or efficacy data. 
Electronic data capture (EDC) will be utilized for this study.  An IXRS will be used to 
assign patient numbers.  A central laboratory will be used for sample management and 
storage until shipment to one of several specialty laboratories or Genentech for analysis.  
An IRF will be used for the collection and possible assessment of radiographic images 
from tumor assessments.  Additional vendors for ECG collection and possible analysis 
and for PRO collection and data entry will be used. 
3.7 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in accordance with the FDA regulations, the International 
Conference on Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP), and 
applicable local, state, and federal laws, as well as other applicable country laws. 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria to be eligible for study entry: 
• 
Signed Informed  
• 
Consent Form(s) 
• 
Age ≥ 18 years  
• 
ECOG Performance Status of 0, 1, or 2 
• 
Life expectancy of at least 12 weeks 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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• 
History of histologically documented relapsed or refractory Grades 1−3a FL or 
relapsed or refractory DLBCL 
• 
Availability of an archival or freshly biopsied tumor tissue sample must be confirmed 
for study enrollment. 
• 
Have a clinical indication for treatment as determined by the investigator 
• 
Must have at least one bidimensionally measurable lesion (> 1.5 cm in its largest 
dimension by computed tomography [CT] scan or MRI) 
• 
Laboratory values (including patients with hepatic or renal involvement), as follows: 
AST and ALT ≤ 2.5 × ULN 
Total bilirubin ≤ 1.5 × ULN 
Platelet count ≥ 75,000/mm3 (unless thrombocytopenia clearly due to marrow 
involvement of NHL and/or disease-related immune thrombocytopenia) 
Absolute neutrophil count ≥ 1000/mm3 (without growth factor support, unless 
neutropenia clearly due to marrow involvement of NHL) 
Total hemoglobin ≥ 9 g/dL (without transfusion support > 14 days prior to 
screening, unless anemia clearly due to marrow involvement of NHL) 
Serum creatinine ≤ 2.0 mg/dL or measured creatinine CL ≥ 50 mL/min 
• 
For female patients of childbearing potential and male patients with female partners 
of childbearing potential, agreement to use one highly effective form of nonhormonal 
contraception or two effective forms of nonhormonal contraception, including at 
least one method with a failure rate of < 1% per year, through the course of 
study treatment and for ≥ 12 months after the last dose of DCDT2980S, 
DCDS4501A, rituximab, or obinutuzumab (whichever is later) in women and at 
least 5 months after the last dose of DCDT2980S, DCDS4501A, rituximab, or 
obinutuzumab (whichever is later) in men 
A woman is considered not to be of childbearing potential if she is 
postmenopausal, defined by amenorrhea of ≥ 12 months duration and age 
≥ 45 years, or has undergone hysterectomy and/or bilateral oophorectomy. 
The following are considered highly effective forms of contraception:  1) true 
abstinence; 2) male sterilization (with post-procedure documentation of absence 
of sperm in the ejaculate).  For female patients, the sterilized male partner should 
be the sole partner. 
The following are considered effective forms of contraception:  1) intrauterine 
device (IUD; copper IUD or hormonal IUDs only) or intrauterine system; 
2) condom with spermicidal foam/gel/film/cream/suppository; 3) occlusive cap 
(diaphragm or cervical/vault cap) with spermicidal 
foam/gel/film/cream/suppository. 
Males must agree to abstain from sperm donation for at least 5 months after the 
last dose of DCDT2980S, DCDS4501A, rituximab, or obinutuzumab 
(whichever is later). 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
88/P GO27834-A3 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Prior use of any MAb, radioimmunoconjugate or ADC within 4 weeks before 
Cycle 1, Day 1 
• 
Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive 
therapy, or any investigational anti-cancer agent within 2 weeks prior to Cycle 1, 
Day 1 
Adverse events except for sensory neuropathy from any previous treatments 
must be resolved or stabilized to Grade ≤ 2 prior to Cycle 1, Day 1. 
• 
Completion of autologous stem cell transplant within 100 days prior to Cycle 1, 
Day 1 
• 
Prior allogeneic stem cell transplant 
• 
Eligibility for autologous SCT (patients with relapsed or refractory DLBCL) 
• 
History of transformation of indolent disease to DLBCL 
• 
History of severe allergic or anaphylactic reactions to MAb therapy (or recombinant 
antibody-related fusion proteins) 
• 
History of other malignancy that could affect compliance with the protocol or 
interpretation of results 
Patients with a history of curatively treated basal or squamous cell carcinoma of 
the skin or in situ carcinoma (e.g., of the cervix or breast) are allowed.  Patients 
with a malignancy that has been treated with curative intent will also be allowed if 
the malignancy has been in remission without treatment for ≥ 2 years prior 
to Cycle 1, Day 1. 
• 
Current or past history of CNS lymphoma 
• 
Current Grade > 1 peripheral neuropathy 
• 
Evidence of significant, uncontrolled, concomitant diseases that could affect 
compliance with the protocol or interpretation of results, including significant 
cardiovascular disease (such as New York Heart Association Class III or IV cardiac 
disease, myocardial infarction within the last 6 months, unstable arrhythmias, or 
unstable angina) or significant pulmonary disease (including obstructive pulmonary 
disease and history of bronchospasm) 
• 
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection 
(excluding fungal infections of nail beds) at study enrollment or any major episode of 
infection requiring treatment with IV antibiotics or hospitalization (relating to the 
completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1 
• 
Recent major surgery within 6 weeks prior to Cycle 1, Day 1, other than 
for diagnosis 
• 
Presence of positive test results for hepatitis B (HBsAg and/or total anti-HBc) or 
hepatitis C (HCV antibody) 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
89/P GO27834-A3 
Patients who are positive for anti-HBc are eligible only if PCR is negative for HBV 
DNA and it is believed by both the investigator and Medical Monitor that it is in 
the patient’s best interest to participate.  
Patients who are positive for HCV antibody must be negative for HCV by PCR to 
be eligible for study participation. 
• 
Vaccination with a live vaccine within 28 days prior to treatment 
• 
Known history of HIV seropositive status 
• 
Women who are pregnant or lactating 
• 
Ongoing corticosteroid use > 30 mg/day prednisone or equivalent 
Patients receiving corticosteroid treatment ≤ 30 mg/day prednisone or equivalent 
must be documented to be on a stable dose prior to study enrollment and 
initiation of therapy 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
This is an open-label study.  After written informed consent has been obtained and 
preliminary eligibility has been established, the study site will submit documentation 
supporting eligibility to the Sponsor via facsimile and obtain the Sponsor’s approval to 
enroll the patient.  Once the Sponsor reviews and approves the patient for enrollment, 
the patient number will be assigned via IXRS.  
As described in Section 3.1.1.2, only select investigator sites that have agreed to 
participate in the non-randomized (Cohorts C and D) portion of the study will enroll 
patients into these cohorts.  Cohorts C and D will be opened sequentially following 
completion of the randomized portion of the study for patients with FL. 
For obinutuzumab-containing cohorts (Cohorts E, G, and H), patients with either 
relapsed or refractory follicular NHL or relapsed or refractory DLBCL will be enrolled.  
After the safety run-in stage for DCDS4501A at 1.8 mg/kg in combination with 
obinutuzumab, the non-randomized dose-expansion portion of the study will enroll 
40 relapsed or refractory FL patients into Cohort G and 40 relapsed or refractory 
DLBCL patients into Cohort H.  
Personnel responsible for performing PK and ATA assays will receive participants’ 
treatment assignments to identify appropriate PK and ATA samples to be analyzed in 
the appropriate corresponding assays.  
4.3 
STUDY TREATMENT  
4.3.1 
DCDT2980S and DCDS4501A 
4.3.1.1 
Formulation and Storage 
a. DCDT2980S 
DCDT2980S will be provided as a lyophilized powder in a single-use 20-cc vial.  
The solution for reconstitution is Sterile Water for Injection (SWFI), and the reconstitution 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
90/P GO27834-A3 
volume is 2.6 mL to yield a final concentration of 20 mg/mL DCDT2980S in 40 mM 
L-histidine hydrochloride, 240 mM sucrose, and 0.02% polysorbate 20, pH 6.0. 
Reconstituted DCDT2980S should be further diluted with sterile 0.9% NaCl to a total 
volume of 250 mL. 
DCDT2980S vials must be refrigerated at 2°C−8°C (36°F−46°F) upon receipt until use.  
DCDT2980S should not be used beyond the expiration date provided by the 
manufacturer.  Vial contents should not be frozen or shaken and should be protected 
from direct sunlight.  After reconstitution, DCDT2980S vials may be stored at room 
temperatures (> 8°C−25°C [> 46°F−77°F]) for up to 4 hours or at refrigerated 
temperatures (2°C−8°C [36°F−46°F]) for up to 8 hours prior to use.  Once DCDT2980S 
has been diluted with sterile 0.9% NaCl, the solution should be used within 4 hours at 
room temperature or within 8 hours at refrigerated temperature.  Vials are intended for 
single use only; therefore, any remaining solution should be discarded. 
For further details, refer to the DCDT2980S Investigator’s Brochure. 
b. DCDS4501A 
DCDS4501A is provided as a liquid formulation and contains no preservatives.  Each 
single-use 20-cc vial is filled to deliver 100 mg of DCDS4501A.  The drug product is 
formulated as 10 mg/mL DCDS4501A in 20 mM L-histidine acetate, 240 mM sucrose, 
0.02% (w/v) polysorbate 20, pH 5.5.  
DCDS4501A will be administered to patients intravenously via syringe pump with an 
IV infusion set containing a 0.22−µm in-line filter with a final volume of DCDS4501A 
determined by the dose and patient weight.  
DCDS4501A vials must be refrigerated at 2°C−8°C (36°F−46°F) upon receipt until use.  
DCDS4501A vials may be stored at room temperature (> 8°C−25°C [46°F−77°F]) for up 
to 8 hours.  DCDS4501A should not be used beyond the expiration date provided by the 
manufacturer.  Vial contents should not be frozen or shaken and should be protected 
from direct sunlight.  Vials are intended for single use only; therefore, any remaining 
solution should be discarded. 
Once the DCDS4501A dose solution has been prepared, the solution should be used 
within 4 hours at room temperature (> 8 °C−25°C [46°F−77°F]) or within 8 hours 
refrigerated at 2°C−8°C (36°F−46°F).  Because the drug product contains no 
preservatives, the Sponsor recommends using DCDS4501A in a syringe and extension 
set as soon as possible to reduce the risk of microbial contamination.   
For further details, refer to the DCDS4501A Investigator Brochure. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
91/P GO27834-A3 
4.3.1.2 
Dosage and Administration 
a. DCDT2980S-Specific Information 
DCDT2980S will be administered to patients by IV infusion.  Compatibility testing has 
shown that DCDT2980S is stable when diluted in polyvinyl chloride (PVC) bags to a 
concentration at or above 0.04 mg/mL in 0.9% NaCl diluent.  The drug product will be 
delivered following dilution in 0.9% NaCl with a final DCDT2980S concentration 
determined based on dose and patient weight.  The study drug will be diluted in a PVC 
bag and delivered using a 0.22 µm in-line filter on the IV infusion set. 
Additional information/instructions regarding study drug administration will be provided in 
the Pharmacy Binder. 
b. DCDS4501A-Specific Information 
DCDS4501A will be administered to patients intravenously via syringe pump with an 
IV infusion set containing a 0.22 µm in-line filter with a final volume of DCDS4501A 
determined by the dose and patient weight.  Compatibility testing has shown that 
DCDS4501A is stable both in syringes made of polypropylene (PP) and in standard 
extension sets with 0.22 µm in-line filter, when stored neat or diluted with 0.9% NaCl 
saline.   
Additional information/instructions regarding study drug administration will be provided in 
the Pharmacy Binder. 
c. General Information 
The total dose of DCDT2980S and DCDS4501A for each patient will depend on the 
patient’s weight within 96 hours prior to Day 1 of each cycle.  The patient weight 
obtained during screening may be used for dose determination at all treatment cycles; if 
the patient’s weight within 96 hours prior to Day 1 of a given treatment cycle differs by 
>10% from the weight obtained during screening, the new weight should be used to 
calculate the dose.   
For both DCDT2980S and DCDS4501A, the initial dose will be administered to 
well-hydrated (based on clinical judgment) patients over 90 (± 10) minutes.  
Premedication with acetaminophen or paracetamol (e.g., 500−1000 mg) and 
diphenhydramine (e.g., 50°C−100 mg) per institutional standard practice may be 
administered prior to each infusion.  Administration of corticosteroids is permitted at the 
discretion of the treating physician.  Patients who do not receive premedications prior to 
the first dose of DCDT2980S and who develop an IRR during the first dose should 
receive premedications prior to subsequent doses (see Table 1). 
The DCDT2980S/DCDS4501A infusion may be slowed or interrupted for patients 
experiencing infusion-associated symptoms.  Following the initial dose, patients will be 
observed for 90 minutes for fever, chills, rigors, hypotension, nausea, or other 
infusion-associated symptoms.  If the infusion is well-tolerated, subsequent doses of 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
92/P GO27834-A3 
DCDT2980S/DCDS4501A may be administered over 30 (± 10) minutes, followed by a 
30-minute observation period post-infusion.   
For instructions on study drug preparation and administration, refer to the DCDT2980S 
and DCDS4501A Investigator Brochure. 
4.3.1.3 
Dosage Modification 
Patients should be assessed clinically for toxicity prior to each dose using the 
NCI CTCAE v4.0 grading scale.  Dosing will occur only if a patient’s clinical assessment 
and laboratory test values are acceptable.  If scheduled dosing coincides with a holiday 
that precludes dosing, dosing should commence on the nearest following date, with 
subsequent dosing continuing on a 21-day schedule as applicable. 
Specific guidelines around dosage modifications for neutropenia and peripheral 
neuropathy are detailed below in Section 4.3.1.6 and Section 4.3.1.7.  Patients who 
experience other treatment-related Grade 3 or 4 toxicity or laboratory abnormalities will 
be allowed to delay dosing of study treatment (both ADC and rituximab or 
obinutuzumab) for up to 2 weeks to allow for recovery.  Patients may continue to receive 
additional infusions of DCDT2980S or DCDS4501A per their treatment assignment 
provided that the toxicity has resolved to Grade ≤ 2 or ≥ 80% of the baseline value, 
whichever is lower, within the 2−week delay period.  The decision for dose modification 
will be made on the basis of the investigator’s assessment of ongoing clinical benefit 
with continued study treatment and in consultation with the Medical Monitor.   
Once dose reductions of DCDT2980S or DCDS4501A are made for toxicity, dose 
re-escalation will not be allowed.   
If a patient develops unacceptable toxicity to DCDT2980S or DCDS4501A, requiring its 
discontinuation, single-agent rituximab may be continued on the basis of the 
investigator’s assessment of ongoing clinical benefit and with the approval of the 
Medical Monitor.  Patients enrolled in obinutuzumab-containing cohorts will not continue 
on single-agent obinutuzumab unless approved by the Medical Monitor. 
4.3.1.4 
Schedule Modification 
Patients in whom toxicities have not resolved to Grade ≤ 2 or ≥ 80% of baseline value, 
whichever is lower, may have their study treatment delayed by up to 2 weeks.  Dosing of 
both DCDT2980S or DCDS4501A and rituximab or obinutuzumab should be held 
during this period.  If all study drug−related toxicities have resolved sufficiently, the 
patient may resume DCDT2980S or DCDS4501A and rituximab or obinutuzumab 
dosing on the regular every-21-day schedule.   
A patient’s dosing may be changed to a 28-day cycle if it is felt by the investigator that 
changing a patient’s dosing regimen from 21-day to 28-day cycles would provide 
sufficient time for recovery from a transient and reversible toxicity⎯for example, 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
93/P GO27834-A3 
cytopenia without requiring repeated treatment delays.  Modifications to the dosing 
schedule in this fashion must be made in consultation with and with the approval of the 
Medical Monitor. 
Patients who do not fulfill the criteria for continuation of dosing after the 2-week delay 
may be discontinued from study treatment and be followed for safety outcomes (see 
Section 4.5.6).  Exceptions on the basis of ongoing clinical benefit may be allowed 
following a careful assessment and discussion of risk versus benefit with the patient by 
the investigator and approval from the Medical Monitor.  
Specific guidelines around schedule modifications for neutropenia and peripheral 
neuropathy are detailed below in Section 4.3.1.6 and Section 4.3.1.7. 
4.3.1.5 
Infusion Reaction 
Patients will be monitored during and after each DCDT2980S/DCDS4501A infusion for 
90 minutes after the first infusion and for 30 minutes after subsequent infusions in the 
absence of infusion-related adverse events.  Patients who experience infusion-related 
symptoms should be managed as described in Table 1.  Precautions for suspected 
anaphylactic reaction during study drug infusions are provided in Appendix D. 
In the event of a life-threatening IRR, which may include pulmonary or cardiac events, or 
an IgE-mediated anaphylactic reaction, administration of 
DCDT2980S/DCDS4501A should be immediately discontinued.  Patients who 
experience these reactions should receive aggressive symptomatic treatment and are 
not eligible to receive any additional study treatment. 
Premedication prior to DCDT2980S/DCDS4501A with acetaminophen/paracetamol, 
antihistamines, or corticosteroids per standard clinical practice is permitted⎯for 
example, in patients with substantial tumor burden and where the risk of cytokine 
release syndrome is high.  In patients who do not receive premedication prior to any 
given dose of DCDT2980S/DCDS4501A and who develop any Grade ≥ 2 
infusion-related toxicity, premedication should be administered prior to subsequent 
doses.  


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
94/P GO27834-A3 
Table 1 
Management of Infusion-Related Symptoms for All Study Drugs 
Infusion-Related  
Symptoms a 
Guidance 
Grade 1−2 
• 
Slow or hold infusion 
• 
Give supportive treatment b 
• 
Upon symptom resolution, may resume/escalate infusion rate at the 
investigator’s discretion c 
• 
Note:  For Grade 2 wheezing or bronchospasm, patient must be 
premedicated for subsequent doses.  If symptoms recur with the same or 
greater severity, the infusion must be stopped immediately and study 
treatment permanently discontinued. 
Grade 3 
• 
Discontinue infusion 
• 
Give supportive treatment b 
• 
Upon symptom resolution, may resume/escalate infusion rate at the 
investigator discretion c 
• 
Note:  If the same adverse event recurs with the same or greater severity, 
treatment must be permanently discontinued. 
• 
Note:  For Grade 3 hypotension or fever, patient must be 
premedicated before re-treatment.  If symptoms recur, then study 
drug must be permanently discontinued. 
• 
Note:  If patient has Grade 3 wheezing or bronchospasm at first occurrence, 
study treatment should be permanently discontinued.   
Grade 4 
• 
Discontinue infusion immediately, treat symptoms aggressively, and 
permanently discontinue patient from study treatment 
IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events. 
a Refer to the NCI CTCAE v4.0 scale for the grading of symptoms.  Management of IgE-mediated 
allergic reactions should be as directed in the text preceding this table. 
b Supportive treatment:  Patients should be treated with acetaminophen/paracetamol and an 
antihistamine such as diphenhydramine if they have not been received in the last 4 hours.  
IV saline may be indicated.  For bronchospasm, urticaria, or dyspnea, patients may require 
antihistamines, oxygen, corticosteroids (e.g., 100 mg IV prednisolone or equivalent), 
and/or bronchodilators.  Patients with hypotension requiring vasopressor support must be 
permanently discontinued from study drug. 
c Infusion rate escalation after re-initiation:  Upon complete resolution of symptoms, the infusion 
may be resumed at 50% of the rate achieved prior to interruption.  In the absence of 
infusion-related symptoms, the rate of infusion may be escalated in increments of 50 mg/hr every 
30 minutes. 
 
4.3.1.6 
Neutropenia 
Because neutropenia is a known risk of DCDT2980S and DCDS4501A 
(see Section 3.4.3.3), the use of growth factor support (G-CSF) as prophylactic and 
therapeutic indications is permitted (see Appendix F) in order to allow continued dosing 
of DCDT2980S/DCDS4501A.  Dose modifications for patients who experience 
treatment-related Grade 3−4 neutropenia in the context of G-CSF usage are as follows: 
• 
Primary prophylaxis with G-CSF (i.e., prior to the first dose of 
DCDT2980S/DCDS4501A) is permitted for patients with clinical factors listed in 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
95/P GO27834-A3 
Appendix F or who otherwise are considered at high risk for developing neutropenia 
on study treatment. 
• 
Patients who experience treatment-related Grade 3−4 neutropenia will be allowed to 
delay dosing of study treatment (both ADC and rituximab or obinutuzumab) for up 
to two weeks to allow for recovery.  Therapeutic G-CSF is permitted as clinically 
indicated (see Appendix F) and to facilitate neutrophil recovery to allow subsequent 
DCDT2980S/DCDS4501A dosing. 
• 
Subsequent dosing of DCDT2980S/DCDS4501A and rituximab/obinutuzumab is 
permitted provided that the neutropenia has resolved to Grade ≤ 2 or ≥ 80% of the 
baseline value, whichever is lower, within the 2-week period.   
• 
If prophylactic G-CSF was not administered prior to the cycle in which the 
Grade 3−4 neutropenia developed, then prophylactic G-CSF may be administered 
prior to subsequent cycles without DCDT2980S/DCDS4501A dose reduction.  The 
dose schedule may be changed from 21-day to 28-day cycles to provide sufficient 
time for neutrophil recovery in subsequent cycles.  In the absence of prophylactic 
G-CSF or dose schedule modification, the dose of DCDT2980S/DCDS4501A in 
subsequent cycles should be reduced to 1.8 mg/kg for Arms A and B.  For 
Cohorts E, G, and H, patients will be given DCDS4501A at a dose of 
1.8 mg/kg, and further dose reductions cannot be made.   
• 
If Grade 3−4 neutropenia recurs with prophylactic G-CSF, the dose for subsequent 
DCDT2980S/DCDS4501A should be reduced to 1.8 mg/kg for Arms A and B.  
Prophylactic G-CSF and dose schedule modifications as described above are 
permitted in order to maintain the reduced DCDT2980S/DCDS4501A dose level and 
schedule. 
• 
If Grade 3−4 neutropenia recurs at the reduced dose despite the administration of 
prophylactic G-CSF, then the patient should be discontinued from study treatment.   
• 
For patients enrolled into the non-randomized portion of the study (Cohorts C 
and D, as well as Cohorts E, G, and H), dose reductions will not be allowed for 
neutropenia.  Administration of therapeutic/prophylactic G-CSF and dose-schedule 
modifications as described above are allowed.  Patients who have persistent or 
recurrent Grade 3−4 neutropenia as defined above should be discontinued from 
study treatment. 
 
The determination of the dose and schedule modifications will be made on the basis of 
the investigator’s assessment of ongoing clinical benefit with continuing study treatment 
and with the approval of the Medical Monitor.   
4.3.1.7 
Peripheral Neuropathy 
Peripheral neuropathy (sensory and/or motor) is a known risk of DCDT2980S and 
DCDS4501A (see Section 3.4.3.5).  For new or worsening drug-related Grade 2 or 3 
peripheral sensory and/or motor neuropathy, dosing should be held for up to 2 weeks 
until peripheral neuropathy improves to Grade 1 or baseline grade.  Continuation of 
study treatment following dose delays beyond 2 weeks will require consultation with and 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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approval of the Medical Monitor based on an assessment of the benefit-risk analysis of 
continuing to delay study treatment. 
For patients enrolled on arms A or B following resolution of peripheral neuropathy 
(sensory and/or motor), subsequent doses of DCDT2980S/DCDS4501A should be 
reduced to 1.8 mg/kg.  If worsening Grade 2 or 3 peripheral neuropathy (sensory and/or 
motor) recurs following dose reduction, study treatment should be discontinued.  For 
Grade 4 peripheral neuropathy (sensory and/or motor), study treatment should be 
discontinued.  
For patients enrolled into Cohorts C and D, dose modifications will not be allowed.  
Patients who have Grade 2 or 3 peripheral neuropathy (sensory and/or motor), as 
defined above, should be discontinued from study treatment.   
For patients enrolled on Cohorts E, G, or H, following resolution of Grade 2 or Grade 3 
peripheral neuropathy (sensory and/or motor), subsequent doses of DCDS4501A should 
be permanently reduced from 1.8 mg/kg to 1.4 mg/kg.  If worsening Grade 2 or Grade 3 
peripheral neuropathy (sensory and/or motor) recurs following dose reduction, study 
treatment should be discontinued.  For Grade 4 peripheral neuropathy (sensory and/or 
motor), study treatment should be discontinued. 
4.3.1.8 
Hyperglycemia 
Hyperglycemia has been observed in patients treated with DCDT2980S and 
DCDS4501A as well as with other ADCs using the same vc-MMAE platform.  
Hyperglycemia has been reversible upon holding or discontinuing treatment of the ADCs 
and/or initiation of improved anti-hyperglycemic medications (see Section 3.4.3.7).   
For symptomatic fasting Grade 3 (> 250−500 mg/dL) or asymptomatic Grade 4 
(> 500 mg/dL) hyperglycemia, medical management should be initiated immediately and 
consultation with a specialist should be considered.  If the hyperglycemia persists for 
> 1 week after initiation of management, dose modification, schedule modification, or 
discontinuation of study treatment should be considered.  In these cases, the study 
Medical Monitor should be consulted to assess the benefit-risk balance of continued 
study treatment. 
4.3.2 
Rituximab 
4.3.2.1 
Formulation 
Rituximab (Rituxan®/MabThera®) is a sterile, clear, colorless, preservative-free liquid 
concentrate for IV administration.  Rituximab is supplied at a concentration of 10 mg/mL 
in 500-mg (50-mL) single-use vials.  A single-unit, 500-mg carton contains one 50-mL 
vial of rituximab (10 mg/mL).  The product is formulated for IV administration in 
9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, and 0.7 mg/mL 
polysorbate 80, after reconstitution with SWFI.  The pH is adjusted to 6.5.  Vials are for 


 
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single use.  Each vial and carton will contain a label (either single-panel or booklet) 
affixed to the vial or carton.   
4.3.2.2 
Dosage, Administration, and Storage 
Rituximab (Rituxan®, MabThera®) will be administered intravenously once per 3-week 
(or 4-week) cycle.  The infusion at 375 mg/m2 for each dose will be based on the 
patient’s body surface area at screening and will remain the same throughout the study.   
If a scheduled dose of rituximab falls outside of the ± 2-day window for reasons other 
than an adverse event, the site must notify and have a discussion with the Genentech 
Medical Monitor prior to rituximab administration.  Such dosing may not necessarily 
qualify as a protocol deviation, if deemed to be in the best interests of the patient, after 
consultation with the Medical Monitor and agreed to in advance by the Medical Monitor.  
Rituximab should not be administered as an IV push or bolus.  Infusion reactions may 
occur.  Premedication consisting of acetaminophen (or paracetamol), diphenhydramine 
(or other suitable antihistamine), and a single dose of hydrocortisone (e.g., up to 100 mg 
or an equivalent dose of methylprednisolone) may also be administered beginning with 
the first infusion, per standard clinical practice.  Premedication may attenuate infusion 
reactions.  Because transient hypotension may occur during rituximab infusion, 
consideration should be given to withholding antihypertensive medications for 12 hours 
prior to rituximab infusion.   
a. First Infusion 
The rituximab solution for infusion should be administered intravenously at an initial rate 
of 50 mg/hr.  Rituximab should not be mixed or diluted with other drugs.  If infusion 
reactions do not occur, the infusion rate should be escalated in 50−mg/hr increments 
every 30 minutes to a maximum of 400 mg/hr.  If an infusion reaction develops, 
the infusion should be temporarily slowed or interrupted.  The infusion can continue at 
one-half the previous rate upon improvement of patient symptoms.   
b. Subsequent Infusions 
If the patient tolerates the first infusion well, subsequent rituximab infusions may be 
administered at an initial rate of 100 mg/hr and increased in 100−mg/hr increments at 
30-minute intervals to a maximum of 400 mg/hr, as tolerated.  If the patient does not 
tolerate the first infusion well, the guidelines for the first infusion should be followed. 
If a patient tolerates the first three cycles of study treatment without significant infusion 
reactions, rituximab may be administered as “rapid infusion” in accordance with local 
institutional guidelines. 
c. Storage 
Rituximab vials must be stored at 2°C−8°C (36°C−46°F).  Rituximab vials should be 
stored in the outer carton in order to protect them from light.  Rituximab solution for 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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infusion may be stored at 2°C−8°C (36°C−46°F) for 24 hours and has been shown to be 
stable for an additional 12 hours at room temperature.  However, because rituximab 
does not contain a preservative, diluted solutions should be stored refrigerated 
(2°C−8°C).  No incompatibilities between rituximab and PVC or polyethylene (PE) bags 
have been observed. 
See the Rituxan® (Rituximab) Package Insert or SmPC (in the European Union) for 
additional information. 
4.3.2.3 
Dosage Modification 
There will be no rituximab dose modification in this study.  Patients at high risk for 
TLS complications (see Section 3.4.3.2) may, at the investigator’s discretion, receive 
their initial dose of rituximab over 2 consecutive days (e.g., 125 mg/m2 on Day 1, 
250 mg/m2 on Day 2; with DCDT2980S/DCDS4501A dose potentially delayed to Day 3). 
Any NCI CTCAE (v4.0) toxicity Grade ≥ 3 in severity that is deemed related to rituximab 
treatment will require interruption of study treatment (both ADC and rituximab) until 
resolution to Grade ≤ 2 or ≥ 80% of baseline, whichever is lower.  Resumption of 
rituximab treatment may be considered in patients with resolution of toxicities to 
Grade ≤ 1 within 2 weeks at the discretion of the investigator, after consultation with the 
Medical Monitor.  Failure of such toxicities to resolve after 2-week delay in study 
treatment will require permanent discontinuation of rituximab.  Continuation of rituximab 
treatment may be permitted on the basis of ongoing clinical benefit following a careful 
assessment and discussion of risk versus benefit with the patient by the investigator and 
approval from the Medical Monitor.   
If a patient develops unacceptable toxicity to rituximab requiring its discontinuation, 
single-agent DCDT2980S or DCDS4501A may be continued on the basis of the 
investigator’s assessment of ongoing clinical benefit and with the approval of the Medical 
Monitor. 
4.3.2.4 
Schedule Modification 
Patients in whom toxicities have not resolved (i.e., to Grade ≤ 1 or ≥ 80% of baseline) 
may have their study treatment delayed by up to 2 weeks.  If after the up to−2-week 
delay, all study drug−related toxicities have resolved sufficiently, the patient may receive 
the scheduled doses of rituximab.  In addition, a patient’s dosing may be changed to a 
28-day cycle if it is felt by the investigator and Medical Monitor that changing a patient’s 
dosing regimen from 21-day to 28-day cycles would provide sufficient time for recovery 
from transient cytopenias without requiring repeated treatment delays. 
Patients who do not fulfill the criteria for dosing after the additional 2 weeks have 
elapsed may be discontinued from study treatment and be followed for safety outcomes 
(see Section 4.5.1).  Exceptions on the basis of ongoing clinical benefit may be allowed 
following a careful assessment and discussion of risk versus benefit with the patient by 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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the investigator and approval from the Medical Monitor.  In addition, delay of therapy 
because of toxicities not attributed to study drug may not require discontinuation and will 
be discussed with the Medical Monitor. 
4.3.2.5 
Infusion Reaction 
Patients will be monitored during and after each rituximab infusion for 90 minutes after 
the first infusion and for 30 minutes after subsequent infusions in the absence of 
infusion-related adverse events.  Patients who experience infusion-related symptoms 
should be managed as directed in Table 1 (see Section 4.3.1.5). 
In the event of a life-threatening IRR (which may include pulmonary or cardiac events) or 
IgE-mediated anaphylactic reaction to rituximab, rituximab should be discontinued and 
no additional rituximab should be administered.  Patients who experience these 
reactions should receive aggressive symptomatic treatment and should be discontinued 
from study treatment. 
4.3.3 
Obinutuzumab 
4.3.3.1 
Formulation 
Obinutuzumab (GA101/Gazyva™/Gazyvaro) is a clear, colorless to slightly brownish 
liquid, provided as a single 1000-mg dose liquid concentrate with a strength of 
25 mg/mL.  It is supplied in 50−mL glass vials containing 40 mL of the 25 mg/mL liquid 
concentrate.  In addition to the antibody, the liquid also contains histidine/histidine-HCl, 
trehalose, poloxamer 188, and highly purified water (HPW). 
4.3.3.2 
Dosage, Administration, and Storage 
Obinutuzumab will be administered by IV infusion as an absolute (flat) dose of 1000 mg 
in combination with DCDS4501A, as outlined in Section 3.1.3.  Obinutuzumab will be 
administered on Days 1, 8, and 15 of Cycle 1 and on Day 1 of Cycles 2−8 (see Table 2).  
No dose modifications of obinutuzumab are allowed. 
All obinutuzumab infusions should be administered after premedication with oral 
acetaminophen and an antihistamine (see Section 4.4.1).  The prophylactic use of 
corticosteroids (e.g., 100 mg of IV prednisolone or equivalent) may also be considered 
for patients thought to be at high risk for IRRs, if deemed appropriate by the investigator, 
and should be administered prior to the obinutuzumab infusion.  On Cycle 1 Day 1, it is 
recommended that oral prednisone, prednisolone, or methylprednisolone be given within 
12 hours as a premedication but at least 60 minutes prior to the obinutuzumab infusion.  
Premedication with prednisone or prednisolone is mandatory in patients who had an IRR 
and should continue until IRRs no longer occur during antibody infusion.  For the 
management of IRRs and anaphylaxis, see Table 1 (Section 4.3.1.5).  
If it is the strong preference of the investigator or of the site (e.g., for logistical reasons) 
or if the patient is at increased risk for an IRR (high tumor burden, high peripheral 
lymphocyte count), the administration of obinutuzumab infusion can be split over 2 days. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Table 2 
Administration of First and Subsequent Infusions of 
Obinutuzumab 
First Infusion (Cycle 1 Day 1) 
Subsequent Infusions 
• Begin infusion at an initial rate of 50 mg/hr. 
• If no infusion-related or hypersensitivity 
reaction occurs, increase the infusion rate in 
50-mg/hour increments every 30 minutes to a 
maximum of 400 mg/hr. 
• If a reaction develops, stop or slow the 
infusion.  Administer medications and 
supportive care in accordance with 
institutional guidelines.  If reaction has 
resolved, resume the infusion at a 
50% reduction in rate (i.e., 50% of rate used 
at the time the reaction occurred). 
• If the patient experienced an infusion-related 
or hypersensitivity reaction during the prior 
infusion, use full premedication including 
100 mg prednisone/prednisolone (until no 
further IRR occurs), begin infusion at an 
initial rate of 50 mg/hr, and follow instructions 
for first infusion. 
• If the patient tolerated the prior infusion well 
(defined by absence of Grade 2 reactions 
during a final infusion rate of ≥ 100 mg/hr), 
begin infusion at a rate of 100 mg/hr. 
• If no reaction occurs, increase the infusion 
rate in 100-mg/hour increments every 
30 minutes, to a maximum of 400 mg/hr. 
• If a reaction develops, stop or slow the 
infusion.  Administer medications and 
supportive care in accordance with 
institutional guidelines.  If reaction has 
resolved, resume the infusion at a 
50% reduction in rate (i.e., 50% of rate used 
at the time the reaction occurred). 
IRR = infusion-related reaction. 
 
In all parts of the study, obinutuzumab must be administered in a clinical (inpatient or 
outpatient) setting.  Full emergency resuscitation facilities should be immediately 
available, and patients should be under the close supervision of the investigator at all 
times.  For the management of IRRs and anaphylaxis, see Table 1 (Section 4.3.1.5). 
Obinutuzumab should be administered as a slow IV infusion through a dedicated line.  
IV infusion pumps should be used to control the infusion rate of obinutuzumab.  Do not 
administer as an IV push or bolus.  Administration sets with PVC, polyurethane (PUR), 
or PE as a product contact surface and IV bags with polyolefin (PO), polypropylene (PP), 
PVC, or PE as a product contact surface are compatible and can be used.  Do not use 
an additional in-line filter because of potential adsorption. 
The recommended storage conditions for obinutuzumab drug product are between 2°C 
and 8°C, protected from light.  For clinical formulation-specific and batch-specific 
instructions and information on in-use stability, see the packaging label.   
4.3.3.3 
Dosage Modification 
There will be no obinutuzumab dose modification in this study.  Patients at high risk for 
TLS complications (see Section 3.4.3.2) may, at the investigator’s discretion, receive 
obinutuzumab over 2 consecutive days (with DCDS4501A dose potentially delayed to 
Day 2 or Day 3). 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Any NCI CTCAE (v4.0) toxicity Grade ≥ 3 in severity that is deemed related to 
obinutuzumab treatment will require interruption of study treatment (both DCDS4501A 
and obinutuzumab) until resolution to Grade ≤ 2 or ≥ 80% of baseline, whichever is lower.  
Resumption of obinutuzumab treatment may be considered in patients with resolution of 
toxicities to Grade ≤ 1 within 2 weeks at the discretion of the investigator, 
after consultation with the Medical Monitor.  Failure of such toxicities to resolve after 
2-week delay in study treatment will require permanent discontinuation of obinutuzumab.  
Continuation of study treatment following dose delays beyond 2 weeks will require 
consultation with and approval of the Medical Monitor based on an assessment of the 
benefit-risk analysis of continuing to delay study treatment.  
If a patient develops unacceptable toxicity to obinutuzumab requiring its discontinuation, 
single-agent DCDS4501A will not be permitted.  
4.3.3.4 
Schedule Modification 
Patients in whom toxicities have not resolved (i.e., to Grade ≤ 1 or ≥ 80% of baseline) 
may have their study treatment delayed by up to 2 weeks.  Dosing of both DCDS4501A 
and obinutuzumab should be held during this period.  If all study drug−related toxicities 
have resolved to Grade ≤ 1 or ≥ 80% of baseline, the patient may resume DCDS4501A 
and obinutuzumab dosing on the regular every−21−day schedule.  In addition, a 
patient’s dosing may be changed to a 28-day cycle if it is felt by the investigator and 
Medical Monitor that changing a patient’s dosing regimen from 21-day to 28-day cycles 
would provide sufficient time for recovery from transient cytopenias without requiring 
repeated treatment delays. 
Patients who do not fulfill the criteria for dosing after the additional 2 weeks have 
elapsed may be discontinued from study treatment and be followed for safety outcomes 
(see Section 4.5.6).  Exceptions on the basis of ongoing clinical benefit may be allowed 
following a careful assessment and discussion of risk versus benefit with the patient by 
the investigator and approval from the Medical Monitor.  In addition, delay of therapy 
because of toxicities not attributed to study drug may not require discontinuation and will 
be discussed with the Medical Monitor. 
Specific guidelines around schedule modifications for thrombocytopenia and febrile 
neutropenia are detailed below in Section 4.3.3.5 and Section 4.3.3.6. 
4.3.3.5 
Thrombocytopenia 
Thrombocytopenia is a known risk of obinutuzumab (see Section 3.4.6.4).  If the clinical 
condition of a patient requires the use of concomitant anticoagulants, the patient is at 
increased risk of bleeding when the platelet count is < 20,000/μL.  When possible, 
replace prior therapy with Vitamin K antagonists, such as warfarin, with low-molecular 
weight heparin (LMWH) or new oral anticoagulants (NOACs) before Cycle 1 Day 1.  
Clinical decision making may be adjusted depending on the patient-specific assessment 
of benefit and risk. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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In the event of severe thrombocytopenia (platelet count < 10,000/μL) and/or symptomatic 
bleeding (irrespective of platelet count) in patients who are not receiving concomitant 
anticoagulants or platelet inhibitors: 
• 
Hold obinutuzumab until thrombocytopenia or symptomatic bleeding resolves.  If 
Cycle 1 Day 8 is delayed, then skip Day 8 and administer Day 15 as previously scheduled 
(if thrombocytopenia or symptomatic bleeding has resolved).  If Cycle 1 Day 15 is delayed, 
then skip Day 15 dosing and administer Cycle 2 Day 1 of obinutuzumab and DCDS4501A 
as scheduled (if thrombocytopenia or symptomatic bleeding has resolved).  
 
In the event of thrombocytopenia with platelet count < 20,000/μL and/or symptomatic 
bleeding (irrespective of platelet count) in patients who are receiving concomitant 
anticoagulants or platelet inhibitors: 
• 
Hold obinutuzumab until thrombocytopenia or symptomatic bleeding resolves.  If 
Cycle 1 Day 8 is delayed, then skip Day 8 and administer Day 15 as previously scheduled (if 
thrombocytopenia or symptomatic bleeding has resolved).  If Cycle 1 Day 15 is delayed, then 
skip Day 15 dosing and administer Cycle 2 Day 1 of obinutuzumab and DCDS4501A as 
scheduled (if thrombocytopenia or symptomatic bleeding has resolved). 
• 
For patients who are on LMWH or NOACs, when platelet count < 20,000/μL 
develops, reduce the dose of LMWH or NOACs used. 
• 
For patients who are on platelet inhibitors when thrombocytopenia with platelet 
count < 20,000/μL develops, consideration should be given to temporarily pausing 
the use of platelet inhibitors. 
4.3.3.6 
Febrile Neutropenia   
In the event of febrile neutropenia or neutropenia with infection, hold obinutuzumab until febrile 
neutropenia or neutropenia with infection resolves.   
• 
If Cycle 1 Day 8 is delayed long enough that the patient is approaching Day 15, then skip 
Day 8 and administer Day 15 as previously scheduled (if infection or fever has resolved) 
• 
If Cycle 1 Day 15 is delayed long enough that the patient approaching Cycle 2, then skip 
Day 15 dosing and administer Cycle 2 Day 1 of DCDS4501 as scheduled (if infection or 
fever has resolved) 
• 
Note:  Obinutuzumab Patients will receive DCDT2980S or DCDS4501A at 1.8 mg/kg 
or 2.4 mg/kg by IV infusion on Day 1 or Day  should not be held for neutropenia without 
fever or infection 
 
4.3.4 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(pinatuzumab vedotin [DCDT2980S], polatuzumab vedotin [DCDS4501A], rituximab, and 
obinutuzumab) will be provided by the Sponsor where required by local health authority 
regulations.  The study site will acknowledge receipt of IMPs to confirm the shipment 
condition and content.  Any damaged shipments will be replaced.  
IMPs will be either disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 


 
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documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. 
4.4 
CONCOMITANT AND EXCLUDED THERAPIES  
4.4.1 
Concomitant Therapy  
Concomitant therapy includes any medication (e.g., prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, and nutritional 
supplements) used by a patient from 7 days prior to the screening evaluation to the 
end of study visits.  All concomitant medications should be reported to the investigator 
and recorded on the appropriate electronic Case Report Form (eCRF).  Patients who 
use oral contraceptives, hormone-replacement therapy, or other maintenance therapy 
should continue their use.  Concomitant use of hematopoietic growth factors is allowed 
in accordance with instructions provided in the package inserts. 
Patients who experience infusion-related temperature elevations of > 38.5°C (> 101.3°F) 
or other minor infusion-related symptoms may be treated symptomatically with 
acetaminophen/paracetamol (≥ 500 mg) and/or H1 and H2 histamine-receptor 
antagonists (e.g., diphenhydramine, ranitidine).  Serious infusion-related events 
manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced 
oxygen saturation, or respiratory distress should be managed with additional supportive 
therapies (e.g., supplemental oxygen, β2-agonists, and/or corticosteroids) as clinically 
indicated according to standard clinical practice (see Table 1).   
For patients enrolled on obinutuzumab-containing regimens, it is recommended that 
corticosteroids (e.g., 100 mg of IV prednisolone or equivalent) be given as premedication 
within 12 hours of, but at least 60 minutes prior to, the obinutuzumab infusion on Cycle 1 
Day 1.  After the first obinutuzumab infusion, additional glucocorticoids are allowed at 
the investigator’s discretion.  For patients who did not experience infusion-related 
symptoms with their previous infusion, premedication at subsequent infusions may be 
omitted at the investigator’s discretion. 
Infusion reaction prophylaxis with medications (e.g., acetaminophen/paracetamol, 
antihistamines, and/or corticosteroids) may be instituted at any point in the study if it is 
determined to be in the best interest of the patient on the basis of the observation of 
IRRs in patients already enrolled in the study.  Patients with Grade 3 hypotension or 
fever must be premedicated prior to retreatment (see Section 4.3.1.5).  Patients with 
hypotension requiring vasopressor support or with Grade 3 wheezing, hypoxia, or 
generalized urticaria must be permanently discontinued from study treatment. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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4.4.2 
Excluded Therapy 
Use of the following therapies is prohibited during the study: 
• 
Cytotoxic chemotherapy 
• 
Radiotherapy 
• 
Immunotherapy including immunosuppressive therapy 
• 
Radioimmunotherapy 
• 
Hormone therapy (other than contraceptives, hormone-replacement therapy, or 
megestrol acetate) 
• 
Biologic agents (other than hematopoietic growth factors, which are allowed 
if clinically indicated and used in accordance with instructions provided in the 
package inserts); guidelines for the use of G-CSF are detailed in Section 4.3.1.6 
and Appendix F. 
• 
Any therapies intended for the treatment of lymphoma or leukemia, whether 
approved by local regulatory authorities or investigational 
 
Patients who require the use of any of these agents will be discontinued from all study 
treatment.  Patients who are discontinued from study treatment will be followed for safety 
outcomes for 30 days following the patient’s last dose of DCDT2980S or DCDS4501A or 
rituximab or obinutuzumab, whichever is later, or until the patient receives another 
anti-cancer therapy, whichever occurs first. 
4.5 
STUDY ASSESSMENTS  
4.5.1 
Definitions of Study Assessments 
4.5.1.1 
Medical History and Demographics 
Medical history includes all clinically significant diseases, prior cancer history, prior 
cancer therapies and procedures, and all medications used by the patient within 7 days 
preceding the screening visit. 
4.5.1.2 
Vital Signs 
Vital signs will include measurements of systolic and diastolic blood pressure while the 
patient is in a sitting or semi-supine position, pulse oximetry, pulse rate, and body 
temperature.  Every effort will be made to ensure that vital signs are obtained from 
patients in a consistent manner and position.  The timing of vital sign collection on the 
days of study treatment administration is as follows: 
• 
For the administration of rituximab or obinutuzumab, vital signs should be 
assessed prior to the start of the infusion, every 15 (± 5) minutes during the first hour 
of the infusion, as clinically indicated during the remainder of the infusion, and 
following the completion of the infusion.  


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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• 
For the administration of DCDT2980S or DCDS4501A, vital signs should be assessed 
prior to the start of the infusion, every 15 (± 5) minutes during the infusion, at the end 
of the infusion, and every 30 (± 10) minutes for 90 minutes post-infusion following 
dosing at Cycle 1 and 30 (± 10) minutes following dosing in subsequent cycles.  
Additional monitoring of vital signs should be performed if clinically indicated. 
4.5.1.3 
Physical Examination 
A complete physical examination should include the evaluation of the head, eyes, ears, 
nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems.   
Targeted physical examinations should be limited to systems of clinical relevance 
(i.e., cardiovascular, respiratory, and any system that might be associated with tumor 
assessment, such as lymph nodes, liver, and spleen) and those systems associated with 
symptoms. 
Changes from baseline should be recorded at each subsequent physical examination.  
New or worsened abnormalities should be recorded as adverse events if appropriate. 
Resolution or any change in grade of peripheral neuropathy AEs and SAEs (with dates) 
should be documented on the Adverse Event eCRF and in the patient’s medical record 
to facilitate source data verification (SDV).  This also applies to AEs for which study drug 
was discontinued or for patients in the follow-up phase after last dose of study treatment 
with either ongoing AEs or new onset of an AE.  For the AEs referring to the follow-up 
phase newly initiated, relevant treatments need to be documented with treatment dates.  
4.5.1.4 
Laboratory Assessments 
On days of study drug administration, pre-infusion laboratory samples should be drawn 
within 4 hours prior to the start of infusion, unless otherwise specified.  Local laboratory 
assessments may be obtained up to 72 hours prior to the start of study treatment 
administration (see below and Section 4.5.3).  Instruction manuals and supply kits will be 
provided for all central laboratory assessments. 
Central Laboratory Assessments 
Samples for flow cytometry, PK, bone marrow, and anti-DCDT2980S, anti-DCDS4501A, 
or anti-obinutuzumab antibody assessments will be sent to one or several laboratories 
or to Genentech for analyses (see Section 3.6).  The following assessments will be 
conducted: 
• 
Leukocyte immunophenotyping/flow cytometry (fluorescence-activated cell sorting 
[FACS] lymphocyte subsets) 
Whole-blood samples will be collected to analyze B-cell subsets (CD19+), T-cell 
counts (CD3+, CD4+, CD8+), and NK cell counts (CD16+, CD56+), by flow 
cytometry. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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• 
ATA assays 
ATAs to DCDT2980S, DCDS4501A, or obinutuzumab will be determined using 
validated ELISAs (see Section 4.9).  
• 
PK and PD assays (see Section 4.5.1.6) 
• 
A plasma sample and blood samples will be collected from patients for exploratory 
research as indicated in Section 4.5.1.9.  
• 
For patients who sign the optional consent, a blood sample will be collected prior to 
the first dose of study treatment for exploratory research. 
• 
Tumor tissue sample (archival or fresh) will be collected from patients for central 
pathologic review as described in Section 4.1.1 and Section 4.5.1.9. 
 
Local Laboratory Assessments 
Samples for hematology, serum chemistry, liver function, and pregnancy will be 
analyzed at the study site’s local laboratory.  Local laboratory assessments may be 
obtained up to 72 hours prior to start of study treatment administration on Day 1 of the 
treatment cycle.   
• 
Hematology:  includes complete blood count (hemoglobin, hematocrit, red blood cell 
count, white blood cell count, platelet count, absolute neutrophil count, and percent 
or absolute differential counts [e.g., segmented neutrophils, bands, lymphocytes, 
eosinophils, monocytes, basophils, and other cells) 
• 
Coagulation:  aPTT, PT, and INR 
• 
Quantitative immunoglobulins (IgA, IgG, and IgM) 
• 
Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen (BUN or local equivalent), creatinine, calcium, magnesium, phosphorus, 
total and direct bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, 
LDH, and uric acid, amylase, and lipase 
• 
Serum γ-glutamyl transpeptidase (GGT) levels will be required at screening only 
• 
Hemoglobin A1c 
• 
Viral serology and detection (screening assessment only and if clinically indicated) 
Hepatitis B (HBsAg and HBcAb; also HBV DNA by PCR if the patient is HBcAb 
positive) 
HCV antibody 
• 
Pregnancy test 
For women of childbearing potential (see Section 4.1.2), a serum pregnancy test 
must be performed within 14 days prior to Cycle 1 Day 1.   
Urine pregnancy tests will be performed during the study treatment period.  If any 
urine test result is positive, patient dosing will be postponed until the result is 
confirmed by a serum pregnancy test.  Any patient with a positive serum test will 
not be allowed to receive any study treatment. 


 
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4.5.1.5 
Electrocardiogram Assessments 
Twelve-lead digital ECG measurements will be obtained in triplicate, with immediately 
consecutive ECGs obtained until three evaluable ECGs are recorded, at the following 
timepoints: 
• 
Screening 
• 
30−60 minutes before the start of DCDT2980S or DCDS4501A infusion in Cycle 1 
• 
30−60 minutes after the completion of DCDT2980S or DCDS4501A infusion in 
Cycle 1 
• 
30−60 minutes after the completion of DCDT2980S or DCDS4501A infusion in 
Cycle 3 
• 
Day 8 (± 1 day) of Cycle 3 time matched (i.e., obtained at the same time of day) with 
post-DCDT2980s/DCDS4501A infusion ECGs for Cycle 3   
• 
Treatment completion/early termination visit 
 
Non-triplicate ECGs should also be performed when clinically indicated in any patient 
with evidence of or suspicion for clinically significant signs or symptoms of cardiac 
dysfunction.  
All ECGs as described above will be submitted to a Sponsor-designated ECG central 
laboratory for storage and potential analysis.  Detailed instructions on ECG acquisitions 
and transmissions to the ECG central laboratory will be provided in the ECG manual 
provided for this study. 
Representative ECGs at each timepoint should be reviewed by the investigator or a 
qualified designee.  Post-screening ECG measurements should be obtained as close as 
possible to scheduled serum and plasma PK samples (see Appendices B-1 and B-2) 
and should be no more than 30 minutes apart.  If QTc prolongation (> 500 ms and 
> 60 ms longer than the pre-dose baseline value) is noted, ECGs should be repeated 
until the prolongation is reversed or stabilized.  If a PK sample is not scheduled at the 
timepoint where QTc prolongation is first observed, then an unscheduled sample should 
be obtained.  An evaluation for potential causes of QT prolongation⎯for 
example, electrolyte imbalances or concomitant medications⎯should be performed, 
study treatment dosing held, and the Medical Monitor notified.  Management of QT/QTc 
prolongation should be performed in accordance with institutional standard of care at the 
discretion of the treating physician. 
4.5.1.6 
Pharmacokinetic and Pharmacodynamic Assessments 
Pharmacokinetics of DCDT2980S and DCDS4501A will be characterized by measuring 
total antibody (conjugated and unconjugated antibody), acMMAE, and free MMAE 
concentrations using validated methods (see Section 4.9).  Plasma samples may also be 
analyzed for other potential MMAE-containing catabolites, per sponsor’s discretion.  
Pharmacokinetics of rituximab will be characterized by measuring rituximab 
concentrations using a validated method (see Section 4.9).  Pharmacokinetics of 


 
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obinutuzumab will be characterized by measuring obinutuzumab concentrations with use 
of a validated method (see Section 4.9).  These assessments will allow for further 
characterization of pharmacokinetics of DCDT2980S and DCDS4501A, the assessment 
of the drug interaction potential when they are given in combination with rituximab or 
obinutuzumab, and the investigation of potential correlations between PK parameters 
and safety and/or activity if data allow and at the sponsor’s discretion.  
Pharmacodynamics of obinutuzumab and DCS4501A may be assessed by monitoring 
the release of tumor associated DNA following treatment. 
4.5.1.7 
Immunogenicity Assessments 
The immunogenicity evaluation will utilize a risk-based strategy and tiered approach 
(Rosenberg and Worobec 2004a, 2004b, 2005; Koren et al. 2008) designed to detect 
and characterize all ATA responses to DCDT2980S and DCDS4501A.  Patient samples 
will first be screened to detect all antibody responses toward DCDT2980S or 
DCDS4501A.  Samples that screen positive will be analyzed in a confirmatory assay 
(competitive binding with DCDT2980S or DCDS4501A) to assess the specificity of the 
positive response.  Titers will be determined for confirmed positive samples.  Further 
characterization will be assessed by competitive binding with the MAb component of 
DCDT2980S or DCDS4501A to characterize whether the ATA responses are primarily to 
the mAb or the linker-drug regions of the ADC.  Positive ATA samples will be stored for 
further characterization of ATA responses, if necessary.   
The schedule of sample collection for ATA assessment is outlined in Appendices B-1, 
B-2, or B-3, depending on the schedule of study treatment administration.  Samples for 
ATA will not be collected during the crossover treatment period. 
ATA responses to obinutuzumab will be detected and confirmed using a similar tiered 
approach.  Patient samples will first be screened to detect all antibody responses to 
obinutuzumab.  Samples that screen positive will be analyzed in a confirmatory assay 
(competitive binding with obinutuzumab) to assess the specificity of the positive 
response.  The relative levels of ATA in confirmed positive samples will be determined in 
a titering assay.  Positive ATA samples will be stored for further characterization of ATA 
responses, if necessary. 
4.5.1.8 
Tumor Response Assessments 
All measurable disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Response assessments will be assessed by the 
investigator, on the basis of physical examinations, CT scans, PET scans, and/or MRI 
scans, and bone marrow examinations, using standard response criteria for NHL 
(Cheson et al. 2007; Cheson et al. 2014) (see Appendix C-1 and C-2). 


 
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a. Radiographic Assessments for Patients on Rituximab-Containing 
Arms/Cohorts 
CT scans with contrast should include chest, abdomen, and pelvis scans; CT scans of 
the neck should be performed at screening and followed only if disease is present at 
screening.  Post-screening radiographic assessments may be limited to areas of prior 
involvement only if required by local health authorities. 
MRI scans may be used instead of CT scans in patients for whom CT scans with IV 
contrast are contraindicated.  Details regarding imaging procedures in these cases will be 
provided in the Imaging Manual. 
An 18F-fluorodeoxyglucose−positron emission tomography (18F-FDG-PET) (hereafter 
referred to as PET) scan is required during screening for all patients with DLBCL.  An 
additional PET scan in DLBCL patients should be obtained at the 6-month tumor 
assessment to ensure consistency of response assessment methodology at this 
timepoint for all patients.  PET scans should additionally be obtained to confirm 
disappearance of metabolically active disease during study treatment and to confirm a 
CR upon discontinuation of study treatment.   
For patients with FL, PET scans are not required but may be obtained on the basis of 
physician preference and if permitted by local health authorities.  Similarly, for DLBCL, 
PET scans on patients with FL should be obtained during screening; for patients whose 
tumors are PET positive during screening, an additional PET scan should be obtained at 
the 6-month tumor assessment.  PET scans should additionally be obtained to confirm 
disappearance of metabolically active disease during study treatment and to confirm a 
CR upon discontinuation of study treatment.  
For all patients regardless of disease subtype, combined PET-CT scans may be used 
instead of CT alone if performed with contrast and if collected with resolution sufficient to 
allow accurate and consistent comparison of target lesion measurements with 
subsequent PET-CT scans.  If a PET-CT scan is to be used during screening, then 
PET-CT scans should be performed for all subsequent tumor assessments in order to 
ensure their consistency across different timepoints. 
All tumor assessments will be submitted to an IRF for storage and possible independent 
centralized review.  Details related to submission of data to the IRF will be defined in a 
separate Imaging Manual. 
b. Radiographic Assessments for Patients on Obinutuzumab-Containing 
Cohorts 
PET scans should minimally extend from skull-base to mid-thigh.  Full-body PET scan 
should be performed when clinically appropriate. 
CT scans with oral and IV contrast should include chest, abdomen, and pelvic scans; CT 
scans of the neck should be included if clinically indicated.  CT scans for response 


 
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assessment may be limited to areas of prior involvement only if required by local health 
authorities.  At the investigator’s discretion, CT scans may be repeated at any time if 
progressive disease is suspected. 
In patients for whom contrast is contraindicated⎯for example, patients with contrast 
allergy or impaired renal CL⎯CT or combined PET/CT scans without contrast are 
permitted so long as they permit consistent and precise measurement of target lesions 
during the study treatment period.   
PET and CT scans are required for follicular NHL and DLBCL patients at screening, after 
Cycle 4 of study treatment (i.e., between Cycle 4 Day 15 and Cycle 5 Day 1), and at 
EOT.  The EOT response assessment should be performed 6−8 weeks after Cycle 8 
Day 1 or last study treatment.  CT scans without PET scans will be obtained every 
6 months for 2 years, with use of Lugano 2014 Response Criteria for NHL 
(see Appendix C-2).   
c. Bone Marrow Assessments 
A bone marrow biopsy for morphology is required at screening and should reflect 
disease status in the bone marrow following documented relapse on the last prior 
therapy or within 3 months of Day 1, whichever occurs later.  For obinutuzumab-containing 
cohorts, only follicular NHL patients are required to undergo a bone marrow biopsy at screening.  
If the bone marrow biopsy at screening demonstrates presence of tumor cells, 
a subsequent bone marrow examination is required only to confirm a CR or if clinically 
indicated.  If the bone marrow biopsy at screening does not demonstrate presence of 
tumor cells, then subsequent bone marrow examination is required only if clinically 
indicated. 
d. Schedule of Tumor Response Assessments for Rituximab-Containing 
Arms/Cohorts 
Tumor response assessments will be performed every 3 months (± 1 week) from the 
initiation of study treatment until study treatment completion or early termination 
(e.g., between Days 14 and 21 of Cycles 4 and 8 for those patients receiving at least 
eight 21-day cycles of treatment).  The schedule of tumor assessments is independent 
of the study treatment dose schedule.  For patients enrolled on rituximab-containing 
arms/cohorts, the schedule of tumor response assessments is detailed in 
Appendix A-1.  As stated above, for all DLBCL patients enrolled on a 
rituximab-containing arm/cohort, PET scans are required during the screening period 
and at the 6-month tumor assessment timepoint. 
The schedule for tumor response assessments for patients who proceed to crossover 
treatment is detailed in Appendix A-2.   


 
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Additional response assessments, after the final dose of study treatment, for patients 
who discontinue from study treatment (either initial or crossover treatment) for reasons 
other than progressive disease, will be performed as described in Appendix A-4.  
Tumor assessments should also be performed within 30 days after the last study drug 
infusion (both initial and crossover treatment) at the treatment completion/early 
termination visit.  Imaging scans are not required at the treatment completion/early 
termination visit if scans have been performed within the previous 8 weeks or if disease 
progression while receiving study treatment is documented. 
If, at any time during the study, disease progression is suspected, a tumor assessment 
must be performed.   
e. Schedule of Tumor Response Assessments for 
Obinutuzumab-Containing Cohorts 
All follicular NHL and DLBCL patients enrolled in obinutuzumab-containing cohorts are 
required to have a combined PET and CT scan at screening, after Cycle 4 of treatment, 
and at EOT.  The schedule for tumor response assessments for patients enrolled on 
obinutuzumab-containing cohorts is detailed in Appendix A-3. 
4.5.1.9 
Exploratory Research 
a. Tumor Tissue Samples 
Required Tumor Tissue Samples 
Tumor tissue samples will be used for central pathologic laboratory review of CD20, 
CD22, and CD79b expression.  Additional studies to fulfill the exploratory objectives in 
Section 3.3.4 will be performed, including, but not limited, to the following: 
• 
Messenger RNA (mRNA) expression profiling for signatures of NHL biology, 
including prognostic subpopulations (Alizadeh et al. 2000; Wright et al. 2003), target 
expression (CD20, CD22 and CD79b), and apoptotic response  
• 
Tissue microarrays (TMAs) from cores taken from provided blocks for 
immunohistochemistry (IHC) and in situ hybridization (ISH) assessments 
for biomarker endpoints involved in response to chemotherapy including quantitation 
of Bcl-2 protein and genetic alterations of bcl-2 including gene rearrangements, 
amplifications, and t(14;18) translocations. Additional IHC markers may include 
those related to the tumor microenvironment. 
• 
Tumor DNA to assess mutations that have been shown to be associated with NHL 
biology and activation of the B-cell receptor, including mutations in CD79b 
(Pasqualucci et al. 2011) 
 
For patients who develop progressive disease and are eligible to receive crossover 
treatment (see Section 3.1.8), a biopsy of a safely accessible site of disease will be 
performed.  Tumor tissue samples obtained at this timepoint will be used to assess 
changes in biology, target expression, and regulators of apoptosis as described above, 
which have occurred and may be linked to progression on initial study treatment. 


 
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Optional Tumor Tissue Samples (Requires Optional Research Informed 
Consent 
For patients who provide informed consent, an optional tumor biopsy will be collected at 
time of progression from the following patients: 
• 
Patients who develop disease progression following initial study treatment and do 
not proceed to receive crossover treatment 
• 
Patients who develop disease progression on crossover treatment 
 
Tumor tissue samples obtained at these timepoints will be used to assess changes in 
biology, target expression, and regulators of apoptosis, as described above, that have 
occurred and may be linked to progression on treatment. 
b. Blood and Plasma Samples 
A plasma sample will be collected prior to treatment. 
Blood samples will be taken aligned with PK sampling to assess the pharmacodynamics 
response by monitoring circulating tumor DNA. 
For patients who sign the Optional Research Informed Consent, an additional blood 
sample will also be taken prior to treatment. 
The plasma and blood samples may be used for the assessment of specific tumor 
biologic markers, including proteins, circulating DNA, and microRNAs.  The information 
obtained from these samples will enable a better understanding of the biology of NHL 
and disease prognosis, identify potential predictors of response to treatment with 
DCDT2980S, DCDS4501A, rituximab, and/or obinutuzumab, improve diagnostic 
assessments, and identify and characterize mechanisms of resistance to DCDT2980S or 
DCDS4501A and rituximab or obinutuzumab activity.   
Because tumorigenesis is a multiple-step process linked to somatic events, any DNA 
analysis will focus on sporadic mutations specifically found in tumor tissue and not on 
inherited changes found in the whole body.  For this purpose, some tumor-containing 
sections may be taken from the tissue block and used for the DNA extraction process.  
Assays on stored tissue samples may be performed at Genentech or at a central 
specialty laboratory. 
4.5.1.10 
Patient-Reported Outcomes 
The MDASI (Cleeland et al., 2000; Appendix E) is a multi-symptom self-report measure 
for clinical and research use. The MDASI’s 13 core-symptom items, plus an additional 
4 items, for a total of 17 symptom items, include those found to have the highest 
frequency and/or severity in patients with various cancers and treatment types.  These 
include pain, fatigue, nausea, disturbed sleep, emotional distress, shortness of breath, 
lack of appetite, drowsiness, dry mouth, sadness, vomiting, difficulty remembering, and 


 
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numbness or tingling.  Six additional items focus on the degree of interference of the 
aforementioned symptoms for a total of 23 items in the questionnaire. 
PRO data will be elicited from all patients in this study (with the exception of Cohorts E, 
G, and H) to more fully characterize the clinical profile of study treatment.  The MDASI 
PRO instrument will be supplied in the local language of each participating country.  
Electronic (handheld computers) will be used for the daily collection of symptoms 
derived from the MDASI.   
4.5.2 
Screening and Pretreatment Assessments 
All screening evaluations must be completed and reviewed by the Genentech Medical 
Monitor or designated CRO Medical Monitor to confirm that patients meet all eligibility 
criteria and are approved for enrollment before the first infusion of study treatment.  
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for patients who are not subsequently enrolled will be maintained at the study site. 
Screening and pretreatment tests and evaluations will be performed within 28 days 
preceding the day of the first dose of study treatment on Cycle 1 Day 1.  Results of 
standard-of-care tests or examinations performed prior to obtaining informed consent 
and within 28 days prior to Cycle 1 Day 1 may be used; such tests do not need to be 
repeated for screening. 
The availability of a patient’s tumor tissue sample for studies (see Section 4.1.1 and 
Section 4.5.1.9) should be confirmed prior to Cycle 1 Day 1.  Such specimens should 
consist of representative core biopsy in a paraffin block, which is the preferred method, 
or at least 15 unstained slides.  Tumor specimens should be submitted with an 
accompanying pathology report and may be obtained at any time prior to entry to study.   
Bone marrow biopsy and aspirate specimens are required at screening (see 
Section 4.5.1.8).  For obinutuzumab-containing cohorts, bone marrow biopsy and aspirate are 
only required for follicular NHL patients.  Unsuccessful attempts at obtaining marrow 
aspirates will not be considered a protocol deviation or violation. 
Refer to the Study Flowchart provided in Appendix A-1 and A-3 for the schedule of 
screening and pretreatment assessments. 
4.5.3 
Assessments During Treatment 
Study drug infusions (rituximab, obinutuzumab, DCDT2980S, or DCDS4501A) should 
occur on the scheduled 21-day (or 28-day) cycle but may be given up to ± 2 days from 
the date scheduled (i.e., with a minimum of 19 days between doses) if required for 
logistical/scheduling reasons.  All other study visits during Cycles 1 and 2 must occur 
within ± 1 day from the scheduled date, unless otherwise noted.  Study visits starting in 
Cycle 3 should occur within ± 2 days from the scheduled date, unless otherwise noted.  


 
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All assessments will be performed on the day of the specified visit unless a time window 
is specified.  Assessments scheduled on the day of study drug administration (Day 1) of 
each cycle should be performed prior to study drug infusion unless otherwise noted.   
Local laboratory assessments may be performed within 72 hours preceding study drug 
administration on Day 1 of each cycle.  Otherwise, laboratory samples should be drawn 
0−4 hours before infusion.  Results must be reviewed and the review documented prior 
to study drug administration. 
Refer to the Study Flowchart provided in Appendix A-1 for the schedule of treatment 
period assessments.  For patients enrolled in the obinutuzumab-containing cohorts, refer 
to the Study Flowchart provided in Appendix A-3. 
4.5.4 
Study Treatment Completion Visit 
Patients who complete study treatment or discontinue from study treatment early will be 
asked to return to the clinic within 30 days after the last DCDT2980S, DCDS4501A, 
rituximab, or obinutuzumab infusion (whichever is later) for a study treatment 
completion visit.  The visit at which response assessment shows progressive disease 
may be used as the early termination visit. 
Refer to the Study Flowchart provided in Appendix A-1 for assessments to be performed 
at the treatment completion/early termination visit.  For patients enrolled on the 
obinutuzumab-containing cohorts, refer to the Study Flowchart provided in 
Appendix A-3. 
Assessments conducted at the treatment completion/early termination visit may be used 
for the purposes of re-screening to determine eligibility to receive crossover treatment 
(see Section 3.1.3 and Section 4.5.5). 
4.5.5 
Crossover Treatment Completion Visit 
Patients who fulfill the criteria to receive crossover treatment (see Section 3.1.6) will 
have assessments during the crossover treatment period as described in Appendix A-2.  
The same guidelines regarding scheduling of assessments for treatment with initial study 
treatment as detailed in Section 4.5.3 will apply to crossover treatment.   
Patients who proceed to receive crossover treatment will have on-treatment 
assessments as described in Appendix A-2. 
Patients who complete the crossover treatment (approximately 1 year/17 cycles) or 
discontinue from crossover treatment early will be asked to return to the clinic within 
30 days after the last DCDT2980S, DCDS4501A, or rituximab infusion (whichever is 
later) for a crossover treatment completion/early termination visit.  The visit at which 
response assessment shows disease progression on crossover treatment may be used 
as the early termination visit. 


 
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Refer to Appendix A-2 for assessments to be performed at the treatment 
completion/early termination visit. 
4.5.6 
Follow-Up Assessments 
Ongoing adverse events thought to be related to DCDT2980S, DCS4501A, rituximab, or 
obinutuzumab will be followed until the event has resolved to baseline (pre-treatment) 
grade, the event is assessed by the investigator as stable, new anti-tumor treatment is 
initiated, the patient is lost to follow-up, the patient withdraws consent, or when it has 
been determined that the study treatment or participation is not the cause of the adverse 
event. 
Patients will be followed after the last dose of study treatment (either initial study 
treatment or crossover treatment) for safety outcomes.  Such follow-up will require an 
assessment (per verbal report, at minimum) of any adverse events and serious adverse 
events for 30 days after the last dose of study drug or until the patient receives another 
anti-cancer therapy, whichever occurs first. 
4.5.6.1 
Follow-Up Assessments for Rituximab-Containing Regimens 
Patients who discontinue from study treatment (either initial study treatment or crossover 
treatment) for reasons other than progressive disease will be followed for response for 
up to 1 year after the last infusion of study treatment or until disease progression or 
initiation of another anti-lymphoma/leukemia therapy, whichever occurs first.  Response 
assessments should occur approximately every 2−3 months following the last infusions 
of DCDT2980S, DCDS4501A, or rituximab.  Post-treatment assessments are described 
in Appendix A-4.  
Following discontinuation of study treatment, patients will be followed for survival 
approximately every 3 months until death, loss to follow-up, withdrawal of consent, or 
study termination. 
4.5.6.2 
Follow-Up Assessments for Obinutuzumab-Containing 
Regimens 
Patients who discontinue from study treatment for reasons other than progressive 
disease will be followed for response for up to 2 years after the last infusion of study 
treatment or until disease progression or initiation of another anti-lymphoma/leukemia 
therapy, whichever occurs first.  Response assessments should occur approximately 
every 2−3 months following the last infusions of DCDS4501A or obinutuzumab for the 
first year after completion of treatment, then every 6 months for the second year after 
completion of treatment.  Post-treatment assessments are described in Appendix A-5.  
Following discontinuation of study treatment, patients will be followed for survival 
approximately every 6 months until death, loss to follow-up, withdrawal of consent, or 
study termination. 


 
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4.6 
PATIENT DISCONTINUATION 
4.6.1 
Discontinuation from Treatment 
Patients may discontinue study treatment early for reasons other than disease 
progression, such as patient/investigator choice or unacceptable toxicity.  The reasons 
for early discontinuation of treatment must be documented on the appropriate eCRF.  
Patients may continue treatment with either DCDT2980S/DCDS4501A or rituximab 
alone following a careful assessment and discussion of risk versus benefit with the 
patient by the investigator and approval from the Medical Monitor. 
Patients who discontinue study treatment early due to toxicity should continue to be 
followed until resolution of toxicity as scheduled. 
Refer to Section 4.5.4 and Section 4.5.5 for assessments that are to be performed for 
patients who discontinue from the study during the study treatment period. 
4.6.2 
Discontinuation from Study 
Patients must be discontinued from the study if they experience disease progression as 
defined using response and progression criteria in Appendix C.  Patients can continue 
crossover treatment following documentation of the first progressive disease event but 
must be discontinued from the study if they experience a second progressive disease 
event on the crossover treatment. 
The investigator has the right to discontinue a patient from the study for any medical 
condition that the investigator determines may jeopardize the patient’s safety if he or she 
continues in the study, for reasons of noncompliance (e.g., missed doses or missed 
visits) or pregnancy or if the investigator determines it is in the best interest of the 
patient. 
Refer to Section 4.5.4 and Section 4.5.5 for assessments that are to be performed for 
patients who prematurely discontinue from the study during the treatment period. 
4.7 
STUDY DISCONTINUATION 
Genentech has the right to terminate this study at any time.  Reasons for terminating the 
study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
• 
Data recording is inaccurate or incomplete. 
 
4.8 
POST-TRIAL ACCESS 
Genentech does not have any plans to provide DCDT2980S, DCDS4501A, rituximab, 
obinutuzumab, or other study interventions to patients after the conclusion of the study 
or if the study is terminated or for patients who withdraw early from the study or 


 
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complete their study treatment.  Genentech will evaluate the appropriateness of 
continuing to provide DCDT2980S, DCDS4501A, rituximab, or obinutuzumab to study 
patients after evaluating the safety and activity data from the study.   
4.9 
ASSAY METHODS  
4.9.1 
Total DCDT2980S/DCDS4501A Antibody ELISA 
Total DCDT2980S or DCDS4501A antibody (conjugated and unconjugated antibody) will 
be measured in serum samples using validated ELISAs. 
4.9.2 
Antibody-Conjugated MMAE (MMAE Affinity Capture 
Enzyme-Release LC/MS-MS) 
acMMAE (a measure of MMAE conjugated to DCDT2980S/DCDS4501A) will be 
measured in plasma samples using validated affinity capture enzyme-release liquid 
chromatography−tandem mass spectrometry (LC-MS/MS) assays. 
4.9.3 
Free MMAE LC-MS/MS 
Free MMAE will be measured in plasma samples using a validated electrospray 
LC-MS/MS method. 
4.9.4 
Rituximab ELISA 
Rituximab will be measured in serum samples using a validated ELISA. 
4.9.5 
Obinutuzumab ELISA 
Obinutuzumab will be measured in serum samples using a validated ELISA.   
4.9.6 
Anti-Therapeutic Antibody 
ATAs against DCDT2980S and DCDS4501A in serum samples will be measured using 
validated bridging antibody ELISAs and characterized by competitive binding assays. 
ATAs against obinutuzumab in serum samples will be measured using a validated 
bridging antibody ELISA and characterized by a competitive binding assay. 
4.9.7 
Biomarker Assays 
Tumor tissue assessment of biomarkers will be assayed using IHC, ISH, qPCR gene 
expression profiling using microarray and mutation detection assays.  Circulating Tumor 
DNA (ctDNA) in plasma samples may be assessed using a next generation sequencing 
approach (CAPP-Seq) to detect and quantitate lymphoma specific markers. 
4.10 
STATISTICAL METHODS 
The final analysis will be based on patient data collected until all patients discontinue 
from the study or the study is terminated by the Sponsor, whichever occurs first.  
The analyses will be based on the safety evaluable population, defined as patients who 


 
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received at least one dose of study treatment.  All summaries will be presented 
according to the disease-specific cohort, treatment group, and assigned dose level. 
4.10.1 
Analysis of the Conduct of the Study 
Enrollment, major protocol violations, and reasons for discontinuations from the study 
will be summarized. 
Demographic and baseline characteristics, such as age, sex, race/ethnicity, weight, 
duration of malignancy, and baseline ECOG Performance Status, will be summarized 
using means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables.  All summaries will be presented overall and by 
treatment group, assigned dose level, and disease-specific cohort. 
Study drug administration data will be listed by the disease-specific cohorts described in 
Section 3.1.1 and Section 3.1.2.  Any dose modifications will be flagged.  Means and 
standard deviations will be used to summarize the total doses of DCDT2980S, 
DCDS4501A, rituximab, and obinutuzumab received.  All summaries will be presented 
by treatment group, assigned dose level, and disease-specific cohort. 
4.10.2 
Safety Analysis 
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in physical findings on physical examinations, and changes in vital 
signs.  All patients who receive any amount of DCDT2980S, DCDS4501A, rituximab, or 
obinutuzumab will be included in the safety analysis and will be assigned to the 
treatment group on the basis of the study treatment received.  Patients who have dose 
level changes from the initial assigned dose level will be summarized by the initial 
assigned dose level of DCDT2980S or DCDS4501A. 
All adverse event data will be listed by study site, patient number, treatment group, 
disease-specific cohort, and cycle.  All adverse events occurring on or after treatment on 
Day 1 of Cycle 1 will be summarized by mapped terms, appropriate thesaurus levels, 
and NCI CTCAE v4.0 toxicity grade.  In addition, all serious adverse events, including 
deaths will be listed separately and summarized.   
Selected laboratory data will be listed, with values outside of normal ranges identified.  
The incidence of antibodies to DCDT2980S and DCDS4501A will be summarized. 
4.10.3 
Pharmacokinetic and Pharmacodynamic Analyses 
Individual and mean serum concentrations of total DCDT2980S or DCDS4501A antibody 
(conjugated and unconjugated antibody) and rituximab or obinutuzumab and plasma 
concentrations of acMMAE and free MMAE versus time data will be tabulated and 
plotted by NHL disease subtype (relapsed or refractory follicular NHL or DLBCL).  The 
pharmacokinetics of the above analytes will be summarized by estimating the 
appropriate PK parameters (e.g., AUC, Cmax, CL, Vss, and t1/2).  Estimates for these 


 
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parameters will be tabulated and summarized (mean, standard deviation, and range).  
Non-compartmental, compartmental, and/or population methods will be used, as data 
allow.  
Exposure-response (safety and efficacy) analysis may be conducted with use of PK data 
and available drug effect (e.g., imaging, measures of tumor burden) and toxicity 
(e.g., clinical pathology) data, at the sponsor’s discretion. 
In addition, population PK methods may be employed to manage sparse data and to 
investigate the effects of certain covariates on the pharmacokinetics of DCDT2980S and 
DCDS4501A, as data allow, and at the sponsor’s discretion. 
4.10.4 
Activity Analyses 
Best overall response, duration of response, and PFS will be listed for all patients. 
ORR from the initial study treatment will be calculated on the basis of data from patients 
who received study treatment.  Objective response is defined as CR or PR as 
determined by the investigator, on the basis of physical examinations, radiographic 
scans, and bone marrow examinations, using modified response criteria for NHL 
(Cheson et al. 2007; see Appendix C) and confirmed by repeat assessments ≥ 4 weeks 
after initial documentation.  Any patient with insufficient data to determine response will 
be classified as a non-responder. 
For patients with DLBCL, primary assessment of tumor response will be based on 
diagnostic imaging scans⎯for example, CT and/or MRI scans and PET scans.  For 
patients with FL enrolled on rituximab-containing arms/cohorts, primary assessment 
of response will be based on CT scans only; the assessment of response in FL based on 
PET scans will be performed for exploratory purposes only. 
For patients on obinutuzumab-containing cohorts, primary response assessment for both 
DLBCL and FL will be based on PET/CT scans using the updated 2014 Lugano 
Response Criteria as determined by an Independent Review Committee (IRC).  Patients 
in Cohorts E, G, and H will be evaluated with a PET-CT scan at screening, between 
Cycle 4 Day 15 and Cycle 5 Day 1, and at the end of treatment (6-8 weeks after 
completing treatment).  The efficacy analysis for these cohorts will, therefore, be 
different from the analysis for Arms A-B and Cohorts C-D (Cheson, et al 2014) 
(see Appendix C-2).  Subsequent imaging can be CT only.  Responses to study 
treatment will also be based on investigator assessments. 
Among patients with an objective response, duration of response will be defined as the 
time from the initial documentation of a CR or PR to the time of disease progression or 
death.  If a patient does not experience death or disease progression before the end of 
the study, duration of response will be censored at the day of the last tumor assessment. 


 
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For the randomized portion of the study (Arms A and B), PFS is defined as the time from 
the date of randomization to the date of disease progression or death from any cause, 
whichever occurs first.  If a patient has not experienced progressive disease or death, 
PFS will be censored at the date of the last tumor assessment.  Patients with no 
post-baseline tumor assessment will be censored on the date of randomization.  For the 
non-randomized portion of the study (Cohorts C through H), PFS is defined as the time 
from the date of study enrollment to the date of disease progression or death from any 
cause, whichever occurs first. 
For the randomized portion of the study (Arms A and B), OS is defined as the time from 
the date of randomization to the date of death from any cause.  For the non-randomized 
portion of the study (Cohorts C through H), OS is defined as the time from the date of 
study enrollment to date of death from any cause. 
4.10.5 
Exploratory Analyses  
Assay results of possible predictive markers will be listed by treatment group and 
response status. 
Frequencies and percentages of missing data for the PRO endpoints will be reported.  Dropouts 
(defined as patients withdrawing from treatment for reasons other than documented disease 
progression or death) will be summarized 
Summary statistics of the MDASI items, scales, and their changes from baseline will be 
calculated at each assessment timepoint.  The mean, standard error, and median of the 
absolute scores and the mean changes from baseline (and 95% CI) within and between 
study arms will be reported for the MDASI scales and single items, as well as the weekly 
averages of the worst symptom rating.  For change scores in the MDASI from baseline, 
patients without baseline scores will not be included in the analyses.  Line charts 
depicting the means and mean changes of subscales over time will be also provided.   
Repeated measures mixed-effects models will explore MDASI subscale scores with a 
baseline score and appropriate covariates added, as appropriate. 
4.10.6 
Handling of Missing Data 
For the endpoint of objective response, patients without a post-baseline tumor 
assessment will be considered non-responders in the all-treated population analysis.  
For duration of response and PFS, data from patients who are lost to follow-up will be 
included in the analysis as censored observations on the last date that the patient is 
known to be progression free, defined as the date of the last tumor assessment, or, if no 
tumor assessments were performed, as the date of last study treatment plus 1 day. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Compliance to PRO data collection will be reported with summary statistics, including 
frequencies of reasons for non-compliance such as patient refusal to complete PRO 
data collection.   
4.10.7 
Determination of Sample Size 
For the randomized portion of the study (Arms A and B), a target of 120 patients will be 
enrolled in two separate cohorts of patients (40 in the follicular NHL cohort and 80 in the 
DLBCL cohort).  The randomized portion of this study is non-comparative in nature.  No 
formal hypothesis testing is planned to compare the treatment arms.  Moreover, there is 
insufficient power to detect minimum clinically meaningful differences between the two 
treatment arms.  Genentech has judged the proposed sample size to provide sufficient 
precision in estimating the anti-tumor activity of DCDT2980S combined with rituximab or 
DCDS4501A combined with rituximab as measured by objective response.  For example, 
with the assumption of an observed response rate of 40%, a 90% confidence interval for 
the response rate would be approximately 22%−58% (i.e., 40% ± 18%) for the follicular 
NHL cohort and approximately 27%−53% (i.e., 40% ± 13%) for the DLBCL cohort.  With 
40 patients, there is an 87% chance of observing at least one adverse event with a true 
incidence of 5%. 
For the non-randomized portions of the study (Cohorts C and D), approximately 
20 patients will be enrolled into each arm, for a total of 40 patients.  With 20 patients 
under an observed response rate of 40%, the exact Clopper-Pearson 90% confidence 
interval for the response rate would be 22%−61%.  With respect to the assessment of 
safety based upon a sample size of 20 patients, the chance of observing at least one 
adverse event with a true incidence of 10% is 88%. 
For the obinutuzumab safety run-in cohort (Cohort E), 6 patients will be enrolled.  For the 
obinutuzumab expansion cohorts (Cohorts G and H), 40 patients with follicular NHL, and 
40 patients with DLBCL will be enrolled at the RP2D to further evaluate safety and 
efficacy of the combination.  Table 3 provides asymptotic 90% confidence intervals for 
the true probability of response for a range of observed proportions based upon a 
sample of 40 patients.  A sample size of 40 patients is deemed sufficient to provide 
adequate precision on the point estimate and for the lower end of the 90% CI to rule out 
a clinically uninteresting rate of 45% assuming observed response rates of 
approximately 60% or higher (~24 responders observed among 40 patients). 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Table 3 
Potential 90% Interval Estimates for the True Response Probability 
Observed Proportion
of Responders 
90% Confidence Interval 
for 
True Probability of 
Response 
0.50 
(0.37, 0.63) 
0.60 
(0.47, 0.73) 
0.65 
(0.53, 0.77) 
0.70 
(0.58, 0.82) 
0.75 
(0.64, 0.86) 
 
Therefore, up to 246 patients may be enrolled in this study.  
4.11 
DATA QUALITY ASSURANCE 
The data will be collected via EDC using eCRFs.  The site will be responsible for data 
entry into the EDC system.  In the event of discrepant data, the CRO will request data 
clarification from the sites, which the sites will resolve electronically in the EDC system.  
The CRO will be responsible for the data management of this trial, including quality 
checking of the data.   
Genentech will perform oversight of the data management of this trial.  Genentech will 
produce an EDC Study Specification document that describes the quality checking to be 
performed on the data.  Central Laboratory data and other electronic data will be sent 
directly to Genentech, using Genentech’s standard procedures to handle and process 
the electronic transfer of these data.  eCRFs and correction documentation will be 
maintained in the EDC system’s audit trail.  System backups for data stored at 
Genentech and records retention for the study data will be consistent with Genentech’s 
standard procedures. 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording protocol-defined adverse 
events (AEs) and serious adverse events (SAEs); measurement of protocol-specified 
hematology, clinical chemistry, and urinalysis variables; measurement of 
protocol-specified vital signs; and physical examinations and other protocol-specified 
tests that are deemed critical to the safety evaluation of the study drug(s). 
Genentech or its designee is responsible for reporting relevant SAEs to the Competent 
Authority, other applicable regulatory authorities, and participating investigators, in 
accordance with ICH guidelines, FDA regulations, European Clinical Trials Directive 
(Directive 2001/20/EC), and/or local regulatory requirements. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Genentech or its designee is responsible for reporting unexpected fatal or 
life-threatening events associated with the use of the study drug to the regulatory 
agencies and competent authorities by telephone or fax within 7 calendar days after 
being notified of the event.  Genentech or its designee will report other relevant SAEs 
associated with the use of the study medication to the appropriate competent authorities 
(according to local guidelines), investigators, and central Institutional Review 
Board/ethics committee (IRBs/ECs, except in the United States where investigators are 
responsible for reporting to their IRBs per local requirements) by a written safety report 
within 15 calendar days of notification.   
5.1.1 
Adverse Event 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an IMP or other protocol-imposed intervention, regardless of 
attribution. 
This includes the following: 
• 
AEs not previously observed in the patient that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with the baseline 
hematologic malignancy (i.e., leukemia or lymphoma) that were not present prior to 
the AE reporting period (see Section 5.2.1) 
• 
Complications that occur as a result of protocol-mandated interventions 
(e.g., invasive procedures such as biopsies) 
• 
AEs that occur prior to assignment of study treatment that are related to a 
protocol-mandated intervention (e.g., medication washout, no treatment run-in, or 
invasive procedures such as biopsies) 
• 
Preexisting medical conditions other than the disease under study that are judged 
by the investigator to have worsened in severity or frequency or changed in 
character during the protocol-specified AE reporting period 
 
5.1.2 
Serious Adverse Event 
An SAE is any AE that is any of the following: 
• 
Fatal (i.e., the AE actually causes or leads to death) 
• 
Life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death) 
• 
Requires or prolongs inpatient hospitalization 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
• 
A congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
the investigational product(s) 
• 
Considered a significant medical event by the investigator (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 


 
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All AEs that do not meet any of the criteria for serious should be regarded as 
non-serious AEs. 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an AE (as in mild, moderate, or severe pain); the event itself may be of relatively minor 
medical significance (such as severe headache).  “Serious” is a regulatory definition and 
is based on patient or event outcome or action criteria usually associated with events 
that pose a threat to a patient’s life or vital functions.  Seriousness (not severity) serves 
as the guide for defining regulatory reporting obligations. 
Severity and seriousness should be independently assessed when recording AEs and 
SAEs on the eCRF.  
5.1.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious adverse events of special interest are required to be reported by the 
investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2 for reporting instructions), irrespective of regulatory seriousness 
criteria.  Adverse events of special interest for this study include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 5.3.1.6; treatment-emergent ALT or AST > 3 × baseline value 
in combination with total bilirubin > 2 × ULN [of which ≥ 35% is direct bilirubin]) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
• 
Tumor lysis syndrome (TLS) of any grade, irrespective of causality 
 
5.2 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all AEs and SAEs (as defined in 
Section 5.1) are recorded on the eCRF and reported to the Sponsor in accordance with 
protocol instructions.  
5.2.1 
Adverse Event Reporting Period 
After informed consent, but prior to initiation of study drug, only SAEs caused by a 
protocol-mandated intervention will be collected (e.g., SAEs related to invasive 
procedures such as biopsies, medication washout, or no treatment run-in). 


 
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After initiation of study drug (the Genentech product(s) or other IMP), all new AEs and 
SAEs regardless of attribution will be collected until 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is later.  
After this period, investigators should report only SAEs that are felt to be related to prior 
study treatment (see Section 5.6).   
5.2.2 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting AEs at all patient 
evaluation timepoints should be adopted.  Examples of non-directive questions include: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?”  
 
5.2.3 
Assessment of Severity and Causality of Adverse Events 
Investigators will seek information on AEs and SAEs at each patient contact.  All AEs 
and SAEs, whether reported by the patient or noted by authorized study personnel, will 
be recorded in the patient’s medical record and on the Adverse Event eCRF. 
For each AE and SAE recorded on the applicable eCRF, the investigator will make an 
assessment of seriousness (see Section 5.1.2 for seriousness criteria), severity, and 
causality.   
Table 4 provides guidance for grading AE severity, and Table 5 provides guidance for 
assessing the causal relationship to the investigational product(s).  
The AE grading (severity) scale found in the NCI CTCAE v4.0 will be used for AE 
reporting.


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Table 4 
Adverse Event Grading (Severity) Scale 
Grade 
Severity 
Alternate Description a 
1 
Mild (apply event-specific 
NCI CTCAE grading criteria) 
Transient or mild discomfort (< 48 hours); 
no interference with the patient’s daily 
activities; no medical intervention/therapy 
required 
2 
Moderate (apply event-specific 
NCI CTCAE grading criteria) 
Mild to moderate interference with the 
patient’s daily activities; no or minimal 
medical intervention/therapy required 
3 
Severe (apply event-specific 
NCI CTCAE grading criteria) 
Considerable interference with the 
patient’s daily activities; medical 
intervention/therapy required; 
hospitalization possible 
4 
Very severe, life threatening, 
or disabling (apply event-specific 
NCI CTCAE grading criteria) 
Extreme limitation in activity; significant 
medical intervention/therapy required, 
hospitalization probable 
5 
Death related to AE 
 
AE=adverse event; NCI CTCAE= National Cancer Institute Common Terminology Criteria 
for Adverse Events; SAE=serious adverse event. 
The NCI CTCAE v4.0 can be found at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.  
Note:  Regardless of severity, some events may also meet regulatory serious criteria.  
Refer to definitions of an SAE (see Section 5.1.2). 
a Use these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or 
reported AE is not in the NCI CTCAE listing. 
 
To ensure consistency of causality assessments, investigators should apply the 
following general guidelines: 
Table 5 
 Causal Attribution Guidance 
Is the AE/SAE suspected to be caused by the investigational product based on facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
The temporal relationship of the AE/SAE to investigational product administration 
makes a causal relationship possible, AND other drugs, therapeutic interventions 
or underlying conditions do not provide sufficient explanation for the AE/SAE.   
NO 
The temporal relationship of the AE/SAE to investigational product administration 
makes a causal relationship unlikely, OR other drugs, therapeutic interventions or 
underlying conditions provide a sufficient explanation for the AE/SAE.   
AE=adverse event; SAE=serious adverse event. 
 
The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the “Yes” or “No” causality assessment for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities.   


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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5.3 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
5.3.1 
Recording Adverse Events on the eCRF 
Investigators should use correct medical terminology/concepts when recording AEs or 
SAEs on the eCRF.  Avoid colloquialisms and abbreviations. 
There is one eCRF page for recording AEs or SAEs. 
Only one medical concept should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.1.1 
Diagnosis versus Signs and Symptoms 
If known, a diagnosis should be recorded on the eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded as an AE or SAE on the eCRF.  If a diagnosis 
is subsequently established, it should be reported as follow-up information. 
5.3.1.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause.  For example, if severe diarrhea is 
known to have resulted in dehydration, it is sufficient to record only diarrhea as an AE or 
SAE on the eCRF.  
However, medically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the eCRF.  For 
example, if a severe gastrointestinal hemorrhage leads to renal failure, both events 
should be recorded separately on the eCRF. 
5.3.1.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between patient 
evaluation timepoints.  Such events should only be recorded once in the eCRF unless 
their severity increases.  If a persistent AE becomes more severe, it should be recorded 
again on the Adverse Event eCRF.   
A recurrent AE is one that occurs and resolves between patient evaluation timepoints 
and subsequently recurs.  All recurrent AEs should be recorded on Adverse Event 
eCRF. 


 
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5.3.1.4 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities that require active management, 
e.g., concomitant medication, will be recorded as AEs or SAEs on the eCRF 
(e.g., abnormalities that require study drug dose modification, discontinuation of study 
treatment, more frequent follow-up assessments, further diagnostic investigation, etc.) 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholecystitis), only the 
diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event eCRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded as an AE or SAE on the eCRF.  If the 
laboratory abnormality can be characterized by a precise clinical term, the clinical term 
should be recorded as the AE or SAE.  For example, an elevated serum potassium level 
of 7.0 mEq/L should be recorded as “hyperkalemia.” 
Specific to this study, lymphopenia and leukopenia due to lymphopenia of any grade are 
expected PD effects of study drug and therefore are not considered to be AEs.  
However, complications of lymphopenia (e.g., infections) will need to be reported as 
AEs.  In addition, because monocytopenia is not reportable and neutropenia is already 
being monitored and reported as an AE, leukopenia does not need to be reported as a 
distinct AE. 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded as AEs or SAEs on the eCRF, unless their severity, 
seriousness, or etiology changes.  
5.3.1.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported 
as an AE if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (including a diagnostic evaluation not mandated in 
this protocol) or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 


 
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Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.1.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an AE the occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as an SAE or a non-serious adverse event of special interest (see 
Section 5.4.2) 
5.3.1.7 
Deaths 
Deaths that occur during the protocol-specified AE reporting period (see Section 5.2.1 ) 
that are attributed by the investigator solely to progression of lymphoma will be recorded 
only on the Study Discontinuation eCRF.  All other on-study deaths, regardless of 
attribution, will be recorded on the Adverse Event eCRF and expeditiously reported to 
the Sponsor. 
When recording a death on an eCRF, the event or condition that caused or contributed 
to the fatal outcome should be recorded as the single medical concept on the eCRF.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
record “Unexplained Death” on the Adverse Event eCRF. 
5.3.1.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study.  Such 
conditions should be recorded on the Medical and Surgical History eCRF. 
A preexisting medical condition should be recorded as an AE or SAE only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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5.3.1.9 
Worsening of Baseline Hematologic Malignancy 
Worsening and/or progression of the baseline hematologic malignancy (e.g. leukemia or 
lymphoma) should not be recorded as an AE or SAE.  These data will be captured as 
efficacy assessment data only.   
5.3.1.10 
Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol.   
There are some hospitalization scenarios that do not require reporting as an SAE when 
there is no occurrence of an AE.  These scenarios include a planned hospitalization or 
prolonged hospitalization to: 
• 
Perform an efficacy measurement for the study 
• 
Undergo a diagnostic or elective surgical procedure for a preexisting medical 
condition that has not changed 
• 
Receive scheduled therapy for the target disease of the study 
 
5.3.1.11 
Pregnancy 
If a female patient becomes pregnant while receiving the study drug or within 12 months 
after the last dose of study treatment, a Pregnancy Report eCRF should be completed 
within 24 hours of learning of the pregnancy.  A pregnancy report will automatically be 
generated and sent to Genentech’s Drug Safety Department or its designee.  Pregnancy 
should not be recorded on the Adverse Event eCRF. 
Male patients must also be instructed to immediately inform the investigator if their 
partner becomes pregnant during the study or within 5 months after the last dose of 
study drug.  If such an event occurs, it should be reported as described below. 
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE 
(as the Sponsor considers these medically significant), recorded on an Adverse Event 
eCRF, and expeditiously reported to the Sponsor (see Section 5.4.2). 
Any congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to study drug should be classified as an SAE, recorded on the Adverse Event eCRF, and 
expeditiously reported to the Sponsor (see Section 5.4.2). 
After the study period, abortions, congenital anomalies/birth defects, and pregnancy 
outcomes should still be reported expeditiously to the Sponsor.   
In the event the EDC system is unavailable, a paper Pregnancy Report form and 
Pregnancy Fax Coversheet should be completed and faxed to Genentech’s Drug Safety 
Department or its designee within 24 hours of learning of the pregnancy, at the fax 
numbers listed in Section 5.4.2. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
131/P GO27834-A3 
a. Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
5 months after the last dose of study drug.  A Pregnancy Report eCRF should be 
completed by the investigator within 1 working day after learning of the pregnancy and 
submitted via the EDC system.  Attempts should be made to collect and report details of 
the course and outcome of any pregnancy in the partner of a male patient exposed to 
study drug.  The pregnant partner will need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
Once the authorization has been signed, the investigator will update the Pregnancy 
Report eCRF with additional information on the course and outcome of the pregnancy.  
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
In the event that the EDC system is unavailable, a paper Pregnancy Report form and 
Pregnancy Fax Coversheet should be completed and faxed to Genentech’s Drug Safety 
Department or its designee within 24 hours of learning of the pregnancy, at the fax 
numbers listed in Section 5.4.2. 
5.4 
EXPEDITED REPORTING REQUIREMENTS FOR SERIOUS 
ADVERSE EVENTS  
5.4.1 
Reporting Requirements for Fatal/Life-Threatening SAEs 
Related to Investigational Product 
Any life-threatening (i.e., imminent risk of death) or fatal AE that is attributed by the 
investigator to the investigational product will be telephoned to the Medical Monitor 
immediately, followed by submission of written case details on an eCRF within 24 hours 
as described in Section 5.4.2. 
Medical Monitor Contact Information for sites in North America: 
Medical Monitor: 
, M.D. 
Telephone No.: 
 
 
Mobile Telephone No.: 
 
  
For sites outside of North America, local contact details and numbers for safety issues 
and safety reporting will be provided in the study reference binder. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
For reports of SAEs and non-serious adverse events of special interest, investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours) on 
the Adverse Event eCRF and submit the report via the EDC system.  A report will be 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
132/P GO27834-A3 
generated and sent to the Sponsor’s Safety Risk Management department by the EDC 
system. 
In the event that the EDC system is unavailable, a paper Serious Adverse 
Event/Non-Serious Adverse Event of Special Interest CRF and Fax Coversheet should 
be completed and faxed to Safety Risk Management or its designee immediately (i.e., no 
more than 24 hours after learning of the event), using the fax numbers provided below.  
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.   
Sites in North America: 
Fax No.:  
 
 
 
Sites in Europe: 
Fax No.:  
 
Relevant follow-up information should be submitted to Genentech’s Drug Safety 
Department or its designee as soon as it becomes available and/or upon request. 
5.5 
TYPE AND DURATION OF FOLLOW-UP OF PATIENTS AFTER 
ADVERSE EVENTS 
The investigator should follow all unresolved AEs and SAEs until the events are resolved 
or stabilized, the patient is lost to follow up, or it has been determined that the study 
treatment or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs 
(with dates) should be documented on the Adverse Event eCRF and in the patient’s 
medical record to facilitate source data verification (SDV). 
For some SAEs, the Sponsor or its designee may follow up by telephone, fax, electronic 
mail, and/or a monitoring visit to obtain additional case details deemed necessary to 
appropriately evaluate the SAE report (e.g., hospital discharge summary, consultant 
report, or autopsy report). 
5.6 
POST-STUDY ADVERSE EVENTS 
At the last scheduled visit, the investigator should instruct each patient to report to the 
investigator any subsequent SAEs that the patient’s personal physician believes could 
be related to prior study treatment.   
The investigator should notify the study Sponsor of any death or other SAE occurring at 
any time after a patient has discontinued or terminated study participation if felt to be 
related to prior study treatment.  The Sponsor should also be notified if the investigator 
should become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a patient that participated in this study.  The 
investigator should report these events to Genentech Drug Safety on the study eCRF.  
If the study eCRF is no longer available, the investigator should report the event directly 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
133/P GO27834-A3 
to Genentech Drug Safety either by faxing or by scanning and emailing the Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form with use of the fax 
number or email address provided below. 
Canada: 
Fax No.:  (905) 542−5864 
Email:  mississauga.drug_safety@roche.com 
 
France: 
Fax No:  33 147617777 
Email:  neuilly.drug_safety@roche.com 
 
Germany: 
Fax No.:  
 
Email:  grenzach.drug_safety@roche.com 
 
Italy: 
Fax No.:  
 
Email:  monza.drug_safety@roche.com 
 
Netherlands: 
Fax No.:  
 
Email:   woerden.drug_safety@roche.com 
 
United States: 
Fax No.:  
 
Email: us_drug.safety@gene.com 
 
6. 
INVESTIGATOR REQUIREMENTS 
6.1 
STUDY INITIATION 
Before the start of this study and any study-related procedures at a specific site, the 
following documents must be on file with Genentech or a Genentech representative: 
• 
FDA Form 1572 for each site (for all studies conducted under U.S. Investigational 
New Drug [IND] regulations), signed by the Principal Investigator 
The names of any subinvestigators must appear on this form.  Investigators 
must also complete all regulatory documentation as required by local and 
national regulations. 
• 
Current curricula vitae and evidence of licensure of the Principal Investigator and all 
subinvestigators 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
134/P GO27834-A3 
• 
Complete financial disclosure forms for the Principal Investigator and all 
subinvestigators listed on the FDA Form 1572  
• 
Federalwide Assurance number or IRB statement of compliance 
• 
Written documentation of IRB/EC approval of the protocol (identified by protocol 
number or title and date of approval) and Informed Consent Form (identified by 
protocol number or title and date of approval) 
• 
A copy of the IRB/EC-approved Informed Consent Form 
Genentech or its designee must review any proposed deviations from the sample 
Informed Consent Form. 
• 
Current laboratory certification of the laboratory performing the analysis (if other 
than a Genentech-approved central laboratory), as well as current references 
ranges for all laboratory tests 
• 
A Clinical Research Agreement signed and dated by the study site 
• 
Investigator Brochure Receipt signed and dated by the Principal Investigator 
• 
Certified translations of an approved Informed Consent Form, and any other written 
information to be given to the patient (when applicable) , IRB/EC approval letters, 
and pertinent correspondence 
• 
A Protocol Acceptance Form signed and dated by the Principal Investigator 
• 
Canada only when applicable:  original Qualified Investigator Undertaking Form, 
signed by each Canadian investigator involved in the study 
• 
For global studies, list documents as appropriate for additional countries. 
 
6.2 
STUDY COMPLETION 
The following data and materials are required by Genentech before a study can be 
considered complete or terminated: 
• 
Laboratory findings, clinical data, and all special test results from screening through 
the end of the study follow-up period 
• 
All laboratory certifications for laboratories performing the analysis (is other  than 
Genentech-approved central laboratory), as well as current normal laboratory 
ranges for all laboratory tests 
• 
eCRFs (including queries) properly completed by appropriate study personnel and 
electronically signed and dated by the investigator 
• 
Completed Drug Accountability Records (Retrieval Record, Drug Inventory Log, and 
Inventory of Returned Clinical Material forms) 
• 
Copies of protocol amendments and IRB/EC approval/notification, if appropriate 
• 
A summary of the study prepared by the Principal Investigator (IRB summary close 
letter is acceptable) 
• 
All essential documents (e.g., curriculum vitae for each Principal Investigator and 
subinvestigator, FDA Form 1572 for each site) 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
135/P GO27834-A3 
• 
A signed and dated Protocol Amendment Acceptance Form(s) [if applicable] 
• 
Updated financial disclosure forms for the Principal Investigator and all 
subinvestigators listed on the FDA Form 1572 (applicable for 1 year after the last 
patient has completed the study) 
 
6.3 
INFORMED CONSENT FORM 
Genentech’s Sample Informed Consent Form will be provided to each site.  Genentech 
or its designee must review and approve any proposed deviations from the Sample 
Informed Consent Form or any alternate consent forms proposed by the site 
(collectively, the “Consent Forms”) before IRB/EC submission.  Patients must be 
re-consented to the most current version of the Consent Forms during their participation 
in the study.  The final IRB/EC-approved Consent Forms must be provided to Genentech 
for regulatory purposes. 
The Consent Forms must be signed by the patient or the patient’s legally authorized 
representative before his or her participation in the study.  The case history for each 
patient shall document the informed consent process and that written informed consent 
was obtained prior to participation in the study.  A copy of each signed Consent Form 
must be provided to the patient or the patient’s legally authorized representative.  
If applicable, it will be provided in a certified translation of the local language. 
All signed and dated Consent Forms must remain in each patient’s study file and must 
be available for verification by study monitors at any time. 
The Informed Consent Form should be revised whenever there are changes to 
procedures outlined in the informed consent or when new information becomes available 
that may affect the willingness of the patient to participate. 
For any updated or revised Consent Forms, the case history for each patient shall 
document the informed consent process and that written informed consent was obtained 
for the updated/revised Consent Form for continued participation in the study.  The final 
revised IRB/EC-approved Informed Consent Form must be provided to Genentech for 
regulatory purposes. 
If the site utilizes a separate Authorization Form for patient authorization to use and 
disclose personal health information under the U.S. Health Insurance Portability and 
Accountability Act (HIPAA) regulations, the review, approval, and other processes 
outlined above apply except that IRB/IEC review and approval may not be required per 
study site policies. 
Optional Research Informed Consent 
Informed consent for the collection and use of fresh tumor tissue at time of progression 
for optional research described in Section 4.5.1.10 will be documented in a section of the 
main Informed Consent Form.  This section provides patients with the option to authorize 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
136/P GO27834-A3 
the collection and use of these samples and personal health information for additional 
research purposes.  Agreement to participate in the optional research (by checking the 
appropriate box in this section of the main Informed Consent Form) is not required for 
enrollment in the trial but is required prior to any optional research sample collection.  
Optional consent may be withdrawn at any time by the patient. 
6.4 
COMMUNICATION WITH THE INSTITUTIONAL REVIEW BOARD 
OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator for review and approval before the study is initiated.  In addition, any patient 
recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the regulatory 
requirements and policies and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol changes or 
amendments and of any unanticipated problems involving risk to human patients 
or others. 
In addition to the requirements to report protocol-defined AEs to the Sponsor, 
investigators are required to promptly report to their respective IRB/EC all unanticipated 
problems involving risk to human patients.  Some IRBs/ECs may want prompt 
notification of all SAEs, whereas others require notification only about events that are 
serious, assessed to be related to study treatment, and are unexpected.  Investigators 
may receive written IND safety reports or other safety-related communications from 
Genentech.  Investigators are responsible for ensuring that such reports are reviewed 
and processed in accordance with regulatory requirements and with the policies and 
procedures established by their IRB/EC and archived in the site’s Study File.  
6.5 
STUDY MONITORING REQUIREMENTS 
Site visits will be conducted by an authorized Genentech representative to inspect site 
facilities and equipment, study source data, patients’ medical records, and eCRFs.  
The Principal Investigator will oversee all aspects of the conduct of this protocol 
and permit Genentech monitors/representatives and collaborators, the FDA, other 
regulatory agencies, Institutional Review Boards, and the respective national or local 
health authorities to inspect facilities and records relevant to this study. 
6.6 
ELECTRONIC CASE REPORT FORMS 
eCRFS are to be completed using the 
 EDC 
system.  Sites will receive training for appropriate eCRF completion.  eCRFs will be 
submitted electronically to Genentech and should be handled in accordance with 
instructions from Genentech. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
137/P GO27834-A3 
All eCRFs should be completed by designated, trained personnel or the study 
coordinator as appropriate.  The eCRF should be reviewed and electronically signed and 
dated by the investigator. 
In addition, at the end of the study, the investigator will receive patient data for his or her 
site in a readable format on a compact disc that must be kept with the study records. 
6.7 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing SDV to confirm that critical protocol data 
(i.e., source data) entered into the eCRFs by authorized site personnel are accurate, 
complete, and verifiable from source documents.  
Source documents are where original patient data are recorded and documented for the 
first time.  They include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, patient diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, certified accurate and 
complete copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at the pharmacy, laboratories, and medico-technical 
departments involved in a clinical trial. 
Original source documents that are required to verify the validity and completeness of 
data entered into the eCRFs must never be obliterated or destroyed. 
To facilitate SDV, the investigator(s) and institution(s) must provide the Sponsor direct 
access to all applicable source documents and reports for trial-related monitoring, 
Sponsor audits, and IRB/EC review.  The investigational site must also allow inspection 
by applicable regulatory authorities. 
6.8 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), 
the electronic record can serve as the source document if the system has been validated 
in accordance with FDA requirements pertaining to computerized systems used in 
clinical research.  An acceptable computerized data collection system (for clinical 
research purposes) would be one that (1) allows data entry only by authorized 
individuals; (2) prevents the deletion or alteration of previously entered data and 
provides an audit trail for such data changes (e.g., modification of file); (3) protects the 
database from tampering; and (4) ensures data preservation. 
In collaboration with the study monitor, Genentech’s Quality Assurance group may assist 
in assessing whether electronic records generated from computerized medical record 
systems used at investigational sites can serve as source documents for the purposes of 
this protocol. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
138/P GO27834-A3 
If a site’s computerized medical record system is not adequately validated for the 
purposes of clinical research (as opposed to general clinical practice), applicable 
hardcopy source documents must be maintained to ensure that critical protocol data 
entered into the eCRFs can be verified. 
6.9 
STUDY MEDICATION ACCOUNTABILITY 
All study drug required for completion of this study will be provided by Genentech.  
The recipient will acknowledge receipt of the drug by returning the appropriate 
documentation form indicating shipment content and condition.  Damaged supplies will 
be replaced. 
Accurate records of all study drug received at, dispensed from, returned to and disposed 
of by the study site should be recorded by using the Drug Inventory Log. 
Study drug will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or returned to Genentech with the appropriate 
documentation, as determined by the study site.  If the study site chooses to destroy 
study drug, the method of destruction must be documented. 
Genentech must evaluate and approve the study site’s drug destruction standard 
operating procedure prior to the initiation of drug destruction by the study site. 
6.10 
DISCLOSURE OF DATA 
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization to use and disclose personal health information) signed by the patient or 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other regulatory agencies, national and local health 
authorities, Genentech monitors/representatives and collaborators, and the IRB/EC for 
each study site, if appropriate. 
6.11 
RETENTION OF RECORDS 
FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see Section 4.9 of 
the guideline) require that records and documents pertaining to the conduct of this study 
and the distribution of investigational drug, including eCRFs, consent forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for 2 years after the last marketing application approval in an ICH region or 
after at least 2 years have elapsed since formal discontinuation of clinical development 
of the investigational product.  All state and local laws for retention of records also apply.  


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
139/P GO27834-A3 
No records should be disposed of without the written approval of Genentech.  Written 
notification should be provided to Genentech prior to transferring any records to another 
party or moving them to another location. 
For studies conducted outside the United States under a U.S. IND, the Principal 
Investigator must comply with the record retention requirements set forth in the FDA IND 
regulations and the relevant national and local health authorities, whichever is longer. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
140/P GO27834-A3 
7. 
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Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
141/P GO27834-A3 
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rituximab. J Clin Oncol 2009;27:605−11.  


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Appendix A-1  
Study Flowchart:  Initial Study Treatment (Arms A-B, Cohorts C-D) 
 
Treatment Period 
Cycle 
Screening
Cycle 1 
Cycles 2−4 
Cycles 5−17 
Day(s)a 
Assessment 
−28 to −1 
1 b 
2 
8 
15 
1 b 
2 
8 
15 
1 b 
2 
15 
Treatment 
Completion/Early 
Termination Visit c 
Safety and 
Survival 
Follow-Up d 
Written informed consent e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height (screening only) and weight 
x 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
Vital signs  
x 
x f 
x f 
x 
x 
x f 
(x) f 
x 
x 
x f 
(x) f 
x 
x 
 
ECOG Performance Status 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
 
x 
 
B symptoms g 
x 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
 
Complete physical examination h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical examination i 
 
x 
x 
x 
 
x 
(x) 
 
 
x 
(x) 
 
x 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
(x) 
x 
x 
x 
(x) 
x 
x 
 
Adverse events j 
x 
x  
x 
x 
x 
x  
(x) 
x 
x 
x  
(x) 
x 
x 
x 
MDASI PRO k 
 
Day 1–8 of Cycles 1–8 
 
 
12-lead electrocardiogram l 
x  
Refer to Footnote “l” 
x  
 
Tumor assessments m 
x 
Every 3 months 
x 
 
PET scan (required for DLBCL; optional 
for FL) m 
x 
6-month tumor assessment and as clinically indicated 
 
 
Rituximab infusion 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
DCDT2980S or DCDS4501A infusion n 
 
 
x 
 
 
x 
(x) 
 
 
x 
(x) 
 
 
 


Appendix A-1 (cont.) 
Study Flowchart:  Initial Study Treatment (Arms A-B, Cohorts C-D) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
144/P GO27834-A3 
 
Treatment Period 
Cycle 
Screening
Cycle 1 
Cycles 2−4 
Cycles 5−17 
Day(s)a 
Assessment 
−28 to −1 
1 b 
2 
8 
15 
1 b 
2 
8 
15 
1 b 
2 
15 
Treatment 
Completion/Early 
Termination Visit c 
Safety and 
Survival 
Follow-Up d 
Local Laboratory Assessments 
HBV and HCV screening o 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology p 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
Serum chemistry q 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
Hemoglobin A1c 
x 
 
 
 
 
 
 
 
 
Cycle 5 Day 1 
 
 
Total IgA, IgG, IgM 
x 
 
 
 
 
 
 
 
 
Cycle 8 Day 1 
x 
 
Coagulation (aPTT, PT, and INR) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test r 
x 
Within 10 days of Day 1 of Cycles 3, 6, 9, 12, and 15 
x 
 
Bone marrow biopsy s 
x 
Perform to confirm CR if positive for disease at screening or if clinically 
indicated 
 
 
Central Laboratory Assessments 
Leukocyte immunophenotyping (FACS) t 
 
Day 1 of Cycle1, Cycle 4, Cycle 8 and Cycle12 
x 
 
Tumor tissue sample u 
x 
 
 
 
 
 
 
 
 
 
 
 
x  
 
Exploratory plasma (required) and blood 
(optional) sample v 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
DCDT2980S or DCDS4501A and 
rituximab pharmacokinetic sampling w 
Serum sample for anti-DCDT2980S or 
anti-DCDS4501A antibody x 
Refer to Appendix B-1 and Appendix B-2 
 


Appendix A-1 (cont.) 
Study Flowchart:  Initial Study Treatment (Arms A-B, Cohorts C-D) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
145/P GO27834-A3 
AE = adverse event; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; CR = completed 
response; CT = computed tomography; DLBCL = ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FACS = fluorescent-activated cell 
sorting; FL = follicular lymphoma; GGT = γ-glutamyl transpeptidase; HBV = hepatitis B virus; HCV = hepatitis C virus; Ig = immunoglobulin; INR = international 
normalized ratio; LDH = lactate dehydrogenase; MDASI = MD Anderson Symptom Inventory; MRI = magnetic resonance imaging; NHL = non-Hodgkin’s 
lymphoma; PET = positron emission tomography; PCR = polymerase chain reaction; PT = prothrombin time; QLQ = Quality of Life Questionnaire; 
SAE = serious adverse event; (x) = Assessment or action to be performed only if study treatment is administered on Day 2 of the Cycle —refer to footnote ‘n’ 
for details. 
a Study drug infusions should occur on the scheduled 21-day cycle up to a maximum of 1 year (approximately 17 cycles on an every-21-day schedule) and 
may be given up to ± 2 days from the date scheduled (i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  
All other study visits during Cycles 1 and 2 must occur within ± 1 day from the scheduled date unless otherwise noted.  Study visits starting in Cycle 3 
should occur within ± 2 days from the scheduled date unless otherwise noted.  Treatment cycles may be extended to 28 days if needed to provide 
sufficient time for recovery from a transient and reversible toxicity (e.g., cytopenia) without reducing the dose of DCDT2980S or DSDA4501A.  Patients 
receiving study treatment on 28-day cycles should also follow the assessment schedule above up to a maximum of 1 year of total study treatment 
(approximately 13 cycles). 
b Local laboratory assessments and targeted physical examination may be performed within 72 hours preceding rituximab administration unless otherwise 
specified; pre-infusion laboratory samples should be drawn 0−4 hours prior to infusion. 
c Perform within 30 days after the last infusion of DCDT2980S, DCDS4501A, or rituximab.  The visit at which response assessment shows progressive 
disease may be used as the early termination visit.  Assessments during the treatment completion/early termination visit may be applied to assessments 
required to determine eligibility to receive crossover treatment.  Patients enrolled into Cohorts C and D are not eligible to receive crossover treatment. 
d Patients will be followed for safety for 30 days after the last infusions of DCDT2980S, DCDS4501A, or rituximab.  Such follow-up will require an 
assessment (per verbal report from the patient, at minimum) of any AEs and/or SAEs through 30 days after the last dose of study drug or until the patient 
receives another anti-cancer therapy including crossover treatment, whichever occurs first.  Patients who discontinue study treatment for reasons other 
than progressive disease will continue to be followed for response for up to 1 year after the last infusions of DCDT2980S or DCDS4501A and rituximab, 
or until disease progression or initiation of another anti-lymphoma/leukemia therapy, whichever occurs first.  Refer to Appendix A-4 for schedule of 
assessments during the post-treatment period.  Patients will also be followed for survival following study treatment discontinuation approximately every 
three months until death, loss to follow-up, withdrawal of consent, or study termination. 
e Informed consent form(s) must be signed by the patient before any study-specific procedures are performed. 
f Vital signs on days of study treatment administration should be recorded according to Section 4.5.1.2 of the protocol. 
g Defined as unexplained weight loss > 10% over previous 6 months, fever (> 38°C/100.4°F), and/or drenching night sweats. 
h Complete physical examination includes all systems described in Section 4.5.1.3.   
i Targeted physical examinations should be limited to systems of clinical relevance (see Section 4.5.1.3) and those systems associated with clinical 
signs/symptoms.  A targeted symptom directed examination is required prior to DCDT2980S or DCDS4501A dosing on Day 2 of each cycle if given on 
separate days from rituximab only if clinically indicated⎯for example, to follow- up on signs or symptoms observed from the examinations performed on 
Day 1. 


Appendix A-1 (cont.) 
Study Flowchart:  Initial Study Treatment (Arms A-B, Cohorts C-D) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
146/P GO27834-A3 
j After informed consent is obtained but prior to initiation of study treatment, only SAEs caused by a protocol-mandated intervention should be reported.  
After initiation of study drug, all AEs and SAEs, regardless of attribution, must be reported until 30 days following the last administration of study drug or 
until the patient receives another anti-cancer therapy, whichever occurs first.  After this period, investigators should report only SAEs considered related 
to prior study treatment. 
k Treatment and disease associated symptoms using the MDASI questionnaire will be collected on hand-held computer devices (see Section 4.5.1.10).   
l Twelve-lead digital electrocardiogram (ECG) measurements must be obtained in triplicate (with immediately consecutive ECGs obtained until 
three evaluable ECGs are recorded) at the timepoints specified in Section 4.5.1.5.  Non-triplicate ECGs should also be performed when clinically 
indicated in any patient with evidence of, or suspicion for, clinically significant signs or symptoms of cardiac dysfunction.  The evaluating physician should 
determine the clinical significance of any abnormal ECGs. 
m Tumor assessments should be performed at screening and every 3 months while receiving study treatment regardless of study treatment dose schedule.  
Tumor assessments should also be performed within 30 days after the last study drug infusion as part of the treatment completion/early termination visit.  
Response should be assessed based on physical examination and imaged-based evaluation, using standard NHL criteria (Appendix C-1).  For DLBCL 
patients, a PET scan is required during screening, at the 6-month tumor assessment timepoint and as clinically indicated.  For patients with FL, a PET 
scan is not required but may be obtained based on physician preference and if permitted by local health authorities.  Refer to Section 4.5.1.8 for 
complete details. 
n Administer DCDT2980S or DCDS4501A over 90 minutes for Cycle 1 and over 30 minutes in subsequent cycles if there are no infusion-related AEs.  For 
Cycle 1 and Cycle 2, DCDT2980S or DCDS4501A should be administered on the day after rituximab is administered⎯for example, Day 2 if rituximab is 
given on Day 1, or Day 3 if rituximab is given as a split dose on Days 1 and 2.  In the absence of any infusion-related AEs, rituximab followed by 
DCDT2980S or DCDS4501A may be administered on the same day in each cycle starting with Cycle 3.  Study drug infusions should occur on the 
scheduled 21-day (or 28-day) cycle but may be given up to ± 2 days from the date scheduled (i.e., with a minimum of 19 days between doses) if required 
for logistical/scheduling reasons.  Doses may also be delayed up to 2 weeks for recovery from reversible toxicity. 
o HBsAg, HBcAb, and Hep C Ab serology required.  If HBcAb or HCV antibody is positive, HBV/HCV DNA by PCR is required. 
p Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, absolute neutrophil count, and 
percent or absolute differential counts [e.g., segmented neutrophils, bands, lymphocytes, eosinophils, monocytes, basophils, and other cells]). 
q Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), creatinine, calcium, magnesium, phosphorus, total 
and direct bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, LDH, and uric acid.  Serum GGT levels will be required at screening only. 
r A serum pregnancy test should be performed for women of childbearing potential within 14 days prior to receiving first study treatment.  In addition, a 
urine pregnancy test must also be performed within 10 days prior to Day 1 of Cycles 3, 6, 9, 12, and 15, and at the treatment completion/early 
termination visit unless patient receives crossover treatment, in which case follow the schedule of pregnancy testing outlined in Appendix A-2.  If any 
urine test result is positive, patient dosing will be postponed until the patient’s status is confirmed by a serum pregnancy test. 
s Bone marrow biopsy for morphology (aspirates for morphology and/or flow studies are optional) is required at screening.  Bone marrow biopsy 
for morphology is required at screening and should reflect disease status in the bone marrow following documented relapse on the last prior therapy 
or within 3 months of Day 1, whichever occurs later.  If the bone marrow biopsy at screening demonstrates presence of tumor cells, a subsequent 
bone marrow examination is required only to confirm a CR or if clinically indicated.  If the bone marrow biopsy at screening does not demonstrate 


Appendix A-1 (cont.) 
Study Flowchart:  Initial Study Treatment (Arms A-B, Cohorts C-D) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
147/P GO27834-A3 
presence of tumor cells, then subsequent bone marrow examination is required only if clinically indicated.  Unsuccessful attempts at marrow aspiration 
will not be considered a protocol violation. 
t A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.   
u Availability of archival or freshly biopsied tumor tissue samples should be confirmed at screening.  Tumor tissue samples should consist of representative 
tumor specimens in paraffin blocks (preferred) or at least 15 unstained slides, with an associated pathology report, obtained at any time prior to entry to 
study.  A biopsy of a safely accessible site of disease, defined as requiring only local anesthesia and in general excluding brain, lungs or any internal 
organs that may subject patients to significant risk, is required for patients who proceed to crossover treatment; if no such lesion exists, then a biopsy is 
not required. 
v All patients who have successfully passed screening and are fully eligible for the study will have a 10-mL plasma sample taken for exploratory research.   
w Pharmacokinetic serum and plasma samples should be drawn according to the schedule provided in Appendices B-1 and B-2. 
x Whole blood samples for assessment of anti-DCDT2980S or anti-DCDS4501A antibodies in serum will be drawn according to the schedule provided in 
Appendices B-1 and B-2. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
148/P GO27834-A3 
Appendix A-2 
Study Flowchart:  Crossover Treatment (Patients Randomized to Arms A or B Only) 
 
 
Treatment Period 
Cycle 
Cycle 1b 
Cycles 2b−4b 
Cycles 5b−17b
Day(s) a 
Assessment  
1 b 
2 
8 
15 
1 b 
2 
8 
15 
1 b 
2 
15 
Crossover 
Treatment 
Completion/Early 
Termination Visit c
Safety  and 
Survival 
Follow-Up d 
Weight 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
Vital signs 
x e 
(x) e 
x 
x 
x e 
(x) e 
x 
x 
x e 
(x) e
x 
x 
 
ECOG Performance Status 
x 
 
x 
x 
x 
 
x 
x 
x 
 
 
x 
 
B symptoms f 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
 
Targeted physical examination g 
x 
(x) 
x 
 
x 
(x) 
 
 
x 
(x) 
 
x 
 
Concomitant medications 
x 
(x) 
x 
x 
x 
(x) 
x 
x 
x 
(x) 
x 
x 
 
Adverse events h 
x  
(x) 
x 
x 
x 
(x) 
x 
x 
x  
(x) 
x 
x 
x  
Tumor assessments i 
Every 3 months 
x 
 
Rituximab infusion 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
DCDT2980S or DCDS4501A infusion j 
x 
(x) 
 
 
x 
(x) 
 
 
x 
(x) 
 
 
 
Local Laboratory Assessments 
Hematology k 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
Serum chemistry l 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
Total IgA, IgG, IgM 
 
 
 
 
 
 
 
 
Cycle 8b Day 1
x 
 
Pregnancy test m 
Day 1 of Cycles 3b, 6b, 9b, 12b, and 15b 
x 
 
Bone marrow biopsy n 
Perform to confirm CR if positive for disease at screening or if clinically indicated
 
 
Central Laboratory Assessments 
Leukocyte immunophenotyping (FACS) o
Day 1 of Cycle 4, 8, and 12 
x 
 
Tumor biopsy/sample 
 
 
 
 
 
 
 
 
 
 
 
x p 
 


Appendix A-2 (cont.) 
Study Flowchart: Crossover Treatment (Patients Randomized to Arms A or B Only) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
149/P GO27834-A3 
AE = adverse event; AL = alanine aminotransferase; AST = aspartate aminotransferase; CR = complete response; LDH = lactate dehydrogenase; 
SAE = serious adverse event; (x) = Assessment or action to be performed only if study treatment is administered on Day 2 of the Cycle—refer to footnote 
‘j’ for details. 
a Study drug infusions should occur on the scheduled 21-day cycle up to a maximum of 1 year (approximately 17 cycles) and may be given up to 
± 2 days from the date scheduled (i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  All other study visits 
during Cycles 1 and 2 must occur within ± 1 day from the scheduled date unless otherwise noted.  Study visits starting in Cycle 3 should occur within 
± 2 days from the scheduled date unless otherwise noted.  Treatment cycles may be extended to 28 days if needed to provide sufficient time for 
recovery from a transient and reversible toxicity (e.g., cytopenia) without reducing the dose of DCDT2980S or DSDA4501A.  Patients receiving study 
treatment on 28-day cycles should also follow the assessment schedule above up to a maximum of 1 year of total study treatment (approximately 
13 cycles). 
b Local laboratory assessments and targeted physical examination may be performed within 72 hours preceding rituximab administration unless 
otherwise specified; pre-infusion laboratory samples should be drawn 0−4 hours prior to infusion. 
c Perform within 30 days after the last infusion of DCDT2980S, DCDS4501A or rituximab.  The visit at which response assessment shows progressive 
disease may be used as the early termination visit. 
d Patients will be followed for safety for 30 days after the last infusions of DCDT2980S, DCDS4501A, or rituximab.  Such follow-up will require an 
assessment (per verbal report, at minimum) of any AEs and/or SAEs through 30 days after the last dose of study drug or until the patient receives 
another anti-cancer therapy including crossover treatment, whichever occurs first.  Patients who discontinue study treatment for reasons other than 
progressive disease will continue to be followed for response for up to 1 year after the last infusions of DCDT2980S or DCDS4501A and rituximab, or 
until disease progression or initiation of another anti-lymphoma/leukemia therapy, whichever occurs first.  Refer to Appendix A-4 for schedule of 
assessments during the post-treatment period.  Patients will also be followed for survival following study treatment discontinuation approximately 
every three months until death, loss to follow-up, withdrawal of consent, or study termination. 
e Vital signs on days of study treatment administration should be recorded according to Section 4.5.1.2 of the protocol. 
f Defined as unexplained weight loss > 10% over previous 6 months, fever (> 38°C/100.4°F), and/or drenching night sweats. 
g Targeted physical examinations should be limited to systems of clinical relevance and those systems associated with clinical signs/symptoms.  
A targeted symptom directed examination is required prior to DCDT2980S or DCDS4501A dosing on Day 2 of each cycle if given on separate days 
from rituximab only if clinically indicated, e.g. to follow -up on signs or symptoms observed from the examinations performed on Day 1. 
h Patients will be followed for safety for 30 days after the last infusions of DCDT2980S, DCDS4501A, or rituximab.  Such follow-up will require an 
assessment (per verbal report, at minimum) of any AEs and/or SAEs through 30 days after the last dose of study drug or until the patient receives 
another anti-cancer therapy including crossover treatment, whichever occurs first.  Patients who discontinue study treatment for reasons other than 
progressive disease will continue to be followed for response for up to 1 year after the last infusions of DCDT2980S or DCDS4501A and rituximab, or 
until disease progression or initiation of another anti-lymphoma/leukemia therapy, whichever occurs first.  Refer to Appendix A-4 for schedule of 
assessments during the post-treatment period.   
i Tumor assessments should be performed at screening and every 3 months while receiving study treatment.  Tumor assessments should also be 


Appendix A-2 (cont.) 
Study Flowchart: Crossover Treatment (Patients Randomized to Arms A or B Only) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
150/P GO27834-A3 
 
performed 28−56 days after the last study drug infusion as part of the crossover treatment completion/early termination visit.  Response should be 
assessed based on physical examination and imaged-based evaluation, using standard NHL criteria (Appendix C-1). 
j Administer DCDT2980S or DCDS4501A over 90 minutes for Cycle 1 and over 30 minutes in subsequent cycles if there are no infusion-related 
adverse events.  For Cycle 1b and Cycle 2b, DCDT2980S or DCDS4501A should be administered on the day after rituximab is administered, 
e.g., Day 2 if rituximab is given on Day 1, or Day 3 if rituximab is given as a split dose on Days 1 and 2.  In the absence of any infusion-related 
adverse events, rituximab followed by DCDT2980S or DCDS4501A may be administered on the same day in subsequent cycles starting with 
Cycle 3b.  Study drug infusions should occur on the scheduled 21-day (or 28-day) cycle, but may be given up to ± 2 days from the date scheduled 
(i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  Doses may also be delayed up to 2 weeks for recovery 
from reversible toxicity. 
k Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, absolute neutrophil count, and 
percent or absolute differential counts [e.g., segmented neutrophils bands, lymphocytes, eosinophils, monocytes, basophils, and other cells]). 
l Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), creatinine, calcium, magnesium, phosphorus, 
total and direct bilirubin, total protein, albumin, ALT), AST, alkaline phosphatase, LDH, and uric acid. 
m A serum pregnancy test should be performed for women of childbearing potential within 14 days prior to receiving first study treatment.  In addition, a 
serum or urine pregnancy test must be performed within 10 days prior to Day 1 of Cycles 3, 6, 9, 12, and 15 and at the crossover treatment 
completion/early termination visit.  If any urine test result is positive, patient dosing will be postponed until the patient’s status is confirmed by a serum 
pregnancy test. 
n Bone marrow biopsy for morphology (aspirate for morphology and/or flow studies are optional) should be repeated only to confirm a CR where 
presence of tumor was documented at the screening bone marrow examination. 
o A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.   
p Optional tumor biopsy of a safely accessible site of disease, defined as requiring only local anesthesia and in general excluding brain, lungs or any 
internal organs that may subject patients to significant risk.  Tumor samples will be used for research purposes. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
151/P GO27834-A3 
Appendix A-3 
Study Flowchart for Obinutuzumab-Containing Cohorts (E, G-H):  Initial Study Treatment 
Treatment Period 
Cycle 
Screening 
Cycle 1 
Cycles 2−4 
Cycle 4
Cycles 5−8 
Day(s)a 
Assessment 
−28 to −1 
1
b 
2 
8 
15
1b 
2 
15c 
1b 
2 
Treatment 
Completion/ Early 
Termination Visitc 
End of Treatment Response 
Assessment (after Cycle 8 
Day 1 or last study treatment 
+ 6−8 weeks) 
Safety and 
Survival 
Follow-Up d 
Written informed consent 
e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Height (screening only) 
and weight 
x 
x 
 
 
 
x 
 
 
x 
 
 
 
 
Vital signs  
x 
x
f 
xf 
xf 
xf 
x f 
(x) f 
 
x f 
(x) f 
x 
 
 
ECOG Performance 
Status 
x 
x 
 
x 
x 
x 
 
 
x 
 
x 
 
 
Complete physical 
examination g 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical 
examination h 
 
x 
x 
x 
 
x 
(x) 
 
x 
(x) 
x 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
(x) 
 
x 
(x) 
x 
 
 
Adverse events i 
x 
x 
x 
x 
x 
x  
(x) 
 
x  
(x) 
x 
 
x 
12-lead 
electrocardiogramj 
x  
Refer to Footnote “j” 
x  
 
 
Tumor/Assessment 
(PET/CT scan (required 
for DLBCL and FL) k 
x 
 
 
 
 
 
 
xm 
 
 
 
x m 
 


Appendix A-3 (cont.) 
Study Flowchart for Obinutuzumab-Containing Cohorts (E, G-H):  Initial Study Treatment 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
152/P GO27834-A3 
Obinutuzumab infusion 
 
x 
 
x 
x 
x 
 
 
x 
 
 
 
 
DCDS4501A infusion l 
 
 
x 
 
 
x 
(x) 
 
x 
(x) 
 
 
 
Local Laboratory Assessments 
HBV and HCV 
screening m 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology n 
x 
x 
 
x 
x 
x 
 
 
x 
 
x 
 
 
Serum chemistry p 
x 
x 
 
x 
x 
x 
 
 
x 
 
x 
 
 
Hemoglobin A1c 
x 
 
 
 
 
 
 
 
Cycle 5 
Day 1 
 
 
 
Total IgA, IgG, IgM 
x 
 
 
 
 
 
 
 
Cycle 8 
Day 1 
x 
 
 
Coagulation (aPTT, PT, 
and INR) 
x 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test p 
x 
Within 10 days of Day 1 of Cycles 3, 6 
x 
 
 
Bone marrow biopsy q 
xq 
Perform to confirm CR if positive for disease at screening or 
if clinically indicated 
 
 
 
Central Laboratory Assessments 
Leukocyte 
immunophenotyping 
(FACS) t 
 
Day 1 of Cycle1, Cycle 4, and Cycle 8  
x 
 
 
Tumor tissue sample u 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
Exploratory plasma 
sample v 
x 
 
 
 
 
 
 
 
 
 
 
 
 
DCDS4501A and 
obinutuzumab 
pharmacokinetic  
samplingw 
Refer to Appendix B-3 
Serum sample for 
anti-DCDS4501A 
antibodyx 
 Refer to Appendix B-3 


Appendix A-3 (cont.) 
Study Flowchart for Obinutuzumab-Containing Cohorts (E, G-H):  Initial Study Treatment 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
153/P GO27834-A3 
AE = adverse event; ALP = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; CR = completed response; 
CT = computed tomography; DLBCL = diffuse large B-cell lymphoma; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
FACS = fluorescent-activated cell sorting; FLL = follicular lymphoma; GGT = γ-glutamyl transpeptidase; HBV = hepatitis B virus; HCV = hepatitis C virus; Ig = immunoglobulin; 
INR = international normalized ratio; LDH = lactase dehydrogenase; MRI = magnetic resonance imaging; NHL = non-Hodgkin’s lymphoma; PET = positron emission 
tomography; PT = prothrombin time; SAE = serious adverse event; (x)  = Assessment or action to be performed only if study treatment is administered on Day 2 of the 
Cycle—refer to footnote ‘n’ for details.  
a Study drug infusions should occur on the scheduled 21-day cycle up to a maximum of 6 months (8 cycles on an every-21-day schedule) and may be given up to 
± 2 days from the date scheduled (i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  All other study visits during Cycle 1 
must occur within ± 1 day from the scheduled date unless otherwise noted.  Study visits starting in Cycle 2 should occur within ± 2 days from the scheduled date unless 
otherwise noted.  Treatment cycles may be extended to 28 days if needed to provide sufficient time for recovery from a transient and reversible toxicity (e.g., cytopenia) 
without reducing the dose of DCDA4501A.  Patients receiving study treatment on 28-day cycles should also follow the assessment schedule above up to a maximum of 
6 months of total study treatment (6 cycles on an every-28-day schedule). 
b Local laboratory assessments and targeted physical examination may be performed within 72 hours preceding obinutuzumab administration unless otherwise specified; 
pre-infusion laboratory samples should be drawn 0−4 hours prior to infusion. 
c Cycle 4 Day 15 assessment should be performed between Cycle 4 Day 15 and Cycle 5 Day 1.  The Treatment Completion/Early Termination Visit should be performed 
within 30 days after the last infusion of DCDS4501A or obinutuzumab.  The visit at which response assessment shows progressive disease may be used as the early 
termination visit. 
d Patients will be followed for safety for 30 days after the last infusions of DCDS4501A or obinutuzumab.  Such follow-up will require an assessment (per verbal report 
from the patient, at minimum) of any AEs and/or SAEs through 30 days after the last dose of study drug or until the patient receives another anti-cancer therapy 
including crossover treatment, whichever occurs first.  Patients who discontinue study treatment for reasons other than progressive disease will continue to be followed 
for response for up to 2 years after the last infusions of DCDS4501A or obinutuzumab, or until disease progression or initiation of another anti-lymphoma/leukemia 
therapy, whichever occurs first.  Refer to Appendix A-5 for schedule of assessments during the post-treatment period.  Patients will also be followed for survival 
following study treatment discontinuation approximately every three months until death, loss to follow-up, withdrawal of consent, or study termination. 
e Informed consent form(s) must be signed by the patient before any study-specific procedures are performed. 
f Vital signs on days of study treatment administration should be recorded according to Section 4.5.1.2of the protocol. 
g Complete physical examination includes all systems described in Section 4.5.1.3.   
h Targeted physical examinations should be limited to systems of clinical relevance (see Section 4.5.1.3) and those systems associated with clinical signs/symptoms.  A 
targeted symptom directed examination is required prior to DCDS4501A dosing on Day 2 of each cycle if given on separate days from obinutuzumab only if clinically 
indicated (e.g., to follow up on signs or symptoms observed from the examinations performed on Day 1). 
i After informed consent is obtained but prior to initiation of study treatment, only SAEs caused by a protocol-mandated intervention should be reported.  After initiation of 
study drug, all AEs and SAEs, regardless of attribution, must be reported until 30 days following the last administration of study drug or until the patient receives another 
anti-cancer therapy, whichever occurs first.  After this period, investigators should report only SAEs considered related to prior study treatment. 
j Twelve-lead digital electrocardiogram (ECG) measurements must be obtained in triplicate (with immediately consecutive ECGs obtained until three evaluable ECGs are 
recorded) at the timepoints specified in Section 4.5.1.5.  Non-triplicate ECGs should also be performed when clinically indicated in any patient with evidence of, or 
suspicion for, clinically significant signs or symptoms of cardiac dysfunction.  The evaluating physician should determine the clinical significance of any abnormal ECGs. 


Appendix A-3 (cont.) 
Study Flowchart for Obinutuzumab-Containing Cohorts (E, G-H):  Initial Study Treatment 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
154/P GO27834-A3 
k Response assessment should be performed using Lugano Response Criteria (Appendix C-2).  For DLBCL and FL patients, a combined PET/CT scan is required during 
screening, between Cycle 4 Day 15 and Cycle 5 Day 1, End of Treatment (EOT) assessment, and as clinically indicated.   The EOT assessment should be performed 
6−8 weeks after Cycle 8 Day 1 or last study treatment. During the follow-up period, scans (CT or PET/CT) should be performed every 6 months for 2 years or until 
study end or at any time that progression is suspected.  Refer to Appendix A-5 for imaging assessment during post-treatment follow-up.  Refer to Section 4.5.1.8 for 
complete details for radiographic assessments.   
l Administer DCDS4501A over 90 minutes for Cycle 1 and over 30 minutes in subsequent cycles if there are no infusion-related adverse events.  For Cycle 1, 
DCDS4501A should be administered on the day after obinutuzumab is administered (e.g., Day 2 if obinutuzumab is given on Day 1, or Day 3 if obinutuzumab is given 
as a split dose on Days 1 and 2).  In the absence of any infusion-related adverse events, obinutuzumab followed by DCDS4501A may be administered on the same day 
in each cycle starting with Cycle 2.  Study drug infusions should occur on the scheduled 21-day (or 28-day) cycle but may be given up to ± 2 days from the date 
scheduled (i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  Doses may also be delayed up to 2 weeks for recovery from 
reversible toxicity. 
m HBsAg, HBcAb, and Hep C Ab serology required.  If HBcAb or HCV antibody is positive, HBV/HCV DNA by PCR is required. 
n Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, absolute neutrophil count, and percent or absolute 
differential counts [e.g., segmented neutrophils, bands, lymphocytes, eosinophils, monocytes, basophils, and other cells]). 
o Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), creatinine, calcium, magnesium, phosphorus, total and direct 
bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, LDH, and uric acid., amylase, and lipase  Serum GGT levels will be required at screening only. 
p A serum pregnancy test should be performed for women of childbearing potential within 14 days prior to receiving first study treatment.  In addition, a urine pregnancy 
test must also be performed within 10 days prior to Day 1 of Cycles 3, and 6 and at the treatment completion/early termination visit.  If any urine test result is positive, 
patient dosing will be postponed until the patient’s status is confirmed by a serum pregnancy test. 
q Bone marrow biopsy for morphology (aspirates for morphology and/or flow studies are optional) is required at screening for follicular NHL patients only and should 
reflect disease status in the bone marrow following documented relapse on the last prior therapy or within 3 months of Day 1, whichever occurs later.  If the bone 
marrow biopsy at screening demonstrates presence of tumor cells, a subsequent bone marrow examination is required only to confirm a CR or if clinically indicated.  If 
the bone marrow biopsy at screening does not demonstrate presence of tumor cells, then subsequent bone marrow examination is required only if clinically indicated.  
Unsuccessful attempts at marrow aspiration will not be considered a protocol violation. 
r A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.   
s Availability of archival or freshly biopsied tumor tissue samples should be confirmed at screening.  Tumor tissue samples should consist of representative tumor 
specimens in paraffin blocks (preferred) or at least 15 unstained slides, with an associated pathology report, obtained at any time prior to entry to study.   
t All patients who have successfully passed screening and are fully eligible for the study will have a 10-mL plasma sample taken for exploratory research prior to 
receiving study treatment.   
u Pharmacokinetic serum and plasma samples and pharmacodynamics blood samples should be drawn according to the schedule provided in Appendix B-3. 
v Whole blood samples for assessment of anti-DCDS4501A or anti-obinutuzumab antibodies in serum will be drawn according to the schedule provided in Appendix B-3. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
155/P GO27834-A3 
Appendix A-4 
Study Flowchart: Post-Treatment Follow-Up for Rituximab-Containing Regimens 
(Arms A-B, Cohorts C-D) 
Assessments/Procedures 
Post-treatment Follow-up 
Months after treatment completion visit
2 Months 
4 Months 
6 Months 
9 Months 
12 Months 
Targeted physical examination a 
x 
x 
x 
x 
x 
Vital signs (blood pressure, pulse rate, and 
body temperature) 
x 
x 
x 
x 
x 
ECOG Performance Status 
x 
x 
x 
x 
x 
B symptoms b 
x 
x 
x 
x 
x 
Tumor assessments c 
x 
x 
x 
x 
x 
Total IgA, IgG, IgM 
x 
x 
x 
x 
x 
Hematology d 
x 
x 
x 
x 
x 
Serum chemistry e 
x 
x 
x 
x 
x 
Bone marrow f 
Perform to confirm CR if positive for disease at screening or if 
clinically indicated 
Central Lab Assessments 
 
 
 
 
 
Leukocyte immunophenotyping (FACS) g 
x 
x 
x 
x 
x 
Pharmacokinetic sampling h 
x 
x 
x 
 
 
Serum sample for anti-DCDT2980S / 
anti-DCDS4501A ATA assay h 
x 
x 
x 
 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ATA = anti-therapeutic antibody; 
CR = completed response; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; 
FACS = fluorescent-activated cell sorting; Ig = immunoglobulin; MRI = magnetic resonance imaging; 
NHL = non-Hodgkin’s lymphoma; PET = positron emission tomography. 
NOTE: Post-treatment assessments apply to patients who discontinue from study treatment (initial or crossover 


Appendix A-4 (cont.) 
Study Flowchart: Post-Treatment Follow-Up for Rituximab-Containing Regimens 
(Arms A-B, Cohorts C-D) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
156/P GO27834-A3 
treatment) for reasons other than disease progression.  The schedule corresponds to visits timed from 
treatment completion/early termination visit or crossover treatment completion/early termination visit until the 
time of disease progression, start of new anti-cancer therapy, or withdrawal from study participation.  
Two-month and 4-month follow-up visits should occur within ± 7 days from the scheduled date, while 
subsequent visits should occur within ± 14 days from the scheduled date. 
a Targeted physical examinations should be limited to systems of clinical relevance (see Section 4.5.1.3) and 
those systems associated with clinical signs/symptoms. 
b Defined as unexplained weight loss > 10% over previous 6 months, fever (> 38°C/100.4°F), and/or drenching 
night sweats. 
c Response should be assessed based on physical examination and imaged-based evaluation, using standard 
NHL criteria (Appendix C).   
d Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, 
platelet count, absolute neutrophil count, and percent or absolute differential counts [e.g., segmented 
neutrophils bands, lymphocytes, eosinophils, monocytes, basophils, and other cells]). 
e Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), 
creatinine, calcium, magnesium, phosphorus, total and direct bilirubin, total protein, albumin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase 
(LDH), and uric acid.  
f Bone marrow biopsy for morphology (aspirate for morphology and/or flow studies are optional) should be 
repeated only to confirm a CR where presence of tumor was documented at the screening bone marrow 
examination. 
g A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.   
h Refer to Appendices B-1 or B-2. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
157/P GO27834-A3 
Appendix A-5 
Study Flowchart: Post-Treatment Follow-Up for Obinutuzumab-Containing Regimens 
(Cohorts E, G-H) 
Assessments/Procedures 
Post-Treatment Follow-Up 
Months after treatment completion visit 
3 Months 
6 Months 
9 Months 12 Months
18 Months 
24 Months 
Targeted physical examination a 
x 
x 
x 
x 
x 
x 
Vital signs (blood pressure, pulse rate, and 
body temperature) 
x 
x 
x 
x 
x 
x 
ECOG Performance Status 
x 
x 
x 
x 
x 
x 
Tumor Assessment (Imaging [PET/CT or 
C]) b 
 
x 
 
x 
x 
x 
Total IgA, IgG, IgM 
x 
x 
x 
x 
x 
x 
Hematology c 
x 
x 
x 
x 
x 
x 
Serum chemistry d 
x 
x 
x 
x 
x 
x 
Bone marrow e 
Perform to confirm CR if positive for disease at screening or if clinically 
indicated 
Central Lab Assessments 
 
 
 
 
 
Leukocyte immunophenotyping (FACS) f 
x 
x 
x 
x 
x 
x 
Pharmacokinetic sampling g 
x 
x 
 
x 
x 
x 
Serum sample for 
anti-DCDT2980S/anti-DCDS4501A, 
anti-obinutuzumab ATA assay g 
x 
x 
 
x g 
x g 
x g 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ATA = anti-therapeutic antibody; CR = completed 
response; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; FACS = fluorescent-activated cell 
sorting; Ig = immunoglobulin; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; NHL = non-Hodgkin’s 
lymphoma; PET = positron emission tomography. 
NOTE: Post-treatment assessments apply to patients who discontinue from study treatment (initial or crossover treatment) 


Appendix A-5 (cont.) 
Study Flowchart: Post-Treatment Follow-Up for Obinutuzumab-Containing Regimens 
(Cohorts E, G-H) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
158/P GO27834-A3 
for reasons other than disease progression.  The schedule corresponds to visits timed from treatment completion/early 
termination visit or crossover treatment completion/early termination visit until the time of disease progression, start of new 
anti-cancer therapy, or withdrawal from study participation.  Two-month and four-month follow-up visits should occur within 
± 7 days from the scheduled date, while subsequent visits should occur within ± 14 days from the scheduled date. 
a Targeted physical examinations should be limited to systems of clinical relevance (see Section 4.5.1.3 ) and those 
systems associated with clinical signs/symptoms. 
b Response should be assessed using Lugano Response Criteria (Appendix C-2).  CT or combined PET/CT scan should be 
obtained during the post-treatment follow-up up every 6 months for 2 years or until study end or at any time that 
progression is suspected.  
c Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, 
absolute neutrophil count, and percent or absolute differential counts [e.g., segmented neutrophils bands, lymphocytes, 
eosinophils, monocytes, basophils, and other cells]). 
d Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), creatinine, calcium, 
magnesium, phosphorus, total and direct bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, LDH, and uric 
acid. 
e Bone marrow biopsy for morphology (aspirate for morphology and/or flow studies are optional) should be repeated only to 
confirm a CR where presence of tumor was documented at the screening bone marrow examination. 
f A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.   
g Refer to Appendix B-3. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
159/P GO27834-A3 
Appendix B-1 
Serum and Plasma Pharmacokinetic Schedule for 
DCDT2980S/DCDS4501A and Rituximab, and ATA Schedule for 
DCDT2980S/DCDS4501A (For Patients Receiving Rituximab on 
Day 1 and DCDT2980S/DCDS4501A on Day 2 of Every Cycle) 
(Arms A-B, Cohorts C-D) 
Study Visit 
Sample Timepoint(s) a 
Samples b 
Cycle 1, Day 1 
Pre-rituximab infusion 
• 
Rituximab PK 
 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Pre-DCDT2980S/DCDS4501A 
infusion 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
DCDT2980S/DCDS4501A PK b 
Cycle 1, Day 2 
30 minutes (± 15 minutes)  
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK 
Cycle 1, Day 8 (± 1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
Cycle 1, Day 15 (± 1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK  
Cycles 2−3, Day 1 
Pre-rituximab dose 
• 
Rituximab PK 
 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Pre-DCDT2980S/DCDS4501A 
infusion 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody c 
• 
DCDT2980S/DCDS4501A PK 
Cycles 2−3, Day 2 
30 minutes (± 15 minutes) 
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK 
Cycle 3, Day 8 (± 1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK  
Cycle 3, Day 15 (±1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
Pre-rituximab infusion 
• 
Rituximab PK 
Cycles 4, and 
every 4th cycle 
thereafter), Day 1 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Pre-DCDT2980S/DCDS4501A 
infusion 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody c 
• 
DCDT2980S/DCDS4501A PK 
Cycles 4, and 
every 4th cycle 
thereafter), Day 2 
30 minutes (± 15 minutes) 
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK 


Appendix B-1 (cont.) 
Serum and Plasma Pharmacokinetic Schedule for 
DCDT2980S/DCDS4501A and Rituximab, and ATA Schedule for 
DCDT2980S/DCDS4501A (For Patients Receiving Rituximab on 
Day 1 and DCDT2980S/DCDS4501A on Day 2 of Every Cycle) 
(Arms A-B, Cohorts C-D) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
160/P GO27834-A3 
Study Visit 
Sample Timepoint(s) a 
Samples b 
Treatment 
Completion/ 
Early Termination 
Visit 
Approximately 15−30 days 
after last infusion  
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK e 
Post-treatment 
Follow-Up Visits d 
2, 4, and 6 months after 
treatment completion visit 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
ATA = Anti-therapeutic antibody; MMAE = monomethyl auristatin E; PK = pharmacokinetic. 
Note:  “Pre-infusion” means prior to the start of infusion; “Post-infusion” means after the infusion is 
completed. 
a A 3-mL whole-blood sample will be taken for each of the following at each specified timepoint: 
anti-DCDT2980S or anti-DCDS4501A antibody; rituximab PK; and/or DCDT2980S/DCDS4501A 
PK.  If rituximab dosing is split over two days, then PK will be obtained prior to the rituximab 
dose on the first day and 30 minutes (± 15 minutes) post-rituximab infusion on the second day. 
b PK sampling will not be obtained from patients who cross-over to another treatment arm. 
c Cycles 2 and 4 only for anti-DCDT2980S or anti-DCDS4501A antibody.  
d Post-treatment follow-up PK and ATA assessments only apply to patients who did not receive 
crossover treatment. 
e DCDT2980S/DCDS4501A PK including serum PK samples for total DCDT2980S and 
DCDS4501A antibody and plasma PK samples for antibody-conjugated MMAE and free MMAE. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
161/P GO27834-A3 
Appendix B-2 
Serum and Plasma Pharmacokinetic Schedule for Rituximab and 
DCDT2980S/DCDS4501A, and ATA Schedule for 
DCDT2980S/DCDS4501A for Patients Receiving Rituximab and 
DCDT29808S/DCDS4501A on Day 1 of Every Cycle Beginning 
Cycle 3 (Arms A-B, Cohorts C-D) 
Study Visit 
Sample Timepoint(s) a 
Samples b 
For Cycle 1 and Cycle 2 PK assessments, refer to Appendix B-1 
Pre-rituximab infusion 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK e 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Cycle 3, Day 1 
 
30 minutes (± 15 minutes) 
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK  
Cycle 3, Day 8 (± 1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK  
Cycle 3, Day 15 (±1 day) 
• 
Rituximab  
• 
DCDT2980S/DCDS4501A PK 
Pre-rituximab infusion 
• 
Rituximab PK 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody c 
• 
DCDT2980S/DCDS4501A PK 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Cycles 4, and 
every 4th cycle 
thereafter), Day 1 
30 minutes (± 15 minutes) 
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK 
Treatment 
Completion/ 
Early Termination 
Visit 
Approximately 15−30 days 
after last infusion  
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
Post-treatment 
Follow-Up Visits d 
2, 4, and 6 months after 
treatment completion visit 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 


Appendix B-2 (cont.) 
Serum and Plasma Pharmacokinetic Schedule for Rituximab and 
DCDT2980S/DCDS4501A, and ATA Schedule for 
DCDT2980S/DCDS4501A for Patients Receiving Rituximab and 
DCDT29808S/DCDS4501A on Day 1 of Every Cycle Beginning 
Cycle 3 (Arms A-B, Cohorts C-D) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
162/P GO27834-A3 
ATA = Anti-therapeutic antibody; MMAE = monomethyl auristatin E; PK = pharmacokinetic. 
Note:  “Pre-infusion” means prior to the start of infusion; “Post-infusion” means after the infusion is 
completed. 
a A 3-mL whole-blood sample will be taken for each of the following at each specified timepoint: 
anti-DCDT2980S or anti-DCDS4501A antibody, rituximab PK, and/or DCDT2980S/DCDS4501A 
PK.  If rituximab dosing is split over two days, then PK will be obtained prior to the rituximab 
dose on the first day and 30 minutes (± 15 minutes) post-rituximab infusion on the second day. 
b PK sampling will not be obtained from patients who cross-over to another treatment arm. 
c Cycles 4 only for anti-DCDT2980S or anti-DCDS4501A antibody.  
d Post-treatment follow-up PK and ATA assessments only apply to patients who did not receive 
crossover treatment. 
e DCDT2980S/DCDS4501A PK including serum PK samples for total DCDT2980S and 
DCDS4501A antibody and plasma PK samples for antibody-conjugated MMAE and free MMAE. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
163/P GO27834-A3 
Appendix B-3 
Serum and Plasma Pharmacokinetic, Blood Pharmacodynamic, and 
ATA Schedule for Obinutuzumab and DCDS4501A 
(Cohorts E, G-H) 
Study Visit 
Sample Timepoint(s) a 
Samples a 
Cycle 1, Day 1 
Pre-obinutuzumab infusion 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
PD Blood c 
 
End of obinutuzumab infusion 
• 
Obinutuzumab PK (serum) 
• 
PD Blood c 
Pre-DCDS4501A infusion 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
Cycle 1, Day 2 
End of DCDS4501A infusion 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
Cycle 1, Day 8 
6 days (± 1 day) after Day 2 
infusion 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
Cycle 1, Day 15 
13 days (± 1 day) after Day 2 
infusion 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
Cycle 2, Day 1 
Pre-obinutuzumab infusion 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
PD Blood c 
 
End of obinutuzumab infusion 
• 
PD Bloodc 
 
Pre-DCDS4501A infusion 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
 
End of DCDS4501A infusion 
• 
PD Blood 
Pre-obinutuzumab infusion 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
Cycle 4, Day 1 
End of obinutuzumab infusion 
• 
Obinutuzumab PK (serum) 
 
Pre-DCDS4501A infusion 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 
 
End of DCDS4501A infusion 
• 
DCDS4501A PK (serum and plasma)b 
Cycle 4  Day 15 
Aligned with PET imaging 
• 
PD Blood c 
Treatment Completion/ 
Early Termination Visit 
Approximately 15−30 days 
after last infusion  
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 
End of Treatment 
Assessment Visit 
6−8 weeks after last study 
dose 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 


Appendix B-3 (cont.) 
Serum and Plasma Pharmacokinetic and ATA Schedule for 
Obinutuzumab and DCDS4501A (Cohorts E, G-H) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
164/P GO27834-A3 
Post-treatment 
Follow-Up Visits  
3 and 6 months after treatment 
completion visit 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
 
9 months after treatment 
completion visit 
• 
PD Blood c 
 
12 and 18 months after 
treatment completion visit 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
PD Blood c 
 
24 months after treatment 
completion visit 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
PD Blood c 
ATA = Anti-therapeutic antibody; MMAE = monomethyl auristatin E; PK = pharmacokinetic. 
Note:  “Pre-infusion” means prior to the start of infusion; “End-of-infusion” samples should be drawn 30 
minutes (± 15 minutes) unless otherwise specified. 
a Up to 10-mL whole-blood samples will be taken for obinutuzumab PK, obinutuzumab ATA, obinutuzumab 
concentration, DCDS4501A PK (DCDS4501A total antibody, unconjugated MMAE and conjugate 
[evaluated as antibody-conjugated MMAE]), DCDS4501A ATA, DCDS4501A concentration, and for 
exploratory studies at each specified point with separate tubes for plasma or serum samples.  If 
obinutuzumab dosing is split over two days, then PK will be obtained prior to the obinutuzumab dose on 
the first day and 30 minutes (± 15 minutes) post-obinutuzumab infusion on the second day. 
b DCDS4501A PK including serum PK samples for total DCDS4501A antibody and plasma PK samples for 
antibody-conjugated MMAE and free MMAE. 
c Up to 10-mL whole-blood samples will be taken for exploratory studies at each specified timepoint with 
separate tubes. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
165/P GO27834-A3 
Appendix C-1  
Modified Response and Progression Criteria for NHL 
Adapted from:  Cheson BD, Pfistner B, Juweid ME, et al. Revised Response Criteria for 
Malignant Lymphoma. J Clin Oncol 2007;25:579–86. 
Selection of Indicator (Target) Lesions 
Up to six of the largest dominant nodes or tumor masses selected according to all of the 
following: 
• 
Clearly measurable in at least two perpendicular dimensions 
Abnormal lymph nodes are those that are either 
> 15 mm in the greatest transverse diameter (GTD) regardless of the short axis 
diameter, or 
> 10 mm in short axis diameter regardless of long axis 
• 
If possible, they should be from disparate regions of the body. 
• 
Should include mediastinal and retroperitoneal areas of disease whenever these sites 
are involved 
• 
Extranodal lesions within the liver or spleen must be at least 1.0 cm in 
two perpendicular dimensions. 
 
PET Scans--Definition of a Positive PET scan 
Visual assessment currently is considered adequate for determining whether a PET scan is 
positive, and use of the standardized uptake value is not necessary.  In brief, a positive scan 
is defined as focal or diffuse FDG uptake above background in a location incompatible with 
normal anatomy or physiology, without a specific standardized uptake value cutoff.  Other 
causes of false-positive scans should be ruled out.  Exceptions include mild and diffusely 
increased FDG uptake at the site of moderate or large-sized masses with an intensity that is 
lower than or equal to the mediastinal blood pool, hepatic or splenic nodules 1.5 cm with 
FDG uptake lower than the surrounding liver/spleen uptake, and diffusely increased bone 
marrow uptake within weeks after treatment. 
Complete Remission (CR) 
1. Complete disappearance of all detectable clinical evidence of disease 
and disease-related symptoms if present prior to therapy.  
Typically FDG-avid lymphoma: in patients with no pre-treatment PET scan or when 
the PET scan was positive before therapy, a post-treatment residual mass of any 
size is permitted as long as it is PET negative. 
Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, the designation 


Appendix C-1 (cont.) 
Modified Response and Progression Criteria for NHL 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
166/P GO27834-A3 
of CR requires all nodal indicator lesions to regress to the size of normal lymph 
nodes.  Lymph nodes that were > 15 mm in GTD regardless of the short axis 
diameter at the screening tumor assessment must regress to ≤ 15 mm in GTD 
regardless of the short axis diameter.  Lymph nodes that were 11 to 15 mm in GTD 
and > 10 mm in the short axis diameter at the screening tumor assessment must 
regress to ≤ 10 mm in the short axis diameter. 
2. The spleen and/or liver, if considered enlarged prior to therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies, and nodules related to lymphoma should 
disappear.  However, determination of splenic involvement is not always reliable 
because a spleen considered normal in size may still contain lymphoma, whereas an 
enlarged spleen may reflect variations in anatomy, blood volume, the use of 
hematopoietic growth factors, or causes other than lymphoma. 
3. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have 
cleared on repeat bone marrow biopsy.  The biopsy sample on which this determination 
is made must be adequate (> 20 mm unilateral core).  If the sample is indeterminate by 
morphology, it should be negative by immunohistochemistry.  A sample that is negative 
by immunohistochemistry but demonstrating a small population of clonal lymphocytes by 
flow cytometry will be considered a CR until data become available demonstrating a 
clear difference in patient outcome.  
Partial Remission (PR) 
1. ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest 
dominant nodes or nodal masses.  These nodes or masses should be selected 
according to the following: (a) they should be clearly measurable in at least 2 
perpendicular dimensions; (b) if possible they should be from disparate regions of the 
body; (c) they should include mediastinal and retroperitoneal areas of disease whenever 
these sites are involved. 
2. No increase in the size of the other nodes, liver, or spleen. 
3. Splenic and hepatic nodules must regress by ≥ 50% in their SPD or, for single nodules, 
in the greatest transverse diameter. 
4. With the exception of splenic and hepatic nodules, involvement of other organs is usually 
assessable and no measurable disease should be present. 
5. Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive prior to treatment.  However, if positive, the cell type should be specified 
(e.g., large-cell lymphoma or small neoplastic B cells).  Patients who achieve a complete 
remission by the above criteria, but who have persistent morphologic bone marrow 
involvement will be considered partial responders. 
6. No new sites of disease should be observed (e.g., nodes > 1.5 cm in any axis). 
7. Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the 


Appendix C-1 (cont.) 
Modified Response and Progression Criteria for NHL 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
167/P GO27834-A3 
PET scan was positive before therapy, the post-treatment PET should be positive in at 
least one previously involved site. 
8. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, CT criteria should be used. 
2. 
In patients with follicular lymphoma, a PET scan is only indicated with one or at most 
two residual masses that have regressed by more than 50% on CT; those with more 
than two residual lesions are unlikely to be PET negative and should be considered 
partial responders. 
Stable Disease (SD) 
1. Failing to attain the criteria needed for a CR or PR, but not fulfilling those for progressive 
disease (see below). 
2. Typically FDG-avid lymphomas: the PET should be positive at prior sites of disease with 
no new areas of involvement on the post- treatment CT or PET. 
3. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment 
PET scan or if the pretreatment PET was negative, there must be no change in the size 
of the previous lesions on the post-treatment CT scan. 
Relapsed Disease (RD; after CR) or Progressive Disease (PD; for Patients 
with PR or SD) 
1. Lymph nodes should be considered abnormal if the long axis is > 1.5 cm, regardless of 
the short axis.  If a lymph node has a long axis of 1.1−1.5 cm, it should only be 
considered abnormal if its short axis is > 1.0.  Lymph nodes ≤ 1.0 cm by ≤ 1.0 cm will not 
be considered as abnormal for relapse or progressive disease. 
2. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size.  Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive disease 
after confirmation with other modalities. 
3. At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a 
single involved node, or the size of other lesions (e.g., splenic or hepatic nodules).  
To be considered progressive disease, a lymph node with a diameter of the short axis of 
less than 1.0 cm must increase by ≥ 50% and to a size of 1.5 × 1.5 cm or more than 
1.5 cm in the long axis. 
4. At least a 50% increase in the longest diameter of any single previously identified node 
more than 1 cm in its short axis. 
5. Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected with 
current PET systems (< 15 mm in its long axis by CT). 


Appendix C-1 (cont.) 
Modified Response and Progression Criteria for NHL 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
168/P GO27834-A3 
6. Measurable extranodal disease should be assessed in a manner similar to that 
for nodal disease.  For these recommendations, the spleen is considered nodal disease. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
169/P GO27834-A3 
Appendix C-2 
Revised Criteria for Response Assessment: The Lugano Classification (Cohort E, G-H) 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin 
and Non-Hodgkin lymphoma:  The Lugano Classification. J Clin Oncol. 2014 Aug [cited 2014 Aug 29]. Available from: 
http://jco.ascopubs.org/content/early/2014/08/11/JCO.2013.54.8800.long. 
Selection of measured dominant (indicator) lesions: 
• 
Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two 
diameters 
A measurable node must have an LDi greater than 1.5 cm. 
A measurable extranodal lesion should have an LDi greater than 1.0 cm. 
• 
Nodes should preferably be from disparate regions of the body and should include, where applicable, mediastinal and 
retroperitoneal areas.  
• 
Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, and lungs), GI involvement, cutaneous lesions, or 
those noted on palpation.  
• 
If possible, they should be from disparate regions of the body. 
• 
Should include mediastinal and retroperitoneal areas of disease whenever these sites are involved 
 
Selection of non-measured (non-indicator) lesions: 
• 
Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured.   
These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not 
meet the requirements for measurability but are still considered abnormal, as well as truly assessable disease, which is any 
site of suspected disease that would be difficult to follow quantitatively with measurement, including pleural effusions, 
ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed 
by imaging.  


Appendix C-2 (cont.) 
Revised Criteria for Response Assessment: The Lugano Classification (Cohort E, G-H) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
170/P GO27834-A3 
In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, and bone marrow), FDG uptake may be greater than in the 
mediastinum with complete metabolic response, but should be no higher than surrounding normal physiologic uptake (e.g., 
with marrow activation as a result of chemotherapy or myeloid growth factors). 
 
Response 
Site 
PET-CT−based Response 
CT-based Response 
 
Complete metabolic response 
Complete radiologic response (all of the following) 
Lymph nodes and 
extralymphatic sites 
Score 1, 2, or 3* with or without a residual mass on 5PS** 
It is recognizes that in Waldeyer’s ring or extranodal sites with 
high physiologic uptake or with activation within spleen or 
marrow (e.g., with chemotherapy or myeloid colony-stimulating 
factors), uptake may be greater than normal mediastinum 
and/or liver.  In this circumstance, complete metabolic 
response may be inferred if uptake at sites of initial 
involvement is no greater than surrounding normal tissue even 
if the tissue has high physiologic uptake 
Target nodes/nodal masses must regress to ≤ 1.5 cm in 
LDi 
No extralymphatic sites of disease 
Nonmeasured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Complete 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology;  if indeterminate, IHC negative 
 
Partial metabolic response 
Partial remission (all of the following) 
Lymph nodes and 
extralymphatic sites 
Score of 4 or 5** with reduced uptake compared with baseline 
and residual mass(es) of any size 
At interim, these findings suggest responding disease 
At end of treatment, these findings indicate residual disease 
≥ 50% decrease in SPD of up to 6 target measureable 
nodes and extranodal sites 
When a lesion is too small to measure on CT, assign 5 
mm × 5 mm as the default value 
When no longer visible, 0 × 0 mm 
For a node > 5 mm × 5 mm, but smaller than normal, 
use actual measurement for calculation 
Nonmeasured 
lesions 
Not applicable 
Absent/normal, regressed, but no increase 
Partial 
Organ enlargement 
Not applicable 
Spleen must have regressed by > 50% in length beyond 


Appendix C-2 (cont.) 
Revised Criteria for Response Assessment: The Lugano Classification (Cohort E, G-H) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
171/P GO27834-A3 
Response 
Site 
PET-CT−based Response 
CT-based Response 
normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake compatible 
with reactive changes from chemotherapy allowed).  If there 
are persistent focal changes in the marrow in the context of a 
nodal response, consideration should be given to further 
evaluation with MRI or biopsy or an interval scan 
Not applicable 
 
No metabolic response 
Stable disease 
Target nodes/nodal 
masses, extranodal 
lesions 
Score 4 or 5** with no significant change in FDG uptake from 
baseline at interim or end of treatment 
< 50% decrease from baseline in SPD for up to 6 
dominant, measurable nodes and extranodal sites;  no 
criteria for progressive disease are met 
Nonmeasured 
lesions 
Not applicable 
No increase consistent with progression 
Organ enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
No response or 
stable disease 
Bone marrow 
No change from baseline 
Not applicable 
 
Progressive metabolic disease 
Progressive disease (requires at least 1 of the 
following) 
Individual target 
nodes/nodal lesions 
Score 4 or 5** with an increase in intensity of uptake from 
baseline and/or 
Extranodal lesions 
New FDG-avid foci consistent with lymphoma at interim or end-
of-treatment assessment 
PPD progression: 
An individual node/lesion must be abnormal with:  
• 
LDi > 1.5 cm AND  
• 
Increase by ≥ 50% from PPD nadir AND  
An increase in LDi or SDi from nadir 
• 
0.5 cm for lesions ≤ 2 cm 
• 
1.0 cm for lesions > 2 cms 
Progressive 
disease  
Nonmeasured 
lesions 
None 
New or clear progression of preexisting  


Appendix C-2 (cont.) 
Revised Criteria for Response Assessment: The Lugano Classification (Cohort E, G-H) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
172/P GO27834-A3 
Response 
Site 
PET-CT−based Response 
CT-based Response 
Organ enlargement 
 
In the setting of splenomegaly, the splenic length must 
increase by > 50% of the extent of its prior increase 
beyond baseline (e.g., 15-cm spleen must increase to 
> 16 cm).  If no prior splenomegaly, must increase by at 
least 2 cm from baseline. 
New or recurrent splenomegaly 
New lesions 
New FDG-avid foci consistent with lymphoma rather than 
another etiology (e.g., infection, inflammation).  If uncertain 
regarding etiology of new lesions, biopsy or interval scan may 
be considered 
Regrowth of previously resolved lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in any axis;  if < 1.0 cm 
in any axis, its presence must be unequivocal and must 
be attributable to lymphoma 
Assessable disease of any size unequivocally 
attributable to lymphoma 
Bone marrow 
New or recurrent FDG-acid foci 
New or recurrent involvement 
5-PS = 5-point scale; CT = computed tomography; FDG = fluorodeoxyglucose; IHC = immunohistochemistry; LDi = longest transverse diameter of a lesion; 
MRI = magnetic resonance imaging; PET = positron emission tomography; PPD = cross product of the LDi and perpendicular diameter; SDi = shortest axis 
perpendicular to the LDi; SPD = sum of the product of the perpendicular diameters for multiple lesions. 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan.   However, in trials involving PET 
where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment). 
**PET 5PS:  1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake < mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly higher 
than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
173/P GO27834-A3 
Appendix D  
Anaphylaxis Management 
The following equipment is needed in the event of a suspected anaphylactic reaction 
during study drug infusion: 
• 
Appropriate monitors (electrocardiogram, blood pressure, pulse oximetry 
• 
Oxygen 
• 
Epinephrine for intravenous, intramuscular, and/or endotracheal administration 
in accordance with institutional guidelines.   
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
 
The following are the procedures to follow in the event of a suspected anaphylactic 
reaction during study drug infusion: 
• 
Stop the study drug infusion. 
• 
Call for additional assistance! 
• 
Maintain an adequate airway. 
• 
Provide oxygen as needed. 
• 
Ensure that appropriate monitoring is in place, with continuous electrocardiogram and 
pulse oximetry monitoring, if possible. 
• 
Administer antihistamines, epinephrine, inhaled bronchodilators, or other medications 
as required by patient status and directed by the physician in charge. 
• 
Continue to observe the patient and document observations. 
 






 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
176/P GO27834-A3 
Appendix F  
Recommendations for the Use of White Blood Cell Growth 
Factors 
Primary Prophylactic G-CSF Administration (First and Subsequent-Cycle Use) 
Primary prophylaxis with G-CSF is recommended if any of the following clinical factors 
are present: 
• 
Age >65 years 
• 
Poor performance status 
• 
Previous history of febrile neutropenia 
• 
Open wounds or active infections 
• 
More advanced cancer 
• 
Extensive prior treatment, including large radiation therapy ports 
• 
Cytopenias due to bone marrow involvement by tumor 
• 
Other serious comorbidities 
 
Secondary Prophylactic G-CSF Administration 
Prophylactic G-CSF administration is recommended for patients who fulfill each of the 
following circumstances: 
• 
Experienced a neutropenic complication from a prior cycle of study treatment 
• 
Primary prophylactic G-CSF was not received; and 
• 
The intent is to avoid dose reduction of the antibody−drug conjugate (ADC), where 
the effect of the reduced dose on disease-free, overall survival or treatment 
outcome is not known 
 
Therapeutic Use of G-CSF 
G-CSF administration should be considered for the following patients: 
• 
Patients with febrile neutropenia who are at high risk for infection-associated 
complications; or 
• 
Patients who have prognostic factors that are predictive of poor clinical outcome, 
e.g., prolonged (>10 days) and profound (<100/μL) neutropenia, age >65 years, 
uncontrolled primary disease, pneumonia, hypotension and multi-organ dysfunction 
(sepsis), invasive fungal infection, being hospitalized at the time of fever 
development 
 
Source:  Smith TJ et al. 2006 Update of Recommendations for the use of White Blood Cell 
Growth Factors: An Evidence-Based Clinical Practice Guideline. JCO 24:3187-3205. 2006. 


 
Title
06-Nov-2014 16:11:09
Date and Time (UTC)
Clinical Science Leader
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
This is a Genentech, Inc., document that contains confidential information.   
It is intended solely for the recipient clinical investigator(s) and must not be disclosed to any other 
party.  This material may be used only for evaluating or conducting clinical investigations; any 
other proposed use requires written consent from Genentech, Inc. 
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
P GO27834-A2 
PROTOCOL
TITLE: 
A RANDOMIZED, OPEN-LABEL, MULTICENTER, 
PHASE II TRIAL EVALUATING THE SAFETY 
AND ACTIVITY OF PINATUZUMAB VEDOTIN 
(DCDT2980S) IN COMBINATION WITH 
RITUXIMAB OR POLATUZUMAB VEDOTIN 
(DCDS4501A) IN COMBINATION WITH 
RITUXIMAB AND A NON-RANDOMIZED 
PHASE Ib/II EVALUATION OF POLATUZUMAB 
VEDOTIN IN COMBINATION WITH 
OBINUTUZUMAB IN PATIENTS WITH 
RELAPSED OR REFRACTORY B-CELL 
NON-HODGKIN’S LYMPHOMA 
PROTOCOL NUMBER: 
GO27834 
EUDRACT NUMBER: 
2011-004377-84 
STUDY DRUG: 
Pinatuzumab Vedotin (DCDT2980S);  
Polatuzumab Vedotin (DCDS4501A) 
IND: 
107713 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc.  
1 DNA Way 
South San Francisco, CA  94080-4990 U.S.A. 
DATE FINAL: 
27 July 2012 
DATE AMENDED: 
Version A1:  
24 June 2013 
Version A2:  
See electronic date stamp below. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
2/P GO27834-A2  Summ 
PROTOCOL AMENDMENT, VERSION A2: 
RATIONALE 
Protocol GO27834 has been amended to enable the following changes: 
• 
Obinutuzumab, a novel type II and glycoengineered anti-CD20 antibody, is currently 
being compared with rituximab in two large Phase III studies in patients with diffuse 
large B-cell lymphoma (DLBCL) and indolent non-Hodgkin’s lymphoma (iNHL), 
potentially altering the standard of care in NHL.  A Phase Ib/II portion of the study 
will be added using obinutuzumab in combination with polatuzumab vedotin 
(DCDS4501A).  Initially, a safety run-in of 6 patients with either relapsed or 
refractory follicular NHL or DLBCL will be treated with DCDS4501A at 1.8 mg/kg in 
combination with obinutuzumab (denoted as Cohort E).  Only patients in the 
United States will participate in this portion of the study. If this cohort safely clears, 
the expansion portion of the study will further evaluate the safety, tolerability, and 
clinical activity of DCDS4501A at 1.8 mg/kg in combination with obinutuzumab in 
patients with relapsed or refractory follicular NHL or DLBCL.  The expansion cohorts 
will contain 40 patients for each histology, follicular NHL or DLBCL (denoted 
Cohorts G and H).  Only investigator sites in the United States and Canada will 
participate in this portion of the study. 
• 
For obinutuzumab-containing cohorts (Cohorts E, G, and H), PET/CT scans will be 
required for both follicular NHL and DLBCL at screening, interim response 
assessment (between Cycle 4 Day 15 and Cycle 5 Day 1), and end of treatment 
(EOT) assessment.  In the post-treatment follow-up period, patients will be followed 
for response for up to 2 years after the last infusion of study treatment. 
• 
The response criteria for NHL have been updated in Appendix C-2. 
• 
DCDT2980S is also known as pinatuzumab vedotin and will be referred to as 
DCDT2980S throughout this protocol. 
• 
DCDS4501A is also known as polatuzumab vedotin and will be referred to as 
DCDS4501A throughout this protocol. 
• 
Arms A and B are no longer open and no longer enrolling patients. 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
3/P GO27834-A2  Summ 
PROTOCOL AMENDMENT, VERSION A2: 
SUMMARY OF CHANGES 
 
GLOBAL CHANGES 
The title of the protocol has been changed. 
DCDT2980S is also known as pinatuzumab vedotin and will be referred to as 
DCDT2980S throughout this protocol. 
DCDS4501A is also known as polatuzumab vedotin and will be referred to as 
DCDS4501A throughout this protocol. 
The Medical Monitor has been changed to 
, M.D. 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.2.4:  Obinutuzumab 
SECTION 1.2.4.1 
Obinutuzumab Mechanism of Action 
Obinutuzumab ([G], also known as RO5072759, GA101, Gazyva™, and Gazyvaro™) is 
a humanized type II and glycoengineered anti-CD20 MAb, derived by humanization of 
the parental B-Ly1 mouse antibody and subsequent glycoengineering leading to the 
following characteristics (Mössner et al. 2010; Golay et al. 2013): 
• 
High-affinity binding to CD20 antigen on B cells 
• 
Type II binding mode to the CD20 antigen, leading to a more even distribution of 
bound antibody to the surface membrane of the B cell due to lack of CD20 
translocation into lipid rafts after antibody binding and low complement activation 
and low complement-dependent cytotoxicity related to the recognition of the CD20 
epitope  
• 
Compared with the type I anti-CD20 antibodies rituximab or ofatumumab, 
increased ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) 
related to an improved binding of obinutuzumab to the different allotypes of 
FcγRIIIa and FcγRIIIb  expressed by natural killer (NK) cells , 
monocytes/macrophages and neutrophils 
• 
Compared with rituximab, increased direct cell-death induction related to an elbow 
hinge amino exchange of the Fab region and type II binding of the CD20 epitope 
 
Obinutuzumab received FDA approval in November 2013 and EMA approval in 
July 2014 on the basis of the CLL-11 Study BO21004 for patients with relapsed 
Chronic Lymphocytic Leukemia.  Obinutuzumab plus chlorambucil showed superiority 
over rituximab plus chlorambucil in all efficacy parameters such as overall response 
rate (ORR), complete remission rate (CRR), minimal residual disease (MRD), 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
4/P GO27834-A2  Summ 
progression-free survival (PFS), event-free survival (EFS), and duration of response 
(DOR) (Goede et al. 2014). 
Obinutuzumab is currently being explored in the treatment of lymphoid malignancies 
such as aggressive and indolent lymphomas (DLBCL, FL, and marginal zone lymphoma 
[MZL]).  Preliminary data suggest possible increased anti-lymphoma efficacy over 
rituximab, a hypothesis that is currently being explored in several randomized trials, 
including a Phase III study of R-CHOP versus G-CHOP in first-line treatment of 
DLBCL, a Phase III study of R-chemotherapy (CHOP, CVP, or bendamustine) followed 
by rituximab maintenance compared with G-chemotherapy (CHOP, CVP, or 
bendamustine) followed by obinutuzumab maintenance in first-line treatment of FL and 
MZL, and a Phase III study of obinutuzumab combined with bendamustine compared 
with bendamustine in patients with rituximab-refractory indolent NHL. 
SECTION 1.2.4.2 
Obinutuzumab Nonclinical Toxicology 
The nonclinical toxicology of obinutuzumab has been evaluated in repeat-dose studies 
in cynomolgus monkeys given weekly IV (30-minute infusion) up to 26 weeks in 
duration and weekly SC injections for 4 weeks in duration.  The high dose of 50 mg/kg 
in the 26-week study resulted in a steady-state area under the concentration-time curve 
from 0 to 24 hours (AUC0−24) exposure of 341,000 μg•hr/mL, which is approximately 
61-fold above that of the clinical exposure of 5584 μg•hr/mL. 
Consistent with expected pharmacologic activity, obinutuzumab caused marked 
decreases in B cells, with corresponding lymphoid depletion in spleen and lymph nodes.  
Circulating CD40-positive mature B cells began to reverse after several months without 
treatment and maximally reversed to 7%−152% of baseline by 37 weeks.  In addition, 
transient decreases in NK cells were observed; this finding is consistent with the 
pharmacologic effect of FcγRIIIa binding.  Suspected opportunistic infections in as 
many as three unscheduled deaths were considered a possible secondary result of B-cell 
depletion. 
Obinutuzumab was immunogenic in the cynomolgus monkey, which led to reduced 
systemic exposures in several animals and abrogation of the pharmacologic activity.  
Hypersensitivity reactions were noted that included systemic inflammation and 
infiltrates consistent with immune complex−mediated hypersensitivity reactions such 
as arteritis/periarteritis, glomerulonephritis, and serosal/adventitial inflammation and 
led to unscheduled termination in six animals. 
Both the clinical IV formulation and the SC formulation of obinutuzumab were locally 
well tolerated across studies.  No effects were present in male and female reproductive 
parameters included in the 26-week IV dose study.  No obinutuzumab-related effects 
were observed on CNS, respiratory, or cardiovascular function. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
5/P GO27834-A2  Summ 
In vitro assays using undiluted human whole blood measured significant increases in 
cytokine secretion caused by obinutuzumab, indicating that obinutuzumab has an 
increased propensity to trigger first infusion−related cytokine release in patients. 
See the Obinutuzumab Investigator’s Brochure for details on the nonclinical studies. 
SECTION 1.2.4.3 
Obinutuzumab Nonclinical Efficacy 
Obinutuzumab has in vivo efficacy superior to rituximab in various human lymphoma 
xenograft models.  Both antibodies were tested in human SUDHL-4 cells (DLBCL 
model) injected subcutaneously in severe combined immunodeficient (SCID) beige mice.  
Rituximab administration was started when tumors were established and rapidly 
growing.  Results showed that rituximab at 10 mg/kg inhibited tumor growth compared 
with rituximab at 1 mg/kg; however, increasing the rituximab dose to 30 mg/kg did not 
result in increased efficacy and rituximab was not able to achieve complete tumor 
regression.  In contrast, obinutuzumab showed a dose-dependent increase in efficacy in 
the range of 1−30 mg/kg.  Results showed complete tumor regression in all animals and 
lasting tumor eradication in 9 of 10 animals at the highest dose of 30 mg/kg and in 
1 of 10 animals at a dose of 10 mg/kg. 
In another experiment, SUDHL4 xenografts in SCID mice were first treated with 
weekly rituximab 30 mg/kg.  When the tumors became refractory to rituximab 
(Day 35), rituximab treatment was continued or changed to either weekly vehicle 
control or obinutuzumab 30 mg/kg.  While tumors in control- and rituximab-treated 
mice continued to grow, obinutuzumab-treated mice showed control of tumor growth 
and lived until Day 61 when control or rituximab-treated mice had already been 
sacrificed.   
Additional studies have also shown similar results, with obinutuzumab treatment 
controlling tumor growth, whereas vehicle- and rituximab-treated tumors were not 
controlled (Mössner et al. 2010). 
See the Obinutuzumab Investigator’s Brochure for details on the nonclinical studies. 
SECTION 1.2.4.4 
Obinutuzumab Clinical Experience 
As of July 2013, more than 1900 patients with CD20-positive malignant disease have 
been treated with obinutuzumab in clinical trials.  Clinical data for obinutuzumab are 
available from six clinical trials, including three Phase I and Phase II studies of 
obinutuzumab monotherapy, a Phase Ib chemotherapy combination study in NHL 
(Study BO21000), and two Phase III studies (Study BO21004 in CLL and 
Study GAO4753g in NHL). 
Infusion-related reactions (IRRs), mostly Grades 1 and 2, are the most common adverse 
events observed during therapy.  IRRs have been associated predominantly with the 
first infusion, generally occurring early during the infusion, shortly after the infusion, 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
6/P GO27834-A2  Summ 
or, in some cases, up to 24 hours after the completion of the infusion.  In a few patients, 
concurrent signs of laboratory tumor lysis syndrome (TLS) were observed.  The 
incidence and intensity of IRRs decreased strongly with subsequent infusions of 
obinutuzumab.  On the basis of preliminary observations, extensive tumor burden, 
tumor factors, and host factors may be predisposing factors for the occurrence of IRRs.  
The frequency and severity of IRRs is also reduced in lymphomas compared with CLL. 
Other frequently observed adverse events include infections and neutropenia.  
Grade 3−4 thrombocytopenia and neutropenia, including febrile neutropenia, have been 
reported with obinutuzumab, associated predominantly with treatment of CLL rather 
than NHL.  Given its anticipated mode of action, which results in profound B-cell 
depletion, obinutuzumab may be associated with an increased risk of infections during 
and after treatment. 
Data from Study BO20999 (obinutuzumab monotherapy) showed safety and efficacy of 
single-agent obinutuzumab in patients with relapsed indolent and aggressive 
lymphomas.  Responses were seen at both lower (400 mg) and higher (1600/800 mg) 
doses, although responses increased at the higher dose, with 54% of patients with 
indolent lymphoma and 32% of patients with aggressive lymphomas showing PR or CR 
at the end of treatment (EOT) (Morschhauser et al. 2013; Salles et al. 2013).   
Study BO21000 (Phase Ib) evaluated obinutuzumab in combination with chemotherapy:  
obinutuzumab with fludarabine and cyclophosphamide and obinutuzumab with CHOP 
(Radford et al. 2013).  Both chemotherapy combinations were shown to be feasible in 
patients with previously untreated or relapsed or refractory FL, with response rates of 
> 90% for both regimens.  Safety was acceptable, with no new or unexpected adverse 
events observed.  The most common adverse event was neutropenia. 
Data from obinutuzumab in combination with chlorambucil in CLL (Phase III 
Study BO21004) showed increased efficacy of this combination over 
rituximab-chlorambucil, with a hazard ratio of 0.39 for PFS.  IRRs were common 
(65% all grades, 20% Grade 3−4, no fatal IRRs) and neutropenia occurred at increased 
frequency with the combination therapy (33% Grade 3−5), but there was no increase in 
infections or treatment-related deaths (Goede et al. 2014). 
See the Obinutuzumab Investigator’s Brochure for additional details on the clinical 
studies. 
SECTION 1.2.4.5 
Obinutuzumab Pharmacokinetics and Pharmacodynamics 
A two-compartment model comprising a time-varying CL pathway and a linear CL 
pathway provides an adequate description of the pharmacokinetics of obinutuzumab 
following IV administration in Study BO20999 and Study BO21003.  Following the 
infusion of obinutuzumab, the elimination appears to be characterized by a linear CL 
pathway that is dependent on time (i.e., starting at a typical value of 630 mL/day and 


 
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then gradually decreasing to an asymptote of 60 mL/day at steady state).  Tumor 
burden may potentially contribute significantly to the CL of obinutuzumab, especially 
at the beginning of treatment when CD20-positive tumor cells are most abundant.  As 
tumor burden decreases, the CL reaches an asymptote, which is considered to be 
primarily a function of the proteolytic metabolic CL.  Some patients with a high tumor 
burden may appear to clear the drug from the plasma faster than patients with a low 
tumor burden because obinutuzumab binds to the CD20-positive tumor cells and is 
effectively removed from the plasma.  The CL of the drug will vary with time because 
repeated treatments with obinutuzumab will reduce the quantity of CD20-positive 
tumor cells.  The number of times obinutuzumab is administered during the first cycle 
of treatment may be expected to reduce the number of CD20-positive tumor cells, thus 
minimizing the impact of the time-varying CL pathway on obinutuzumab exposure. 
Treatment with obinutuzumab resulted in extensive B-cell depletion, with all patients 
showing a reduction in B-cell counts to absolute zero at some stage of their treatment 
cycle.  Overall, there has been no notable increase in complement levels before and after 
infusion, but transient increases occurring during the administration of obinutuzumab 
have been observed in the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, 
IL-8, IL-10, and interferon (IFN)-γ. 
SECTION 1.3:  RATIONALE FOR DOING THIS STUDY 
The goals of this Phase II study are to continue to assess the safety, tolerability, and 
biologic and clinical activity of the combinations of DCDT2980S and rituximab and 
DCDS4501A and rituximab in two specific NHL patient populations:  patients with 
relapsed or refractory follicular NHL and patients with relapsed or refractory DLBCL.  An 
additional goal of this study is to assess the safety, tolerability, and potential biologic 
and clinical activity of DCDS4501A in combination with obinutuzumab, an anti-CD20 
antibody, in the aforementioned NHL patient populations.  These patients continue to 
have an extremely poor prognosis with no curative options available.  Consequently, 
new therapeutic options are needed.   
DCDT2980S, DCDS4501A and, rituximab, and obinutuzumab each target antigens 
specific to B-cell malignancies including follicular NHL and DLBCL (see Figures 1 
and 2).  
The randomized component of the Phase II study design permits an assessment of the 
clinical benefit provided by each of these molecules in combination with rituximab, which 
has established clinical activity in B-cell malignancies both as monotherapy and in 
combination with chemotherapy.  Data from this study will help inform the feasibility of 
the combination regimens in earlier lines of therapy (e.g., as first-line therapy in newly 
diagnosed patients).   
The non-randomized component of the study will further evaluate the safety and 
tolerability and clinical activity of DCDS4501A in combination with obinutuzumab in 


 
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patients with relapsed or refractory follicular lymphoma or DLBCL and will also 
provide preliminary evidence as to which anti-CD20 agent, rituximab or 
obinutuzumab, in combination with DCDS4501A, provides a better benefit-risk profile 
in the target population being studied.  
Given the relatively poor prognosis of patients with relapsed or refractory hematologic 
malignancies that have failed standard therapies, the nonclinical toxicity profile 
associated with DCDT2980S and DCDS4501A treatment, and the clinical safety profile 
observed to date for both ADCs, the benefit-risk ratio of a clinical study of DCDT2980S 
and DCDS4501A, each combined with rituximab or obinutuzumab, is considered 
acceptable. 
SECTION 1.3.2:  Rationale for Assessing DCDS4501A in Combination 
with Obinutuzumab in Relapsed or Refractory NHL 
The development of next-generation anti-CD20−directed therapy may further enhance 
the efficacy of current standard regimens for NHL.  Obinutuzumab, also known as 
RO5072759, GA101, and Gazyva™/Gazyvaro™, a novel type II and glycoengineered 
anti-CD20 antibody, has shown superiority over rituximab in a Phase III trial in 
first-line CLL (Goede et al. 2014).  Obinutuzumab is currently being compared with 
rituximab in two large Phase III studies in patients with newly diagnosed DLBCL 
(Study BO21005) and with previously untreated iNHL, including FL 
(Study BO21223).  Assuming these studies demonstrate greater clinical benefit with 
obinutuzumab- vs. rituximab-containing regimens, potentially altering the standard of 
care in NHL, it will be important to also assess the safety and efficacy of combining 
DCDS4501A with obinutuzumab-containing regimens. 
The goals of the non-randomized portion of the Phase Ib/II study are to assess the 
safety, tolerability, and potential biologic and clinical activity of DCDS4501A at 
1.8 mg/kg in combination with obinutuzumab in patients with relapsed or refractory 
follicular NHL or DLBCL.  The RP2D, the Phase II dose-expansion portion of the 
study, will further evaluate the safety and tolerability and clinical activity of 
DCDS4501A at 1.8 mg/kg in combination with obinutuzumab in patients with relapsed 
or refractory follicular NHL or DLBCL.  
SECTION 2.1:  PRIMARY OBJECTIVES 
The primary objectives of this study are the following: 
• 
To assess the safety and tolerability of the combination of DCDS4501A and 
obinutuzumab when administered to patients with relapsed or refractory follicular 
NHL or DLBCL 
• 
To assess the anti-tumor activity of the combination of DCDS4501A and 
obinutuzumab in patients with relapsed or refractory follicular NHL and DLBCL 
 


 
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SECTION 2.2.1:  Safety Objectives 
The secondary safety objectives of this study are the following: 
• 
To assess the incidence of antibody formation to DCDT2980S, and DCDS4501A, 
and obinutuzumab as measured by the formation of ATAs 
• 
To compare the safety and tolerability of the combination of DCT2980S and 
rituximab and DCDS4501A and rituximab or obinutuzumab 
 
SECTION 2.2.2:  Activity Objective 
The secondary activity objective of the study is the following: 
• 
To compare the anti-tumor activity of the combination of DCT2980S and rituximab 
and DCDS4501A and rituximab or obinutuzumab 
 
SECTION 2.2.3:  Pharmacokinetic Objectives 
The PK objectives of this study are the following: 
• 
To characterize the pharmacokinetics of DCDS4501A and rituximab or 
obinutuzumab in patients with relapsed or refractory NHL when the two drugs are 
given in combination 
 
SECTION 2.3.1:  Biomarker Objectives 
The objectives of this study related to assessment of biologic markers are the following: 
• 
To make a preliminary assessment of biologic markers that might act as predictors 
of DCDS4501A + rituximab or obinutuzumab combination anti-tumor activity and 
allow assessment of response in different prognostic subgroups of DLBCL and 
follicular NHL 
 
SECTION 2.3.2:  Patient-Reported Outcomes Objective Quality of Life 
Objective 
The objective of this study related to assessment of patient quality of life 
patient-reported outcomes (PRO) is the following: 
• 
To assess patient-reported tolerability to study treatment and the impact of study 
treatment on patient quality of lifefunctioning on the basis of patient reported 
outcomes (PRO) 
 
SECTION 3.1:  DESCRIPTION OF THE STUDY 
This is a Phase Ib/II, multicenter, open-label study.  Up to approximately 252 A total of 
approximately 140 160 patients (approximately 60 80 patients with relapsed or 
refractory follicular NHL and approximately 80 patients with relapsed or refractory 
FL and DLBCL) will be enrolled at approximately 30−40 investigative sites worldwide.  
Additional patients may be enrolled in order to obtain additional safety and/or efficacy 
data.  Arms A and B and Cohort C are no longer enrolling patients. 


 
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For Obinutuzumab Cohorts: 
Only investigational sites in the United States will enroll patients into Cohort E.  
Investigational sites in the United States and Canada will participate in Cohorts G 
and H). 
SECTION 3.1.1:  Rituximab-Containing Regimens with DCDT2980S or 
DCDS4501A 
SECTION 3.1.1.2:  Non-Randomized Portion of the Study with Rituximab 
(Cohorts C and D) 
SECTION 3.1.2:  All Patients on Rituximab-Containing Arms/Cohorts 
All patients on rituximab-containing regimens, regardless of assigned arm/cohort, will 
receive DCDT2980S or DCDS4501A and rituximab administered by IV infusion on a 
21-day cycle. 
Patients will be evaluated for safety and efficacy according to the Schedules 
of Assessments outlined in Appendices A-1, A-2, and  A 3-4.  Initial response 
assessments in this study will be performed every 3 months from the initiation of therapy 
until study treatment completion or early termination (e.g., between Days 14 and 21 of 
Cycles 4 and 8 for those patients receiving at least eight 21-day cycles of treatment).  
Additional response assessments for patients who proceed to crossover treatment (see 
Section 3.1.6) will be performed as described in Appendix A-2; response assessments 
for patients who discontinue study treatment (both initially assigned treatment and 
crossover treatment) for reasons other than disease progression will be performed as 
described in Appendix A 3-4. 
SECTION 3.1.3:  Obinutuzumab-Containing Regimen with DCDS4501A 
(Cohorts E, G, and H) 
DCDS4501A at 1.8 mg/kg will be given in combination with obinutuzumab to patients 
with relapsed or refractory follicular NHL and DLBCL in two stages:  (1) safety run-in 
and (2) expansion. 
Study treatment will be given in 21-day cycles for both follicular NHL and DLBCL.  
Patients will be treated for up to a total of 8 cycles.  For the first cycle, obinutuzumab 
will be administered by IV infusion on Days 1, 8, and 15.  DCDS4501A will be given 
on Day 2 for Cycle 1.  In the absence of any infusion-related adverse events, 
obinutuzumab and DCDS4501A may be administered on the same day (Day 1) in 
subsequent cycles beginning with the second cycle.  If obinutuzumab and DCDS4501A 
are administered on the same day, the study drugs will be given sequentially.  
Obinutuzumab will be administered first, followed by DCDS4501A.  In certain 
circumstances⎯for example, IRRs requiring interruption or slowing of infusion 
rate⎯obinutuzumab may be administered over 2 days (e.g., Day 1 and Day 2 of the 
cycle); in this case, DCDS4501A may be administered on Day 2 following completion of 
the obinutuzumab infusion. 


 
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SECTION 3.1.3.1:  Obinutuzumab-Containing Regimens in Phase Ib:  Safety 
Run-in (Cohort E) 
This portion of the study will consist of a safety run-in that will evaluate the safety of 
DCDS4501A at 1.8 mg/kg in combination with obinutuzumab in 6 patients (Cohort E).  
The safety run-in is described in detail in Section 3.4.  In case an amendment to the 
protocol allows to study higher doses of DCDS4501A, the safety run-in for the 
1.8 mg/kg may be shortened to 3 patients. 
Obinutuzumab-Containing Regimens in Phase II:  Expansion Stage 
(Cohorts G and H) 
After the safety run-in has demonstrated that DCDS4501A at 1.8 mg/kg in 
combination with obinutuzumab is safe to administer, patients will be enrolled into two 
expansion cohorts based on histology of follicular NHL or DLBCL (Cohorts G and H, 
respectively).  Forty patients will be enrolled into each expansion cohort.  An 
additional cohort(s) may be added in the future. 
SECTION 3.1.4:  Follicular NHL Cohort Patients for Rituximab-Containing 
Arms/Cohorts 
SECTION 3.1.5:  Follicular NHL Patients for Obinutuzumab-Containing 
Cohorts 
Patients with relapsed or refractory follicular NHL will be enrolled into the study as 
defined by the following: 
• 
Relapsed to prior regimen(s) after having a documented history of response (CR, 
CRu, or PR) of ≥ 6 months in duration from completion of regimen(s)   
• 
Refractory to any prior regimen, defined as no response to the prior therapy, or 
progression within 6 months of completion of the last dose of therapy 
 
SECTION 3.1.6:  DLBCL Cohort Patients for Rituximab-Containing 
Arms/Cohorts 
Patients with relapsed or refractory DLBCL who are determined by the investigator to be 
ineligible for high-dose therapy with autologous stem cell rescue/stem cell transplant 
(SCT) as determined by the investigator will be enrolled into the study as defined by the 
following: 
SECTION 3.1.7:  DLBCL Patients for Obinutuzumab-Containing Cohorts 
Patients with relapsed or refractory DLBCL who are determined by the investigator to 
be ineligible for high-dose therapy with autologous stem cell rescue/SCT as determined 
by the investigator will be enrolled into the study as defined by the following: 
• 
Second-line SCT-ineligible patients with progressive disease or no response 
(SD) < 12 months from start of initial therapy (second-line refractory) 
• 
Second-line SCT-ineligible patients with disease relapse after initial response 
≥ 12 months from start of initial therapy (second-line relapsed) 
• 
Third-line (or beyond) SCT-ineligible patients with progressive disease or no 
response (SD) < 6 months from start of prior therapy (third-line + refractory) 


 
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• 
Third-line (or beyond) SCT-ineligible patients with disease relapse after initial 
response ≥ 6 months from start of prior therapy (third-line + relapsed) 
 
SECTION 3.1.8:  Crossover Treatment (Randomized Patients in Arms A and 
B Only) 
Patients will be treated with the crossover treatment until a second disease progression 
event relative to the tumor assessment, documenting progressive disease on the initial 
study treatment, clinical deterioration, and/or intolerance to the crossover treatment for 
up to a maximum of 1 year (17 cycles on an every-21-day schedule).  Patients will be 
evaluated for safety and efficacy according to the schedules of assessments outlined in 
Appendices A-2.  Response assessments for patients who discontinue study treatment 
for reasons other than disease progression will be performed as described in 
Appendix A-34. 
Clinical data and exploratory data derived from tumor biopsies obtained prior to 
crossover treatment will be monitored on an ongoing basis.  Genentech has the right to 
restrict or suspend enrollment into crossover treatment at any time.  Reasons for this 
may include, but are not limited to, the following: 
• 
Patients who are enrolled into the non-randomized portion of the study (Cohorts C, 
D, E, G, and H) will not have the option to receive crossover treatment upon 
disease progression (see Section 3.2 for rationale). 
 
SECTION 3.2:  RATIONALE FOR STUDY DESIGN 
The primary rationale for the non-randomized portion of the study (Cohorts C and D) is 
to assess the therapeutic index (i.e., the balance of efficacy and tolerability of 
DCDT2980S and DCDS4501A at a dose of 1.8 mg/kg in patients with relapsed or 
refractory follicular NHL).  An informal comparison between patients with follicular NHL 
treated at the two doses of the ADC will help determine if tolerability is improved at the 
lower ADC dose without substantial compromise of efficacy.   
The primary rationale for the non-randomized Phase Ib/II obinutuzumab-containing 
cohorts (Cohorts E−H) is to assess safety and clinical activity for the combination of 
obinutuzumab and DCDS4501A in patients with relapsed/refractory NHL (Cohorts E, 
G, and H).  Obinutuzumab (also known as RO5072759, GA101 and 
Gazyva™/Gazyvaro™), a novel type II and glycoengineered anti-CD20 antibody, has 
shown superiority over rituximab in a Phase III trial in first-line CLL (Goede et al. 
2014).  Obinutuzumab is currently being compared with rituximab in two large 
Phase III studies in patients with newly diagnosed DLBCL (Study BO21005) and 
previously untreated iNHL, including FL (Study BO21223).  Assuming these studies 
demonstrate greater clinical benefit with obinutuzumab- vs. rituximab-containing 
regimens, potentially altering the standard of care in NHL, it will be important to also 
assess the safety and efficacy of combining DCDS4501A with obinutuzumab-
containing regimens. 


 
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Study drug dosing will occur on Days 1 or and 2 of each 21-day (or 28-day) cycle to 
allow for recovery from potential bone marrow toxicity. 
SECTION 3.2.1:  Rationale for the PK Sample Schedule 
PK data obtained in this study will be important in informing potential future trials with 
this combination.  Given the likely changing effect of peripheral B-cell counts, tumor 
burden, and target antigen expression on target-mediated drug CL over multiple doses 
of DCDT2980S or DCDS4501A plus rituximab or obinutuzumab when the two drugs are 
given in combination, the drug levels of DCDT2980S or DCDS4501A-related analytes 
and rituximab or obinutuzumab will be assessed in this combination study.   
In Studies DCT4862g and DCS4968g, single-agent DCDT2980S and DCDS4501A 
administered by IV infusion every 21 days were evaluated at doses ranging from 0.1 to 
3.2 mg/kg for DCDT2980S and 0.1 mg/kg to 2.4 mg/kg for DCDS4501A in patients with 
NHL.  Intensive PK sampling of all patients in the ongoing Phase I studies will provide 
sufficient data to allow complete profiling of the distribution and elimination phases for 
DCDT2980S and DCDS4501A and the investigation of potential correlations between 
various PK parameters and efficacy and/or toxicity.  Consequently a reduced PK 
sampling scheme of DCDT2980S and DCDS4501A will be used in this Phase II study.  
The PK data collected in this Phase II study will allow further characterization of the 
PK properties of DCDT2980S and DCDS4501A.  In addition, the DCDT2980S and 
DCDS4501A concentration results from this study will be compared with available data 
from the single-agent clinical studies to evaluate whether concurrent administration of 
rituximab affects the exposure of DCDT2980S and/or DCDS4501A.   
Limited sampling of serum concentrations of obinutuzumab will be assessed and 
compared with historical data to evaluate potential PK interactions with DCDS4501A. 
SECTION 3.3.1:  Safety Outcome Measures 
The safety and tolerability of the combination of DCDT2980S and rituximab and 
DCDS4501A and rituximab or obinutuzumab will be assessed using the following safety 
outcome measures: 
• 
Incidence of anti-DCDT2980S or, anti-DCDS4501A, or anti-obinutuzumab 
antibodies 
SECTION 3.3.2:  Pharmacokinetic/Pharmacodynamic Outcome Measures 
The following PK parameters will be derived from the serum concentration-time profiles 
of total antibody (the sum of conjugated and unconjugated antibody), including rituximab 
or obinutuzumab, and plasma concentration-time profiles of acMMAE and free MMAE 
following administration of DCDT2980S or DCDS4501A, when appropriate, as data 
allow: 
The following PD outcome measures will be assessed when appropriate, as data allow: 
• 
Assessment of the kinetics of circulating tumor DNA 


 
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SECTION 3.3.3:  Activity Outcome Measures 
The following activity outcome measures will be assessed: 
• 
Duration of objective response, defined as the duration of time from the first 
occurrence of a documented objective response tountil the time of relapse or death 
from any cause 
• 
PFS, defined as the duration from initial date of randomization to the first 
occurrence of progression or death within 30 days of the last administration of study 
drug, whichever occurs first 
• 
OS, defined as the duration time from the date of randomization/enrollment to the 
date of death from any cause 
 
SECTION 3.3.4:  Exploratory Outcome Measures 
The exploratory outcome measures will include, but will not be limited to, the following:  
• 
Additional assessments related to the understanding of the mechanism of action of 
DCDT2980S, DCDS4501A, and rituximab, and obinutuzumab, e.g., assessment of 
circulating tumor DNA(ctDNA) to monitor response, mechanisms of resistance to 
DCDT2980S, DCDS4501A and, rituximab, and obinutuzumab, and/or NHL 
pathogenesis may be included. 
• 
Quality of lifeTreatment and disease symptom assessments using the M.D. 
Anderson Symptom Inventory (MDASI) 
 
SECTION 3.4:  SAFETY PLAN 
Safety will be evaluated through the monitoring of the following: 
• 
All adverse events from Cycle 1, Day 1 until 30 days after the last dose of 
DCDT2980S, DCDS4501A or, rituximab, or obinutuzumab, whichever is later, 
including doses that were administered as part of crossover treatment 
• 
All serious adverse events from Cycle 1, Day 1 until 30 days after the last dose of 
DCDT2980S, DCDS4501A or, rituximab, or obinutuzumab, whichever is later, 
including doses that were administered as part of crossover treatment 
• 
All serious adverse events from the last dose of DCDT2980S, DCDS4501A or, 
rituximab, or obinutuzumab, whichever is later, including doses that were 
administered as part of crossover treatment, and which are judged to be caused by 
DCDT2980S, DCDS4501A or, rituximab, or obinutuzumab, regardless of time of 
onset 
SECTION 3.4.1:  Safety Run-In Analysis 
As outlined in Figure 3b and Section 3.1.3.1, a safety run-in analysis (Cohort E) will 
be conducted by the Internal Monitoring Committee (IMC) to evaluate the combination 
of DCDS4501A at a dose of 1.8 mg/kg with obinutuzumab.  This analysis will include 
data from the first 6 patients treated through Day 21 of Cycle 1.  Three patients will 
initially be enrolled, and then an additional 3 patients will be enrolled after the first 
3 patients have safely completed the first cycle.  At the IMC’s discretion, and at any 


 
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point during enrollment of the safety run-in, a decision could be made that more than 
6 patients are needed to evaluate safety.  In this case, the protocol will be amended to 
allow for more than 6 patients in the safety run-in.  In case the study is amended to test 
additional doses the safety run-in for 1.8 mg/kg may be shortened to three patients. 
Safety summaries will be assessed at the safety run-in for SAEs; Grade 3-5 treatment-
related AEs; all AEs; all Grade 3-5 AEs;  and AEs leading to treatment discontinuation 
or dose modification/interruption. 
• 
During the 6-patient safety run-in, if any patient experiences a treatment-related 
death, then the obinutuzumab-containing portion of the study will be closed to 
further recruitment. 
• 
During the 6-patient safety run-in: 
If 2 or more of the first 3 patients enrolled experience Grade 4 febrile 
neutropenia or serious (i.e., SAE) documented infection requiring IV antibiotics 
in the presence of Grade 3−4 neutropenia, then the obinutuzumab-containing 
portion of the study will be closed to further recruitment 
If 1 of the first 3 patients enrolled experiences Grade 4 febrile neutropenia or 
serious (i.e., SAE) documented infection requiring IV antibiotics in the presence 
of Grade 3−4 neutropenia, then an additional 3 patients will be recruited.  If 
2 or more of these first 3 patients experience Grade 4 febrile neutropenia or 
serious (i.e., SAE) infection with Grade 3−4 neutropenia, then the 
obinutuzumab-containing portion of the study will be closed to further 
recruitment. 
If 2 or more of the first 6 patients to be enrolled experiences Grade 4 febrile 
neutropenia or serious (i.e., SAE) documented infection requiring IV antibiotics 
in the presence of Grade 3−4 neutropenia, then the obinutuzumab-containing 
portion of the study will be closed to further recruitment. 
Before the expansion portion of the study can begin (enrollment of Cohorts G 
and H), the following criteria must be met: 
Six patients must have competed enrollment in the safety run-in 
(Cohort E). 
Three patients must have completed at least 4 cycles of treatment. 
 
SECTION 3.4.2:  Internal Monitoring Committee 
In addition to the ongoing assessment of the incidence and nature of adverse events, 
serious adverse events, and laboratory abnormalities by the Investigator and the Medical 
Monitor, the IMC will review the aforementioned data at least twice during the study.   
Throughout the course of the study, the IMC will meet, as needed, at the request of the 
Medical Monitor (e.g., on the basis of unexpected safety signals).  The IMC may make 


 
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recommendations regarding study conduct, including, but not limited to, performing 
additional safety analyses, amending the study protocol, holding patient enrollment to 
one or both treatment arms pending further safety evaluations, holding/discontinuing 
study treatment, or terminating the study. 
Complete details of the IMC will be described in the IMC charter. 
For Arms A and B:  The first planned review will occur after approximately 10 patients 
are randomized and have at least 6 weeks follow-up, and the next formal review will 
occur when approximately 60 patients are randomized and have at least 6 weeks 
follow-up.  Additionally, the IMC will meet as needed at the request of the Medical 
Monitor (e.g., on the basis of unexpected safety signals).  The IMC may make 
recommendations regarding study conduct, including, but not limited to, performing 
additional safety analyses, amending the study protocol, holding patient enrollment to 
one or both treatment arms pending further safety evaluations, holding/discontinuing 
study treatment, or terminating the study. 
Complete details of the IMC will be described in the IMC charter. 
SECTION 3.4.3.3:  Bone Marrow Toxicity/Neutropenia 
Adequate hematologic function should be confirmed before initiation of study treatment.  
Patients receiving study treatment will be regularly monitored for evidence of marrow 
toxicity with complete blood counts.  Study treatment may be delayed or modified due to 
Treatment for hematologic toxicities, may be delayed or modified as described in 
Section 4.3.1.  
Febrile neutropenia is commonly associated with myelotoxicity, which is considered a class effect 
of MMAE because it is commonly reported with ADCETRIS®, other similar ADCs, and 
vincristine sulfate. 
Clinical data show that among the most common SAEs reported in both DCS4968g and 
DCT4862g studies were febrile neutropenia and pyrexia. 
SECTION 3.4.3.4:  Immunogenicity 
As expected with any recombinant antibody, DCDT2980S, and DCDS4501A, and 
obinutuzumab may elicit an immune response and patients may develop antibodies 
against DCDT2980S, and DCDS4501A, or obinutuzumab.  Patients will be closely 
monitored for any potential immune response to DCDT2980S, and DCDS4501A, and 
obinutuzumab.  Appropriate screening and confirmatory assays will be employed to 
detect ATAs at multiple timepoints before, during, and after treatment with DCDT2980S, 
or DCDS4501A, and obinutuzumab.  Considering the historically low immunogenicity rate 
of rituximab in NHL patients, ATAs against rituximab will not be monitored in this study. 


 
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SECTION 3.4.3.5:  Peripheral Sensory  Neuropathy 
On the basis of clinical data from the ongoing Phase I Studies DCT4862g and 
DCS4968g and data from brentuximab vedotin studies, an anti-CD30-vc-MMAE ADC 
(see Section 3.4.2), peripheral sensory neuropathy (sensory and motor) has been 
identified as a known risk (adverse drug reaction) for both DCDT2980S and 
DCDS4501A. 
Careful clinical evaluation of patients for neuropathy should be conducted prior to 
initiation of study drug.  Patients should be monitored for signs of peripheral neuropathy 
or worsening neuropathy and appropriate action taken per protocol guidelines.  Study 
treatment dose and schedule modifications for significant and prolonged neuropathic 
toxicity and dose-reduction are described in Section 4.3.1.7.   
SECTION 3.4.3.7:  Hyperglycemia 
Hyperglycemia has been observed in patients treated with DCDT2980S and 
DCDS4501A as well as with other ADCs using the same vc-MMAE platform.  Several 
patients given both DCDT2980S and DCDS4501A had abnormal fasting blood sugar (FBS)  at 
screening with elevations of glucose following steroid administration prior to rituximab dose.  
Hyperglycemia has been reversible upon holding or discontinuing treatment of the ADCs 
and/or initiation or adjustment of anti-hyperglycemic medications.  Emerging data suggest 
that hyperglycemia may occur more commonly in individuals with abnormal FBS values or 
known diabetes.  This is also reported for ADCETRIS® (2013 SmPC and 2013 USPI).  
SECTION 3.4.3.8:  Hepatotoxicity 
Hepatotoxicity is a potential risk of the ADCs.  Definitive attribution of hepatotoxicity to 
the ADCs has not been established.  Transient dose related increases in hepatic 
enzyme levels were observed in rats treated with DCDT2980S and DCDS4501A.  
Elevations in transaminase and/or bilirubin levels requiring dose modifications and 
treatment discontinuations have been reported in the ongoing clinical studies.   
SECTION 3.4.3.9:  Commonly Reported Side Effects 
Other commonly reported side effects of both DCDT2980S or DCDS4501A in the Phase I clinical 
trials and within this study include fatigue, nausea, decreased appetite, vomiting, hair thinning 
or loss, joint pains, loss of appetite, diarrhea, muscle aches, constipation, increases in blood 
glucose, and headaches. 
SECTION 3.4.6:  Risks Associated with Obinutuzumab Therapy 
No evidence available at the time of the approval of this protocol indicates that special 
warnings or precautions are appropriate other than those noted in the Obinutuzumab 
Investigator’s Brochure and as described in the following sections. 
SECTION 3.4.6.1:  Infusion-Related Reactions and Hypersensitivity 
Reactions (including Anaphylaxis) 
The commonly experienced IRRs have been characterized by fever, chills, flushing, 
nausea, vomiting, hypotension, hypertension, fatigue, and other symptoms. 


 
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Respiratory infusion-related symptoms, such as hypoxia, dyspnea, bronchospasm, 
larynx and throat irritation, and laryngeal edema, have also been reported.  These IRRs 
were mostly mild or moderate (NCI CTCAE v3.0, Grade 1 and 2 events), and < 10% of 
the events were severe (Grade 3 events), occurring predominantly during the first hour 
of the infusion or shortly after the first infusion had finished.  The events resolved with 
the slowing or interruption of the infusion and supportive care.  The incidence and 
severity of IRRs decreased with subsequent infusions.  Extensive tumor burden 
predominantly localized in the blood circulation (e.g., high peripheral lymphocyte count 
in patients with CLL) may be a predisposing factor for the development of IRRs. 
IRRs may be clinically indistinguishable from IgE-mediated allergic or anaphylactic 
reactions. 
SECTION 3.4.6.2:  Tumor Lysis Syndrome 
TLS has been reported with obinutuzumab administration.  Patients with a high tumor 
burden, including patients with a lymphocyte count ≥ 25 × 109/L, particularly patients 
with B-cell CLL and MCL, are at increased risk for TLS and severe IRRs.  All patients 
with peripheral blood lymphocyte counts of ≥ 25 × 109/L or bulky adenopathy must 
receive prophylaxis for TLS prior to the initiation of study treatment.  This includes 
appropriate hydration, consisting of fluid intake of approximately 3 L/day, starting 
1−2 days prior to the first dose of obinutuzumab, and administration of allopurinol 
(300 mg/day orally) or a suitable alternative (i.e., rasburicase) treatment, starting at 
least 72 hours prior to the first infusion of obinutuzumab (Cycle 1, Day 1).  All 
patients should then be carefully monitored during the initial weeks of treatment.  
Patients still considered at risk for TLS because of persistently high tumor burden 
(i.e., peripheral blood lymphocyte counts ≥ 25 × 109/L) before the second and subsequent 
infusions of obinutuzumab should receive continuous TLS prophylaxis with allopurinol 
or a suitable alternative (i.e., rasburicase) and adequate hydration until the risk is 
abated, as determined by the investigator.  


 
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SECTION 3.4.6.3:  Neutropenia 
Cases of Grade 3 or 4 neutropenia, including febrile neutropenia, have been reported 
with obinutuzumab administration.  Grade 3 or 4 neutropenia has predominantly been 
observed in patients with CLL.  Patients who experience Grade 3 or 4 neutropenia 
should be monitored until neutrophil values return to at least Grade 2.  Use of G-CSF 
has been found to result in a rapid normalization of neutrophils, similar to what has 
been observed in patients treated with rituximab.  The use of G-CSF is allowed for 
treatment of neutropenia in this study.  Primary prophylaxis with G-CSF is 
recommended according to the American Society of Clinical Oncology (ASCO), 
European Organisation for Research and Treatment of Cancer (EORTC), and European 
Society for Medical Oncology (ESMO) guidelines, namely for patients who are 
≥ 60 years old and/or with co-morbidities (Lyman et al. 2004).   
SECTION 3.4.6.4:  Thrombocytopenia 
Severe and life-threatening thrombocytopenia, including acute thrombocytopenia 
(occurring within 24 hours after the infusion), has been observed during treatment 
with obinutuzumab.  Fatal hemorrhagic events have also been reported in patients 
treated with obinutuzumab.  It seems that the first cycle is the greatest risk of 
hemorrhage in patients treated with obinutuzumab.  A clear relationship between 
thrombocytopenia and hemorrhagic events has not been established.  Patients treated 
with concomitant medication, which could possibly worsen thrombocytopenia-related 
events (e.g., platelet inhibitors and anticoagulants), may be at greater risk of bleeding.  
Patients should be closely monitored for thrombocytopenia, especially during the first 
cycle; regular laboratory tests should be performed until the event resolves, and dose 
delays should be considered in case of severe or life-threatening thrombocytopenia.  
Transfusion of blood products (i.e., platelet transfusion) according to institutional 
practice is at the discretion of the treating physician.  
SECTION 3.4.6.5:  Infection 
On the basis of its anticipated mode of action, resulting in profound B-cell depletion, 
obinutuzumab may be associated with an increased risk of infections.  Infections have 
been reported in patients receiving obinutuzumab.  Therefore, obinutuzumab should not 
be administered to patients with active severe infections. 
A “black-box” warning for obinutuzumab states that reactivation of hepatitis B as well 
as other serious viral infections (e.g., infections caused by cytomegalovirus, Varicella 
zoster virus, herpes simplex virus, JC virus, and HCV) that were new, reactivated, or 
exacerbated have been reported with the B cell−depleting antibody rituximab mainly in 
patients who had received the drug in combination with chemotherapy or as part of a 
hematopoietic SCT.  The risk of such infections with obinutuzumab is unknown.  
Particular attention should be given to patients who have previously received 
significant immunosuppressive treatment, such as high-dose chemotherapy and SCT. 


 
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A “black-box” warning for obinutuzumab states that JC viral infection (including 
fatal) that resulted in PML with destructive infection of oligodendrocytes of the CNS 
white matter) have been reported in patients treated with anti-CD20 therapies, 
including rituximab and obinutuzumab. 
The diagnosis of PML should be considered in any patient presenting with new-onset 
neurologic manifestations.  The symptoms of PML are unspecific and can vary 
depending on the affected region of the brain.  Motor involvement with corticospinal 
tract findings, sensory involvement, cerebellar deficits, and visual field defects are 
common.  Some syndromes regarded as cortical (e.g., aphasia or visual-spatial 
disorientation) can occur. 
Evaluation of PML includes, but is not limited to, consultation with a neurologist, 
brain MRI, and lumbar puncture (cerebrospinal fluid testing for JC viral DNA).  
Therapy with obinutuzumab should be withheld during the investigation of potential 
PML and permanently discontinued in case of confirmed PML.  Discontinuation or 
reduction of any concomitant chemotherapy or immunosuppressive therapy should also 
be considered.  The patient should be referred to a neurologist for the diagnosis and 
management of PML. 
SECTION 3.5:  MINIMIZATION OF BIAS 
For theThis is a randomized, non-comparative, open-label portion of the study,.  
pPatients werewill be randomly allocated to two treatment arms in a 1:1 ratio through use 
of an Interactive Voice and Web Response System (IXRS).  A dynamic stratified 
randomization scheme waswill be employed to ensure balance in the stratification factors 
as specified in Section 3.1.  This portion of the study (Arms A and B) is now closed to 
enrollment. 
SECTION 3.6:  ADMINISTRATIVE STRUCTURE 
Approximately 40 study centers in the United States, Canada, and Europe will 
participate in the study to enroll approximately 252120 patients.  Additional patients may 
be enrolled in order to obtain additional safety and/or efficacy data. 
SECTION 4.1.1:  Inclusion Criteria 
Patients must meet the following criteria to be eligible for study entry: 
• 
For female patients of childbearing potential and male patients with female partners 
of childbearing potential, agreement to use one highly effective form of nonhormonal 
contraception or two effective forms of nonhormonal contraception, including at 
least one method with a failure rate of < 1% per year, through the course of 
study treatment and for ≥ 12 months at least 3 months after the last dose of 
DCDT2980S or, DCDS4501A or, rituximab, or obinutuzumab (whichever is later) in 
women and at least 5 months after the last dose of DCDT2980S or, DCDS4501A 
or, rituximab, or obinutuzumab (whichever is later) in men 


 
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Males must agree to abstain from sperm donation for at least 5 months after the 
last dose of DCDT2980S or, DCDS4501A or, rituximab, or obinutuzumab 
(whichever is later). 
 
SECTION 4.2:  METHOD OF TREATMENT ASSIGNMENT 
As described in Section 3.1.1.2, only select investigator sites that have agreed to 
participate in the non-randomized (Cohorts C and D) portion of the study will enroll 
patients into these cohorts.  Cohorts C and D will be opened sequentially following 
completion of the randomized portion of the study for patients with FL. 
For obinutuzumab-containing cohorts (Cohorts E, G, and H), patients with either 
relapsed or refractory follicular NHL or relapsed or refractory DLBCL will be enrolled.  
After the safety run-in stage for DCDS4501A at 1.8 mg/kg in combination with 
obinutuzumab, the patients will be enrolled into the dose-expansion portion with 
40 patients in each histology group. 
SECTION 4.3.1.3:  Dosage Modification 
Specific guidelines around dosage modifications for neutropenia and peripheral 
neuropathy are detailed below in Sections 4.3.1.6 and 4.3.1.7.  Patients who experience 
other treatment-related Grade 3 or 4 toxicity or laboratory abnormalities will be allowed 
to delay dosing of study treatment (both ADC and rituximab or obinutuzumab) for up to 
2 weeks to allow for recovery.  Patients may continue to receive additional infusions of 
DCDT2980S or DCDS4501A per their treatment assignment provided that the toxicity 
has resolved to Grade ≤ 2 or ≥ 80% of the baseline value, whichever is lower, within the 
2−week delay period.  Upon resolution, the dose for subsequent infusions may be 
reduced to 1.8 mg/kg (in Cohorts C and D).  If the toxicity that resulted in the dose 
reduction persists or recurs at the reduced dose, then the patient should be discontinued 
from study treatment.  The decision for dose modification will be made on the basis of 
the investigator’s assessment of ongoing clinical benefit with continued study treatment 
and in consultation with the Medical Monitor.   
Once dose reductions of DCDT2980S or DCDS4501A are made for toxicity, dose 
re-escalation will not be allowed.  Patients who are enrolled in the non-randomized 
portion of the study (Cohorts C and D), are dosed at an ADC dose of 1.8 mg/kg, and 
have progressive disease in the absence of any drug-related toxicity may have their 
ADC dose increased to 2.4 mg/kg if it is felt that there is reasonable justification for 
ongoing clinical benefit.  The decision to increase the dose must be made in consultation 
with and approval of the Medical Monitor.  Patients in Cohorts E, G, and H 
(obinutuzumab-containing cohorts) will not be eligible for dose escalation. 
If a patient develops unacceptable toxicity to DCDT2980S or DCDS4501A, requiring its 
discontinuation, single-agent rituximab may be continued on the basis of the 
investigator’s assessment of ongoing clinical benefit and with the approval of the Medical 


 
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Monitor.  Patients enrolled in obinutuzumab-containing cohorts will not continue on 
single-agent obinutuzumab unless approved by the Medical Monitor. 
SECTION 4.3.1.4:  Schedule Modification 
Patients in whom toxicities have not resolved to Grade ≤ 2 or ≥ 80% of baseline value, 
whichever is lower, may have their study treatment delayed by up to 2 weeks.  Dosing of 
both DCDT2980S or DCDS4501A and rituximab or obinutuzumab should be held during 
this period.  If all study drug−related toxicities have resolved sufficiently, the patient may 
resume DCDT2980S or DCDS4501A and rituximab or obinutuzumab dosing on the 
regular every-21-day schedule.   
SECTION 4.3.1.6:  Neutropenia 
Because neutropenia is a known risk of DCDT2980S and DCDS4501A (see 
Section 3.4.2.3), the use of growth factor support (G-CSF) as prophylactic and 
therapeutic indications is permitted (see Appendix F) in order to allow continued dosing 
of DCDT2980S/DCDS4501A.  Dose modifications for patients who experience 
treatment-related Grade 3−4 neutropenia in the context of G-CSF usage are as follows: 
• 
Patients who experience treatment-related Grade 3−4 neutropenia will be allowed to 
delay dosing of study treatment (both ADC and rituximab or obinutuzumab) for up 
to two weeks to allow for recovery.  Therapeutic G-CSF is permitted as clinically 
indicated (see Appendix F) and to facilitate neutrophil recovery to allow subsequent 
DCDT2980S/DCDS4501A dosing. 
• 
Subsequent dosing of DCDT2980S/DCDS4501A and rituximab/obinutuzumab is 
permitted provided that the neutropenia has resolved to Grade ≤ 2 or ≥ 80% of the 
baseline value, whichever is lower, within the 2-week period.   
• 
If prophylactic G-CSF was not administered prior to the cycle in which the 
Grade 3−4 neutropenia developed, then prophylactic G-CSF may be administered 
prior to subsequent cycles without DCDT2980S/DCDS4501A dose reduction.  The 
dose schedule may be changed from 21-day to 28-day cycles to provide sufficient 
time for neutrophil recovery in subsequent cycles.  In the absence of prophylactic 
G-CSF or dose schedule modification, the dose of DCDT2980S/DCDS4501A in 
subsequent cycles should be reduced to 1.8 mg/kg.  For Cohorts E, G, and H, 
patients will be given DCDS4501A at a dose of 1.8 mg/kg, and further dose 
reductions cannot be made.   
• 
For patients enrolled into the non-randomized portion of the study (Cohorts C 
and D, as well as Cohorts E, G, and H), dose modifications will not be allowed.  
Administration of therapeutic/prophylactic G-CSF and dose-schedule modifications 
as described above are allowed.  Patients who have persistent or recurrent 
Grade 3−4 neutropenia as defined above should be discontinued from study 
treatment. 
 
SECTION 4.3.1.7:  Peripheral Sensory/Motor Neuropathy 
Peripheral sensory neuropathy (sensory or motor) is a known risk of DCDT2980S and 
DCDS4501A (see Section 3.4.2.5).  For new or worsening drug-related Grade 2 or 3 


 
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peripheral sensory and/or motor neuropathy, dosing should be held for up to 2 weeks 
until peripheral sensory neuropathy (sensory or motor) improves to Grade 1 or baseline 
grade.  Continuation of study treatment following dose delays beyond 2 weeks will 
require consultation with and approval of the Medical Monitor based on an assessment 
of the benefit-risk analysis of continuing to delay study treatment. 
Following resolution of peripheral sensory neuropathy (sensory and/or motor), 
subsequent doses of DCDT2980S/DCDS4501A should be reduced to 1.8 mg/kg.  
DCDS4501A should not be reduced to a dose lower than 1.8 mg/kg.   If worsening 
Grade 2 or 3 peripheral sensory neuropathy (sensory and/or motor) recurs following 
dose reduction, study treatment should be discontinued.  For Grade 34 peripheral 
sensory neuropathy (sensory and/or motor), study treatment should be discontinued.  
For patients enrolled into the non-randomized portion of the study (Cohorts C and D), 
dose modifications will not be allowed.  Patients who have Grade 2 or 3 peripheral 
sensory neuropathy (sensory and/or motor), as defined above, should be discontinued 
from study treatment.   
SECTION 4.3.3:  Obinutuzumab 
SECTION 4.3.3.1:  Formulation 
Obinutuzumab (GA101/Gazyva™/Gazyvaro) is a clear, colorless to slightly brownish 
liquid, provided as a single 1000-mg dose liquid concentrate with a strength of 
25 mg/mL.  It is supplied in 50−mL glass vials containing 40 mL of the 25 mg/mL 
liquid concentrate.  In addition to the antibody, the liquid also contains 
histidine/histidine-HCl, trehalose, poloxamer 188, and highly purified water (HPW). 
SECTION 4.3.3.2:  Dosage, Administration and Storage 
Obinutuzumab will be administered by IV infusion as an absolute (flat) dose of 
1000 mg in combination with DCDS4501A, as outlined in Section 3.1.3.  
Obinutuzumab will be administered on Days 1, 8, and 15 of Cycle 1 and on Day 1 of 
Cycles 2−8 (see Table 2).  No dose modifications of obinutuzumab are allowed. 
All obinutuzumab infusions should be administered after premedication with oral 
acetaminophen and an antihistamine (see Section 4.4.1).  The prophylactic use of 
corticosteroids (e.g., 100 mg of IV prednisolone or equivalent) may also be considered 
for patients thought to be at high risk for IRRs, if deemed appropriate by the 
investigator, and should be administered prior to the obinutuzumab infusion.  On 
Cycle 1 Day 1, it is recommended that oral prednisone, prednisolone, or 
methylprednisolone be given within 12 hours as a premedication but at least 
60 minutes prior to the obinutuzumab infusion.  Premedication with prednisone or 
prednisolone is mandatory in patients who had an IRR and should continue until IRRs 
no longer occur during antibody infusion.  For the management of IRRs and 
anaphylaxis, see Table 1 (Section 4.3.1.5).  


 
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If it is the strong preference of the investigator or of the site (e.g., for logistical reasons) 
or if the patient is at increased risk for an IRR (high tumor burden, high peripheral 
lymphocyte count), the administration of obinutuzumab infusion can be split over 
2 days. 
In all parts of the study, obinutuzumab must be administered in a clinical (inpatient or 
outpatient) setting.  Full emergency resuscitation facilities should be immediately 
available, and patients should be under the close supervision of the investigator at all 
times.  For the management of IRRs and anaphylaxis, see Table 1 (Section 4.3.1.5). 
Obinutuzumab should be administered as a slow IV infusion through a dedicated line.  
IV infusion pumps should be used to control the infusion rate of obinutuzumab.  Do not 
administer as an IV push or bolus.  Administration sets with PVC, polyurethane 
(PUR), or PE as a product contact surface and IV bags with polyolefin (PO), 
polypropylene (PP), PVC, or PE as a product contact surface are compatible and can be 
used.  Do not use an additional in-line filter because of potential adsorption. 
The recommended storage conditions for obinutuzumab drug product are between 2°C 
and 8°C, protected from light.  For clinical formulation-specific and batch-specific 
instructions and information on in-use stability, see the packaging label.   
SECTION 4.3.3.3:  Dosage Modification 
There will be no obinutuzumab dose modification in this study.  Patients at high risk 
for TLS complications (see Section 3.4.2.2) may, at the investigator’s discretion, receive 
obinutuzumab over 2 consecutive days (with DCDS4501A dose potentially delayed to 
Day 2 or Day 3). 
Any NCI CTCAE (v4.0) toxicity Grade ≥ 3 in severity that is deemed related to 
obinutuzumab treatment will require interruption of study treatment (both 
DCDS4501A and obinutuzumab) until resolution to Grade ≤ 2 or ≥ 80% of baseline, 
whichever is lower.  Resumption of obinutuzumab treatment may be considered in 
patients with resolution of toxicities to Grade ≤ 1 within 2 weeks at the discretion of the 
investigator, after consultation with the Medical Monitor.  Failure of such toxicities to 
resolve after 2-week delay in study treatment will require permanent discontinuation of 
obinutuzumab.  Continuation of study treatment following dose delays beyond 2 weeks 
will require consultation with and approval of the Medical Monitor based on an 
assessment of the benefit-risk analysis of continuing to delay study treatment.  
If a patient develops unacceptable toxicity to obinutuzumab requiring its 
discontinuation, single-agent DCDS4501A will not be permitted.  
SECTION 4.3.3.4:  Schedule Modification 
Patients in whom toxicities have not resolved (i.e., to Grade ≤ 1 or ≥ 80% of baseline) 
may have their study treatment delayed by up to 2 weeks.  Dosing of both DCDS4501A 


 
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and obinutuzumab should be held during this period.  If all study drug−related 
toxicities have resolved to Grade ≤ 1 or ≥ 80% of baseline, the patient may resume 
DCDS4501A and obinutuzumab dosing on the regular every−21−day schedule.  In 
addition, a patient’s dosing may be changed to a 28-day cycle if it is felt by the 
investigator and Medical Monitor that changing a patient’s dosing regimen from 
21-day to 28-day cycles would provide sufficient time for recovery from transient 
cytopenias without requiring repeated treatment delays. 
Patients who do not fulfill the criteria for dosing after the additional 2 weeks have 
elapsed may be discontinued from study treatment and be followed for safety outcomes 
(see Section 4.5.6).  Exceptions on the basis of ongoing clinical benefit may be allowed 
following a careful assessment and discussion of risk versus benefit with the patient by 
the investigator and approval from the Medical Monitor.  In addition, delay of therapy 
because of toxicities not attributed to study drug may not require discontinuation and 
will be discussed with the Medical Monitor. 
Specific guidelines around schedule modifications for thrombocytopenia are detailed 
below in Section 4.3.3.5. 
SECTION 4.3.3.5:  Thrombocytopenia 
Thrombocytopenia is a known risk of obinutuzumab (see Section 3.4.5.4).  If the clinical 
condition of a patient requires the use of concomitant anticoagulants, the patient is at 
increased risk of bleeding when the platelet count is < 20,000/μL.  When possible, 
replace prior therapy with Vitamin K antagonists, such as warfarin, with low-
molecular weight heparin (LMWH) or new oral anticoagulants (NOACs) before Cycle 1 
Day 1.  Clinical decision making may be adjusted depending on the patient-specific 
assessment of benefit and risk. 
In the event of severe thrombocytopenia (platelet count < 10,000/μL) and/or 
symptomatic bleeding (irrespective of platelet count) in patients who are not receiving 
concomitant anticoagulants or platelet inhibitors: 
• 
Hold obinutuzumab until thrombocytopenia or symptomatic bleeding resolves, but 
do not skip any doses of obinutuzumab for the sake of maintaining the study 
treatment schedule. 
 
In the event of thrombocytopenia with platelet count < 20,000/μL and/or symptomatic 
bleeding (irrespective of platelet count) in patients who are receiving concomitant 
anticoagulants or platelet inhibitors: 
• 
Hold obinutuzumab  until thrombocytopenia or symptomatic bleeding resolves, but 
do not skip any doses of obinutuzumab for the sake of maintaining the study 
treatment schedule. 
• 
For patients who are on LMWH or NOACs, when platelet count < 20,000/μL 
develops, reduce the dose of LMWH or NOACs used. 


 
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• 
For patients who are on platelet inhibitors when thrombocytopenia with platelet 
count < 20,000/μL develops, consideration should be given to temporarily pausing 
the use of platelet inhibitors. 
 
SECTION 4.3.4:  Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(pinatuzumab vedotin [DCDT2980S], polatuzumab vedotin [DCDS4501A], rituximab, 
and obinutuzumab) will be provided by the Sponsor where required by local health 
authority regulations.  The study site will acknowledge receipt of IMPs to confirm the 
shipment condition and content.  Any damaged shipments will be replaced.  
IMPs will be either disposed of at the study site according to the study site’s 
institutional standard operating procedure or returned to the Sponsor with the 
appropriate documentation.  The site's method of IMP destruction must be agreed to by 
the Sponsor.  The site must obtain written authorization from the Sponsor before any 
IMP is destroyed, and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
SECTION 4.4.1:  Concomitant Therapy 
Concomitant therapy includes any medication (e.g., prescription drugs, medications or 
over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) 
preparations used by a patient frombetween the 7 days prior topreceding the screening 
evaluation and to the end of study visits.  All concomitant medications should be 
reported to the investigator and recorded on the appropriate electronic Case Report 
Form (eCRF).  Patients who use oral contraceptives, hormone-replacement therapy, or 
other maintenance therapy should continue their use.  Concomitant use of hematopoietic 
growth factors is allowed in accordance with instructions provided in the package inserts. 
For patients enrolled on obinutuzumab-containing regimens, it is recommended that 
oral prednisone, prednisolone, or methylprednisolone be given as premedication within 
12 hours of, but at least 60 minutes prior to, the obinutuzumab infusion on Cycle 1 
Day 1.  After the first obinutuzumab infusion, additional glucocorticoids are allowed at 
the investigator’s discretion.  For patients who did not experience infusion-related 
symptoms with their previous infusion, premedication at subsequent infusions may be 
omitted at the investigator’s discretion. 
SECTION 4.4.2:  Excluded Therapy 
Patients who require the use of any of these agents will be discontinued from all study 
treatment.  Patients who are discontinued from study treatment will be followed for safety 
outcomes for 30 days following the patient’s last dose of DCDT2980S or DCDS4501A or 
rituximab or obinutuzumab, whichever is later, or until the patient receives another 
anti-cancer therapy, whichever occurs first. 


 
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SECTION 4.5.1.2:  Vital Signs 
Vital signs will include measurements of systolic and diastolic blood pressure while the 
patient is in a sitting or semi-supine position, pulse oximetry, pulse rate, and body 
temperature.  Every effort will be made to ensure that vital signs are obtained from 
patients in a consistent manner and position.  The timing of vital sign collection on the 
days of study treatment administration is as follows: 
• 
For the administration of rituximab or obinutuzumab, vital signs should be assessed 
prior to the start of the infusion, every 15 (± 5) minutes during the first hour of the 
infusion, as clinically indicated during the remainder of the infusion, and following 
the completion of the infusion.  
 
SECTION 4.5.1.3:  Physical Examination 
Resolution or any change in grade  of peripheral neuropathy AEs and SAEs (with dates) should 
be documented on the Adverse Event eCRF and in the patient’s medical record to facilitate source 
data verification (SDV).  This also applies to AEs for which study drug was discontinued or for 
patients in the follow-up phase after last dose of study treatment with either ongoing AEs or new 
onset of an AE.  For the AEs referring to the follow-up phase newly initiated, relevant treatments 
need to be documented with treatment dates.  
SECTION 4.5.1.4:  Laboratory Assessments 
Central Laboratory Assessments 
Samples for flow cytometry, PK, bone marrow, and anti-DCDT2980S or, 
anti-DCDS4501A, or anti-obinutuzumab antibody assessments will be sent to one or 
several laboratories or to Genentech for analyses (see Section 3.6).  The following 
assessments will be conducted: 
• 
ATA assays 
ATAs to DCDT2980S or, DCDS4501A, or obinutuzumab will be determined at 
Genentech using a validated ELISA (see Section 4.9).  
• 
PK and PD assays (see Section 4.5.1.6) 
• 
A plasma sample and blood samples will be collected from patients for exploratory 
research as indicated in Section 4.5.1.9 
 
SECTION 4.5.1.5:  Electrocardiogram Assessments 
Twelve-lead digital ECG measurements will be obtained in triplicate, with immediately 
consecutive ECGs obtained until three evaluable ECGs are recorded, at the following 
timepoints: 
• 
Day 8 (± 1 day) of Cycle 3 time matched (i.e., obtained at the same time of day) with 
post-DCDT2980s/DCDS4501A infusion ECGs for Cycle 3 only for 
rituximab-containing arms/cohorts 
 
SECTION 4.5.1.6:  Pharmacokinetic and Pharmacodynamic Assessments 
Pharmacokinetics of DCDT2980S and DCDS4501A will be characterized by measuring 
total antibody (conjugated and unconjugated antibody), acMMAE, and free MMAE 


 
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concentrations using validated methods (see Section 4.9).  Plasma samples may also be 
analyzed for other potential MMAE-containing catabolites, per sponsor’s discretion.  
Pharmacokinetics of rituximab will be characterized by measuring rituximab 
concentrations using a validated method (see Section 4.9).  Pharmacokinetics of 
obinutuzumab will be characterized by measuring obinutuzumab concentrations with 
use of a validated method (see Section 4.9).  These assessments will allow for further 
characterization of pharmacokinetics of DCDT2980S and DCDS4501A, the assessment 
of the drug interaction potential when they are given in combination with rituximab or 
obinutuzumab, and the investigation of potential correlations between PK parameters 
and safety and/or activity if data allow and at the sponsor’s discretion.  
Pharmacodynamics of obinutuzumab and DCS4501A may be assessed by monitoring 
the release of tumor associated DNA following treatment. 
SECTION 4.5.1.7:  Immunogenicity Assessments 
The schedule of sample collection for ATA assessment is outlined in Appendices B-1, 
and B-2, or B-3, depending on the schedule of study treatment administration.  Samples 
for ATA will not be collected during the crossover treatment period. 
ATA responses to obinutuzumab will be detected and confirmed using a similar tiered 
approach.  Patient samples will first be screened to detect all antibody responses to 
obinutuzumab.  Samples that screen positive will be analyzed in a confirmatory assay 
(competitive binding with obinutuzumab) to assess the specificity of the positive 
response.  The relative levels of ATA in confirmed positive samples will be determined 
in a titering assay.  Positive ATA samples will be stored for further characterization of 
ATA responses, if necessary. 
SECTION 4.5.1.8:  Tumor Response Assessments 
All measurable disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Response assessments will be assessed by the 
investigator, on the basis of physical examinations, CT scans, PET scans, and/or MRI 
scans, and bone marrow examinations, using standard response criteria for NHL 
(Cheson et al. 2007) (see Appendix C-1 and C-2). 
a. Radiographic Assessments for Patients on Rituximab-Containing 
Arms/Cohorts 
b. Radiographic Assessments for Patients on Obinutuzumab-Containing 
Cohorts 
PET scans should minimally extend from skull-base to mid-thigh.  Full-body PET scan 
should be performed when clinically appropriate. 
CT scans with oral and IV contrast should include chest, abdomen, and pelvic scans;  
CT scans of the neck should be included if clinically indicated.  CT scans for response 
assessment may be limited to areas of prior involvement only if required by local health 


 
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authorities.  At the investigator’s discretion, CT scans may be repeated at any time if 
progressive disease is suspected. 
In patients for whom contrast is contraindicated⎯for example, patients with contrast 
allergy or impaired renal CL⎯CT or combined PET/CT scans without contrast are 
permitted so long as they permit consistent and precise measurement of target lesions 
during the study treatment period.   
PET and CT scans are required for follicular NHL and DLBCL patients at screening, 
after Cycle 4 of study treatment (i.e., between Cycle 4 Day 15 and Cycle 5 Day 1), and 
at EOT.  The EOT response assessment should be performed 6−8 weeks after Cycle 8 
Day 1 or last study treatment.  CT scans without PET scans will be obtained every 
3 months for 1 year, then every 6 months for 1 year, for a total of approximately 2 years 
after the treatment completion visit, with use of standard response criteria for NHL 
(see Appendix C-2).   
cd. Schedule of Tumor Response Assessments for Rituximab-Containing 
Arms/Cohorts 
Tumor response assessments will be performed every 3 months (± 1 week) from the 
initiation of study treatment until study treatment completion or early termination 
(e.g., between Days 14 and 21 of Cycles 4 and 8 for those patients receiving at least 
eight 21-day cycles of treatment).  The schedule of tumor assessments isshould be 
independent of the study treatment dose schedule.  For patients enrolled on 
rituximab-containing arms/cohorts, the schedule of tumor response assessments is 
detailed in Appendix A-1.  As stated above, for all DLBCL patients enrolled on a 
rituximab-containing arm/cohort, PET scans are required during the screening period 
and at the 6-month tumor assessment timepoint. 
Additional response assessments, after the final dose of study treatment, for patients 
who discontinue from study treatment (either initial or crossover treatment) for reasons 
other than progressive disease, will be performed as described in Appendix A- 34.  
e. Schedule of Tumor Response Assessments for Obinutuzumab-Containing 
Cohorts 
All follicular NHL and DLBCL patients enrolled in obinutuzumab-containing cohorts 
are required to have a combined PET and CT scan at screening, after Cycle 4 of 
treatment, and at EOT.  The schedule for tumor response assessments for patients 
enrolled on obinutuzumab-containing cohorts is detailed in Appendix A-3. 
SECTION 4.5.1.9:  Exploratory Research 
a. Tumor Tissue Samples 
Required Tumor Tissue Samples 
• 
Tissue microarrays (TMAs) from cores taken from provided blocks for 
immunohistochemistry (IHC) and in situ hybridization (ISH) assessments , including 


 
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1) DLBCL classifiers in tissue obtained from patients with DLBCL (CD10; GCET, 
Mum1; FoxP1 LMO2 (Meyer et al. 2011); and 2)for biomarker endpoints involved in 
response to chemotherapy including quantitation of Bcl-2 protein and genetic 
alterations of bcl-2 including gene rearrangements, amplifications, and t(14;18) 
translocations. Additional IHC markers may include those related to the tumor 
microenvironment. 
b. Blood and Plasma Samples 
Blood samples will be taken aligned with PK sampling to assess the pharmacodynamics 
response by monitoring circulating tumor DNA. 
The plasma and blood samples may be used for the assessment of specific tumor 
biologic markers, including proteins, circulating DNA, and microRNAs.  The information 
obtained from these samples will enable a better understanding of the biology of NHL 
and disease prognosis, identify potential predictors of response to treatment with 
DCDT2980S, DCDS4501A, and/or rituximab, and/or obinutuzumab, improve diagnostic 
assessments, and identify and characterize mechanisms of resistance to DCDT2980S or 
DCDS4501A and rituximab or obinutuzumab activity.   
SECTION 4.5.1.10:  Patient-Reported Outcomes 
The MDASI (Cleeland et al., 2000; Appendix E) is a multi-symptom PROself-report 
measure for clinical and research use. The MDASI’s 13 core-symptom items, plus an 
additional 4 items, for a total of 17 symptom items, include those found to have the 
highest frequency and/or severity in patients with various cancers and treatment types.  
These include pain, fatigue, nausea, disturbed sleep, emotional distress, shortness of 
breath, lack of appetite, drowsiness, dry mouth, sadness, vomiting, difficulty 
remembering, and numbness or tingling.  Six additional items focus on the degree of 
interference of the aforementioned symptoms for a total of 23 items in the questionnaire. 
SECTION 4.5.2:  Screening and Pretreatment Assessments 
Refer to the Study Flowchart provided in Appendix A-1 and A-3 for the schedule of 
screening and pretreatment assessments. 
SECTION 4.5.3:  Assessments during Treatment 
Study drug infusions (rituximab, obinutuzumab, DCDT2980S, or DCDS4501A) should 
occur on the scheduled 21-day (or 28-day) cycle but may be given up to ± 2 days from 
the date scheduled (i.e., with a minimum of 19 days between doses) if required for 
logistical/scheduling reasons.  All other study visits during Cycles 1 and 2 must occur 
within ± 1 day from the scheduled date, unless otherwise noted.  Study visits starting in 
Cycle 3 should occur within ± 2 days from the scheduled date, unless otherwise noted.  
All assessments will be performed on the day of the specified visit unless a time window 
is specified.  Assessments scheduled on the day of study drug administration (Day 1) of 
each cycle should be performed prior to study drug infusion unless otherwise noted.   


 
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Refer to the Study Flowchart provided in Appendix A-1 for the schedule of treatment 
period assessments.  For patients enrolled in the obinutuzumab-containing cohorts, 
refer to the Study Flowchart provided in Appendix A-3. 
SECTION 4.5.4:  Study Treatment Completion Visit 
Patients who complete study treatment (approximately 1 year/17 cycles) or discontinue 
from study treatment early will be asked to return to the clinic within 30 days after the 
last DCDT2980S or, DCDS4501A or, rituximab, or obinutuzumab infusion (whichever is 
later) for a study treatment completion visit.  The visit at which response assessment 
shows progressive disease may be used as the early termination visit. 
Refer to the Study Flowchart provided in Appendix A-1 for assessments to be performed 
at the treatment completion/early termination visit.  For patients enrolled on the 
obinutuzumab-containing cohorts, refer to the Study Flowchart provided in Appendix 
A-3. 
SECTION 4.5.6:  Follow-Up Assessments 
Ongoing adverse events thought to be related to DCDT2980S, DCS4501A, or rituximab, 
or obinutuzumab will be followed until the event has resolved to baseline (pre-treatment) 
grade, the event is assessed by the investigator as stable, new anti-tumor treatment is 
initiated, the patient is lost to follow-up, the patient withdraws consent, or when it has 
been determined that the study treatment or participation is not the cause of the adverse 
event. 
SECTION 4.5.6.1:  Follow-Up Assessments for Rituximab-Containing Regimens 
Patients who discontinue from study treatment (either initial study treatment or crossover 
treatment) for reasons other than progressive disease will be followed for response for 
up to 1 year after the last infusion of study treatment or until disease progression or 
initiation of another anti-lymphoma/leukemia therapy, whichever occurs first.  Response 
assessments should occur approximately every 2−3 months following the last infusions 
of DCDT2980S, DCDS4501A, or rituximab.  Post-treatment assessments are described 
in Appendix A-34.  
SECTION 4.5.6.2:  Follow-Up Assessments for Obinutuzumab-Containing 
Regimens 
Patients who discontinue from study treatment for reasons other than progressive 
disease will be followed for response for up to 2 years after the last infusion of study 
treatment or until disease progression or initiation of another anti-lymphoma/leukemia 
therapy, whichever occurs first.  Response assessments should occur approximately 
every 2−3 months following the last infusions of DCDS4501A or obinutuzumab for the 
first year after completion of treatment, then every 6 months for the second year after 
completion of treatment.  Post-treatment assessments are described in Appendix A-5.  


 
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Following discontinuation of study treatment, patients will be followed for survival 
approximately every 6 months until death, loss to follow-up, withdrawal of consent, or 
study termination. 
SECTION 4.8:  POST-TRIAL ACCESS 
Genentech does not have any plans to provide DCDT2980S, DCDS4501A, rituximab, 
obinutuzumab, or other study interventions to patients after the conclusion of the study 
or if the study is terminated or for patients who withdraw early from the study or 
complete their study treatment.  Genentech will evaluate the appropriateness of 
continuing to provide DCDT2980S, DCDS4501A, or rituximab, or obinutuzumab to study 
patients after evaluating the safety and activity data from the study.   
SECTION 4.9.5:  Obinutuzumab ELISA 
Obinutuzumab will be measured in serum samples using a validated ELISA.   
SECTION 4.9.6:  Anti-Therapeutic Antibody 
ATAs against obinutuzumab in serum samples will be measured using a validated 
bridging antibody ELISA. 
SECTION 4.9.7:  Biomarker Assays 
Tumor tissue assessment of biomarkers will be assayed using IHC, ISH, qPCR gene 
expression profiling using microarray and mutation detection assays.  and flow 
cytometry. Circulating Tumor DNA (ctDNA) in plasma samples will be assessed using 
a next generation sequencing approach (CAPP-Seq) to detect and quantitate lymphoma 
specific markers (Newman et al. 2014). 
SECTION 4.10:  STATISTICAL METHODS 
The final analysis will be based on patient data collected through patient discontinuation 
until all patients discontinue or from the study discontinuation or the study is 
terminated by the Sponsor, whichever occurs first.  The analyses will be based on the 
safety evaluable population, defined as patients who received at least one dose of study 
treatment.  All summaries will be presented according to the disease-specific cohort, 
treatment group, and assigned dose level. 
SECTION 4.10.1:  Analysis of the Conduct of the Study 
Study drug administration data will be listed by the disease-specific cohorts described in 
Sections 3.1.1 and 3.1.2.  Any dose modifications will be flagged.  Means and standard 
deviations will be used to summarize the total doses of DCDT2980S, DCDS4501A and, 
rituximab, and obinutuzumab received.  All summaries will be presented by treatment 
group, assigned dose level, and disease-specific cohort. 
SECTION 4.10.2:  Safety Analysis 
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in physical findings on physical examinations, and changes in vital 
signs.  All patients who receive any amount of DCDT2980S, DCDS4501A or, rituximab, 


 
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or obinutuzumab will be included in the safety analysis and will be assigned to the 
treatment group on the basis of the study treatment received.  Patients who have dose 
level changes from the initial assigned dose level will be summarized by the initial 
assigned dose level of DCDT2980S or DCDS4501A. 
SECTION 4.10.3:  Pharmacokinetic and Pharmacodynamic Analyses 
Individual and mean serum concentrations of total DCDT2980S or DCDS4501A antibody 
(conjugated and unconjugated antibody) and rituximab or obinutuzumab and plasma 
concentrations of acMMAE and free MMAE versus time data will be tabulated and 
plotted by NHL disease subtype (relapsed or refractory follicular NHL or DLBCL).  The 
pharmacokinetics of the above analytes will be summarized by estimating the 
appropriate PK parameters (e.g., AUC, Cmax, CL, Vss, and t1/2).  Estimates for these 
parameters will be tabulated and summarized (mean, standard deviation, and range).  
Non-compartmental, compartmental, and/or population methods will be used, as data 
allow.  
SECTION 4.10.4:  Activity Analyses 
ORR from the initial study treatment will be calculated on the basis of data from patients 
who received study treatment and had at least one post baseline response assessment.  
Objective response is defined as CR or PR as determined by the investigator, on the 
basis of physical examinations, radiographic scans, and bone marrow examinations, 
using modified response criteria for NHL (Cheson et al. 2007; see Appendix C) and 
confirmed by repeat assessments ≥ 4 weeks after initial documentation.  Any patient with 
insufficient data to determine response will be classified as a non-responder. 
For patients with DLBCL, primary assessment of tumor response will be based on 
diagnostic imaging scans⎯for example, CT and/or MRI scans and PET scans.  For 
patients with FL enrolled on rituximab-containing arms/cohorts, primary assessment of 
response will be based on CT scans only; the assessment of response in FL based on 
PET scans will be performed for exploratory purposes only. 
For patients with DLBCL or FL on obinutuzumab-containing cohorts, primary 
assessment of tumor response will be based on PET/CT scans.  Given the new Lugano 
Classification, 2014, criteria which recommend that complete response (PET-CR) be 
determined by PET-CT scan, patients in Cohorts E, G, and H will be evaluated with a 
PET-CT scan at screening, between Cycle 4 Day 15 and Cycle 5 Day 1, and at 6-8 weeks 
after completing treatment.  The efficacy analysis for these cohorts will, therefore, be 
different from the analysis for Arms A-B and Cohorts C-D. (Cheson, et al 2014) 
(see Appendix C-2). 
Among patients with an objective response, duration of response will be defined as the 
time from the initial documentation of a CR or PR to the time of disease progression or 
death.  If a patient does not experience death or disease progression before the end of 
the study, duration of response will be censored at the day of the last tumor assessment. 


 
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For the randomized portion of the study (Arms A and B), PFS is defined as the time from 
the date of randomization to the date of disease progression or death from any cause, 
whichever occurs first.  If a patient has not experienced progressive disease or death, 
PFS will be censored at the day date of the last tumor assessment.  Patients with no 
post-baseline tumor assessment will be censored on the date of randomization.  For the 
non-randomized portion of the study (Cohorts C and Dthrough H), PFS is defined as the 
time from the date of study enrollment to the date of disease progression or death from 
any cause, whichever occurs first. 
For the randomized portion of the study (Arms A and B), OS is defined as the time from 
the date of randomization to the date of death from any cause.  For the non-randomized 
portion of the study (Cohorts C and Dthrough H), OS is defined as the time from the 
date of study enrollment to date of death from any cause. 
SECTION 4.10.7:  Determination of Sample Size 
For the randomized portion of the study (Arms A and B), a target of 120 patients will be 
enrolled in two separate cohorts of patients (40 in the follicular NHL cohort and 80 in the 
DLBCL cohort).  Genentech has judged thisThe randomized portion of this study is 
non-comparative in nature.  No formal hypothesis testing is planned to compare the 
treatment arms.  Moreover, there is insufficient power to detect minimum clinically 
meaningful differences between the two treatment arms.  Genentech has judged the 
proposed sample size to provide sufficient precision in estimating the anti-tumor activity of 
DCDT2980S combined with rituximab or DCDS4501A combined with rituximab as 
measured by objective response.  For example, with the assumption of an observed 
response rate of 40%, a 90% confidence interval for the response rate would be 
approximately 22%−58% (i.e., 40% ± 18%) for the follicular NHL cohort and approximately 
27%−53% (i.e., 40% ± 13%) for the DLBCL cohort.  With 40 patients, there is an 87% 
chance of observing at least one adverse event with a true incidence of 5%. 
This is a non comparative hypothesis generating study.  There is no formal hypothesis 
testing planned to compare the treatment arms.  Specifically, for the randomized portion 
of the study, there is insufficient power to detect minimum clinically meaningful differences 
between the two treatment arms.For the non-randomized portions of the study (Cohorts C 
and D), approximately 20 patients will be enrolled into each arm, for a total of 40 
patients.   With 20 patients under an observed response rate of 40%, the exact 
Clopper-Pearson 90% confidence interval for the response rate would be 22%−61%.  
With respect to the assessment of safety based upon a sample size of 20 patients, the 
chance of observing at least one adverse event with a true incidence of 10% is 88%. 
For the obinutuzumab safety run-in cohort (Cohort E), 6 patients will be enrolled.  For 
the obinutuzumab expansion cohorts (Cohorts G and H), 40 patients with follicular NHL 
and the other with 20−40 patients with DLBCL, will be enrolled at the RP2D to further 
evaluate safety and efficacy of the combination.  Table 3 provides asymptotic 90% confidence 
intervals for the true probability of response for a range of observed proportions based upon a 


 
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sample of 40 patients.  A sample size of 40 patients is deemed sufficient to provide adequate 
precision on the point estimate and for the lower end of the 90% CI to rule out a clinically 
uninteresting rate of 45% assuming observed response rates of approximately 60% or higher (~24 
responders observed among 40 patients). 
Therefore, up to 252 patients may be enrolled in this study.  
SECTION 5.4.1:  Reporting Requirements for Fatal/Life-Threatening SAEs 
Related to Investigational Product 
Medical Monitor Contact Information for sites in North America: 
Medical Monitor: 
 M.D. 
Telephone No.: 
 
 
Mobile Telephone No.: 
 
SECTION 5.4.2:  Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
Sites in North America: 
Fax No.:  
 (
 
 
Alternate 
Fax No.:  
(
 
 
Sites outside of North America: Refer to the study reference binder for contact 
information. 
SECTION 5.6:  POST-STUDY ADVERSE EVENTS 
The investigator should notify the study Sponsor of any death or other SAE occurring at 
any time after a patient has discontinued or terminated study participation if felt to be 
related to prior study treatment.  The Sponsor should also be notified if the investigator 
should become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a patient that participated in this study.  The 
investigator should report these events to Genentech Drug Safety on the study eCRF.  
If the study eCRF is no longer available, the investigator should report the event directly 
to Genentech Drug Safety via phone ateither by faxing or by scanning and emailing the 
Serious Adverse Event/Adverse Event of Special Interest Reporting Form with use of 
the fax number or email address provided below. 
Canada: 
Fax No.:  (905) 542−5864 
Email: mississauga.drug_safety@roche.com 888 835 2555. 
 
United States: 
Fax No.:  
 


 
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Email: us_drug.safety@gene.com 
SECTION 6.5:  STUDY MONITORING REQUIREMENTS 
Site visits will be conducted by an authorized Genentech representative to inspect site 
facilities and equipment, study source data, patients’ medical records, and eCRFs.  The 
Principal Investigator will oversee all aspects of the conduct of this protocol and permit 
Genentech monitors/representatives and collaborators, the FDA, other regulatory 
agencies, Institutional Review Boards, and the respective national or local health 
authorities to inspect facilities and records relevant to this study. 
SECTION 6.5:  SOURCE DATA DOCUMENTATION 
Source documents are where original patient data are recorded and documented for the 
first time.  They include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, patient diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, certified accurate and 
complete copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at the pharmacy, laboratories, and medico-technical 
departments involved in a clinical trial. 
Original sSource documents that are required to verify the validity and completeness of 
data entered into the eCRFs must never be obliterated or destroyed. 
To facilitate SDV, the investigator(s) and institution(s) must provide the Sponsor direct 
access to all applicable source documents and reports for trial-related monitoring, 
Sponsor audits, and IRB/EC review.  The investigational site must also allow inspection 
by applicable regulatory authorities. 
FIGURE 3a:  Study Schema for Rituximab-Containing Arms/Cohorts 
Figure 3a has been revised to reflect changes to the protocol.  
FIGURE 3b:  Study Schema for Obinutuzumab-Containing Arms/ Cohorts 
Figure 3b has been added to reflect changes to the protocol. 
TABLE 1:  Management of Infusion-Related Symptoms for All Study Drugs 
Table 1 has been revised to reflect changes to the protocol. 
TABLE 2:  Administration of First and Subsequent Infusions of 
Obinutuzumab 
Table 2 has been added.  Subsequent tables have been renumbered accordingly. 
TABLE 3:  Potential 90% Interval Estimates for the True Response 
Probability 
Table 3 has been added.  Subsequent tables have been renumbered accordingly. 


 
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REFERENCES: 
The references have been updated to reflect changes to the protocol. 
APPENDIX A-1:  Study Flowchart:  Initial Study Treatment (Arms A-B, 
Cohorts C-D) 
Appendix A-1 has been revised to reflect the changes to the protocol. 
APPENDIX A-2:  Study Flowchart:  Crossover Treatment (Patients 
Randomized to Arms A or B Only) 
Appendix A-2 has been revised to reflect the changes to the protocol. 
APPENDIX A-3:  Study Flowchart for Obinutuzumab-Containing Cohorts 
(E, G-H) :  Initial Study Treatment 
Appendix A-3 has been revised to reflect the changes to the protocol.  
APPENDIX A-4:  Study Flowchart: Post-Treatment Follow-Up for 
Rituximab-Containing Regimens (Arms A-B, Cohorts C-D) 
Appendix A-4 has been revised to reflect changes to the protocol.  
APPENDIX A-5:  Study Flowchart: Post-Treatment Follow-Up for 
Obinutuzumab-Containing Regimens 
Appendix A-5 has been added.  
APPENDIX B-1:  Serum and Plasma Pharmacokinetic Schedule for 
DCDT2980S/DCDS4501A and Rituximab, and ATA Schedule for 
DCDT2980S/DCDS4501A (For Patients Receiving Rituximab on Day 1 and 
DCDT2980S/DCDS4501A on Day 2 of Every Cycle) 
(Arms A-B, Cohorts C-D) 
APPENDIX B-2:  Serum and Plasma Pharmacokinetic Schedule for 
Rituximab and DCDT2980S/DCDS4501A, and ATA Schedule for 
DCDT2980S/DCDS4501A for Patients Receiving Rituximab and 
DCDT29808S/DCDS4501A on Day 1 of Every Cycle Beginning Cycle 3 
(Arms A-B, Cohorts C-D) 
APPENDIX B-3:  Serum and Plasma Pharmacokinetic, Blood 
Pharmacodynamic, and ATA Schedule for Obinutuzumab and DCDS4501A 
(Cohorts E, G-H) 
Appendix B-3 has been added.  
APPENDIX C-1:  Modified Response and Progression Criteria for NHL 
Appendix C has been renamed Appendix C-1. 
APPENDIX C-2:  Revised Criteria for Response Assessment: The Lugano 
Classification (Cohort E, G-H) 
Appendix C-2 has been added.  


 
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APPENDIX D:  Anaphylaxis Management 
Appendix D has been revised to reflect changes to the protocol. 
SAMPLE INFORMED CONSENT FORM 
The sample Informed Consent Form has been revised to reflect the changes to the 
protocol. 


 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 48 
1. 
BACKGROUND .......................................................................................... 66 
1.1 
Background on Disease......................................................... 66 
1.2 
Background on the Molecules ............................................... 66 
1.2.1 
DCDT2980S .......................................................................... 66 
1.2.1.1  Background and Preclinical Data ......................................... 66 
1.2.1.2  DCDT2980S Clinical Data.................................................... 68 
1.2.2 
DCDS4501A.......................................................................... 71 
1.2.2.1  Background and Preclinical Data ......................................... 71 
1.2.2.2  DCDS4501A Clinical Data.................................................... 74 
1.2.3 
Rituximab............................................................................... 77 
1.2.4 
Obinutuzumab ...................................................................... 78 
1.2.4.1  Obinutuzumab Mechanism of Action .................................. 78 
1.2.4.2  Obinutuzumab Nonclinical Toxicology ............................... 79 
1.2.4.3  Obinutuzumab Nonclinical Efficacy .................................... 79 
1.2.4.4  Obinutuzumab Clinical Experience ..................................... 80 
1.2.4.5  Obinutuzumab Pharmacokinetics and 
Pharmacodynamics............................................................................. 81 
1.3 
Rationale for Doing this Study ............................................... 82 
1.3.1 
Rationale for Assessing ADC Dose of 1.8 mg/kg 
Combined with Rituximab in iNHL ........................................................... 83 
1.3.2 
Rationale for Assessing DCDS4501A in 
Combination with Obinutuzumab in Relapsed or Refractory 
NHL 
.............................................................................................. 83 
2. 
OBJECTIVES.............................................................................................. 84 
2.1 
Primary Objectives ................................................................ 84 
2.2 
Secondary Objectives............................................................ 84 
2.2.1 
Safety Objectives................................................................... 84 
2.2.2 
Activity Objective ................................................................... 85 
2.2.3 
Pharmacokinetic Objectives .................................................. 85 
2.3 
Exploratory Objectives........................................................... 85 
2.3.1 
Biomarker Objectives ............................................................ 85 


 
TABLE OF CONTENTS (cont’d) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
40/P GO27834-A2 
2.3.2 
Patient-Reported Outcomes Objective ....................................... 85 
2.3.3 
Crossover Treatment Objective............................................. 85 
3. 
STUDY DESIGN ......................................................................................... 85 
3.1 
Description of the Study......................................................... 85 
3.1.1 
Rituximab-Containing Regimens with 
DCDT2980S or DCDS4501A.................................................................. 88 
3.1.1.1  Randomized Portion of the Study (Arms A 
and B) 
............................................................................................ 88 
3.1.1.2  Non-Randomized Portion of the Study with 
Rituximab (Cohorts C and D)............................................................. 88 
3.1.2 
All Patients on Rituximab-Containing 
Arms/Cohorts .......................................................................................... 89 
3.1.3 
Obinutuzumab-Containing Regimen with 
DCDS4501A (Cohorts E, G, and H)........................................................ 89 
3.1.3.1  Obinutuzumab-Containing Regimen in Phase 
Ib: Safety Run-In (Cohort E).............................................................. 90 
3.1.4 
Follicular NHL Patients for 
Rituximab-Containing Arms/Cohorts ..................................................... 90 
3.1.5 
Follicular NHL Patients for 
Obinutuzumab-Containing Cohorts ........................................................ 91 
3.1.6 
DLBCL Patients for Rituximab-Containing 
Arms/Cohorts .......................................................................................... 91 
3.1.7 
DLBCL Patients for Obinutuzumab-Containing 
Cohorts 
.............................................................................................. 92 
3.1.8 
Crossover Treatment (Randomized Patients in 
Arms A and B Only) ................................................................................ 92 
3.2 
Rationale for Study Design.................................................... 94 
3.2.1 
Rationale for the PK Sample Schedule ................................. 95 
3.3 
Outcome Measures ............................................................... 96 
3.3.1 
Safety Outcome Measures .................................................... 96 
3.3.2 
Pharmacokinetic/Pharmacodynamic Outcome 
Measures .............................................................................................. 96 
3.3.3 
Activity Outcome Measures................................................... 97 
3.3.4 
Exploratory Outcome Measures ............................................ 97 
3.4 
Safety Plan ............................................................................ 97 
3.4.1 
Safety Run-In Analysis ......................................................... 98 


 
TABLE OF CONTENTS (cont’d) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
41/P GO27834-A2 
3.4.2 
Internal Monitoring Committee............................................... 99 
3.4.3 
Risks Associated with DCDT2980S and 
DCDS4501A .......................................................................................... 100 
3.4.3.1  Infusion-Related Events ..................................................... 100 
3.4.3.2  Tumor Lysis Syndrome ...................................................... 100 
3.4.3.3  Bone Marrow Toxicity/Neutropenia .................................... 101 
3.4.3.4  Immunogenicity .................................................................. 101 
3.4.3.5  Peripheral  Neuropathy ...................................................... 102 
3.4.3.6  Reproductive Toxicity......................................................... 102 
3.4.3.7  Hyperglycemia ................................................................... 102 
3.4.3.8  Hepatotoxicity..................................................................... 102 
3.4.3.9  Commonly Reported Side Effects............................................. 102 
3.4.4 
Risks Associated with ADCETRIS® (Brentuximab 
Vedotin) 
............................................................................................ 102 
3.4.5 
Risks Associated with Rituximab Therapy and 
Their Management................................................................................. 103 
3.4.5.1  Infusion Reactions.............................................................. 103 
3.4.5.2  Management of Severe Infusion Reactions........................ 104 
3.4.5.3  Tumor Lysis Syndrome ...................................................... 104 
3.4.5.4  Hepatitis B Reactivation with Related Fulminant 
Hepatitis and Other Viral Infections .................................................. 104 
3.4.5.5  Cardiovascular Events ....................................................... 105 
3.4.5.6  Bowel Obstruction and Perforation..................................... 105 
3.4.5.7  Immunization...................................................................... 105 
3.4.6 
Risks Associated with Obinutuzumab Therapy ................... 106 
3.4.6.1  Infusion-Related Reactions and 
Hypersensitivity Reactions (including Anaphylaxis) ...................... 106 
3.4.6.2  Tumor Lysis Syndrome ...................................................... 106 
3.4.6.3  Neutropenia ....................................................................... 107 
3.4.6.4  Thrombocytopenia .............................................................. 107 
3.4.6.5  Infection ............................................................................. 107 
3.5 
Minimization of Bias............................................................. 108 
3.6 
Administrative Structure....................................................... 108 
3.7 
Compliance with Laws and Regulations .............................. 109 


 
TABLE OF CONTENTS (cont’d) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
42/P GO27834-A2 
4. 
MATERIALS AND METHODS .................................................................. 109 
4.1 
Patients................................................................................ 109 
4.1.1 
Inclusion Criteria.................................................................. 109 
4.1.2 
Exclusion Criteria................................................................. 110 
4.2 
Method of Treatment Assignment........................................ 111 
4.3 
Study Treatment.................................................................. 112 
4.3.1 
DCDT2980S and DCDS4501A............................................ 112 
4.3.1.1  Formulation and Storage.................................................... 112 
4.3.1.2  Dosage and Administration ................................................ 113 
4.3.1.3  Dosage Modification........................................................... 114 
4.3.1.4  Schedule Modification ........................................................ 115 
4.3.1.5  Infusion Reaction ............................................................... 116 
4.3.1.6  Neutropenia........................................................................ 118 
4.3.1.7  Peripheral  Neuropathy ...................................................... 119 
4.3.1.8  Hyperglycemia ................................................................... 119 
4.3.2 
Rituximab............................................................................. 119 
4.3.2.1  Formulation ........................................................................ 119 
4.3.2.2  Dosage, Administration, and Storage................................. 120 
4.3.2.3  Dosage Modification........................................................... 121 
4.3.2.4  Schedule Modification ........................................................ 121 
4.3.2.5  Infusion Reaction ............................................................... 122 
4.3.3 
Obinutuzumab .................................................................... 122 
4.3.3.1  Formulation ....................................................................... 122 
4.3.3.2  Dosage, Administration and Storage ................................. 122 
4.3.3.3  Dosage Modification .......................................................... 124 
4.3.3.4  Schedule Modification........................................................ 124 
4.3.3.5  Thrombocytopenia .............................................................. 125 
4.3.4 
Investigational Medicinal Product 
Accountability ....................................................................................... 125 
4.4 
Concomitant and Excluded Therapies................................. 126 
4.4.1 
Concomitant Therapy .......................................................... 126 
4.4.2 
Excluded Therapy................................................................ 126 
4.5 
Study Assessments ............................................................. 127 


 
TABLE OF CONTENTS (cont’d) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
43/P GO27834-A2 
4.5.1 
Definitions of Study Assessments ....................................... 127 
4.5.1.1  Medical History and Demographics.................................... 127 
4.5.1.2  Vital Signs .......................................................................... 127 
4.5.1.3  Physical Examination ......................................................... 127 
4.5.1.4  Laboratory Assessments.................................................... 128 
4.5.1.5  Electrocardiogram Assessments........................................ 129 
4.5.1.6  Pharmacokinetic and Pharmacodynamic 
Assessments .................................................................................... 130 
4.5.1.7  Immunogenicity Assessments............................................ 131 
4.5.1.8  Tumor Response Assessments ......................................... 131 
4.5.1.9  Exploratory Research......................................................... 134 
4.5.1.10  Patient-Reported Outcomes ............................................. 135 
4.5.2 
Screening and Pretreatment Assessments.......................... 135 
4.5.3 
Assessments during Treatment........................................... 136 
4.5.4 
Study Treatment Completion Visit ....................................... 137 
4.5.5 
Crossover Treatment Completion Visit ................................ 137 
4.5.6 
Follow-Up Assessments ...................................................... 137 
4.5.6.1  Follow-Up Assessments for Rituximab-Containing 
Regimens ........................................................................................... 138 
4.5.6.2  Follow-Up Assessments for Obinutuzumab-
Containing Regimens.......................................................................... 138 
4.6 
Patient Discontinuation........................................................ 138 
4.6.1 
Discontinuation from Treatment........................................... 138 
4.6.2 
Discontinuation from Study.................................................. 139 
4.7 
Study Discontinuation.......................................................... 139 
4.8 
Post-Trial Access................................................................. 139 
4.9 
Assay Methods.................................................................... 139 
4.9.1 
Total DCDT2980S/DCDS4501A Antibody ELISA................ 139 
4.9.2 
Antibody-Conjugated MMAE (MMAE Affinity 
Capture Enzyme-Release LC/MS-MS) .................................................. 140 
4.9.3 
Free MMAE LC-MS/MS....................................................... 140 
4.9.4 
Rituximab ELISA ................................................................. 140 
4.9.5 
Obinutuzumab ELISA......................................................... 140 
4.9.6 
Anti-Therapeutic Antibody ................................................... 140 


 
TABLE OF CONTENTS (cont’d) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
44/P GO27834-A2 
4.9.7 
Biomarker Assays................................................................ 140 
4.10 
Statistical Methods .............................................................. 140 
4.10.1 
Analysis of the Conduct of the Study................................... 140 
4.10.2 
Safety Analysis.................................................................... 141 
4.10.3 
Pharmacokinetic and Pharmacodynamic 
Analyses 
............................................................................................ 141 
4.10.4 
Activity Analyses.................................................................. 142 
4.10.5 
Exploratory Analyses........................................................... 143 
4.10.6 
Handling of Missing Data..................................................... 143 
4.10.7 
Determination of Sample Size ............................................. 143 
4.11 
Data Quality Assurance....................................................... 144 
5. 
ASSESSMENT OF SAFETY..................................................................... 145 
5.1 
Safety Parameters and definitions....................................... 145 
5.1.1 
Adverse Event ..................................................................... 145 
5.1.2 
Serious Adverse Event ........................................................ 146 
5.1.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................................. 147 
5.2 
Methods and Timing for capturing and Assessing 
Safety Parameters............................................................... 147 
5.2.1 
Adverse Event Reporting Period ......................................... 147 
5.2.2 
Eliciting Adverse Events ...................................................... 147 
5.2.3 
Assessment of Severity and Causality of Adverse 
Events 
............................................................................................ 147 
5.3 
Procedures for Recording Adverse Events.......................... 149 
5.3.1 
Recording Adverse Events on the eCRF............................. 149 
5.3.1.1  Diagnosis versus Signs and Symptoms ............................. 149 
5.3.1.2  Adverse Events Occurring Secondary to Other 
Events 
........................................................................................... 149 
5.3.1.3  Persistent or Recurrent Adverse Events ............................ 150 
5.3.1.4  Abnormal Laboratory Values.............................................. 150 
5.3.1.5  Abnormal Vital Sign Values................................................ 150 
5.3.1.6  Abnormal Liver Function Tests........................................... 151 
5.3.1.7  Deaths................................................................................ 151 
5.3.1.8  Preexisting Medical Conditions .......................................... 152 


 
TABLE OF CONTENTS (cont’d) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
45/P GO27834-A2 
5.3.1.9  Worsening of Baseline Hematologic Malignancy ............... 152 
5.3.1.10  Hospitalization, Prolonged Hospitalization or 
Surgery 
......................................................................................... 152 
5.3.1.11  Pregnancy ........................................................................ 152 
5.4 
Expedited Reporting Requirements for Serious 
Adverse Events ................................................................... 153 
5.4.1 
Reporting Requirements for 
Fatal/Life-Threatening SAEs Related to Investigational 
Product 
............................................................................................ 153 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of Special Interest ................ 154 
5.5 
Type and Duration of Follow-Up of Patients after 
Adverse Events ................................................................... 154 
5.6 
Post-Study Adverse Events................................................. 155 
6. 
INVESTIGATOR REQUIREMENTS.......................................................... 155 
6.1 
Study Initiation..................................................................... 155 
6.2 
Study Completion ................................................................ 156 
6.3 
Informed Consent Form....................................................... 157 
6.4 
Communication with the Institutional Review 
Board or Ethics Committee.................................................. 158 
6.5 
Study Monitoring Requirements .......................................... 158 
6.6 
Electronic Case Report Forms............................................. 158 
6.7 
Source Data Documentation................................................ 159 
6.8 
Use of Computerized Systems ............................................ 159 
6.9 
Study Medication Accountability.......................................... 160 
6.10 
Disclosure of Data ............................................................... 160 
6.11 
Retention of Records........................................................... 160 
7. 
REFERENCES ......................................................................................... 162 
 
 
LIST OF TABLES 
Table 1 
Management of Infusion-Related Symptoms for All Study 
Drugs........................................................................................ 117 
Table 2 
Administration of First and Subsequent Infusions of 
Obinutuzumab.......................................................................... 123 


 
TABLE OF CONTENTS (cont’d) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
46/P GO27834-A2 
Table 3 
Potential 90% Interval Estimates for the True Response 
Probability.................................................................................. 144 
Table 4 
Adverse Event Grading (Severity) Scale................................... 148 
Table 5 
 Causal Attribution Guidance .................................................... 149 
 
 
LIST OF FIGURES 
Figure 1 
CD22 Expression Levels on B-Cell Tumor Cells......................... 67 
Figure 2 
CD79b Expression Levels on B-Cell Tumor Cells....................... 72 
Figure 3a 
Study Schema for Rituximab-Containing Arms/Cohorts ................ 87 
Figure 3b 
Study Schema for Obinutuzumab-Containing Arms/Cohorts ............ 87 
 
 
LIST OF APPENDICES 
Appendix A-1  Study Flowchart:  Initial Study Treatment (Arms A-B, 
Cohorts C-D) ............................................................................ 165 
Appendix A-2 Study Flowchart:  Crossover Treatment (Patients 
Randomized to Arms A or B Only)............................................ 170 
Appendix A-3 Study Flowchart for Obinutuzumab-Containing Cohorts (E, G-
H):  Initial Study Treatment ........................................................ 173 
Appendix A-4 Study Flowchart: Post-Treatment Follow-Up for 
Rituximab-Containing Regimens (Arms A-B, Cohorts C-D)........ 178 
Appendix A-5 Study Flowchart: Post-Treatment Follow-Up for Obinutuzumab-
Containing Regimens (Cohorts E, G-H)...................................... 180 
Appendix B-1 Serum and Plasma Pharmacokinetic Schedule for 
DCDT2980S/DCDS4501A and Rituximab, and ATA 
Schedule for DCDT2980S/DCDS4501A (For Patients 
Receiving Rituximab on Day 1 and 
DCDT2980S/DCDS4501A on Day 2 of Every Cycle) 
(Arms A-B, Cohorts C-D)......................................................... 182 
Appendix B-2 Serum and Plasma Pharmacokinetic Schedule for Rituximab 
and DCDT2980S/DCDS4501A, and ATA Schedule for 
DCDT2980S/DCDS4501A for Patients Receiving Rituximab 
and DCDT29808S/DCDS4501A on Day 1 of Every 
Cycle Beginning Cycle 3 (Arms A-B, Cohorts C-D) ................. 184 
Appendix B-3 Serum and Plasma Pharmacokinetic, Blood Pharmacodynamic, and 
ATA Schedule for Obinutuzumab and DCDS4501A 
(Cohorts E, G-H) ...................................................................... 186 
Appendix C-1  Modified Response and Progression Criteria for NHL............... 188 
Appendix C-2 Revised Criteria for Response Assessment: The Lugano 
Classification (Cohort E, G-H) ................................................... 192 
Appendix D  Anaphylaxis Management............................................................ 196 
Appendix E  M. D. Anderson Symptom Inventory (MDASI).............................. 197 


 
TABLE OF CONTENTS (cont’d) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
47/P GO27834-A2 
Appendix F  Recommendations for the Use of White Blood Cell Growth 
Factors...................................................................................... 199 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
48/P GO27834-A2 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A RANDOMIZED, OPEN-LABEL, MULTICENTER, 
PHASE II TRIAL EVALUATING THE SAFETY AND 
ACTIVITY OF PINATUZUMAB VEDOTIN 
(DCDT2980S) IN COMBINATION WITH RITUXIMAB 
OR POLATUZUMAB VEDOTIN (DCDS4501A) IN 
COMBINATION WITH RITUXIMAB AND A NON-
RANDOMIZED PHASE Ib/II EVALUATION OF 
POLATUZUMAB VEDOTIN IN COMBINATION 
WITH OBINUTUZUMAB IN PATIENTS WITH 
RELAPSED OR REFRACTORY B-CELL 
NON-HODGKIN’S LYMPHOMA 
PROTOCOL NUMBER: GO27834 
EUDRACT NUMBER: 
2011−004377−84 
STUDY DRUG: 
Pinatuzumab Vedotin (DCDT2980S);  
Polatuzumab Vedotin (DCDS4501A) 
IND: 
107713 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA  94080-4990  U.S.A. 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return a copy of the form to the CRO Monitor at your site.  Please retain the 
original for your study files. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
49/P GO27834-A2 
PROTOCOL SYNOPSIS 
TITLE: 
A RANDOMIZED, OPEN-LABEL, MULTICENTER, PHASE II 
TRIAL EVALUATING THE SAFETY AND ACTIVITY OF 
PINATUZUMAB VEDOTIN (DCDT2980S) IN 
COMBINATION WITH RITUXIMAB OR POLATUZUMAB 
VEDOTIN (DCDS4501A) IN COMBINATION WITH 
RITUXIMAB AND A NON-RANDOMIZED PHASE Ib/II 
EVALUATION OF POLATUZUMAB VEDOTIN IN 
COMBINATION WITH OBINUTUZUMAB IN PATIENTS 
WITH RELAPSED OR REFRACTORY B-CELL 
NON-HODGKIN’S LYMPHOMA 
PROTOCOL NUMBER: 
GO27834 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2011-004377-84 
IND: 
107713 
STUDY DRUG: 
Pinatuzumab Vedotin (DCDT2980S);  
Polatuzumab Vedotin (DCDS4501A) 
PHASE: 
II 
INDICATION: 
Relapsed or refractory B-cell NHL 
SPONSOR: 
Genentech, Inc. 
 
Objectives 
Primary Objectives 
The primary objectives of this study are the following: 
• 
To assess the safety and tolerability of the combination of DCDT2980S and rituximab 
administered to patients with relapsed or refractory follicular non-Hodgkin’s lymphoma 
(NHL) and diffuse large B-cell lymphoma (DLBCL) 
• 
To assess the safety and tolerability of the combination of DCDS4501A and rituximab 
administered to patients with relapsed or refractory follicular NHL and DLBCL  
• 
To assess the safety and tolerability of the combination of DCDS4501A and 
obinutuzumab when administered to patients with relapsed or refractory follicular NHL 
or DLBCL 
• 
To assess the anti-tumor activity of the combination of DCDT2980S and rituximab in 
patients with relapsed or refractory follicular NHL and DLBCL 
• 
To assess the anti-tumor activity of the combination of DCDS4501A and rituximab in 
patients with relapsed or refractory follicular NHL and DLBCL 
• 
To assess the anti-tumor activity of the combination of DCDS4501A and obinutuzumab 
in patients with relapsed or refractory follicular NHL and DLBCL 
 
The secondary safety objectives of this study are the following: 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
50/P GO27834-A2 
• 
To assess the incidence of antibody formation to DCDT2980S, DCDS4501A, and 
obinutuzumab as measured by the formation of anti-therapeutic antibodies (ATAs) 
• 
To compare the safety and tolerability of the combination of DCT2980S and rituximab and 
DCDS4501A and rituximab or obinutuzumab 
 
Activity Objectives 
The secondary activity objective of the study is the following: 
• 
To compare the anti-tumor activity of the combination of DCT2980S and rituximab and 
DCDS4501A and rituximab or obinutuzumab 
 
Pharmacokinetic Objectives 
The pharmacokinetic (PK) objectives of this study are the following: 
• 
To characterize the pharmacokinetics of DCDT2980S and rituximab in patients with 
relapsed or refractory NHL when the two drugs are given in combination 
• 
To characterize the pharmacokinetics of DCDS4501A and rituximab or obinutuzumab in 
patients with relapsed or refractory NHL when the two drugs are given in combination 
 
Patient-Reported Outcome Objectives 
The objective of this study related to assessment of patient-reported outcomes (PRO) is the 
following: 
• 
To assess patient-reported tolerability to study treatment and the impact of study treatment 
on patient functioning, on the basis of PRO 
 
Biomarker Objectives 
The objectives of this study related to assessment of biologic markers are the following: 
• 
To make a preliminary assessment of biologic markers that might act as predictors of 
DCDT2980S + rituximab combination anti-tumor activity and allow assessment of response 
in different prognostic subgroups of DLBCL and follicular NHL 
• 
To make a preliminary assessment of biologic markers that might act as predictors of 
DCDS4501A + rituximab or obinutuzumab combination anti-tumor activity and allow 
assessment of response in different prognostic subgroups of DLBCL and follicular NHL 
 
Study Design 
Description of Study 
This is a Phase Ib/II, multicenter, open-label study.  Up to approximately 252 patients with 
relapsed or refractory FL and DLBCL will be enrolled at approximately 30−40 investigative sites 
worldwide.  Additional patients may be enrolled in order to obtain additional safety and/or 
efficacy data. Arms A and B and Cohort C are no longer enrolling patients. 
For Obinutuzumab Cohorts: 
Only investigational sites in the United States will enroll patients into Cohort E.  
Investigational sites in the United States and Canada will participate in Cohorts G and H). 
The study will be composed of a randomized portion and a non-randomized portion, as 
described in the protocol. 
Rituximab-Containing Regimens with DCDT2980S or DCDS4501A 
Randomized Portion of the Study (Arms A and B) 
Following determination of eligibility, patients within each disease group will be randomized in a 
1:1 ratio to receive one of two treatments: 
• 
Arm A:  Rituximab (375 mg/m2) followed by DCDT2980S (2.4 mg/kg) every 21 days; 
• 
Arm B:  Rituximab (375 mg/m2) followed by DCDS4501A (2.4 mg/kg) every 21 days 
 
The first day of treatment constitutes Day 1 of each cycle.  A typical cycle is 21 days in duration. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
51/P GO27834-A2 
A dynamic hierarchical randomization scheme will be employed with respect to the following 
stratification factors: 
• 
For patients with follicular lymphoma (FL) (see the protocol for definitions) 
Rituximab refractory disease (no response or disease relapse < 6 months from last 
rituximab treatment) versus rituximab relapsed disease (disease relapse after 
response ≥  6 months from last rituximab treatment) 
• 
For patients with DLBCL (see the protocol for definitions) 
Second-line versus third-line (or beyond) therapy 
For second-line patients, disease relapse or no objective response (complete response 
[CR], unconfirmed CR [CRu], or partial response [PR]) <12 months from the start of 
initial therapy versus disease relapse, after initial objective response (CR, unconfirmed 
response [CRu] or PR), ≥ 12 months from start of initial therapy  
For third-line patients, failure to achieve a CR or progression < 6 months from start of 
most recent therapy versus CR or progression ≥ 6 months from start of most recent 
therapy 
No formal testing comparing the two treatment arms in the randomized portion of the study is 
planned. 
Non-Randomized Portion of the Study with Rituximab (Cohorts C and D) 
Only select investigator sites that have agreed to participate in the non-randomized portion of 
the study will enroll patients into these cohorts. 
Patients with relapsed or refractory follicular NHL will be enrolled in Cohorts C and D to receive 
rituximab (375 mg/m2) combined with DCDT2980S or DCDS4501A at a dose of 1.8 mg/kg.  The 
first day of treatment constitutes Day 1 of each cycle.  A typical cycle will be 21 days in duration. 
The opening of either or both cohorts will be at the Sponsor’s discretion and only after the 
enrollment of patients with FL into the randomized portion of the study is completed.  Patients 
will not be randomized to receive one treatment or the other.  It is anticipated that Cohort C 
and D will be opened sequentially.   
All Patients on Rituximab-Containing Arms/Cohorts 
All patients on rituximab-containing regimens, regardless of assigned arm/cohort, will receive 
DCDT2980S or DCDS4501A and rituximab administered by intravenous (IV) infusion on a 
21-day cycle.  For the first two cycles, rituximab will be administered by IV infusion on Day 1 
and DCDT2980S or DCDS4501A will be administered by IV infusion on Day 2.  In the absence 
of any infusion-related adverse events, rituximab and DCDT2980S or DCDS4501A may be 
administered on the same day (Day 1) in subsequent cycles beginning with the third cycle.  In 
this instance, rituximab will be administered first, followed by DCDT2980S or DCDS4501A.  In 
certain circumstances⎯for example, infusion-related reactions (IRRs) requiring interruption or 
slowing of infusion rate⎯rituximab may be administered over 2 days (e.g., Day 1 and Day 2 of 
the cycle); in this case, DCDT2980S or DCDS4501A may be administered on Day 2 following 
completion of the rituximab infusion or on Day 3 of the cycle. 
Patients may receive treatments for up to 1 year (17 cycles on an every-21-day schedule) if not 
discontinued because of significant toxicity, disease progression, or withdrawal from study. 
Patients will be evaluated for safety and efficacy according to the Schedules of Assessments 
outlined in the protocol.  Initial response assessments in this study will be performed every 
3 months from the initiation of therapy until study treatment completion or early termination 
(e.g., between Days 14 and 21 of Cycles 4 and 8 for those patients receiving at least 
eight 21-day cycles of treatment).  Additional response assessments for patients who proceed 
to crossover treatment will be performed as described in the protocol; response assessments 
for patients who discontinue study treatment (both initially assigned treatment and crossover 
treatment) for reasons other than disease progression will be performed as described in the 
protocol. 
Responses to study treatment will be based on investigator assessments.  In addition, tumor 
assessment data will be transmitted to an Independent Review Facility (IRF) for collection and 
possible independent review. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
52/P GO27834-A2 
Obinutuzumab-Containing Regimens with DCDS4501A (Cohorts E,  G, and H) 
DCDS4501A at 1.8 mg/kg will be given in combination with obinutuzumab to patients with 
relapsed or refractory follicular NHL and DLBCL in two stages: (1) safety run-in and (2) 
expansion. 
Study treatment will be given in 21-day cycles for both follicular NHL and DLBCL.  Patients 
will be treated for up to a total of 8 cycles.  For the first cycle, obinutuzumab will be 
administered by IV infusion on Days 1, 8, and 15.  DCDS4501A will be given on Day 2 for 
Cycle 1.  In the absence of any infusion-related adverse events, obinutuzumab and 
DCDS4501A may be administered on the same day (Day 1) in subsequent cycles beginning 
with the second cycle.  If obinutuzumab and DCDS4501A are administered on the same day, 
the study drugs will be given sequentially.  Obinutuzumab will be administered first, 
followed by DCDS4501A.  In certain circumstances⎯for example, IRRs requiring 
interruption or slowing of infusion rate⎯obinutuzumab may be administered over 2 days 
(e.g., Day 1 and Day 2 of the cycle); in this case, DCDS4501A may be administered on Day 2 
following completion of the obinutuzumab infusion. 
Obinutuzumab-Containing Regimen in Phase Ib: Safety Run-In (Cohort E) 
This portion of the study will consist of a safety run-in that will evaluate the safety of 
DCDS4501A at 1.8 mg/kg in combination with obinutuzumab in 6 patients (Cohort E).  The 
safety run-in is described in detail in the protocol.  In case an amendment to the protocol 
allows to study higher doses of DCDS4501A, the safety run-in for the 1.8 mg/kg may be 
shortened to 3 patients. 
Obinutuzumab-Containing Regimens in Phase II:  Expansion Stage (Cohorts G and H) 
After the safety run-in has demonstrated that DCDS4501A at 1.8 mg/kg in combination with 
obinutuzumab is safe to administer, patients will be enrolled into two expansion cohorts based 
on histology of follicular NHL or DLBCL (Cohorts G and H respectively).  Forty patients will 
be enrolled into each expansion cohort.  An additional cohort(s) may be added in the future. 
Follicular NHL Patients for Rituximab-Containing Arms/Cohorts 
Patients with relapsed or refractory follicular NHL will be enrolled into the study as defined by 
the following: 
• 
Relapsed to regimens containing rituximab, defined as documented history of response 
(CR, CRu, or PR) of ≥ 6 months in duration from completion of all prior rituximab-containing 
regimens.  A rituximab-containing regimen is defined as rituximab as a single agent during 
induction and/or maintenance or in combination with other agents during induction and/or 
maintenance. 
• 
Refractory to any prior regimen containing rituximab, defined as no response to or 
progression within 6 months of completion of the last dose of rituximab therapy (either as 
monotherapy or in combination with chemotherapy), including: 
Patients with progressive disease while receiving rituximab monotherapy, 
rituximab combined with chemotherapy, or rituximab maintenance therapy; patients 
must have received at least one full dose (375 mg/m2) of rituximab. 
Patients with no objective response (PR or CR) to a rituximab-containing regimen 
consisting of at least 4 weekly doses of rituximab monotherapy or at least 4 cycles of 
rituximab combined with chemotherapy 
Patients with disease relapse, after having achieved an objective response, within 
6 months of completion of the last dose of rituximab therapy in a regimen consisting of 
at least four weekly doses of rituximab monotherapy or at least 4 cycles of rituximab 
combined with chemotherapy 
 
Enrollment of patients with refractory disease as defined above may be limited to no greater 
than 60% of the total follicular NHL cohort, in order to avoid overrepresentation of the refractory 
disease population. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
53/P GO27834-A2 
Follicular NHL Patients for Obinutuzumab-Containing Cohorts 
Patients with relapsed or refractory follicular NHL will be enrolled into the study as defined by the 
following: 
• 
Relapsed to prior regimen(s) after having a documented history of response (CR, CRu, or PR) of 
≥ 6 months in duration from completion of regimen(s)   
• 
Refractory to any prior regimen, defined as no response to the prior therapy, or progression within 
6 months of completion of the last dose of therapy 
DLBCL Patients for Rituximab-Containing Arms/Cohorts 
Patients with relapsed or refractory DLBCL who are determined by the investigator to be 
ineligible for high-dose therapy with autologous stem cell rescue/stem cell transplant (SCT) will 
be enrolled into the study as defined by the following: 
• 
Second-line SCT-ineligible patients with progressive disease or no response 
(SD) < 12 months from start of initial therapy (second-line refractory) 
• 
Second-line SCT-ineligible patients with disease relapse after initial response ≥ 12 months 
from start of initial therapy (second-line relapsed) 
• 
Third-line (or beyond) SCT-ineligible patients with progressive disease or no response 
(SD) < 6 months from start of prior therapy (third-line + refractory) 
• 
Third-line (or beyond) SCT-ineligible patients with disease relapse after initial response 
≥ 6 months from start of prior therapy (third-line + relapsed) 
 
Enrollment into any of the above four categories may be limited to no greater than 40% of the 
DLBCL cohort—and to no more than 60% of the two refractory categories combined—in order 
to avoid overrepresentation of any specific subpopulation, refractory patients in particular. 
DLBCL Patients for Obinutuzumab-Containing Cohorts 
Patients with relapsed or refractory DLBCL who are determined by the investigator to be ineligible for 
high-dose therapy with autologous stem cell rescue/SCT as determined by the investigator will be 
enrolled into the study as defined by the following: 
• 
Second-line SCT-ineligible patients with progressive disease or no response (SD) < 12 months from 
start of initial therapy (second-line refractory) 
• 
Second-line SCT-ineligible patients with disease relapse after initial response ≥ 12 months from start 
of initial therapy (second-line relapsed) 
• 
Third-line (or beyond) SCT-ineligible patients with progressive disease or no response 
(SD) < 6 months from start of prior therapy (third-line + refractory) 
• 
Third-line (or beyond) SCT-ineligible patients with disease relapse after initial response ≥ 6 months 
from start of prior therapy (third-line + relapsed) 
 
Crossover Treatment (Randomized Patients in Arms A and B Only) 
Patients randomized to Arm A or Arm B who develop progressive disease may be eligible to 
receive crossover treatment consisting of rituximab and the other antibody-drug conjugate 
(ADC) or the other ADC alone⎯for example, Arm B treatment for patients who have disease 
progression while receiving Arm A treatment, and vice versa⎯provided the following conditions 
are met: 
• 
Patients must not have experienced a toxicity requiring the discontinuation of 
DCDT2980S/DCDS4501A treatment OR experienced toxicity during the last dose of study 
treatment that would preclude treatment with the crossover regimen. 
Patients who had modifications to dosing and/or schedule on the initial study treatment 
will be permitted to receive crossover treatment in the absence of toxicities on the 
modified dose and/or schedule.  The dose and schedule of crossover treatment will be 
determined by the investigator and the Medical Monitor. 
Patients who had rituximab discontinued and continued on single-agent 
DCDT2980S/DCDS4501A treatment may receive crossover treatment of single-agent 
DCDS4501A/ DCDT2980S. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
54/P GO27834-A2 
• 
Patients must have radiographically documented disease progression. 
• 
Patients must meet all inclusion and exclusion criteria described in the Inclusion Criteria 
and Exclusion Criteria sections below, except for those related to prior rituximab treatment. 
• 
Acceptable toxicity:  All study drug–related adverse events from the initial study treatment 
must have decreased to Grade 1 or baseline grade on or before the first day of treatment 
on the crossover regimen.  Exceptions may be allowed after a careful assessment and 
discussion of the benefit-risk balance with the patient by the investigator and approval from 
the Medical Monitor. 
• 
Administration of crossover treatment must be in the best interests of the patient as 
determined after a careful assessment and discussion of benefit-risk balance with the 
patient by the investigator and approval from the Medical Monitor. 
• 
A tumor biopsy (described in the protocol) will be required for patients with safely accessible 
site of disease, defined as requiring only local anesthesia and, in general, excluding the 
brain, lungs or any internal organs that may subject patients to significant risk.  
Patients for whom a safely accessible site of disease is not present may still receive 
crossover treatment without undergoing a biopsy.  Eligibility to receive crossover 
treatment should be discussed with and approved by the Medical Monitor. 
A tumor biopsy of a safely accessible site of disease is optional for patients who are 
not eligible for study cross over.  
 Patients who are determined to be eligible for study cross over will be treated as follows: 
• 
Assessments obtained at the initial study treatment discontinuation visit (described in the 
protocol) may be used as screening assessments for crossover treatment.  The following 
re-screening assessments must be repeated/obtained within 1 week prior to starting 
treatment on the crossover regimen, in order to re-establish baseline pretreatment clinical 
and disease status:  targeted physical exam, Eastern Cooperative Oncology Group (ECOG) 
status, and hematology and serum chemistry laboratory tests. 
Re-screening tests for hepatitis B and C do not need to be performed unless there is 
clinical suspicion of hepatitis B and/or C positivity. 
A radiographic tumor assessment must also be performed, unless already done to 
document disease progression, within 6 weeks prior to starting crossover treatment. 
• 
Crossover treatment will begin no later than 42 days after the last dose of the prior study 
treatment. 
 
Patients will be treated with the crossover treatment until a second disease progression event 
relative to the tumor assessment, documenting progressive disease on the initial study 
treatment, clinical deterioration, and/or intolerance to the crossover treatment for up to a 
maximum of 1 year (17 cycles on an every-21-day schedule).  Patients will be evaluated for 
safety and efficacy according to the schedules of assessments outlined in the protocol.  
Response assessments for patients who discontinue study treatment for reasons other than 
disease progression will be performed as described in the protocol.  
Clinical data and exploratory data derived from tumor biopsies obtained prior to crossover 
treatment will be monitored on an ongoing basis.  Genentech has the right to restrict or suspend 
enrollment into crossover treatment at any time.  Reasons for this may include, but are not 
limited to, the following: 
• 
The incidence or severity of adverse events during crossover treatment indicates a potential 
safety hazard to patients. 
• 
Patient enrollment into crossover treatment is unsatisfactory. 
• 
Data recording is inaccurate or incomplete.  
• 
Patients who are enrolled into the non-randomized portion of the study (Cohorts C, D, E , 
G, and H) will not have the option to receive crossover treatment upon disease progression. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
55/P GO27834-A2 
Number of Patients 
Up to approximately 252 patients with relapsed or refractory FL and DLBCL will be enrolled at 
approximately 30−40 investigative sites worldwide.  Additional patients may be enrolled in order 
to obtain additional safety and/or efficacy data.  
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form(s) 
• 
Age ≥ 18 years  
• 
ECOG Performance Status of 0, 1, or 2 
• 
Life expectancy of at least 12 weeks 
• 
History of histologically documented relapsed or refractory Grades 1−3a FL or relapsed or 
refractory DLBCL 
• 
Availability of an archival or freshly biopsied tumor tissue sample must be confirmed for 
study enrollment. 
• 
Have a clinical indication for treatment as determined by the investigator 
• 
Must have at least one bidimensionally measurable lesion (> 1.5 cm in its largest dimension 
by computed tomography [CT] scan or magnetic resonance imaging [MRI]) 
• 
Laboratory values (including patients with hepatic or renal involvement), as follows: 
AST and ALT ≤ 2.5 × ULN 
Total bilirubin ≤ 1.5 × ULN 
Platelet count ≥ 75,000/mm3 (unless thrombocytopenia clearly due to marrow 
involvement of NHL and/or disease-related immune thrombocytopenia) 
Absolute neutrophil count ≥ 1000/mm3 (without growth factor support, unless 
neutropenia clearly due to marrow involvement of NHL) 
Total hemoglobin ≥ 9 g/dL (without transfusion support > 14 days prior to screening, 
unless anemia clearly due to marrow involvement of NHL) 
Serum creatinine ≤ 2.0 mg/dL or measured creatinine CL ≥ 50 mL/min 
• 
For female patients of childbearing potential and male patients with female partners of 
childbearing potential, agreement to use one highly effective form of nonhormonal 
contraception or two effective forms of nonhormonal contraception, including at least one 
method with a failure rate of < 1% per year, through the course of study treatment and for 
≥ 12 months after the last dose of DCDT2980S, DCDS4501A, rituximab, or obinutuzumab 
(whichever is later) in women and at least 5 months after the last dose of DCDT2980S, 
DCDS4501A, rituximab, or obinutuzumab (whichever is later) in men 
A woman is considered not to be of childbearing potential if she is postmenopausal, 
defined by amenorrhea of ≥ 12 months duration and age ≥ 45 years, or has undergone 
hysterectomy and/or bilateral oophorectomy. 
The following are considered highly effective forms of contraception:  1) true 
abstinence; 2) male sterilization (with post-procedure documentation of absence of 
sperm in the ejaculate).  For female patients, the sterilized male partner should be the 
sole partner. 
The following are considered effective forms of contraception:  1) intrauterine device 
(IUD; copper IUD or hormonal IUDs only) or intrauterine system; 2) condom with 
spermicidal foam/gel/film/cream/suppository; 3) occlusive cap (diaphragm or 
cervical/vault cap) with spermicidal foam/gel/film/cream/suppository. 
Males must agree to abstain from sperm donation for at least 5 months after the last 
dose of DCDT2980S or, DCDS4501A or, rituximab, or obinutuzumab (whichever is 
later). 
 
Exclusion Criteria 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
56/P GO27834-A2 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Prior use of any MAb, radioimmunoconjugate or ADC within 4 weeks before Cycle 1, Day 1 
• 
Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, 
or any investigational anti-cancer agent within 2 weeks prior to Cycle 1, Day 1 
Adverse events except for sensory neuropathy from any previous treatments must be 
resolved or stabilized to Grade ≤ 2 prior to Cycle 1, Day 1. 
• 
Completion of autologous stem cell transplant within 100 days prior to Cycle 1, Day 1 
• 
Prior allogeneic stem cell transplant 
• 
Eligibility for autologous SCT (patients with relapsed or refractory DLBCL) 
• 
History of transformation of indolent disease to DLBCL 
• 
History of severe allergic or anaphylactic reactions to MAb therapy (or recombinant 
antibody-related fusion proteins) 
• 
History of other malignancy that could affect compliance with the protocol or interpretation 
of results 
Patients with a history of curatively treated basal or squamous cell carcinoma of the 
skin or in situ carcinoma (e.g., of the cervix or breast) are allowed.  Patients with a 
malignancy that has been treated with curative intent will also be allowed if the 
malignancy has been in remission without treatment for ≥ 2 years prior to Cycle 1, 
Day 1. 
• 
Current or past history of CNS lymphoma 
• 
Current Grade > 1 peripheral neuropathy 
• 
Evidence of significant, uncontrolled, concomitant diseases that could affect compliance 
with the protocol or interpretation of results, including significant cardiovascular disease 
(such as New York Heart Association Class III or IV cardiac disease, myocardial infarction 
within the last 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary 
disease (including obstructive pulmonary disease and history of bronchospasm) 
• 
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding 
fungal infections of nail beds) at study enrollment or any major episode of infection requiring 
treatment with IV antibiotics or hospitalization (relating to the completion of the course of 
antibiotics) within 4 weeks prior to Cycle 1, Day 1 
• 
Recent major surgery within 6 weeks prior to Cycle 1, Day 1, other than for diagnosis 
• 
Presence of positive test results for hepatitis B (HBsAg and/or total anti-HBc) or hepatitis C 
(HCV antibody) 
Patients who are positive for anti-HBc are eligible only if polymerase chain reaction 
(PCR) is negative for HBV DNA and it is believed by both the investigator and Medical 
Monitor that it is in the patient’s best interest to participate.  
Patients who are positive for HCV antibody must be negative for HCV by PCR to be 
eligible for study participation. 
• 
Known history of HIV seropositive status 
• 
Women who are pregnant or lactating 
• 
Ongoing corticosteroid use > 30 mg/day prednisone or equivalent 
Patients receiving corticosteroid treatment ≤ 30 mg/day prednisone or equivalent must 
be documented to be on a stable dose prior to study enrollment and initiation of 
therapy 
 
Length of Study 
The length of study will be the time from screening of the first enrolled patient through 2 years 
after the Treatment Completion Visit for the last enrolled patient on an obinutuzumab-containing 
regimen.  The length of the study for the obinutuzumab-containing cohorts is expected to be 
approximately 48 months. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
57/P GO27834-A2 
End of Study 
The end of study is defined as the timepoint at which patients enrolled in the 
obinutuzumab-containing regimens in the study have had at least 2 years of follow-up from the 
time of the Treatment Completion Visit or have discontinued from the study. 
Outcome Measures 
Safety Outcome Measures 
The safety and tolerability of the combination of DCDT2980S and rituximab and DCDS4501A 
and rituximab or obinutuzumab will be assessed using the following safety outcome measures: 
• 
Incidence, nature, and severity of adverse events 
• 
Incidence of anti-DCDT2980S, anti-DCDS4501A, or anti-obinutuzumab antibodies 
• 
Changes in vital signs 
• 
Changes in laboratory values 
 
The determination of the DCDS4501A RP2D in combination with obinutuzumab will be 
assessed using the following primary safety outcome measures for the Phase Ib portion of the 
study: 
• 
Incidence and nature of DLTs 
• 
Incidence, nature, and severity of adverse events and serious adverse events 
• 
Changes in vital signs, physical findings, ECGs, and clinical laboratory values during 
and following study treatment administration 
 
Pharmacokinetic/ Pharmacodynamic Outcome Measures 
The following PK parameters will be derived from the serum concentration–time profiles of total 
antibody (the sum of conjugated and unconjugated antibody), including rituximab or 
obinutuzumab, and plasma concentration-time profiles of antibody-conjugated monomethyl 
auristatin E (acMMAE) and free MMAE following administration of DCDT2980S or DCDS4501A, 
when appropriate, as data allow: 
• 
Total exposure (area under the concentration-time curve [AUC]) 
• 
Maximum plasma and serum concentration (Cmax) 
• 
Clearance (CL) 
• 
Terminal half-life (t1/2) 
• 
Steady-state volume of distribution (Vss) 
 
Compartmental, non-compartmental, and/or population methods may be used.  Other 
parameters, such as accumulation ratio and trough plasma and serum concentration (Cmin), may 
also be calculated. 
The following PD outcome measures will be assessed when appropriate, as data allow: 
• 
Peripheral blood B-cell depletion and recovery.  For each visit at which CD19+ B-cell 
measurements are taken, B-cell data will be listed for each patient by dose level as follows: 
Absolute blood cell counts 
Percent change relative to the baseline blood counts 
CD19+ B-cell recovery, defined as the timepoint when the values return to baseline 
levels or ≥ 50% of baseline levels 
 
Activity Outcome Measures 
The following activity outcome measures will be assessed: 
• 
Objective response, defined as a PR or CR 
• 
Duration of objective response, defined as the duration of time from the first occurrence of 
a documented objective response to time of relapse or death from any cause 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
58/P GO27834-A2 
• 
Progression-free survival (PFS), defined as the duration from initial randomization to the 
first occurrence of progression or death within 30 days of the last administration of study 
drug, whichever occurs first 
• 
Overall survival (OS), defined as the duration from the date of randomization/enrollment to 
the date of death from any cause 
 
Objective response and disease progression will be determined using standard criteria for NHL. 
Exploratory Outcome Measures 
The exploratory outcome measures will include, but will not be limited to, the following:  
• 
Confirmation and quantitation of CD22, CD79b, and CD20 expression levels in either 
archival or freshly obtained (when available) tumor specimens (tumor biopsies, 
bone marrow biopsies, peripheral blood) by immunohistochemistry/flow 
cytometry/quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) 
• 
Additional assessments related to the understanding of the mechanism of action of 
DCDT2980S, DCDS4501A, rituximab, and obinutuzumab, mechanisms of resistance to 
DCDT2980S, DCDS4501A, rituximab, and obinutuzumab, and/or NHL pathogenesis may 
be included. 
• 
Treatment and disease symptom assessments using the M.D. Anderson Symptom 
Inventory (MDASI) 
 
Investigational Medicinal Products 
Test Product 
Pinatuzumab Vedotin (DCDT2980S) and Polatuzumab Vedotin (DCDS4501A) 
Patients will receive DCDT2980S or DCDS4501A at 1.8 mg/kg or 2.4 mg/kg by IV infusion on 
Day 1 or Day 2 for each cycle.  The total dose of DCDT2980S or DCDS4501A for each patient 
will be determined by the dose cohort to which the patient is assigned and depend on the 
patient’s weight within 96 hours prior to Day 1 of each cycle. 
Rituximab 
All patients in rituximab-containing arms/cohorts will receive DCDT2980S or DCDS4501A and 
rituximab administered by IV infusion on a 21-day cycle.  For the first two cycles, patients will 
receive rituximab 375 mg/m2 by IV infusion on Day 1 and DCDT2980S or DCDS4501A by IV 
infusion on Day 2.  In the absence of any infusion-related adverse events, rituximab 375 mg/m2 
and DCDT2980S or DCDS4501A may be administered on the same day (Day 1) in subsequent 
cycles beginning with the third cycle.  In this case, rituximab will be administered first, followed 
by DCDT2980S or DCDS4501A. 
Obinutuzumab 
Patients in obinutuzumab-containing cohorts will receive DCDS4501A and obinutuzumab 
administered by IV infusion on a 21-day cycle.  For the first cycle, patients will receive 
obinutuzumab 1000 mg by IV infusion on Days 1, 8, and 15.  DCDS4501A will be given on 
Day 2 for Cycle 1.  In the absence of any infusion-related adverse events, obinutuzumab and 
DCDS4501A may be administered on the same day (Day 1) in subsequent cycles beginning 
with the second cycle. 
Non-Investigational Medicinal Products 
Not applicable. 
Statistical Methods 
The final analysis will be based on patient data collected until all patients discontinue from the 
study or the study is terminated by the Sponsor, whichever occurs first.  The analyses will be 
based on the safety evaluable population, defined as patients who received at least one dose of 
study treatment.  All summaries will be presented according to the disease-specific cohort, 
treatment group, and assigned dose level. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
59/P GO27834-A2 
Analysis of the Conduct of the Study 
Enrollment, major protocol violations, and reasons for discontinuations from the study will be 
summarized. 
Demographic and baseline characteristics, such as age, sex, race/ethnicity, weight, duration of 
malignancy, and baseline ECOG Performance Status, will be summarized using means, 
standard deviations, medians, and ranges for continuous variables and proportions for 
categorical variables.  All summaries will be presented overall and by treatment group, assigned 
dose level, and disease-specific cohort. 
Study drug administration data will be listed by the disease-specific cohorts described in the 
protocol.  Any dose modifications will be flagged.  Means and standard deviations will be used 
to summarize the total doses of DCDT2980S, DCDS4501A, rituximab, and obinutuzumab 
received.  All summaries will be presented by treatment group, assigned dose level, and 
disease-specific cohort. 
Safety Analysis 
Safety will be assessed through summaries of adverse events, changes in laboratory test 
results, changes in physical findings on physical examinations, and changes in vital signs.  All 
patients who receive any amount of DCDT2980S, DCDS4501A, rituximab, or obinutuzumab 
will be included in the safety analysis and will be assigned to the treatment group on the basis 
of the study treatment received.  Patients who have dose level changes from the initial assigned 
dose level will be summarized by the initial assigned dose level of DCDT2980S or DCDS4501A. 
All adverse event data will be listed by study site, patient number, treatment group, 
disease-specific cohort, and cycle.  All adverse events occurring on or after treatment on Day 1 
of Cycle 1 will be summarized by mapped terms, appropriate thesaurus levels, and 
NCI CTCAE v4.0 toxicity grade.  In addition, all serious adverse events, including deaths will be 
listed separately and summarized.   
Selected laboratory data will be listed, with values outside of normal ranges identified.  The 
incidence of antibodies to DCDT2980S and DCDS4501A will be summarized. 
Pharmacokinetic and Pharmacodynamic Analyses 
Individual and mean serum concentrations of total DCDT2980S or DCDS4501A antibody 
(conjugated and unconjugated antibody) and rituximab or obinutuzumab and plasma 
concentrations of acMMAE and free MMAE versus time data will be tabulated and plotted by 
NHL disease subtype (relapsed or refractory follicular NHL or DLBCL).  The pharmacokinetics 
of the above analytes will be summarized by estimating the appropriate PK parameters 
(e.g., AUC, Cmax, CL, Vss, and t1/2).  Estimates for these parameters will be tabulated and 
summarized (mean, standard deviation, and range).  Non-compartmental, compartmental, 
and/or population methods will be used, as data allow.  
Exposure-response (safety and efficacy) analysis may be conducted with use of PK data and 
available drug effect (e.g., imaging, measures of tumor burden) and toxicity (e.g., clinical 
pathology) data, at the sponsor’s discretion. 
In addition, population PK methods may be employed to manage sparse data and to investigate 
the effects of certain covariates on the pharmacokinetics of DCDT2980S and DCDS4501A, as 
data allow, and at the sponsor’s discretion. 
Activity Analyses 
Best overall response, duration of response, and PFS will be listed for all patients. 
Overall response rate (ORR) from the initial study treatment will be calculated on the basis of 
data from patients who received study treatment.  Objective response is defined as CR or PR 
as determined by the investigator, on the basis of physical examinations, radiographic scans, 
and bone marrow examinations, using modified response criteria for NHL and confirmed by 
repeat assessments ≥ 4 weeks after initial documentation.  Any patient with insufficient data to 
determine response will be classified as a non-responder. 
For patients with DLBCL, primary assessment of tumor response will be based on diagnostic 
imaging scans⎯for example, CT and/or MRI scans and positron emission tomography (PET) 
scans.  For patients with FL enrolled on rituximab-containing arms/cohorts, primary 
assessment of response will be based on CT scans only; the assessment of response in FL 
based on PET scans will be performed for exploratory purposes only. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
60/P GO27834-A2 
For patients with DLBCL or FL on obinutuzumab-containing cohorts, primary assessment of 
tumor response will be based on PET/CT scans.  Given the new Lugano Classification, 2014, 
criteria which recommend that complete response (PET-CR) be determined by PET-CT scan, 
patients in Cohorts E, G, and H will be evaluated with a PET-CT scan at screening, between 
Cycle 4 Day 15 and Cycle 5 Day 1, and at 6-8 weeks after completing treatment.  The efficacy 
analysis for these cohorts will, therefore, be different from the analysis for Arms A-B and 
Cohorts C-D. (Cheson, et al 2014) (see Appendix C-2) 
Among patients with an objective response, duration of response will be defined as the time 
from the initial documentation of a CR or PR to the time of disease progression or death.  If a 
patient does not experience death or disease progression before the end of the study, duration 
of response will be censored at the day of the last tumor assessment. 
For the randomized portion of the study (Arms A and B), PFS is defined as the time from the 
date of randomization to the date of disease progression or death from any cause, whichever 
occurs first.  If a patient has not experienced progressive disease or death, PFS will be 
censored at the date of the last tumor assessment.  Patients with no post-baseline tumor 
assessment will be censored on the date of randomization.  For the non-randomized portion of 
the study (Cohorts C through H), PFS is defined as the time from the date of study enrollment 
to the date of disease progression or death from any cause, whichever occurs first. 
For the randomized portion of the study (Arms A and B), OS is defined as the time from the date 
of randomization to the date of death from any cause.  For the non-randomized portion of the 
study (Cohorts C through H), OS is defined as the time from the date of study enrollment to 
date of death from any cause. 
Exploratory Analyses 
Assay results of possible predictive markers will be listed by treatment group and response 
status. 
Summary statistics of the MDASI items, scales, and their changes from baseline will be 
calculated at each assessment timepoint.  The mean, standard error, and median of the 
absolute scores and the mean changes from baseline (and 95% CI) within and between study 
arms will be reported for the MDASI scales and single items, as well as the weekly averages of 
the worst symptom rating.  For change scores in the MDASI from baseline, patients without 
baseline scores will not be included in the analyses.  Line charts depicting the means and mean 
changes of subscales over time will be also provided.   
Frequencies and percentages of missing data for the PRO endpoints will be reported.  Dropouts 
(defined as patients withdrawing from treatment for reasons other than documented disease 
progression or death) will be summarized. 
Repeated measures mixed-effects models will explore MDASI subscale scores with a baseline 
score and appropriate covariates added, as appropriate. 
Handling of Missing Data 
For the endpoint of objective response, patients without a post-baseline tumor assessment will 
be considered non-responders in the all-treated population analysis.  
For duration of response and PFS, data from patients who are lost to follow-up will be included 
in the analysis as censored observations on the last date that the patient is known to be 
progression free, defined as the date of the last tumor assessment, or, if no tumor assessments 
were performed, as the date of last study treatment plus 1 day. 
Compliance to PRO data collection will be reported with summary statistics, including 
frequencies of reasons for non-compliance such as patient refusal to complete PRO data 
collection.   
Determination of Sample Size 
For the randomized portion of the study (Arms A and B), a target of 120 patients will be enrolled 
in two separate cohorts of patients (40 in the follicular NHL cohort and 80 in the DLBCL cohort).  
The randomized portion of this study is non-comparative in nature.  No formal hypothesis 
testing is planned to compare the treatment arms.  Moreover, there is insufficient power to 
detect minimum clinically meaningful differences between the two treatment arms.  
Genentech has judged the proposed sample size to provide sufficient precision in estimating the 
anti-tumor activity of DCDT2980S combined with rituximab or DCDS4501A combined with 


 
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rituximab as measured by objective response.  For example, with the assumption of an 
observed response rate of 40%, a 90% confidence interval for the response rate would be 
approximately 22%−58% (i.e., 40% ± 18%) for the follicular NHL cohort and approximately 
27%−53% (i.e., 40% ± 13%) for the DLBCL cohort.  With 40 patients, there is an 87% chance 
of observing at least one adverse event with a true incidence of 5%. 
For the non-randomized portions of the study (Cohorts C and D), approximately 20 patients 
will be enrolled into each arm, for a total of 40 patients.   With 20 patients under an observed 
response rate of 40%, the exact Clopper-Pearson 90% confidence interval for the response rate 
would be 22%−61%.  With respect to the assessment of safety based upon a sample size of 
20 patients, the chance of observing at least one adverse event with a true incidence of 10% is 
88%. 
For the obinutuzumab safety run-in cohort (Cohort E), 6 patients will be enrolled.  For the 
obinutuzumab expansion cohorts (Cohorts G and H), 40 patients with follicular NHL and 
40 patients with DLBCL will be enrolled at the RP2D to further evaluate safety and efficacy 
of the combination.  Table 3 in the protocol provides asymptotic 90% confidence intervals for the true 
probability of response for a range of observed proportions based upon a sample of 40 patients.  A sample 
size of 40 patients is deemed sufficient to provide adequate precision on the point estimate and for the 
lower end of the 90% CI to rule out a clinically uninteresting rate of 45% assuming observed response 
rates of approximately 60% or higher (~24 responders observed among 40 patients). 
Therefore, up to 252 patients may be enrolled in this study.  
 


 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ac 
antibody-conjugated 
ADC 
antibody−drug conjugate  
ADCC 
antibody-dependent cellular cytotoxicity 
ADCP 
antibody-dependent cell-mediated phagocytosis 
AE 
adverse event 
anti-HBc 
hepatitis B core antibody 
ASCO 
American Society of Clinical Oncology 
ATA 
anti-therapeutic antibody 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from 0 to 24 hours 
AUCinf 
area under the concentration-time curve from 0 to infinity 
CDC 
complement-dependent cytotoxicity  
CHOP 
cyclophosphamide, doxorubicin, vincristine, and prednisone 
CL 
clearance  
CLL 
chronic lymphocytic leukemia  
Cmax 
maximum plasma and serum concentration 
Cmin 
trough plasma and serum concentration 
CR 
complete response 
CRu 
unconfirmed response 
CT 
computed tomography (scan) 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVP 
cyclophosphamide, vincristine, and prednisone 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EC 
ethics committee 
eCRF 
electronic Case Report Form  
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture  
EFS 
event-free survival 
EMA 
European Medicines Agency 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
EOT 
end of treatment 
FACS 
fluorescence-activated cell sorting 


 
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Abbreviation 
Definition 
FBS 
fasting blood sugar 
FDA 
U.S. Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FL 
follicular lymphoma 
G 
GA101 or obinutuzumab 
G-CHOP 
obinutuzumab, cyclophosphamide, doxorubicin, vincristine, 
and prednisone 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
HbsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HNSTD 
highest non-severely toxic dose 
HPW 
highly purified water 
ICH 
International Conference on Harmonisation 
IgG1 
immunoglobulin-G1  
IHC 
immunohistochemistry 
IL 
interleukin 
IMC 
Internal Monitoring Committee 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
iNHL 
indolent non-Hodgkin’s lymphoma 
IP 
interferon-inducible protein 
IRB 
Institutional Review Board 
IRF 
Independent Review Facility 
IRR 
infusion-related reaction 
ISH 
in situ hybridization 
IV 
intravenous 
IXRS 
Interactive Voice and Web Response System 
JC 
John Cunningham 
Kd 
equilibrium dissociation constant 
LC-MS/MS 
liquid chromatography–tandem mass spectrometry 
LMWH 
low-molecular weight heparin 
MCL 
mantle cell lymphoma 
MC-VC-PABC 
maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl 
MDASI 
M.D. Anderson Symptom Inventory 
MMAE 
monomethyl auristatin E  


 
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Abbreviation 
Definition 
MAb 
monoclonal antibody 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose  
MZL 
marginal zone lymphoma 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphoma 
NK 
natural killer 
NOAC 
new oral anticoagulant 
ORR 
overall response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PE 
polyethylene 
PET 
positron emission topography 
PD 
pharmacodynamic 
PFS 
progression-free survival 
PK 
pharmacokinetic  
PML 
progressive multifocal leukoencephalopathy 
PP 
polypropylene 
PR 
partial response 
PRO 
patient-reported outcomes 
PVC 
polyvinyl chloride 
PUR 
polyurethane 
qRT-PCR 
quantitative reverse transcriptase polymerase chain reaction 
q3w 
every 3 weeks 
R 
rituximab 
R-CHOP 
rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone 
RP2D 
recommended Phase II dose 
SAE 
serious adverse event 
SC 
subcutaneous 
SCID 
severe combined immunodeficient 
SCT 
stem cell transplant 
SD 
stable disease 
SDV 
source data verification 
SmPC 
Summary of Product Characteristics 


 
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Abbreviation 
Definition 
STD10 
severely toxic dose to 10% 
SWFI 
Sterile Water for Injection 
t1/2 
terminal half-life 
TLS 
tumor lysis syndrome  
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
Vss 
steady-state volume of distribution 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON DISEASE  
B-cell lymphoproliferative disorders are a heterogeneous group of malignancies, ranging 
from slow-growing indolent and incurable diseases with a median survival of 8−10 years 
(such as follicular non-Hodgkin’s lymphoma [NHL]) to more aggressive intermediate- to 
high-grade lymphomas (such as diffuse large-cell lymphoma), which can have a median 
survival of 6 months if left untreated or long-term remission in more than 50% of patients 
with appropriate treatment.  Diffuse large B-cell lymphoma (DLBCL) is the most common 
type of NHL accounting for approximately 30%−40% of all new patients, whereas 
follicular lymphoma (FL) accounts for approximately 20%−25% of new lymphomas.   
Despite advances in the clinical outcomes of patients with NHL using treatments such as 
the CD20-specific monoclonal antibody (MAb) rituximab (Rituxan®, MabThera®) in 
combination with chemotherapy, indolent B-cell malignancies remain incurable, as do 
approximately half of aggressive NHL patients.  Thus, there is still a need for treatments 
that can be combined with chemoimmunotherapy and can significantly extend 
disease-free and overall survival (OS) in these patients, with at least acceptable, if not 
superior, safety profiles. 
1.2 
BACKGROUND ON THE MOLECULES 
1.2.1 
DCDT2980S 
1.2.1.1 
Background and Preclinical Data 
CD22 is a cell-surface antigen whose expression is restricted to all mature B cells except 
plasma cells.  It is expressed in a majority of the B cell−derived malignancies, including 
nearly all NHL and chronic lymphocytic leukemia (CLL) samples tested (see Figure 1).  
Antibodies bound to CD22 are rapidly internalized, making CD22 ideally suited for 
targeted delivery of cytotoxic agents (Shan and Press 1995).   
DCDT2980S is an antibody−drug conjugate (ADC) that consists of a potent anti-mitotic 
agent, monomethyl auristatin E (MMAE) conjugated to a humanized immunoglobulin-G1 
(IgG1) anti-CD22 MAb, MCDT2219A, via a protease-labile linker, 
maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-VC-PABC).  
MMAE has a mode of action similar to vincristine, which is a component of standard 
chemotherapy used in lymphoma therapy.  This therapeutic approach takes advantage 
of the specific targeting capability of the antibody and the cytotoxic activity of MMAE.  
Following internalization, the MMAE is deconjugated from DCDT2980S by lysosomal 
enzymes, binds to tubulin, and disrupts the microtubule network, resulting in inhibition of 
cell division and cell growth and induction of apoptosis (Doronina et al. 2003).  


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Figure 1 CD22 Expression Levels on B-Cell Tumor Cells 
0
1000
2000
3000
CLL
DLBCL
FL
MCL
MZL
0
1000
2000
3000
CLL
DLBCL
FL
MCL
MZL
 
CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; FL = follicular 
lymphoma; MCL = mantle cell lymphoma; MFI = mean fluorescence intensity; MZL =  marginal 
zone lymphoma. 
CD22 expression levels (MFI) on B-cell tumor cells were assessed by flow cytometry in patients 
diagnosed with the following B-cell lymphomas:  CLL (n = 49), DLBCL (n = 59), FL (n = 58), 
MCL (n = 20), and MZL (n = 60).  
 
Comprehensive pharmacologic, pharmacokinetic (PK), pharmacodynamic (PD), and 
toxicology evaluations were conducted to support the use of DCDT2980S in clinical 
trials.  DCDT2980S binds human CD22 with a high affinity (equilibrium dissociation 
constant [Kd] = 1.7 ± 0.2 nM) and showed similar binding affinity to cynomolgus monkey 
CD22.  No binding activity was observed with mouse and rat peripheral blood 
mononuclear cells (PBMCs).   
The unconjugated antibody MCDT2219A did not appear to induce antibody-dependent 
cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) in vitro.  
In contrast, DCDT2980S displayed potent and selective inhibition of cell proliferation in 
vitro (50% of the maximal inhibitory concentration [IC50] = 0.33 nM) by cell viability 
assays.  Efficacy studies conducted in murine xenograft models of human lymphoma 
(CD22-positive WSU-DLCL2 and BJAB cell lines) showed that a single dose of 
DCDT2980S resulted in regression of tumor growth at doses ranging from 1 to 4 mg/kg.  
PD studies with DCDT2980S showed that a single dose of 1−6 mg/kg resulted in partial 
depletion of peripheral blood B cells in cynomolgus monkeys with a corresponding 
depletion in germinal center B cells in lymphoid tissue. 


 
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The PK profiles of DCDT2980S were observed to be linear in rodents and moderately 
non-linear in cynomolgus monkeys over the tested dose range.  The non-linear 
clearance (CL) observed in cynomolgus monkeys with DCDT2980S is likely due to the 
contribution of B cell-mediated CL to the total CL.  The free MMAE concentrations in 
cynomolgus monkeys following DCDT2980S administration were generally 10,000 times 
lower than the concentration of DCDT2980S.   
Cynomolgus monkeys were selected as the most relevant nonclinical species for the 
toxicology and PK/PD studies of DCDT2980S, given the comparable sequence 
homology of human and cynomolgus monkey CD22, similar binding affinity of 
DCDT2980S to human and cynomolgus monkey CD22, and comparable tissue 
cross-reactivity in both human and cynomolgus monkey tissues.  DCDT2980S was well 
tolerated at doses of up to 3 mg/kg (highest non-severely toxic dose [HNSTD]) in 
monkeys and up to or greater than 10 mg/kg in rats (severely toxic dose to 10% [STD10] 
of rats ≥ 10 mg/kg).  Reversible bone marrow toxicity and associated hematopoietic 
changes were observed in both rats and monkeys treated with DCDT2980S or MMAE, 
suggesting that the toxicity of DCDT2980S is related to MMAE.  Additional effects on 
liver and lung in rats were minimal in severity and reversible and did not occur in 
cynomolgus monkeys, which may be due to differences in species sensitivity, exposure, 
and/or pharmacokinetics.   
Complete details of preclinical studies of DCDT2980S can be found in the DCDT2980S 
Investigator’s Brochure. 
1.2.1.2 
DCDT2980S Clinical Data 
a. Patient Enrollment 
Both DCDT2980S monotherapy and combination therapy with rituximab have been 
studied in a Phase I study (Study DCT4862g) of patients with relapsed or refractory 
B-cell malignancies expected to express CD22, including indolent NHL, DLBCL, mantle 
cell lymphoma (MCL), and CLL. 
All data presented herein is based on a data entry cutoff of 22 February 2013, with 
clinical data available from 65 patients with NHL (excluding patients with CLL) enrolled in 
dose-escalation and expansion cohorts.  These include 49 patients who were treated 
with single-agent DCDT2980S at doses ranging from 0.1 to 3.2 mg/kg administered 
intravenously every 21 days and 16 patients who were enrolled into two Phase Ib 
cohorts with DCDT2980S administered at doses of 1.8 mg/kg (5 patients) and 2.4 mg/kg 
(11 patients) in combination with 375 mg/m2 rituximab. 
Enrollment into CLL dose escalation cohorts was closed on 31 May 2013.  Refer to the 
DCDT2980S Investigator Brochure for details regarding clinical data in CLL patients. 


 
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b. Pharmacokinetics 
The pharmacokinetics of DCDT2980S have been characterized in the Phase I 
Study DCT4862g.  DCDT2980S was administered to patients with NHL at dose levels 
ranging from 0.1 to 3.2 mg/kg every 3 weeks (q3w).  Three analytes were quantified:  
antibody-conjugated MMAE (acMMAE), total antibody, and free MMAE.  
Preliminary PK analysis based on available data as of 22 June 2012 is summarized 
below.   
The mean value of CL estimates of acMMAE and total antibody of each dose level for 
doses of ≥ 1.0 mg/kg ranged from 17.6 to 21.3 mL/day/kg and from 10.5 to 
16.2 mL/day/kg, respectively.  Similar CL estimates for doses ≥ 1.0 mg/kg suggested 
dose-proportional increase of acMMAE and total antibody exposure.  CL estimates 
appeared to be slightly higher at doses < 1.0 mg/kg (0.1, 0.25, and 0.5 mg/kg), although 
data from these dose levels are limited.  The CL of acMMAE was faster than that of total 
antibody at each dose level.   
In patients with NHL, the mean value of the steady-state volume of distribution (Vss) of 
acMMAE and total antibody of each dose level ranged from 69.2 to 130 mL/kg and from 
97.4 to 154 mL/kg, respectively, across the dose levels tested, approximating human 
serum volume.  Vss values did not appear to change substantially with dose.  The half-life 
for acMMAE and total antibody ranged from 2.9 to 7.0 days and from 4.4 to 13 days, 
respectively.   
For acMMAE and total antibody, the time to maximum concentration occurred 
immediately after infusion.  For free MMAE, the time to maximum concentration was 
approximately 2 to 3 days after infusion.  Maximum plasma and serum concentration 
(Cmax) and area under the concentration-time curve from Time 0 to infinity (AUCinf) of free 
MMAE appeared to increase with dose across the dose levels tested.  A half-life of 
3-4 days for free MMAE was observed, which is relatively long and similar to that of its 
parent conjugate, suggesting formation rate−limited kinetics of free MMAE.  No 
accumulation of free MMAE is expected for the q3w regimen.  The Cmax values of free 
MMAE in NHL patients were at least 100-fold lower than acMMAE concentrations at 
each dose level, suggesting a slow release of free MMAE from acMMAE and potentially 
fast elimination once it is formed.  
Preliminary comparisons of pharmacokinetics between patients with NHL and CLL (for 
which patients are enrolled into separate dose-escalation cohorts) treated with identical 
doses of DCDT2980S provide some insight into the factors that affect pharmacokinetics.  
Both acMMAE and total antibody were cleared faster in CLL patients than in NHL 
patients.  This observation is likely to be related to the high number of circulating B cells 
generally observed in CLL patients, which may result in significant target-mediated CL of 
DCDT2980S.  The free MMAE exposure in CLL patients was relatively low compared to 
that of its parent conjugate.   


 
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The exposure parameters (Cmax and AUCinf) of total antibody, acMMAE, and free MMAE 
were similar between DCDT2980S and DCDT2980S + rituximab at doses of 1.8 and 
2.4 mg/kg, based on preliminary data.  This observation suggests that when given in 
combination, rituximab does not impact the pharmacokinetics of DCDT2980S; the effect 
of DCDT2980S on rituximab pharmacokinetics will be assessed. 
All observations will be verified with additional data from the ongoing Phase I study as 
well as this study.  
Refer to the DCDT2980S Investigator Brochure for complete and updated details. 
c. Safety 
Dose Limiting Toxicity 
Study DCT4862g utilizes a standard 3 + 3 dose-escalation cohort enrollment scheme.  
Patients enrolled into each dose-escalation cohort in Study DCT4862g have been 
observed for dose-limiting toxicities (DLT) for a minimum of 21 days after their first dose 
of DCDT2980S.  Any patient who did not complete the DLT observation period for any 
reason other than a DLT was replaced. 
Separate dose-escalation cohorts enrolled patients with B-cell NHL and CLL.  For the 
NHL dose escalation, DLTs of Grade 4 neutropenia occurred in 1 patient out of 
3 DLT-evaluable patients in the 3.2 mg/kg single-agent cohort and 1 patient out of 
11 DLT-evaluable patients in the 2.4 mg/kg + rituximab cohort.  Consequently, 
DCDT2980S at 2.4 mg/kg was determined to be the recommended Phase II dose 
(RP2D) as both monotherapy and in combination with rituximab.   
For the CLL dose-escalation cohorts, one DLT was reported to date.  This Grade 5 event 
of febrile neutropenia resulted in the patient’s death.  Whereas the contribution of the 
study drug to the neutropenia could not be completely ruled out, other factors, including 
bone marrow involvement of disease that resulted in baseline anemia, thrombocytopenia 
and neutropenia, and clinical evidence of disease progression may have also played a 
contributory role. 
Single-Agent DCDT2980S and DCDT2980S Combined with Rituximab in 
NHL 
Forty-nine patients received single-agent DCDT2980S at a starting dose of  ≥ 1.8 mg/kg 
(7 at 1.8 mg/kg, 42 at 2.4 mg/kg); 16 patients received DCDT2980S at a starting dose 
of ≥ 1.8 mg/kg in combination with rituximab (5 at 1.8 mg/kg, 11 at 2.4 mg/kg).  Overall 
the safety profile of DCDT2980S combined with rituximab did not differ from that of 
single-agent DCDT2980S. 
Treatment-emergent hematologic and commonly reported nonhematologic adverse 
events for all grades in patients treated with single-agent DCDT2980S and DCDT2980S 
plus rituximab included neutropenia (29%), febrile neutropenia (3%), infection (system 
organ class; 43%), anemia (25%), thrombocytopenia (12%), peripheral neuropathy 


 
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(28%), diarrhea (40%), pyrexia (14%), nausea (34%), and fatigue (55%).  
Treatment-emergent Grade ≥ 3 adverse events included neutropenia (25%), febrile 
neutropenia (3%), infection (system organ class; 11%), anemia (5%), peripheral 
neuropathy (3%), diarrhea (5%), pyrexia (2%), and fatigue (3%).  Serious adverse 
events assessed by the treating investigator to be related to DCDT2980S were reported 
in 21% of patients.   Dose discontinuations for adverse events were reported in 20% of 
patients. 
Refer to the DCDT2980S Investigator’s Brochure for complete and updated details 
related to safety.  
d. Efficacy in Non-Hodgkin’s Lymphoma 
Investigator-based objective responses were observed in 17 of 43 (40%) patients treated 
with single-agent DCDT2980S and 5 of 15 (33%) patients treated with DCDT2980S 
combined with rituximab.  Among patients with relapsed or refractory DLBCL, 11 of 28 
(39%) objective responses (5 complete responses [CR] and 6 partial responses [PR]) 
were observed with single-agent DCDT2980S and 3 of 7 (43%; 2 CR, 1 PR) with 
DCDT2980S combined with rituximab.  Among patients with relapsed or refractory 
indolent NHL (iNHL), 6 of 13 (46%) objective responses (2 CR, 4 PR) were observed 
with single-agent DCDT2980S and 1 of 4 (PR) with DCDT2980S combined with 
rituximab.   
Refer to the DCDT2980S Investigator Brochure for complete and updated details related 
to anti-tumor activity. 
1.2.2 
DCDS4501A 
1.2.2.1 
Background and Preclinical Data 
CD79b is a cell-surface antigen whose expression is restricted to all mature 
B cells except plasma cells.  It is expressed in a majority of B cell−derived malignancies, 
including nearly all NHL and CLL samples tested (see Figure 2) (Dornan et al. 2009).  
Antibodies bound to CD79b are rapidly internalized, making CD79b ideally suited 
for targeted delivery of cytotoxic agents (Polson et al. 2007, 2009).   
Similar to DCDT2980S, DCDS4501A is an ADC that contains a humanized 
immunoglobulin-G1 (IgG1) anti−human CD79b MAb (MCDS4409A) and MMAE linked 
through MC-VC-PABC.   
Comprehensive pharmacologic, PK, PD, and toxicological evaluations were undertaken to 
support the entry of DCDS4501A into clinical trials.  Because DCDS4501A specifically 
recognizes CD79b on B cells of human but not on those of cynomolgus monkey, rat, or 
mouse, a surrogate ADC (DCDS5017A) that binds to cynomolgus monkey CD79b was 
generated to assess the antigen-dependent pharmacological, toxicological, and PK/PD 
activities in cynomolgus monkeys.  The structure, binding epitope, and binding affinity of 
the surrogate ADC are similar to those of DCDS4501A. 


 
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Figure 2 CD79b Expression Levels on B-Cell Tumor Cells 
 
CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; 
FL = follicular lymphoma; MCL = mantle cell lymphoma; MFI = mean fluorescence intensity; 
MZL = marginal zone lymphoma.  
CD79b expression levels (MFI) on B-cell tumor cells were assessed by flow cytometry in patients 
diagnosed with the following B-cell lymphomas:  CLL (n = 49), DLBCL (n = 59), FL (n = 58), 
MCL (n = 20), and MZL (n = 60). 
 
DCDS4501A bound human CD79b with high affinity (Kd = 1.83± 0.26 nM); the surrogate 
ADC also showed similar high binding affinity to cynomolgus monkey CD79b.  
DCDS4501A displayed potent and selective inhibition of tumor cell proliferation in vitro 
(IC50 = 0.071 nM ± 0.01 nM) in cell viability assays.  Moderate ADCC but no CDC activity 
was observed with the unconjugated clinical candidate antibody MCDS4409A.  Both 
clinical and surrogate unconjugated antibodies showed no appreciable cytokine release 
when evaluated in in vitro cytokine release assays with PBMCs.  Moderate elevations 
in interleukin (IL)-1α and interferon-inducible protein (IP)-10 were observed only with the 
unconjugated clinical antibody, however the clinical significance of these observations 
are not known because IL-1α and IP-10 are not produced by B cells, are not involved in 
B-cell signaling through CD79b, and are not associated with cytokine-release syndromes 
in vivo. 
Single intravenous (IV) doses of DCDS4501A resulted in inhibition of tumor growth in 
murine xenograft models of lymphoma.  Tumor regression was observed at doses 
ranging from 0.5 to 3 mg/kg.  In contrast, MCDS4409A showed no activity.  DCDS4501A 
administered at 5 mg/kg demonstrated better anti-tumor activity compared to a current 
standard-of-care regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, 
and prednisone [R-CHOP]) in xenograft models of NHL.  PD studies demonstrated that 
doses of the surrogate ADC ranging from 0.3 to 5 mg/kg resulted in a decrease of 


 
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peripheral blood B cells in cynomolgus monkeys.  A preferential decrease of proliferating 
B cells (CD20+ Ki67+) compared to the resting B cells (CD20+ Ki67−) ) by the surrogate 
ADC was demonstrated in cynomolgus monkeys, in line with the expected mechanism of 
action of an anti-mitotic agent, MMAE. 
Due to B cell−mediated CL, non-linear pharmacokinetics were observed with the 
surrogate ADC in cynomolgus monkeys following single IV doses of 0.3−3 mg/kg or four 
doses of 3 and 5 mg/kg given q3w.  The total antibody exposure after the fourth dose 
increased approximately 1.2- to 1.5-fold compared to the first dose.  As expected, the 
toxicokinetic profile of the clinical ADC in rats and cynomolgus monkeys was linear in the 
tested dose range.  Consistent with the half-life of the clinical ADC, minimal 
accumulation was observed following weekly dosing in rats and no accumulation was 
observed following q3w dosing in cynomolgus monkeys.  The free MMAE concentrations 
in plasma following administration of the clinical or surrogate ADCs were generally low 
and overall did not exceed 2 ng/mL, regardless of dose.  The overall incidence of 
anti-therapeutic antibodies (ATAs) was 20%−67% following administration of the clinical 
or surrogate ADCs in cynomolgus monkeys; however, the ATAs did not appear to impact 
the toxicokinetic/PK parameter estimates. 
In repeat-dose toxicity studies in rats and cynomolgus monkeys, DCDS4501A and 
the surrogate ADC were well tolerated in monkeys up to doses of 5 mg/kg and 3 mg/kg 
respectively, with 3 mg/kg considered the HNSTD.  In rats, DCDS4501A was well 
tolerated up to 6 mg/kg (STD10 = 10 mg/kg).  The predominant antigen-independent 
findings associated with DCDS4501A or surrogate ADC exposure were reversible bone 
marrow toxicity and associated peripheral blood cell effects in both monkeys and rats.  
Administration of the surrogate ADC to monkeys also resulted in expected 
antigen-dependent reversible decreases in peripheral blood B cells and the 
disappearance of B-cell germinal centers in splenic lymphoid follicles at doses ≥ 3 mg/kg.  
Additional findings observed in rats but not in monkeys included thymic lymphoid 
depletion at ≥ 6 mg/kg, minimal to mild liver toxicities (at ≥ 6 mg/kg), lung toxicities at 
10 mg/kg in male animals only, and a slight increase in apoptosis and mitoses in multiple 
tissues, including skin and adnexa.  Hepatobiliary toxicity consisted of transient 
dose-dependent liver enzyme elevations accompanied by minimal to slight 
dose-dependent increases in mitotic figures/apoptosis in hepatocytes, sinusoidal cells, 
and bile duct epithelium as well as minimal to slight dose-dependent random focal 
hepatic necrosis.  Pulmonary toxicity was characterized by minimal to slight 
dose-dependent alveolar macrophage infiltration, sometimes accompanied by minimal to 
slight type II pneumocyte hyperplasia/hypertrophy.  These findings were consistent with 
the expected pharmacologic effect of MMAE on inducing mitotic arrest due to inhibition 
of tubulin polymerization.  Except for two individual instances (one female given 
10 mg/kg in the liver and one male given 10 mg/kg in the lung), these findings were 
completely reversible after a 6-week recovery period.  Non-reversible male reproductive 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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toxicity, characterized by degeneration of testicular seminiferous tubules, was observed 
in rats at all doses.  
Complete details of preclinical studies of DCDS4501A can be found in the DCDS4501A 
Investigator’s Brochure. 
1.2.2.2 
DCDS4501A Clinical Data 
a. Patient Enrollment 
Both DCDS4501A monotherapy and combination therapy with rituximab are being 
studied in a Phase I study (Study DCS4968g) of patients with relapsed or refractory 
B-cell malignancies expected to express CD79b, including indolent NHL, DLBCL, MCL, 
and CLL.   
All data presented herein is based on a data entry cutoff of 28 February 2013, with 
clinical data available from 60 patients with NHL (excluding patients with CLL) enrolled in 
dose-escalation and expansion cohorts.  These include 51 patients who were treated 
with single-agent DCDS4501A ranging from 0.1 to 2.4 mg/kg administered intravenously 
every 21 days and 9 patients who were enrolled into a single Phase Ib cohort with 
DCDS4501A administered at a dose of 2.4 mg/kg in combination with 375 mg/m2 
rituximab. 
In the CLL dose-escalation cohorts, two DLTs were reported at the single-agent dose of 
1.8 mg/kg.   Enrollment into the CLL cohorts was stopped on 7 January 2013.  Refer to 
the DCDS4501A Investigator Brochure for details regarding clinical data in CLL patients.   
b. Pharmacokinetics 
The pharmacokinetics of DCDS4501A were characterized in the Phase I Study 
DCDS4501A.  DCDS4501A was administered in patients with NHL at escalating doses 
of 0.1 to 2.4 mg/kg q3w as monotherapy and following administration of rituximab in the 
Phase Ib cohort.  Three analytes were quantified:  acMMAE, total antibody, and free 
MMAE.  
Preliminary PK analysis based on available data as of 22 June 2012 is summarized 
below.  The CL estimates of acMMAE and total antibody of each dose level is in the 
range of 14.9–21.2 mL/day/kg and 7.12–27.9 mL/day/kg, respectively.  CL estimates 
were similar across doses of 0.1–2.4 mg/kg tested, suggesting dose-proportional 
increase of acMMAE and total antibody exposure.  The CL of acMMAE was faster than 
that of total antibody at each dose level.   
The mean value of Vss of acMMAE and total antibody of each dose level ranged from 
61 to 80.8 mL/kg and from 59.4 to 114.3 mL/kg, respectively, across the dose levels 
tested, which approximated human serum volume.  Vss values did not appear to change 
substantially with dose.  The half-lives for acMMAE and total antibody are from 2.4 to 
5.5 days and 2.9 to 7 days, respectively.  


 
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In a single-agent dose-escalation study, for acMMAE and total antibody, the time to 
maximum concentration occurred immediately after infusion.  For free MMAE, the time to 
maximum concentration was approximately 2 to 3 days after infusion.  Cmax and AUCinf of 
free MMAE appear increased with dose across the dose levels.  A half-life of 3–4 days 
for free MMAE was observed, which is relatively long and similar to acMMAE and 
suggests formation rate−limited kinetics for free MMAE.  No accumulation of free MMAE 
is expected for the q3w regimen.  The Cmax values of free MMAE in NHL patients were at 
least 100-fold lower compared with acMMAE concentrations at each dose level, 
suggesting a slow release of free MMAE from acMMAE and potentially fast elimination 
once it is formed.   
Preliminary comparisons of pharmacokinetics between patients with NHL and CLL (for 
which patients are enrolled into separate dose-escalation cohorts) treated with identical 
doses of DCDS4501A provide some insight into the factors that affect pharmacokinetics.  
Both acMMAE and total antibody were cleared faster in CLL patients than in NHL 
patients.  This observation is likely to be related to the high number of circulating B cells 
generally observed in CLL patients, which may result in significant target-mediated CL of 
DCDS4501A.  The free MMAE exposure in CLL patients was relatively low compared 
with that of its parent conjugate. 
To date, PK data for patients treated with DCDS4501A in combination with rituximab is 
limited.  Consequently, full comparison with single-agent DCDS4501A pharmacokinetics 
is not possible.  On the basis of very limited data from 3 patients, total antibody 
pharmacokinetics was comparable between 2.4 mg/kg of DCDS4501A administered as 
a single agent and following rituximab administration, suggesting that when given in 
combination, rituximab does not affect the pharmacokinetics of DCDS4501A; the effect 
of DCDS4501A on rituximab pharmacokinetics will be assessed.   
All observations will be verified with additional data from the ongoing Phase I study as 
well as this study. 
Refer to the DCDS4501A Investigator Brochure for complete and updated details. 
c. Safety 
Dose-Limiting Toxicities 
Study DCS4968g utilizes a standard 3 + 3 dose escalation cohort enrollment scheme.  
Patients enrolled into each dose-escalation cohort in Study DCS4968g have been 
observed for DLTs for a minimum of 21 days after their first dose of DCDS4501A.  
Any patient who did not complete the DLT observation period for any reason other than 
a DLT was replaced. 
DLT of Grade 4 neutropenia occurred in 1 patient out of 10 DLT-evaluable patients in the 
2.4 mg/kg single-agent cohort and 1 patient out of 9 DLT-evaluable patients in the 
2.4 mg/kg + rituximab cohort.  Doses of DCDS4501A greater than 2.4 mg/kg as 


 
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monotherapy or in combination with rituximab were not assessed.  Consequently, 
DCDS4501A at 2.4 mg/kg was therefore determined to be the RP2D as both 
monotherapy and in combination with rituximab.  Patients are currently being enrolled in 
monotherapy expansion cohorts for various types of NHL in order to collect and further 
characterize both single-agent and combination safety data.  
In the CLL dose-escalation cohorts, two DLTs were reported at the single-agent dose of 
1.8 mg/kg.  One patient had a Grade 4 neutropenia, and 1 patient had a Grade 4 
invasive fungal infection.   
Single-Agent DCDS4501A and DCDS4501A Combined with Rituximab 
Fifty-one patients received single-agent DCDS4501A at a starting dose of ≥ 1.8 mg/kg 
(6 at 1.8 mg/kg, 45 at 2.4 mg/kg); an additional 9 patients received DCDS4501A at a 
dose of 2.4 mg/kg in combination with rituximab.  Overall, the safety profile of 
DCDS4501A combined with rituximab did not differ from that of single-agent 
DCDS4501A. 
Treatment-emergent hematologic and commonly reported non-hematologic adverse 
events of all grades in patients treated with single-agent DCDS4501A and DCDS4501A 
plus rituximab included neutropenia (50%), febrile neutropenia (5%), infection (system 
organ class; 35%), anemia (13%), thrombocytopenia (18%), peripheral neuropathy 
(32%), diarrhea (43%), pyrexia (37%), nausea (35%), and fatigue (18%).  
Treatment-emergent Grade ≥ 3 adverse events included neutropenia (43%), febrile 
neutropenia (5%), infection (system organ class; 10%), anemia (8%), peripheral 
neuropathy (7%), diarrhea (3%), pyrexia (2%), and fatigue (5%).   Serious adverse 
events assessed by the treating investigator to be related to DCDS4501A were reported 
in 20% of patients.   Dose discontinuations for adverse events were reported in 33% of 
patients. 
Refer to the DCDS4501A Investigator’s Brochure for complete and updated details 
related to safety.   
d. Efficacy 
Investigator-based objective responses were observed in 28 of 49 (57%) patients treated 
with single-agent DCDS4501A and 7 of 9 patients (78%) treated with DCDS4501A 
combined with rituximab.  Among patients with relapsed or refractory DLBCL, objective 
responses were observed in 16 of 30 (53%; 4 CR, 12 PR) patients treated with 
DCDS4501A; 1 patient with DLBCL was treated with DCDS4501A combined with 
rituximab and achieved a PR.  Among patients with relapsed or refractory iNHL, 
objective responses were observed in 7 of 14 (50%; 2 CR, 5 PR) patients treated with 
single-agent DCDS4501A and 5 of 5 (100%; 2 CR, 3 PR) patients treated with 
DCDS4501A plus rituximab.  


 
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Refer to the DCDS4501A Investigator Brochure for complete and updated details 
regarding anti-tumor activity. 
1.2.3 
Rituximab 
Rituximab has been shown to be an effective treatment for CD20-positive B-cell 
malignancies and is commonly used both as a single agent and in combination with 
cytotoxic chemotherapy.  Rituximab binds to CD20, a hydrophobic, transmembrane 
protein that is present on pre–B cells and mature B cells and in ≥ 90% of B-cell NHLs.  
It exerts its cytotoxic effects via complement-mediated B-cell lysis, ADCC, and induction 
of apoptosis (Cartron et al. 2004). 
In the United States, rituximab has been approved by the U.S. Food and Drug 
Administration (FDA) for the following indications in NHL:  as a single agent for the 
treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive 
B-cell NHL; for the treatment of relapsed or refractory, low-grade or follicular, 
CD20-positive B-cell NHL, including initial treatment weekly for eight doses and 
re-treatment (weekly for four doses) in patients who responded to an initial course of 
rituximab; for the treatment of low-grade, CD20-positive B-cell NHL, in combination with 
cyclophosphamide, vincristine, and prednisone (CVP) induction chemotherapy in 
previously untreated patients with follicular, CD20-positive NHL; as treatment in 
previously untreated patients with low-grade, CD20-positive NHL who achieve an 
objective response or stable disease (SD) following CVP induction; and as maintenance 
therapy for previously untreated follicular CD20-positive B-cell NHL after achieving a 
response to a regimen including chemotherapy and rituximab. 
In the European Union, rituximab (MabThera®) is approved for the treatment of the 
following indications in NHL:  treatment of patients with Stage III–IV follicular NHL who 
are chemotherapy-resistant or in their second or subsequent relapse after 
chemotherapy; treatment of patients with CD20-positive DLBCL in combination with 
cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy; as 
front-line therapy in Stage III–IV follicular NHL in combination with CVP chemotherapy; 
as maintenance therapy in patients with relapsed or refractory, follicular NHL responding 
to induction treatment with CHOP or R-CHOP; and as maintenance treatment for 
patients with FL who have responded to initial treatment with rituximab plus 
chemotherapy. 
Rituximab has also been approved for the treatment of CLL.  The European Medicines 
Agency (EMA) granted an approval for the use of rituximab in combination with 
chemotherapy for previously untreated CLL.  The FDA approved the use of rituximab in 
combination with fludarabine and cyclophosphamide for patients with previously 
untreated and previously treated CD20-positive CLL.   


 
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Refer to the Rituximab Product Insert/Summary of Product Characteristics for complete 
details regarding clinical data related to approved indications.  For rituximab safety 
information, refer to local rituximab prescribing information. 
1.2.4 
Obinutuzumab 
1.2.4.1 
Obinutuzumab Mechanism of Action 
Obinutuzumab ([G], also known as RO5072759, GA101, Gazyva™, and Gazyvaro™) is 
a humanized type II and glycoengineered anti-CD20 MAb, derived by humanization of 
the parental B-Ly1 mouse antibody and subsequent glycoengineering leading to the 
following characteristics (Mössner et al. 2010; Golay et al. 2013): 
• 
High-affinity binding to CD20 antigen on B cells 
• 
Type II binding mode to the CD20 antigen, leading to a more even distribution of 
bound antibody to the surface membrane of the B cell due to lack of CD20 
translocation into lipid rafts after antibody binding and low complement activation 
and low complement-dependent cytotoxicity related to the recognition of the CD20 
epitope  
• 
Compared with the type I anti-CD20 antibodies rituximab or ofatumumab, 
increased ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) 
related to an improved binding of obinutuzumab to the different allotypes of 
FcγRIIIa and FcγRIIIb  expressed by natural killer (NK) cells , 
monocytes/macrophages and neutrophils 
• 
Compared with rituximab, increased direct cell-death induction related to an elbow 
hinge amino exchange of the Fab region and type II binding of the CD20 epitope 
 
Obinutuzumab received FDA approval in November 2013 and EMA approval in 
July 2014 on the basis of the CLL-11 Study BO21004 for patients with relapsed 
Chronic Lymphocytic Leukemia.  Obinutuzumab plus chlorambucil showed superiority 
over rituximab plus chlorambucil in all efficacy parameters such as overall response 
rate (ORR), complete remission rate (CRR), minimal residual disease (MRD), 
progression-free survival (PFS), event-free survival (EFS), and duration of response 
(DOR) (Goede et al. 2014). 
Obinutuzumab is currently being explored in the treatment of lymphoid malignancies 
such as aggressive and indolent lymphomas (DLBCL, FL, and marginal zone lymphoma 
[MZL]).  Preliminary data suggest possible increased anti-lymphoma efficacy over 
rituximab, a hypothesis that is currently being explored in several randomized trials, 
including a Phase III study of R-CHOP versus G-CHOP in first-line treatment of 
DLBCL, a Phase III study of R-chemotherapy (CHOP, CVP, or bendamustine) followed 
by rituximab maintenance compared with G-chemotherapy (CHOP, CVP, or 
bendamustine) followed by obinutuzumab maintenance in first-line treatment of FL and 
MZL, and a Phase III study of obinutuzumab combined with bendamustine compared 
with bendamustine in patients with rituximab-refractory indolent NHL. 


 
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1.2.4.2 
Obinutuzumab Nonclinical Toxicology 
The nonclinical toxicology of obinutuzumab has been evaluated in repeat-dose studies 
in cynomolgus monkeys given weekly IV (30-minute infusion) up to 26 weeks in 
duration and weekly SC injections for 4 weeks in duration.  The high dose of 50 mg/kg 
in the 26-week study resulted in a steady-state area under the concentration-time curve 
from 0 to 24 hours (AUC0−24) exposure of 341,000 μg•hr/mL, which is approximately 
61-fold above that of the clinical exposure of 5584 μg•hr/mL. 
Consistent with expected pharmacologic activity, obinutuzumab caused marked 
decreases in B cells, with corresponding lymphoid depletion in spleen and lymph nodes.  
Circulating CD40-positive mature B cells began to reverse after several months without 
treatment and maximally reversed to 7%−152% of baseline by 37 weeks.  In addition, 
transient decreases in NK cells were observed; this finding is consistent with the 
pharmacologic effect of FcγRIIIa binding.  Suspected opportunistic infections in as 
many as three unscheduled deaths were considered a possible secondary result of B-cell 
depletion. 
Obinutuzumab was immunogenic in the cynomolgus monkey, which led to reduced 
systemic exposures in several animals and abrogation of the pharmacologic activity.  
Hypersensitivity reactions were noted that included systemic inflammation and 
infiltrates consistent with immune complex−mediated hypersensitivity reactions such 
as arteritis/periarteritis, glomerulonephritis, and serosal/adventitial inflammation and 
led to unscheduled termination in six animals. 
Both the clinical IV formulation and the SC formulation of obinutuzumab were locally 
well tolerated across studies.  No effects were present in male and female reproductive 
parameters included in the 26-week IV dose study.  No obinutuzumab-related effects 
were observed on CNS, respiratory, or cardiovascular function. 
In vitro assays using undiluted human whole blood measured significant increases in 
cytokine secretion caused by obinutuzumab, indicating that obinutuzumab has an 
increased propensity to trigger first infusion−related cytokine release in patients. 
See the Obinutuzumab Investigator’s Brochure for details on the nonclinical studies. 
1.2.4.3 
Obinutuzumab Nonclinical Efficacy 
Obinutuzumab has in vivo efficacy superior to rituximab in various human lymphoma 
xenograft models.  Both antibodies were tested in human SUDHL-4 cells (DLBCL 
model) injected subcutaneously in severe combined immunodeficient (SCID) beige mice.  
Rituximab administration was started when tumors were established and rapidly 
growing.  Results showed that rituximab at 10 mg/kg inhibited tumor growth compared 
with rituximab at 1 mg/kg; however, increasing the rituximab dose to 30 mg/kg did not 
result in increased efficacy and rituximab was not able to achieve complete tumor 
regression.  In contrast, obinutuzumab showed a dose-dependent increase in efficacy in 


 
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the range of 1−30 mg/kg.  Results showed complete tumor regression in all animals and 
lasting tumor eradication in 9 of 10 animals at the highest dose of 30 mg/kg and in 
1 of 10 animals at a dose of 10 mg/kg. 
In another experiment, SUDHL4 xenografts in SCID mice were first treated with 
weekly rituximab 30 mg/kg.  When the tumors became refractory to rituximab 
(Day 35), rituximab treatment was continued or changed to either weekly vehicle 
control or obinutuzumab 30 mg/kg.  While tumors in control- and rituximab-treated 
mice continued to grow, obinutuzumab-treated mice showed control of tumor growth 
and lived until Day 61 when control or rituximab-treated mice had already been 
sacrificed.   
Additional studies have also shown similar results, with obinutuzumab treatment 
controlling tumor growth, whereas vehicle- and rituximab-treated tumors were not 
controlled (Mössner et al. 2010). 
See the Obinutuzumab Investigator’s Brochure for details on the nonclinical studies. 
1.2.4.4 
Obinutuzumab Clinical Experience 
As of July 2013, more than 1900 patients with CD20-positive malignant disease have 
been treated with obinutuzumab in clinical trials.  Clinical data for obinutuzumab are 
available from six clinical trials, including three Phase I and Phase II studies of 
obinutuzumab monotherapy, a Phase Ib chemotherapy combination study in NHL 
(Study BO21000), and two Phase III studies (Study BO21004 in CLL and 
Study GAO4753g in NHL). 
Infusion-related reactions (IRRs), mostly Grades 1 and 2, are the most common adverse 
events observed during therapy.  IRRs have been associated predominantly with the 
first infusion, generally occurring early during the infusion, shortly after the infusion, 
or, in some cases, up to 24 hours after the completion of the infusion.  In a few patients, 
concurrent signs of laboratory tumor lysis syndrome (TLS) were observed.  The 
incidence and intensity of IRRs decreased strongly with subsequent infusions of 
obinutuzumab.  On the basis of preliminary observations, extensive tumor burden, 
tumor factors, and host factors may be predisposing factors for the occurrence of IRRs.  
The frequency and severity of IRRs is also reduced in lymphomas compared with CLL. 
Other frequently observed adverse events include infections and neutropenia.  
Grade 3−4 thrombocytopenia and neutropenia, including febrile neutropenia, have been 
reported with obinutuzumab, associated predominantly with treatment of CLL rather 
than NHL.  Given its anticipated mode of action, which results in profound B-cell 
depletion, obinutuzumab may be associated with an increased risk of infections during 
and after treatment. 


 
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Data from Study BO20999 (obinutuzumab monotherapy) showed safety and efficacy of 
single-agent obinutuzumab in patients with relapsed indolent and aggressive 
lymphomas.  Responses were seen at both lower (400 mg) and higher (1600/800 mg) 
doses, although responses increased at the higher dose, with 54% of patients with 
indolent lymphoma and 32% of patients with aggressive lymphomas showing PR or CR 
at the end of treatment (EOT) (Morschhauser et al. 2013; Salles et al. 2013).   
Study BO21000 (Phase Ib) evaluated obinutuzumab in combination with chemotherapy:  
obinutuzumab with fludarabine and cyclophosphamide and obinutuzumab with CHOP 
(Radford et al. 2013).  Both chemotherapy combinations were shown to be feasible in 
patients with previously untreated or relapsed or refractory FL, with response rates of 
> 90% for both regimens.  Safety was acceptable, with no new or unexpected adverse 
events observed.  The most common adverse event was neutropenia. 
Data from obinutuzumab in combination with chlorambucil in CLL (Phase III 
Study BO21004) showed increased efficacy of this combination over 
rituximab-chlorambucil, with a hazard ratio of 0.39 for PFS.  IRRs were common 
(65% all grades, 20% Grade 3−4, no fatal IRRs) and neutropenia occurred at increased 
frequency with the combination therapy (33% Grade 3−5), but there was no increase in 
infections or treatment-related deaths (Goede et al. 2014). 
See the Obinutuzumab Investigator’s Brochure for additional details on the clinical 
studies. 
1.2.4.5 
Obinutuzumab Pharmacokinetics and Pharmacodynamics 
A two-compartment model comprising a time-varying CL pathway and a linear CL 
pathway provides an adequate description of the pharmacokinetics of obinutuzumab 
following IV administration in Study BO20999 and Study BO21003.  Following the 
infusion of obinutuzumab, the elimination appears to be characterized by a linear CL 
pathway that is dependent on time (i.e., starting at a typical value of 630 mL/day and 
then gradually decreasing to an asymptote of 60 mL/day at steady state).  Tumor 
burden may potentially contribute significantly to the CL of obinutuzumab, especially 
at the beginning of treatment when CD20-positive tumor cells are most abundant.  As 
tumor burden decreases, the CL reaches an asymptote, which is considered to be 
primarily a function of the proteolytic metabolic CL.  Some patients with a high tumor 
burden may appear to clear the drug from the plasma faster than patients with a low 
tumor burden because obinutuzumab binds to the CD20-positive tumor cells and is 
effectively removed from the plasma.  The CL of the drug will vary with time because 
repeated treatments with obinutuzumab will reduce the quantity of CD20-positive 
tumor cells.  The number of times obinutuzumab is administered during the first cycle 
of treatment may be expected to reduce the number of CD20-positive tumor cells, thus 
minimizing the impact of the time-varying CL pathway on obinutuzumab exposure. 


 
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Treatment with obinutuzumab resulted in extensive B-cell depletion, with all patients 
showing a reduction in B-cell counts to absolute zero at some stage of their treatment 
cycle.  Overall, there has been no notable increase in complement levels before and after 
infusion, but transient increases occurring during the administration of obinutuzumab 
have been observed in the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, 
IL-8, IL-10, and interferon (IFN)-γ. 
1.3 
RATIONALE FOR DOING THIS STUDY 
The goals of this study are to continue to assess the safety, tolerability, and biologic and 
clinical activity of the combinations of DCDT2980S and rituximab and DCDS4501A and 
rituximab in two specific NHL patient populations:  patients with relapsed or refractory 
follicular NHL and patients with relapsed or refractory DLBCL.  An additional goal of this 
study is to assess the safety, tolerability, and potential biologic and clinical activity of 
DCDS4501A in combination with obinutuzumab, an anti-CD20 antibody, in the 
aforementioned NHL patient populations.  These patients continue to have an 
extremely poor prognosis with no curative options available.  Consequently, new 
therapeutic options are needed.   
DCDT2980S, DCDS4501A, rituximab, and obinutuzumab each target antigens specific 
to B-cell malignancies including follicular NHL and DLBCL (see Figures 1 and 2).  
The randomized component of the Phase II study design permits an assessment of the 
clinical benefit provided by each of these molecules in combination with rituximab, which 
has established clinical activity in B-cell malignancies both as monotherapy and in 
combination with chemotherapy.  Data from this study will help inform the feasibility of 
the combination regimens in earlier lines of therapy (e.g., as first-line therapy in newly 
diagnosed patients).   
The non-randomized component of the study will further evaluate the safety and 
tolerability and clinical activity of DCDS4501A in combination with obinutuzumab in 
patients with relapsed or refractory follicular lymphoma or DLBCL and will also 
provide preliminary evidence as to which anti-CD20 agent, rituximab or 
obinutuzumab, in combination with DCDS4501A, provides a better benefit-risk profile 
in the target population being studied.  
The feasibility of combining an ADC with rituximab has previously been tested clinically 
with the combination of another, different CD22-specific ADC, inotuzumab ozogamicin 
(CMC-544), with results suggesting that the addition of rituximab may have increased 
clinical activity without significant increase in toxicity over the ADC alone in patients with 
aggressive NHL (Luis et al. 2006; Nam et al. 2009; Nina et al. 2010).  As noted in 
Sections 1.2.1 and 1.2.2, the combinations of DCDT2980S and rituximab, and 
DCDS4501A and rituximab have been shown to have acceptable safety in patients with 
relapsed or refractory NHL in the Phase I studies (Studies DCT4862g and DCS4968g).   


 
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Given the relatively poor prognosis of patients with relapsed or refractory hematologic 
malignancies that have failed standard therapies, the nonclinical toxicity profile 
associated with DCDT2980S and DCDS4501A treatment, and the clinical safety profile 
observed to date for both ADCs, the benefit-risk ratio of a clinical study of DCDT2980S 
and DCDS4501A, each combined with rituximab or obinutuzumab, is considered 
acceptable.  
1.3.1 
Rationale for Assessing ADC Dose of 1.8 mg/kg Combined with 
Rituximab in iNHL 
On the basis of available Phase I data (see Sections 1.2.1 and 1.2.2), both DCDT2980S 
and DCDS4501A as single agents and combined with rituximab have shown early signs 
of clinical activity in heavily pretreated patients with relapsed or refractory NHL.  
However, early evidence in the Phase I studies indicate that duration of study treatment 
may be limited by tolerability to ADC.  Specifically, for both ADCs, peripheral sensory 
neuropathy has been identified as a known risk (see Section 3.4.3.5).  Notably, 4 of 7 
and 5 of 11 discontinuations for adverse events in Studies DCT4862g and DCS4968g, 
respectively, were the result of peripheral neuropathy.   
Because of the chronic course and incurability of iNHL, treatment paradigms are 
increasingly emphasizing tolerability to treatment in addition to efficacy.  As both 
DCDT2980S and DCDS4501A have shown single-agent activity at the 1.8 mg/kg dose 
level (Advani et al. 2012; Palanca-Wessels et al. 2012), the purpose of enrolling 
additional cohorts of patients with FL is to determine whether lower doses of ADC in 
combination with standard doses of rituximab result in improved tolerability while 
maintaining efficacy in FL.   
In contrast to iNHL, treatment paradigms in relapsed or refractory aggressive 
lymphomas such as DLBCL continue to place a premium on anti-tumor activity and 
higher tolerance for treatment-related toxicity, given that durations of disease control and 
survival are substantially shorter and that treatment options are extremely limited.  Early 
Phase I data suggest lower rates of study treatment discontinuation for adverse events 
among patients with DLBCL compared with patients with iNHL.  Taken together with 
anti-tumor activity observed to date, the benefit-risk profile of the currently tested ADC 
dose of 2.4 mg/kg is considered acceptable  
1.3.2 
Rationale for Assessing DCDS4501A in Combination with 
Obinutuzumab in Relapsed or Refractory NHL 
The development of next-generation anti-CD20−directed therapy may further enhance 
the efficacy of current standard regimens for NHL.  Obinutuzumab, also known as 
RO5072759, GA101, and Gazyva™/Gazyvaro™, a novel type II and glycoengineered 
anti-CD20 antibody, has shown superiority over rituximab in a Phase III trial in 
first-line CLL (Goede et al. 2014).  Obinutuzumab is currently being compared with 
rituximab in two large Phase III studies in patients with newly diagnosed DLBCL 
(Study BO21005) and with previously untreated iNHL, including FL 


 
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(Study BO21223).  Assuming these studies demonstrate greater clinical benefit with 
obinutuzumab- vs. rituximab-containing regimens, potentially altering the standard of 
care in NHL, it will be important to also assess the safety and efficacy of combining 
DCDS4501A with obinutuzumab-containing regimens. 
The goals of the non-randomized portion of the Phase Ib study are to assess the safety, 
tolerability, and potential biologic and clinical activity of DCDS4501A at 1.8 mg/kg in 
combination with obinutuzumab in patients with relapsed or refractory follicular NHL 
or DLBCL.  The RP2D, the Phase II dose-expansion portion of the study, will further 
evaluate the safety and tolerability and clinical activity of DCDS4501A at 1.8 mg/kg in 
combination with obinutuzumab in patients with relapsed or refractory follicular NHL 
or DLBCL.   
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
The primary objectives of this study are the following: 
• 
To assess the safety and tolerability of the combination of DCDT2980S and 
rituximab administered to patients with relapsed or refractory follicular NHL and 
DLBCL 
• 
To assess the safety and tolerability of the combination of DCDS4501A and 
rituximab administered to patients with relapsed or refractory follicular NHL and 
DLBCL  
• 
To assess the safety and tolerability of the combination of DCDS4501A and 
obinutuzumab when administered to patients with relapsed or refractory follicular 
NHL or DLBCL 
• 
To assess the anti-tumor activity of the combination of DCDT2980S and rituximab in 
patients with relapsed or refractory follicular NHL and DLBCL 
• 
To assess the anti-tumor activity of the combination of DCDS4501A and rituximab in 
patients with relapsed or refractory follicular NHL and DLBCL 
• 
To assess the anti-tumor activity of the combination of DCDS4501A and 
obinutuzumab in patients with relapsed or refractory follicular NHL and DLBCL 
 
2.2 
SECONDARY OBJECTIVES 
2.2.1 
Safety Objectives 
The secondary safety objectives of this study are the following: 
• 
To assess the incidence of antibody formation to DCDT2980S, DCDS4501A, and 
obinutuzumab as measured by the formation of ATAs 
• 
To compare the safety and tolerability of the combination of DCT2980S and 
rituximab and DCDS4501A and rituximab or obinutuzumab 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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2.2.2 
Activity Objective 
The secondary activity objective of the study is the following: 
• 
To compare the anti-tumor activity of the combination of DCT2980S and rituximab 
and DCDS4501A and rituximab or obinutuzumab 
 
2.2.3 
Pharmacokinetic Objectives 
The PK objectives of this study are the following: 
• 
To characterize the pharmacokinetics of DCDT2980S and rituximab in patients with 
relapsed or refractory NHL when the two drugs are given in combination 
• 
To characterize the pharmacokinetics of DCDS4501A and rituximab or 
obinutuzumab in patients with relapsed or refractory NHL when the two drugs are 
given in combination 
 
2.3 
EXPLORATORY OBJECTIVES 
2.3.1 
Biomarker Objectives 
The objectives of this study related to assessment of biologic markers are the following: 
• 
To make a preliminary assessment of biologic markers that might act as predictors 
of DCDT2980S + rituximab combination anti-tumor activity and allow assessment of 
response in different prognostic subgroups of DLBCL and follicular NHL 
• 
To make a preliminary assessment of biologic markers that might act as predictors 
of DCDS4501A + rituximab or obinutuzumab combination anti-tumor activity and 
allow assessment of response in different prognostic subgroups of DLBCL and 
follicular NHL 
 
2.3.2 
Patient-Reported Outcomes Objective 
The objective of this study related to assessment of patient-reported outcomes (PRO) is 
the following: 
• 
To assess patient-reported tolerability to study treatment and the impact of study 
treatment on patient functioning on the basis of PRO 
 
2.3.3 
Crossover Treatment Objective 
The objective of this study related to assessment of crossover treatment is the following: 
• 
To preliminarily assess the safety, tolerability, and anti-tumor activity of DCDT2980S 
and DCDS4501A, either as a single-agent or in combination with rituximab, as 
crossover treatment following disease progression on initial study treatment. (Note:  
This objective applies only to patients enrolled in Arms A and B [see Section 3.1].) 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a Phase Ib/II, multicenter, open-label study.  Up to approximately 252 patients 
with relapsed or refractory FL and DLBCL will be enrolled at approximately 30−40 
investigative sites worldwide.  Additional patients may be enrolled in order to obtain 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
86/P GO27834-A2 
additional safety and/or efficacy data.  Arms A and B and Cohort C are no longer 
enrolling patients. 
For Obinutuzumab Cohorts: 
Only investigational sites in the United States will enroll patients into Cohort E.  
Investigational sites in the United States and Canada will participate in Cohorts G 
and H).   
The study will be composed of a randomized portion and a non-randomized portion, as 
illustrated in Figure 3. 




 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
88/P GO27834-A2 
3.1.1 
Rituximab-Containing Regimens with DCDT2980S or 
DCDS4501A 
3.1.1.1 
Randomized Portion of the Study (Arms A and B) 
Following determination of eligibility, patients within each disease group will be 
randomized in a 1:1 ratio to receive one of two treatments: 
• 
Arm A:  Rituximab (375 mg/m2) followed by DCDT2980S (2.4 mg/kg) every 21 days; 
• 
Arm B:  Rituximab (375 mg/m2) followed by DCDS4501A (2.4 mg/kg) every 21 days 
 
The first day of treatment constitutes Day 1 of each cycle.  A typical cycle is 21 days in 
duration. 
A dynamic hierarchical randomization scheme will be employed with respect to the 
following stratification factors: 
• 
For patients with FL (see Section 3.1.4 for definitions) 
Rituximab refractory disease (no response or disease relapse < 6 months from 
last rituximab treatment) versus rituximab relapsed disease (disease relapse 
after response ≥  6 months from last rituximab treatment) 
• 
For patients with DLBCL (see Section 3.1.5 for definitions) 
Second-line versus third-line (or beyond) therapy 
For second-line patients, disease relapse or no objective response (CR, 
unconfirmed CR [CRu], or PR) <12 months from the start of initial therapy versus 
disease relapse, after initial objective response (CR, unconfirmed response 
[CRu] or PR), ≥ 12 months from start of initial therapy  
For third-line patients, failure to achieve a CR or progression < 6 months from 
start of most recent therapy versus CR or progression ≥ 6 months from start of 
most recent therapy 
No formal testing comparing the two treatment arms in the randomized portion of the 
study is planned. 
3.1.1.2 
Non-Randomized Portion of the Study with Rituximab 
(Cohorts C and D) 
Only select investigator sites that have agreed to participate in the non-randomized 
portion of the study will enroll patients into these cohorts. 
Patients with relapsed or refractory follicular NHL will be enrolled in Cohorts C and D to 
receive rituximab (375 mg/m2) combined with DCDT2980S or DCDS4501A at a dose of 
1.8 mg/kg.  The first day of treatment constitutes Day 1 of each cycle.  A typical cycle will 
be 21 days in duration. 
The opening of either or both cohorts will be at the Sponsor’s discretion and only after 
the enrollment of patients with FL into the randomized portion of the study is completed.  


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Patients will not be randomized to receive one treatment or the other.  It is anticipated 
that Cohort C and D will be opened sequentially.   
3.1.2 
All Patients on Rituximab-Containing Arms/Cohorts  
All patients on rituximab-containing regimens, regardless of assigned arm/cohort, will 
receive DCDT2980S or DCDS4501A and rituximab administered by IV infusion on a 
21-day cycle.  For the first two cycles, rituximab will be administered by IV infusion on 
Day 1 and DCDT2980S or DCDS4501A will be administered by IV infusion on Day 2.  In 
the absence of any infusion-related adverse events, rituximab and DCDT2980S or 
DCDS4501A may be administered on the same day (Day 1) in subsequent cycles 
beginning with the third cycle.  In this instance, rituximab will be administered first, 
followed by DCDT2980S or DCDS4501A.  In certain circumstances⎯for example, IRRs 
requiring interruption or slowing of infusion rate⎯rituximab may be administered over 
2 days (e.g., Day 1 and Day 2 of the cycle); in this case, DCDT2980S or DCDS4501A 
may be administered on Day 2 following completion of the rituximab infusion or on Day 3 
of the cycle. 
Patients may receive treatments for up to 1 year (17 cycles on an every-21-day 
schedule) if not discontinued because of significant toxicity, disease progression, or 
withdrawal from study. 
Patients will be evaluated for safety and efficacy according to the Schedules 
of Assessments outlined in Appendices A-1, A-2, and A-4.  Initial response assessments 
in this study will be performed every 3 months from the initiation of therapy until study 
treatment completion or early termination (e.g., between Days 14 and 21 of Cycles 4 
and 8 for those patients receiving at least eight 21-day cycles of treatment).  Additional 
response assessments for patients who proceed to crossover treatment (see 
Section 3.1.6) will be performed as described in Appendix A-2; response assessments 
for patients who discontinue study treatment (both initially assigned treatment and 
crossover treatment) for reasons other than disease progression will be performed as 
described in Appendix A-4. 
Responses to study treatment will be based on investigator assessments.  In addition, 
tumor assessment data will be transmitted to an Independent Review Facility (IRF) for 
collection and possible independent review. 
3.1.3 
Obinutuzumab-Containing Regimen with DCDS4501A (Cohorts E, 
G, and H) 
DCDS4501A at 1.8 mg/kg will be given in combination with obinutuzumab to patients 
with relapsed or refractory follicular NHL and DLBCL in two stages:  (1) safety run-in 
and (2) expansion. 
Study treatment will be given in 21-day cycles for both follicular NHL and DLBCL.  
Patients will be treated for up to a total of 8 cycles.  For the first cycle, obinutuzumab 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
90/P GO27834-A2 
will be administered by IV infusion on Days 1, 8, and 15.  DCDS4501A will be given 
on Day 2 for Cycle 1.  In the absence of any infusion-related adverse events, 
obinutuzumab and DCDS4501A may be administered on the same day (Day 1) in 
subsequent cycles beginning with the second cycle.  If obinutuzumab and DCDS4501A 
are administered on the same day, the study drugs will be given sequentially.  
Obinutuzumab will be administered first, followed by DCDS4501A.  In certain 
circumstances⎯for example, IRRs requiring interruption or slowing of infusion 
rate⎯obinutuzumab may be administered over 2 days (e.g., Day 1 and Day 2 of the 
cycle); in this case, DCDS4501A may be administered on Day 2 following completion of 
the obinutuzumab infusion. 
3.1.3.1 
 Obinutuzumab-Containing Regimen in Phase Ib: Safety 
Run-In (Cohort E) 
This portion of the study will consist of a safety run-in that will evaluate the safety of 
DCDS4501A at 1.8 mg/kg in combination with obinutuzumab in 6 patients (Cohort E).  
The safety run-in is described in detail in Section 3.4.  In case an amendment to the 
protocol allows to study higher doses of DCDS4501A, the safety run-in for the 
1.8 mg/kg may be shortened to 3 patients. 
Obinutuzumab-Containing Regimens in Phase II:  Expansion Stage 
(Cohorts G and H) 
After the safety run-in has demonstrated that DCDS4501A at 1.8 mg/kg in 
combination with obinutuzumab is safe to administer, patients will be enrolled into two 
expansion cohorts based on histology of follicular NHL or DLBCL (Cohorts G and H, 
respectively).  Forty patients will be enrolled into each expansion cohort.  An 
additional cohort(s) may be added in the future. 
3.1.4 
Follicular NHL Patients for Rituximab-Containing 
Arms/Cohorts 
Patients with relapsed or refractory follicular NHL will be enrolled into the study as 
defined by the following: 
• 
Relapsed as documented history of response (CR, CRu, or PR) of ≥ 6 months in 
duration from completion of all prior rituximab-containing regimens.  A 
rituximab-containing regimen is defined as rituximab as a single agent during 
induction and/or maintenance or in combination with other agents during induction 
and/or maintenance. 
• 
Refractory to any prior regimen containing rituximab, defined as no response to or 
progression within 6 months of completion of the last dose of rituximab therapy 
(either as monotherapy or in combination with chemotherapy), including: 
Patients with progressive disease while receiving rituximab monotherapy, 
rituximab combined with chemotherapy, or rituximab maintenance therapy; 
patients must have received at least one full dose (375 mg/m2) of rituximab. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Patients with no objective response (PR or CR) to a rituximab-containing regimen 
consisting of at least 4 weekly doses of rituximab monotherapy or at least 
4 cycles of rituximab combined with chemotherapy 
Patients with disease relapse, after having achieved an objective response, 
within 6 months of completion of the last dose of rituximab therapy in a regimen 
consisting of at least four weekly doses of rituximab monotherapy or at least 
4 cycles of rituximab combined with chemotherapy 
 
Enrollment of patients with refractory disease as defined above may be limited to no 
greater than 60% of the total follicular NHL cohort, in order to avoid overrepresentation 
of the refractory disease population. 
3.1.5 
Follicular NHL Patients for Obinutuzumab-Containing 
Cohorts 
Patients with relapsed or refractory follicular NHL will be enrolled into the study as 
defined by the following: 
• 
Relapsed to prior regimen(s) after having a documented history of response (CR, 
CRu, or PR) of ≥ 6 months in duration from completion of regimen(s)   
• 
Refractory to any prior regimen, defined as no response to the prior therapy, or 
progression within 6 months of completion of the last dose of therapy 
 
3.1.6 
DLBCL Patients for Rituximab-Containing Arms/Cohorts 
Patients with relapsed or refractory DLBCL who are determined by the investigator to be 
ineligible for high-dose therapy with autologous stem cell rescue/stem cell transplant 
(SCT) will be enrolled into the study as defined by the following: 
• 
Second-line SCT-ineligible patients with progressive disease or no response 
(SD) < 12 months from start of initial therapy (second-line refractory) 
• 
Second-line SCT-ineligible patients with disease relapse after initial response 
≥ 12 months from start of initial therapy (second-line relapsed) 
• 
Third-line (or beyond) SCT-ineligible patients with progressive disease or no 
response (SD) < 6 months from start of prior therapy (third-line + refractory) 
• 
Third-line (or beyond) SCT-ineligible patients with disease relapse after initial 
response ≥ 6 months from start of prior therapy (third-line + relapsed) 
 
Enrollment into any of the above four categories may be limited to no greater than 40% 
of the DLBCL cohort—and to no more than 60% of the two refractory categories 
combined—in order to avoid overrepresentation of any specific subpopulation, refractory 
patients in particular. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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3.1.7 
DLBCL Patients for Obinutuzumab-Containing Cohorts 
Patients with relapsed or refractory DLBCL who are determined by the investigator to 
be ineligible for high-dose therapy with autologous stem cell rescue/SCT will be 
enrolled into the study as defined by the following: 
• 
Second-line SCT-ineligible patients with progressive disease or no response 
(SD) < 12 months from start of initial therapy (second-line refractory) 
• 
Second-line SCT-ineligible patients with disease relapse after initial response 
≥ 12 months from start of initial therapy (second-line relapsed) 
• 
Third-line (or beyond) SCT-ineligible patients with progressive disease or no 
response (SD) < 6 months from start of prior therapy (third-line + refractory) 
• 
Third-line (or beyond) SCT-ineligible patients with disease relapse after initial 
response ≥ 6 months from start of prior therapy (third-line + relapsed) 
 
3.1.8 
Crossover Treatment (Randomized Patients in Arms A and B 
Only) 
Patients randomized to Arm A or Arm B who develop progressive disease may be 
eligible to receive crossover treatment consisting of rituximab and the other ADC or the 
other ADC alone⎯for example, Arm B treatment for patients who have disease 
progression while receiving Arm A treatment, and vice versa⎯provided the following 
conditions are met: 
• 
Patients must not have experienced a toxicity requiring the discontinuation of 
DCDT2980S/DCDS4501A treatment OR experienced toxicity during the last dose of 
study treatment that would preclude treatment with the crossover regimen. 
Patients who had modifications to dosing and/or schedule on the initial study 
treatment will be permitted to receive crossover treatment in the absence of 
toxicities on the modified dose and/or schedule.  The dose and schedule of 
crossover treatment will be determined by the investigator and the Medical 
Monitor. 
Patients who had rituximab discontinued and continued on single-agent 
DCDT2980S/DCDS4501A treatment may receive crossover treatment of 
single-agent DCDS4501A/ DCDT2980S. 
• 
Patients must have radiographically documented disease progression. 
• 
Patients must meet all inclusion and exclusion criteria described in Sections 4.1.1 
and 4.1.2, except for those related to prior rituximab treatment. 
• 
Acceptable toxicity:  All study drug–related adverse events from the initial study 
treatment must have decreased to Grade 1 or baseline grade on or before the first 
day of treatment on the crossover regimen.  Exceptions may be allowed after a 
careful assessment and discussion of the benefit-risk balance with the patient by the 
investigator and approval from the Medical Monitor. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
93/P GO27834-A2 
• 
Administration of crossover treatment must be in the best interests of the patient as 
determined after a careful assessment and discussion of benefit-risk balance with 
the patient by the investigator and approval from the Medical Monitor. 
• 
A tumor biopsy (see Section 4.5.1.9) will be required for patients with safely 
accessible site of disease, defined as requiring only local anesthesia and, in 
general, excluding the brain, lungs or any internal organs that may subject patients 
to significant risk.  
Patients for whom a safely accessible site of disease is not present may still 
receive crossover treatment without undergoing a biopsy.  Eligibility to receive 
crossover treatment should be discussed with and approved by the Medical 
Monitor. 
A tumor biopsy of a safely accessible site of disease is optional for patients who 
are not eligible for study cross over.  
 
Patients who are determined to be eligible for study cross over will be treated as follows: 
• 
Assessments obtained at the initial study treatment discontinuation visit 
(see Section 4.5.4) may be used as screening assessments for crossover treatment.  
The following re-screening assessments must be repeated/obtained within 1 week 
prior to starting treatment on the crossover regimen, in order to re-establish baseline 
pretreatment clinical and disease status:  targeted physical exam, Eastern 
Cooperative Oncology Group (ECOG) status, and hematology and serum chemistry 
laboratory tests. 
Re-screening tests for hepatitis B and C do not need to be performed unless 
there is clinical suspicion of hepatitis B and/or C positivity. 
A radiographic tumor assessment must also be performed, unless already done 
to document disease progression, within 6 weeks prior to starting crossover 
treatment. 
• 
Crossover treatment will begin no later than 42 days after the last dose of the prior 
study treatment. 
 
Patients will be treated with the crossover treatment until a second disease progression 
event relative to the tumor assessment, documenting progressive disease on the initial 
study treatment, clinical deterioration, and/or intolerance to the crossover treatment for 
up to a maximum of 1 year (17 cycles on an every-21-day schedule).  Patients will be 
evaluated for safety and efficacy according to the schedules of assessments outlined in 
Appendices A-2.  Response assessments for patients who discontinue study treatment 
for reasons other than disease progression will be performed as described in 
Appendix A-4.  


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
94/P GO27834-A2 
Clinical data and exploratory data derived from tumor biopsies obtained prior to 
crossover treatment will be monitored on an ongoing basis.  Genentech has the right to 
restrict or suspend enrollment into crossover treatment at any time.  Reasons for this 
may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events during crossover treatment indicates a 
potential safety hazard to patients. 
• 
Patient enrollment into crossover treatment is unsatisfactory. 
• 
Data recording is inaccurate or incomplete.  
• 
Patients who are enrolled into the non-randomized portion of the study (Cohorts C, 
D, E, G, and H) will not have the option to receive crossover treatment upon 
disease progression (see Section 3.2 for rationale). 
 
3.2 
RATIONALE FOR STUDY DESIGN 
The primary rationale for the randomized non-comparative portion of the study is to 
assess clinical activity for the ADCs DCDT2980S and DCDS4501A in patients with 
relapsed or refractory NHL.  The study design ensures that the patient populations under 
study are balanced with respect to critical variables such as prior therapy and ensures 
consistent clinical assessment of safety and efficacy.  The collection and assessment of 
tumor tissue obtained prior to first study treatment and following progressive disease will 
provide further understanding of disease biology, possible mechanisms of resistance to 
the study treatment, and initial insights into tumor subtypes based on tumor biomarkers 
that are sensitive to study treatment.  Finally, the inclusion of study treatment crossover 
(see Section 3.1.8) will address important questions regarding efficacy and tolerability of 
a second ADC-rituximab combination following disease progression on the initial 
ADC-rituximab combination.  
The primary rationale for the non-randomized portion of the study (Cohorts C and D) is 
to assess the therapeutic index (i.e., the balance of efficacy and tolerability of 
DCDT2980S and DCDS4501A at a dose of 1.8 mg/kg in patients with relapsed or 
refractory follicular NHL).  An informal comparison between patients with follicular NHL 
treated at the two doses of the ADC will help determine if tolerability is improved at the 
lower ADC dose without substantial compromise of efficacy.   
The clinical feasibility of an ADC-rituximab combination regimen in patients with relapsed 
or refractory NHL has been previously studied.  Results from studies of rituximab in 
combination with a different CD22-specific ADC, inotuzumab ozogamicin, demonstrated 
that when combined with rituximab, the ADC was able to be given at the single-agent 
MTD without the need for dose reduction of the ADC because of the lack of significant 
overlapping toxicity (Luis et al. 2006; Nam et al. 2009; Nina et al. 2010). 
DCDT2980S and DCDS4501A are both being evaluated as single agents and in 
combination with rituximab in the ongoing Phase I studies Study DCT4862g and 
Study DCS4968g, respectively.  Results from these trials have determined an MTD of 
2.4 mg/kg for single-agent DCDT2980S and an RP2D of 2.4 mg/kg for single-agent 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
95/P GO27834-A2 
DCDS4501A in patients with mixed NHL.  In addition, the RP2D of DCT2980S and 
DCDS4501 each in combination with rituximab (375 mg/m2) on an every-21-day 
schedule was determined to be 2.4 mg/kg.  Study GO27834 will continue to assess the 
cumulative safety and longer-term tolerability of ADC-rituximab combination therapy. 
The primary rationale for the non-randomized Phase Ib/II obinutuzumab-containing 
cohorts (Cohorts E−H) is to assess safety and clinical activity for the combination of 
obinutuzumab and DCDS4501A in patients with relapsed/refractory NHL (Cohorts E, 
G, and H).  Obinutuzumab (also known as RO5072759, GA101 and 
Gazyva™/Gazyvaro™), a novel type II and glycoengineered anti-CD20 antibody, has 
shown superiority over rituximab in a Phase III trial in first-line CLL (Goede et al. 
2014).  Obinutuzumab is currently being compared with rituximab in two large 
Phase III studies in patients with newly diagnosed DLBCL (Study BO21005) and 
previously untreated iNHL, including FL (Study BO21223).  Assuming these studies 
demonstrate greater clinical benefit with obinutuzumab- vs. rituximab-containing 
regimens, potentially altering the standard of care in NHL, it will be important to also 
assess the safety and efficacy of combining DCDS4501A with obinutuzumab-
containing regimens. 
Study drug dosing will occur on Days 1 or 2 of each 21-day (or 28-day) cycle to allow for 
recovery from potential bone marrow toxicity. 
3.2.1 
Rationale for the PK Sample Schedule 
PK data obtained in this study will be important in informing potential future trials with 
this combination.  Given the likely changing effect of peripheral B-cell counts, tumor 
burden, and target antigen expression on target-mediated drug CL over multiple doses 
of DCDT2980S or DCDS4501A plus rituximab or obinutuzumab when the two drugs are 
given in combination, the drug levels of DCDT2980S or DCDS4501A-related analytes 
and rituximab or obinutuzumab will be assessed in this combination study.   
In Studies DCT4862g and DCS4968g, single-agent DCDT2980S and DCDS4501A 
administered by IV infusion every 21 days were evaluated at doses ranging from 0.1 to 
3.2 mg/kg for DCDT2980S and 0.1 mg/kg to 2.4 mg/kg for DCDS4501A in patients with 
NHL.  Intensive PK sampling of all patients in the ongoing Phase I studies will provide 
sufficient data to allow complete profiling of the distribution and elimination phases for 
DCDT2980S and DCDS4501A and the investigation of potential correlations between 
various PK parameters and efficacy and/or toxicity.  Consequently a reduced PK 
sampling scheme of DCDT2980S and DCDS4501A will be used in this study.  
The PK data collected in this study will allow further characterization of the PK properties 
of DCDT2980S and DCDS4501A.  In addition, the DCDT2980S and DCDS4501A 
concentration results from this study will be compared with available data from the 
single-agent clinical studies to evaluate whether concurrent administration of rituximab 
affects the exposure of DCDT2980S and/or DCDS4501A.   


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Rituximab serum concentration measurements from this study will be compared with 
PK data from historical rituximab clinical studies to evaluate whether the combination 
with DCDT2980S and/or DCDS4501A affects the pharmacokinetics of rituximab.  
Limited sampling of serum concentrations of obinutuzumab will be assessed and 
compared with historical data to evaluate potential PK interactions with DCDS4501A. 
3.3 
OUTCOME MEASURES 
3.3.1 
Safety Outcome Measures 
The safety and tolerability of the combination of DCDT2980S and rituximab and 
DCDS4501A and rituximab or obinutuzumab will be assessed using the following safety 
outcome measures: 
• 
Incidence, nature, and severity of adverse events 
• 
Incidence of anti-DCDT2980S, anti-DCDS4501A, or anti-obinutuzumab antibodies 
• 
Changes in vital signs 
• 
Changes in laboratory values 
  
3.3.2 
Pharmacokinetic/Pharmacodynamic Outcome Measures 
The following PK parameters will be derived from the serum concentration–time profiles 
of total antibody (the sum of conjugated and unconjugated antibody), including rituximab 
or obinutuzumab, and plasma concentration-time profiles of acMMAE and free MMAE 
following administration of DCDT2980S or DCDS4501A, when appropriate, as data 
allow: 
• 
Total exposure (area under the concentration-time curve [AUC]) 
• 
Maximum plasma and serum concentration (Cmax) 
• 
CL 
• 
Terminal half-life (t1/2) 
• 
Vss 
 
Compartmental, non-compartmental, and/or population methods may be used.  Other 
parameters, such as accumulation ratio and trough plasma and serum concentration 
(Cmin), may also be calculated. 
The following PD outcome measures will be assessed when appropriate, as data allow: 
• 
Peripheral blood B-cell depletion and recovery.  For each visit at which CD19+ B-cell 
measurements are taken, B-cell data will be listed for each patient by dose level as 
follows: 
Absolute blood cell counts 
Percent change relative to the baseline blood counts 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
97/P GO27834-A2 
CD19+ B-cell recovery, defined as the timepoint when the values return to 
baseline levels or ≥ 50% of baseline levels 
• 
Assessment of the kinetics of circulating tumor DNA 
 
3.3.3 
Activity Outcome Measures 
The following activity outcome measures will be assessed: 
• 
Objective response, defined as a PR or CR 
• 
Duration of objective response, defined as the duration of time from the first 
occurrence of a documented objective response to time of relapse or death from 
any cause 
• 
PFS, defined as the duration from randomization to the first occurrence of 
progression or death within 30 days of the last administration of study drug, 
whichever occurs first 
• 
OS, defined as the duration from the date of randomization/enrollment to the date 
of death from any cause 
 
Objective response and disease progression will be determined using standard criteria 
for NHL (Cheson et al. 2007, 2014; see Appendix C-1 and Appendix C-2). 
3.3.4 
Exploratory Outcome Measures  
The exploratory outcome measures will include, but will not be limited to, the following:  
• 
Confirmation and quantitation of CD22, CD79b, and CD20 expression levels in 
either archival or freshly obtained (when available) tumor specimens (tumor 
biopsies, bone marrow biopsies, peripheral blood) by immunohistochemistry/flow 
cytometry/quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) 
• 
Additional assessments related to the understanding of the mechanism of action of 
DCDT2980S, DCDS4501A, rituximab, and obinutuzumab, e.g., assessment of 
circulating tumor DNA(ctDNA) to monitor response, mechanisms of resistance to 
DCDT2980S, DCDS4501A, rituximab, and obinutuzumab, and/or NHL pathogenesis 
may be included. 
• 
Treatment and disease symptom assessments using the M.D. Anderson Symptom 
Inventory (MDASI) 
 
3.4 
SAFETY PLAN  
See Section 5 (Assessment of Safety) for complete details of the safety evaluation for 
this study. 
Safety will be evaluated through the monitoring of the following: 
• 
Serious adverse events that are attributed to protocol-mandated interventions from 
the time of signing of the Informed Consent Form until the first dose of study 
treatment on Cycle 1, Day 1 


 
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• 
All adverse events from Cycle 1, Day 1 until 30 days after the last dose of 
DCDT2980S, DCDS4501A, rituximab, or obinutuzumab, whichever is later, 
including doses that were administered as part of crossover treatment 
• 
All serious adverse events from Cycle 1, Day 1 until 30 days after the last dose of 
DCDT2980S, DCDS4501A, rituximab, or obinutuzumab, whichever is later, 
including doses that were administered as part of crossover treatment 
• 
All serious adverse events from the last dose of DCDT2980S, DCDS4501A, 
rituximab, or obinutuzumab, whichever is later, including doses that were 
administered as part of crossover treatment, and which are judged to be caused by 
DCDT2980S, DCDS4501A, rituximab, or obinutuzumab, regardless of time of onset 
• 
Measurements of protocol-specified hematology and clinical chemistry laboratory 
values 
• 
Measurements of protocol-specified vital signs 
• 
Assessment of ECGs 
• 
Assessment of physical findings on clinical physical examinations 
 
Patients who have an ongoing study drug−related adverse event will be followed until 
the event has resolved to baseline grade, the event is assessed by the investigator as 
stable, new anti-tumor treatment is initiated, the patient is lost to follow-up, the patient 
withdraws consent, it is determined that the study treatment or participation is not the 
cause of the adverse event, or the study is terminated. 
See Section 5.2.3 for assessment of causality for adverse events. 
3.4.1 
Safety Run-In Analysis 
As outlined in Figure 3b and Section 3.1.3.1, a safety run-in analysis (Cohort E) will 
be conducted by the Internal Monitoring Committee (IMC) to evaluate the combination 
of DCDS4501A at a dose of 1.8 mg/kg with obinutuzumab.  This analysis will include 
data from the first 6 patients treated through Day 21 of Cycle 1.  Three patients will 
initially be enrolled, and then an additional 3 patients will be enrolled after the first 
3 patients have safely completed the first cycle.  At the IMC’s discretion, and at any 
point during enrollment of the safety run-in, a decision could be made that more than 
6 patients are needed to evaluate safety.  In this case, the protocol will be amended to 
allow for more than 6 patients in the safety run-in.  In case the study is amended to test 
additional doses the safety run-in for 1.8 mg/kg may be shortened to three patients. 
Safety summaries will be assessed at the safety run-in for SAEs; Grade 3-5 treatment-
related AEs; all AEs; all Grade 3-5 AEs;  and AEs leading to treatment discontinuation 
or dose modification/interruption. 
• 
During the 6-patient safety run-in, if any patient experiences a treatment-related 
death, then the obinutuzumab-containing portion of the study will be closed to 
further recruitment. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
99/P GO27834-A2 
• 
During the 6-patient safety run-in: 
If 2 or more of the first 3 patients enrolled experience Grade 4 febrile 
neutropenia or serious (i.e., SAE) documented infection requiring IV antibiotics 
in the presence of Grade 3−4 neutropenia, then the obinutuzumab-containing 
portion of the study will be closed to further recruitment 
If 1 of the first 3 patients enrolled experiences Grade 4 febrile neutropenia or 
serious (i.e., SAE) documented infection requiring IV antibiotics in the presence 
of Grade 3−4 neutropenia, then an additional 3 patients will be recruited.  If 2 
or more of these first 3 patients experience Grade 4 febrile neutropenia or 
serious (i.e., SAE) infection with Grade 3−4 neutropenia, then the 
obinutuzumab-containing portion of the study will be closed to further 
recruitment. 
If 2 or more of the first 6 patients to be enrolled experiences Grade 4 febrile 
neutropenia or serious (i.e., SAE) documented infection requiring IV antibiotics 
in the presence of Grade 3−4 neutropenia, then the obinutuzumab-containing 
portion of the study will be closed to further recruitment. 
Before the expansion portion of the study can begin (enrollment of Cohorts G 
and H), the following criteria must be met: 
Six patients must have competed enrollment in the safety run-in 
(Cohort E). 
Three patients must have completed at least 4 cycles of treatment. 
 
3.4.2 
Internal Monitoring Committee 
This study will employ an Internal Monitoring Committee (IMC).  The purpose of the IMC 
will be to make recommendations regarding study conduct on the basis of trial safety 
data to ensure patient safety while receiving study treatment. 
The IMC will include a sponsor Medical Monitor not affiliated with the study, a 
Drug Safety Scientist, a biostatistician, and a statistical programmer.  Representatives 
from other Sponsor functional areas may be included as additional ad hoc members. In 
addition to the ongoing assessment of the incidence and nature of adverse events, 
serious adverse events, and laboratory abnormalities by the Investigator and the Medical 
Monitor, the IMC will review the aforementioned data at least twice during the study.  
Throughout the course of the study, the IMC will meet, as needed, at the request of the 
Medical Monitor (e.g., on the basis of unexpected safety signals).  The IMC may make 
recommendations regarding study conduct, including, but not limited to, performing 
additional safety analyses, amending the study protocol, holding patient enrollment to 
one or both treatment arms pending further safety evaluations, holding/discontinuing 
study treatment, or terminating the study. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Complete details of the IMC will be described in the IMC charter. 
For Arms A and B: The first planned review will occur after approximately 10 patients 
are randomized and have at least 6 weeks follow-up, and the next formal review will 
occur when approximately 60 patients are randomized and have at least 6 weeks 
follow-up.   
3.4.3 
Risks Associated with DCDT2980S and DCDS4501A 
The clinical safety profile of DCDT2980S and DCDS4501A based on clinical data 
obtained in the ongoing Phase I studies are summarized in Sections 1.2.1.2 and 1.2.2.2.  
Known and suspected risks, based on clinical data to date, are described below.  
Guidelines regarding the management of these risks through dose and schedule 
modifications are described in Sections 4.3.1.3 and 4.3.1.4.   
Refer also to the Investigator Brochure for complete and updated details. 
3.4.3.1 
Infusion-Related Events 
Some MAbs may be associated with the development of allergic or anaphylactic 
reactions, to either the active protein or excipients.  True allergic or anaphylactic 
reactions are rare after the first dose of a product, as they require prior sensitization.  
Patients with true allergic or anaphylactic reactions should not receive further doses of 
the product. 
MAbs may also be associated with reactions that are clinically indistinguishable from 
true allergic or anaphylactic reactions but are mediated through direct release of 
cytokines or other pro-inflammatory mediators.  Such reactions are often termed IRRs.  
IRRs typically occur with the first infusion of a MAb product and are generally less 
frequent and/or less severe with subsequent infusions.  They can often be managed by 
slowing the infusion rate and/or pre-treatment with various medications. 
Allergic or anaphylactic reactions and IRRs typically begin during or within several hours 
of completing the infusion.  The onset of symptoms may be rapid, and some reactions 
may be life threatening. 
Patients should be monitored for these types of reactions during and after receiving 
DCDT2908S and DCDS4501A.  DCDT2980S and DCDS4501A should be administered 
in an environment under close supervision of a physician and where full resuscitation 
facilities are immediately available.  Specific guidelines for additional precautions to be 
taken during and following DCDT2980S and DCDS4501A administration are provided in 
Sections 4.3.1.5. 
3.4.3.2 
Tumor Lysis Syndrome 
There is a potential risk of TLS if treatment with DCDT2980S or DCDS4501A results in 
the rapid destruction of a large number of tumor cells.  If any evidence of this occurs 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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during the study, TLS prophylaxis measures will be instituted.  Patients who are 
considered to have a high tumor burden (e.g., lymphocyte count ≥ 25 × 109/L) or bulky 
lymphadenopathy and who are considered to be at risk for TLS by the investigator will 
receive TLS prophylaxis (e.g., allopurinol ≥ 300 mg/day orally or a suitable alternative 
treatment according to institutional practice starting 12−24 hours prior to study 
treatment) and must be well hydrated prior to the initiation of study treatment at Cycle 1, 
Day 1.  These patients should continue to receive repeated prophylaxis with allopurinol 
and adequate hydration prior to each subsequent infusion as deemed appropriate by the 
investigator. 
3.4.3.3 
Bone Marrow Toxicity/Neutropenia 
Based on preclinical toxicity studies in rats and cynomolgus monkeys and clinical data 
from the ongoing Phase I Studies DCT4862g and DCS4968g, neutropenia has been 
identified as a known risk (adverse drug reaction) of both DCDT2908S and 
DCDS4501A.  Neutropenia and neutropenia-associated events were reversible but in 
some cases resulted in protocol-mandated dose reductions and/or delays.   
Adequate hematologic function should be confirmed before initiation of study treatment.  
Patients receiving study treatment will be regularly monitored for evidence of marrow 
toxicity with complete blood counts.  Study treatment may be delayed or modified due to 
hematologic toxicities, as described in Section 4.3.1.  
The use of G-CSF for neutropenia is described in Section 4.3.1.6.  Transfusion support 
for anemia and thrombocytopenia is also permitted at the discretion of the treating 
physician. 
Febrile neutropenia is commonly associated with myelotoxicity, which is considered a class effect 
of MMAE because it is commonly reported with ADCETRIS®, other similar ADCs, and 
vincristine sulfate. 
Clinical data show that among the most common SAEs reported in both DCS4968g and 
DCT4862g studies were febrile neutropenia and pyrexia. 
3.4.3.4 
Immunogenicity 
As expected with any recombinant antibody, DCDT2980S, DCDS4501A, and 
obinutuzumab may elicit an immune response and patients may develop antibodies 
against DCDT2980S, DCDS4501A, or obinutuzumab.  Patients will be closely monitored 
for any potential immune response to DCDT2980S, DCDS4501A, and obinutuzumab.  
Appropriate screening and confirmatory assays will be employed to detect ATAs at 
multiple timepoints before, during, and after treatment with DCDT2980S, DCDS4501A, 
and obinutuzumab.  Considering the historically low immunogenicity rate of rituximab in 
NHL patients, ATAs against rituximab will not be monitored in this study. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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3.4.3.5 
Peripheral  Neuropathy 
On the basis of clinical data from the ongoing Phase I Studies DCT4862g and 
DCS4968g and data from brentuximab vedotin studies, an anti-CD30-vc-MMAE ADC 
(see Section 3.4.2), peripheral neuropathy (sensory and motor) has been identified as a 
known risk (adverse drug reaction) for both DCDT2980S and DCDS4501A. 
Careful clinical evaluation of patients for neuropathy should be conducted prior to 
initiation of study drug.  Patients should be monitored for signs of peripheral neuropathy 
or worsening neuropathy and appropriate action taken per protocol guidelines.  Study 
treatment dose and schedule modifications for significant and prolonged neuropathic 
toxicity and dose-reduction are described in Section 4.3.1.7.   
3.4.3.6 
Reproductive Toxicity 
Adverse effects on human reproduction and fertility are anticipated with the 
administration of DCDT2980S and DCDS4501A, given the mechanism of action of 
MMAE.  Standard exclusion criteria will be used to ensure that patients of childbearing 
potential (male or female) are using adequate contraceptive methods.  
3.4.3.7 
Hyperglycemia 
Hyperglycemia has been observed in patients treated with DCDT2980S and 
DCDS4501A as well as with other ADCs using the same vc-MMAE platform.  Several 
patients given both DCDT2980S and DCDS4501A had abnormal fasting blood sugar (FBS)  at 
screening with elevations of glucose following steroid administration prior to rituximab dose.  
Hyperglycemia has been reversible upon holding or discontinuing treatment of the ADCs 
and/or initiation or adjustment of anti-hyperglycemic medications.  Emerging data suggest 
that hyperglycemia may occur more commonly in individuals with abnormal FBS values or 
known diabetes.  This is also reported for ADCETRIS® (2013 SmPC and 2013 USPI).  
3.4.3.8 
Hepatotoxicity 
Elevations in transaminase and/or bilirubin levels requiring dose modifications and 
treatment discontinuations have been reported in the ongoing clinical studies.   
3.4.3.9 
Commonly Reported Side Effects 
Other commonly reported side effects of both DCDT2980S or DCDS4501A in the Phase I clinical 
trials and within this study include fatigue, nausea, decreased appetite, vomiting, hair thinning 
or loss, joint pains, loss of appetite, diarrhea, muscle aches, constipation, increases in blood 
glucose, and headaches. 
3.4.4 
Risks Associated with ADCETRIS® (Brentuximab Vedotin) 
An ADC using the same MMAE drug and linker as that used in DCDT2980S and 
DCDS4501A, but coupled to an antibody targeting the CD30 antigen (brentuximab 
vedotin, ADCETRIS®, Seattle Genetics), was recently approved by the FDA for use in 
the treatment of specific subsets of patients with relapsed Hodgkin lymphoma and 
systemic anaplastic large-cell lymphoma.   


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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The most common adverse reactions observed in studies with brentuximab vedotin 
(occurring in at least 20% of patients) were neutropenia, peripheral sensory neuropathy, 
fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, 
thrombocytopenia, cough, and vomiting.   
Serious adverse reactions were reported in 31% of patients receiving ADCETRIS®.  The 
most common occurring in > 2% of patients included peripheral motor neuropathy, 
abdominal pain, septic shock, supraventricular arrhythmia, pain in extremity, and urinary 
tract infection.  In addition, John Cunningham (JC) virus infection resulting in progressive 
multifocal leukoencephalopathy (PML) and death has been reported.   
Because of the use of the same MMAE drug, it is possible that the adverse events 
observed with the use of brentuximab vedotin can also be observed with the use of 
DCDT2980S and DCDS4501A.   
Refer to the current version of the ADCETRIS® Prescribing Information for full and 
updated details. 
3.4.5 
Risks Associated with Rituximab Therapy and Their 
Management 
3.4.5.1 
Infusion Reactions 
In single-agent clinical trials of rituximab and in post-marketing surveillance studies, mild 
to moderate infusion reactions consisting of fever and chills/rigors occurred in the 
majority of patients during the first rituximab infusion.  Other frequent infusion reaction 
signs and symptoms included nausea, pruritus, angioedema, asthenia, hypotension, 
headache, bronchospasm, throat irritation, rhinitis, urticaria, rash, vomiting, myalgia, 
dizziness, and hypertension.  These reactions generally occurred within 30−120 minutes 
of beginning the first infusion, and they resolved with slowing or interruption of the 
rituximab infusion and with supportive care (diphenhydramine, 
acetaminophen/paracetamol, IV saline, meperidine, and vasopressors).  The incidence 
of infusion reactions was highest during the first infusion and decreased with each 
subsequent infusion. 
Rituximab has caused severe infusion reactions.  In some cases, these reactions were 
fatal.  These severe reactions typically occurred during the first infusion with a time to 
onset of 30−120 minutes.  Signs and symptoms of severe infusion reactions may include 
urticaria, hypotension, angioedema, hypoxia, or bronchospasm and may require 
interruption of rituximab administration.  The most severe manifestations and sequelae 
include pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, 
ventricular fibrillation, cardiogenic shock, and anaphylactic and anaphylactoid events 
(see Appendix D).  Approximately 80% of fatal infusion reactions occurred in association 
with the first infusion of rituximab.  Because of this, patients should receive 
premedication with acetaminophen/paracetamol, antihistamines, or corticosteroids, in 
accordance with standard clinical practice, prior to rituximab infusions. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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3.4.5.2 
Management of Severe Infusion Reactions 
Administration of rituximab will occur in a setting with emergency equipment and staff 
who are trained to monitor for and respond to medical emergencies.  The rituximab 
infusion should be interrupted for severe reactions on the basis of clinical judgment.   
Medications and supportive care measures⎯including, but not limited to, epinephrine, 
antihistamines, glucocorticoids, IV fluids, vasopressors, oxygen, bronchodilators and 
acetaminophen/paracetamol⎯should be available for immediate use and instituted as 
medically indicated for use in the event of a reaction during administration.   
In most cases, the infusion can be resumed at a 50% reduction in rate (e.g., from 
100 mg/hr to 50 mg/hr) when symptoms have completely resolved.  Patients requiring 
close monitoring during all rituximab infusions include those with preexisting cardiac and 
pulmonary conditions, those with prior clinically significant cardiopulmonary adverse 
events, and those with high numbers of circulating malignant cells (≥ 25,000/μL) with or 
without evidence of high tumor burden. 
3.4.5.3 
Tumor Lysis Syndrome 
Rapid reductions in tumor volume followed by acute renal failure, hyperkalemia, 
hypocalcemia, hyperuricemia, or hyperphosphatemia have been reported within 
12−24 hours after the first infusion of rituximab.  Rare instances of fatal outcome have 
been reported in the setting of TLS following treatment with rituximab.  The risks of TLS 
appear to be greater in patients with high tumor burden.  Patients deemed to be at high 
risk for TLS complications may, at the investigator’s discretion, receive their initial dose 
of rituximab over 2 consecutive days (see Section 4.3.2.3).  Correction of electrolyte 
abnormalities, monitoring of renal function and fluid balance, and administration of 
supportive care, including dialysis, should be initiated as indicated.  Following complete 
resolution of TLS complications, rituximab has been tolerated when re-administered in 
conjunction with prophylactic therapy for TLS in a limited number of cases. 
3.4.5.4 
Hepatitis B Reactivation with Related Fulminant Hepatitis and 
Other Viral Infections 
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death 
has been reported for some patients with hematologic malignancies treated with 
rituximab.  The majority of these patients received rituximab in combination with 
chemotherapy.  The median time to the diagnosis of hepatitis was approximately 
4 months after the initiation of rituximab and approximately 1 month after the last dose of 
rituximab.  Patients with serologic findings consistent with chronic HBV (hepatitis B 
surface antigen [HBsAg] positivity) or hepatitis C virus (HCV) infection (HCV RNA or 
antibody positivity) are ineligible for this study.  Patients who are not chronically infected 
with HBV but have serologic evidence of prior infection at baseline (IgG hepatitis B core 
antibody[anti-HBc] positive but HBV DNA negative) may be eligible (if believed to be in 
the patient’s best interest by the investigator and Medical Monitor) and would be 
monitored closely for perturbations in liver function during the period of rituximab 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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treatment and every 2−4 weeks thereafter.  Such patients would also be required to 
receive prophylactic anti-viral therapy with lamivudine for at least 6 months after 
completion of rituximab therapy (Yeo et al. 2009). 
Additional serious viral infections, new, reactivated, or exacerbated (e.g., infections 
caused by cytomegalovirus, varicella zoster virus, herpes simplex virus, West Nile virus, 
parvovirus B19, JC virus, and HCV) have been reported with rituximab, mainly in 
patients who had received rituximab in combination with chemotherapy or as part of a 
hematopoietic stem cell transplant.  Particular attention should be given to patients who 
have had significant prior immunosuppressive treatment such as high-dose 
chemotherapy and stem cell transplant.  JC virus infection resulting in PML and death 
has been observed in rituximab-treated patients with hematologic malignancies or with 
autoimmune diseases.  Most cases of PML were diagnosed within 12 months of the 
patient’s last infusion of rituximab.  Physicians should consider the diagnosis of PML in 
any patient presenting with new-onset neurologic manifestations.  Evaluation of PML 
includes, but is not limited to, consultation with a neurologist, brain magnetic resonance 
imaging (MRI), and lumbar puncture.  Physicians should discontinue rituximab (and 
DCDT2980S and/or DCDS4501A) and consider discontinuation or reduction of any 
immunosuppressive therapy in patients who develop PML. 
3.4.5.5 
Cardiovascular Events 
Infusions should be discontinued in the event of serious or life-threatening cardiac 
arrhythmias.  Patients who develop clinically significant arrhythmias should undergo 
cardiac monitoring during and after subsequent infusions of rituximab.  Patients with 
preexisting cardiac conditions, including arrhythmias and angina, who have had 
recurrences of these events during rituximab therapy should be monitored throughout 
the infusion and the immediate post-infusion period. 
3.4.5.6 
Bowel Obstruction and Perforation 
Abdominal pain, bowel obstruction, and perforation, in some cases leading to death, 
were observed in patients receiving rituximab in combination with chemotherapy for 
DLBCL.  In post-marketing reports, which include patients with low-grade or follicular 
NHL and patients with DLBCL, the mean time to onset of symptoms was 6 days 
(range, 1−77 days) in patients with documented gastrointestinal perforation.  Complaints 
of abdominal pain, especially early in the course of treatment, should prompt a thorough 
diagnostic evaluation and appropriate treatment.   
3.4.5.7 
Immunization 
The safety of immunization with live viral vaccines following rituximab therapy has not 
been studied.  Patients who participate in this study may not receive either primary or 
booster vaccination with live virus vaccines for at least 6 months prior to initiation of 
rituximab or at any time during study treatment.  Investigators should review the 
vaccination status of potential study patients being considered for this study and follow 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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the U.S. Centers for Disease Control and Prevention guidelines for adult vaccination with 
non-live vaccines intended to prevent infectious diseases prior to study therapy. 
Refer to the Rituxan®/MabThera® (Rituximab) Package Insert/Summary of Product 
Characteristics (SmPC) for additional safety information. 
3.4.6 
Risks Associated with Obinutuzumab Therapy 
No evidence available at the time of the approval of this protocol indicates that special 
warnings or precautions are appropriate other than those noted in the Obinutuzumab 
Investigator’s Brochure and as described in the following sections. 
3.4.6.1 
Infusion-Related Reactions and Hypersensitivity Reactions 
(including Anaphylaxis) 
The commonly experienced IRRs have been characterized by fever, chills, flushing, 
nausea, vomiting, hypotension, hypertension, fatigue, and other symptoms. 
Respiratory infusion-related symptoms, such as hypoxia, dyspnea, bronchospasm, 
larynx and throat irritation, and laryngeal edema, have also been reported.  These IRRs 
were mostly mild or moderate (NCI CTCAE v4.0, Grade 1 and 2 events), and < 10% of 
the events were severe (Grade 3 events), occurring predominantly during the first hour 
of the infusion or shortly after the first infusion had finished.  The events resolved with 
the slowing or interruption of the infusion and supportive care.  The incidence and 
severity of IRRs decreased with subsequent infusions.  Extensive tumor burden 
predominantly localized in the blood circulation (e.g., high peripheral lymphocyte count 
in patients with CLL) may be a predisposing factor for the development of IRRs. 
IRRs may be clinically indistinguishable from IgE-mediated allergic or anaphylactic 
reactions. 
3.4.6.2 
Tumor Lysis Syndrome 
TLS has been reported with obinutuzumab administration.  Patients with a high tumor 
burden, including patients with a lymphocyte count ≥ 25 × 109/L, particularly patients 
with B-cell CLL and MCL, are at increased risk for TLS and severe IRRs.  All patients 
with peripheral blood lymphocyte counts of ≥ 25 × 109/L or bulky adenopathy must 
receive prophylaxis for TLS prior to the initiation of study treatment.  This includes 
appropriate hydration, consisting of fluid intake of approximately 3 L/day, starting 
1−2 days prior to the first dose of obinutuzumab, and administration of allopurinol 
(300 mg/day orally) or a suitable alternative (i.e., rasburicase) treatment, starting at 
least 72 hours prior to the first infusion of obinutuzumab (Cycle 1, Day 1).  All 
patients should then be carefully monitored during the initial weeks of treatment.  
Patients still considered at risk for TLS because of persistently high tumor burden 
(i.e., peripheral blood lymphocyte counts ≥ 25 × 109/L) before the second and subsequent 
infusions of obinutuzumab should receive continuous TLS prophylaxis with allopurinol 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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or a suitable alternative (i.e., rasburicase) and adequate hydration until the risk is 
abated, as determined by the investigator.  
3.4.6.3 
Neutropenia 
Cases of Grade 3 or 4 neutropenia, including febrile neutropenia, have been reported 
with obinutuzumab administration.  Grade 3 or 4 neutropenia has predominantly been 
observed in patients with CLL.  Patients who experience Grade 3 or 4 neutropenia 
should be monitored until neutrophil values return to at least Grade 2.  Use of G-CSF 
has been found to result in a rapid normalization of neutrophils, similar to what has 
been observed in patients treated with rituximab.  The use of G-CSF is allowed for 
treatment of neutropenia in this study.  Primary prophylaxis with G-CSF is 
recommended according to the American Society of Clinical Oncology (ASCO), 
European Organisation for Research and Treatment of Cancer (EORTC), and European 
Society for Medical Oncology (ESMO) guidelines, namely for patients who are 
≥ 60 years old and/or with co-morbidities (Lyman et al. 2004).   
3.4.6.4 
Thrombocytopenia 
Severe and life-threatening thrombocytopenia, including acute thrombocytopenia 
(occurring within 24 hours after the infusion), has been observed during treatment 
with obinutuzumab.  Fatal hemorrhagic events have also been reported in patients 
treated with obinutuzumab.  It seems that the first cycle is the greatest risk of 
hemorrhage in patients treated with obinutuzumab.  A clear relationship between 
thrombocytopenia and hemorrhagic events has not been established.  Patients treated 
with concomitant medication, which could possibly worsen thrombocytopenia-related 
events (e.g., platelet inhibitors and anticoagulants), may be at greater risk of bleeding.  
Patients should be closely monitored for thrombocytopenia, especially during the first 
cycle; regular laboratory tests should be performed until the event resolves, and dose 
delays should be considered in case of severe or life-threatening thrombocytopenia.  
Transfusion of blood products (i.e., platelet transfusion) according to institutional 
practice is at the discretion of the treating physician.  
3.4.6.5 
Infection 
On the basis of its anticipated mode of action, resulting in profound B-cell depletion, 
obinutuzumab may be associated with an increased risk of infections.  Infections have 
been reported in patients receiving obinutuzumab.  Therefore, obinutuzumab should not 
be administered to patients with active severe infections. 
A “black-box” warning for obinutuzumab states that reactivation of hepatitis B as well 
as other serious viral infections (e.g., infections caused by cytomegalovirus, Varicella 
zoster virus, herpes simplex virus, JC virus, and HCV) that were new, reactivated, or 
exacerbated have been reported with the B cell−depleting antibody rituximab mainly in 
patients who had received the drug in combination with chemotherapy or as part of a 
hematopoietic SCT.  The risk of such infections with obinutuzumab is unknown.  


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Particular attention should be given to patients who have previously received 
significant immunosuppressive treatment, such as high-dose chemotherapy and SCT. 
A “black-box” warning for obinutuzumab states that JC viral infection (including 
fatal) that resulted in PML with destructive infection of oligodendrocytes of the CNS 
white matte have been reported in patients treated with anti-CD20 therapies, including 
rituximab and obinutuzumab. 
The diagnosis of PML should be considered in any patient presenting with new-onset 
neurologic manifestations.  The symptoms of PML are unspecific and can vary 
depending on the affected region of the brain.  Motor involvement with corticospinal 
tract findings, sensory involvement, cerebellar deficits, and visual field defects are 
common.  Some syndromes regarded as cortical (e.g., aphasia or visual-spatial 
disorientation) can occur. 
Evaluation of PML includes, but is not limited to, consultation with a neurologist, 
brain MRI, and lumbar puncture (cerebrospinal fluid testing for JC viral DNA).  
Therapy with obinutuzumab should be withheld during the investigation of potential 
PML and permanently discontinued in case of confirmed PML.  Discontinuation or 
reduction of any concomitant chemotherapy or immunosuppressive therapy should also 
be considered.  The patient should be referred to a neurologist for the diagnosis and 
management of PML. 
3.5 
MINIMIZATION OF BIAS  
For the randomized, non-comparative, open-label portion of the study, patients were 
randomly allocated to two treatment arms in a 1:1 ratio through use of an Interactive 
Voice and Web Response System (IXRS).  A dynamic stratified randomization scheme 
was employed to ensure balance in the stratification factors as specified in Section 3.1.  
This portion of the study (Arms A and B) is now closed to enrollment. 
3.6 
ADMINISTRATIVE STRUCTURE  
Genentech, Inc., a member of the Roche group, will sponsor this study.  A Contract 
Research Organization (CRO) will be utilized to perform project management, study 
management, and clinical monitoring.  Genentech will conduct CRO oversight, approve 
patient eligibility, and perform dose escalation decision-making, medical monitoring, and 
statistical programming and analysis.  An IMC (see Section 3.4) will provide an 
additional level of safety monitoring for the study.  
Approximately 40 study centers in the United States, Canada, and Europe will 
participate in the study to enroll approximately 252 patients.  Additional patients may be 
enrolled in order to obtain additional safety and/or efficacy data. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Electronic data capture (EDC) will be utilized for this study.  An IXRS will be used to 
assign patient numbers.  A central laboratory will be used for sample management and 
storage until shipment to one of several specialty laboratories or Genentech for analysis.  
An IRF will be used for the collection and possible assessment of radiographic images 
from tumor assessments.  Additional vendors for ECG collection and possible analysis 
and for PRO collection and data entry will be used. 
3.7 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in accordance with the FDA regulations, the International 
Conference on Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP), and 
applicable local, state, and federal laws, as well as other applicable country laws. 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria to be eligible for study entry: 
• 
Signed Informed  
• 
Consent Form(s) 
• 
Age ≥ 18 years  
• 
ECOG Performance Status of 0, 1, or 2 
• 
Life expectancy of at least 12 weeks 
• 
History of histologically documented relapsed or refractory Grades 1−3a FL or 
relapsed or refractory DLBCL 
• 
Availability of an archival or freshly biopsied tumor tissue sample must be confirmed 
for study enrollment. 
• 
Have a clinical indication for treatment as determined by the investigator 
• 
Must have at least one bidimensionally measurable lesion (> 1.5 cm in its largest 
dimension by computed tomography [CT] scan or MRI) 
• 
Laboratory values (including patients with hepatic or renal involvement), as follows: 
AST and ALT ≤ 2.5 × ULN 
Total bilirubin ≤ 1.5 × ULN 
Platelet count ≥ 75,000/mm3 (unless thrombocytopenia clearly due to marrow 
involvement of NHL and/or disease-related immune thrombocytopenia) 
Absolute neutrophil count ≥ 1000/mm3 (without growth factor support, unless 
neutropenia clearly due to marrow involvement of NHL) 
Total hemoglobin ≥ 9 g/dL (without transfusion support > 14 days prior to 
screening, unless anemia clearly due to marrow involvement of NHL) 
Serum creatinine ≤ 2.0 mg/dL or measured creatinine CL ≥ 50 mL/min 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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• 
For female patients of childbearing potential and male patients with female partners 
of childbearing potential, agreement to use one highly effective form of nonhormonal 
contraception or two effective forms of nonhormonal contraception, including at 
least one method with a failure rate of < 1% per year, through the course of 
study treatment and for ≥ 12 months after the last dose of DCDT2980S, 
DCDS4501A, rituximab, or obinutuzumab (whichever is later) in women and at least 
5 months after the last dose of DCDT2980S, DCDS4501A, rituximab, or 
obinutuzumab (whichever is later) in men 
A woman is considered not to be of childbearing potential if she is 
postmenopausal, defined by amenorrhea of ≥ 12 months duration and age 
≥ 45 years, or has undergone hysterectomy and/or bilateral oophorectomy. 
The following are considered highly effective forms of contraception:  1) true 
abstinence; 2) male sterilization (with post-procedure documentation of absence 
of sperm in the ejaculate).  For female patients, the sterilized male partner should 
be the sole partner. 
The following are considered effective forms of contraception:  1) intrauterine 
device (IUD; copper IUD or hormonal IUDs only) or intrauterine system; 
2) condom with spermicidal foam/gel/film/cream/suppository; 3) occlusive cap 
(diaphragm or cervical/vault cap) with spermicidal 
foam/gel/film/cream/suppository. 
Males must agree to abstain from sperm donation for at least 5 months after the 
last dose of DCDT2980S, DCDS4501A, rituximab, or obinutuzumab 
(whichever is later). 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Prior use of any MAb, radioimmunoconjugate or ADC within 4 weeks before 
Cycle 1, Day 1 
• 
Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive 
therapy, or any investigational anti-cancer agent within 2 weeks prior to Cycle 1, 
Day 1 
Adverse events except for sensory neuropathy from any previous treatments 
must be resolved or stabilized to Grade ≤ 2 prior to Cycle 1, Day 1. 
• 
Completion of autologous stem cell transplant within 100 days prior to Cycle 1, 
Day 1 
• 
Prior allogeneic stem cell transplant 
• 
Eligibility for autologous SCT (patients with relapsed or refractory DLBCL) 
• 
History of transformation of indolent disease to DLBCL 
• 
History of severe allergic or anaphylactic reactions to MAb therapy (or recombinant 
antibody-related fusion proteins) 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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• 
History of other malignancy that could affect compliance with the protocol or 
interpretation of results 
Patients with a history of curatively treated basal or squamous cell carcinoma of 
the skin or in situ carcinoma (e.g., of the cervix or breast) are allowed.  Patients 
with a malignancy that has been treated with curative intent will also be allowed if 
the malignancy has been in remission without treatment for ≥ 2 years prior 
to Cycle 1, Day 1. 
• 
Current or past history of CNS lymphoma 
• 
Current Grade > 1 peripheral neuropathy 
• 
Evidence of significant, uncontrolled, concomitant diseases that could affect 
compliance with the protocol or interpretation of results, including significant 
cardiovascular disease (such as New York Heart Association Class III or IV cardiac 
disease, myocardial infarction within the last 6 months, unstable arrhythmias, or 
unstable angina) or significant pulmonary disease (including obstructive pulmonary 
disease and history of bronchospasm) 
• 
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection 
(excluding fungal infections of nail beds) at study enrollment or any major episode of 
infection requiring treatment with IV antibiotics or hospitalization (relating to the 
completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1 
• 
Recent major surgery within 6 weeks prior to Cycle 1, Day 1, other than 
for diagnosis 
• 
Presence of positive test results for hepatitis B (HBsAg and/or total anti-HBc) or 
hepatitis C (HCV antibody) 
Patients who are positive for anti-HBc are eligible only if PCR is negative for HBV 
DNA and it is believed by both the investigator and Medical Monitor that it is in 
the patient’s best interest to participate.  
Patients who are positive for HCV antibody must be negative for HCV by PCR to 
be eligible for study participation. 
• 
Known history of HIV seropositive status 
• 
Women who are pregnant or lactating 
• 
Ongoing corticosteroid use > 30 mg/day prednisone or equivalent 
Patients receiving corticosteroid treatment ≤ 30 mg/day prednisone or equivalent 
must be documented to be on a stable dose prior to study enrollment and 
initiation of therapy 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
This is an open-label study.  After written informed consent has been obtained and 
preliminary eligibility has been established, the study site will submit documentation 
supporting eligibility to the Sponsor via facsimile and obtain the Sponsor’s approval to 
enroll the patient.  Once the Sponsor reviews and approves the patient for enrollment, 
the patient number will be assigned via IXRS.  


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
112/P GO27834-A2 
As described in Section 3.1.1.2, only select investigator sites that have agreed to 
participate in the non-randomized (Cohorts C and D) portion of the study will enroll 
patients into these cohorts.  Cohorts C and D will be opened sequentially following 
completion of the randomized portion of the study for patients with FL. 
For obinutuzumab-containing cohorts (Cohorts E, G, and H), patients with either 
relapsed or refractory follicular NHL or relapsed or refractory DLBCL will be enrolled.  
After the safety run-in stage for DCDS4501A at 1.8 mg/kg in combination with 
obinutuzumab, the patients will be enrolled into the dose-expansion portion with 
40 patients in each histology group. 
Personnel responsible for performing PK and ATA assays will receive participants’ 
treatment assignments to identify appropriate PK and ATA samples to be analyzed in 
the appropriate corresponding assays.  
4.3 
STUDY TREATMENT  
4.3.1 
DCDT2980S and DCDS4501A 
4.3.1.1 
Formulation and Storage 
a. DCDT2980S 
DCDT2980S will be provided as a lyophilized powder in a single-use 20-cc vial.  
The solution for reconstitution is Sterile Water for Injection (SWFI), and the reconstitution 
volume is 2.6 mL to yield a final concentration of 20 mg/mL DCDT2980S in 40 mM 
L-histidine hydrochloride, 240 mM sucrose, and 0.02% polysorbate 20, pH 6.0. 
Reconstituted DCDT2980S should be further diluted with sterile 0.9% NaCl to a total 
volume of 250 mL. 
DCDT2980S vials must be refrigerated at 2°C−8°C (36°F−46°F) upon receipt until use.  
DCDT2980S should not be used beyond the expiration date provided by the 
manufacturer.  Vial contents should not be frozen or shaken and should be protected 
from direct sunlight.  After reconstitution, DCDT2980S vials may be stored at room 
temperatures (> 8°C−25°C [> 46°F−77°F]) for up to 4 hours or at refrigerated 
temperatures (2°C−8°C [36°F−46°F]) for up to 8 hours prior to use.  Once DCDT2980S 
has been diluted with sterile 0.9% NaCl, the solution should be used within 4 hours at 
room temperature or within 8 hours at refrigerated temperature.  Vials are intended for 
single use only; therefore, any remaining solution should be discarded. 
For further details, refer to the DCDT2980S Investigator Brochure. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
113/P GO27834-A2 
b. DCDS4501A 
DCDS4501A is provided as a liquid formulation and contains no preservatives.  Each 
single-use 20-cc vial is filled to deliver 100 mg of DCDS4501A.  The drug product is 
formulated as 10 mg/mL DCDS4501A in 20 mM L-histidine acetate, 240 mM sucrose, 
0.02% (w/v) polysorbate 20, pH 5.5.  
DCDS4501A will be administered to patients intravenously via syringe pump with an 
IV infusion set containing a 0.22−µm in-line filter with a final volume of DCDS4501A 
determined by the dose and patient weight.  
DCDS4501A vials must be refrigerated at 2°C−8°C (36°F−46°F) upon receipt until use.  
DCDS4501A vials may be stored at room temperature (> 8°C−25°C [46°F−77°F]) for up 
to 8 hours.  DCDS4501A should not be used beyond the expiration date provided by the 
manufacturer.  Vial contents should not be frozen or shaken and should be protected 
from direct sunlight.  Vials are intended for single use only; therefore, any remaining 
solution should be discarded. 
Once the DCDS4501A dose solution has been prepared, the solution should be used 
within 4 hours at room temperature (> 8 °C−25°C [46°F−77°F]) or within 8 hours 
refrigerated at 2°C−8°C (36°F−46°F).  Because the drug product contains no 
preservatives, the Sponsor recommends using DCDS4501A in a syringe and extension 
set as soon as possible to reduce the risk of microbial contamination.   
For further details, refer to the DCDS4501A Investigator Brochure. 
4.3.1.2 
Dosage and Administration 
a. DCDT2980S-Specific Information 
DCDT2980S will be administered to patients by IV infusion.  Compatibility testing has 
shown that DCDT2980S is stable when diluted in polyvinyl chloride (PVC) bags to a 
concentration at or above 0.04 mg/mL in 0.9% NaCl diluent.  The drug product will be 
delivered following dilution in 0.9% NaCl with a final DCDT2980S concentration 
determined based on dose and patient weight.  The study drug will be diluted in a PVC 
bag and delivered using a 0.22 µm in-line filter on the IV infusion set. 
Additional information/instructions regarding study drug administration will be provided in 
the Pharmacy Binder. 
b. DCDS4501A-Specific Information 
DCDS4501A will be administered to patients intravenously via syringe pump with an 
IV infusion set containing a 0.22 µm in-line filter with a final volume of DCDS4501A 
determined by the dose and patient weight.  Compatibility testing has shown that 
DCDS4501A is stable both in syringes made of polypropylene (PP) and in standard 
extension sets with 0.22 µm in-line filter, when stored neat or diluted with 0.9% NaCl 
saline.   


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
114/P GO27834-A2 
Additional information/instructions regarding study drug administration will be provided in 
the Pharmacy Binder. 
c. General Information 
The total dose of DCDT2980S and DCDS4501A for each patient will depend on the 
patient’s weight within 96 hours prior to Day 1 of each cycle.  The patient weight 
obtained during screening may be used for dose determination at all treatment cycles; if 
the patient’s weight within 96 hours prior to Day 1 of a given treatment cycle differs by 
>10% from the weight obtained during screening, then the new weight should be used to 
calculate the dose.   
For both DCDT2980S and DCDS4501A, the initial dose will be administered to 
well-hydrated (based on clinical judgment) patients over 90 (± 10) minutes.  
Premedication with acetaminophen or paracetamol (e.g., 500−1000 mg) and 
diphenhydramine (e.g., 50°C−100 mg) per institutional standard practice may be 
administered prior to each infusion.  Administration of corticosteroids is permitted at the 
discretion of the treating physician.  Patients who do not receive premedications prior to 
the first dose of DCDT2980S and who develop an IRR during the first dose should 
receive premedications prior to subsequent doses (see Table 1). 
The DCDT2980S/DCDS4501A infusion may be slowed or interrupted for patients 
experiencing infusion-associated symptoms.  Following the initial dose, patients will be 
observed for 90 minutes for fever, chills, rigors, hypotension, nausea, or other 
infusion-associated symptoms.  If the infusion is well-tolerated, subsequent doses of 
DCDT2980S/DCDS4501A may be administered over 30 (± 10) minutes, followed by a 
30-minute observation period post-infusion.   
For instructions on study drug preparation and administration, refer to the DCDT2980S 
and DCDS4501A Investigator Brochure. 
4.3.1.3 
Dosage Modification 
Patients should be assessed clinically for toxicity prior to each dose using the 
NCI CTCAE v4.0 grading scale.  Dosing will occur only if a patient’s clinical assessment 
and laboratory test values are acceptable.  If scheduled dosing coincides with a holiday 
that precludes dosing, dosing should commence on the nearest following date, with 
subsequent dosing continuing on a 21-day schedule as applicable. 
Specific guidelines around dosage modifications for neutropenia and peripheral 
neuropathy are detailed below in Sections 4.3.1.6 and 4.3.1.7.  Patients who experience 
other treatment-related Grade 3 or 4 toxicity or laboratory abnormalities will be allowed 
to delay dosing of study treatment (both ADC and rituximab or obinutuzumab) for up to 
2 weeks to allow for recovery.  Patients may continue to receive additional infusions of 
DCDT2980S or DCDS4501A per their treatment assignment provided that the toxicity 
has resolved to Grade ≤ 2 or ≥ 80% of the baseline value, whichever is lower, within the 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
115/P GO27834-A2 
2−week delay period.  Upon resolution, the dose for subsequent infusions may be 
reduced to 1.8 mg/kg (in Cohorts C and D).  If the toxicity that resulted in the dose 
reduction persists or recurs at the reduced dose, then the patient should be discontinued 
from study treatment.  The decision for dose modification will be made on the basis of 
the investigator’s assessment of ongoing clinical benefit with continued study treatment 
and in consultation with the Medical Monitor.   
Once dose reductions of DCDT2980S or DCDS4501A are made for toxicity, dose 
re-escalation will not be allowed.  Patients who are enrolled in the non-randomized 
portion of the study (Cohorts C and D), are dosed at an ADC dose of 1.8 mg/kg, and 
have progressive disease in the absence of any drug-related toxicity may have their 
ADC dose increased to 2.4 mg/kg if it is felt that there is reasonable justification for 
ongoing clinical benefit.  The decision to increase the dose must be made in consultation 
with and approval of the Medical Monitor.  Patients in Cohorts E, G, and H 
(obinutuzumab-containing cohorts) will not be eligible for dose escalation. 
If a patient develops unacceptable toxicity to DCDT2980S or DCDS4501A, requiring its 
discontinuation, single-agent rituximab may be continued on the basis of the 
investigator’s assessment of ongoing clinical benefit and with the approval of the Medical 
Monitor.  Patients enrolled in obinutuzumab-containing cohorts will not continue on 
single-agent obinutuzumab unless approved by the Medical Monitor. 
4.3.1.4 
Schedule Modification 
Patients in whom toxicities have not resolved to Grade ≤ 2 or ≥ 80% of baseline value, 
whichever is lower, may have their study treatment delayed by up to 2 weeks.  Dosing of 
both DCDT2980S or DCDS4501A and rituximab or obinutuzumab should be held during 
this period.  If all study drug−related toxicities have resolved sufficiently, the patient may 
resume DCDT2980S or DCDS4501A and rituximab or obinutuzumab dosing on the 
regular every-21-day schedule.   
A patient’s dosing may be changed to a 28-day cycle if it is felt by the investigator that 
changing a patient’s dosing regimen from 21-day to 28-day cycles would provide 
sufficient time for recovery from a transient and reversible toxicity⎯for example, 
cytopenia without requiring repeated treatment delays.  Modifications to the dosing 
schedule in this fashion must be made in consultation with and with the approval of the 
Medical Monitor. 
Patients who do not fulfill the criteria for continuation of dosing after the 2-week delay 
may be discontinued from study treatment and be followed for safety outcomes (see 
Section 4.5.6).  Exceptions on the basis of ongoing clinical benefit may be allowed 
following a careful assessment and discussion of risk versus benefit with the patient by 
the investigator and approval from the Medical Monitor.  


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
116/P GO27834-A2 
Specific guidelines around schedule modifications for neutropenia and peripheral 
neuropathy are detailed below in Sections 4.3.1.6 and 4.3.1.7. 
4.3.1.5 
Infusion Reaction 
Patients will be monitored during and after each DCDT2980S/DCDS4501A infusion for 
90 minutes after the first infusion and for 30 minutes after subsequent infusions in the 
absence of infusion-related adverse events.  Patients who experience infusion-related 
symptoms should be managed as described in Table 1.  Precautions for suspected 
anaphylactic reaction during study drug infusions are provided in Appendix D. 
In the event of a life-threatening IRR, which may include pulmonary or cardiac events, or 
an IgE-mediated anaphylactic reaction, administration of 
DCDT2980S/DCDS4501A should be immediately discontinued.  Patients who 
experience these reactions should receive aggressive symptomatic treatment and are 
not eligible to receive any additional study treatment. 
Premedication prior to DCDT2980S/DCDS4501A with acetaminophen/paracetamol, 
antihistamines, or corticosteroids per standard clinical practice is permitted⎯for 
example, in patients with substantial tumor burden and where the risk of cytokine 
release syndrome is high.  In patients who do not receive premedication prior to any 
given dose of DCDT2980S/DCDS4501A and who develop any Grade ≥ 2 
infusion-related toxicity, premedication should be administered prior to subsequent 
doses.  


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Table 1 
Management of Infusion-Related Symptoms for All Study Drugs 
Infusion-Related  
Symptoms a 
Guidance 
Grade 1−2 
• 
Slow or hold infusion 
• 
Give supportive treatment b 
• 
Upon symptom resolution, may resume/escalate infusion rate at the 
investigator’s discretion c 
• 
Note:  For Grade 2 wheezing or bronchospasm, patient must be 
premedicated for subsequent doses.  If symptoms recur with the same or 
greater severity, the infusion must be stopped immediately and study 
treatment permanently discontinued. 
Grade 3 
• 
Discontinue infusion 
• 
Give supportive treatment b 
• 
Upon symptom resolution, may resume/escalate infusion rate at the 
investigator discretion c 
• 
Note:  If the same adverse event recurs with the same or greater severity, 
treatment must be permanently discontinued. 
• 
Note:  For Grade 3 hypotension or fever, patient must be premedicated 
before re-treatment.  If symptoms recur, then study drug must be 
permanently discontinued. 
• 
Note:  If patient has Grade 3 wheezing or bronchospasm at first occurrence, 
study treatment should be permanently discontinued.   
Grade 4 
• 
Discontinue infusion immediately, treat symptoms aggressively, and 
permanently discontinue patient from study treatment 
IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events. 
a Refer to the NCI CTCAE v4.0 scale for the grading of symptoms.  Management of IgE-mediated 
allergic reactions should be as directed in the text preceding this table. 
b Supportive treatment:  Patients should be treated with acetaminophen/paracetamol and an 
antihistamine such as diphenhydramine if they have not been received in the last 4 hours.  
IV saline may be indicated.  For bronchospasm, urticaria, or dyspnea, patients may require 
antihistamines, oxygen, corticosteroids (e.g., 100 mg IV prednisolone or equivalent), 
and/or bronchodilators.  Patients with hypotension requiring vasopressor support must be 
permanently discontinued from study drug. 
c Infusion rate escalation after re-initiation:  Upon complete resolution of symptoms, the infusion 
may be resumed at 50% of the rate achieved prior to interruption.  In the absence of 
infusion-related symptoms, the rate of infusion may be escalated in increments of 50 mg/hr every 
30 minutes. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
118/P GO27834-A2 
4.3.1.6 
Neutropenia 
Because neutropenia is a known risk of DCDT2980S and DCDS4501A (see 
Section 3.4.3.3), the use of growth factor support (G-CSF) as prophylactic and 
therapeutic indications is permitted (see Appendix F) in order to allow continued dosing 
of DCDT2980S/DCDS4501A.  Dose modifications for patients who experience 
treatment-related Grade 3−4 neutropenia in the context of G-CSF usage are as follows: 
• 
Primary prophylaxis with G-CSF (i.e., prior to the first dose of 
DCDT2980S/DCDS4501A) is permitted for patients with clinical factors listed in 
Appendix F or who otherwise are considered at high risk for developing neutropenia 
on study treatment. 
• 
Patients who experience treatment-related Grade 3−4 neutropenia will be allowed to 
delay dosing of study treatment (both ADC and rituximab or obinutuzumab) for up 
to two weeks to allow for recovery.  Therapeutic G-CSF is permitted as clinically 
indicated (see Appendix F) and to facilitate neutrophil recovery to allow subsequent 
DCDT2980S/DCDS4501A dosing. 
• 
Subsequent dosing of DCDT2980S/DCDS4501A and rituximab/obinutuzumab is 
permitted provided that the neutropenia has resolved to Grade ≤ 2 or ≥ 80% of the 
baseline value, whichever is lower, within the 2-week period.   
• 
If prophylactic G-CSF was not administered prior to the cycle in which the 
Grade 3−4 neutropenia developed, then prophylactic G-CSF may be administered 
prior to subsequent cycles without DCDT2980S/DCDS4501A dose reduction.  The 
dose schedule may be changed from 21-day to 28-day cycles to provide sufficient 
time for neutrophil recovery in subsequent cycles.  In the absence of prophylactic 
G-CSF or dose schedule modification, the dose of DCDT2980S/DCDS4501A in 
subsequent cycles should be reduced to 1.8 mg/kg.  For Cohorts E, G, and H, 
patients will be given DCDS4501A at a dose of 1.8 mg/kg, and further dose 
reductions cannot be made.   
• 
If Grade 3−4 neutropenia recurs with prophylactic G-CSF, the dose for subsequent 
DCDT2980S/DCDS4501A should be reduced to 1.8 mg/kg.  Prophylactic G-CSF 
and dose schedule modifications as described above are permitted in order to 
maintain the reduced DCDT2980S/DCDS4501A dose level and schedule. 
• 
If Grade 3−4 neutropenia recurs at the reduced dose despite the administration of 
prophylactic G-CSF, then the patient should be discontinued from study treatment.   
• 
For patients enrolled into the non-randomized portion of the study (Cohorts C 
and D, as well as Cohorts E, G, and H), dose modifications will not be allowed.  
Administration of therapeutic/prophylactic G-CSF and dose-schedule modifications 
as described above are allowed.  Patients who have persistent or recurrent 
Grade 3−4 neutropenia as defined above should be discontinued from study 
treatment. 
 
The determination of the dose and schedule modifications will be made on the basis of 
the investigator’s assessment of ongoing clinical benefit with continuing study treatment 
and with the approval of the Medical Monitor.   


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
119/P GO27834-A2 
4.3.1.7 
Peripheral  Neuropathy 
Peripheral neuropathy (sensory or motor) is a known risk of DCDT2980S and 
DCDS4501A (see Section 3.4.2.5).  For new or worsening drug-related Grade 2 or 3 
peripheral sensory and/or motor neuropathy, dosing should be held for up to 2 weeks 
until peripheral neuropathy (sensory or motor) improves to Grade 1 or baseline grade.  
Continuation of study treatment following dose delays beyond 2 weeks will require 
consultation with and approval of the Medical Monitor based on an assessment of the 
benefit-risk analysis of continuing to delay study treatment. 
Following resolution of peripheral neuropathy (sensory and/or motor), subsequent doses 
of DCDT2980S/DCDS4501A should be reduced to 1.8 mg/kg.  DCDS4501A should not 
be reduced to a dose lower than 1.8 mg/kg.   If worsening Grade 2 or 3 peripheral 
neuropathy (sensory and/or motor) recurs following dose reduction, study treatment 
should be discontinued.  For Grade 3 peripheral neuropathy (sensory and/or motor), 
study treatment should be discontinued.  
For patients enrolled into the non-randomized portion of the study (Cohorts C and D), 
dose modifications will not be allowed.  Patients who have Grade 2 or 3 peripheral 
neuropathy (sensory and/or motor), as defined above, should be discontinued from 
study treatment. 
4.3.1.8 
Hyperglycemia 
Hyperglycemia has been observed in patients treated with DCDT2980S and 
DCDS4501A as well as with other ADCs using the same vc-MMAE platform.  
Hyperglycemia has been reversible upon holding or discontinuing treatment of the ADCs 
and/or initiation of improved anti-hyperglycemic medications (see Section 3.4.3.7).   
For symptomatic fasting Grade 3 (> 250−500 mg/dL) or asymptomatic Grade 4 
(> 500 mg/dL) hyperglycemia, medical management should be initiated immediately and 
consultation with a specialist should be considered.  If the hyperglycemia persists for 
> 1 week after initiation of management, dose modification, schedule modification, or 
discontinuation of study treatment should be considered.  In these cases, the study 
Medical Monitor should be consulted to assess the benefit-risk balance of continued 
study treatment. 
4.3.2 
Rituximab 
4.3.2.1 
Formulation 
Rituximab (Rituxan®/MabThera®) is a sterile, clear, colorless, preservative-free liquid 
concentrate for IV administration.  Rituximab is supplied at a concentration of 10 mg/mL 
in 500-mg (50-mL) single-use vials.  A single-unit, 500-mg carton contains one 50-mL 
vial of rituximab (10 mg/mL).  The product is formulated for IV administration in 
9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, and 0.7 mg/mL 
polysorbate 80, after reconstitution with SWFI.  The pH is adjusted to 6.5.  Vials are for 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
120/P GO27834-A2 
single use.  Each vial and carton will contain a label (either single-panel or booklet) 
affixed to the vial or carton.   
4.3.2.2 
Dosage, Administration, and Storage 
Rituximab (Rituxan®, MabThera®) will be administered intravenously once per 3-week 
(or 4-week) cycle.  The infusion at 375 mg/m2 for each dose will be based on the 
patient’s body surface area at screening and will remain the same throughout the study.   
If a scheduled dose of rituximab falls outside of the ± 2-day window for reasons other 
than an adverse event, the site must notify and have a discussion with the Genentech 
Medical Monitor prior to rituximab administration.  Such dosing may not necessarily 
qualify as a protocol deviation, if deemed to be in the best interests of the patient, after 
consultation with the Medical Monitor and agreed to in advance by the Medical Monitor.  
Rituximab should not be administered as an IV push or bolus.  Infusion reactions may 
occur.  Premedication consisting of acetaminophen (or paracetamol), diphenhydramine 
(or other suitable antihistamine), and a single dose of hydrocortisone (e.g., up to 100 mg 
or an equivalent dose of methylprednisolone) may also be administered beginning with 
the first infusion, per standard clinical practice.  Premedication may attenuate infusion 
reactions.  Because transient hypotension may occur during rituximab infusion, 
consideration should be given to withholding antihypertensive medications for 12 hours 
prior to rituximab infusion.   
a. First Infusion 
The rituximab solution for infusion should be administered intravenously at an initial rate 
of 50 mg/hr.  Rituximab should not be mixed or diluted with other drugs.  If infusion 
reactions do not occur, the infusion rate should be escalated in 50−mg/hr increments 
every 30 minutes to a maximum of 400 mg/hr.  If an infusion reaction develops, 
the infusion should be temporarily slowed or interrupted.  The infusion can continue at 
one-half the previous rate upon improvement of patient symptoms.   
b. Subsequent Infusions 
If the patient tolerates the first infusion well, subsequent rituximab infusions may be 
administered at an initial rate of 100 mg/hr and increased in 100−mg/hr increments at 
30-minute intervals to a maximum of 400 mg/hr, as tolerated.  If the patient does not 
tolerate the first infusion well, the guidelines for the first infusion should be followed. 
If a patient tolerates the first three cycles of study treatment without significant infusion 
reactions, rituximab may be administered as “rapid infusion” in accordance with local 
institutional guidelines. 
c. Storage 
Rituximab vials must be stored at 2°C−8°C (36°C−46°F).  Rituximab vials should be 
stored in the outer carton in order to protect them from light.  Rituximab solution for 


 
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infusion may be stored at 2°C−8°C (36°C−46°F) for 24 hours and has been shown to be 
stable for an additional 12 hours at room temperature.  However, because rituximab 
does not contain a preservative, diluted solutions should be stored refrigerated 
(2°C−8°C).  No incompatibilities between rituximab and PVC or polyethylene (PE) bags 
have been observed. 
See the Rituxan® (Rituximab) Package Insert or SmPC (in the European Union) for 
additional information. 
4.3.2.3 
Dosage Modification 
There will be no rituximab dose modification in this study.  Patients at high risk for 
TLS complications (see Section 3.4.3.2) may, at the investigator’s discretion, receive 
their initial dose of rituximab over 2 consecutive days (e.g., 125 mg/m2 on Day 1, 
250 mg/m2 on Day 2; with DCDT2980S/DCDS4501A dose potentially delayed to Day 3). 
Any NCI CTCAE (v4.0) toxicity Grade ≥ 3 in severity that is deemed related to rituximab 
treatment will require interruption of study treatment (both ADC and rituximab) until 
resolution to Grade ≤ 2 or ≥ 80% of baseline, whichever is lower.  Resumption of 
rituximab treatment may be considered in patients with resolution of toxicities to 
Grade ≤ 1 within 2 weeks at the discretion of the investigator, after consultation with the 
Medical Monitor.  Failure of such toxicities to resolve after 2-week delay in study 
treatment will require permanent discontinuation of rituximab.  Continuation of rituximab 
treatment may be permitted on the basis of ongoing clinical benefit following a careful 
assessment and discussion of risk versus benefit with the patient by the investigator and 
approval from the Medical Monitor.   
If a patient develops unacceptable toxicity to rituximab requiring its discontinuation, 
single-agent DCDT2980S or DCDS4501A may be continued on the basis of the 
investigator’s assessment of ongoing clinical benefit and with the approval of the Medical 
Monitor. 
4.3.2.4 
Schedule Modification 
Patients in whom toxicities have not resolved (i.e., to Grade ≤ 1 or ≥ 80% of baseline) 
may have their study treatment delayed by up to 2 weeks.  If after the up to−2-week 
delay, all study drug−related toxicities have resolved sufficiently, the patient may receive 
the scheduled doses of rituximab.  In addition, a patient’s dosing may be changed to a 
28-day cycle if it is felt by the investigator and Medical Monitor that changing a patient’s 
dosing regimen from 21-day to 28-day cycles would provide sufficient time for recovery 
from transient cytopenias without requiring repeated treatment delays. 
Patients who do not fulfill the criteria for dosing after the additional 2 weeks have 
elapsed may be discontinued from study treatment and be followed for safety outcomes 
(see Section 4.5.1).  Exceptions on the basis of ongoing clinical benefit may be allowed 
following a careful assessment and discussion of risk versus benefit with the patient by 


 
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the investigator and approval from the Medical Monitor.  In addition, delay of therapy 
because of toxicities not attributed to study drug may not require discontinuation and will 
be discussed with the Medical Monitor. 
4.3.2.5 
Infusion Reaction 
Patients will be monitored during and after each rituximab infusion for 90 minutes after 
the first infusion and for 30 minutes after subsequent infusions in the absence of 
infusion-related adverse events.  Patients who experience infusion-related symptoms 
should be managed as directed in Table 1 (see Section 4.3.1.5). 
In the event of a life-threatening IRR (which may include pulmonary or cardiac events) or 
IgE-mediated anaphylactic reaction to rituximab, rituximab should be discontinued and 
no additional rituximab should be administered.  Patients who experience these 
reactions should receive aggressive symptomatic treatment and should be discontinued 
from study treatment. 
4.3.3 
Obinutuzumab 
4.3.3.1 
Formulation 
Obinutuzumab (GA101/Gazyva™/Gazyvaro) is a clear, colorless to slightly brownish 
liquid, provided as a single 1000-mg dose liquid concentrate with a strength of 
25 mg/mL.  It is supplied in 50−mL glass vials containing 40 mL of the 25 mg/mL 
liquid concentrate.  In addition to the antibody, the liquid also contains 
histidine/histidine-HCl, trehalose, poloxamer 188, and highly purified water (HPW). 
4.3.3.2 
Dosage, Administration and Storage 
Obinutuzumab will be administered by IV infusion as an absolute (flat) dose of 
1000 mg in combination with DCDS4501A, as outlined in Section 3.1.3.  
Obinutuzumab will be administered on Days 1, 8, and 15 of Cycle 1 and on Day 1 of 
Cycles 2−8 (see Table 2).  No dose modifications of obinutuzumab are allowed. 
All obinutuzumab infusions should be administered after premedication with oral 
acetaminophen and an antihistamine (see Section 4.4.1).  The prophylactic use of 
corticosteroids (e.g., 100 mg of IV prednisolone or equivalent) may also be considered 
for patients thought to be at high risk for IRRs, if deemed appropriate by the 
investigator, and should be administered prior to the obinutuzumab infusion.  On 
Cycle 1 Day 1, it is recommended that oral prednisone, prednisolone, or 
methylprednisolone be given within 12 hours as a premedication but at least 
60 minutes prior to the obinutuzumab infusion.  Premedication with prednisone or 
prednisolone is mandatory in patients who had an IRR and should continue until IRRs 
no longer occur during antibody infusion.  For the management of IRRs and 
anaphylaxis, see Table 1 (Section 4.3.1.5).  
If it is the strong preference of the investigator or of the site (e.g., for logistical reasons) 
or if the patient is at increased risk for an IRR (high tumor burden, high peripheral 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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lymphocyte count), the administration of obinutuzumab infusion can be split over 
2 days. 
Table 2 
Administration of First and Subsequent Infusions of 
Obinutuzumab 
First Infusion (Cycle 1 Day 1) 
Subsequent Infusions 
• Begin infusion at an initial rate of 
50 mg/hr. 
• If no infusion-related or hypersensitivity 
reaction occurs, increase the infusion rate in 
50-mg/hour increments every 30 minutes to 
a maximum of 400 mg/hr. 
• If a reaction develops, stop or slow the 
infusion.  Administer medications and 
supportive care in accordance with 
institutional guidelines.  If reaction has 
resolved, resume the infusion at a 
50% reduction in rate (i.e., 50% of rate used 
at the time the reaction occurred). 
• If the patient experienced an 
infusion-related or hypersensitivity reaction 
during the prior infusion, use full 
premedication including 100 mg 
prednisone/prednisolone (until no further 
IRR occurs), begin infusion at an initial 
rate of 50 mg/hr, and follow instructions for 
first infusion. 
• If the patient tolerated the prior infusion 
well (defined by absence of Grade 2 
reactions during a final infusion rate of 
≥ 100 mg/hr), begin infusion at a rate of 
100 mg/hr. 
• If no reaction occurs, increase the infusion 
rate in 100-mg/hour increments every 
30 minutes, to a maximum of 400 mg/hr. 
• If a reaction develops, stop or slow the 
infusion.  Administer medications and 
supportive care in accordance with 
institutional guidelines.  If reaction has 
resolved, resume the infusion at a 
50% reduction in rate (i.e., 50% of rate used 
at the time the reaction occurred). 
IRR = infusion-related reaction. 
 
In all parts of the study, obinutuzumab must be administered in a clinical (inpatient or 
outpatient) setting.  Full emergency resuscitation facilities should be immediately 
available, and patients should be under the close supervision of the investigator at all 
times.  For the management of IRRs and anaphylaxis, see Table 1 (Section 4.3.1.5). 
Obinutuzumab should be administered as a slow IV infusion through a dedicated line.  
IV infusion pumps should be used to control the infusion rate of obinutuzumab.  Do not 
administer as an IV push or bolus.  Administration sets with PVC, polyurethane 
(PUR), or PE as a product contact surface and IV bags with polyolefin (PO), 
polypropylene (PP), PVC, or PE as a product contact surface are compatible and can be 
used.  Do not use an additional in-line filter because of potential adsorption. 
The recommended storage conditions for obinutuzumab drug product are between 2°C 
and 8°C, protected from light.  For clinical formulation-specific and batch-specific 
instructions and information on in-use stability, see the packaging label.   


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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4.3.3.3 
Dosage Modification 
There will be no obinutuzumab dose modification in this study.  Patients at high risk 
for TLS complications (see Section 3.4.2.2) may, at the investigator’s discretion, receive 
obinutuzumab over 2 consecutive days (with DCDS4501A dose potentially delayed to 
Day 2 or Day 3). 
Any NCI CTCAE (v4.0) toxicity Grade ≥ 3 in severity that is deemed related to 
obinutuzumab treatment will require interruption of study treatment (both 
DCDS4501A and obinutuzumab) until resolution to Grade ≤ 2 or ≥ 80% of baseline, 
whichever is lower.  Resumption of obinutuzumab treatment may be considered in 
patients with resolution of toxicities to Grade ≤ 1 within 2 weeks at the discretion of the 
investigator, after consultation with the Medical Monitor.  Failure of such toxicities to 
resolve after 2-week delay in study treatment will require permanent discontinuation of 
obinutuzumab.  Continuation of study treatment following dose delays beyond 2 weeks 
will require consultation with and approval of the Medical Monitor based on an 
assessment of the benefit-risk analysis of continuing to delay study treatment.  
If a patient develops unacceptable toxicity to obinutuzumab requiring its 
discontinuation, single-agent DCDS4501A will not be permitted.  
4.3.3.4 
Schedule Modification 
Patients in whom toxicities have not resolved (i.e., to Grade ≤ 1 or ≥ 80% of baseline) 
may have their study treatment delayed by up to 2 weeks.  Dosing of both DCDS4501A 
and obinutuzumab should be held during this period.  If all study drug−related 
toxicities have resolved to Grade ≤ 1 or ≥ 80% of baseline, the patient may resume 
DCDS4501A and obinutuzumab dosing on the regular every−21−day schedule.  In 
addition, a patient’s dosing may be changed to a 28-day cycle if it is felt by the 
investigator and Medical Monitor that changing a patient’s dosing regimen from 
21-day to 28-day cycles would provide sufficient time for recovery from transient 
cytopenias without requiring repeated treatment delays. 
Patients who do not fulfill the criteria for dosing after the additional 2 weeks have 
elapsed may be discontinued from study treatment and be followed for safety outcomes 
(see Section 4.5.6).  Exceptions on the basis of ongoing clinical benefit may be allowed 
following a careful assessment and discussion of risk versus benefit with the patient by 
the investigator and approval from the Medical Monitor.  In addition, delay of therapy 
because of toxicities not attributed to study drug may not require discontinuation and 
will be discussed with the Medical Monitor. 
Specific guidelines around schedule modifications for thrombocytopenia are detailed 
below in Section 4.3.3.5. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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4.3.3.5 
Thrombocytopenia 
Thrombocytopenia is a known risk of obinutuzumab (see Section 3.4.6.4).  If the clinical 
condition of a patient requires the use of concomitant anticoagulants, the patient is at 
increased risk of bleeding when the platelet count is < 20,000/μL.  When possible, 
replace prior therapy with Vitamin K antagonists, such as warfarin, with low-
molecular weight heparin (LMWH) or new oral anticoagulants (NOACs) before Cycle 1 
Day 1.  Clinical decision making may be adjusted depending on the patient-specific 
assessment of benefit and risk. 
In the event of severe thrombocytopenia (platelet count < 10,000/μL) and/or 
symptomatic bleeding (irrespective of platelet count) in patients who are not receiving 
concomitant anticoagulants or platelet inhibitors: 
• 
Hold obinutuzumab until thrombocytopenia or symptomatic bleeding resolves, but 
do not skip any doses of obinutuzumab for the sake of maintaining the study 
treatment schedule. 
 
In the event of thrombocytopenia with platelet count < 20,000/μL and/or symptomatic 
bleeding (irrespective of platelet count) in patients who are receiving concomitant 
anticoagulants or platelet inhibitors: 
• 
Hold obinutuzumab until thrombocytopenia or symptomatic bleeding resolves, but 
do not skip any doses of obinutuzumab for the sake of maintaining the study 
treatment schedule. 
• 
For patients who are on LMWH or NOACs, when platelet count < 20,000/μL 
develops, reduce the dose of LMWH or NOACs used. 
• 
For patients who are on platelet inhibitors when thrombocytopenia with platelet 
count < 20,000/μL develops, consideration should be given to temporarily pausing 
the use of platelet inhibitors. 
 
4.3.4 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(pinatuzumab vedotin [DCDT2980S], polatuzumab vedotin [DCDS4501A], rituximab, 
and obinutuzumab) will be provided by the Sponsor where required by local health 
authority regulations.  The study site will acknowledge receipt of IMPs to confirm the 
shipment condition and content.  Any damaged shipments will be replaced.  
IMPs will be either disposed of at the study site according to the study site’s 
institutional standard operating procedure or returned to the Sponsor with the 
appropriate documentation.  The site's method of IMP destruction must be agreed to by 
the Sponsor.  The site must obtain written authorization from the Sponsor before any 
IMP is destroyed, and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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4.4 
CONCOMITANT AND EXCLUDED THERAPIES  
4.4.1 
Concomitant Therapy  
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, and nutritional supplements) used by a patient 
from 7 days prior to the screening evaluation to the end of study visits.  All concomitant 
medications should be reported to the investigator and recorded on the appropriate 
electronic Case Report Form (eCRF).  Patients who use oral contraceptives, 
hormone-replacement therapy, or other maintenance therapy should continue their use.  
Concomitant use of hematopoietic growth factors is allowed in accordance with 
instructions provided in the package inserts. 
Patients who experience infusion-related temperature elevations of > 38.5°C (> 101.3°F) 
or other minor infusion-related symptoms may be treated symptomatically with 
acetaminophen/paracetamol (≥ 500 mg) and/or H1 and H2 histamine-receptor 
antagonists (e.g., diphenhydramine, ranitidine).  Serious infusion-related events 
manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced 
oxygen saturation, or respiratory distress should be managed with additional supportive 
therapies (e.g., supplemental oxygen, β2-agonists, and/or corticosteroids) as clinically 
indicated according to standard clinical practice (see Table 1).   
For patients enrolled on obinutuzumab-containing regimens, it is recommended that 
oral prednisone, prednisolone, or methylprednisolone be given as premedication within 
12 hours of, but at least 60 minutes prior to, the obinutuzumab infusion on Cycle 1 
Day 1.  After the first obinutuzumab infusion, additional glucocorticoids are allowed at 
the investigator’s discretion.  For patients who did not experience infusion-related 
symptoms with their previous infusion, premedication at subsequent infusions may be 
omitted at the investigator’s discretion. 
Infusion reaction prophylaxis with medications (e.g., acetaminophen/paracetamol, 
antihistamines, and/or corticosteroids) may be instituted at any point in the study if it is 
determined to be in the best interest of the patient on the basis of the observation of 
IRRs in patients already enrolled in the study.  Patients with Grade 3 hypotension or 
fever must be premedicated prior to retreatment (see Section 4.3.1.5).  Patients with 
hypotension requiring vasopressor support or with Grade 3 wheezing, hypoxia, or 
generalized urticaria must be permanently discontinued from study treatment. 
4.4.2 
Excluded Therapy 
Use of the following therapies is prohibited during the study: 
• 
Cytotoxic chemotherapy 
• 
Radiotherapy 
• 
Immunotherapy including immunosuppressive therapy 
• 
Radioimmunotherapy 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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• 
Hormone therapy (other than contraceptives, hormone-replacement therapy, or 
megestrol acetate) 
• 
Biologic agents (other than hematopoietic growth factors, which are allowed 
if clinically indicated and used in accordance with instructions provided in the 
package inserts); guidelines for the use of G-CSF are detailed in Section 4.3.1.6 
and Appendix F. 
• 
Any therapies intended for the treatment of lymphoma or leukemia, whether 
approved by local regulatory authorities or investigational 
 
Patients who require the use of any of these agents will be discontinued from all study 
treatment.  Patients who are discontinued from study treatment will be followed for safety 
outcomes for 30 days following the patient’s last dose of DCDT2980S or DCDS4501A or 
rituximab or obinutuzumab, whichever is later, or until the patient receives another 
anti-cancer therapy, whichever occurs first. 
4.5 
STUDY ASSESSMENTS  
4.5.1 
Definitions of Study Assessments 
4.5.1.1 
Medical History and Demographics 
Medical history includes all clinically significant diseases, prior cancer history, prior 
cancer therapies and procedures, and all medications used by the patient within 7 days 
preceding the screening visit. 
4.5.1.2 
Vital Signs 
Vital signs will include measurements of systolic and diastolic blood pressure while the 
patient is in a sitting or semi-supine position, pulse oximetry, pulse rate, and body 
temperature.  Every effort will be made to ensure that vital signs are obtained from 
patients in a consistent manner and position.  The timing of vital sign collection on the 
days of study treatment administration is as follows: 
• 
For the administration of rituximab or obinutuzumab, vital signs should be assessed 
prior to the start of the infusion, every 15 (± 5) minutes during the first hour of the 
infusion, as clinically indicated during the remainder of the infusion, and following 
the completion of the infusion.  
• 
For the administration of DCDT2980S or DCDS4501A, vital signs should be assessed 
prior to the start of the infusion, every 15 (± 5) minutes during the infusion, at the end 
of the infusion, and every 30 (± 10) minutes for 90 minutes post-infusion following 
dosing at Cycle 1 and 30 (± 10) minutes following dosing in subsequent cycles.  
Additional monitoring of vital signs should be performed if clinically indicated. 
4.5.1.3 
Physical Examination 
A complete physical examination should include the evaluation of the head, eyes, ears, 
nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems.   


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Targeted physical examinations should be limited to systems of clinical relevance 
(i.e., cardiovascular, respiratory, and any system that might be associated with tumor 
assessment, such as lymph nodes, liver, and spleen) and those systems associated with 
symptoms. 
Changes from baseline should be recorded at each subsequent physical examination.  
New or worsened abnormalities should be recorded as adverse events if appropriate. 
Resolution or any change in grade  of peripheral neuropathy AEs and SAEs (with dates) should 
be documented on the Adverse Event eCRF and in the patient’s medical record to facilitate source 
data verification (SDV).  This also applies to AEs for which study drug was discontinued or for 
patients in the follow-up phase after last dose of study treatment with either ongoing AEs or new 
onset of an AE.  For the AEs referring to the follow-up phase newly initiated, relevant treatments 
need to be documented with treatment dates.  
4.5.1.4 
Laboratory Assessments 
On days of study drug administration, pre-infusion laboratory samples should be drawn 
within 4 hours prior to the start of infusion, unless otherwise specified.  Local laboratory 
assessments may be obtained up to 72 hours prior to the start of study treatment 
administration (see below and Section 4.5.3).  Instruction manuals and supply kits will be 
provided for all central laboratory assessments. 
Central Laboratory Assessments 
Samples for flow cytometry, PK, bone marrow, and anti-DCDT2980S, anti-DCDS4501A, 
or anti-obinutuzumab antibody assessments will be sent to one or several laboratories 
or to Genentech for analyses (see Section 3.6).  The following assessments will be 
conducted: 
• 
Leukocyte immunophenotyping/flow cytometry (fluorescence-activated cell sorting 
[FACS] lymphocyte subsets) 
Whole-blood samples will be collected to analyze B-cell subsets (CD19+), T-cell 
counts (CD3+, CD4+, CD8+), and NK cell counts (CD16+, CD56+), by flow 
cytometry. 
• 
ATA assays 
ATAs to DCDT2980S, DCDS4501A, or obinutuzumab will be determined at 
Genentech using a validated ELISA (see Section 4.9).  
• 
PK and PD assays (see Section 4.5.1.6) 
• 
A plasma sample and blood samples will be collected from patients for exploratory 
research as indicated in Section 4.5.1.9.  
• 
For patients who sign the optional consent, a blood sample will be collected prior to 
the first dose of study treatment for exploratory research. 
• 
Tumor tissue sample (archival or fresh) will be collected from patients for central 
pathologic review as described in Sections 4.1.1 and 4.5.1.9. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Local Laboratory Assessments 
Samples for hematology, serum chemistry, liver function, and pregnancy will be 
analyzed at the study site’s local laboratory.  Local laboratory assessments may be 
obtained up to 72 hours prior to start of study treatment administration on Day 1 of the 
treatment cycle.   
• 
Hematology:  includes complete blood count (hemoglobin, hematocrit, red blood cell 
count, white blood cell count, platelet count, absolute neutrophil count, and percent 
or absolute differential counts [e.g., segmented neutrophils, bands, lymphocytes, 
eosinophils, monocytes, basophils, and other cells) 
• 
Coagulation:  aPTT, PT, and INR 
• 
Quantitative immunoglobulins (IgA, IgG, and IgM) 
• 
Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen (BUN or local equivalent), creatinine, calcium, magnesium, phosphorus, 
total and direct bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, 
LDH, and uric acid 
• 
Serum γ-glutamyl transpeptidase (GGT) levels will be required at screening only 
• 
Hemoglobin A1c 
• 
Viral serology and detection (screening assessment only and if clinically indicated) 
Hepatitis B (HBsAg and HBcAb; also HBV DNA by PCR if the patient is HBcAb 
positive) 
HCV antibody 
• 
Pregnancy test 
For women of childbearing potential (see Section 4.1.2), a serum pregnancy test 
must be performed within 14 days prior to Cycle 1 Day 1.   
Urine pregnancy tests will be performed during the study treatment period.  If any 
urine test result is positive, patient dosing will be postponed until the result is 
confirmed by a serum pregnancy test.  Any patient with a positive serum test will 
not be allowed to receive any study treatment. 
4.5.1.5 
Electrocardiogram Assessments 
Twelve-lead digital ECG measurements will be obtained in triplicate, with immediately 
consecutive ECGs obtained until three evaluable ECGs are recorded, at the following 
timepoints: 
• 
Screening 
• 
30−60 minutes before the start of DCDT2980S or DCDS4501A infusion in Cycle 1 
• 
30−60 minutes after the completion of DCDT2980S or DCDS4501A infusion in 
Cycle 1 
• 
30−60 minutes after the completion of DCDT2980S or DCDS4501A infusion in 
Cycle 3 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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• 
Day 8 (± 1 day) of Cycle 3 time matched (i.e., obtained at the same time of day) with 
post-DCDT2980s/DCDS4501A infusion ECGs for Cycle 3 only for 
rituximab-containing arms/cohorts 
• 
Treatment completion/early termination visit 
 
Non-triplicate ECGs should also be performed when clinically indicated in any patient 
with evidence of or suspicion for clinically significant signs or symptoms of cardiac 
dysfunction.  
All ECGs as described above will be submitted to a Sponsor-designated ECG central 
laboratory for storage and potential analysis.  Detailed instructions on ECG acquisitions 
and transmissions to the ECG central laboratory will be provided in the ECG manual 
provided for this study. 
Representative ECGs at each timepoint should be reviewed by the investigator or a 
qualified designee.  Post-screening ECG measurements should be obtained as close as 
possible to scheduled serum and plasma PK samples (see Appendices B-1 and B-2) 
and should be no more than 30 minutes apart.  If QTc prolongation (> 500 ms and 
> 60 ms longer than the pre-dose baseline value) is noted, ECGs should be repeated 
until the prolongation is reversed or stabilized.  If a PK sample is not scheduled at the 
timepoint where QTc prolongation is first observed, then an unscheduled sample should 
be obtained.  An evaluation for potential causes of QT prolongation⎯for 
example, electrolyte imbalances or concomitant medications⎯should be performed, 
study treatment dosing held, and the Medical Monitor notified.  Management of QT/QTc 
prolongation should be performed in accordance with institutional standard of care at the 
discretion of the treating physician. 
4.5.1.6 
Pharmacokinetic and Pharmacodynamic Assessments 
Pharmacokinetics of DCDT2980S and DCDS4501A will be characterized by measuring 
total antibody (conjugated and unconjugated antibody), acMMAE, and free MMAE 
concentrations using validated methods (see Section 4.9).  Plasma samples may also be 
analyzed for other potential MMAE-containing catabolites, per sponsor’s discretion.  
Pharmacokinetics of rituximab will be characterized by measuring rituximab 
concentrations using a validated method (see Section 4.9).  Pharmacokinetics of 
obinutuzumab will be characterized by measuring obinutuzumab concentrations with 
use of a validated method (see Section 4.9).  These assessments will allow for further 
characterization of pharmacokinetics of DCDT2980S and DCDS4501A, the assessment 
of the drug interaction potential when they are given in combination with rituximab or 
obinutuzumab, and the investigation of potential correlations between PK parameters 
and safety and/or activity if data allow and at the sponsor’s discretion.  
Pharmacodynamics of obinutuzumab and DCS4501A may be assessed by monitoring 
the release of tumor associated DNA following treatment. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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4.5.1.7 
Immunogenicity Assessments 
The immunogenicity evaluation will utilize a risk-based strategy and tiered approach 
(Rosenberg and Worobec 2004a, 2004b, 2005; Koren et al. 2008) designed to detect 
and characterize all ATA responses to DCDT2980S and DCDS4501A.  Patient samples 
will first be screened to detect all antibody responses toward DCDT2980S or 
DCDS4501A.  Samples that screen positive will be analyzed in a confirmatory assay 
(competitive binding with DCDT2980S or DCDS4501A) to assess the specificity of the 
positive response.  Titers will be determined for confirmed positive samples.  Further 
characterization will be assessed by competitive binding with the MAb component of 
DCDT2980S or DCDS4501A to characterize whether the ATA responses are primarily to 
the mAb or the linker-drug regions of the ADC.  Positive ATA samples will be stored for 
further characterization of ATA responses, if necessary.   
The schedule of sample collection for ATA assessment is outlined in Appendices B-1, 
B-2, or B-3, depending on the schedule of study treatment administration.  Samples for 
ATA will not be collected during the crossover treatment period. 
ATA responses to obinutuzumab will be detected and confirmed using a similar tiered 
approach.  Patient samples will first be screened to detect all antibody responses to 
obinutuzumab.  Samples that screen positive will be analyzed in a confirmatory assay 
(competitive binding with obinutuzumab) to assess the specificity of the positive 
response.  The relative levels of ATA in confirmed positive samples will be determined 
in a titering assay.  Positive ATA samples will be stored for further characterization of 
ATA responses, if necessary. 
4.5.1.8 
Tumor Response Assessments 
All measurable disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Response assessments will be assessed by the 
investigator, on the basis of physical examinations, CT scans, PET scans, and/or MRI 
scans, and bone marrow examinations, using standard response criteria for NHL 
(Cheson et al. 2007) (see Appendix C-1 and C-2). 
a. Radiographic Assessments for Patients on Rituximab-Containing 
Arms/Cohorts 
CT scans with contrast should include chest, abdomen, and pelvis scans; CT scans of 
the neck should be performed at screening and followed only if disease is present at 
screening.   Post-screening radiographic assessments may be limited to areas of prior 
involvement only if required by local health authorities. 
MRI scans may be used instead of CT scans in patients for whom CT scans with IV 
contrast are contraindicated.  Details regarding imaging procedures in these cases will be 
provided in the Imaging Manual. 


 
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An 18F-fluorodeoxyglucose−positron emission tomography (18F-FDG-PET) (hereafter 
referred to as PET) scan is required during screening for all patients with DLBCL.  An 
additional PET scan in DLBCL patients should be obtained at the 6-month tumor 
assessment to ensure consistency of response assessment methodology at this 
timepoint for all patients.  PET scans should additionally be obtained to confirm 
disappearance of metabolically active disease during study treatment and to confirm a 
CR upon discontinuation of study treatment.   
For patients with FL, PET scans are not required but may be obtained on the basis of 
physician preference and if permitted by local health authorities.  Similarly, for DLBCL, 
PET scans on patients with FL should be obtained during screening; for patients whose 
tumors are PET positive during screening, an additional PET scan should be obtained at 
the 6-month tumor assessment.  PET scans should additionally be obtained to confirm 
disappearance of metabolically active disease during study treatment and to confirm a 
CR upon discontinuation of study treatment.  
For all patients regardless of disease subtype, combined PET-CT scans may be used 
instead of CT alone if performed with contrast and if collected with resolution sufficient to 
allow accurate and consistent comparison of target lesion measurements with 
subsequent PET-CT scans.  If a PET-CT scan is to be used during screening, then 
PET-CT scans should be performed for all subsequent tumor assessments in order to 
ensure their consistency across different timepoints. 
All tumor assessments will be submitted to an IRF for storage and possible independent 
centralized review.  Details related to submission of data to the IRF will be defined in a 
separate Imaging Manual. 
b. Radiographic Assessments for Patients on Obinutuzumab-Containing 
Cohorts 
PET scans should minimally extend from skull-base to mid-thigh.  Full-body PET scan 
should be performed when clinically appropriate. 
CT scans with oral and IV contrast should include chest, abdomen, and pelvic scans; 
CT scans of the neck should be included if clinically indicated.  CT scans for response 
assessment may be limited to areas of prior involvement only if required by local health 
authorities.  At the investigator’s discretion, CT scans may be repeated at any time if 
progressive disease is suspected. 
In patients for whom contrast is contraindicated⎯for example, patients with contrast 
allergy or impaired renal CL⎯CT or combined PET/CT scans without contrast are 
permitted so long as they permit consistent and precise measurement of target lesions 
during the study treatment period.   


 
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PET and CT scans are required for follicular NHL and DLBCL patients at screening, 
after Cycle 4 of study treatment (i.e., between Cycle 4 Day 15 and Cycle 5 Day 1), and 
at EOT.  The EOT response assessment should be performed 6−8 weeks after Cycle 8 
Day 1 or last study treatment.  CT scans without PET scans will be obtained every 
3 months for 1 year, then every 6 months for 1 year, for a total of approximately 2 years 
after the treatment completion visit, with use of standard response criteria for NHL 
(see Appendix C-2).   
c. Bone Marrow Assessments 
A bone marrow biopsy for morphology is required at screening and should reflect 
disease status in the bone marrow following documented relapse on the last prior 
therapy or within 3 months of Day 1, whichever occurs later.  If the bone marrow biopsy 
at screening demonstrates presence of tumor cells, a subsequent bone marrow 
examination is required only to confirm a CR or if clinically indicated.  If the bone marrow 
biopsy at screening does not demonstrate presence of tumor cells, then subsequent 
bone marrow examination is required only if clinically indicated. 
d. Schedule of Tumor Response Assessments for Rituximab-Containing 
Arms/Cohorts 
Tumor response assessments will be performed every 3 months (± 1 week) from the 
initiation of study treatment until study treatment completion or early termination 
(e.g., between Days 14 and 21 of Cycles 4 and 8 for those patients receiving at least 
eight 21-day cycles of treatment).  The schedule of tumor assessments is independent 
of the study treatment dose schedule.  For patients enrolled on rituximab-containing 
arms/cohorts, the schedule of tumor response assessments is detailed in Appendix A-1.  
As stated above, for all DLBCL patients enrolled on a rituximab-containing arm/cohort, 
PET scans are required during the screening period and at the 6-month tumor 
assessment timepoint. 
The schedule for tumor response assessments for patients who proceed to crossover 
treatment is detailed in Appendix A-2.   
Additional response assessments, after the final dose of study treatment, for patients 
who discontinue from study treatment (either initial or crossover treatment) for reasons 
other than progressive disease, will be performed as described in Appendix A-4.  
Tumor assessments should also be performed within 30 days after the last study drug 
infusion (both initial and crossover treatment) at the treatment completion/early 
termination visit.  Imaging scans are not required at the treatment completion/early 
termination visit if scans have been performed within the previous 8 weeks or if disease 
progression while receiving study treatment is documented. 
If, at any time during the study, disease progression is suspected, a tumor assessment 
must be performed.   


 
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e. Schedule of Tumor Response Assessments for Obinutuzumab-Containing 
Cohorts 
All follicular NHL and DLBCL patients enrolled in obinutuzumab-containing cohorts 
are required to have a combined PET and CT scan at screening, after Cycle 4 of 
treatment, and at EOT.  The schedule for tumor response assessments for patients 
enrolled on obinutuzumab-containing cohorts is detailed in Appendix A-3. 
4.5.1.9 
Exploratory Research 
a. Tumor Tissue Samples 
Required Tumor Tissue Samples 
Tumor tissue samples will be used for central pathologic laboratory review of CD20, 
CD22, and CD79b expression.  Additional studies to fulfill the exploratory objectives in 
Section 3.3.4 will be performed, including, but not limited, to the following: 
• 
Messenger RNA (mRNA) expression profiling for signatures of NHL biology, 
including prognostic subpopulations (Alizadeh et al. 2000; Wright et al. 2003), target 
expression (CD20, CD22 and CD79b), and apoptotic response  
• 
Tissue microarrays (TMAs) from cores taken from provided blocks for 
immunohistochemistry (IHC) and in situ hybridization (ISH) assessments 
for biomarker endpoints involved in response to chemotherapy including quantitation 
of Bcl-2 protein and genetic alterations of bcl-2 including gene rearrangements, 
amplifications, and t(14;18) translocations. Additional IHC markers may include 
those related to the tumor microenvironment. 
• 
Tumor DNA to assess mutations that have been shown to be associated with NHL 
biology and activation of the B-cell receptor, including mutations in CD79b 
(Pasqualucci et al. 2011) 
 
For patients who develop progressive disease and are eligible to receive crossover 
treatment (see Section 3.1.8), a biopsy of a safely accessible site of disease will be 
performed.  Tumor tissue samples obtained at this timepoint will be used to assess 
changes in biology, target expression, and regulators of apoptosis as described above, 
which have occurred and may be linked to progression on initial study treatment. 
Optional Tumor Tissue Samples (Requires Optional Research Informed 
Consent 
For patients who provide informed consent, an optional tumor biopsy will be collected at 
time of progression from the following patients: 
• 
Patients who develop disease progression following initial study treatment and do 
not proceed to receive crossover treatment 
• 
Patients who develop disease progression on crossover treatment 
 
Tumor tissue samples obtained at these timepoints will be used to assess changes in 
biology, target expression, and regulators of apoptosis, as described above, that have 
occurred and may be linked to progression on treatment. 


 
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b. Blood and Plasma Samples 
A plasma sample will be collected prior to treatment. 
Blood samples will be taken aligned with PK sampling to assess the pharmacodynamics 
response by monitoring circulating tumor DNA. 
For patients who sign the Optional Research Informed Consent, an additional blood 
sample will also be taken prior to treatment. 
The plasma and blood samples may be used for the assessment of specific tumor 
biologic markers, including proteins, circulating DNA, and microRNAs.  The information 
obtained from these samples will enable a better understanding of the biology of NHL 
and disease prognosis, identify potential predictors of response to treatment with 
DCDT2980S, DCDS4501A, rituximab, and/or obinutuzumab, improve diagnostic 
assessments, and identify and characterize mechanisms of resistance to DCDT2980S or 
DCDS4501A and rituximab or obinutuzumab activity.   
Because tumorigenesis is a multiple-step process linked to somatic events, any DNA 
analysis will focus on sporadic mutations specifically found in tumor tissue and not on 
inherited changes found in the whole body.  For this purpose, some tumor-containing 
sections may be taken from the tissue block and used for the DNA extraction process.  
Assays on stored tissue samples may be performed at Genentech or at a central 
specialty laboratory. 
4.5.1.10 
Patient-Reported Outcomes 
The MDASI (Cleeland et al., 2000; Appendix E) is a multi-symptom self-report measure 
for clinical and research use. The MDASI’s 13 core-symptom items, plus an additional 
4 items, for a total of 17 symptom items, include those found to have the highest 
frequency and/or severity in patients with various cancers and treatment types.  These 
include pain, fatigue, nausea, disturbed sleep, emotional distress, shortness of breath, 
lack of appetite, drowsiness, dry mouth, sadness, vomiting, difficulty remembering, and 
numbness or tingling.  Six additional items focus on the degree of interference of the 
aforementioned symptoms for a total of 23 items in the questionnaire. 
PRO data will be elicited from all patients in this study to more fully characterize the 
clinical profile of study treatment.  The MDASI PRO instrument will be supplied in the 
local language of each participating country.  Electronic (handheld computers) will be 
used for the daily collection of symptoms derived from the MDASI.   
4.5.2 
Screening and Pretreatment Assessments 
All screening evaluations must be completed and reviewed by the Genentech Medical 
Monitor or designated CRO Medical Monitor to confirm that patients meet all eligibility 
criteria and are approved for enrollment before the first infusion of study treatment.  
Written informed consent for participation in the study must be obtained before 


 
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performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for patients who are not subsequently enrolled will be maintained at the study site. 
Screening and pretreatment tests and evaluations will be performed within 28 days 
preceding the day of the first dose of study treatment on Cycle 1 Day 1.  Results of 
standard-of-care tests or examinations performed prior to obtaining informed consent 
and within 28 days prior to Cycle 1 Day 1 may be used; such tests do not need to be 
repeated for screening. 
The availability of a patient’s tumor tissue sample for studies (see Sections 4.1.1 and 
4.5.1.9) should be confirmed prior to Cycle 1 Day 1.  Such specimens should consist of 
representative core biopsy in a paraffin block, which is the preferred method, or at least 
15 unstained slides.  Tumor specimens should be submitted with an accompanying 
pathology report and may be obtained at any time prior to entry to study.   
Bone marrow biopsy and aspirate specimens are required at screening (see 
Section 4.5.1.8).  Unsuccessful attempts at obtaining marrow aspirates will not be 
considered a protocol deviation or violation. 
Refer to the Study Flowchart provided in Appendix A-1 and A-3 for the schedule of 
screening and pretreatment assessments. 
4.5.3 
Assessments during Treatment 
Study drug infusions (rituximab, obinutuzumab, DCDT2980S, or DCDS4501A) should 
occur on the scheduled 21-day (or 28-day) cycle but may be given up to ± 2 days from 
the date scheduled (i.e., with a minimum of 19 days between doses) if required for 
logistical/scheduling reasons.  All other study visits during Cycles 1 and 2 must occur 
within ± 1 day from the scheduled date, unless otherwise noted.  Study visits starting in 
Cycle 3 should occur within ± 2 days from the scheduled date, unless otherwise noted.  
All assessments will be performed on the day of the specified visit unless a time window 
is specified.  Assessments scheduled on the day of study drug administration (Day 1) of 
each cycle should be performed prior to study drug infusion unless otherwise noted.   
Local laboratory assessments may be performed within 72 hours preceding study drug 
administration on Day 1 of each cycle.  Otherwise, laboratory samples should be drawn 
0−4 hours before infusion.  Results must be reviewed and the review documented prior 
to study drug administration. 
Refer to the Study Flowchart provided in Appendix A-1 for the schedule of treatment 
period assessments.  For patients enrolled in the obinutuzumab-containing cohorts, 
refer to the Study Flowchart provided in Appendix A-3. 


 
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4.5.4 
Study Treatment Completion Visit 
Patients who complete study treatment or discontinue from study treatment early will be 
asked to return to the clinic within 30 days after the last DCDT2980S, DCDS4501A, 
rituximab, or obinutuzumab infusion (whichever is later) for a study treatment completion 
visit.  The visit at which response assessment shows progressive disease may be used 
as the early termination visit. 
Refer to the Study Flowchart provided in Appendix A-1 for assessments to be performed 
at the treatment completion/early termination visit.  For patients enrolled on the 
obinutuzumab-containing cohorts, refer to the Study Flowchart provided in Appendix 
A-3. 
Assessments conducted at the treatment completion/early termination visit may be used 
for the purposes of re-screening to determine eligibility to receive crossover treatment 
(see Section 3.1.3 and Section 4.5.5). 
4.5.5 
Crossover Treatment Completion Visit 
Patients who fulfill the criteria to receive crossover treatment (see Section 3.1.6) will 
have assessments during the crossover treatment period as described in Appendix A-2.  
The same guidelines regarding scheduling of assessments for treatment with initial study 
treatment as detailed in Section 4.5.3 will apply to crossover treatment.   
Patients who proceed to receive crossover treatment will have on-treatment 
assessments as described in Appendix A-2. 
Patients who complete the crossover treatment (approximately 1 year/17 cycles) or 
discontinue from crossover treatment early will be asked to return to the clinic within 
30 days after the last DCDT2980S, DCDS4501A, or rituximab infusion (whichever is 
later) for a crossover treatment completion/early termination visit.  The visit at which 
response assessment shows disease progression on crossover treatment may be used 
as the early termination visit. 
Refer to Appendix A-2 for assessments to be performed at the treatment 
completion/early termination visit. 
4.5.6 
Follow-Up Assessments 
Ongoing adverse events thought to be related to DCDT2980S, DCS4501A, rituximab, or 
obinutuzumab will be followed until the event has resolved to baseline (pre-treatment) 
grade, the event is assessed by the investigator as stable, new anti-tumor treatment is 
initiated, the patient is lost to follow-up, the patient withdraws consent, or when it has 
been determined that the study treatment or participation is not the cause of the adverse 
event. 


 
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Patients will be followed after the last dose of study treatment (either initial study 
treatment or crossover treatment) for safety outcomes.  Such follow-up will require an 
assessment (per verbal report, at minimum) of any adverse events and serious adverse 
events for 30 days after the last dose of study drug or until the patient receives another 
anti-cancer therapy, whichever occurs first. 
4.5.6.1 
Follow-Up Assessments for Rituximab-Containing Regimens 
Patients who discontinue from study treatment (either initial study treatment or crossover 
treatment) for reasons other than progressive disease will be followed for response for 
up to 1 year after the last infusion of study treatment or until disease progression or 
initiation of another anti-lymphoma/leukemia therapy, whichever occurs first.  Response 
assessments should occur approximately every 2−3 months following the last infusions 
of DCDT2980S, DCDS4501A, or rituximab.  Post-treatment assessments are described 
in Appendix A-4.  
Following discontinuation of study treatment, patients will be followed for survival 
approximately every 3 months until death, loss to follow-up, withdrawal of consent, or 
study termination. 
4.5.6.2 
Follow-Up Assessments for Obinutuzumab-Containing Regimens 
Patients who discontinue from study treatment for reasons other than progressive 
disease will be followed for response for up to 2 years after the last infusion of study 
treatment or until disease progression or initiation of another anti-lymphoma/leukemia 
therapy, whichever occurs first.  Response assessments should occur approximately 
every 2−3 months following the last infusions of DCDS4501A or obinutuzumab for the 
first year after completion of treatment, then every 6 months for the second year after 
completion of treatment.  Post-treatment assessments are described in Appendix A-5.  
Following discontinuation of study treatment, patients will be followed for survival 
approximately every 6 months until death, loss to follow-up, withdrawal of consent, or 
study termination. 
4.6 
PATIENT DISCONTINUATION 
4.6.1 
Discontinuation from Treatment 
Patients may discontinue study treatment early for reasons other than disease 
progression, such as patient/investigator choice or unacceptable toxicity.  The reasons 
for early discontinuation of treatment must be documented on the appropriate eCRF.  
Patients may continue treatment with either DCDT2980S/DCDS4501A or rituximab 
alone following a careful assessment and discussion of risk versus benefit with the 
patient by the investigator and approval from the Medical Monitor. 
Patients who discontinue study treatment early due to toxicity should continue to be 
followed until resolution of toxicity as scheduled. 


 
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Refer to Sections 4.5.4 and 4.5.5 for assessments that are to be performed for patients 
who discontinue from the study during the study treatment period. 
4.6.2 
Discontinuation from Study 
Patients must be discontinued from the study if they experience disease progression as 
defined using response and progression criteria in Appendix C.  Patients can continue 
crossover treatment following documentation of the first progressive disease event but 
must be discontinued from the study if they experience a second progressive disease 
event on the crossover treatment. 
The investigator has the right to discontinue a patient from the study for any medical 
condition that the investigator determines may jeopardize the patient’s safety if he or she 
continues in the study, for reasons of noncompliance (e.g., missed doses or missed 
visits) or pregnancy or if the investigator determines it is in the best interest of the 
patient. 
Refer to Sections 4.5.4 and 4.5.5 for assessments that are to be performed for patients 
who prematurely discontinue from the study during the treatment period. 
4.7 
STUDY DISCONTINUATION 
Genentech has the right to terminate this study at any time.  Reasons for terminating the 
study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
• 
Data recording is inaccurate or incomplete. 
 
4.8 
POST-TRIAL ACCESS 
Genentech does not have any plans to provide DCDT2980S, DCDS4501A, rituximab, 
obinutuzumab, or other study interventions to patients after the conclusion of the study 
or if the study is terminated or for patients who withdraw early from the study or 
complete their study treatment.  Genentech will evaluate the appropriateness of 
continuing to provide DCDT2980S, DCDS4501A, rituximab, or obinutuzumab to study 
patients after evaluating the safety and activity data from the study.   
4.9 
ASSAY METHODS  
4.9.1 
Total DCDT2980S/DCDS4501A Antibody ELISA 
Total DCDT2980S or DCDS4501A antibody (conjugated and unconjugated antibody) will 
be measured in serum samples using validated ELISAs. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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4.9.2 
Antibody-Conjugated MMAE (MMAE Affinity Capture 
Enzyme-Release LC/MS-MS) 
acMMAE (a measure of MMAE conjugated to DCDT2980S/DCDS4501A) will be 
measured in plasma samples using validated affinity capture enzyme-release liquid 
chromatography−tandem mass spectrometry (LC-MS/MS) assays. 
4.9.3 
Free MMAE LC-MS/MS 
Free MMAE will be measured in plasma samples using a validated electrospray 
LC-MS/MS method. 
4.9.4 
Rituximab ELISA 
Rituximab will be measured in serum samples using a validated ELISA. 
4.9.5 
Obinutuzumab ELISA 
Obinutuzumab will be measured in serum samples using a validated ELISA.   
4.9.6 
Anti-Therapeutic Antibody 
ATAs against DCDT2980S and DCDS4501A in serum samples will be measured using 
validated bridging antibody ELISAs and characterized by competitive binding assays. 
ATAs against obinutuzumab in serum samples will be measured using a validated 
bridging antibody ELISA. 
4.9.7 
Biomarker Assays 
Tumor tissue assessment of biomarkers will be assayed using IHC, ISH, qPCR gene 
expression profiling using microarray and mutation detection assays.  Circulating Tumor 
DNA (ctDNA) in plasma samples will be assessed using a next generation sequencing 
approach (CAPP-Seq) to detect and quantitate lymphoma specific markers (Newman et 
al. 2014). 
4.10 
STATISTICAL METHODS 
The final analysis will be based on patient data collected until all patients discontinue 
from the study or the study is terminated by the Sponsor, whichever occurs first.  The 
analyses will be based on the safety evaluable population, defined as patients who 
received at least one dose of study treatment.  All summaries will be presented 
according to the disease-specific cohort, treatment group, and assigned dose level. 
4.10.1 
Analysis of the Conduct of the Study 
Enrollment, major protocol violations, and reasons for discontinuations from the study 
will be summarized. 
Demographic and baseline characteristics, such as age, sex, race/ethnicity, weight, 
duration of malignancy, and baseline ECOG Performance Status, will be summarized 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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using means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables.  All summaries will be presented overall and by 
treatment group, assigned dose level, and disease-specific cohort. 
Study drug administration data will be listed by the disease-specific cohorts described in 
Sections 3.1.1 and 3.1.2.  Any dose modifications will be flagged.  Means and standard 
deviations will be used to summarize the total doses of DCDT2980S, DCDS4501A, 
rituximab, and obinutuzumab received.  All summaries will be presented by treatment 
group, assigned dose level, and disease-specific cohort. 
4.10.2 
Safety Analysis 
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in physical findings on physical examinations, and changes in vital 
signs.  All patients who receive any amount of DCDT2980S, DCDS4501A, rituximab, or 
obinutuzumab will be included in the safety analysis and will be assigned to the 
treatment group on the basis of the study treatment received.  Patients who have dose 
level changes from the initial assigned dose level will be summarized by the initial 
assigned dose level of DCDT2980S or DCDS4501A. 
All adverse event data will be listed by study site, patient number, treatment group, 
disease-specific cohort, and cycle.  All adverse events occurring on or after treatment on 
Day 1 of Cycle 1 will be summarized by mapped terms, appropriate thesaurus levels, 
and NCI CTCAE v4.0 toxicity grade.  In addition, all serious adverse events, including 
deaths will be listed separately and summarized.   
Selected laboratory data will be listed, with values outside of normal ranges identified.  
The incidence of antibodies to DCDT2980S and DCDS4501A will be summarized. 
4.10.3 
Pharmacokinetic and Pharmacodynamic Analyses 
Individual and mean serum concentrations of total DCDT2980S or DCDS4501A antibody 
(conjugated and unconjugated antibody) and rituximab or obinutuzumab and plasma 
concentrations of acMMAE and free MMAE versus time data will be tabulated and 
plotted by NHL disease subtype (relapsed or refractory follicular NHL or DLBCL).  The 
pharmacokinetics of the above analytes will be summarized by estimating the 
appropriate PK parameters (e.g., AUC, Cmax, CL, Vss, and t1/2).  Estimates for these 
parameters will be tabulated and summarized (mean, standard deviation, and range).  
Non-compartmental, compartmental, and/or population methods will be used, as data 
allow.  
Exposure-response (safety and efficacy) analysis may be conducted with use of PK data 
and available drug effect (e.g., imaging, measures of tumor burden) and toxicity 
(e.g., clinical pathology) data, at the sponsor’s discretion. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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In addition, population PK methods may be employed to manage sparse data and to 
investigate the effects of certain covariates on the pharmacokinetics of DCDT2980S and 
DCDS4501A, as data allow, and at the sponsor’s discretion. 
4.10.4 
Activity Analyses 
Best overall response, duration of response, and PFS will be listed for all patients. 
ORR from the initial study treatment will be calculated on the basis of data from patients 
who received study treatment.  Objective response is defined as CR or PR as 
determined by the investigator, on the basis of physical examinations, radiographic 
scans, and bone marrow examinations, using modified response criteria for NHL 
(Cheson et al. 2007; see Appendix C) and confirmed by repeat assessments ≥ 4 weeks 
after initial documentation.  Any patient with insufficient data to determine response will 
be classified as a non-responder. 
For patients with DLBCL, primary assessment of tumor response will be based on 
diagnostic imaging scans⎯for example, CT and/or MRI scans and PET scans.  For 
patients with FL enrolled on rituximab-containing arms/cohorts, primary assessment of 
response will be based on CT scans only; the assessment of response in FL based on 
PET scans will be performed for exploratory purposes only. 
For patients with DLBCL or FL on obinutuzumab-containing cohorts, primary 
assessment of tumor response will be based on PET/CT scans.  Given the new Lugano 
Classification, 2014, criteria which recommend that complete response (PET-CR) be 
determined by PET-CT scan, patients in Cohorts E, G, and H will be evaluated with a 
PET-CT scan at screening, between Cycle 4 Day 15 and Cycle 5 Day 1, and at 6-8 weeks 
after completing treatment.  The efficacy analysis for these cohorts will, therefore, be 
different from the analysis for Arms A-B and Cohorts C-D. (Cheson, et al 2014) 
(see Appendix C-2). 
Among patients with an objective response, duration of response will be defined as the 
time from the initial documentation of a CR or PR to the time of disease progression or 
death.  If a patient does not experience death or disease progression before the end of 
the study, duration of response will be censored at the day of the last tumor assessment. 
For the randomized portion of the study (Arms A and B), PFS is defined as the time from 
the date of randomization to the date of disease progression or death from any cause, 
whichever occurs first.  If a patient has not experienced progressive disease or death, 
PFS will be censored at the date of the last tumor assessment.  Patients with no 
post-baseline tumor assessment will be censored on the date of randomization.  For the 
non-randomized portion of the study (Cohorts C through H), PFS is defined as the time 
from the date of study enrollment to the date of disease progression or death from any 
cause, whichever occurs first. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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For the randomized portion of the study (Arms A and B), OS is defined as the time from 
the date of randomization to the date of death from any cause.  For the non-randomized 
portion of the study (Cohorts C through H), OS is defined as the time from the date of 
study enrollment to date of death from any cause. 
4.10.5 
Exploratory Analyses  
Assay results of possible predictive markers will be listed by treatment group and 
response status. 
Summary statistics of the MDASI items, scales, and their changes from baseline will be 
calculated at each assessment timepoint.  The mean, standard error, and median of the 
absolute scores and the mean changes from baseline (and 95% CI) within and between 
study arms will be reported for the MDASI scales and single items, as well as the weekly 
averages of the worst symptom rating.  For change scores in the MDASI from baseline, 
patients without baseline scores will not be included in the analyses.  Line charts 
depicting the means and mean changes of subscales over time will be also provided.   
Frequencies and percentages of missing data for the PRO endpoints will be reported.  
Dropouts (defined as patients withdrawing from treatment for reasons other than 
documented disease progression or death) will be summarized. 
Repeated measures mixed-effects models will explore MDASI subscale scores with a 
baseline score and appropriate covariates added, as appropriate. 
4.10.6 
Handling of Missing Data 
For the endpoint of objective response, patients without a post-baseline tumor 
assessment will be considered non-responders in the all-treated population analysis.  
For duration of response and PFS, data from patients who are lost to follow-up will be 
included in the analysis as censored observations on the last date that the patient is 
known to be progression free, defined as the date of the last tumor assessment, or, if no 
tumor assessments were performed, as the date of last study treatment plus 1 day. 
Compliance to PRO data collection will be reported with summary statistics, including 
frequencies of reasons for non-compliance such as patient refusal to complete PRO 
data collection.   
4.10.7 
Determination of Sample Size 
For the randomized portion of the study (Arms A and B), a target of 120 patients will be 
enrolled in two separate cohorts of patients (40 in the follicular NHL cohort and 80 in the 
DLBCL cohort).  The randomized portion of this study is non-comparative in nature.  No 
formal hypothesis testing is planned to compare the treatment arms.  Moreover, there is 
insufficient power to detect minimum clinically meaningful differences between the two 
treatment arms.  Genentech has judged the proposed sample size to provide sufficient 


 
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precision in estimating the anti-tumor activity of DCDT2980S combined with rituximab or 
DCDS4501A combined with rituximab as measured by objective response.  For example, 
with the assumption of an observed response rate of 40%, a 90% confidence interval for 
the response rate would be approximately 22%−58% (i.e., 40% ± 18%) for the follicular 
NHL cohort and approximately 27%−53% (i.e., 40% ± 13%) for the DLBCL cohort.  With 
40 patients, there is an 87% chance of observing at least one adverse event with a true 
incidence of 5%. 
For the non-randomized portions of the study (Cohorts C and D), approximately 
20 patients will be enrolled into each arm, for a total of 40 patients.  With 20 patients 
under an observed response rate of 40%, the exact Clopper-Pearson 90% confidence 
interval for the response rate would be 22%−61%.  With respect to the assessment of 
safety based upon a sample size of 20 patients, the chance of observing at least one 
adverse event with a true incidence of 10% is 88%. 
For the obinutuzumab safety run-in cohort (Cohort E), 6 patients will be enrolled.  For 
the obinutuzumab expansion cohorts (Cohorts G and H), 40 patients with follicular 
NHL, and 40 patients with DLBCL will be enrolled at the RP2D to further evaluate 
safety and efficacy of the combination.  Table 3 provides asymptotic 90% confidence intervals 
for the true probability of response for a range of observed proportions based upon a sample of 40 
patients.  A sample size of 40 patients is deemed sufficient to provide adequate precision on the 
point estimate and for the lower end of the 90% CI to rule out a clinically uninteresting rate of 45% 
assuming observed response rates of approximately 60% or higher (~24 responders observed among 
40 patients). 
Table 3 
Potential 90% Interval Estimates for the True Response Probability 
Observed Proportion
of Responders 
90% Confidence Interval for 
True Probability of Response 
0.50 
(0.37, 0.63) 
0.60 
(0.47, 0.73) 
0.65 
(0.53, 0.77) 
0.70 
(0.58, 0.82) 
0.75 
(0.64, 0.86) 
 
Therefore, up to 252 patients may be enrolled in this study.  
4.11 
DATA QUALITY ASSURANCE 
The data will be collected via EDC using eCRFs.  The site will be responsible for data 
entry into the EDC system.  In the event of discrepant data, the CRO will request data 
clarification from the sites, which the sites will resolve electronically in the EDC system.  
The CRO will be responsible for the data management of this trial, including quality 
checking of the data.   


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Genentech will perform oversight of the data management of this trial.  Genentech will 
produce an EDC Study Specification document that describes the quality checking to be 
performed on the data.  Central Laboratory data and other electronic data will be sent 
directly to Genentech, using Genentech’s standard procedures to handle and process 
the electronic transfer of these data.  eCRFs and correction documentation will be 
maintained in the EDC system’s audit trail.  System backups for data stored at 
Genentech and records retention for the study data will be consistent with Genentech’s 
standard procedures. 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording protocol-defined adverse 
events (AEs) and serious adverse events (SAEs); measurement of protocol-specified 
hematology, clinical chemistry, and urinalysis variables; measurement of 
protocol-specified vital signs; and physical examinations and other protocol-specified 
tests that are deemed critical to the safety evaluation of the study drug(s). 
Genentech or its designee is responsible for reporting relevant SAEs to the Competent 
Authority, other applicable regulatory authorities, and participating investigators, in 
accordance with ICH guidelines, FDA regulations, European Clinical Trials Directive 
(Directive 2001/20/EC), and/or local regulatory requirements. 
Genentech or its designee is responsible for reporting unexpected fatal or 
life-threatening events associated with the use of the study drug to the regulatory 
agencies and competent authorities by telephone or fax within 7 calendar days after 
being notified of the event.  Genentech or its designee will report other relevant SAEs 
associated with the use of the study medication to the appropriate competent authorities 
(according to local guidelines), investigators, and central Institutional Review 
Board/ethics committee (IRBs/ECs, except in the United States where investigators are 
responsible for reporting to their IRBs per local requirements) by a written safety report 
within 15 calendar days of notification.   
5.1.1 
Adverse Event 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an IMP or other protocol-imposed intervention, regardless of 
attribution. 
This includes the following: 
• 
AEs not previously observed in the patient that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with the baseline 
hematologic malignancy (i.e., leukemia or lymphoma) that were not present prior to 
the AE reporting period (see Section 5.2.1) 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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• 
Complications that occur as a result of protocol-mandated interventions 
(e.g., invasive procedures such as biopsies) 
• 
AEs that occur prior to assignment of study treatment that are related to a 
protocol-mandated intervention (e.g., medication washout, no treatment run-in, or 
invasive procedures such as biopsies) 
• 
Preexisting medical conditions other than the disease under study that are judged 
by the investigator to have worsened in severity or frequency or changed in 
character during the protocol-specified AE reporting period 
 
5.1.2 
Serious Adverse Event 
An SAE is any AE that is any of the following: 
• 
Fatal (i.e., the AE actually causes or leads to death) 
• 
Life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death) 
• 
Requires or prolongs inpatient hospitalization 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
• 
A congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
the investigational product(s) 
• 
Considered a significant medical event by the investigator (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
All AEs that do not meet any of the criteria for serious should be regarded as 
non-serious AEs. 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an AE (as in mild, moderate, or severe pain); the event itself may be of relatively minor 
medical significance (such as severe headache).  “Serious” is a regulatory definition and 
is based on patient or event outcome or action criteria usually associated with events 
that pose a threat to a patient’s life or vital functions.  Seriousness (not severity) serves 
as the guide for defining regulatory reporting obligations. 
Severity and seriousness should be independently assessed when recording AEs and 
SAEs on the eCRF.  


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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5.1.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious adverse events of special interest are required to be reported by the 
investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2 for reporting instructions), irrespective of regulatory seriousness 
criteria.  Adverse events of special interest for this study include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 5.3.1.6; treatment-emergent ALT or AST > 3 × baseline value 
in combination with total bilirubin > 2 × ULN [of which ≥ 35% is direct bilirubin]) 
• 
Suspected transmission of an infectious agent by the study drug 
• 
Grade ≥2 motor neuropathy 
• 
Grade ≥2 infusion reactions 
 
5.2 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all AEs and SAEs (as defined in 
Section 5.1) are recorded on the eCRF and reported to the Sponsor in accordance with 
protocol instructions.  
5.2.1 
Adverse Event Reporting Period 
After informed consent, but prior to initiation of study drug, only SAEs caused by a 
protocol-mandated intervention will be collected (e.g., SAEs related to invasive 
procedures such as biopsies, medication washout, or no treatment run-in). 
After initiation of study drug (the Genentech product(s) or other IMP), all new AEs and 
SAEs regardless of attribution will be collected until 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is later.  
After this period, investigators should report only SAEs that are felt to be related to prior 
study treatment (see Section 5.6).   
5.2.2 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting AEs at all patient 
evaluation timepoints should be adopted.  Examples of non-directive questions include: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?”  
 
5.2.3 
Assessment of Severity and Causality of Adverse Events 
Investigators will seek information on AEs and SAEs at each patient contact.  All AEs 
and SAEs, whether reported by the patient or noted by authorized study personnel, will 
be recorded in the patient’s medical record and on the Adverse Event eCRF. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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For each AE and SAE recorded on the applicable eCRF, the investigator will make an 
assessment of seriousness (see Section 5.1.2 for seriousness criteria), severity, and 
causality.   
Table 4 provides guidance for grading AE severity, and Table 5 provides guidance for 
assessing the causal relationship to the investigational product(s).  
The AE grading (severity) scale found in the NCI CTCAE v4.0 will be used for AE 
reporting. 
Table 4 
Adverse Event Grading (Severity) Scale 
Grade 
Severity 
Alternate Description a 
1 
Mild (apply event-specific 
NCI CTCAE grading criteria) 
Transient or mild discomfort (< 48 hours); 
no interference with the patient’s daily 
activities; no medical intervention/therapy 
required 
2 
Moderate (apply event-specific 
NCI CTCAE grading criteria) 
Mild to moderate interference with the 
patient’s daily activities; no or minimal 
medical intervention/therapy required 
3 
Severe (apply event-specific 
NCI CTCAE grading criteria) 
Considerable interference with the 
patient’s daily activities; medical 
intervention/therapy required; 
hospitalization possible 
4 
Very severe, life threatening, 
or disabling (apply event-specific 
NCI CTCAE grading criteria) 
Extreme limitation in activity; significant 
medical intervention/therapy required, 
hospitalization probable 
5 
Death related to AE 
 
AE=adverse event; NCI CTCAE= National Cancer Institute Common Terminology Criteria 
for Adverse Events; SAE=serious adverse event. 
The NCI CTCAE v4.0 can be found at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03 2010-06-14 QuickReference 5x7.pdf.  
Note:  Regardless of severity, some events may also meet regulatory serious criteria.  
Refer to definitions of an SAE (see Section 5.1.2). 
a Use these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or 
reported AE is not in the NCI CTCAE listing. 
 
To ensure consistency of causality assessments, investigators should apply the 
following general guidelines: 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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Table 5 
 Causal Attribution Guidance 
Is the AE/SAE suspected to be caused by the investigational product based on facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
The temporal relationship of the AE/SAE to investigational product administration 
makes a causal relationship possible, AND other drugs, therapeutic interventions 
or underlying conditions do not provide sufficient explanation for the AE/SAE.   
NO 
The temporal relationship of the AE/SAE to investigational product administration 
makes a causal relationship unlikely, OR other drugs, therapeutic interventions or 
underlying conditions provide a sufficient explanation for the AE/SAE.   
AE=adverse event; SAE=serious adverse event. 
 
The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the “Yes” or “No” causality assessment for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities.   
5.3 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
5.3.1 
Recording Adverse Events on the eCRF 
Investigators should use correct medical terminology/concepts when recording AEs or 
SAEs on the eCRF.  Avoid colloquialisms and abbreviations. 
There is one eCRF page for recording AEs or SAEs. 
Only one medical concept should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.1.1 
Diagnosis versus Signs and Symptoms 
If known, a diagnosis should be recorded on the eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded as an AE or SAE on the eCRF.  If a diagnosis 
is subsequently established, it should be reported as follow-up information. 
5.3.1.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause.  For example, if severe diarrhea is 
known to have resulted in dehydration, it is sufficient to record only diarrhea as an AE or 
SAE on the eCRF.  
However, medically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the eCRF.  For 
example, if a severe gastrointestinal hemorrhage leads to renal failure, both events 
should be recorded separately on the eCRF. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
150/P GO27834-A2 
5.3.1.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between patient 
evaluation timepoints.  Such events should only be recorded once in the eCRF unless 
their severity increases.  If a persistent AE becomes more severe, it should be recorded 
again on the Adverse Event eCRF.   
A recurrent AE is one that occurs and resolves between patient evaluation timepoints 
and subsequently recurs.  All recurrent AEs should be recorded on Adverse Event 
eCRF. 
5.3.1.4 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities that require active management, 
e.g., concomitant medication, will be recorded as AEs or SAEs on the eCRF 
(e.g., abnormalities that require study drug dose modification, discontinuation of study 
treatment, more frequent follow-up assessments, further diagnostic investigation, etc.) 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholecystitis), only the 
diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event eCRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded as an AE or SAE on the eCRF.  If the 
laboratory abnormality can be characterized by a precise clinical term, the clinical term 
should be recorded as the AE or SAE.  For example, an elevated serum potassium level 
of 7.0 mEq/L should be recorded as “hyperkalemia.” 
Specific to this study, lymphopenia and leukopenia due to lymphopenia of any grade are 
expected PD effects of study drug and therefore are not considered to be AEs.  
However, complications of lymphopenia (e.g., infections) will need to be reported as 
AEs.  In addition, because monocytopenia is not reportable and neutropenia is already 
being monitored and reported as an AE, leukopenia does not need to be reported as a 
distinct AE. 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded as AEs or SAEs on the eCRF, unless their severity, 
seriousness, or etiology changes.  
5.3.1.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported 
as an AE if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
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• 
Results in a medical intervention (including a diagnostic evaluation not mandated in 
this protocol) or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.1.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an AE the occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as an SAE or a non-serious adverse event of special interest (see 
Section 5.4.2) 
5.3.1.7 
Deaths 
Deaths that occur during the protocol-specified AE reporting period (see Section 5.2.1) 
that are attributed by the investigator solely to progression of lymphoma will be recorded 
only on the Study Discontinuation eCRF.  All other on-study deaths, regardless of 
attribution, will be recorded on the Adverse Event eCRF and expeditiously reported to 
the Sponsor. 
When recording a death on an eCRF, the event or condition that caused or contributed 
to the fatal outcome should be recorded as the single medical concept on the eCRF.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
record “Unexplained Death” on the Adverse Event eCRF. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
152/P GO27834-A2 
5.3.1.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study.  Such 
conditions should be recorded on the Medical and Surgical History eCRF. 
A preexisting medical condition should be recorded as an AE or SAE only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
5.3.1.9 
Worsening of Baseline Hematologic Malignancy 
Worsening and/or progression of the baseline hematologic malignancy (e.g. leukemia or 
lymphoma) should not be recorded as an AE or SAE.  These data will be captured as 
efficacy assessment data only.   
5.3.1.10 
Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol.   
There are some hospitalization scenarios that do not require reporting as an SAE when 
there is no occurrence of an AE.  These scenarios include a planned hospitalization or 
prolonged hospitalization to: 
• 
Perform an efficacy measurement for the study 
• 
Undergo a diagnostic or elective surgical procedure for a preexisting medical 
condition that has not changed 
• 
Receive scheduled therapy for the target disease of the study 
 
5.3.1.11 
Pregnancy 
If a female patient becomes pregnant while receiving the study drug or within 6 months 
after the last dose of investigational product, a Pregnancy Report eCRF should be 
completed within 24 hours of learning of the pregnancy.  A pregnancy report will 
automatically be generated and sent to Genentech’s Drug Safety Department or its 
designee.  Pregnancy should not be recorded on the Adverse Event eCRF. 
Male patients must also be instructed to immediately inform the investigator if their 
partner becomes pregnant during the study or within 6 months after the last dose of 
study drug.  If such an event occurs, it should be reported as described below. 
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE 
(as the Sponsor considers these medically significant), recorded on an Adverse Event 
eCRF, and expeditiously reported to the Sponsor (see Section 5.4.2). 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
153/P GO27834-A2 
Any congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to study drug should be classified as an SAE, recorded on the Adverse Event eCRF, and 
expeditiously reported to the Sponsor (see Section 5.4.2). 
After the study period, abortions, congenital anomalies/birth defects, and pregnancy 
outcomes should still be reported expeditiously to the Sponsor.   
In the event the EDC system is unavailable, a paper Pregnancy Report form and 
Pregnancy Fax Coversheet should be completed and faxed to Genentech’s Drug Safety 
Department or its designee within 24 hours of learning of the pregnancy, at the fax 
numbers listed in Section 5.4.2. 
a. Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
5 months after the last dose of study drug.  A Pregnancy Report eCRF should be 
completed by the investigator within 1 working day after learning of the pregnancy and 
submitted via the EDC system.  Attempts should be made to collect and report details of 
the course and outcome of any pregnancy in the partner of a male patient exposed to 
study drug.  The pregnant partner will need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
Once the authorization has been signed, the investigator will update the Pregnancy 
Report eCRF with additional information on the course and outcome of the pregnancy.  
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
In the event that the EDC system is unavailable, a paper Pregnancy Report form and 
Pregnancy Fax Coversheet should be completed and faxed to Genentech’s Drug Safety 
Department or its designee within 24 hours of learning of the pregnancy, at the fax 
numbers listed in Section 5.4.2. 
5.4 
EXPEDITED REPORTING REQUIREMENTS FOR SERIOUS 
ADVERSE EVENTS  
5.4.1 
Reporting Requirements for Fatal/Life-Threatening SAEs 
Related to Investigational Product 
Any life-threatening (i.e., imminent risk of death) or fatal AE that is attributed by the 
investigator to the investigational product will be telephoned to the Medical Monitor 
immediately, followed by submission of written case details on an eCRF within 24 hours 
as described in Section 5.4.2. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
154/P GO27834-A2 
Medical Monitor Contact Information for sites in North America: 
Medical Monitor: 
, M.D. 
Telephone No.: 
 
 
Mobile Telephone No.: 
 
Alternate Telephone No.: 
 (888) 835-2555 (U.S. sites only) 
For sites outside of North America, local contact details and numbers for safety issues 
and safety reporting will be provided in the study reference binder. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
For reports of SAEs and non-serious adverse events of special interest, investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours) on 
the Adverse Event eCRF and submit the report via the EDC system.  A report will be 
generated and sent to the Sponsor’s Safety Risk Management department by the EDC 
system. 
In the event that the EDC system is unavailable, a paper Serious Adverse 
Event/Non-Serious Adverse Event of Special Interest CRF and Fax Coversheet should 
be completed and faxed to Safety Risk Management or its designee immediately (i.e., no 
more than 24 hours after learning of the event), using the fax numbers provided below.  
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.   
Sites in North America: 
Fax No.:  
 
 
 
Relevant follow-up information should be submitted to Genentech’s Drug Safety 
Department or its designee as soon as it becomes available and/or upon request. 
5.5 
TYPE AND DURATION OF FOLLOW-UP OF PATIENTS AFTER 
ADVERSE EVENTS 
The investigator should follow all unresolved AEs and SAEs until the events are resolved 
or stabilized, the patient is lost to follow up, or it has been determined that the study 
treatment or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs 
(with dates) should be documented on the Adverse Event eCRF and in the patient’s 
medical record to facilitate source data verification (SDV). 
For some SAEs, the Sponsor or its designee may follow up by telephone, fax, electronic 
mail, and/or a monitoring visit to obtain additional case details deemed necessary to 
appropriately evaluate the SAE report (e.g., hospital discharge summary, consultant 
report, or autopsy report). 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
155/P GO27834-A2 
5.6 
POST-STUDY ADVERSE EVENTS 
At the last scheduled visit, the investigator should instruct each patient to report to the 
investigator any subsequent SAEs that the patient’s personal physician believes could 
be related to prior study treatment.   
The investigator should notify the study Sponsor of any death or other SAE occurring at 
any time after a patient has discontinued or terminated study participation if felt to be 
related to prior study treatment.  The Sponsor should also be notified if the investigator 
should become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a patient that participated in this study.  The 
investigator should report these events to Genentech Drug Safety on the study eCRF.  
If the study eCRF is no longer available, the investigator should report the event directly 
to Genentech Drug Safety either by faxing or by scanning and emailing the Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form with use of the fax 
number or email address provided below. 
Canada: 
Fax No.:  (905) 542−5864 
Email:  mississauga.drug_safety@roche.com 
 
United States: 
Fax No.:  
 
Email: us_drug.safety@gene.com 
 
6. 
INVESTIGATOR REQUIREMENTS 
6.1 
STUDY INITIATION 
Before the start of this study and any study-related procedures at a specific site, the 
following documents must be on file with Genentech or a Genentech representative: 
• 
FDA Form 1572 for each site (for all studies conducted under U.S. Investigational 
New Drug [IND] regulations), signed by the Principal Investigator 
The names of any subinvestigators must appear on this form.  Investigators 
must also complete all regulatory documentation as required by local and 
national regulations. 
• 
Current curricula vitae and evidence of licensure of the Principal Investigator and all 
subinvestigators 
• 
Complete financial disclosure forms for the Principal Investigator and all 
subinvestigators listed on the FDA Form 1572  
• 
Federalwide Assurance number or IRB statement of compliance 
• 
Written documentation of IRB/EC approval of the protocol (identified by protocol 
number or title and date of approval) and Informed Consent Form (identified by 
protocol number or title and date of approval) 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
156/P GO27834-A2 
• 
A copy of the IRB/EC-approved Informed Consent Form 
Genentech or its designee must review any proposed deviations from the sample 
Informed Consent Form. 
• 
Current laboratory certification of the laboratory performing the analysis (if other 
than a Genentech-approved central laboratory), as well as current references 
ranges for all laboratory tests 
• 
A Clinical Research Agreement signed and dated by the study site 
• 
Investigator Brochure Receipt signed and dated by the Principal Investigator 
• 
Certified translations of an approved Informed Consent Form, and any other written 
information to be given to the patient (when applicable) , IRB/EC approval letters, 
and pertinent correspondence 
• 
A Protocol Acceptance Form signed and dated by the Principal Investigator 
• 
Canada only when applicable:  original Qualified Investigator Undertaking Form, 
signed by each Canadian investigator involved in the study 
• 
For global studies, list documents as appropriate for additional countries. 
 
6.2 
STUDY COMPLETION 
The following data and materials are required by Genentech before a study can be 
considered complete or terminated: 
• 
Laboratory findings, clinical data, and all special test results from screening through 
the end of the study follow-up period 
• 
All laboratory certifications for laboratories performing the analysis (is other  than 
Genentech-approved central laboratory), as well as current normal laboratory 
ranges for all laboratory tests 
• 
eCRFs (including queries) properly completed by appropriate study personnel and 
electronically signed and dated by the investigator 
• 
Completed Drug Accountability Records (Retrieval Record, Drug Inventory Log, and 
Inventory of Returned Clinical Material forms) 
• 
Copies of protocol amendments and IRB/EC approval/notification, if appropriate 
• 
A summary of the study prepared by the Principal Investigator (IRB summary close 
letter is acceptable) 
• 
All essential documents (e.g., curriculum vitae for each Principal Investigator and 
subinvestigator, FDA Form 1572 for each site) 
• 
A signed and dated Protocol Amendment Acceptance Form(s) [if applicable] 
• 
Updated financial disclosure forms for the Principal Investigator and all 
subinvestigators listed on the FDA Form 1572 (applicable for 1 year after the last 
patient has completed the study) 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
157/P GO27834-A2 
6.3 
INFORMED CONSENT FORM 
Genentech’s Sample Informed Consent Form will be provided to each site.  Genentech 
or its designee must review and approve any proposed deviations from the Sample 
Informed Consent Form or any alternate consent forms proposed by the site 
(collectively, the “Consent Forms”) before IRB/EC submission.  Patients must be 
re-consented to the most current version of the Consent Forms during their participation 
in the study.  The final IRB/EC-approved Consent Forms must be provided to Genentech 
for regulatory purposes. 
The Consent Forms must be signed by the patient or the patient’s legally authorized 
representative before his or her participation in the study.  The case history for each 
patient shall document the informed consent process and that written informed consent 
was obtained prior to participation in the study.  A copy of each signed Consent Form 
must be provided to the patient or the patient’s legally authorized representative.  
If applicable, it will be provided in a certified translation of the local language. 
All signed and dated Consent Forms must remain in each patient’s study file and must 
be available for verification by study monitors at any time. 
The Informed Consent Form should be revised whenever there are changes to 
procedures outlined in the informed consent or when new information becomes available 
that may affect the willingness of the patient to participate. 
For any updated or revised Consent Forms, the case history for each patient shall 
document the informed consent process and that written informed consent was obtained 
for the updated/revised Consent Form for continued participation in the study.  The final 
revised IRB/EC-approved Informed Consent Form must be provided to Genentech for 
regulatory purposes. 
If the site utilizes a separate Authorization Form for patient authorization to use and 
disclose personal health information under the U.S. Health Insurance Portability and 
Accountability Act (HIPAA) regulations, the review, approval, and other processes 
outlined above apply except that IRB/IEC review and approval may not be required per 
study site policies. 
Optional Research Informed Consent 
Informed consent for the collection and use of fresh tumor tissue at time of progression 
for optional research described in Section 4.5.1.10 will be documented in a section of the 
main Informed Consent Form.  This section provides patients with the option to authorize 
the collection and use of these samples and personal health information for additional 
research purposes.  Agreement to participate in the optional research (by checking the 
appropriate box in this section of the main Informed Consent Form) is not required for 
enrollment in the trial but is required prior to any optional research sample collection.  
Optional consent may be withdrawn at any time by the patient. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
158/P GO27834-A2 
6.4 
COMMUNICATION WITH THE INSTITUTIONAL REVIEW BOARD 
OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator for review and approval before the study is initiated.  In addition, any patient 
recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the regulatory 
requirements and policies and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol changes or 
amendments and of any unanticipated problems involving risk to human patients 
or others. 
In addition to the requirements to report protocol-defined AEs to the Sponsor, 
investigators are required to promptly report to their respective IRB/EC all unanticipated 
problems involving risk to human patients.  Some IRBs/ECs may want prompt 
notification of all SAEs, whereas others require notification only about events that are 
serious, assessed to be related to study treatment, and are unexpected.  Investigators 
may receive written IND safety reports or other safety-related communications from 
Genentech.  Investigators are responsible for ensuring that such reports are reviewed 
and processed in accordance with regulatory requirements and with the policies and 
procedures established by their IRB/EC and archived in the site’s Study File.  
6.5 
STUDY MONITORING REQUIREMENTS 
Site visits will be conducted by an authorized Genentech representative to inspect site 
facilities and equipment, study source data, patients’ medical records, and eCRFs.  The 
Principal Investigator will oversee all aspects of the conduct of this protocol and permit 
Genentech monitors/representatives and collaborators, the FDA, other regulatory 
agencies, Institutional Review Boards, and the respective national or local health 
authorities to inspect facilities and records relevant to this study. 
6.6 
ELECTRONIC CASE REPORT FORMS 
eCRFS are to be completed using the 
 EDC 
system.  Sites will receive training for appropriate eCRF completion.  eCRFs will be 
submitted electronically to Genentech and should be handled in accordance with 
instructions from Genentech. 
All eCRFs should be completed by designated, trained personnel or the study 
coordinator as appropriate.  The eCRF should be reviewed and electronically signed and 
dated by the investigator. 
In addition, at the end of the study, the investigator will receive patient data for his or her 
site in a readable format on a compact disc that must be kept with the study records. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
159/P GO27834-A2 
6.7 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing SDV to confirm that critical protocol data 
(i.e., source data) entered into the eCRFs by authorized site personnel are accurate, 
complete, and verifiable from source documents.  
Source documents are where original patient data are recorded and documented for the 
first time.  They include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, patient diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, certified accurate and 
complete copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at the pharmacy, laboratories, and medico-technical 
departments involved in a clinical trial. 
Original source documents that are required to verify the validity and completeness of 
data entered into the eCRFs must never be obliterated or destroyed. 
To facilitate SDV, the investigator(s) and institution(s) must provide the Sponsor direct 
access to all applicable source documents and reports for trial-related monitoring, 
Sponsor audits, and IRB/EC review.  The investigational site must also allow inspection 
by applicable regulatory authorities. 
6.8 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), 
the electronic record can serve as the source document if the system has been validated 
in accordance with FDA requirements pertaining to computerized systems used in 
clinical research.  An acceptable computerized data collection system (for clinical 
research purposes) would be one that (1) allows data entry only by authorized 
individuals; (2) prevents the deletion or alteration of previously entered data and 
provides an audit trail for such data changes (e.g., modification of file); (3) protects the 
database from tampering; and (4) ensures data preservation. 
In collaboration with the study monitor, Genentech’s Quality Assurance group may assist 
in assessing whether electronic records generated from computerized medical record 
systems used at investigational sites can serve as source documents for the purposes of 
this protocol. 
If a site’s computerized medical record system is not adequately validated for the 
purposes of clinical research (as opposed to general clinical practice), applicable 
hardcopy source documents must be maintained to ensure that critical protocol data 
entered into the eCRFs can be verified. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
160/P GO27834-A2 
6.9 
STUDY MEDICATION ACCOUNTABILITY 
All study drug required for completion of this study will be provided by Genentech.  
The recipient will acknowledge receipt of the drug by returning the appropriate 
documentation form indicating shipment content and condition.  Damaged supplies will 
be replaced. 
Accurate records of all study drug received at, dispensed from, returned to and disposed 
of by the study site should be recorded by using the Drug Inventory Log. 
Study drug will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or returned to Genentech with the appropriate 
documentation, as determined by the study site.  If the study site chooses to destroy 
study drug, the method of destruction must be documented. 
Genentech must evaluate and approve the study site’s drug destruction standard 
operating procedure prior to the initiation of drug destruction by the study site. 
6.10 
DISCLOSURE OF DATA 
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization to use and disclose personal health information) signed by the patient or 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other regulatory agencies, national and local health 
authorities, Genentech monitors/representatives and collaborators, and the IRB/EC for 
each study site, if appropriate. 
6.11 
RETENTION OF RECORDS 
FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see Section 4.9 of 
the guideline) require that records and documents pertaining to the conduct of this study 
and the distribution of investigational drug, including eCRFs, consent forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for 2 years after the last marketing application approval in an ICH region or 
after at least 2 years have elapsed since formal discontinuation of clinical development 
of the investigational product.  All state and local laws for retention of records also apply.  
No records should be disposed of without the written approval of Genentech.  Written 
notification should be provided to Genentech prior to transferring any records to another 
party or moving them to another location. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
161/P GO27834-A2 
For studies conducted outside the United States under a U.S. IND, the Principal 
Investigator must comply with the record retention requirements set forth in the FDA IND 
regulations and the relevant national and local health authorities, whichever is longer. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
162/P GO27834-A2 
7. 
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Meyer PN, Fu K, Greiner TC, et al. Immunohistochemical methods for predicting cell 
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rituximab. J Clin Oncol 2011; 29:200−7. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
163/P GO27834-A2 
Morschhauser FA, Cartron G, Thieblemont C, et al. Obinutuzumab (GA101) in 
patients with R/R diffuse large B-cell lymphoma or Mantle-cell lymphoma: results 
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Mössner E, Brunker P, Moser S, et al. Increasing the efficacy of CD20 antibody 
therapy through the engineering of a new type II anti-CD20 antibody with enhanced 
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Nam HD, Mitchell RS, Fritz O, et al. Anti-CD22 immunoconjugate inotuzumab 
ozogamicin (CMC-544) + rituximab: clinical activity including survival in patients with 
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Nina W-J, Andre G, Tatyana F, et al. Anti-CD22 immunoconjugate inotuzumab 
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Palanca-Wessels MC, Flinn IW, Sehn LH, et al. A phase I study of DCDS4501A, an 
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non-Hodgkin’s lymphoma (NHL) [abstract]. Blood 2012;120: 56A. Available from: 
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Pasqualucci L, Vladimir T, Fabri G, et al. Analysis of the coding genome of diffuse 
large b-cell lymphoma. Nat Genet 2011; 43:830–7.  
Polson AG, Calemine-Fenaux J, Chan P, et al. Antibody-drug conjugates for the 
treatment of non-Hodgkin's lymphoma: target and linker-drug selection. Cancer Res 
2009;69:2358–64. 
Polson AG, Yu SF, Elkins K, et al. Antibody-drug conjugates targeted to CD79 for 
the treatment of non-Hodgkin lymphoma. Blood 2007;110:616–23. 
Radford J, Davies A, Cartron G, et al. Obinutuzumab (GA101) plus CHOP or FC in 
R/R follicular lymphoma: results of the GAUDI study (BO21000). Blood 
2013;122:1137−43. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
164/P GO27834-A2 
Rituxan® (Rituximab) Package Insert. Biogen Idec Inc. and Genentech Inc. 
Rosenberg AS, Worobec A. A risk-based approach to immunogenicity concerns of 
therapeutic protein products, part 1: considering consequences of the immune 
response to a protein. BioPharm International, November 2004a;22−6. 
Rosenberg AS, Worobec A. A risk-based approach to immunogenicity concerns of 
therapeutic protein products, part 2: considering hose-specific and product-specific 
factors impacting immunogenicity. BioPharm International, December 2004b;34−42. 
Rosenberg AS, Worobec A. A risk-based approach to immunogenicity concerns of 
therapeutic protein products. part 3: effects of manufacturing changes on 
immunogenicity and the utility of animal immunogenicity studies. BioPharm 
International, January 2005;32−36. 
Salles GA, Morschhauser F, Solal-Céligny P, et al. Obinutuzumab (GA101) in 
patients with R/R indolent non-Hodgkin lymphoma: results from the Phase II 
GAUGUIN study. J Clin Oncol 2013;31:2920−6. 
Shan D, Press OW. Constitutive endocytosis and degradation of CD22 by human 
B cells. J Immunol 1995;154:4466−75. 
Wright G, Tan B, Rosenwald A, et al. A gene expression-based method to diagnose 
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Yeo W, Chan TC, Leung NWY, et al. Hepatitis B virus reactivation in lymphoma 
patients with prior resolved hepatitis B undergoing anticancer therapy with or without 
rituximab. J Clin Oncol 2009;27:605−11.  


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
165/P GO27834-A2 
Appendix A-1  
Study Flowchart:  Initial Study Treatment (Arms A-B, Cohorts C-D) 
 
Treatment Period 
Cycle 
Screening
Cycle 1 
Cycles 2−4 
Cycles 5−17 
Day(s)a 
Assessment 
−28 to −1 
1 b 
2 
8 
15 
1 b 
2 
8 
15 
1 b 
2 
15 
Treatment 
Completion/Early 
Termination Visit c 
Safety and 
Survival 
Follow-Up d 
Written informed consent e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height (screening only) and weight 
x 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
Vital signs  
x 
x f 
x f 
x 
x 
x f 
(x) f 
x 
x 
x f 
(x) f 
x 
x 
 
ECOG Performance Status 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
 
x 
 
B symptoms g 
x 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
 
Complete physical examination h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical examination i 
 
x 
x 
x 
 
x 
(x) 
 
 
x 
(x) 
 
x 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
(x) 
x 
x 
x 
(x) 
x 
x 
 
Adverse events j 
x 
x  
x 
x 
x 
x  
(x) 
x 
x 
x  
(x) 
x 
x 
x 
MDASI PRO k 
 
Day 1–8 of Cycles 1–8 
 
 
12-lead electrocardiogram l 
x  
Refer to Footnote “l” 
x  
 
Tumor assessments m 
x 
Every 3 months 
x 
 
PET scan (required for DLBCL; optional 
for FL) m 
x 
6-month tumor assessment and as clinically indicated 
 
 
Rituximab infusion 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
DCDT2980S or DCDS4501A infusion n 
 
 
x 
 
 
x 
(x) 
 
 
x 
(x) 
 
 
 


Appendix A-1 (cont.) 
Study Flowchart:  Initial Study Treatment (Arms A-B, Cohorts C-D) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
166/P GO27834-A2 
 
Treatment Period 
Cycle 
Screening
Cycle 1 
Cycles 2−4 
Cycles 5−17 
Day(s)a 
Assessment 
−28 to −1 
1 b 
2 
8 
15 
1 b 
2 
8 
15 
1 b 
2 
15 
Treatment 
Completion/Early 
Termination Visit c 
Safety and 
Survival 
Follow-Up d 
Local Laboratory Assessments 
HBV and HCV screening o 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology p 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
Serum chemistry q 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
Hemoglobin A1c 
x 
 
 
 
 
 
 
 
 
Cycle 5 Day 1 
 
 
Total IgA, IgG, IgM 
x 
 
 
 
 
 
 
 
 
Cycle 8 Day 1 
x 
 
Coagulation (aPTT, PT, and INR) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test r 
x 
Within 10 days of Day 1 of Cycles 3, 6, 9, 12, and 15 
x 
 
Bone marrow biopsy s 
x 
Perform to confirm CR if positive for disease at screening or if clinically 
indicated 
 
 
Central Laboratory Assessments 
Leukocyte immunophenotyping (FACS) t 
 
Day 1 of Cycle1, Cycle 4, Cycle 8 and Cycle12 
x 
 
Tumor tissue sample u 
x 
 
 
 
 
 
 
 
 
 
 
 
x  
 
Exploratory plasma (required) and blood 
(optional) sample v 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
DCDT2980S or DCDS4501A and 
rituximab pharmacokinetic sampling w 
Serum sample for anti-DCDT2980S or 
anti-DCDS4501A antibody x 
Refer to Appendix B-1 and Appendix B-2 
 


Appendix A-1 (cont.) 
Study Flowchart:  Initial Study Treatment (Arms A-B, Cohorts C-D) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
167/P GO27834-A2 
AE = adverse event; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; CR = completed 
response; CT = computed tomography; DLBCL = ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FACS = fluorescent-activated cell 
sorting; FL = follicular lymphoma; GGT = γ-glutamyl transpeptidase; HBV = hepatitis B virus; HCV = hepatitis C virus; Ig = immunoglobulin; INR = international 
normalized ratio; LDH = lactate dehydrogenase; MDASI = MD Anderson Symptom Inventory; MRI = magnetic resonance imaging; NHL = non-Hodgkin’s 
lymphoma; PET = positron emission tomography; PCR = polymerase chain reaction; PT = prothrombin time; QLQ = Quality of Life Questionnaire; 
SAE = serious adverse event; (x) = Assessment or action to be performed only if study treatment is administered on Day 2 of the Cycle —refer to footnote ‘n’ 
for details. 
a Study drug infusions should occur on the scheduled 21-day cycle up to a maximum of 1 year (approximately 17 cycles on an every-21-day schedule) and 
may be given up to ± 2 days from the date scheduled (i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  
All other study visits during Cycles 1 and 2 must occur within ± 1 day from the scheduled date unless otherwise noted.  Study visits starting in Cycle 3 
should occur within ± 2 days from the scheduled date unless otherwise noted.  Treatment cycles may be extended to 28 days if needed to provide 
sufficient time for recovery from a transient and reversible toxicity (e.g., cytopenia) without reducing the dose of DCDT2980S or DSDA4501A.  Patients 
receiving study treatment on 28-day cycles should also follow the assessment schedule above up to a maximum of 1 year of total study treatment 
(approximately 13 cycles). 
b Local laboratory assessments and targeted physical examination may be performed within 72 hours preceding rituximab administration unless otherwise 
specified; pre-infusion laboratory samples should be drawn 0−4 hours prior to infusion. 
c Perform within 30 days after the last infusion of DCDT2980S, DCDS4501A, or rituximab.  The visit at which response assessment shows progressive 
disease may be used as the early termination visit.  Assessments during the treatment completion/early termination visit may be applied to assessments 
required to determine eligibility to receive crossover treatment.  Patients enrolled into Cohorts C and D are not eligible to receive crossover treatment. 
d Patients will be followed for safety for 30 days after the last infusions of DCDT2980S, DCDS4501A, or rituximab.  Such follow-up will require an 
assessment (per verbal report from the patient, at minimum) of any AEs and/or SAEs through 30 days after the last dose of study drug or until the patient 
receives another anti-cancer therapy including crossover treatment, whichever occurs first.  Patients who discontinue study treatment for reasons other 
than progressive disease will continue to be followed for response for up to 1 year after the last infusions of DCDT2980S or DCDS4501A and rituximab, 
or until disease progression or initiation of another anti-lymphoma/leukemia therapy, whichever occurs first.  Refer to Appendix A-4 for schedule of 
assessments during the post-treatment period.  Patients will also be followed for survival following study treatment discontinuation approximately every 
three months until death, loss to follow-up, withdrawal of consent, or study termination. 
e Informed consent form(s) must be signed by the patient before any study-specific procedures are performed. 
f Vital signs on days of study treatment administration should be recorded according to Section 4.5.1.2 of the protocol. 
g Defined as unexplained weight loss > 10% over previous 6 months, fever (> 38°C/100.4°F), and/or drenching night sweats. 
h Complete physical examination includes all systems described in Section 4.5.1.3.   
i Targeted physical examinations should be limited to systems of clinical relevance (see Section 4.5.1.3) and those systems associated with clinical 
signs/symptoms.  A targeted symptom directed examination is required prior to DCDT2980S or DCDS4501A dosing on Day 2 of each cycle if given on 
separate days from rituximab only if clinically indicated⎯for example, to follow- up on signs or symptoms observed from the examinations performed on 
Day 1. 


Appendix A-1 (cont.) 
Study Flowchart:  Initial Study Treatment (Arms A-B, Cohorts C-D) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
168/P GO27834-A2 
j After informed consent is obtained but prior to initiation of study treatment, only SAEs caused by a protocol-mandated intervention should be reported.  
After initiation of study drug, all AEs and SAEs, regardless of attribution, must be reported until 30 days following the last administration of study drug or 
until the patient receives another anti-cancer therapy, whichever occurs first.  After this period, investigators should report only SAEs considered related 
to prior study treatment. 
k Treatment and disease associated symptoms using the MDASI questionnaire will be collected on hand-held computer devices (see Section 4.5.1.10).   
l Twelve-lead digital electrocardiogram (ECG) measurements must be obtained in triplicate (with immediately consecutive ECGs obtained until 
three evaluable ECGs are recorded) at the timepoints specified in Section 4.5.1.5.  Non-triplicate ECGs should also be performed when clinically 
indicated in any patient with evidence of, or suspicion for, clinically significant signs or symptoms of cardiac dysfunction.  The evaluating physician should 
determine the clinical significance of any abnormal ECGs. 
m Tumor assessments should be performed at screening and every 3 months while receiving study treatment regardless of study treatment dose schedule.  
Tumor assessments should also be performed within 30 days after the last study drug infusion as part of the treatment completion/early termination visit.  
Response should be assessed based on physical examination and imaged-based evaluation, using standard NHL criteria (Appendix C-1).  For DLBCL 
patients, a PET scan is required during screening, at the 6-month tumor assessment timepoint and as clinically indicated.  For patients with FL, a PET 
scan is not required but may be obtained based on physician preference and if permitted by local health authorities.  Refer to Section 4.5.1.8 for 
complete details. 
n Administer DCDT2980S or DCDS4501A over 90 minutes for Cycle 1 and over 30 minutes in subsequent cycles if there are no infusion-related AEs.  For 
Cycle 1 and Cycle 2, DCDT2980S or DCDS4501A should be administered on the day after rituximab is administered⎯for example, Day 2 if rituximab is 
given on Day 1, or Day 3 if rituximab is given as a split dose on Days 1 and 2.  In the absence of any infusion-related AEs, rituximab followed by 
DCDT2980S or DCDS4501A may be administered on the same day in each cycle starting with Cycle 3.  Study drug infusions should occur on the 
scheduled 21-day (or 28-day) cycle but may be given up to ± 2 days from the date scheduled (i.e., with a minimum of 19 days between doses) if required 
for logistical/scheduling reasons.  Doses may also be delayed up to 2 weeks for recovery from reversible toxicity. 
o HBsAg, HBcAb, and Hep C Ab serology required.  If HBcAb or HCV antibody is positive, HBV/HCV DNA by PCR is required. 
p Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, absolute neutrophil count, and 
percent or absolute differential counts [e.g., segmented neutrophils, bands, lymphocytes, eosinophils, monocytes, basophils, and other cells]). 
q Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), creatinine, calcium, magnesium, phosphorus, total 
and direct bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, LDH, and uric acid.  Serum GGT levels will be required at screening only. 
r A serum pregnancy test should be performed for women of childbearing potential within 14 days prior to receiving first study treatment.  In addition, a 
urine pregnancy test must also be performed within 10 days prior to Day 1 of Cycles 3, 6, 9, 12, and 15, and at the treatment completion/early 
termination visit unless patient receives crossover treatment, in which case follow the schedule of pregnancy testing outlined in Appendix A-2.  If any 
urine test result is positive, patient dosing will be postponed until the patient’s status is confirmed by a serum pregnancy test. 
s Bone marrow biopsy for morphology (aspirates for morphology and/or flow studies are optional) is required at screening.  Bone marrow biopsy 
for morphology is required at screening and should reflect disease status in the bone marrow following documented relapse on the last prior therapy 
or within 3 months of Day 1, whichever occurs later.  If the bone marrow biopsy at screening demonstrates presence of tumor cells, a subsequent 
bone marrow examination is required only to confirm a CR or if clinically indicated.  If the bone marrow biopsy at screening does not demonstrate 


Appendix A-1 (cont.) 
Study Flowchart:  Initial Study Treatment (Arms A-B, Cohorts C-D) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
169/P GO27834-A2 
presence of tumor cells, then subsequent bone marrow examination is required only if clinically indicated.  Unsuccessful attempts at marrow aspiration 
will not be considered a protocol violation. 
t A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.   
u Availability of archival or freshly biopsied tumor tissue samples should be confirmed at screening.  Tumor tissue samples should consist of representative 
tumor specimens in paraffin blocks (preferred) or at least 15 unstained slides, with an associated pathology report, obtained at any time prior to entry to 
study.  A biopsy of a safely accessible site of disease, defined as requiring only local anesthesia and in general excluding brain, lungs or any internal 
organs that may subject patients to significant risk, is required for patients who proceed to crossover treatment; if no such lesion exists, then a biopsy is 
not required. 
v All patients who have successfully passed screening and are fully eligible for the study will have a 10-mL plasma sample taken for exploratory research.   
w Pharmacokinetic serum and plasma samples should be drawn according to the schedule provided in Appendices B-1 and B-2. 
x Whole blood samples for assessment of anti-DCDT2980S or anti-DCDS4501A antibodies in serum will be drawn according to the schedule provided in 
Appendices B-1 and B-2. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
170/P GO27834-A2 
Appendix A-2 
Study Flowchart:  Crossover Treatment (Patients Randomized to Arms A or B Only) 
 
 
Treatment Period 
Cycle 
Cycle 1b 
Cycles 2b−4b 
Cycles 5b−17b
Day(s) a 
Assessment  
1 b 
2 
8 
15 
1 b 
2 
8 
15 
1 b 
2 
15 
Crossover 
Treatment 
Completion/Early 
Termination Visit c
Safety  and 
Survival 
Follow-Up d 
Weight 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
Vital signs 
x e 
(x) e 
x 
x 
x e 
(x) e 
x 
x 
x e 
(x) e
x 
x 
 
ECOG Performance Status 
x 
 
x 
x 
x 
 
x 
x 
x 
 
 
x 
 
B symptoms f 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
 
Targeted physical examination g 
x 
(x) 
x 
 
x 
(x) 
 
 
x 
(x) 
 
x 
 
Concomitant medications 
x 
(x) 
x 
x 
x 
(x) 
x 
x 
x 
(x) 
x 
x 
 
Adverse events h 
x  
(x) 
x 
x 
x 
(x) 
x 
x 
x  
(x) 
x 
x 
x  
Tumor assessments i 
Every 3 months 
x 
 
Rituximab infusion 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
DCDT2980S or DCDS4501A infusion j 
x 
(x) 
 
 
x 
(x) 
 
 
x 
(x) 
 
 
 
Local Laboratory Assessments 
Hematology k 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
Serum chemistry l 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
Total IgA, IgG, IgM 
 
 
 
 
 
 
 
 
Cycle 8b Day 1
x 
 
Pregnancy test m 
Day 1 of Cycles 3b, 6b, 9b, 12b, and 15b 
x 
 
Bone marrow biopsy n 
Perform to confirm CR if positive for disease at screening or if clinically indicated
 
 
Central Laboratory Assessments 
Leukocyte immunophenotyping (FACS) o
Day 1 of Cycle 4, 8, and 12 
x 
 
Tumor biopsy/sample 
 
 
 
 
 
 
 
 
 
 
 
x p 
 


Appendix A-2 (cont.) 
Study Flowchart: Crossover Treatment (Patients Randomized to Arms A or B Only) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
171/P GO27834-A2 
AE = adverse event; AL = alanine aminotransferase; AST = aspartate aminotransferase; CR = complete response; LDH = lactate dehydrogenase; 
SAE = serious adverse event; (x) = Assessment or action to be performed only if study treatment is administered on Day 2 of the Cycle—refer to footnote 
‘j’ for details. 
a Study drug infusions should occur on the scheduled 21-day cycle up to a maximum of 1 year (approximately 17 cycles) and may be given up to 
± 2 days from the date scheduled (i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  All other study visits 
during Cycles 1 and 2 must occur within ± 1 day from the scheduled date unless otherwise noted.  Study visits starting in Cycle 3 should occur within 
± 2 days from the scheduled date unless otherwise noted.  Treatment cycles may be extended to 28 days if needed to provide sufficient time for 
recovery from a transient and reversible toxicity (e.g., cytopenia) without reducing the dose of DCDT2980S or DSDA4501A.  Patients receiving study 
treatment on 28-day cycles should also follow the assessment schedule above up to a maximum of 1 year of total study treatment (approximately 
13 cycles). 
b Local laboratory assessments and targeted physical examination may be performed within 72 hours preceding rituximab administration unless 
otherwise specified; pre-infusion laboratory samples should be drawn 0−4 hours prior to infusion. 
c Perform within 30 days after the last infusion of DCDT2980S, DCDS4501A or rituximab.  The visit at which response assessment shows progressive 
disease may be used as the early termination visit. 
d Patients will be followed for safety for 30 days after the last infusions of DCDT2980S, DCDS4501A, or rituximab.  Such follow-up will require an 
assessment (per verbal report, at minimum) of any AEs and/or SAEs through 30 days after the last dose of study drug or until the patient receives 
another anti-cancer therapy including crossover treatment, whichever occurs first.  Patients who discontinue study treatment for reasons other than 
progressive disease will continue to be followed for response for up to 1 year after the last infusions of DCDT2980S or DCDS4501A and rituximab, or 
until disease progression or initiation of another anti-lymphoma/leukemia therapy, whichever occurs first.  Refer to Appendix A-4 for schedule of 
assessments during the post-treatment period.  Patients will also be followed for survival following study treatment discontinuation approximately 
every three months until death, loss to follow-up, withdrawal of consent, or study termination. 
e Vital signs on days of study treatment administration should be recorded according to Section 4.5.1.2 of the protocol. 
f Defined as unexplained weight loss > 10% over previous 6 months, fever (> 38°C/100.4°F), and/or drenching night sweats. 
g Targeted physical examinations should be limited to systems of clinical relevance and those systems associated with clinical signs/symptoms.  
A targeted symptom directed examination is required prior to DCDT2980S or DCDS4501A dosing on Day 2 of each cycle if given on separate days 
from rituximab only if clinically indicated, e.g. to follow -up on signs or symptoms observed from the examinations performed on Day 1. 
h Patients will be followed for safety for 30 days after the last infusions of DCDT2980S, DCDS4501A, or rituximab.  Such follow-up will require an 
assessment (per verbal report, at minimum) of any AEs and/or SAEs through 30 days after the last dose of study drug or until the patient receives 
another anti-cancer therapy including crossover treatment, whichever occurs first.  Patients who discontinue study treatment for reasons other than 
progressive disease will continue to be followed for response for up to 1 year after the last infusions of DCDT2980S or DCDS4501A and rituximab, or 
until disease progression or initiation of another anti-lymphoma/leukemia therapy, whichever occurs first.  Refer to Appendix A-4 for schedule of 
assessments during the post-treatment period.   
i Tumor assessments should be performed at screening and every 3 months while receiving study treatment.  Tumor assessments should also be 


Appendix A-2 (cont.) 
Study Flowchart: Crossover Treatment (Patients Randomized to Arms A or B Only) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
172/P GO27834-A2 
 
performed 28−56 days after the last study drug infusion as part of the crossover treatment completion/early termination visit.  Response should be 
assessed based on physical examination and imaged-based evaluation, using standard NHL criteria (Appendix C-1). 
j Administer DCDT2980S or DCDS4501A over 90 minutes for Cycle 1 and over 30 minutes in subsequent cycles if there are no infusion-related 
adverse events.  For Cycle 1b and Cycle 2b, DCDT2980S or DCDS4501A should be administered on the day after rituximab is administered, 
e.g., Day 2 if rituximab is given on Day 1, or Day 3 if rituximab is given as a split dose on Days 1 and 2.  In the absence of any infusion-related 
adverse events, rituximab followed by DCDT2980S or DCDS4501A may be administered on the same day in subsequent cycles starting with 
Cycle 3b.  Study drug infusions should occur on the scheduled 21-day (or 28-day) cycle, but may be given up to ± 2 days from the date scheduled 
(i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  Doses may also be delayed up to 2 weeks for recovery 
from reversible toxicity. 
k Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, absolute neutrophil count, and 
percent or absolute differential counts [e.g., segmented neutrophils bands, lymphocytes, eosinophils, monocytes, basophils, and other cells]). 
l Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), creatinine, calcium, magnesium, phosphorus, 
total and direct bilirubin, total protein, albumin, ALT), AST, alkaline phosphatase, LDH, and uric acid. 
m A serum pregnancy test should be performed for women of childbearing potential within 14 days prior to receiving first study treatment.  In addition, a 
serum or urine pregnancy test must be performed within 10 days prior to Day 1 of Cycles 3, 6, 9, 12, and 15 and at the crossover treatment 
completion/early termination visit.  If any urine test result is positive, patient dosing will be postponed until the patient’s status is confirmed by a serum 
pregnancy test. 
n Bone marrow biopsy for morphology (aspirate for morphology and/or flow studies are optional) should be repeated only to confirm a CR where 
presence of tumor was documented at the screening bone marrow examination. 
o A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.   
p Optional tumor biopsy of a safely accessible site of disease, defined as requiring only local anesthesia and in general excluding brain, lungs or any 
internal organs that may subject patients to significant risk.  Tumor samples will be used for research purposes. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
173/P GO27834-A2 
Appendix A-3 
Study Flowchart for Obinutuzumab-Containing Cohorts (E, G-H):  Initial Study Treatment 
Treatment Period 
Cycle 
Screening 
Cycle 1 
Cycles 2−4 
Cycle 4
Cycles 5−8 
Day(s)a 
Assessment 
−28 to −1 
1
b 
2 
8 
15
1b 
2 
15c 
1b 
2 
Treatment 
Completion/ Early 
Termination Visitc 
End of Treatment Response 
Assessment (after Cycle 6 
Day 1 or last study treatment 
+ 6−8 weeks) 
Safety and 
Survival 
Follow-Up d 
Written informed consent 
e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Height (screening only) 
and weight 
x 
x 
 
 
 
x 
 
 
x 
 
 
 
 
Vital signs  
x 
x
f 
xf 
xf 
xf 
x f 
(x) f 
 
x f 
(x) f 
x 
 
 
ECOG Performance 
Status 
x 
x 
 
x 
x 
x 
 
 
x 
 
x 
 
 
B symptoms g 
x 
x 
 
 
 
x 
 
 
x 
 
x 
 
 
Complete physical 
examination h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical 
examination i 
 
x 
x 
x 
 
x 
(x) 
 
x 
(x) 
x 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
(x) 
 
x 
(x) 
x 
 
 
Adverse events j 
x 
x 
x 
x 
x 
x  
(x) 
 
x  
(x) 
x 
 
x 
MDASI PRO k 
 
Day 1–8 of Cycles 1–8 
 
 
 
12-lead 
electrocardiograml 
x  
Refer to Footnote “l” 
x  
 
 


Appendix A-3 (cont.) 
Study Flowchart for Obinutuzumab-Containing Cohorts (E, G-H):  Initial Study Treatment 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
174/P GO27834-A2 
Tumor assessmentsm 
x 
Every 3 months 
x 
x 
 
PET/CT scan (required for 
DLBCL and FL) m 
x 
 
 
 
 
 
 
xm 
 
 
 
x m 
 
Obinutuzumab infusion 
 
x 
 
x 
x 
x 
 
 
x 
 
 
 
 
DCDS4501A infusion n 
 
 
x 
 
 
x 
(x) 
 
x 
(x) 
 
 
 
Local Laboratory Assessments 
HBV and HCV screening o 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology p 
x 
x 
 
x 
x 
x 
 
 
x 
 
x 
 
 
Serum chemistry q 
x 
x 
 
x 
x 
x 
 
 
x 
 
x 
 
 
Hemoglobin A1c 
x 
 
 
 
 
 
 
 
Cycle 5 
Day 1 
 
 
 
Total IgA, IgG, IgM 
x 
 
 
 
 
 
 
 
Cycle 8 
Day 1 
x 
 
 
Coagulation (aPTT, PT, 
and INR) 
x 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test r 
x 
Within 10 days of Day 1 of Cycles 3, 6 
x 
 
 
Bone marrow biopsy s 
x 
Perform to confirm CR if positive for disease at screening or 
if clinically indicated 
 
 
 
 


Appendix A-3 (cont.) 
Study Flowchart for Obinutuzumab-Containing Cohorts (E, G-H):  Initial Study Treatment 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
175/P GO27834-A2 
Central Laboratory Assessments 
Leukocyte 
immunophenotyping 
(FACS) t 
 
Day 1 of Cycle1, Cycle 4, and Cycle 8  
x 
 
 
Tumor tissue sample u 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
Exploratory plasma 
sample v 
x 
 
 
 
 
 
 
 
 
 
 
 
 
DCDS4501A and 
obinutuzumab 
pharmacokinetic  
samplingw 
Refer to Appendix B-3 
Serum sample for 
anti-DCDS4501A 
antibodyx 
 Refer to Appendix B-3 


Appendix A-3 (cont.) 
Study Flowchart for Obinutuzumab-Containing Cohorts (E, G-H):  Initial Study Treatment 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
176/P GO27834-A2 
AE = adverse event; ALP = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; CR = completed response; 
CT = computed tomography; DLBCL = diffuse large B-cell lymphoma; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
FACS = fluorescent-activated cell sorting; FLL = follicular lymphoma; GGT = γ-glutamyl transpeptidase; HBV = hepatitis B virus; HCV = hepatitis C virus; Ig = immunoglobulin; 
INR = international normalized ratio; LDH = lactase dehydrogenase; MDASI = MD Anderson Symptom Inventory; MRI = magnetic resonance imaging; NHL = non-Hodgkin’s 
lymphoma; PET = positron emission tomography; PT = prothrombin time; QLQ = Quality of Life Questionnaire; SAE = serious adverse event; (x)  = Assessment or action to be 
performed only if study treatment is administered on Day 2 of the Cycle—refer to footnote ‘n’ for details.  
a Study drug infusions should occur on the scheduled 21-day cycle up to a maximum of 6 months (8 cycles on an every-21-day schedule) and may be given up to 
± 2 days from the date scheduled (i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  All other study visits during Cycle 1 
must occur within ± 1 day from the scheduled date unless otherwise noted.  Study visits starting in Cycle 2 should occur within ± 2 days from the scheduled date unless 
otherwise noted.  Treatment cycles may be extended to 28 days if needed to provide sufficient time for recovery from a transient and reversible toxicity (e.g., cytopenia) 
without reducing the dose of DSDA4501A.  Patients receiving study treatment on 28-day cycles should also follow the assessment schedule above up to a maximum of 
6 months of total study treatment (6 cycles on an every-28-day schedule). 
b Local laboratory assessments and targeted physical examination may be performed within 72 hours preceding obinutuzumab administration unless otherwise specified; 
pre-infusion laboratory samples should be drawn 0−4 hours prior to infusion. 
c Cycle 4 Day 15 assessment should be performed between Cycle 4 Day 15 and Cycle 5 Day 1.  The Treatment Completion/Early Termination Visit should be performed within 30 days 
after the last infusion of DCDS4501A or obinutuzumab.  The visit at which response assessment shows progressive disease may be used as the early termination visit. 
d Patients will be followed for safety for 30 days after the last infusions of DCDS4501A or obinutuzumab.  Such follow-up will require an assessment (per verbal report 
from the patient, at minimum) of any AEs and/or SAEs through 30 days after the last dose of study drug or until the patient receives another anti-cancer therapy 
including crossover treatment, whichever occurs first.  Patients who discontinue study treatment for reasons other than progressive disease will continue to be followed 
for response for up to 1 year after the last infusions of DCDS4501A or obinutuzumab, or until disease progression or initiation of another anti-lymphoma/leukemia 
therapy, whichever occurs first.  Refer to Appendix A-4 for schedule of assessments during the post-treatment period.  Patients will also be followed for survival 
following study treatment discontinuation approximately every three months until death, loss to follow-up, withdrawal of consent, or study termination. 
e Informed consent form(s) must be signed by the patient before any study-specific procedures are performed. 
f Vital signs on days of study treatment administration should be recorded according to Section 4.5.1.2 of the protocol. 
g Defined as unexplained weight loss > 10% over previous 6 months, fever (> 38°C/100.4°F), and/or drenching night sweats. 
h Complete physical examination includes all systems described in Section 4.5.1.3.   
i Targeted physical examinations should be limited to systems of clinical relevance (see Section 4.5.1.3) and those systems associated with clinical signs/symptoms.  A 
targeted symptom directed examination is required prior to DCDS4501A dosing on Day 2 of each cycle if given on separate days from obinutuzumab only if clinically 
indicated (e.g., to follow up on signs or symptoms observed from the examinations performed on Day 1). 
j After informed consent is obtained but prior to initiation of study treatment, only SAEs caused by a protocol-mandated intervention should be reported.  After initiation of 
study drug, all AEs and SAEs, regardless of attribution, must be reported until 30 days following the last administration of study drug or until the patient receives another 
anti-cancer therapy, whichever occurs first.  After this period, investigators should report only SAEs considered related to prior study treatment. 
k Treatment and disease associated symptoms using the MDASI questionnaire will be collected on hand-held computer devices (see Section 4.5.1.10).  MDASI 
questionnaire will only be implemented in expansion cohorts (Cohorts G and H).   


Appendix A-3 (cont.) 
Study Flowchart for Obinutuzumab-Containing Cohorts (E, G-H):  Initial Study Treatment 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
177/P GO27834-A2 
l Twelve-lead digital electrocardiogram (ECG) measurements must be obtained in triplicate (with immediately consecutive ECGs obtained until three evaluable ECGs are 
recorded) at the timepoints specified in Section 4.5.1.5.  Non-triplicate ECGs should also be performed when clinically indicated in any patient with evidence of, or 
suspicion for, clinically significant signs or symptoms of cardiac dysfunction.  The evaluating physician should determine the clinical significance of any abnormal ECGs. 
m Response should be assessed on the basis of physical examination and imaged-based evaluation, using standard NHL criteria (Appendix C-2).  For DLBCL and FL 
patients, a combined PET/CT scan is required during screening, between Cycle 4 Day 15 and Cycle 5 Day 1, End of Treatment (EOT) assessment, and as clinically 
indicated.   The EOT assessment should be performed 6−8 weeks after Cycle 8 Day 1 or last study treatment. During the follow-up period, refer to Appendix A-5 for 
imaging assessment during post-treatment follow-up.  Refer to Section 4.5.1.8 for complete details for radiographic assessments.   
n Administer DCDS4501A over 90 minutes for Cycle 1 and over 30 minutes in subsequent cycles if there are no infusion-related adverse events.  For Cycle 1, 
DCDS4501A should be administered on the day after obinutuzumab is administered (e.g., Day 2 if obinutuzumab is given on Day 1, or Day 3 if obinutuzumab is given 
as a split dose on Days 1 and 2).  In the absence of any infusion-related adverse events, obinutuzumab followed by DCDS4501A may be administered on the same day 
in each cycle starting with Cycle 2.  Study drug infusions should occur on the scheduled 21-day (or 28-day) cycle but may be given up to ± 2 days from the date 
scheduled (i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  Doses may also be delayed up to 2 weeks for recovery from 
reversible toxicity. 
o HBsAg, HBcAb, and Hep C Ab serology required.  If HBcAb or HCV antibody is positive, HBV/HCV DNA by PCR is required. 
p Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, absolute neutrophil count, and percent or absolute 
differential counts [e.g., segmented neutrophils, bands, lymphocytes, eosinophils, monocytes, basophils, and other cells]). 
q Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), creatinine, calcium, magnesium, phosphorus, total and direct 
bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, LDH, and uric acid.  Serum GGT levels will be required at screening only. 
r    A serum pregnancy test should be performed for women of childbearing potential within 14 days prior to receiving first study treatment.  In addition, a urine pregnancy 
test must also be performed within 10 days prior to Day 1 of Cycles 3, and 6 and at the treatment completion/early termination visit.  If any urine test result is positive, 
patient dosing will be postponed until the patient’s status is confirmed by a serum pregnancy test. 
s Bone marrow biopsy for morphology (aspirates for morphology and/or flow studies are optional) is required at screening and should reflect disease status in the bone 
marrow following documented relapse on the last prior therapy or within 3 months of Day 1, whichever occurs later.  If the bone marrow biopsy at screening 
demonstrates presence of tumor cells, a subsequent bone marrow examination is required only to confirm a CR or if clinically indicated.  If the bone marrow biopsy at 
screening does not demonstrate presence of tumor cells, then subsequent bone marrow examination is required only if clinically indicated.  Unsuccessful attempts at 
marrow aspiration will not be considered a protocol violation. 
t A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.   
u Availability of archival or freshly biopsied tumor tissue samples should be confirmed at screening.  Tumor tissue samples should consist of representative tumor 
specimens in paraffin blocks (preferred) or at least 15 unstained slides, with an associated pathology report, obtained at any time prior to entry to study.   
v All patients who have successfully passed screening and are fully eligible for the study will have a 10-mL plasma sample taken for exploratory research prior to 
receiving study treatment.   
w Pharmacokinetic serum and plasma samples and pharmacodynamics blood samples should be drawn according to the schedule provided in Appendix B-3. 
x Whole blood samples for assessment of anti-DCDS4501A or anti-obinutuzumab antibodies in serum will be drawn according to the schedule provided in Appendix B-3. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
178/P GO27834-A2 
Appendix A-4 
Study Flowchart: Post-Treatment Follow-Up for Rituximab-Containing Regimens 
(Arms A-B, Cohorts C-D) 
Assessments/Procedures 
Post-treatment Follow-up 
Months after treatment completion visit
2 Months 
4 Months 
6 Months 
9 Months 
12 Months 
Targeted physical examination a 
x 
x 
x 
x 
x 
Vital signs (blood pressure, pulse rate, and 
body temperature) 
x 
x 
x 
x 
x 
ECOG Performance Status 
x 
x 
x 
x 
x 
B symptoms b 
x 
x 
x 
x 
x 
Tumor assessments c 
x 
x 
x 
x 
x 
Total IgA, IgG, IgM 
x 
x 
x 
x 
x 
Hematology d 
x 
x 
x 
x 
x 
Serum chemistry e 
x 
x 
x 
x 
x 
Bone marrow f 
Perform to confirm CR if positive for disease at screening or if 
clinically indicated 
Central Lab Assessments 
 
 
 
 
 
Leukocyte immunophenotyping (FACS) g 
x 
x 
x 
x 
x 
Pharmacokinetic sampling h 
x 
x 
x 
 
 
Serum sample for anti-DCDT2980S / 
anti-DCDS4501A ATA assay h 
x 
x 
x 
 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ATA = anti-therapeutic antibody; 
CR = completed response; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; 
FACS = fluorescent-activated cell sorting; Ig = immunoglobulin; MRI = magnetic resonance imaging; 
NHL = non-Hodgkin’s lymphoma; PET = positron emission tomography. 
NOTE: Post-treatment assessments apply to patients who discontinue from study treatment (initial or crossover 


Appendix A-4 (cont.) 
Study Flowchart: Post-Treatment Follow-Up for Rituximab-Containing Regimens 
(Arms A-B, Cohorts C-D) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
179/P GO27834-A2 
treatment) for reasons other than disease progression.  The schedule corresponds to visits timed from 
treatment completion/early termination visit or crossover treatment completion/early termination visit until the 
time of disease progression, start of new anti-cancer therapy, or withdrawal from study participation.  
Two-month and 4-month follow-up visits should occur within ± 7 days from the scheduled date, while 
subsequent visits should occur within ± 14 days from the scheduled date. 
a Targeted physical examinations should be limited to systems of clinical relevance (see Section 4.5.1.3) and 
those systems associated with clinical signs/symptoms. 
b Defined as unexplained weight loss > 10% over previous 6 months, fever (> 38°C/100.4°F), and/or drenching 
night sweats. 
c Response should be assessed based on physical examination and imaged-based evaluation, using standard 
NHL criteria (Appendix C).   
d Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, 
platelet count, absolute neutrophil count, and percent or absolute differential counts [e.g., segmented 
neutrophils bands, lymphocytes, eosinophils, monocytes, basophils, and other cells]). 
e Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), 
creatinine, calcium, magnesium, phosphorus, total and direct bilirubin, total protein, albumin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase 
(LDH), and uric acid.  
f Bone marrow biopsy for morphology (aspirate for morphology and/or flow studies are optional) should be 
repeated only to confirm a CR where presence of tumor was documented at the screening bone marrow 
examination. 
g A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.   
h Refer to Appendices B-1 or B-2. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
180/P GO27834-A2 
Appendix A-5 
Study Flowchart: Post-Treatment Follow-Up for Obinutuzumab-Containing Regimens 
(Cohorts E, G-H) 
Assessments/Procedures 
Post-Treatment Follow-Up 
Months after treatment completion visit 
3 Months 
6 Months 
9 Months 12 Months
18 Months 
24 Months 
Targeted physical examination a 
x 
x 
x 
x 
x 
x 
Vital signs (blood pressure, pulse rate, and 
body temperature) 
x 
x 
x 
x 
x 
x 
ECOG Performance Status 
x 
x 
x 
x 
x 
x 
B symptoms b 
x 
x 
x 
x 
x 
x 
Tumor assessments c 
x 
x 
x 
x 
x 
x 
Total IgA, IgG, IgM 
x 
x 
x 
x 
x 
x 
Hematology d 
x 
x 
x 
x 
x 
x 
Serum chemistry e 
x 
x 
x 
x 
x 
x 
Bone marrow f 
Perform to confirm CR if positive for disease at screening or if clinically 
indicated 
Central Lab Assessments 
 
 
 
 
 
Leukocyte immunophenotyping (FACS) g 
x 
x 
x 
x 
x 
x 
Pharmacokinetic sampling h 
x 
x 
 
 
 
 
Serum sample for 
anti-DCDT2980S/anti-DCDS4501A, 
anti-obinutuzumab ATA assay h 
x 
x 
 
x h 
 
x h 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ATA = anti-therapeutic antibody; CR = completed 
response; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; FACS = fluorescent-activated cell 
sorting; Ig = immunoglobulin; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; NHL = non-Hodgkin’s 
lymphoma; PET = positron emission tomography. 


Appendix A-5 (cont.) 
Study Flowchart: Post-Treatment Follow-Up for Obinutuzumab-Containing Regimens 
(Cohorts E, G-H) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
181/P GO27834-A2 
NOTE: Post-treatment assessments apply to patients who discontinue from study treatment (initial or crossover treatment) 
for reasons other than disease progression.  The schedule corresponds to visits timed from treatment completion/early 
termination visit or crossover treatment completion/early termination visit until the time of disease progression, start of new 
anti-cancer therapy, or withdrawal from study participation.  Two-month and four-month follow-up visits should occur within 
± 7 days from the scheduled date, while subsequent visits should occur within ± 14 days from the scheduled date. 
a Targeted physical examinations should be limited to systems of clinical relevance (see Section 4.5.1.3) and those systems 
associated with clinical signs/symptoms. 
b Defined as unexplained weight loss > 10% over previous 6 months, fever (> 38°C/100.4°F), and/or drenching night sweats.
c Response should be assessed on the basis of physical examination and imaged-based evaluation, using standard NHL 
criteria (Appendix C-2).  CT or combined PET/CT scan should be obtained during the post-treatment follow-up.  
d Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, 
absolute neutrophil count, and percent or absolute differential counts [e.g., segmented neutrophils bands, lymphocytes, 
eosinophils, monocytes, basophils, and other cells]). 
e Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), creatinine, calcium, 
magnesium, phosphorus, total and direct bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, LDH, and uric 
acid. 
f Bone marrow biopsy for morphology (aspirate for morphology and/or flow studies are optional) should be repeated only to 
confirm a CR where presence of tumor was documented at the screening bone marrow examination. 
g A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.   
h Refer to Appendix B-3. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
182/P GO27834-A2 
Appendix B-1 
Serum and Plasma Pharmacokinetic Schedule for 
DCDT2980S/DCDS4501A and Rituximab, and ATA Schedule for 
DCDT2980S/DCDS4501A (For Patients Receiving Rituximab on 
Day 1 and DCDT2980S/DCDS4501A on Day 2 of Every Cycle) 
(Arms A-B, Cohorts C-D) 
Study Visit 
Sample Timepoint(s) a 
Samples b 
Cycle 1, Day 1 
Pre-rituximab infusion 
• 
Rituximab PK 
 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Pre-DCDT2980S/DCDS4501A 
infusion 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
DCDT2980S/DCDS4501A PK b 
Cycle 1, Day 2 
30 minutes (± 15 minutes)  
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK 
Cycle 1, Day 8 (± 1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
Cycle 1, Day 15 (± 1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK  
Cycles 2−3, Day 1 
Pre-rituximab dose 
• 
Rituximab PK 
 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Pre-DCDT2980S/DCDS4501A 
infusion 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody c 
• 
DCDT2980S/DCDS4501A PK 
Cycles 2−3, Day 2 
30 minutes (± 15 minutes) 
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK 
Cycle 3, Day 8 (± 1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK  
Cycle 3, Day 15 (±1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
Pre-rituximab infusion 
• 
Rituximab PK 
Cycles 4, and 
every 4th cycle 
thereafter), Day 1 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Pre-DCDT2980S/DCDS4501A 
infusion 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody c 
• 
DCDT2980S/DCDS4501A PK 
Cycles 4, and 
every 4th cycle 
thereafter), Day 2 
30 minutes (± 15 minutes) 
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK 


Appendix B-1 (cont.) 
Serum and Plasma Pharmacokinetic Schedule for 
DCDT2980S/DCDS4501A and Rituximab, and ATA Schedule for 
DCDT2980S/DCDS4501A (For Patients Receiving Rituximab on 
Day 1 and DCDT2980S/DCDS4501A on Day 2 of Every Cycle) 
(Arms A-B, Cohorts C-D) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
183/P GO27834-A2 
Study Visit 
Sample Timepoint(s) a 
Samples b 
Treatment 
Completion/ 
Early Termination 
Visit 
Approximately 15−30 days 
after last infusion  
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK e 
Post-treatment 
Follow-Up Visits d 
2, 4, and 6 months after 
treatment completion visit 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
ATA = Anti-therapeutic antibody; MMAE = monomethyl auristatin E; PK = pharmacokinetic. 
Note:  “Pre-infusion” means prior to the start of infusion; “Post-infusion” means after the infusion is 
completed. 
a A 3-mL whole-blood sample will be taken for each of the following at each specified timepoint: 
anti-DCDT2980S or anti-DCDS4501A antibody; rituximab PK; and/or DCDT2980S/DCDS4501A 
PK.  If rituximab dosing is split over two days, then PK will be obtained prior to the rituximab 
dose on the first day and 30 minutes (± 15 minutes) post-rituximab infusion on the second day. 
b PK sampling will not be obtained from patients who cross-over to another treatment arm. 
c Cycles 2 and 4 only for anti-DCDT2980S or anti-DCDS4501A antibody.  
d Post-treatment follow-up PK and ATA assessments only apply to patients who did not receive 
crossover treatment. 
e DCDT2980S/DCDS4501A PK including serum PK samples for total DCDT2980S and 
DCDS4501A antibody and plasma PK samples for antibody-conjugated MMAE and free MMAE. 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
184/P GO27834-A2 
Appendix B-2 
Serum and Plasma Pharmacokinetic Schedule for Rituximab and 
DCDT2980S/DCDS4501A, and ATA Schedule for 
DCDT2980S/DCDS4501A for Patients Receiving Rituximab and 
DCDT29808S/DCDS4501A on Day 1 of Every Cycle Beginning 
Cycle 3 (Arms A-B, Cohorts C-D) 
Study Visit 
Sample Timepoint(s) a 
Samples b 
For Cycle 1 and Cycle 2 PK assessments, refer to Appendix B-1 
Pre-rituximab infusion 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK e 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Cycle 3, Day 1 
 
30 minutes (± 15 minutes) 
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK  
Cycle 3, Day 8 (± 1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK  
Cycle 3, Day 15 (±1 day) 
• 
Rituximab  
• 
DCDT2980S/DCDS4501A PK 
Pre-rituximab infusion 
• 
Rituximab PK 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody c 
• 
DCDT2980S/DCDS4501A PK 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Cycles 4, and 
every 4th cycle 
thereafter), Day 1 
30 minutes (± 15 minutes) 
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK 
Treatment 
Completion/ 
Early Termination 
Visit 
Approximately 15−30 days 
after last infusion  
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
Post-treatment 
Follow-Up Visits d 
2, 4, and 6 months after 
treatment completion visit 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 


Appendix B-2 (cont.) 
Serum and Plasma Pharmacokinetic Schedule for Rituximab and 
DCDT2980S/DCDS4501A, and ATA Schedule for 
DCDT2980S/DCDS4501A for Patients Receiving Rituximab and 
DCDT29808S/DCDS4501A on Day 1 of Every Cycle Beginning 
Cycle 3 (Arms A-B, Cohorts C-D) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
185/P GO27834-A2 
ATA = Anti-therapeutic antibody; MMAE = monomethyl auristatin E; PK = pharmacokinetic. 
Note:  “Pre-infusion” means prior to the start of infusion; “Post-infusion” means after the infusion is 
completed. 
a A 3-mL whole-blood sample will be taken for each of the following at each specified timepoint: 
anti-DCDT2980S or anti-DCDS4501A antibody, rituximab PK, and/or DCDT2980S/DCDS4501A 
PK.  If rituximab dosing is split over two days, then PK will be obtained prior to the rituximab 
dose on the first day and 30 minutes (± 15 minutes) post-rituximab infusion on the second day. 
b PK sampling will not be obtained from patients who cross-over to another treatment arm. 
c Cycles 4 only for anti-DCDT2980S or anti-DCDS4501A antibody.  
d Post-treatment follow-up PK and ATA assessments only apply to patients who did not receive 
crossover treatment. 
e DCDT2980S/DCDS4501A PK including serum PK samples for total DCDT2980S and 
DCDS4501A antibody and plasma PK samples for antibody-conjugated MMAE and free MMAE. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
186/P GO27834-A2 
Appendix B-3 
Serum and Plasma Pharmacokinetic, Blood Pharmacodynamic, and 
ATA Schedule for Obinutuzumab and DCDS4501A (Cohorts E, G-H) 
Study Visit 
Sample Timepoint(s) a 
Samples a 
Cycle 1, Day 1 
Pre-obinutuzumab infusion 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
PD Blood c 
 
End of obinutuzumab infusion 
• 
Obinutuzumab PK (serum) 
• 
PD Blood c 
Pre-DCDS4501A infusion 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
Cycle 1, Day 2 
End of DCDS4501A infusion 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
Cycle 1, Day 8 
6 days (± 1 day) after Day 2 
infusion 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
Cycle 1, Day 15 
13 days (± 1 day) after Day 2 
infusion 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
Cycle 2, Day 1 
Pre-obinutuzumab infusion 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
PD Blood c 
 
End of obinutuzumab infusion 
• 
PD Bloodc 
 
Pre-DCDS4501A infusion 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
 
End of DCDS4501A infusion 
• 
PD Blood 
Pre-obinutuzumab infusion 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
Cycle 4, Day 1 
End of obinutuzumab infusion 
• 
Obinutuzumab PK (serum) 
 
Pre-DCDS4501A infusion 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 
 
End of DCDS4501A infusion 
• 
DCDS4501A PK (serum and plasma)b 
Cycle 4  Day 15 
Aligned with PET imaging 
• 
PD Blood c 
Treatment Completion/ 
Early Termination Visit 
Approximately 15−30 days 
after last infusion  
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 
End of Treatment 
Assessment Visit 
6−8 weeks after last study 
dose 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 


Appendix B-3 (cont.) 
Serum and Plasma Pharmacokinetic and ATA Schedule for Obinutuzumab and 
DCDS4501A (Cohorts E, G-H) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
187/P GO27834-A2 
Post-treatment 
Follow-Up Visits  
3 and 6 months after treatment 
completion visit 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
DCDS4501A ATA (serum) 
• 
DCDS4501A PK (serum and plasma)b 
• 
PD Blood c 
 
9 months after treatment 
completion visit 
• 
PD Blood c 
 
12 and 18 months after treatment 
completion visit 
• 
Obinutuzumab ATA (serum) 
• 
Obinutuzumab PK (serum) 
• 
PD Blood c 
 
24 months after treatment 
completion visit 
• 
PD Blood c 
ATA = Anti-therapeutic antibody; MMAE = monomethyl auristatin E; PK = pharmacokinetic. 
Note:  “Pre-infusion” means prior to the start of infusion; “End-of-infusion” samples should be drawn 30 
minutes (± 15 minutes) unless otherwise specified. 
a Up to 10-mL whole-blood samples will be taken for obinutuzumab PK, obinutuzumab ATA, obinutuzumab 
concentration, DCDS4501A PK (DCDS4501A total antibody, unconjugated MMAE and conjugate 
[evaluated as antibody-conjugated MMAE]), DCDS4501A ATA, DCDS4501A concentration, and for 
exploratory studies at each specified point with separate tubes for plasma or serum samples.  If 
obinutuzumab dosing is split over two days, then PK will be obtained prior to the obinutuzumab dose on 
the first day and 30 minutes (± 15 minutes) post-obinutuzumab infusion on the second day. 
b DCDS4501A PK including serum PK samples for total DCDS4501A antibody and plasma PK samples for 
antibody-conjugated MMAE and free MMAE. 
c Up to 10-mL whole-blood samples will be taken for exploratory studies at each specified timepoint with separate 
tubes. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
188/P GO27834-A2 
Appendix C-1  
Modified Response and Progression Criteria for NHL 
Adapted from:  Cheson BD, Pfistner B, Juweid ME, et al. Revised Response Criteria for 
Malignant Lymphoma. J Clin Oncol 2007;25:579–86. 
Selection of Indicator (Target) Lesions 
Up to six of the largest dominant nodes or tumor masses selected according to all of the 
following: 
• 
Clearly measurable in at least two perpendicular dimensions 
Abnormal lymph nodes are those that are either 
> 15 mm in the greatest transverse diameter (GTD) regardless of the short axis 
diameter, or 
> 10 mm in short axis diameter regardless of long axis 
• 
If possible, they should be from disparate regions of the body. 
• 
Should include mediastinal and retroperitoneal areas of disease whenever these sites 
are involved 
• 
Extranodal lesions within the liver or spleen must be at least 1.0 cm in 
two perpendicular dimensions. 
 
PET Scans--Definition of a Positive PET scan 
Visual assessment currently is considered adequate for determining whether a PET scan is 
positive, and use of the standardized uptake value is not necessary.  In brief, a positive scan 
is defined as focal or diffuse FDG uptake above background in a location incompatible with 
normal anatomy or physiology, without a specific standardized uptake value cutoff.  Other 
causes of false-positive scans should be ruled out.  Exceptions include mild and diffusely 
increased FDG uptake at the site of moderate or large-sized masses with an intensity that is 
lower than or equal to the mediastinal blood pool, hepatic or splenic nodules 1.5 cm with 
FDG uptake lower than the surrounding liver/spleen uptake, and diffusely increased bone 
marrow uptake within weeks after treatment. 
Complete Remission (CR) 
1. Complete disappearance of all detectable clinical evidence of disease 
and disease-related symptoms if present prior to therapy.  
Typically FDG-avid lymphoma: in patients with no pre-treatment PET scan or when 
the PET scan was positive before therapy, a post-treatment residual mass of any 
size is permitted as long as it is PET negative. 
Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, the designation 


Appendix C-1 (cont.) 
Modified Response and Progression Criteria for NHL 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
189/P GO27834-A2 
of CR requires all nodal indicator lesions to regress to the size of normal lymph 
nodes.  Lymph nodes that were > 15 mm in GTD regardless of the short axis 
diameter at the screening tumor assessment must regress to ≤ 15 mm in GTD 
regardless of the short axis diameter.  Lymph nodes that were 11 to 15 mm in GTD 
and > 10 mm in the short axis diameter at the screening tumor assessment must 
regress to ≤ 10 mm in the short axis diameter. 
2. The spleen and/or liver, if considered enlarged prior to therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies, and nodules related to lymphoma should 
disappear.  However, determination of splenic involvement is not always reliable 
because a spleen considered normal in size may still contain lymphoma, whereas an 
enlarged spleen may reflect variations in anatomy, blood volume, the use of 
hematopoietic growth factors, or causes other than lymphoma. 
3. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have 
cleared on repeat bone marrow biopsy.  The biopsy sample on which this determination 
is made must be adequate (> 20 mm unilateral core).  If the sample is indeterminate by 
morphology, it should be negative by immunohistochemistry.  A sample that is negative 
by immunohistochemistry but demonstrating a small population of clonal lymphocytes by 
flow cytometry will be considered a CR until data become available demonstrating a 
clear difference in patient outcome.  
Partial Remission (PR) 
1. ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest 
dominant nodes or nodal masses.  These nodes or masses should be selected 
according to the following: (a) they should be clearly measurable in at least 2 
perpendicular dimensions; (b) if possible they should be from disparate regions of the 
body; (c) they should include mediastinal and retroperitoneal areas of disease whenever 
these sites are involved. 
2. No increase in the size of the other nodes, liver, or spleen. 
3. Splenic and hepatic nodules must regress by ≥ 50% in their SPD or, for single nodules, 
in the greatest transverse diameter. 
4. With the exception of splenic and hepatic nodules, involvement of other organs is usually 
assessable and no measurable disease should be present. 
5. Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive prior to treatment.  However, if positive, the cell type should be specified 
(e.g., large-cell lymphoma or small neoplastic B cells).  Patients who achieve a complete 
remission by the above criteria, but who have persistent morphologic bone marrow 
involvement will be considered partial responders. 
6. No new sites of disease should be observed (e.g., nodes > 1.5 cm in any axis). 


Appendix C-1 (cont.) 
Modified Response and Progression Criteria for NHL 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
190/P GO27834-A2 
7. Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the 
PET scan was positive before therapy, the post-treatment PET should be positive in at 
least one previously involved site. 
8. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, CT criteria should be used. 
1. 
In patients with follicular lymphoma, a PET scan is only indicated with one or at most 
two residual masses that have regressed by more than 50% on CT; those with more 
than two residual lesions are unlikely to be PET negative and should be considered 
partial responders. 
Stable Disease (SD) 
1. Failing to attain the criteria needed for a CR or PR, but not fulfilling those for progressive 
disease (see below). 
2. Typically FDG-avid lymphomas: the PET should be positive at prior sites of disease with 
no new areas of involvement on the post- treatment CT or PET. 
3. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment 
PET scan or if the pretreatment PET was negative, there must be no change in the size 
of the previous lesions on the post-treatment CT scan. 
Relapsed Disease (RD; after CR) or Progressive Disease (PD; for Patients 
with PR or SD) 
1. Lymph nodes should be considered abnormal if the long axis is > 1.5 cm, regardless of 
the short axis.  If a lymph node has a long axis of 1.1−1.5 cm, it should only be 
considered abnormal if its short axis is > 1.0.  Lymph nodes ≤ 1.0 cm by ≤ 1.0 cm will not 
be considered as abnormal for relapse or progressive disease. 
2. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size.  Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive disease 
after confirmation with other modalities. 
3. At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a 
single involved node, or the size of other lesions (e.g., splenic or hepatic nodules).  
To be considered progressive disease, a lymph node with a diameter of the short axis of 
less than 1.0 cm must increase by ≥ 50% and to a size of 1.5 × 1.5 cm or more than 
1.5 cm in the long axis. 
4. At least a 50% increase in the longest diameter of any single previously identified node 
more than 1 cm in its short axis. 
5. Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected with 
current PET systems (< 15 mm in its long axis by CT). 


Appendix C-1 (cont.) 
Modified Response and Progression Criteria for NHL 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
191/P GO27834-A2 
6. Measurable extranodal disease should be assessed in a manner similar to that 
for nodal disease.  For these recommendations, the spleen is considered nodal disease. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
192/P GO27834-A2 
Appendix C-2 
Revised Criteria for Response Assessment: The Lugano Classification (Cohort E, G-H) 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin 
and Non-Hodgkin lymphoma:  The Lugano Classification. J Clin Oncol. 2014 Aug [cited 2014 Aug 29]. Available from: 
http://jco.ascopubs.org/content/early/2014/08/11/JCO.2013.54.8800.long. 
Selection of measured dominant (indicator) lesions: 
• 
Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two 
diameters 
A measurable node must have an LDi greater than 1.5 cm. 
A measurable extranodal lesion should have an LDi greater than 1.0 cm. 
• 
Nodes should preferably be from disparate regions of the body and should include, where applicable, mediastinal and 
retroperitoneal areas.  
• 
Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, and lungs), GI involvement, cutaneous lesions, or 
those noted on palpation.  
• 
If possible, they should be from disparate regions of the body. 
• 
Should include mediastinal and retroperitoneal areas of disease whenever these sites are involved 
 
Selection of non-measured (non-indicator) lesions: 
• 
Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured.   
These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not 
meet the requirements for measurability but are still considered abnormal, as well as truly assessable disease, which is any 
site of suspected disease that would be difficult to follow quantitatively with measurement, including pleural effusions, 
ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed 
by imaging.  


Appendix C-2 (cont.) 
Revised Criteria for Response Assessment: The Lugano Classification (Cohort E, G-H) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
193/P GO27834-A2 
In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, and bone marrow), FDG uptake may be greater than in the 
mediastinum with complete metabolic response, but should be no higher than surrounding normal physiologic uptake (e.g., 
with marrow activation as a result of chemotherapy or myeloid growth factors). 
 
Response 
Site 
PET-CT−based Response 
CT-based Response 
 
Complete metabolic response 
Complete radiologic response (all of the following) 
Lymph nodes and 
extralymphatic sites 
Score 1, 2, or 3* with or without a residual mass on 5PS** 
It is recognizes that in Waldeyer’s ring or extranodal sites with 
high physiologic uptake or with activation within spleen or 
marrow (e.g., with chemotherapy or myeloid colony-stimulating 
factors), uptake may be greater than normal mediastinum 
and/or liver.  In this circumstance, complete metabolic 
response may be inferred if uptake at sites of initial 
involvement is no greater than surrounding normal tissue even 
if the tissue has high physiologic uptake 
Target nodes/nodal masses must regress to ≤ 1.5 cm in 
LDi 
No extralymphatic sites of disease 
Nonmeasured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Complete 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology;  if indeterminate, IHC negative 
 
Partial metabolic response 
Partial remission (all of the following) 
Lymph nodes and 
extralymphatic sites 
Score of 4 or 5** with reduced uptake compared with baseline 
and residual mass(es) of any size 
At interim, these findings suggest responding disease 
At end of treatment, these findings indicate residual disease 
≥ 50% decrease in SPD of up to 6 target measureable 
nodes and extranodal sites 
When a lesion is too small to measure on CT, assign 5 
mm × 5 mm as the default value 
When no longer visible, 0 × 0 mm 
For a node > 5 mm × 5 mm, but smaller than normal, 
use actual measurement for calculation 
Nonmeasured 
lesions 
Not applicable 
Absent/normal, regressed, but no increase 
Partial 
Organ enlargement 
Not applicable 
Spleen must have regressed by > 50% in length beyond 


Appendix C-2 (cont.) 
Revised Criteria for Response Assessment: The Lugano Classification (Cohort E, G-H) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
194/P GO27834-A2 
Response 
Site 
PET-CT−based Response 
CT-based Response 
normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake compatible 
with reactive changes from chemotherapy allowed).  If there 
are persistent focal changes in the marrow in the context of a 
nodal response, consideration should be given to further 
evaluation with MRI or biopsy or an interval scan 
Not applicable 
 
No metabolic response 
Stable disease 
Target nodes/nodal 
masses, extranodal 
lesions 
Score 4 or 5** with no significant change in FDG uptake from 
baseline at interim or end of treatment 
< 50% decrease from baseline in SPD for up to 6 
dominant, measurable nodes and extranodal sites;  no 
criteria for progressive disease are met 
Nonmeasured 
lesions 
Not applicable 
No increase consistent with progression 
Organ enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
No response or 
stable disease 
Bone marrow 
No change from baseline 
Not applicable 
 
Progressive metabolic disease 
Progressive disease (requires at least 1 of the 
following) 
Individual target 
nodes/nodal lesions 
Score 4 or 5** with an increase in intensity of uptake from 
baseline and/or 
Extranodal lesions 
New FDG-avid foci consistent with lymphoma at interim or end-
of-treatment assessment 
PPD progression: 
An individual node/lesion must be abnormal with:  
• 
LDi > 1.5 cm AND  
• 
Increase by ≥ 50% from PPD nadir AND  
An increase in LDi or SDi from nadir 
• 
0.5 cm for lesions ≤ 2 cm 
• 
1.0 cm for lesions > 2 cms 
Progressive 
disease  
Nonmeasured 
lesions 
None 
New or clear progression of preexisting  


Appendix C-2 (cont.) 
Revised Criteria for Response Assessment: The Lugano Classification (Cohort E, G-H) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
195/P GO27834-A2 
Response 
Site 
PET-CT−based Response 
CT-based Response 
Organ enlargement 
 
In the setting of splenomegaly, the splenic length must 
increase by > 50% of the extent of its prior increase 
beyond baseline (e.g., 15-cm spleen must increase to 
> 16 cm).  If no prior splenomegaly, must increase by at 
least 2 cm from baseline. 
New or recurrent splenomegaly 
New lesions 
New FDG-avid foci consistent with lymphoma rather than 
another etiology (e.g., infection, inflammation).  If uncertain 
regarding etiology of new lesions, biopsy or interval scan may 
be considered 
Regrowth of previously resolved lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in any axis;  if < 1.0 cm 
in any axis, its presence must be unequivocal and must 
be attributable to lymphoma 
Assessable disease of any size unequivocally 
attributable to lymphoma 
Bone marrow 
New or recurrent FDG-acid foci 
New or recurrent involvement 
5-PS = 5-point scale; CT = computed tomography; FDG = fluorodeoxyglucose; IHC = immunohistochemistry; LDi = longest transverse diameter of a lesion; 
MRI = magnetic resonance imaging; PET = positron emission tomography; PPD = cross product of the LDi and perpendicular diameter; SDi = shortest axis 
perpendicular to the LDi; SPD = sum of the product of the perpendicular diameters for multiple lesions. 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan.   However, in trials involving PET 
where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment). 
**PET 5PS:  1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake < mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly higher 
than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma. 
 


 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
196/P GO27834-A2 
Appendix D  
Anaphylaxis Management 
The following equipment is needed in the event of a suspected anaphylactic reaction 
during study drug infusion: 
• 
Appropriate monitors (electrocardiogram, blood pressure, pulse oximetry 
• 
Oxygen 
• 
Epinephrine for intravenous, intramuscular, and/or endotracheal administration 
in accordance with institutional guidelines.   
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
 
The following are the procedures to follow in the event of a suspected anaphylactic 
reaction during study drug infusion: 
• 
Stop the study drug infusion. 
• 
Call for additional assistance! 
• 
Maintain an adequate airway. 
• 
Provide oxygen as needed. 
• 
Ensure that appropriate monitoring is in place, with continuous electrocardiogram and 
pulse oximetry monitoring, if possible. 
• 
Administer antihistamines, epinephrine, inhaled bronchodilators, or other medications as 
required by patient status and directed by the physician in charge. 
• 
Continue to observe the patient and document observations. 
 






 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc. 
199/P GO27834-A2 
Appendix F  
Recommendations for the Use of White Blood Cell Growth 
Factors 
Primary Prophylactic G-CSF Administration (First and Subsequent-Cycle Use) 
Primary prophylaxis with G-CSF is recommended if any of the following clinical factors 
are present: 
• 
Age >65 years 
• 
Poor performance status 
• 
Previous history of febrile neutropenia 
• 
Open wounds or active infections 
• 
More advanced cancer 
• 
Extensive prior treatment, including large radiation therapy ports 
• 
Cytopenias due to bone marrow involvement by tumor 
• 
Other serious comorbidities 
 
Secondary Prophylactic G-CSF Administration 
Prophylactic G-CSF administration is recommended for patients who fulfill each of the 
following circumstances: 
• 
Experienced a neutropenic complication from a prior cycle of study treatment 
• 
Primary prophylactic G-CSF was not received; and 
• 
The intent is to avoid dose reduction of the antibody−drug conjugate (ADC), where 
the effect of the reduced dose on disease-free, overall survival or treatment 
outcome is not known 
 
Therapeutic Use of G-CSF 
G-CSF administration should be considered for the following patients: 
• 
Patients with febrile neutropenia who are at high risk for infection-associated 
complications; or 
• 
Patients who have prognostic factors that are predictive of poor clinical outcome, 
e.g., prolonged (>10 days) and profound (<100/μL) neutropenia, age >65 years, 
uncontrolled primary disease, pneumonia, hypotension and multi-organ dysfunction 
(sepsis), invasive fungal infection, being hospitalized at the time of fever 
development 
 
Source:  Smith TJ et al. 2006 Update of Recommendations for the use of White Blood Cell 
Growth Factors: An Evidence-Based Clinical Practice Guideline. JCO 24:3187-3205. 2006. 


 
Title
24-Jun-2013 17:51:55
Date and Time (UTC)
Company Signatory
Approver's Name
FINAL PROTOCOL APPROVAL 
 
 
 
CONFIDENTIAL 
 
This is a Genentech, Inc., document that contains confidential information.   
It is intended solely for the recipient clinical investigator(s) and must not be disclosed to any 
other party.  This material may be used only for evaluating or conducting clinical 
investigations; any other proposed use requires written consent from Genentech, Inc. 
 
PROTOCOL 
TITLE: 
A RANDOMIZED, OPEN-LABEL, MULTICENTER, 
PHASE II TRIAL EVALUATING THE SAFETY AND 
ACTIVITY OF DCDT2980S IN COMBINATION WITH 
RITUXIMAB OR DCDS4501A IN COMBINATION 
WITH RITUXIMAB IN PATIENTS WITH RELAPSED 
OR REFRACTORY B-CELL NON-HODGKIN’S 
LYMPHOMA 
PROTOCOL NUMBER: 
GO27834 
EUDRACT NUMBER: 
2011-004377-84 
STUDY DRUG: 
DCDT2980S; DCDS4501A 
IND: 
107713 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA  94080-4990  U.S.A. 
DATE FINAL: 
27 July 2012 
DATE AMENDED: 
Version 1:  See electronic date stamp below 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
P GO27834 A-1 


PROTOCOL AMENDMENT SUMMARY: 
VERSION 1 
RATIONALE 
Protocol GO27834 has been amended to enable the following changes: 
• 
Additional cohorts of approximately 20 patients each (denoted Cohort C and 
Cohort D) to assess DCDT2980S and DCDS4501A at a dose of 1.8 mg/kg in 
combination with rituximab at a dose of 375 mg/m2 in patients with 
relapsed/refractory follicular lymphoma have been added.  The purpose of enrolling 
additional cohorts of patients with follicular lymphoma is to determine whether the 
lower dose level of antibody−drug conjugate (ADC) in combination with standard 
doses of rituximab result in improved tolerability while maintaining efficacy in 
follicular lymphoma.  The opening of either or both cohorts will be at the Sponsor’s 
discretion based on safety and clinical activity observed in the randomized part of 
the study.  Patients will not be randomized to one cohort or another.  Only select 
investigator sites that have agreed to participate in this nonrandomized portion of 
the study will enroll patients into these cohorts.   
• 
Patients enrolled into Cohorts C and D will not be eligible to receive crossover 
treatment.  Cohorts C and D will support the study’s primary objectives to assess 
safety, tolerability, and anti-tumor activity of the ADCs (plus rituximab) at the 
1.8-mg/kg dose level. 
• 
Updated safety and efficacy information from the ongoing Phase I studies 
(DCT4862g and DCS4968g) have been provided (see Sections 1.2.1 and 1.2.2). 
• 
The definitions of progression free survival (PFS) and overall survival have been 
updated (see Section 4.10.4). 
• 
Procedures for reporting non-serious adverse events of special interest and serious 
adverse events have been updated (see Sections 5.1.3 and 5.4). 
 
Additional minor changes have been made to improve clarity and consistency.   
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
2/P GO27834 A-1  Summ


SUMMARY OF CHANGES:  
VERSION 1 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
A Protocol Amendment Acceptance Form has been added.   
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.2.1.2:  DCDT2980S Clinical Data 
a. Patient Enrollment 
All data presented herein is based on a data entry cutoff of 22 February 201322 June 
2012, with clinical data available from 6549 patients with NHL (excluding patients with 
CLL) enrolled in dose-escalation and expansion cohorts.  These include 3649 patients 
who were treated with single-agent DCDT2980S at doses ranging from 0.1 to 3.2 mg/kg 
administered intravenously every 21 days, and 1316 patients who were enrolled into two 
Phase Ib cohorts with DCDT2980S administered at doses of 1.8 mg/kg (5 patients) and 
2.4 mg/kg (811 patients) in combination with 375 mg/m2 rituximab. 
Seven patients have been enrolled Enrollment into CLL dose escalation cohorts was 
closed on 31 May 2013to date.  Refer to the DCDT2980S Investigator Brochure for 
details regarding clinical data in CLL patients. 
b. Pharmacokinetics 
Preliminary pharmacokinetic analysis based on available data as of 22 June 2012 is 
summarized below.   
c. Safety 
Dose Limiting Toxicity 
Separate dose-escalation cohorts enrolled patients with B-cell NHL and CLL.  For the 
NHL dose escalation, DLTs of Grade 4 neutropenia occurred in 1 patient out of 
3 DLT-evaluable patients in the 3.2 mg/kg single agent cohort and 1 patient out of 8 
11 DLT-evaluable patients in the 2.4 mg/kg + rituximab cohort.  Consequently, 
DCDT2980S at 2.4 mg/kg was determined to be the recommended Phase II dose 
(RP2D) as both monotherapy and in combination with rituximab.   Patients are currently 
being enrolled in monotherapy expansion cohorts for various types of NHL in order to 
collect and further characterize both single agent and combination safety data. 
For the CLL dose-escalation cohorts, one DLT out of six DLT evaluable patients was 
reported to date… 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
3/P GO27834 A-1  Summ


Single-Agent DCDT2980S and DCDT2980S Combined with Rituximab in NHL 
Enrollment into NHL indication-specific monotherapy expansion cohorts and the 
DCDT2980S plus rituximab cohorts has been completed. 
Forty-nine patients received single-agent DCDT2980S at a starting dose of ≥ 1.8 mg/kg 
(7 at 1.8 mg/kg, 42 at 2.4 mg/kg); 16 patients received DCDT2980S at a starting dose 
of ≥ 1.8 mg/kg in combination with rituximab (5 at 1.8 mg/kg, 11 at 2.4 mg/kg).  
Overall the safety profile of DCDT2980S combined with rituximab did not differ from 
that of single-agent DCDT2980S. 
Treatment emergent hematologic and commonly reported nonhematologic adverse 
events for all grades in patients treated with single-agent DCDT2980S and 
DCDT2980S plus rituximab included neutropenia (29%), febrile neutropenia (3%), 
infection (system organ class; 43%), anemia (25%), thrombocytopenia (12%), 
peripheral neuropathy (28%), diarrhea (40%), pyrexia (14%), nausea (34%), and 
fatigue (55%).  Treatment emergent Grade ≥ 3 adverse events included neutropenia 
(25%), febrile neutropenia (3%), infection (system organ class; 11%), anemia (5%), 
peripheral neuropathy (3%), diarrhea (5%), pyrexia (2%), and fatigue (3%).  Serious 
adverse events assessed by the treating investigator to be related to DCDT2980S were 
reported in 21% of patients.  Dose discontinuations for adverse events were reported in 
20% of patients. 
Refer to the DCDT2980S Investigator’s Brochure for complete and updated details 
related to safety. Adverse events regardless of relationship to study drug were reported 
in 32 of 36 NHL patients (97.0%) enrolled into the single agent dose cohorts. 
The most common of these adverse events in ≥ 10% of patients were neutropenia 
(7 patients 21.2%), anaemia (7 patients 21.2%), nausea (10 patients 30.3%), diarrhea 
(11 patients 33.3%), constipation (7 patients 21.2%), vomiting (7 patients 21.2%), 
abdominal pain (8 patients 24.2%), fatigue (11 patients 33.3%), peripheral oedema 
(7 patients 21.2%), pyrexia (6 patients 18.2%), chest discomfort (4 patients 12.1%), 
upper respiratory tract infection (5 patients 15.2%), decreased appetite (8 patients
24.2%), pain (10 patients 30.3%), dizziness (6 patients 18.2%), cough (6 patients
18.2%), dyspnea (6 patients 18.2%), nasal congestion (4 patients 12.1%), rash 
(5 patients 15.2%) and neuropathy (5 patients 15.2%). 
All patients treated at the RP2D of 2.4 mg/kg (n = 10 enrolled in dose escalation and 
expansion cohorts) experienced an adverse event.  The most common adverse events 
of all grades in ≥ 2 patients were anaemia (3 patients), nausea (3 patients), fatigue 
(3 patients), dizziness (3 patients), vomiting (2 patients), constipation (2 patients), chills 
(2 patients), decreased appetite (2 patients), dyspnea (2 patients), alopecia (2 patients), 
and peripheral neuropathy (2 patients). 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
4/P GO27834 A-1  Summ


Grade ≥3 adverse events regardless of relationship to study drug were reported in 21 
(58.3%) of 36 NHL patients enrolled into the single agent dose cohorts.  Neutropenia 
was reported in 8 (24.2%) patients.  Grade 3 5 adverse events reported in ≥ 2 patients 
included hyperglycemia (3 patients), anemia (3 patients), diarrhea, hyponatremia, 
hypoxia, pneumonia, peripheral neuropathy, and dehydration (2 patients each). 
Six patients treated at the RP2D of 2.4 mg/kg (n = 10 enrolled in dose escalation and 
expansion cohorts) experienced a Grade 3 5 adverse event.  Grade 3 4 neutropenia 
was reported in 2 patients.  No other Grade 3 5 adverse event was reported in more 
than 1 patient. 
Across all treatment cohorts a total of 24 serious adverse events have been reported in 
14 patients (25.0%).  Three of these serious adverse events occurring in 3 patients 
(12.5%) were considered related to study drug treatment.  These included the Grade 5 
febrile neutropenia in a CLL patient treated with one cycle of DCDT2980S at 1.0 mg/kg 
(described in the previous section), a Grade 3 pneumonia in a CLL patient treated one 
cycle of DCDT2980S at 1.8 mg/kg, and a Grade 3 dehydration in a NHL patient enrolled 
in the 3.2 mg/kg single agent DCDT2980S dose escalation cohort.  
No serious adverse events were reported among patients treated at the RP2D of 
2.4 mg/kg single agent DCDT2980S.   
DCDT2980S in Combination with Rituximab 
DCDT2980S in combination with rituximab was administered in two dose cohorts of 
1.8 mg/kg and 2.4 mg/kg.  Adverse events regardless of relationship to study drug were 
reported in 9 patients receiving rituximab in combination with DCDT2980S.  The most 
common of these adverse events in ≥ 2 patients were nausea (3 patients), fatigue 
(3 patients), and rash (3 patients). 
Four of 8 patients treated at the RP2D of 2.4 mg/kg of DCDT2980S experienced an 
adverse event.  Adverse events occurring in 2 or more patients included nausea and 
decreased appetite. 
Grade ≥3 adverse events regardless of relationship to study drug were reported in 6 
(46.2%) of patients taking rituximab in combination with DCDT2980S.  The most 
common event occurring in 2 or more patients was neutropenia, with 1 patient in each of 
the two combination therapy cohorts (1.8 mg/kg and 2.4 mg/kg of DCDT2980S) 
reporting Grade 3 5 neutropenia.  No other Grade 3 5 adverse event was reported in 
more than 1 patient. 
One serious adverse event of shortness of breath unrelated to DCDT2980S was 
reported in a patient treated with 2.4 mg/kg DCDT2980S in combination with rituximab. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
5/P GO27834 A-1  Summ


d. Preliminary Efficacy in Non-Hodgkin’s Lymphoma 
Investigator-based objective responses were observed in 17 of 43 (40%) patients treated 
with single-agent DCDT2980S and 5 of 15 (33%) patients treated with DCDT2980S 
combined with rituximab.  Among patients with relapsed/refractory DLBCL, 11 of 28 
(39%) objective responses (5 complete responses [CR] and 6 partial responses [PR]) 
were observed with single-agent DCDT2980S and 3 of 7 (43%; 2 CR, 1 PR) with 
DCDT2980S combined with rituximab.  Among patients with relapsed/refractory 
indolent (iNHL), 6 of 13 (46%) objective responses (2 CR, 4 PR) were observed with 
single-agent DCDT2980S and 1 of 4 (PR) with DCDT2980S combined with rituximab.  
To date, no formal analysis of anti tumor activity has been performed for 
Study DCT4862g.  Anti tumor activity has been reported in patients treated with 
single agent DCDT2980S as well as DCDT2980S when combined with rituximab.   
Refer to the DCDT2980S Investigator Brochure for complete and updated details related 
to regarding anti-tumor activity. 
SECTION 1.2.2.2:  DCDS4501A Clinical Data 
a. Patient Enrollment 
All data presented herein is based on a data entry cutoff of 28 February 201322 June 
2012, with clinical data available from 6039 patients with NHL (excluding patients with 
CLL) enrolled in dose-escalation and expansion cohorts.  These include 5132 patients 
who were treated with single-agent DCDS4501A ranging from 0.1 to 2.4 mg/kg 
administered intravenously every 21 days, and 97 patients who were enrolled into a 
single Phase Ib cohort with DCDS4501A administered at a dose of 2.4 mg/kg 
(8 patients) in combination with 375 mg/m2 rituximab. 
Ten patients have been enrolled into CLL dose escalation cohorts to date.  In the CLL 
dose escalation cohorts, two DLTs were reported at the single-agent dose of 1.8 mg/kg.  
Enrollment into the CLL cohorts was stopped on 7 January 2013.   Refer to the 
DCDS4501A Investigator Brochure for details regarding clinical data in CLL patients.   
b. Pharmacokinetics 
Preliminary pharmacokinetic analysis based on available data as of 22 June 2012 is 
summarized below… 
c. Safety 
Dose-Limiting Toxicities 
DLT of Grade 4 neutropenia occurred in 1 patient out of 10 DLT-evaluable patients in the 
2.4 mg/kg single agent cohort and 1 patient out of 7 9 DLT-evaluable patients in the 
2.4 mg/kg + rituximab cohort…  
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
6/P GO27834 A-1  Summ


In the CLL dose-escalation cohorts, two DLTs were reported at the single-agent dose of 
1.8 mg/kg.  One patient had a Grade 4 neutropenia, and 1 patient had a Grade 4 
invasive fungal infection.   
Single-Agent DCDS4501A and DCDS4501A Combined with Rituximab 
Fifty-one patients received single agent DCDS4501A at a starting dose of ≥ 1.8 mg/kg 
(6 at 1.8 mg/kg, 45 at 2.4 mg/kg); an additional 9 patients received DCDS4501A at a 
dose of 2.4 mg/kg in combination with rituximab.  Overall, the safety profile of 
DCDS4501A combined with rituximab did not differ from that of single-agent 
DCDS4501A. 
Treatment emergent hematologic and commonly reported non-hematologic adverse 
events for all grades in patients treated with single-agent DCDS4501A and 
DCDS4501A plus rituximab included neutropenia (50%), febrile neutropenia (5%), 
infection (system organ class; 35%), anemia (13%), thrombocytopenia (18%), 
peripheral neuropathy (32%), diarrhea (43%), pyrexia (37%), nausea (35%), and 
fatigue (18%).  Treatment emergent Grade ≥ 3 adverse events included neutropenia 
(43%), febrile neutropenia (5%), infection (system organ class; 10%), anemia (8%), 
peripheral neuropathy (7%), diarrhea (3%), pyrexia (2%), and fatigue (5%).  Serious 
adverse events assessed by the treating investigator to be related to DCDS4501A were 
reported in 20% of patients.  Dose discontinuations for adverse events were reported in 
33% of patients. 
Refer to the DCDS4501A Investigator’s Brochure for complete and updated details 
related to safety.   
Adverse events regardless of relationship to study drug were reported in 31 (96.9%) 
NHL patients enrolled into the single agent dose  escalation cohorts.  Across all 
dose escalation cohorts, the most common adverse events in  ≥ 10% of treated patients 
were neutropenia/febrile neutropenia (17 patients 53.1%), anaemia (6 patients 18.8%), 
leukopenia (9 patients  28.1%), thrombocytopenia (6 patients 18.8%), nausea 
(10 patients 31.2%), diarrhea (9 patients 28.1%), constipation (9 patients 28.1%), 
vomiting (5 patients 15.6%), pyrexia (11 patients 34.4%), fatigue (10 patients 31.2%), 
chills (8 patients 25.0%), peripheral oedema (4 patients 12.5%), hyperglycaemia 
(10 patients 31.2%), decreased appetite (5 patients 15.6%), dizziness (4 patients
12.5%), dysgeusia (4 patients 12.5%), peripheral neuropathy (6 patients 18.8%), cough 
(8 patients 25.0%) and dyspnoea (5 patients 15.6%). 
Eleven of twelve patients treated at the RP2D of 2.4 mg/kg (91.7%) experienced an 
adverse event.  The most common adverse events of all Grades in ≥ 2 patients were 
neutropenia (unmapped term, 4 patients), neutropenia (mapped term, 3 patients), 
diarrhea (3 patients), anemia, nausea, pyrexia, alopecia, thrombocytopenia (unmapped 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
7/P GO27834 A-1  Summ


term), leukopenia (unmapped term), hypokalemia (unmapped term), and hyperglycemia 
(unmapped term). 
Grade ≥ 3 adverse events regardless of relationship to study drug were reported in 22 
(68.8%) of NHL patients treated with single agent DCDS4501A across all dose levels.  
The most common of these events in ≥ 10% of patients were neutropenia (13 patients
40.6%) and leukopenia (5 patients 15.6%). 
Seven of twelve patients treated at the RP2D of 2.4 mg/kg experienced a Grade 3 5 
adverse event.  Grade 3 4 events in reported in 2 or more patients included neutropenia 
(unmapped term, 4 patients), neutropenia (mapped term), leukopenia (unmapped term), 
and anemia, (2 patients each). 
A total of 27 serious adverse events were reported in 15 patients (30.6%) across all 
dose levels.  Six of these events, occurring in 4 patients, were considered related to 
study treatment.  These included Grade 3 peripheral neuropathy in 3 patients, and 
Grade 2 pyrexia and Grade 3 lobar pneumonia in 1 patient each.  Three separately 
reported but concurrent serious adverse events of Grade 4 neutropenia, Grade 4 febrile 
neutropenia and Grade 4 pneumonia were reported in another patient. 
DCDS4501A in Combination with Rituximab 
Adverse events regardless of relationship to study drug were reported in 6 patients 
receiving DCDS4501A at a dose of 2.4 mg/kg combined with rituximab in the Phase Ib 
cohorts.  The most common of these adverse events in more than 2 patients were 
anaemia (2 patients), leukopenia (2 patients), neutropenia/febrile neutropenia 
(3 patients), nausea (3 patients), fatigue (2 patients), constipation (2 patients) and 
pyrexia (4 patients). 
Grade ≥3 adverse events regardless of relationship to study drug were reported in 
4 patients taking rituximab in combination with DCDS4501A.  Grade 3 4 neutropenia 
was reported in 2 patients.  One Grade 3 adverse event of streptococcal bacteremia 
unrelated to study treatment was reported in 1 patient.  One Grade 4 adverse event of 
renal failure resulting from a septic arthritis and unrelated to study treatment was 
reported in 1 patient. 
One serious adverse event of Grade 4 febrile neutropenia attributed to study treatment 
was reported among patients treated at the RP2D of 2.4 mg/kg single agent 
DCDS4501A.  One serious adverse event of Grade 2 pyrexia related to study drug was 
reported in a patient receiving 2.4 mg/kg DCDS4501A combined with rituximab. 
d. Efficacy 
Investigator-based objective responses were observed in 28 of 49 (57%) patients treated 
with single-agent DCDS4501A and 7 of 9 patients (78%) treated with DCDS4501A 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
8/P GO27834 A-1  Summ


combined with rituximab.  Among patients with relapsed/refractory DLBCL, objective 
responses were observed in 16 of 30 (53%; 4 CR, 12 PR) patients treated with 
DCDS4501A; 1 patient with DLBCL was treated with DCDS4501A combined with 
rituximab and achieved a PR.  Among patients with relapsed/refractory iNHL, objective 
responses were observed in 7 of 14 (50%; 2 CR, 5 PR) patients treated with single-agent 
DCDS4501A and 5 of 5 (100%; 2 CR, 3 PR) patients treated with DCDS4501A plus 
rituximab. To date, no formal analysis of anti tumor activity has been performed for 
Study DCS4968g.  Anti tumor activity has been reported in patients treated with 
single agent DCDS4501A as well as DCDS4501A when combined with rituximab.   
SECTION 1.3.1:  Rationale for Assessing ADC Dose of 1.8 mg/kg Combined 
with Rituximab in iNHL 
Based on available Phase I data (see Section 1.2.1 and 1.2.2), both DCDT2980S and 
DCDS4501A as single-agents and combined with rituximab have shown early signs of 
clinical activity in heavily pretreated patients with relapsed/refractory NHL.  However, 
early evidence in the Phase I studies indicate that duration of study treatment may be 
limited by tolerability to ADC.  Specifically, for both ADCs, peripheral sensory 
neuropathy has been identified as a known risk (see Section 3.4.2).  Notably, 4 of 7 and 
5 of 11 discontinuations for adverse events in Studies DCT4862g and DCS4968g, 
respectively, were the result of peripheral neuropathy.   
Because of the chronic course and incurability of iNHL, treatment paradigms are 
increasingly emphasizing tolerability to treatment in addition to efficacy.  As both 
DCDT2980S and DCDS4501A have shown single-agent activity at the 1.8 mg/kg dose 
level (Advani et al. 2012; Palanca-Wessels et al. 2012), the purpose of enrolling 
additional cohorts of patients with follicular lymphoma is to determine whether lower 
doses of ADC in combination with standard doses of rituximab result in improved 
tolerability while maintaining efficacy in follicular lymphoma.   
In contrast to iNHL, treatment paradigms in relapsed/refractory aggressive lymphomas 
such as DLBCL continue to place a premium on anti-tumor activity and higher 
tolerance for treatment-related toxicity given that durations of disease control and 
survival are substantially shorter and that treatment options are extremely limited.  
Early Phase I data suggest lower rates of study treatment discontinuation for adverse 
events among patients with DLBCL compared with patients with iNHL.  Taken 
together with anti-tumor activity observed to date, the risk-benefit profile of the 
currently tested ADC dose of 2.4 mg/kg is considered acceptable  
SECTION 2.3.3:  Crossover Treatment Objective 
• 
To preliminarily assess the safety and tolerability and anti-tumor activity of 
DCDT2980S and DCDS4501A, either as a single-agent or in combination with 
rituximab, as crossover treatment following disease progression on initial study 
treatment (Note:  This objective only applies to patients enrolled in Arms A and B 
[see Section 3.1]) 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
9/P GO27834 A-1  Summ


SECTION 3.1:  DESCRIPTION OF THE STUDY 
This is a Phase II, randomized, multicenter, open-label study.  No formal testing 
comparing the two treatment arms is planned.  A total of approximately 
140120−160 patients (approximately 60−8040 patients with relapsed or refractory 
follicular NHL and approximately 80 patients with relapsed/refractory DLBCL) will be 
enrolled at approximately 30–40 investigative sites worldwide.  Additional patients may 
be enrolled in order to obtain additional safety and/or efficacy data.  
The study will be composed of a randomized portion and a nonrandomized portion, as 
illustrated in Figure 3. 
Figure 3 (Study Schema) has been added. 
SECTION 3.1.1:  Randomized Portion of the Study (Arms A and B) 
No formal testing comparing the two treatment arms in the randomized portion of the 
study is planned.   
SECTION 3.1.2:  Nonrandomized Portion of the Study (Cohorts C and D) 
Only select investigator sites that have agreed to participate in the nonrandomized 
portion of the study will enroll patients into these cohorts. 
Patients with relapsed or refractory follicular NHL will be enrolled in Cohorts C and D 
to receive rituximab (375 mg/m2) combined with DCDT2980S or DCDS4501A at a 
dose of 1.8 mg/kg.  The first day of treatment constitutes Day 1 of each cycle.  A typical 
cycle will be 21 days in duration. 
The opening of either or both cohorts will be at the Sponsor’s discretion and only after 
the enrollment of follicular lymphoma patients into the randomized portion of the study 
is completed.  Patients will not be randomized to receive one treatment or the other.  
It is anticipated that Cohort C and D will be opened sequentially.   
SECTION 3.1.3:  All Patients 
All patients, regardless of assigned arm/cohort Patients will receive DCDT2980S or 
DCDS4501A and rituximab administered by IV infusion on a 21-day cycle… 
SECTION 3.1.6:  Crossover Treatment (Randomized Patients Only) 
Patients randomized assigned to Arm A or Arm B who develop progressive disease may be 
eligible to receive crossover treatment consisting of rituximab and the other ADC, or the 
other ADC alone, e.g., Arm B treatment for patients who have disease progression while 
receiving Arm A treatment and vice versa, provided the following conditions are met: 
• 
Patients who are enrolled into the nonrandomized portion of the study (Cohorts C 
and D) will not have the option to receive crossover treatment upon disease 
progression (see Section 3.2 for rationale). 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
10/P GO27834 A-1  Summ


SECTION 3.2:  RATIONALE FOR STUDY DESIGN 
The primary rationale for the this randomized non-comparative Phase II study design 
portion of the study is to assess clinical activity for the ADCs DCDT2980S and 
DCDS4501A in patients with relapsed/refractory NHL…  
The primary rationale for the nonrandomized portion of the study is to assess the 
therapeutic index (i.e., the balance of efficacy and tolerability of DCDT2980S and 
DCDS4501A at a dose of 1.8 mg/kg in patients with relapsed or refractory follicular 
NHL).  An informal comparison between patients with follicular NHL treated at the 
two doses of the ADC will help determine if tolerability is improved at the lower ADC 
dose without substantial compromise of efficacy.   
SECTION 3.4.2.7:  Hyperglycemia 
Hyperglycemia has been observed in patients treated with DCDT2980S and 
DCDS4501A as well as with other antibody-drug conjugates using the same vc-MMAE 
platform.  Hyperglycemia has been reversible upon holding or discontinuing treatment 
of the ADCs and/or initiation or adjustment of anti-hyperglycemic medications. 
SECTION 3.4.2.8:  Hepatotoxicity 
Hepatotoxicity is a potential risk of the ADCs.  Definitive attribution of hepatotoxicity 
to the ADCs has not been established.  Transient dose-related increases in hepatic 
enzyme levels were observed in rats treated with DCDT2980S and DCDS4501A.  
Elevations in transaminase and/or bilirubin levels requiring dose modifications have 
been reported in the ongoing clinical studies. 
SECTION 4.1.1:  Inclusion Criteria 
• 
For female patients of childbearing potential and male patients with female 
partners of childbearing potential, agreement to use one highly effective form of 
nonhormonal contraceptionor two effective forms of nonhormonal contraception, 
including at least one method with a failure rate of < 1% per year through the 
course of study treatment and for at least 3 months after the last dose of 
DCDT2980S or DCDS4501A or rituximab (whichever is later) in women and at 
least 5 months after the last dose of DCDT2980S or DCDS4501A or rituximab 
(whichever is later) in men. 
A woman is considered not to be of childbearing potential if she is 
postmenopausal, defined by amenorrhea of ≥ 12 months duration and age 
≥ 45 years, or has undergone hysterectomy and/or bilateral oophorectomy. 
The following are considered highly effective forms of contraception:  1) true 
abstinence; 2) male sterilization (with postprocedure documentation of absence 
of sperm in the ejaculate).  For female patients, the sterilized male partner 
should be the sole partner. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
11/P GO27834 A-1  Summ


The following are considered effective forms of contraception:  1) intrauterine 
device (copper IUD or hormonal IUDs only) or intrauterine system; 2) condom 
with spermicidal foam/gel/film/cream/suppository; 3) occlusive cap (diaphragm 
or cervical/vault cap) with spermicidal foam/gel/film/cream/suppository. 
Males must agree to abstain from sperm donation for at least 5 months after the 
last dose of DCDT2980S or DCDS4501A or rituximab (whichever is later). 
 
SECTION 4.1.2:  Exclusion Criteria 
• 
For female patients of childbearing potential and male patients with female partners 
of childbearing potential, agreement to use one highly effective form of 
non hormonal contraception or two effective forms of non hormonal contraception 
through the course of study treatment and for at least 3 months after the last dose of 
DCDT2980S or DCDS4501A or rituximab (whichever is later) in women and at least 
5 months after the last dose of DCDT2980S or DCDS4501A or rituximab (whichever 
is later) in men. 
A woman is considered not to be of childbearing potential if she is 
postmenopausal, defined by amenorrhea of ≥ 12 months duration and age 
≥ 45 years, or has undergone hysterectomy and/or bilateral oophorectomy. 
The following are considered highly effective forms of contraception:  1) true 
abstinence; 2) male sterilization (with post procedure documentation of absence 
of sperm in the ejaculate).  For female patients, the sterilized male partner should 
be the sole partner. 
The following are considered effective forms of contraception:  1) intrauterine 
device (copper IUD or hormonal IUDs only) or intrauterine system; 2) condom 
with spermicidal foam/gel/film/cream/suppository; 3) occlusive cap (diaphragm or 
cervical/vault cap) with spermicidal foam/gel/film/cream/suppository. 
Males must agree to abstain from sperm donation for at least 5 months after the 
last dose of DCDT2980S or DCDS4501A or rituximab (whichever is later). 
SECTION 4.2:  METHOD OF TREATMENT ASSIGNMENT 
As described in Section 3.1.2, only select investigator sites that have agreed to 
participate in the nonrandomized portion of the study will enroll patients into these 
cohorts.  Cohorts C and D will be opened sequentially following completion of the 
randomized portion of the study for follicular lymphoma patients. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
12/P GO27834 A-1  Summ


SECTION 4.3.1.1:  Formulation and Storage 
b. DCDS4501A 
DCDS4501A will be administered to patients by IV via syringe pump with IV infusion 
set containing a 0.22 µm in-line filter with a final volume of DCDS4501A determined 
by the dose and patient weight.  
DCDS4501A vials must be refrigerated at 2−8°C (36−46°F) upon receipt until use.  
DCDS4501A vials may be stored at room temperature (> 8°C to 25°C [46°F−77°F]) for 
up to 8 hours.  DCDS4501A should not be used beyond the expiration date provided by 
the manufacturer.  Vial contents should not be frozen or shaken and should be protected 
from direct sunlight.  Vials are intended for single use only; therefore, any remaining 
solution should be discarded. 
DCDS4501A vials may be stored at Once the DCDS4501A dose solution has been 
prepared, the solution should be used within 4 hours at room temperature (> 8°C to 
25°C [46°F−77°F]) or within 8 hours refrigerated at 2°C−8°C (36°F−46°F).for up to 
8 hours.  DCDS4501A may be stored at room temperature (> 8°C to 25°C [46°F 77°F]) 
in an extension set and polypropylene syringe for up to 8 hours.  The maximum allowed 
time in the syringe and extension set should not exceed 8 hours.  Because the Drug 
Product contains no preservatives, the Sponsor recommends using DCDS4501A in a 
syringe and extension set as soon as possible to reduce the risk of microbial 
contamination.  Vials are intended for single use only; therefore, any remaining solution 
should be discarded. 
SECTION 4.3.1.2:  Dosage and Administration 
b. DCDS4501A-Specific Information 
DCDS4501A will be administered to patients by IV via syringe pump with IV infusion 
set containing a 0.22 µm in-line filter with a final volume of DCDS4501A determined 
by the dose and patient weight.  Compatibility testing has shown that DCDS4501A is 
stable in both syringes made of polypropylene (PP) and in standard extension sets with 
0.22 µm in-line filter, when stored neat or diluted with 0.9% NaCl saline.  
DCDS4501A will be administered to patients by IV infusion using standard medical 
syringes and syringe pumps.  Compatibility testing has shown that DCDS4501A is stable 
in extension sets and polypropylene syringes.  The Drug Product will be delivered by 
syringe pump via an IV infusion set containing a 0.22 µm in line filter with a final 
DCDS4501A volume determined by the dose and patient weight. 
SECTION 4.3.1.3:  Dosage Modification 
Once dose reductions of DCDT2980S or DCDS4501A are made for toxicity, dose 
re-escalation will not be allowed.   Patients who are enrolled in the nonrandomized 
portion of the study (Cohorts C and D), are dosed at an ADC dose of 1.8 mg/kg, and 
have progressive disease in the absence of any drug-related toxicity may have their 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
13/P GO27834 A-1  Summ


ADC dose increased to 2.4 mg/kg if it is felt that there is reasonable justification for 
ongoing clinical benefit.  The decision to increase the dose must be made in consultation 
with and approval of the Medical Monitor. 
SECTION 4.3.1.6:  Neutropenia 
• 
For patients enrolled into the nonrandomized portion of the study (Cohorts C 
and D), dose modifications will not be allowed.  Administration of 
therapeutic/prophylactic G-CSF and dose-schedule modifications as described above 
are allowed.  Patients who have persistent or recurrent Grade 3−4 neutropenia as 
defined above should be discontinued from study treatment. 
 
SECTION 4.3.1.7:  Peripheral Sensory Neuropathy 
For patients enrolled into the nonrandomized portion of the study (Cohorts C and D), 
dose modifications will not be allowed.  Patients who have Grade 2 or 3 peripheral 
sensory neuropathy as defined above should be discontinued from study treatment. 
SECTION 4.3.1.8:  Hyperglycemia 
Hyperglycemia has been observed in patients treated with DCDT2980S and 
DCDS4501A as well as with other antibody-drug conjugates using the same vc-MMAE 
platform.  Hyperglycemia has been reversible upon holding or discontinuing treatment 
of the ADCs and/or initiation of improved anti-hyperglycemic medications (see 
Section 3.4.2.7).   
For symptomatic fasting Grade 3 (> 250−500 mg/dL) or asymptomatic Grade 4 
(> 500 mg/dL) hyperglycemia, medical management should be initiated immediately and 
consultation with a specialist should be considered.  If the hyperglycemia persists for 
> 1 week after initiation of management, dose modification, schedule modification, or 
discontinuation of study treatment should be considered.  In these cases the study 
Medical Monitor should be consulted to assess the risk-benefit balance of continued 
study treatment. 
SECTION 4.5.6:  Follow-Up Assessments 
Following discontinuation of study treatment, patients will be followed for survival 
approximately every three months until death, loss to follow-up, withdrawal of consent, 
or study termination. 
SECTION 4.10:  STATISTICAL METHODS 
The final analysis will be based on patient data collected through patient discontinuation 
or study discontinuation, whichever occurs first.  The analyses will be based on the 
safety evaluable population defined as patients who received at least one dose of study 
treatment.  All summaries will be presented according to the assigned dose level 
regardless of crossover treatment disease specific cohort, treatment group, and assigned 
dose level. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
14/P GO27834 A-1  Summ


SECTION 4.10.1:  Analysis of the Conduct of the Study 
Demographic and baseline characteristics, such as age, sex, race/ethnicity, weight, 
duration of malignancy, and baseline ECOG Performance Status, will be summarized 
using means, standard deviations, medians, and ranges for continuous variables, and 
proportions for categorical variables.  All summaries will be presented overall and by 
treatment group, assigned dose level, and disease-specific cohort. 
Study drug administration data will be listed by the disease-specific cohorts described in 
Section 3.1.1 and 3.1.2.  Any dose modifications will be flagged.  Means and standard 
deviations will be used to summarize the total doses of DCDT2980S, DCDS4501A and 
rituximab received.  All summaries will be presented by treatment group, assigned dose 
level, and disease-specific cohort. 
SECTION 4.10.2:  Safety Analysis 
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in physical findings on physical examinations, and changes in vital 
signs.  All patients who receive any amount of DCDT2980S, DCDS4501A or rituximab 
will be included in the safety analysis and will be assigned to the treatment group arm 
based on the study treatment received.  Patients who have dose level changes from the 
initial assigned dose level will be summarized by the initial assigned dose level of 
DCDT2980S or DCDS4501A. 
SECTION 4.10.4:  Activity Analyses 
For the randomized portion of the study (Arms A and B), PFS is defined as the time 
from the date of randomization to the date of disease progression or death within 
30 days of the last study drug administration from any cause, whichever occurs first.  If a 
patient has not experienced progressive disease or death, PFS will be censored at the 
day of the last tumor assessment.  Patients with no post-baseline tumor assessment will 
be censored on the date of randomization.  For the nonrandomized portion of the study 
(Cohorts C and D), PFS is defined as the time from the date of study enrollment to the 
date of disease progression or death from any cause, whichever occurs first. 
For the randomized portion of the study (Arms A and B), oOverall survival is defined as 
the time from the date of randomization to the date of death from any cause.  For the 
nonrandomized portion of the study (Cohorts C and D), overall survival is defined as 
the time from the date of study enrollment to date of death from any cause. 
SECTION 4.10.7:  Determination of Sample Size 
For the randomized portion of the study (Arms A and B), aA target of 120 patients will 
be enrolled in two separate cohorts of patients (40 in the follicular NHL cohort and 80 in 
the DLBCL cohort)… 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
15/P GO27834 A-1  Summ


This is a non-comparative hypothesis-generating study.  There is no formal hypothesis 
testing planned to compare the two treatment arms.  Specifically, for the randomized 
portion of the study, and there is insufficient power to detect minimum clinically 
meaningful differences between the two treatment arms. 
SECTION 5.1.3:  Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) 
Non-serious adverse events of special interest are required to be reported by the 
investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2 for reporting instructions), irrespective of regulatory 
seriousness criteria.  Adverse events of special interest for this study include the 
following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST 
in combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 5.3.1.6; treatment-emergent ALT or AST > 3 × baseline value 
in combination with total bilirubin > 2 × ULN [of which 35% is direct bilirubin]) 
• 
Suspected transmission of an infectious agent by the study drug 
• 
Grade ≥2 motor neuropathy 
• 
Grade ≥2 infusion reactions 
 
SECTION 5.3.1.5:  Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (including a diagnostic evaluation not mandated 
in this protocol) or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated vital sign 
abnormality should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
16/P GO27834 A-1  Summ


Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
SECTION 5.3.1.6:  Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis 
or other causes of hyperbilirubinemia is considered to be an indicator of severe liver 
injury.  Therefore, investigators must report as an adverse event the occurrence of 
either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.1) and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2) 
SECTION 5.4.2:  Reporting Requirements for All SAEs Reporting 
Requirements for Serious Adverse Events and Non-Serious Adverse 
Events of Special Interest 
For reports of serious adverse events and non-serious adverse events of special interest, 
investigators should record all case details that can be gathered immediately 
(i.e., within 24 hours) on the Adverse Event eCRF and submit the report via the EDC 
system.  A report will be generated and sent to the Sponsor’s Safety Risk Management 
department by the EDC system. 
In the event that the EDC system is unavailable, a paper Serious Adverse 
Event/Non-serious Adverse Event of Special Interest CRF and Fax Coversheet should 
be completed and faxed to Safety Risk Management or its designee immediately (i.e., no 
more than 24 hours after learning of the event), using the fax numbers provided below.  
Once the EDC system is available, all information will need to be entered and 
submitted via the EDC system.   
Investigators will submit reports of all SAEs, regardless of attribution, to Genentech 
within 24 hours of learning of the events.  For initial SAE reports, investigators should 
record all case details that can be gathered within 24 hours on the Adverse Event eCRF 
and submit the report via the EDC system.  A report will be generated and sent to 
Genentech’s Drug Safety Department.  In the event that the EDC system is unavailable, 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
17/P GO27834 A-1  Summ


a paper Serious/Non Serious Expedited Adverse Event CRF and Fax Cover Page 
should be completed and faxed immediately to Genentech’s Drug Safety Department or 
its designee at the fax numbers indicated below.  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system. 
 
REFERENCES 
The following references have been added:   
• 
Advani et al. 2012 
• 
Palanca-Wessels et al. 2012 
 
APPENDIX A-1:  Study Flowchart:  Initial Study Treatment 
The Study Flowchart has been revised to reflect the changes to the protocol. 
APPENDIX A-2:  Study Flowchart:  Crossover Treatment (Patients 
Randomized to Arms A or B Only) 
The Study Flowchart has been revised to reflect the changes to the protocol. 
SAMPLE INFORMED CONSENT FORM 
The sample Informed Consent Form has been revised to reflect the changes to the 
protocol.   
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
18/P GO27834 A-1  Summ


 
TABLE OF CONTENTS 
 
 
Page 
PROTOCOL AMENDMENT FINALIZATION SIGNATURE PAGE ..................... 25 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 26 
PROTOCOL SYNOPSIS .................................................................................... 27 
1. 
BACKGROUND .......................................................................................... 41 
1.1 
Background on Disease......................................................... 41 
1.2 
Background on the Molecules ............................................... 41 
1.2.1 
DCDT2980S .......................................................................... 41 
1.2.2 
DCDS4501A.......................................................................... 46 
1.2.3 
Rituximab............................................................................... 51 
1.3 
Rationale for Doing this Study ............................................... 52 
1.3.1 
Rationale for Assessing ADC Dose of 1.8 mg/kg 
Combined with Rituximab in iNHL...................................... 53 
2. 
OBJECTIVES.............................................................................................. 54 
2.1 
Primary Objectives ................................................................ 54 
2.2 
Secondary Objectives............................................................ 54 
2.2.1 
Safety Objectives................................................................... 54 
2.2.2 
Activity Objective ................................................................... 54 
2.2.3 
Pharmacokinetic Objectives .................................................. 55 
2.3 
Exploratory Objectives........................................................... 55 
2.3.1 
Biomarker Objectives ............................................................ 55 
2.3.2 
Patient Quality of Life Objective............................................. 55 
2.3.3 
Crossover Treatment Objective............................................. 55 
3. 
STUDY DESIGN ......................................................................................... 55 
3.1 
Description of the Study......................................................... 55 
3.1.1 
Randomized Portion of the Study (Arms A and B) ............... 56 
3.1.2 
Nonrandomized Portion of the Study (Cohorts C 
and D)................................................................................... 57 
3.1.3 
All Patients ........................................................................... 57 
3.1.4 
Follicular NHL Cohort ............................................................ 58 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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TABLE OF CONTENTS (cont.) 
 
 
Page 
3.1.5 
DLBCL Cohort ....................................................................... 59 
3.1.6 
Crossover Treatment (Randomized Patients Only)............... 59 
3.2 
Rationale for Study Design.................................................... 61 
3.2.1 
Rationale for the PK sample schedule................................... 62 
3.3 
Outcome Measures ............................................................... 62 
3.3.1 
Safety Outcome Measures .................................................... 62 
3.3.2 
Pharmacokinetic/Pharmacodynamic Outcome 
Measures .............................................................................. 63 
3.3.3 
Activity Outcome Measures................................................... 63 
3.3.4 
Exploratory Outcome Measures ............................................ 64 
3.4 
Safety Plan ............................................................................ 64 
3.4.1 
Internal Monitoring Committee (IMC)..................................... 65 
3.4.2 
Risks Associated with DCDT2980S and DCDS4501A .......... 65 
3.4.3 
Risks Associated with Adcetris (Brentuximab vedotin) .......... 67 
3.4.4 
Risks Associated with Rituximab Therapy and Their 
Management ......................................................................... 68 
3.5 
Minimization of Bias............................................................... 71 
3.6 
Administrative Structure......................................................... 71 
3.7 
Compliance with Laws and Regulations ................................ 71 
4. 
MATERIALS AND METHODS .................................................................... 72 
4.1 
Patients.................................................................................. 72 
4.1.1 
Inclusion Criteria.................................................................... 72 
4.1.2 
Exclusion Criteria................................................................... 73 
4.2 
Method of Treatment Assignment.......................................... 74 
4.3 
Study Treatment.................................................................... 75 
4.3.1 
DCDT2980S and DCDS4501A.............................................. 75 
4.3.2 
Rituximab............................................................................... 81 
4.4 
Concomitant and Excluded Therapies................................... 84 
4.4.1 
Concomitant Therapy ............................................................ 84 
4.4.2 
Excluded Therapy.................................................................. 85 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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TABLE OF CONTENTS (cont.) 
 
 
Page 
4.5 
Study Assessments ............................................................... 85 
4.5.1 
Definitions of Study Assessments ......................................... 85 
4.5.2 
Screening and Pretreatment Assessments............................ 93 
4.5.3 
Assessments during Treatment............................................. 93 
4.5.4 
Study treatment Completion Visit .......................................... 94 
4.5.5 
Crossover Treatment Completion Visit .................................. 94 
4.5.6 
Follow-Up Assessments ........................................................ 95 
4.6 
Patient Discontinuation.......................................................... 95 
4.6.1 
Discontinuation from Treatment............................................. 95 
4.6.2 
Discontinuation from Study.................................................... 96 
4.7 
Study Discontinuation............................................................ 96 
4.8 
Post-Trial Access................................................................... 96 
4.9 
Assay Methods...................................................................... 96 
4.9.1 
Total DCDT2980S/DCDS4501A Antibody ELISA.................. 96 
4.9.2 
Antibody-Conjugated MMAE (MMAE Affinity Capture 
Enzyme-Release LC/MS-MS) ............................................... 96 
4.9.3 
Free MMAE LC-MS/MS......................................................... 97 
4.9.4 
Rituximab ELISA ................................................................... 97 
4.9.5 
Anti-Therapeutic Antibody ..................................................... 97 
4.9.6 
Biomarker Assays.................................................................. 97 
4.10 
Statistical Methods ................................................................ 97 
4.10.1 
Analysis of the Conduct of the Study..................................... 97 
4.10.2 
Safety Analysis...................................................................... 97 
4.10.3 
Pharmacokinetic and Pharmacodynamic Analyses............... 98 
4.10.4 
Activity Analyses.................................................................... 98 
4.10.5 
Exploratory Analyses............................................................. 99 
4.10.6 
Handling of Missing Data..................................................... 100 
4.10.7 
Determination of Sample Size ............................................. 100 
4.11 
Data Quality Assurance....................................................... 100 
5. 
ASSESSMENT OF SAFETY..................................................................... 101 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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TABLE OF CONTENTS (cont.) 
 
 
Page 
5.1 
Safety Parameters and definitions....................................... 101 
5.1.1 
Adverse Event ..................................................................... 101 
5.1.2 
Serious Adverse Event ........................................................ 102 
5.1.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) ............................ 102 
5.2 
Methods and Timing for capturing and Assessing 
Safety Parameters............................................................... 103 
5.2.1 
Adverse Event Reporting Period ......................................... 103 
5.2.2 
Eliciting Adverse Events ...................................................... 103 
5.2.3 
Assessment of Severity and Causality of Adverse 
Events................................................................................. 103 
5.3 
Procedures for Recording Adverse Events.......................... 105 
5.3.1 
Recording Adverse Events on the eCRF............................. 105 
5.4 
Expedited Reporting Requirements for Serious 
Adverse Events ................................................................... 109 
5.4.1 
Reporting Requirements for Fatal/Life-Threatening 
SAEs Related to Investigational Product............................. 109 
5.4.2 
Reporting Requirements for Serious Adverse Events 
and Non-Serious Adverse Events of Special Interest .......... 110 
5.5 
Type and Duration of Follow-Up of Patients after 
Adverse Events ................................................................... 110 
5.6 
Post-Study Adverse Events................................................. 110 
6. 
INVESTIGATOR REQUIREMENTS.......................................................... 111 
6.1 
Study Initiation..................................................................... 111 
6.2 
Study Completion ................................................................ 112 
6.3 
Informed Consent Form....................................................... 112 
6.4 
Communication with the Institutional Review 
Board or Ethics Committee.................................................. 113 
6.5 
Study Monitoring Requirements .......................................... 114 
6.6 
Electronic Case Report Forms............................................. 114 
6.7 
Source Data Documentation................................................ 114 
6.8 
Use of Computerized Systems ............................................ 115 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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TABLE OF CONTENTS (cont.) 
 
 
Page 
6.9 
Study Medication Accountability.......................................... 115 
6.10 
Disclosure of Data ............................................................... 116 
6.11 
Retention of Records........................................................... 116 
REFFERENCES............................................................................................... 117 
 
 
LIST OF TABLES 
Table 1 
Management of Infusion-Related Symptoms .............................. 81 
Table 2 
Adverse Event Grading (Severity) Scale................................... 104 
Table 3 
Causal Attribution Guidance ..................................................... 104 
 
 
LIST OF FIGURES 
Figure 1 
CD22 Expression Levels on B-Cell Tumor Cells......................... 42 
Figure 2 
CD79b Expression Levels on B-Cell Tumor Cells....................... 47 
Figure 3 
Study Schema ............................................................................. 56 
 
 
LIST OF APPENDICES 
Appendix A-1 
Study Flowchart: Initial Study Treatment.............................. 120 
Appendix A-2 
Study Flowchart: Crossover Treatment (Patients 
Randomized to Arms A or B Only) ....................................... 125 
Appendix A-3 
Study Flowchart: Post-Treatment Follow-Up........................ 128 
Appendix B–1 
Serum and Plasma Pharmacokinetic Schedule for 
DCDT2980S/DCDS4501A and Rituximab, and ATA 
Schedule for DCDT2980S/DCDS4501A (For Patients 
Receiving Rituximab on Day 1 and 
DCDT2980S/DCDS4501A on Day 2 of Every Cycle) ........... 130
Appendix B–2 
Serum and Plasma Pharmacokinetic Schedule for 
Rituximab and DCDT2980S/DCDS4501A, and ATA 
Schedule for DCDT2980S/DCDS4501A for Patients 
Receiving Rituximab and DCDT29808S/DCDS4501A on 
Day 1 of Every Cycle Beginning Cycle 3 .............................. 132 
Appendix C 
Modified Response and Progression Criteria for NHL.......... 134 
Appendix D 
Anaphylaxis Management .................................................... 138
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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TABLE OF CONTENTS (cont.) 
 
 
Page 
Appendix E 
M. D. Anderson Symptom Inventory (MDASI) ...................... 139 
Appendix F 
Recommendations for the Use of White Blood Cell 
Growth Factors..................................................................... 141 
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A RANDOMIZED, OPEN-LABEL, MULTICENTER, 
PHASE II TRIAL EVALUATING THE SAFETY AND 
ACTIVITY OF DCDT2980S IN COMBINATION WITH 
RITUXIMAB OR DCDS4501A IN COMBINATION WITH 
RITUXIMAB IN PATIENTS WITH RELAPSED OR 
REFRACTORY B-CELL NON-HODGKIN’S 
LYMPHOMA 
PROTOCOL NUMBER: 
GO27834 
EUDRACT NUMBER: 
2011-004377-84 
STUDY DRUG: 
DCDT2980S; DCDS4501A 
IND: 
107713 
MEDICAL MONITOR: 
 M.D. 
SPONSOR: 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA  94080-4990  U.S.A. 
DATE FINAL: 
27 July 2012 
DATE AMENDED: 
Version 1:  See electronic date on cover page 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return a copy of the form to the CRO Monitor at your site.  Please retain the 
original for your study files. 
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
26/P GO27834 A-1


PROTOCOL SYNOPSIS 
TITLE: 
A RANDOMIZED, OPEN-LABEL, MULTICENTER, PHASE II 
TRIAL EVALUATING THE SAFETY AND ACTIVITY OF 
DCDT2980S IN COMBINATION WITH RITUXIMAB OR 
DCDS4501A IN COMBINATION WITH RITUXIMAB IN 
PATIENTS WITH RELAPSED OR REFRACTORY B-CELL 
NON-HODGKIN’S LYMPHOMA 
PROTOCOL NUMBER: 
GO27834 
EUDRACT NUMBER: 
2011-004377-84 
STUDY DRUG: 
DCDT2980S; DCDS4501A 
PHASE: 
II 
INDICATION: 
Relapsed or refractory B-cell NHL  
IND: 
107713 
SPONSOR: 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA  94080-4990  U.S.A. 
DATE FINAL: 
27 July 2012 
DATE AMENDED: 
Version 1:  See electronic date on cover page 
 
Objectives 
Primary Objectives 
The primary objectives of this study are the following: 
• 
To assess the safety and tolerability of the combination of DCDT2980S and rituximab 
administered to patients with relapsed or refractory follicular NHL and DLBCL 
• 
To assess the safety and tolerability of the combination of DCDS4501A and rituximab 
administered to patients with relapsed or refractory follicular NHL and DLBCL 
• 
To assess the anti-tumor activity of the combination of DCDT2980S and rituximab in 
patients with relapsed or refractory follicular NHL and DLBCL 
• 
To assess the anti-tumor activity of the combination of DCDS4501A and rituximab in 
patients with relapsed or refractory follicular NHL and DLBCL 
Secondary Objectives 
The secondary safety objectives of this study are the following: 
• 
To assess the incidence of antibody formation to DCDT2980S and DCDS4501A 
• 
To compare the safety and tolerability of the combination of DCT2980S and rituximab and 
DCDS4501A and rituximab 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
27/P GO27834 A-1


Activity Objective 
The secondary activity objective of the study is the following: 
• 
To compare the anti-tumor activity of the combination of DCT2980S and rituximab and 
DCDS4501A and rituximab 
Pharmacokinetic Objectives 
The PK objectives of this study are the following: 
• 
To characterize the pharmacokinetics of DCDT2980S and rituximab in patients with 
relapsed or refractory NHL when the two drugs are given in combination 
• 
To characterize the pharmacokinetics of DCDS4501A and rituximab in patients with 
relapsed or refractory NHL when the two drugs are given in combination 
Study Design 
This is a Phase II, multicenter, open-label study.  A total of approximately 140−160 patients 
(approximately 60−80 patients with relapsed or refractory follicular NHL and approximately 
80 patients with relapsed/refractory DLBCL) will be enrolled at approximately 30–40 
investigative sites worldwide.  Additional patients may be enrolled in order to obtain additional 
safety and/or efficacy data. 
Randomized Portion of the Study (Arms A and B) 
Following determination of eligibility, patients within each disease group will be randomized in a 
1:1 ratio to receive one of two treatments: 
• 
Arm A: Rituximab (375 mg/m2) followed by DCDT2980S (2.4 mg/kg) every 21 days; 
• 
Arm B: Rituximab (375 mg/m2) followed by DCDS4501A (2.4 mg/kg) every 21 days 
The first day of treatment constitutes Day 1 of each cycle.  A typical cycle is 21 days in duration. 
A dynamic hierarchical randomization scheme will be employed with respect to the following 
stratification factors: 
• 
For patients with follicular lymphoma (see Section 3.1.1 for definitions) 
Rituximab refractory disease (no response or disease relapse < 6 months from last 
rituximab treatment) vs. rituximab relapsed disease (disease relapse after 
response ≥ 6 months from last rituximab treatment) 
• 
For patients with DLBCL (see Section 3.1.2 for definitions) 
Second-line vs. third-line (or beyond) therapy 
For second-line patients, disease relapse or no objective response (CR, CRu or PR) 
<12 months from the start of initial therapy versus disease relapse, after initial objective 
response (CR, CRu or PR), ≥12 months from start of initial therapy  
For third-line patients, failure to achieve a CR or progression < 6 months of start of most 
recent therapy versus CR or progression ≥ 6 months from start of most recent therapy 
No formal testing comparing the two treatment arms in the randomized portion of the study 
is planned. 
Nonrandomized Portion of the Study (Cohorts C and D) 
Only select investigator sites that have agreed to participate in the nonrandomized portion of 
the study will enroll patients into these cohorts. 
Patients with relapsed or refractory follicular NHL will be enrolled in Cohorts C and D to 
receive rituximab (375 mg/m2) combined with DCDT2980S or DCDS4501A at a dose of 
1.8 mg/kg.  The first day of treatment constitutes Day 1 of each cycle.  A typical cycle will be 
21 days in duration. 
The opening of either or both cohorts will be at the Sponsor’s discretion and only after the 
enrollment of follicular lymphoma patients into the randomized portion of the study is 
completed.  Patients will not be randomized to receive one treatment or the other.  It is 
anticipated that Cohort C and D will be opened sequentially.   
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
28/P GO27834 A-1


All Patients 
All patients, regardless of assigned arm/cohort will receive DCDT2980S or DCDS4501A and 
rituximab administered by IV infusion on a 21-day cycle.  For the first two cycles, rituximab will 
be administered by IV infusion on Day 1 and DCDT2980S or DCDS4501A will be administered 
by IV infusion on Day 2.  In the absence of any infusion-related adverse events, rituximab and 
DCDT2980S or DCDS4501A may be administered on the same day (Day 1) in subsequent 
cycles beginning with the third cycle.  In this instance, rituximab will be administered first, 
followed by DCDT2980S or DCDS4501A.  In certain circumstances, e.g., infusion-related 
reactions requiring interruption or slowing of infusion rate, rituximab may be administered over 
2 days, e.g., Day 1 and Day 2 of the cycle; in this case, DCDT2980S or DCDS4501A may be 
administered on Day 2 following completion of the rituximab infusion or on Day 3 of the cycle. 
Patients may receive treatments for up to 1 year (17 cycles on an every-21-day schedule) if not 
discontinued due to significant toxicity, disease progression, or withdrawal from study. 
Patients will be evaluated for safety and efficacy according to the schedules of assessments 
outlined in Appendices A-1, A-2, and A-3.  Initial response assessments in this study will be 
performed every 3 months from the initiation of therapy until study treatment completion or early 
termination (e.g., between Days 14 and 21 of Cycles 4 and 8 for those patients receiving at 
least eight 21-day cycles of treatment).  Additional response assessments for patients who 
proceed to crossover treatment (see Section 3.1.3) will be performed as described in 
Appendix A-2; response assessments for patients who discontinue study treatment 
(both initially assigned treatment and crossover treatment) for reasons other than disease 
progression will be performed as described in Appendix A-3. 
Responses to study treatment will be based on investigator assessments.  In addition, tumor 
assessment data will be transmitted to an Independent Review Facility (IRF) for collection and 
possible independent review. 
Follicular NHL Cohort 
Patients with relapsed or refractory follicular NHL will be enrolled into the study as defined by 
the following: 
• 
Relapsed to regimens containing rituximab, defined as documented history of response 
(complete response [CR], unconfirmed CR [CRu], or partial response [PR]) of ≥ 6 months in 
duration from completion of all prior rituximab-containing regimens.  A rituximab-containing 
regimen is defined as rituximab as a single agent during induction and/or maintenance, or in 
combination with other agents during induction and/or maintenance. 
• 
Refractory to any prior regimen containing rituximab, defined as no response to, 
or progression within 6 months of completion of, the last dose of rituximab therapy 
(either as monotherapy or in combination with chemotherapy), including: 
Patients with progressive disease while receiving rituximab monotherapy, 
rituximab combined with chemotherapy, or rituximab maintenance therapy; patients 
must have received at least one full dose (375 mg/m2) of rituximab 
Patients with no objective response (PR or CR) to a rituximab-containing regimen 
consisting of at least 4 weekly doses of rituximab monotherapy or at least 4 cycles of 
rituximab combined with chemotherapy 
Patients with disease relapse, after having achieved an objective response, within 
6 months of completion of the last dose of rituximab therapy in a regimen consisting of at 
least four weekly doses of rituximab monotherapy or at least 4 cycles of 
rituximab combined with chemotherapy 
 
Enrollment of patients with refractory disease as defined above may be limited to no greater 
than 60% of the total Follicular NHL cohort, in order to avoid overrepresentation of the refractory 
disease population. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
29/P GO27834 A-1


DLBCL Cohort 
Patients with relapsed or refractory DLBCL who are determined by the investigator to be 
ineligible for high dose therapy with autologous stem cell rescue/stem cell transplant (SCT) as 
determined by the investigator will be enrolled into the study as defined by the following: 
• 
Second-line SCT-ineligible patients with progressive disease or no response 
(SD) < 12 months from start of initial therapy (2L refractory) 
• 
Second-line SCT-ineligible patients with disease relapse after initial response ≥ 12 months 
from start of initial therapy (2L relapsed) 
• 
Third-line (or beyond) SCT-ineligible patients with progressive disease or no response 
(SD) < 6 months from start of prior therapy (3L + refractory) 
• 
Third-line (or beyond) SCT-ineligible patients with disease relapse after initial response 
≥ 6 months from start of prior therapy (3L+ relapsed) 
 
Enrollment to any of the above four categories may be limited to no greater than 40% of the 
DLBCL cohort—and to no more than 60% of the two refractory categories combined—in order 
to avoid overrepresentation of any specific subpopulation, refractory patients in particular. 
Crossover Treatment (Randomized Patients Only) 
Patients randomized to Arm A or Arm B who develop progressive disease may be eligible to 
receive crossover treatment consisting of rituximab and the other ADC, or the other ADC alone, 
e.g., Arm B treatment for patients who have disease progression while receiving Arm A 
treatment and vice versa, provided the following conditions are met: 
• 
Patients must not have experienced a toxicity requiring the discontinuation of 
DCDT2980S/DCDS4501A treatment OR experienced toxicity during the last dose of study 
treatment that would preclude treatment with the crossover regimen. 
Patients who had modifications to dosing and/or schedule on the initial study treatment 
will be permitted to receive crossover treatment in the absence of toxicities on the 
modified dose and/or schedule.  The dose and schedule of crossover treatment will be 
determined by the investigator and the Medical Monitor. 
Patients who had rituximab discontinued and continued on single-agent 
DCDT2980S/DCDS4501A treatment may receive crossover treatment of single-agent 
DCDS4501A/ DCDT2980S  
• 
Patients must have radiographically documented disease progression 
• 
Patients must meet all inclusion and exclusion criteria described in Sections 4.1.1 and 
4.1.2, except for those related to prior rituximab treatment. 
• 
Acceptable toxicity:  All study drug–related adverse events from the initial study treatment 
must have decreased to Grade 1 or baseline grade on or before the first day of treatment 
on the crossover regimen.  Exceptions may be allowed after a careful assessment 
and discussion of the risk-benefit balance with the patient by the investigator and approval 
from the Medical Monitor. 
• 
Administration of crossover treatment must be in the best interests of the patient 
as determined after a careful assessment and discussion of risk-benefit balance with the 
patient by the investigator and approval from the Medical Monitor. 
• 
A tumor biopsy will be required for patients with safely accessible site of disease, defined as 
requiring only local anesthesia and in general excluding brain, lungs or any internal organs 
that may subject patients to significant risk.  
Patients for whom a safely accessible site of disease is not present may still receive 
crossover treatment without undergoing a biopsy.  Eligibility to receive crossover 
treatment should be discussed with and approved by the Medical Monitor. 
A tumor biopsy of a safely accessible site of disease is optional for patients who are not 
eligible for study cross over.  
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
30/P GO27834 A-1


Patients who are determined to be eligible for study crossover will be treated as follows: 
• 
Assessments obtained at the initial study treatment discontinuation visit may be used as 
screening assessments for crossover treatment.  The following re-screening assessments 
must be repeated/obtained within 1 week prior to starting treatment on the crossover 
regimen in order to re-establish baseline pretreatment clinical and disease status:  targeted 
physical exam, ECOG status and hematology and serum chemistry laboratories. 
Re-screening tests for Hepatitis B and C do not need to be performed unless there is 
clinical suspicion of Hepatitis B and/or C positivity. 
A radiographic tumor assessment must also be performed, unless already done to 
document disease progression, within 6 weeks prior to starting crossover treatment. 
• 
Crossover treatment will begin no later than 42 days after the last dose of the prior study 
treatment. 
Patients will be treated with the crossover treatment until a second disease progression event 
relative to the tumor assessment documenting progressive disease on the initial study 
treatment, clinical deterioration and/or intolerance to the crossover treatment for up to a 
maximum of 1 year (17 cycles on an every-21-day schedule).  Patients will be evaluated for 
safety and efficacy according to the schedules of assessments outlined in Appendices A-2.  
Response assessments for patients who discontinue study treatment for reasons other than 
disease progression will be performed as described in Appendix A-3.  
Clinical data and exploratory data derived from tumor biopsies obtained prior to crossover 
treatment will be monitored on an ongoing basis.  Genentech has the right to restrict or suspend 
enrollment into crossover treatment at any time.  Reasons for this may include, but are not 
limited to, the following: 
• 
The incidence or severity of adverse events during crossover treatment indicates a potential 
safety hazard to patients. 
• 
Patient enrollment into crossover treatment is unsatisfactory. 
• 
Data recording is inaccurate or incomplete. 
• 
Patients who are enrolled into the nonrandomized portion of the study (Cohorts C and D) 
will not have the option to receive crossover treatment upon disease progression. 
Outcome Measures 
Safety Outcome Measures 
The safety and tolerability of the combination of DCDT2980S and rituximab and DCDS4501A 
and rituximab will be assessed using the following safety outcome measures: 
• 
Incidence, nature, and severity of adverse events 
• 
Incidence of anti-DCDT2980S or anti-DCDS4501A antibodies 
• 
Changes in vital signs 
• 
Changes in laboratory values 
Pharmacokinetic/Pharmacodynamic Outcome Measures 
The following PK parameters will be derived from the serum concentration–time profiles of total 
antibody (the sum of conjugated and unconjugated antibody), including rituximab, and plasma 
concentration-time profiles of antibody conjugated-MMAE (acMMAE) and free MMAE following 
administration of DCDT2980S or DCDS4501A, when appropriate as data allow: 
• 
Total exposure (area under the concentration-time curve [AUC]) 
• 
Maximum plasma and serum concentration (Cmax) 
• 
Clearance (CL) 
• 
Terminal half-life (t1/2) 
• 
Steady state volume of distribution (Vss). 
Compartmental, non-compartmental, and/or population methods may be used.  Other 
parameters, such as accumulation ratio and trough plasma and serum concentration (Cmin), 
may also be calculated. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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The following PD outcome measures will be assessed when appropriate, as data allow: 
• 
Peripheral blood B-cell depletion and recovery.  For each visit at which CD19+ B-cell 
measurements are taken, B-cell data will be listed for each patient by dose level as follows: 
Absolute blood cell counts 
Percent change relative to the baseline blood counts 
CD19+ B-cell recovery, defined as the timepoint when the values return to baseline 
levels or ≥ 50% of baseline levels 
Activity Outcome Measures 
The following activity outcome measures will be assessed: 
• 
Objective response, defined as a PR or CR 
• 
Duration of objective response, defined as the first occurrence of a documented objective 
response until the time of relapse or death from any cause 
• 
Progression-free survival (PFS), defined as the date of randomization to the first occurrence 
of progression or death within 30 days of the last administration of study drug, whichever 
occurs first 
• 
Overall survival (OS), defined as the time from the date of randomization to the date of 
death from any cause 
Objective response and disease progression will be determined using standard criteria for NHL 
(Cheson et al. 2007; see Appendix C). 
 
Safety Plan 
See Section 5 (Assessment of Safety) for complete details of the safety evaluation for this 
study. 
Safety will be evaluated through the monitoring of the following: 
• 
Serious adverse events that are attributed to protocol-mandated interventions from the time 
of signing informed consent until the first dose of study treatment on Cycle 1, Day 1 
• 
All adverse events from Cycle 1, Day 1 until 30 days after the last dose of DCDT2980S, 
DCDS4501A or rituximab whichever is later, including doses that were administered as part 
of crossover treatment 
• 
All serious adverse events from Cycle 1, Day 1 until 30 days after the last dose of 
DCDT2980S, DCDS4501A or rituximab whichever is later, including doses that were 
administered as part of crossover treatment 
• 
All serious adverse events from the last dose of DCDT2980S, DCDS4501A or rituximab 
whichever is later, including doses that were administered as part of crossover treatment, 
and which is judged to be caused by DCDT2980S, DCDS4501A or rituximab, regardless of 
time of onset 
• 
Measurements of protocol-specified hematology and clinical chemistry laboratory values 
• 
Measurements of protocol-specified vital signs 
• 
Assessment of ECGs 
• 
Assessment of physical findings on clinical physical examinations 
Patients who have an ongoing study drug-related adverse event will be followed until the event 
has resolved to baseline grade, the event is assessed by the investigator as stable, 
new anti-tumor treatment is initiated, the patient is lost to follow-up, the patient withdraws 
consent, when it has been determined that the study treatment or participation is not the cause 
of the adverse event, or the study is terminated. 
See Section 5.2.3 for assessment of causality for adverse events. 
INTERNAL MONITORING COMMITTEE (IMC) 
This study will employ an Internal Monitoring Committee (IMC).  The purpose of the IMC will be 
to make recommendations regarding study conduct on the basis of trial safety data to ensure 
patient safety while receiving study treatment. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
32/P GO27834 A-1


The IMC will include a sponsor Medical Monitor not affiliated with the study, Drug Safety 
Scientist, biostatistician, and statistical programmer.  Representatives from other Sponsor 
functional areas may be included as additional ad hoc members. 
In addition to the ongoing assessment of the incidence and nature of adverse events, serious 
adverse events, and laboratory abnormalities by the Investigator and the Medical Monitor, the 
IMC will review the aforementioned data at least twice during the study.  The first planned 
review will occur after approximately 10 patients are randomized and have at least 6 weeks 
follow-up and the next formal review will occur when approximately 60 patients are randomized 
and have at least 6 weeks follow-up.  Additionally, the IMC will meet as needed at the request of 
the Medical Monitor, e.g., based on unexpected safety signals.  The IMC may make 
recommendations regarding study conduct, including but not limited to: performing additional 
safety analyses, amending the study protocol, holding patient enrollment to one or both 
treatment arms pending further safety evaluations, holding/discontinuing study treatment, or 
terminating the study. 
Complete details of the IMC will be described in the IMC charter. 
Risks Associated with DCDT2980S and DCDS4501A 
The clinical safety profile of DCDT2980S and DCDS4501A based on clinical data obtained in 
the ongoing Phase I studies are summarized in Sections 1.2.1.2 and 1.2.2.2.  Based on clinical 
data to date, the following known and suspected risks are described below.  Guidelines around 
the management of these risks through dose and schedule modifications are described in 
Sections 4.3.1 and 4.3.2.  Refer also to the Investigator Brochure for complete and updated 
details. 
Infusion-Related Events 
Some monoclonal antibodies may be associated with the development of allergic or 
anaphylactic reactions, to either the active protein or excipients.  True allergic/anaphylactic 
reactions are rare after the first dose of a product, as they require prior sensitization.  Patients 
with true allergic/anaphylactic reactions should not receive further doses of the product.  
Monoclonal antibodies may also be associated with reactions that are clinically indistinguishable 
from true allergic/anaphylactic reactions, but which are mediated through direct release of 
cytokines or other pro-inflammatory mediators.  Such reactions are often termed 
infusion-related reactions.  Infusion-related reactions typically occur with the first infusion of a 
monoclonal antibody product and are generally less frequent and/or less severe with 
subsequent infusions.  They can often be managed by slowing the infusion rate and/or 
pre-treatment with various medications. 
Allergic/anaphylactic reactions and infusion-related reactions typically begin during or within 
several hours of completing the infusion.  The onset of symptoms may be rapid, and some 
reactions may be life threatening. 
Patients should be monitored for these types of reactions during and after receiving 
DCDT2908S and DCDS4501A.  DCDT2980S and DCDS4501A should be administered in an 
environment under close supervision of a physician and where full resuscitation facilities are 
immediately available.  Specific guidelines for additional precautions to be taken during and 
following DCDT2980S and DCDS4501A administration are provided in Sections 4.3.1.5. 
Tumor Lysis Syndrome 
There is a potential risk of tumor lysis syndrome (TLS) if treatment with DCDT2980S or 
DCDS4501A results in the rapid destruction of a large number of tumor cells.  If any evidence of 
this occurs during the study, tumor lysis prophylaxis measures will be instituted.  Patients who 
are considered to have a high tumor burden, e.g., lymphocyte count ≥ 25 x 109/L or bulky 
lymphadenopathy and who are considered to be at risk for tumor lysis by the investigator will 
receive tumor lysis prophylaxis, e.g., allopurinol ≥ 300 mg/day orally or a suitable alternative 
treatment according to institutional practice starting 12−24 hours prior to study treatment, and 
must be well hydrated prior to the initiation of study treatment at Cycle 1, Day 1.  These patients 
should continue to receive repeated prophylaxis with allopurinol and adequate hydration prior to 
each subsequent infusion as deemed appropriate by the investigator. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
33/P GO27834 A-1


Bone Marrow Toxicity/Neutropenia 
Based on preclinical toxicity studies in rats and cynomolgus monkeys and clinical data from the 
ongoing Phase I studies DCT4862g and DCS4968g, neutropenia has been identified as a 
known risk (adverse drug reaction) of both DCDT2908S and DCDS4501A.  Neutropenia and 
neutropenia-associated events were reversible but in some cases resulted in 
protocol-mandated dose reductions and/or delays.   
Adequate hematologic function should be confirmed before initiation of study treatment.  
Patients receiving study treatment will be regularly monitored for evidence of marrow toxicity 
with complete blood counts.  Treatment for hematologic toxicities may be delayed or modified 
as described in Section 4.3.1.  
The use of G-CSF for neutropenia is described in Section 4.3.1.6.  Transfusion support for 
anemia and thrombocytopenia is also permitted at the discretion of the treating physician. 
Immunogenicity 
As expected with any recombinant antibody, DCDT2980S and DCDS4501A may elicit an 
immune response and patients may develop antibodies against DCDT2980S and DCDS4501A.  
Patients will be closely monitored for any potential immune response to DCDT2980S and 
DCDS4501A.  Appropriate screening and confirmatory assays will be employed to detect ATAs 
at multiple timepoints before, during, and after treatment with DCDT2980S or DCDS4501A.   
Considering the historically low immunogenicity rate of rituximab in NHL patients, ATAs against 
rituximab will not be monitored in this study. 
Peripheral Sensory Neuropathy 
Based on clinical data from the ongoing Phase I studies DCT4862g and DCS4968g and data 
from brentuximab vedotin, an anti-CD30-vc-MMAE ADC (see Section 3.4.2) peripheral sensory 
neuropathy has been identified as a known risk (adverse drug reaction) for both DCDT2980S 
and DCDS4501A. 
Patients should be monitored for signs of neuropathy or worsening neuropathy and appropriate 
action taken per protocol guidelines.  Study treatment dose and schedule modifications for 
significant and prolonged neuropathic toxicity and dose-reduction are described in 
Section 4.3.1.7.   
Reproductive Toxicity 
Adverse effects on human reproduction and fertility are anticipated with the administration of 
DCDT2980S and DCDS4501A given the mechanism of action of MMAE.  Standard exclusion 
criteria will be used to ensure that patients of childbearing potential (male or female) are using 
adequate contraceptive methods.  
Hyperglycemia 
Hyperglycemia has been observed in patients treated with DCDT2980S and DCDS4501A as 
well as with other antibody-drug conjugates using the same vc-MMAE platform.  
Hyperglycemia has been reversible upon holding or discontinuing treatment of the ADCs 
and/or initiation or adjustment of anti-hyperglycemic medications. 
Hepatotoxicity 
Hepatotoxicity is a potential risk of the ADCs.  Definitive attribution of hepatotoxicity to the 
ADCs has not been established.  Transient dose-related increases in hepatic enzyme levels 
were observed in rats treated with DCDT2980S and DCDS4501A.  Elevations in 
transaminase and/or bilirubin levels requiring dose modifications have been reported in the 
ongoing clinical studies. 
 
Study Treatment 
DCDT2980S-Specific Information 
DCDT2980S will be administered to patients by IV infusion.  Compatibility testing has shown 
that DCDT2980S is stable when diluted in polyvinyl chloride (PVC) bags to a concentration at or 
above 0.04 mg/mL in 0.9% NaCl diluent.  The Drug Product will be delivered following dilution in 
0.9% NaCl with a final DCDT2980S concentration determined based on dose and patient 
weight.  The study drug will be diluted in a PVC bag and delivered using a 0.22µm in-line filter 
on the IV infusion set. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
34/P GO27834 A-1


Additional information/instructions regarding study drug administration will be provided in the 
Pharmacy Binder. 
DCDS4501A-Specific Information 
DCDS4501A will be administered to patients by IV via syringe pump with IV infusion set 
containing a 0.22 µm in-line filter with a final volume of DCDS4501A determined by the 
dose and patient weight.  Compatibility testing has shown that DCDS4501A is stable in both 
syringes made of polypropylene (PP) and in standard extension sets with 0.22 µm in-line 
filter, when stored neat or diluted with 0.9% NaCl saline.   
Additional information/instructions regarding study drug administration will be provided in the 
Pharmacy Binder. 
General Information 
The total dose of DCDT2980S and DCDS4501A for each patient will depend on the patient’s 
weight within 96 hours prior to Day 1 of each cycle.  The patient weight obtained during 
screening may be used for dose determination at all treatment cycles; if the patient’s weight 
within 96 hours prior to Day 1 of a given treatment cycle differs by >10% from the weight 
obtained during screening, then the new weight should be used to calculate the dose.   
For both DCDT2980S and DCDS4501A, the initial dose will be administered to well-hydrated 
(based on clinical judgment) patients over 90 (± 10) minutes.  Pre-medication with 
acetaminophen or paracetamol (e.g., 500–1000 mg) and diphenhydramine (e.g., 50–100 mg) 
per institutional standard practice may be administered prior to each infusion.  Administration of 
corticosteroids is permitted at the discretion of the treating physician.  For patients who do not 
receive pre-medications prior to the first dose of DCDT2980S and who develop an infusion 
related reaction during the first dose should receive pre-medications prior to subsequent doses 
(see Table 1). 
The DCDT2980S/DCDS4501A infusion may be slowed or interrupted for patients experiencing 
infusion-associated symptoms.  Following the initial dose, patients will be observed for 
90 minutes for fever, chills, rigors, hypotension, nausea, or other infusion-associated symptoms.  
If the infusion is well-tolerated, subsequent doses of DCDT2980S/DCDS4501A may be 
administered over 30 (± 10) minutes, followed by a 30-minute observation period post-infusion.   
For further details, see Section 4.3 
Concomitant Therapy and Clinical Practice 
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a patient between the 7 days preceding the screening evaluation and the end of study 
visits.  All concomitant medications should be reported to the investigator and recorded on the 
appropriate electronic Case Report Form (eCRF). 
Patients who use oral contraceptives, hormone-replacement therapy, or other maintenance 
therapy should continue their use.  Concomitant use of hematopoietic growth factors is allowed 
in accordance with instructions provided in the package inserts. 
Patients who experience infusion-related temperature elevations of > 38.5°C (> 101.3°F) or 
other minor infusion-related symptoms may be treated symptomatically with 
acetaminophen/paracetamol (≥ 500 mg) and/or H1 and H2 histamine-receptor antagonists 
(e.g., diphenhydramine, ranitidine).  Serious infusion-related events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory 
distress should be managed with additional supportive therapies (e.g., supplemental oxygen, 
β2-agonists, and/or corticosteroids) as clinically indicated according to standard clinical practice.   
Infusion reaction prophylaxis with medications (e.g., acetaminophen/paracetamol, 
antihistamines, and/or corticosteroids) may be instituted at any point in the study if it is 
determined to be in the best interest of the patient based on observation of IRRs in patients 
already enrolled in the study.  Patients with Grade 3 hypotension or fever must be 
pre-medicated prior to retreatment.  Patients with hypotension requiring vasopressor support, or 
with Grade 3 wheezing, hypoxia, or generalized urticaria, must be permanently discontinued 
from study treatment. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
35/P GO27834 A-1


Excluded Therapy 
Use of the following therapies is prohibited during the study: 
• 
Cytotoxic chemotherapy 
• 
Radiotherapy 
• 
Immunotherapy including immunosuppressive therapy 
• 
Radioimmunotherapy 
• 
Hormone therapy (other than contraceptives, hormone-replacement therapy, or 
megestrol acetate) 
• 
Biologic agents (other than hematopoietic growth factors, which are allowed if clinically 
indicated and used in accordance with instructions provided in the package inserts); 
guidelines for the use of G-CSF are detailed in Section 4.3.1.6 and Appendix F. 
• 
Any therapies intended for the treatment of lymphoma or leukemia, whether approved by 
local regulatory authorities or investigational 
 
Patients who require the use of any of these agents will be discontinued from all study 
treatment.  Patients who are discontinued from study treatment will be followed for safety 
outcomes for 30 days following the patient’s last dose of DCDT2980S or DCDS4501A or 
rituximab, whichever is later, or until the patient receives another anti-cancer therapy whichever 
occurs first. 
Statistical Methods 
Safety Analysis 
Safety will be assessed through summaries of adverse events, changes in laboratory test 
results, changes in physical findings on physical examinations, and changes in vital signs.  
All patients who receive any amount of DCDT2980S, DCDS4501A or rituximab will be included 
in the safety analysis and will be assigned to the treatment group based on the study treatment 
received.  Patients who have dose level changes from the initial assigned dose level will be 
summarized by the initial assigned dose level of DCDT2980S or DCDS4501A. 
All adverse event data will be listed by study site, patient number, treatment group, 
disease-specific cohort, and cycle.  All adverse events occurring on or after treatment on Day 1 
of Cycle 1 will be summarized by mapped terms, appropriate thesaurus levels, and 
NCI CTCAE v4.0 toxicity grade.  In addition, all serious adverse events, including deaths will be 
listed separately and summarized.   
Selected laboratory data will be listed, with values outside of normal ranges identified.  The 
incidence of antibodies to DCDT2980S and DCDS4501A will be summarized. 
Activity Analysis 
Best overall response, duration of response, and PFS will be listed for all patients. 
Objective response rate from the initial study treatment will be calculated based on data from 
patients who received study treatment and had at least one post-baseline response 
assessment.  Objective response is defined as complete response (CR) or partial response 
(PR) as determined by the investigator, based on physical examinations, radiographic scans, 
and bone marrow examinations, using modified response criteria for NHL (Cheson et al. 2007; 
see Appendix C), and confirmed by repeat assessments ≥ 4 weeks after initial documentation.  
Any patient with insufficient data to determine response will be classified as a non-responder. 
For patients with DLBCL, primary assessment of tumor response will be based on diagnostic 
imaging scans, e.g., CT and/or MRI, and PET scans.  For patients with FL, primary assessment 
of response will be based on CT scans only; the assessment of response in FL based on 
PET scans will be performed for exploratory purposes only. 
Among patients with an objective response, duration of response will be defined as the time 
from the initial CR or PR to the time of disease progression or death.  If a patient does not 
experience death or disease progression before the end of the study, duration of response will 
be censored at the day of the last tumor assessment. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
36/P GO27834 A-1


For the randomized portion of the study (Arms A and B), PFS is defined as the time from the 
date of randomization to the date of disease progression or death from any cause, whichever 
occurs first.  If a patient has not experienced progressive disease or death, PFS will be 
censored at the day of the last tumor assessment.  Patients with no post-baseline tumor 
assessment will be censored on the date of randomization.  For the nonrandomized portion of 
the study (Cohorts C and D), PFS is defined as the time from the date of study enrollment to 
the date of disease progression or death from any cause, whichever occurs first. 
For the randomized portion of the study (Arms A and B), overall survival is defined as the time 
from the date of randomization to the date of death from any cause.  For the nonrandomized 
portion of the study (Cohorts C and D), overall survival is defined as the time from the date of 
study enrollment to date of death from any cause. 
Missing Data  
For the endpoint of objective response, patients without a post-baseline tumor assessment will 
be considered non-responders in the all-treated population analysis.  
For duration of response and PFS, data from patients who are lost to follow-up will be included 
in the analysis as censored observations on the last date that the patient is known to be 
progression free, defined as the date of the last tumor assessment, or, if no tumor assessments 
were performed, as the date of last study treatment plus 1 day. 
Compliance to PRO data collection will be reported with summary statistics, including 
frequencies of reasons for non-compliance such as patient refusal to complete PRO data 
collection.   
Determination of Sample Size   
For the randomized portion of the study (Arms A and B), a target of 120 patients will be 
enrolled in two separate cohorts of patients (40 in the follicular NHL cohort and 80 in the DLBCL 
cohort).  Genentech has judged this sample size to provide sufficient precision in estimating the 
anti-tumor activity of DCDT2980S combined with rituximab or DCDS4501A combined with 
rituximab as measured by objective response.  For example, with the assumption of an 
observed response rate of 40%, a 90% confidence interval for the response rate would be 
approximately 22%−58% (i.e., 40% ± 18%) for the follicular NHL cohort and approximately 
27%−53% (i.e., 40% ± 13%) for the DLBCL cohort. 
This is a non-comparative hypothesis-generating study.  There is no formal hypothesis testing 
planned to compare the treatment arms.  Specifically, for the randomized portion of the study, 
there is insufficient power to detect minimum clinically meaningful differences between the two 
treatment arms. 
  
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
37/P GO27834 A-1


LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ADC 
antibody−drug conjugate  
ADCC 
antibody-dependent cellular cytotoxicity 
AE 
adverse event 
ALT 
alanine aminotransferase 
anti-HBc 
Hepatitis B core antibody 
AST 
aspartate aminotransferase 
ATA 
Anti-therapeutic antibody 
AUC 
area under the concentration-time curve 
CDC 
complement-dependent cytotoxicity  
CHOP 
cyclophosphamide, doxorubicin, vincristine, and prednisone 
CL 
clearance  
CLL 
chronic lymphocytic leukemia  
Cmax 
maximum plasma and serum concentration 
Cmin 
trough plasma and serum concentration 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVP 
cyclophosphamide, vincristine, and prednisone 
DLBCL 
diffuse large B-cell lymphoma 
EC 
ethics committee 
ECG 
electrocardiogram  
eCRF 
electronic Case Report Form  
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture  
ELISA 
enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
FACS 
fluorescence-activated cell sorting 
FDA 
Food and Drug Administration 
FL 
follicular lymphoma  
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
38/P GO27834 A-1


Abbreviation 
Definition 
HNSTD 
highest non-severely toxic dose 
ICH 
International Conference on Harmonisation 
IgG1 
IMC 
immunoglobulin-G1  
Internal Monitoring Committee 
IND 
Investigational New Drug 
iNHL 
indolent  
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IV 
intravenous 
IXRS 
Interactive Voice and Web Response System 
LC-MS/MS 
Liquid chromatography–tandem mass spectrometry 
MCL 
mantle cell lymphoma 
MC-VC-PABC 
maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl 
MDASI 
M.D. Anderson Symptom Inventory 
MFI 
mean fluorescence intensity 
MMAE 
monomethyl auristatin E  
MTD 
maximum tolerated dose  
MRI 
magnetic resonance imaging 
MZL 
marginal zone lymphoma 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphoma 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PET 
positron emission topography 
PD 
pharmacodynamic 
PFS 
progression-free survival 
PK 
pharmacokinetic  
PML 
progressive multifocal leukencephalopathy 
PR 
partial response 
PT 
prothrombin time 
PVC 
polyvinyl chloride 
RP2D 
recommended phase II dose 
SAE 
serious adverse event 
SCT 
stem cell transplant 
SD 
stable disease 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
39/P GO27834 A-1


Abbreviation 
Definition 
SDV 
source data verification 
SLL 
small lymphocytic lymphoma 
SWFI 
Sterile Water for Injection 
t1/2 
terminal half-life 
TLS 
tumor lysis syndrome  
ULN 
upper limit of normal 
Vss 
steady state volume of distribution 
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
40/P GO27834 A-1


1. 
BACKGROUND 
1.1 
BACKGROUND ON DISEASE  
B-cell lymphoproliferative disorders are a heterogeneous group of malignancies, ranging 
from slow-growing indolent and incurable diseases with a median survival of 8−10 years 
(such as follicular non-Hodgkin’s lymphoma [NHL]) to more aggressive intermediate- to 
high-grade lymphomas (such as diffuse large-cell lymphoma), which can have a median 
survival of 6 months if left untreated or long-term remission in more than 50% of patients 
with appropriate treatment.  Diffuse large B-cell lymphoma (DLBCL) is the most common 
type of NHL accounting for approximately 30%−40% of all new patients, whereas 
follicular lymphoma (FL) accounts for approximately 20%−25% of new lymphomas, 
respectively.   
Despite advances in the clinical outcomes of patients with NHL using treatments such as 
the CD20-specific monoclonal antibody rituximab (Rituxan®, MabThera®) in combination 
with chemotherapy, indolent B-cell malignancies remain incurable as are approximately 
half of aggressive NHL patients.  Thus, there is still a need for treatments that can be 
combined with chemoimmunotherapy and can significantly extend disease-free and 
overall survival in these patients, with at least acceptable, if not superior, safety profiles. 
1.2 
BACKGROUND ON THE MOLECULES 
1.2.1 
DCDT2980S 
1.2.1.1 
Background and Preclinical Data 
CD22 is a cell-surface antigen whose expression is restricted to all mature B cells except 
plasma cells.  It is expressed in a majority of the B-cell−derived malignancies, including 
nearly all NHL and chronic lymphocytic leukemia (CLL) samples tested (see Figure 1).  
Antibodies bound to CD22 are rapidly internalized, making CD22 ideally suited for 
targeted delivery of cytotoxic agents (Shan and Press 1995).   
DCDT2980S is an antibody−drug conjugate (ADC) that consists of a potent anti-mitotic 
agent, monomethyl auristatin E (MMAE) conjugated to a humanized immunoglobulin-G1 
(IgGI) anti-CD22 monoclonal antibody, MCDT2219A, via a protease-labile linker, 
maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-VC-PABC).  
MMAE has a mode of action similar to vincristine, which is a component of standard 
chemotherapy used in lymphoma therapy.  This therapeutic approach takes advantage 
of the specific targeting capability of the antibody and the cytotoxic activity of MMAE.  
Following internalization, the MMAE is deconjugated from DCDT2980S by lysosomal 
enzymes, binds to tubulin and disrupts the microtubule network, resulting in inhibition of 
cell division and cell growth and induction of apoptosis (Doronina et al. 2003).  
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
41/P GO27834 A-1


Figure 1 CD22 Expression Levels on B-Cell Tumor Cells 
0
1000
2000
3000
CLL
DLBCL
FL
MCL
MZL
0
1000
2000
3000
CLL
DLBCL
FL
MCL
MZL
 
CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; FL = follicular 
lymphoma; MCL = mantle cell lymphoma; MFI = mean fluorescence intensity; MZL =  marginal 
zone lymphoma. 
CD22 expression levels (MFI) on B-cell tumor cells were assessed by flow cytometry in patients 
diagnosed with the following B-cell lymphomas:  CLL (n = 49), DLBCL (n = 59), FL (n = 58), 
MCL (n = 20), and MZL (n = 60).  
 
Comprehensive pharmacology, pharmacokinetic (PK), pharmacodynamic (PD), and 
toxicology evaluations were conducted to support the use of DCDT2980S in clinical 
trials.  DCDT2980S binds human CD22 with a high affinity (equilibrium dissociation 
constant [Kd] = 1.7 ± 0.2 nM) and showed similar binding affinity to cynomolgus monkey 
CD22.  No binding activity was observed with mouse and rat peripheral blood 
mononuclear cells (PBMCs).   
The unconjugated antibody MCDT2219A did not appear to induce antibody-dependent 
cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) in vitro.  
In contrast, DCDT2980S displayed potent and selective inhibition of cell proliferation in 
vitro (50% of the maximal inhibitory concentration [IC50] = 0.33 nM) by cell viability 
assays.  Efficacy studies conducted in murine xenograft models of human lymphoma 
(CD22-positive WSU-DLCL2 and BJAB cell lines) showed that a single dose of 
DCDT2980S resulted in regression of tumor growth at doses ranging from 1 to 4 mg/kg.  
PD studies with DCDT2980S showed that a single dose of 1−6 mg/kg resulted in partial 
depletion of peripheral blood B-cells in cynomolgus monkeys with a corresponding 
depletion in germinal center B-cells in lymphoid tissue. 
The PK profiles of DCDT2980S were observed to be linear in rodents and moderately 
non-linear in cynomolgus monkeys over the tested dose range.  The non-linear 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
42/P GO27834 A-1


clearance (CL) observed in cynomolgus monkeys with DCDT2980S is likely due to the 
contribution of B-cell-mediated CL to the total clearance.  The free MMAE concentrations 
in cynomolgus monkeys following DCDT2980S administration were generally 
10000 times lower than the concentration of DCDT2980S.   
Cynomolgus monkeys were selected as the most relevant nonclinical species for the 
toxicology and PK/PD studies of DCDT2980S, given the comparable sequence 
homology of human and cynomolgus monkey CD22, similar binding affinity of 
DCDT2980S to human and cynomolgus monkey CD22, and comparable tissue 
cross-reactivity in both human and cynomolgus monkey tissues.  DCDT2980S was well 
tolerated at doses of up to 3 mg/kg (highest non-severely toxic dose [HNSTD]) in 
monkeys, and up to or greater than 10 mg/kg in rats (severely toxic dose to 10% of rats 
[STD10] ≥ 10 mg/kg).  Reversible bone marrow toxicity and associated hematopoietic 
changes were observed in both rats and monkeys treated with DCDT2980S or MMAE, 
suggesting that the toxicity of DCDT2980S is related to MMAE.  Additional effects on 
liver and lung in rats were minimal in severity and reversible, and did not occur in 
cynomolgus monkeys, which may be due to differences in species sensitivity, exposure, 
and/or pharmacokinetics.   
Complete details of preclinical studies of DCDT2980S can be found in the DCDT2980S 
Investigator’s Brochure. 
1.2.1.2 
DCDT2980S Clinical Data 
a. 
Patient Enrollment 
Both DCDT2980S monotherapy and combination therapy with rituximab have been 
studied in a Phase I study (DCT4862g) of patients with relapsed or refractory B-cell 
malignancies expected to express CD22, including indolent NHL, DLBCL, mantle cell 
lymphoma (MCL), and CLL. 
All data presented herein is based on a data entry cutoff of 22 February 2013, with 
clinical data available from 65 patients with NHL (excluding patients with CLL) enrolled 
in dose-escalation and expansion cohorts.  These include 49 patients who were treated 
with single-agent DCDT2980S at doses ranging from 0.1 to 3.2 mg/kg administered 
intravenously every 21 days, and 16 patients who were enrolled into two Phase Ib 
cohorts with DCDT2980S administered at doses of 1.8 mg/kg (5 patients) and 2.4 mg/kg 
(11 patients) in combination with 375 mg/m2 rituximab. 
Enrollment into CLL dose escalation cohorts was closed on 31 May 2013.  Refer to the 
DCDT2980S Investigator Brochure for details regarding clinical data in CLL patients. 
b. 
Pharmacokinetics 
The pharmacokinetics of DCDT2980S have been characterized in the Phase I Study 
DCT4862g.  DCDT2980S was administered to patients with NHL at dose levels ranging 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
43/P GO27834 A-1


from 0.1 to 3.2 mg/kg every-3-weeks (q3w).  Three analytes were quantified: 
antibody-conjugated MMAE (acMMAE), total antibody, and free MMAE.  
Preliminary pharmacokinetic analysis based on available data as of 22 June 2012 is 
summarized below.   
The mean value of CL estimates of acMMAE and total antibody of each dose level for 
doses of ≥ 1.0 mg/kg ranged from 17.6 to 21.3 mL/day/kg and from 10.5 to 
16.2 mL/day/kg, respectively.  Similar CL estimates for doses ≥ 1.0 mg/kg suggested 
dose proportional increase of acMMAE and total antibody exposure.  CL estimates 
appeared to be slightly higher at doses < 1.0 mg/kg (0.1, 0.25, and 0.5 mg/kg), although 
data from these dose levels is limited.  The CL of acMMAE was faster than total antibody 
at each dose level.   
In patients with NHL, the mean value of the volume of distribution (Vss) of acMMAE and 
total antibody of each dose level ranged from 69.2 to 130 mL/kg and from 97.4 to 
154 mL/kg, respectively, across the dose levels tested, approximating human serum 
volume.  Vss values did not appear to change substantially with dose.  The half-life for 
acMMAE and total antibody ranged from 2.9 to 7.0 days and from 4.4 to 13 days, 
respectively.   
For acMMAE and total antibody, the time to maximum concentration occurred 
immediately after infusion.  For free MMAE, the time to maximum concentration was 
approximately 2 to 3 days after infusion. Cmax and AUCinf of free MMAE appeared to 
increase with dose across the dose levels tested.  A half-life of 3–4 days for free MMAE 
was observed, which is relatively long and similar to its parent conjugate, suggesting 
formation rate limited kinetics of free MMAE.  No accumulation of free MMAE is 
expected for the q3w regimen.  The Cmax values of free MMAE in NHL patients were at 
least 100-fold lower compared to acMMAE concentrations at each dose level, 
suggesting a slow release of free MMAE from acMMME and potentially fast elimination 
once it is formed.    
Preliminary comparisons of PK between patients with NHL and CLL (for which patients 
are enrolled into separate dose-escalation cohorts) treated with identical doses of 
DCDT2980S provide some insight into the factors that affect PK.  Both acMMAE and 
total antibody were cleared faster in CLL patients than in NHL patients.  This observation 
is likely to be related to the high number of circulating B cells generally observed in CLL 
patients, which may result in significant target-mediated clearance of DCDT2980S.  
The free MMAE exposure in CLL patients was relatively low compared to its parent 
conjugate.   
The exposure parameters (Cmax and AUCinf) of total antibody, acMMAE and free MMAE 
were similar between DCDT2980S and DCDT2980S + rituximab at doses of 1.8 and 
2.4 mg/kg, based on preliminary data.  This observation suggests that, when given in 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
44/P GO27834 A-1


combination, rituxumab does not impact the PK of DCDT2980S; the effect of 
DCDT2980S on rituximab PK will be assessed.   
All observations will be verified with additional data from the ongoing Phase I study as 
well as this study.  
Refer to the DCDT2980S Investigator Brochure for complete and updated details. 
c. 
Safety 
Dose Limiting Toxicity 
Study DCT4862g utilizes a standard 3+3 dose-escalation cohort enrollment scheme.  
Patients enrolled into each dose-escalation cohort in Study DCT4862g have been 
observed for dose-limiting toxicities (DLT) for a minimum of 21 days after their first dose 
of DCDT2980S.  Any patient who did not complete the DLT observation period for any 
reason other than a DLT was replaced. 
Separate dose-escalation cohorts enrolled patients with B-cell NHL and CLL.  For the 
NHL dose escalation, DLTs of Grade 4 neutropenia occurred in 1 patient out of 
3 DLT-evaluable patients in the 3.2 mg/kg single agent cohort and 1 patient out of 
11 DLT-evaluable patients in the 2.4 mg/kg + rituximab cohort.  Consequently, 
DCDT2980S at 2.4 mg/kg was determined to be the recommended Phase II dose 
(RP2D) as both monotherapy and in combination with rituximab.   
For the CLL dose-escalation cohorts, one DLT was reported to date.  This Grade 5 event 
of febrile neutropenia resulted in the patient’s death.  While the contribution of the study 
drug to the neutropenia could not be completely ruled out, other factors, including bone 
marrow involvement of disease that resulted in baseline anemia, thrombocytopenia and 
neutropenia, and clinical evidence of disease progression may have also played a 
contributory role. 
Single-Agent DCDT2980S and DCDT2980S Combined with Rituximab in NHL 
Forty-nine patients received single-agent DCDT2980S at a starting dose of ≥ 1.8 mg/kg 
(7 at 1.8 mg/kg, 42 at 2.4 mg/kg); 16 patients received DCDT2980S at a starting dose 
of ≥ 1.8 mg/kg in combination with rituximab (5 at 1.8 mg/kg, 11 at 2.4 mg/kg).  
Overall the safety profile of DCDT2980S combined with rituximab did not differ from 
that of single-agent DCDT2980S. 
Treatment emergent hematologic and commonly reported nonhematologic adverse 
events for all grades in patients treated with single-agent DCDT2980S and 
DCDT2980S plus rituximab included neutropenia (29%), febrile neutropenia (3%), 
infection (system organ class; 43%), anemia (25%), thrombocytopenia (12%), 
peripheral neuropathy (28%), diarrhea (40%), pyrexia (14%), nausea (34%), and 
fatigue (55%).  Treatment emergent Grade ≥ 3 adverse events included neutropenia 
(25%), febrile neutropenia (3%), infection (system organ class; 11%), anemia (5%), 
45/P GO27834 A-1
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.


peripheral neuropathy (3%), diarrhea (5%), pyrexia (2%), and fatigue (3%).  Serious 
adverse events assessed by the treating investigator to be related to DCDT2980S were 
reported in 21% of patients.  Dose discontinuations for adverse events were reported in 
20% of patients. 
Refer to the DCDT2980S Investigator’s Brochure for complete and updated details 
related to safety.  
d. 
Efficacy in Non-Hodgkin’s Lymphoma 
Investigator-based objective responses were observed in 17 of 43 (40%) patients treated 
with single-agent DCDT2980S and 5 of 15 (33%) patients treated with DCDT2980S 
combined with rituximab.  Among patients with relapsed/refractory DLBCL, 11 of 28 
(39%) objective responses (5 complete responses [CR] and 6 partial responses [PR]) 
were observed with single-agent DCDT2980S and 3 of 7 (43%; 2 CR, 1 PR) with 
DCDT2980S combined with rituximab.  Among patients with relapsed/refractory 
indolent (iNHL), 6 of 13 (46%) objective responses (2 CR, 4 PR) were observed with 
single-agent DCDT2980S and 1 of 4 (PR) with DCDT2980S combined with rituximab.   
Refer to the DCDT2980S Investigator Brochure for complete and updated details related 
to anti-tumor activity. 
1.2.2 
DCDS4501A 
1.2.2.1 
Background and Preclinical Data 
CD79b is a cell-surface antigen whose expression is restricted to all mature 
B cells except plasma cells.  It is expressed in a majority of B-cell−derived malignancies, 
including nearly all NHL and CLL samples tested (see Figure 2) (Dornan et al. 2009).  
Antibodies bound to CD79b are rapidly internalized, making CD79b ideally suited 
for targeted delivery of cytotoxic agents (Polson 2007; 2009).   
Similar to DCDT2980S, DCDS4501A is an ADC that contains a humanized 
immunoglobulin-G1 (IgG1) anti−human CD79b monoclonal antibody (MCDS4409A) and 
MMAE linked through MC-VC-PABC.   
Comprehensive pharmacologic, PK, PD, and toxicological evaluations were undertaken to 
support the entry of DCDS4501A into clinical trials.  Because DCDS4501A specifically 
recognizes CD79b on B cells of human but not on those of cynomolgus monkey, rat, or 
mouse, a surrogate ADC (DCDS5017A) that binds to cynomolgus monkey CD79b was 
generated to assess the antigen-dependent pharmacological, toxicological and 
pharmacokinetic/pharmacodynamic activities in cynomolgus monkeys.  The structure, 
binding epitope, and binding affinity of the surrogate ADC are similar to DCDS4501A. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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Figure 2 CD79b Expression Levels on B-Cell Tumor Cells 
 
CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; 
FL = follicular lymphoma; MCL = mantle cell lymphoma; MZL = marginal zone lymphoma.  
CD79b expression levels (MFI, mean fluorescence intensity) on B-cell tumor cells were assessed 
by flow cytometry in patients diagnosed with the following B-cell lymphomas:  CLL (n = 49), 
DLBCL (n = 59), FL (n = 58), MCL (n = 20), and MZL (n = 60). 
 
DCDS4501A bound human CD79b with high affinity (Kd = 1.83± 0.26 nM); the surrogate 
ADC also showed similar high binding affinity to cynomolgus monkey CD79b.  
DCDS4501A displayed potent and selective inhibition of tumor cell proliferation in vitro 
(IC50 = 0.071 nM ± 0.01 nM) in cell viability assays.  Moderate ADCC but no CDC activity 
was observed with the unconjugated clinical candidate antibody MCDS4409A.  Both 
clinical and surrogate unconjugated antibodies showed no appreciable cytokine release 
when evaluated in in vitro cytokine release assays with peripheral blood mononuclear 
cells (PBMCs).  Moderate elevations in IL-1α and IP-10 were observed only with the 
unconjugated clinical antibody, however the clinical significance of these observations 
are not known since IL-1α and IP-10 are not produced by B-cells, are not involved in 
B-cell signaling through CD79b, and are not associated with cytokine-release syndromes 
in vivo. 
Single intravenous (IV) doses of DCDS4501A resulted in inhibition of tumor growth in 
murine xenograft models of lymphoma.  Tumor regression was observed at doses 
ranging from 0.5 to 3 mg/kg.  In contrast, MCDS4409A showed no activity.  DCDS4501A 
administered at 5 mg/kg demonstrated better anti-tumor activity compared to a current 
standard-of-care regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, 
and prednisone [R-CHOP]) in xenograft models of NHL.  PD studies demonstrated that 
at doses of the surrogate ADC ranging from 0.3 to 5 mg/kg resulted in a decrease of 
peripheral-blood B cells in cynomolgus monkeys.  A preferential decrease of proliferating 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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B-cells (CD20 + Ki67 +) compared to the resting B cells (CD20 + Ki67−) by the surrogate 
ADC was demonstrated in cynomolgus monkeys, in line with the expected mechanism of 
action of an anti-mitotic agent, MMAE. 
Due to B-cell-mediated CL, non-linear pharmacokinetics were observed with the 
surrogate ADC in cynomolgus monkeys following single IV doses of 0.3−3 mg/kg or four 
doses of 3 and 5 mg/kg given q3w.  The total antibody exposure after the fourth dose 
increased approximately 1.2- to 1.5-fold compared to the first dose.  As expected, the 
toxicokinetic profile of the clinical ADC in rats and cynomolgus monkeys was linear in the 
tested dose range.  Consistent with the half-life of the clinical ADC, minimal 
accumulation was observed following weekly dosing in rats and no accumulation was 
observed following every-3-week dosing in cynomolgus monkeys.  The free MMAE 
concentrations in plasma following administration of the clinical or surrogate ADCs were 
generally low and overall did not exceed 2 ng/mL, regardless of dose.  The overall 
incidence of anti-therapeutic antibodies (ATAs) was 20%−67% following administration 
of the clinical or surrogate ADCs in cynomolgus monkeys; however, the ATAs did not 
appear to impact the toxicokinetic/pharmacokinetic parameter estimates. 
In repeat-dose toxicity studies in rats and cynomolgus monkeys, DCDS4501A and 
the surrogate ADC were well tolerated in monkeys up to 5 mg/kg and 3 mg/kg 
respectively, with 3 mg/kg considered the highest non-severely toxic dose (HNSTD).  
In rats, DCDS4501A was well tolerated up to 6 mg/kg (STD10 = 10 mg/kg).  
The predominant antigen-independent findings associated with DCDS4501A or 
surrogate ADC exposure were reversible bone marrow toxicity and associated peripheral 
blood cell effects in both monkeys and rats.  Administration of the surrogate ADC to 
monkeys also resulted in expected antigen-dependent reversible decreases in peripheral 
blood B cells and the disappearance of B-cell germinal centers in splenic lymphoid 
follicles at doses ≥ 3 mg/kg.  Additional findings observed in rats but not in monkeys 
included thymic lymphoid depletion at ≥ 6 mg/kg, minimal to mild liver toxicities (at 
≥ 6 mg/kg), lung toxicities at 10 mg/kg in male animals only, and a slight increase in 
apoptosis and mitoses in multiple tissues, including skin and adnexa.  Hepatobiliary 
toxicity consisted of transient dose-dependent liver enzyme elevations accompanied by 
minimal to slight dose-dependent increases in mitotic figures/apoptosis in hepatocytes, 
sinusoidal cells, and bile duct epithelium as well as minimal to slight dose-dependent 
random focal hepatic necrosis.  Pulmonary toxicity was characterized by minimal to 
slight dose-dependent alveolar macrophage infiltration, sometimes accompanied by 
minimal to slight type II pneumocyte hyperplasia/hypertrophy.  These findings were 
consistent with the expected pharmacologic effect of MMAE on inducing mitotic arrest 
due to inhibition of tubulin polymerization.  Except for two individual instances 
(one female given 10 mg/kg in the liver and one male given 10 mg/kg in the lung), these 
findings were completely reversible after a 6-week recovery period.  Non-reversible male 
reproductive toxicity, characterized by degeneration of testicular seminiferous tubules, 
was observed in rats at all doses.  
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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Complete details of preclinical studies of DCDS4501A can be found in the DCDS4501A 
Investigator’s Brochure. 
1.2.2.2 
DCDS4501A Clinical Data 
a. 
Patient Enrollment 
Both DCDS4501A monotherapy and combination therapy with rituximab are being 
studied in a Phase I study (DCS4968g) of patients with relapsed or refractory B-cell 
malignancies expected to express CD79b, including indolent NHL, DLBCL, mantle cell 
lymphoma (MCL), and CLL.   
All data presented herein is based on a data entry cutoff of 28 February 2013, with 
clinical data available from 60 patients with NHL (excluding patients with CLL) enrolled 
in dose-escalation and expansion cohorts.  These include 51 patients who were treated 
with single-agent DCDS4501A ranging from 0.1 to 2.4 mg/kg administered intravenously 
every 21 days, and 9 patients who were enrolled into a single Phase Ib cohort with 
DCDS4501A administered at a dose of 2.4 mg/kg in combination with 375 mg/m2 
rituximab. 
In the CLL dose escalation cohorts, two DLTs were reported at the single-agent dose of 
1.8 mg/kg.  Enrollment into the CLL cohorts was stopped on 7 January 2013.   Refer to 
the DCDS4501A Investigator Brochure for details regarding clinical data in CLL patients.   
b. 
Pharmacokinetics 
The pharmacokinetics of DCDS4501A were characterized in a Phase I study 
DCDS4501A.  DCDS4501A was administered in patients with NHL at escalating doses 
of 0.1 to 2.4 mg/kg q3w as monotherapy and following administration of rituximab in the 
Phase Ib cohort.  Three analytes were quantified: antibody-conjugated MMAE 
(acMMAE), total antibody, and free MMAE.  
Preliminary pharmacokinetic analysis based on available data as of 22 June 2012 is 
summarized below.  The CL estimates of acMMAE and total antibody of each dose level 
is in the range of 14.9–21.2 mL/day/kg and 7.12 to 27.9 mL/day/kg, respectively.  
CL estimates were similar across doses of 0.1–2.4 mg/kg tested, suggesting dose 
proportional increase of acMMAE and total antibody exposure.  The clearance of 
acMMAE was faster than total antibody at each dose level.   
The mean value of the volume of distribution (Vss) of acMMAE and total antibody of each 
dose level ranged from 61 to 80.8 mL/kg and from 59.4 to 114.3 mL/kg, respectively, 
across the dose levels tested, which approximated human serum volume. Vss values did 
not appear to change substantially with dose. The half-lives for acMMAE and total 
antibody are from 2.4 to 5.5 days and 2.9 to 7 days, respectively.  
In a single agent dose-escalation study, for acMMAE and total antibody, the time to 
maximum concentration occurred immediately after infusion.  For free MMAE, the time to 
maximum concentration was approximately 2 to 3 days after infusion.  Cmax and AUCinf of 
free MMAE appear increased with dose across the dose levels.  A half-life of 3–4 days 
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for free MMAE was observed, which is relatively long and similar to acMMAE and 
suggests formation rate limited kinetics for free MMAE.  No accumulation of free MMAE 
is expected for the q3w regimen.  The Cmax values of free MMAE in NHL patients were at 
least 100-fold lower compared to acMMAE concentrations at each dose level, 
suggesting a slow release of free MMAE from acMMAE and potentially fast elimination 
once it is formed.   
Preliminary comparisons of PK between patients with NHL and CLL (for which patients 
are enrolled into separate dose-escalation cohorts) treated with identical doses of 
DCDS4501A provide some insight into the factors that affect PK.  Both acMMAE and 
total antibody were cleared faster in CLL patients than in NHL patients.  This observation 
is likely to be related to the high number of circulating B cells generally observed in CLL 
patients, which may result in significant target-mediated clearance of DCDS4501A.  
The free MMAE exposure in CLL patients was relatively low compared to its parent 
conjugate. 
To date, PK data for patients treated with DCDS4501A in combination with rituximab is 
limited.  Consequently, full comparison with single-agent DCDS4501A PK is not 
possible.  Based on very limited data from 3 patients, total antibody PK was comparable 
between 2.4 mg/kg of DCDS4501A administered as single-agent and following rituximab 
administration, suggesting that when given in combination, rituximab does not affect the 
PK of DCDS4501A; the effect of DCDS4501A on rituximab PK will be assessed.   
All observations will be verified with additional data from the ongoing Phase I study as 
well as this study. 
Refer to the DCDS4501A Investigator Brochure for complete and updated details. 
c. 
Safety 
Dose-Limiting Toxicities 
Study DCS4968g utilizes a standard 3+3 dose escalation cohort enrollment scheme.  
Patients enrolled into each dose-escalation cohort in Study DCS4968g have been 
observed for DLTs for a minimum of 21 days after their first dose of DCDS4501A.  
Any patient who did not complete the DLT observation period for any reason other than 
a DLT was replaced. 
DLT of Grade 4 neutropenia occurred in 1 patient out of 10 DLT-evaluable patients in the 
2.4 mg/kg single agent cohort and 1 patient out of 9 DLT-evaluable patients in the 
2.4 mg/kg + rituximab cohort.  Doses of DCDS4501A greater than 2.4 mg/kg as 
monotherapy or in combination with rituximab were not assessed.  Consequently, 
DCDS4501A at 2.4 mg/kg was therefore determined to be the RP2D as both 
monotherapy and in combination with rituximab.  Patients are currently being enrolled in 
monotherapy expansion cohorts for various types of NHL in order to collect and further 
characterize both single agent and combination safety data.  
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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In the CLL dose-escalation cohorts, two DLTs were reported at the single-agent dose of 
1.8 mg/kg.  One patient had a Grade 4 neutropenia, and 1 patient had a Grade 4 
invasive fungal infection.   
Single-Agent DCDS4501A and DCDS4501A Combined with Rituximab 
Fifty-one patients received single agent DCDS4501A at a starting dose of ≥ 1.8 mg/kg 
(6 at 1.8 mg/kg, 45 at 2.4 mg/kg); an additional 9 patients received DCDS4501A at a 
dose of 2.4 mg/kg in combination with rituximab.  Overall, the safety profile of 
DCDS4501A combined with rituximab did not differ from that of single-agent 
DCDS4501A. 
Treatment emergent hematologic and commonly reported non-hematologic adverse 
events for all grades in patients treated with single-agent DCDS4501A and 
DCDS4501A plus rituximab included neutropenia (50%), febrile neutropenia (5%), 
infection (system organ class; 35%), anemia (13%), thrombocytopenia (18%), 
peripheral neuropathy (32%), diarrhea (43%), pyrexia (37%), nausea (35%), and 
fatigue (18%).  Treatment emergent Grade ≥ 3 adverse events included neutropenia 
(43%), febrile neutropenia (5%), infection (system organ class; 10%), anemia (8%), 
peripheral neuropathy (7%), diarrhea (3%), pyrexia (2%), and fatigue (5%).  Serious 
adverse events assessed by the treating investigator to be related to DCDS4501A were 
reported in 20% of patients.  Dose discontinuations for adverse events were reported in 
33% of patients. 
Refer to the DCDS4501A Investigator’s Brochure for complete and updated details 
related to safety.   
d. 
Efficacy 
Investigator-based objective responses were observed in 28 of 49 (57%) patients treated 
with single-agent DCDS4501A and 7 of 9 patients (78%) treated with DCDS4501A 
combined with rituximab.  Among patients with relapsed/refractory DLBCL, objective 
responses were observed in 16 of 30 (53%; 4 CR, 12 PR) patients treated with 
DCDS4501A; 1 patient with DLBCL was treated with DCDS4501A combined with 
rituximab and achieved a PR.  Among patients with relapsed/refractory iNHL, objective 
responses were observed in 7 of 14 (50%; 2 CR, 5 PR) patients treated with 
single-agent DCDS4501A and 5 of 5 (100%; 2 CR, 3 PR) patients treated with 
DCDS4501A plus rituximab.  
Refer to the DCDS4501A Investigator Brochure for complete and updated details 
regarding anti-tumor activity. 
1.2.3 
Rituximab 
Rituximab has been shown to be an effective treatment for CD20-positive B-cell 
malignancies and is commonly used both as a single agent and in combination with 
cytotoxic chemotherapy.  Rituximab binds to CD20, a hydrophobic, transmembrane 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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protein that is present on pre–B and mature B cells and in > 90% of B-cell NHLs.  
It exerts its cytotoxic effects via complement-mediated B-cell lysis, ADCC, and induction 
of apoptosis (Cartron et al. 2004). 
In the United States, rituximab has been approved by the U.S. Food and Drug 
Administration (FDA) for the following indications in NHL: as a single agent for the 
treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive 
B-cell NHL; for the treatment of relapsed or refractory, low-grade or follicular, 
CD20-positive B-cell NHL, including initial treatment weekly for eight doses and 
re-treatment (weekly for four doses) in patients who responded to an initial course of 
rituximab; for the treatment of low-grade, CD20-positive B-cell NHL, in combination with 
cyclophosphamide, vincristine, and prednisone (CVP) induction chemotherapy in 
previously untreated patients with follicular, CD20-positive NHL; as treatment in 
previously untreated patients with low-grade, CD20-positive NHL who achieve an 
objective response or stable disease (SD) following CVP induction; as maintenance 
therapy for previously untreated follicular CD20-positive B-cell NHL after achieving a 
response to a regimen including chemotherapy and rituximab. 
In the European Union, rituximab (MabThera®) is approved for the treatment of the 
following indications in NHL: treatment of patients with Stage III–IV follicular NHL who 
are chemotherapy-resistant or in their second or subsequent relapse after 
chemotherapy; treatment of patients with CD20-positive DLBCL in combination with 
cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy; 
as front-line therapy in Stage III–IV follicular NHL in combination with CVP 
chemotherapy; as maintenance therapy in patients with relapsed or refractory, follicular 
NHL responding to induction treatment with CHOP or rituximab + CHOP; and as 
maintenance treatment for patients with follicular lymphoma who have responded to 
initial treatment with rituximab plus chemotherapy. 
Rituximab has also been approved for the treatment of CLL.  The European Medicines 
Agency (EMA) granted an approval for the use of rituximab in combination with 
chemotherapy for previously untreated CLL.  The FDA approved the use of rituximab in 
combination with fludarabine and cyclophosphamide for patients with previously 
untreated and previously treated CD20-positive CLL.   
Refer to the Rituximab Product Insert/Summary of Product Characteristics for complete 
details regarding clinical data related to approved indications.  For rituximab safety 
information, refer to local rituximab prescribing information. 
1.3 
RATIONALE FOR DOING THIS STUDY 
The goals of this Phase II study are to continue to assess the safety, tolerability, and 
biologic and clinical activity of the combinations of DCDT2980S and rituximab and 
DCDS4501A and rituximab in two specific NHL patient populations:  patients with 
relapsed or refractory follicular NHL, and patients with relapsed or refractory DLBCL.  
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These patients continue to have an extremely poor prognosis with no curative options 
available.  Consequently new therapeutic options are needed.   
DCDT2980S, DCDS4501A and rituximab each target antigens specific to B-cell 
malignancies including follicular NHL and DLBCL (see Figures 1 and 2).  
The Phase II study design permits an assessment of the clinical benefit provided by 
each of these molecules in combination with rituximab, which has established clinical 
activity in B-cell malignancies both as monotherapy and in combination with 
chemotherapy.  Data from this study will help inform the feasibility of the combination 
regimens in earlier lines of therapy (e.g., as first-line therapy in newly diagnosed 
patients). 
The feasibility of combining an ADC with rituximab has previously been tested clinically 
with the combination of another, different CD22-specific ADC, inotuzumab ozogamicin 
(CMC-544), with results suggesting that the addition of rituximab may have increased 
clinical activity without significant increase in toxicity over the ADC alone in patients with 
aggressive NHL (Luis et al. 2006; Nam et al. 2009; Nina et al. 2010).  As noted in 
Sections 1.2.1 and 1.2.2, the combinations of DCDT2980S and rituximab, and 
DCDS4501A and rituximab have been shown to have acceptable safety in patients with 
relapsed or refractory NHL in the Phase I studies (DCT4862g and DCS4968g).   
Given the relatively poor prognosis of patients with relapsed or refractory hematologic 
malignancies that have failed standard therapies and the nonclinical toxicity profile 
associated with DCDT2980S and DCDS4501A treatment, and the clinical safety profile 
observed to date for both ADCs, the risk-benefit ratio of a clinical study of DCDT2980S 
and DCDS4501A, each combined with rituximab, is considered acceptable.  
1.3.1 
Rationale for Assessing ADC Dose of 1.8 mg/kg Combined 
with Rituximab in iNHL 
Based on available Phase I data (see Section 1.2.1 and 1.2.2), both DCDT2980S and 
DCDS4501A as single-agents and combined with rituximab have shown early signs of 
clinical activity in heavily pretreated patients with relapsed/refractory NHL.  However, 
early evidence in the Phase I studies indicate that duration of study treatment may be 
limited by tolerability to ADC.  Specifically, for both ADCs, peripheral sensory 
neuropathy has been identified as a known risk (see Section 3.4.2).  Notably, 4 of 7 and 
5 of 11 discontinuations for adverse events in Studies DCT4862g and DCS4968g, 
respectively, were the result of peripheral neuropathy.   
Because of the chronic course and incurability of iNHL, treatment paradigms are 
increasingly emphasizing tolerability to treatment in addition to efficacy.  As both 
DCDT2980S and DCDS4501A have shown single-agent activity at the 1.8 mg/kg dose 
level (Advani et al. 2012; Palanca-Wessels et al. 2012), the purpose of enrolling 
additional cohorts of patients with follicular lymphoma is to determine whether lower 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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doses of ADC in combination with standard doses of rituximab result in improved 
tolerability while maintaining efficacy in follicular lymphoma.   
In contrast to iNHL, treatment paradigms in relapsed/refractory aggressive lymphomas 
such as DLBCL continue to place a premium on anti-tumor activity and higher 
tolerance for treatment-related toxicity given that durations of disease control and 
survival are substantially shorter and that treatment options are extremely limited.  
Early Phase I data suggest lower rates of study treatment discontinuation for adverse 
events among patients with DLBCL compared with patients with iNHL.  Taken 
together with anti-tumor activity observed to date, the risk-benefit profile of the 
currently tested ADC dose of 2.4 mg/kg is considered acceptable  
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
The primary objectives of this study are the following: 
• 
To assess the safety and tolerability of the combination of DCDT2980S and 
rituximab administered to patients with relapsed or refractory follicular NHL and 
DLBCL 
• 
To assess the safety and tolerability of the combination of DCDS4501A and 
rituximab administered to patients with relapsed or refractory follicular NHL and 
DLBCL 
• 
To assess the anti-tumor activity of the combination of DCDT2980S and rituximab in 
patients with relapsed or refractory follicular NHL and DLBCL 
• 
To assess the anti-tumor activity of the combination of DCDS4501A and rituximab in 
patients with relapsed or refractory follicular NHL and DLBCL 
 
2.2 
SECONDARY OBJECTIVES 
2.2.1 
Safety Objectives 
The secondary safety objectives of this study are the following: 
• 
To assess the incidence of antibody formation to DCDT2980S and DCDS4501A 
• 
To compare the safety and tolerability of the combination of DCT2980S and 
rituximab and DCDS4501A and rituximab 
 
2.2.2 
Activity Objective 
The secondary activity objective of the study is the following: 
• 
To compare the anti-tumor activity of the combination of DCT2980S and rituximab 
and DCDS4501A and rituximab 
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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2.2.3 
Pharmacokinetic Objectives 
The PK objectives of this study are the following: 
• 
To characterize the pharmacokinetics of DCDT2980S and rituximab in patients with 
relapsed or refractory NHL when the two drugs are given in combination 
• 
To characterize the pharmacokinetics of DCDS4501A and rituximab in patients with 
relapsed or refractory NHL when the two drugs are given in combination 
 
2.3 
EXPLORATORY OBJECTIVES 
2.3.1 
Biomarker Objectives 
The objectives of this study related to assessment of biologic markers are the following: 
• 
To make a preliminary assessment of biologic markers that might act as predictors 
of DCDT2980S + rituximab combination anti-tumor activity and allow assessment of 
response in different prognostic subgroups of DLBCL and follicular NHL 
• 
To make a preliminary assessment of biologic markers that might act as predictors 
of DCDS4501A + rituximab combination anti-tumor activity and allow assessment of 
response in different prognostic subgroups of DLBCL and follicular NHL 
 
2.3.2 
Patient Quality of Life Objective 
The objective of this study related to assessment of patient quality of life is the following: 
• 
To assess patient tolerability to study treatment and the impact of study treatment 
on patient quality of life based on patient reported outcomes (PRO) 
 
2.3.3 
Crossover Treatment Objective 
The objective of this study related to assessment of crossover treatment is the following: 
• 
To preliminarily assess the safety and tolerability and anti-tumor activity of 
DCDT2980S and DCDS4501A, either as a single-agent or in combination with 
rituximab, as crossover treatment following disease progression on initial study 
treatment (Note:  This objective only applies to patients enrolled in Arms A and B 
[see Section 3.1]) 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a Phase II, multicenter, open-label study.  A total of approximately 
140−160 patients (approximately 60−80 patients with relapsed or refractory follicular 
NHL and approximately 80 patients with relapsed/refractory DLBCL) will be enrolled at 
approximately 30–40 investigative sites worldwide.  Additional patients may be enrolled 
in order to obtain additional safety and/or efficacy data.  
The study will be composed of a randomized portion and a nonrandomized portion, as 
illustrated in Figure 3. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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Figure 3 Study Schema 
Arms A and B:  RTX (375 mg/m2) + ADC (2.4 mg/kg) administered in every-21-day cycles.
Cohorts C and D: RTX (375 mg/m2) + ADC (1.8 mg/kg) administered in every-21-day cycles.
RTX + DCDT2980S ADC
RTX + DCDS4501A ADC
Randomize
1:1
PD
PD
RTX + DCDS4501A ADC
RTX + DCDT2980S ADC
Arm A
Arm B
RTX + DCDS4501A ADC
Cohort C
r/r FL=40
r/r DLBCL=80
r/r FL=20
Total N = 140−160
RTX + DCDT2980S ADC
Cohort D
r/r FL=20
• No crossover
• No randomization
• Cohorts open at Sponsor 
discretion
• Cohorts open after FL cohorts 
in Arms A and B are filled
 
DLBCL=diffuse large B-cell lymphoma; FL=follicular lymphoma; PD=progressive disease; 
r/r=relapsed or refractory; RTX=rituximab.  
  
3.1.1 
Randomized Portion of the Study (Arms A and B) 
Following determination of eligibility, patients within each disease group will be 
randomized in a 1:1 ratio to receive one of two treatments: 
• 
Arm A:  Rituximab (375 mg/m2) followed by DCDT2980S (2.4 mg/kg) every 21 days; 
• 
Arm B:  Rituximab (375 mg/m2) followed by DCDS4501A (2.4 mg/kg) every 21 days 
The first day of treatment constitutes Day 1 of each cycle.  A typical cycle is 21 days in 
duration. 
A dynamic hierarchical randomization scheme will be employed with respect to the 
following stratification factors: 
• 
For patients with follicular lymphoma (see Section 3.1.1 for definitions) 
Rituximab refractory disease (no response or disease relapse < 6 months from 
last rituximab treatment) vs. rituximab relapsed disease (disease relapse after 
response ≥ 6 months from last rituximab treatment) 
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• 
For patients with DLBCL (see Section 3.1.2 for definitions) 
Second-line vs. third-line (or beyond) therapy 
For second-line patients, disease relapse or no objective response (CR, 
unconfirmed CR [Cru], or PR) <12 months from the start of initial therapy versus 
disease relapse, after initial objective response (CR, CRu or PR), ≥12 months 
from start of initial therapy  
For third-line patients, failure to achieve a CR or progression < 6 months of start 
of most recent therapy versus CR or progression ≥ 6 months from start of most 
recent therapy 
No formal testing comparing the two treatment arms in the randomized portion of the 
study is planned. 
3.1.2 
Nonrandomized Portion of the Study (Cohorts C and D) 
Only select investigator sites that have agreed to participate in the nonrandomized 
portion of the study will enroll patients into these cohorts. 
Patients with relapsed or refractory follicular NHL will be enrolled in Cohorts C and D 
to receive rituximab (375 mg/m2) combined with DCDT2980S or DCDS4501A at a 
dose of 1.8 mg/kg.  The first day of treatment constitutes Day 1 of each cycle.  A typical 
cycle will be 21 days in duration. 
The opening of either or both cohorts will be at the Sponsor’s discretion and only after 
the enrollment of follicular lymphoma patients into the randomized portion of the study 
is completed.  Patients will not be randomized to receive one treatment or the other.  
It is anticipated that Cohort C and D will be opened sequentially.   
3.1.3 
All Patients 
All patients, regardless of assigned arm/cohort will receive DCDT2980S or DCDS4501A 
and rituximab administered by IV infusion on a 21-day cycle.  For the first two cycles, 
rituximab will be administered by IV infusion on Day 1 and DCDT2980S or DCDS4501A 
will be administered by IV infusion on Day 2.  In the absence of any infusion-related 
adverse events, rituximab and DCDT2980S or DCDS4501A may be administered on the 
same day (Day 1) in subsequent cycles beginning with the third cycle.  In this instance, 
rituximab will be administered first, followed by DCDT2980S or DCDS4501A.  In certain 
circumstances, e.g., infusion-related reactions requiring interruption or slowing of 
infusion rate, rituximab may be administered over 2 days, e.g., Day 1 and Day 2 of the 
cycle; in this case, DCDT2980S or DCDS4501A may be administered on Day 2 following 
completion of the rituximab infusion or on Day 3 of the cycle. 
Patients may receive treatments for up to 1 year (17 cycles on an every-21-day 
schedule) if not discontinued due to significant toxicity, disease progression, or 
withdrawal from study. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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Patients will be evaluated for safety and efficacy according to the schedules 
of assessments outlined in Appendices A-1, A-2, and A-3.  Initial response assessments 
in this study will be performed every 3 months from the initiation of therapy until study 
treatment completion or early termination (e.g., between Days 14 and 21 of Cycles 4 
and 8 for those patients receiving at least eight 21-day cycles of treatment).  Additional 
response assessments for patients who proceed to crossover treatment (see 
Section 3.1.3) will be performed as described in Appendix A-2; response assessments 
for patients who discontinue study treatment (both initially assigned treatment and 
crossover treatment) for reasons other than disease progression will be performed as 
described in Appendix A-3. 
Responses to study treatment will be based on investigator assessments.  In addition, 
tumor assessment data will be transmitted to an Independent Review Facility (IRF) for 
collection and possible independent review. 
3.1.4 
Follicular NHL Cohort 
Patients with relapsed or refractory follicular NHL will be enrolled into the study as 
defined by the following: 
• 
Relapsed to regimens containing rituximab, defined as documented history of 
response (CR, CRu, or PR) of ≥ 6 months in duration from completion of all prior 
rituximab-containing regimens.  A rituximab-containing regimen is defined as 
rituximab as a single agent during induction and/or maintenance, or in combination 
with other agents during induction and/or maintenance. 
• 
Refractory to any prior regimen containing rituximab, defined as no response to, or 
progression within 6 months of completion of, the last dose of rituximab therapy 
(either as monotherapy or in combination with chemotherapy), including: 
Patients with progressive disease while receiving rituximab monotherapy, 
rituximab combined with chemotherapy, or rituximab maintenance therapy; 
patients must have received at least one full dose (375 mg/m2) of rituximab 
Patients with no objective response (PR or CR) to a rituximab-containing regimen 
consisting of at least 4 weekly doses of rituximab monotherapy or at least 
4 cycles of rituximab combined with chemotherapy 
Patients with disease relapse, after having achieved an objective response, 
within 6 months of completion of the last dose of rituximab therapy in a regimen 
consisting of at least four weekly doses of rituximab monotherapy or at least 
4 cycles of rituximab combined with chemotherapy 
Enrollment of patients with refractory disease as defined above may be limited to no 
greater than 60% of the total follicular NHL cohort, in order to avoid overrepresentation 
of the refractory disease population. 
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3.1.5 
DLBCL Cohort 
Patients with relapsed or refractory DLBCL who are determined by the investigator to be 
ineligible for high dose therapy with autologous stem cell rescue/stem cell transplant 
(SCT) as determined by the investigator will be enrolled into the study as defined by the 
following: 
• 
Second-line SCT-ineligible patients with progressive disease or no response 
(SD) < 12 months from start of initial therapy (2L refractory) 
• 
Second-line SCT-ineligible patients with disease relapse after initial response 
≥ 12 months from start of initial therapy (2L relapsed) 
• 
Third-line (or beyond) SCT-ineligible patients with progressive disease or no 
response (SD) < 6 months from start of prior therapy (3L + refractory) 
• 
Third-line (or beyond) SCT-ineligible patients with disease relapse after initial 
response ≥ 6 months from start of prior therapy (3L+ relapsed) 
 
Enrollment to any of the above four categories may be limited to no greater than 40% of 
the DLBCL cohort—and to no more than 60% of the two refractory categories 
combined—in order to avoid overrepresentation of any specific subpopulation, refractory 
patients in particular. 
3.1.6 
Crossover Treatment (Randomized Patients Only) 
Patients randomized to Arm A or Arm B who develop progressive disease may be 
eligible to receive crossover treatment consisting of rituximab and the other ADC, or the 
other ADC alone, e.g., Arm B treatment for patients who have disease progression while 
receiving Arm A treatment and vice versa, provided the following conditions are met: 
• 
Patients must not have experienced a toxicity requiring the discontinuation of 
DCDT2980S/DCDS4501A treatment OR experienced toxicity during the last dose of 
study treatment that would preclude treatment with the crossover regimen. 
Patients who had modifications to dosing and/or schedule on the initial study 
treatment will be permitted to receive crossover treatment in the absence of 
toxicities on the modified dose and/or schedule.  The dose and schedule of 
crossover treatment will be determined by the investigator and the Medical 
Monitor. 
Patients who had rituximab discontinued and continued on single-agent 
DCDT2980S/DCDS4501A treatment may receive crossover treatment of 
single-agent DCDS4501A/ DCDT2980S  
• 
Patients must have radiographically documented disease progression 
• 
Patients must meet all inclusion and exclusion criteria described in Sections 4.1.1 
and 4.1.2, except for those related to prior rituximab treatment. 
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• 
Acceptable toxicity:  All study drug–related adverse events from the initial study 
treatment must have decreased to Grade 1 or baseline grade on or before the first 
day of treatment on the crossover regimen.  Exceptions may be allowed after a 
careful assessment and discussion of the risk-benefit balance with the patient by the 
investigator and approval from the Medical Monitor. 
• 
Administration of crossover treatment must be in the best interests of the patient 
as determined after a careful assessment and discussion of risk-benefit balance 
with the patient by the investigator and approval from the Medical Monitor. 
• 
A tumor biopsy (see Section 4.5.1.9) will be required for patients with safely 
accessible site of disease, defined as requiring only local anesthesia and in general 
excluding brain, lungs or any internal organs that may subject patients to significant 
risk.  
Patients for whom a safely accessible site of disease is not present may still 
receive crossover treatment without undergoing a biopsy.  Eligibility to receive 
crossover treatment should be discussed with and approved by the Medical 
Monitor. 
A tumor biopsy of a safely accessible site of disease is optional for patients who 
are not eligible for study cross over.  
Patients who are determined to be eligible for study crossover will be treated as follows: 
• 
Assessments obtained at the initial study treatment discontinuation visit 
(see Section 4.5.4) may be used as screening assessments for crossover treatment.  
The following re-screening assessments must be repeated/obtained within 1 week 
prior to starting treatment on the crossover regimen in order to re-establish baseline 
pretreatment clinical and disease status:  targeted physical exam, ECOG status and 
hematology and serum chemistry laboratories. 
Re-screening tests for Hepatitis B and C do not need to be performed unless 
there is clinical suspicion of Hepatitis B and/or C positivity. 
A radiographic tumor assessment must also be performed, unless already done 
to document disease progression, within 6 weeks prior to starting crossover 
treatment. 
• 
Crossover treatment will begin no later than 42 days after the last dose of the prior 
study treatment. 
Patients will be treated with the crossover treatment until a second disease progression 
event relative to the tumor assessment documenting progressive disease on the initial 
study treatment, clinical deterioration and/or intolerance to the crossover treatment for 
up to a maximum of 1 year (17 cycles on an every-21-day schedule).  Patients will be 
evaluated for safety and efficacy according to the schedules of assessments outlined in 
Appendices A-2.  Response assessments for patients who discontinue study treatment 
for reasons other than disease progression will be performed as described in 
Appendix A-3.  
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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Clinical data and exploratory data derived from tumor biopsies obtained prior to 
crossover treatment will be monitored on an ongoing basis.  Genentech has the right to 
restrict or suspend enrollment into crossover treatment at any time.  Reasons for this 
may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events during crossover treatment indicates a 
potential safety hazard to patients. 
• 
Patient enrollment into crossover treatment is unsatisfactory. 
• 
Data recording is inaccurate or incomplete.  
• 
Patients who are enrolled into the nonrandomized portion of the study (Cohorts C 
and D) will not have the option to receive crossover treatment upon disease 
progression (see Section 3.2 for rationale). 
 
3.2 
RATIONALE FOR STUDY DESIGN 
The primary rationale for the randomized non-comparative portion of the study is to 
assess clinical activity for the ADCs DCDT2980S and DCDS4501A in patients with 
relapsed/refractory NHL.  The study design ensures that the patient populations under 
study are balanced with respect to critical variables such as prior therapy and ensures 
consistent clinical assessment of safety and efficacy.  The collection and assessment of 
tumor tissue obtained prior to first study treatment and following progressive disease will 
provide further understanding of disease biology, possible mechanisms of resistance to 
the study treatment and initial insights into tumor subtypes based on tumor biomarkers 
that are sensitive to study treatment.  Finally, the inclusion of study treatment crossover 
(see Section 3.1.3) will address important questions regarding efficacy and tolerability of 
a second ADC-rituximab combination following disease progression on the initial 
ADC-rituximab combination.  
The primary rationale for the nonrandomized portion of the study is to assess the 
therapeutic index (i.e., the balance of efficacy and tolerability of DCDT2980S and 
DCDS4501A at a dose of 1.8 mg/kg in patients with relapsed or refractory follicular 
NHL).  An informal comparison between patients with follicular NHL treated at the 
two doses of the ADC will help determine if tolerability is improved at the lower ADC 
dose without substantial compromise of efficacy.   
The clinical feasibility of an ADC-rituximab combination regimen in patients with 
relapsed/refractory NHL has been previously studied.  Results from studies of rituximab 
in combination with a different CD22-specific ADC, inotuzumab ozogamicin, 
demonstrated that when combined with rituximab the ADC was able to be given at the 
single-agent MTD without the need for dose reduction of the ADC due to the lack of 
significant overlapping toxicity (Luis et al. 2006; Nam et al. 2009; Nina et al. 2010).   
DCDT2980S and DCDS4501A are both being evaluated as single agents and in 
combination with rituximab in ongoing Phase I studies DCT4862g and DCS4968g, 
respectively.  Results from these ongoing Phase I trials have determined an MTD of 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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2.4 mg/kg for single-agent DCDT2980S and the RP2D of 2.4 mg/kg for single-agent 
DCDS4501A in patients with mixed NHL.  In addition, the RP2D of DCT2980S and 
DCDS4501 each in combination with rituximab (375 mg/m2) on an every-21-day 
schedule was determined to be 2.4 mg/kg.  Study GO27834 will continue to assess the 
cumulative safety and longer-term tolerability of ADC-rituximab combination therapy. 
Study drug dosing will occur on Days 1 and 2 of each 21-day (or 28-day) cycle to allow 
for recovery from potential bone marrow toxicity. 
3.2.1 
Rationale for the PK sample schedule 
PK data obtained in this study will be important in informing potential future trials with 
this combination.  Given the likely changing effect of peripheral B-cell counts, tumor 
burden, and target antigen expression on target-mediated drug clearance over multiple 
doses of DCDT2980S or DCDS4501A plus rituximab when the two drugs are given in 
combination, the drug levels of DCDT2980S or DCDS4501A-related analytes and 
rituximab will be assessed in this combination study.   
In Studies DCT4862g and DCS4968g, single-agent DCDT2980S and DCDS4501A 
administered by IV infusion every 21 days was evaluated at doses ranging from 0.1 to 
3.2 mg/kg for DCDT2980S, and 0.1 mg/kg to 2.4 mg/kg for DCDS4501A, in patients with 
NHL.  Intensive PK sampling of all patients in the ongoing Phase I studies will provide 
sufficient data to allow complete profiling of the distribution and elimination phases for 
DCDT2980S and DCDS4501A and the investigation of potential correlations between 
various PK parameters and efficacy and/or toxicity.  Consequently a reduced PK 
sampling scheme of DCDT2980S and DCDS4501A will be used in this Phase II study.  
The PK data collected in this Phase II study will allow further characterization of the 
PK properties of DCDT2980S and DCDS4501A.  In addition, the DCDT2980S and 
DCDS4501A concentration results from this study will be compared with available data 
from the single-agent clinical studies to evaluate whether concurrent administration of 
rituximab affects the exposure of DCDT2980S and/or DCDS4501A.   
Rituximab serum concentration measurements from this study will be compared with 
PK data from historical rituximab clinical studies to evaluate whether the combination 
with DCDT2980S and/or DCDS4501A affects the PK of rituximab.  
3.3 
OUTCOME MEASURES 
3.3.1 
Safety Outcome Measures 
The safety and tolerability of the combination of DCDT2980S and rituximab and 
DCDS4501A and rituximab will be assessed using the following safety outcome 
measures: 
• 
Incidence, nature, and severity of adverse events 
• 
Incidence of anti-DCDT2980S or anti-DCDS4501A antibodies 
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• 
Changes in vital signs 
• 
Changes in laboratory values 
 
3.3.2 
Pharmacokinetic/Pharmacodynamic Outcome Measures 
The following PK parameters will be derived from the serum concentration–time profiles 
of total antibody (the sum of conjugated and unconjugated antibody), including rituximab, 
and plasma concentration-time profiles of antibody conjugated-MMAE (acMMAE) and 
free MMAE following administration of DCDT2980S or DCDS4501A, when appropriate 
as data allow: 
• 
Total exposure (area under the concentration-time curve [AUC]) 
• 
Maximum plasma and serum concentration (Cmax) 
• 
Clearance (CL) 
• 
Terminal half-life (t1/2) 
• 
Steady state volume of distribution (Vss). 
Compartmental, non-compartmental, and/or population methods may be used.  Other 
parameters, such as accumulation ratio and trough plasma and serum concentration 
(Cmin), may also be calculated. 
The following PD outcome measures will be assessed when appropriate, as data allow: 
• 
Peripheral blood B-cell depletion and recovery.  For each visit at which CD19+ B-cell 
measurements are taken, B-cell data will be listed for each patient by dose level as 
follows: 
Absolute blood cell counts 
Percent change relative to the baseline blood counts 
CD19+ B-cell recovery, defined as the timepoint when the values return to 
baseline levels or ≥ 50% of baseline levels 
 
3.3.3 
Activity Outcome Measures 
The following activity outcome measures will be assessed: 
• 
Objective response, defined as a PR or CR 
• 
Duration of objective response, defined as the first occurrence of a documented 
objective response until the time of relapse or death from any cause 
• 
Progression-free survival (PFS), defined as the date of randomization to the first 
occurrence of progression or death within 30 days of the last administration of study 
drug, whichever occurs first 
• 
Overall survival (OS), defined as the time from the date of randomization to the date 
of death from any cause 
 
Objective response and disease progression will be determined using standard criteria 
for NHL (Cheson et al. 2007; see Appendix C). 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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3.3.4 
Exploratory Outcome Measures  
The exploratory outcome measures will include, but will not be limited to, the following:  
• 
Confirmation and quantitation of CD22, CD79b and CD20 expression levels in either 
archival or freshly obtained (when available) tumor specimens (tumor biopsies, 
bone marrow biopsies, peripheral blood) by immunohistochemistry/flow 
cytometry/qRT-PCR 
• 
Additional assessments related to the understanding of the mechanism of action of 
DCDT2980S, DCDS4501A and rituximab, mechanisms of resistance to DCDT2980S, 
DCDS4501A and rituximab, and/or NHL pathogenesis may be included 
• 
Quality of life assessments using the M.D. Anderson Symptom Inventory (MDASI) 
 
3.4 
SAFETY PLAN  
See Section 5 (Assessment of Safety) for complete details of the safety evaluation for 
this study. 
Safety will be evaluated through the monitoring of the following: 
• 
Serious adverse events that are attributed to protocol-mandated interventions from 
the time of signing informed consent until the first dose of study treatment on 
Cycle 1, Day 1 
• 
All adverse events from Cycle 1, Day 1 until 30 days after the last dose of 
DCDT2980S, DCDS4501A or rituximab whichever is later, including doses that were 
administered as part of crossover treatment 
• 
All serious adverse events from Cycle 1, Day 1 until 30 days after the last dose of 
DCDT2980S, DCDS4501A or rituximab whichever is later, including doses that were 
administered as part of crossover treatment 
• 
All serious adverse events from the last dose of DCDT2980S, DCDS4501A or 
rituximab whichever is later, including doses that were administered as part of 
crossover treatment, and which is judged to be caused by DCDT2980S, 
DCDS4501A or rituximab, regardless of time of onset 
• 
Measurements of protocol-specified hematology and clinical chemistry laboratory 
values 
• 
Measurements of protocol-specified vital signs 
• 
Assessment of ECGs 
• 
Assessment of physical findings on clinical physical examinations 
Patients who have an ongoing study drug-related adverse event will be followed until the 
event has resolved to baseline grade, the event is assessed by the investigator as 
stable, new anti-tumor treatment is initiated, the patient is lost to follow-up, the patient 
withdraws consent, when it has been determined that the study treatment or participation 
is not the cause of the adverse event, or the study is terminated. 
See Section 5.2.3 for assessment of causality for adverse events. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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3.4.1 
Internal Monitoring Committee (IMC) 
This study will employ an Internal Monitoring Committee (IMC).  The purpose of the IMC 
will be to make recommendations regarding study conduct on the basis of trial safety 
data to ensure patient safety while receiving study treatment. 
The IMC will include a sponsor Medical Monitor not affiliated with the study, Drug Safety 
Scientist, biostatistician, and statistical programmer.  Representatives from other 
Sponsor functional areas may be included as additional ad hoc members. 
In addition to the ongoing assessment of the incidence and nature of adverse events, 
serious adverse events, and laboratory abnormalities by the Investigator and the Medical 
Monitor, the IMC will review the aforementioned data at least twice during the study.  
The first planned review will occur after approximately 10 patients are randomized 
and have at least 6 weeks follow-up and the next formal review will occur when 
approximately 60 patients are randomized and have at least 6 weeks follow-up.  
Additionally, the IMC will meet as needed at the request of the Medical Monitor 
(e.g., based on unexpected safety signals).  The IMC may make recommendations 
regarding study conduct, including but not limited to: performing additional safety 
analyses, amending the study protocol, holding patient enrollment to one or both 
treatment arms pending further safety evaluations, holding/discontinuing study 
treatment, or terminating the study. 
Complete details of the IMC will be described in the IMC charter. 
3.4.2 
Risks Associated with DCDT2980S and DCDS4501A 
The clinical safety profile of DCDT2980S and DCDS4501A based on clinical data 
obtained in the ongoing Phase I studies are summarized in Sections 1.2.1.2 and 1.2.2.2.  
Based on clinical data to date, the following known and suspected risks are described 
below.  Guidelines around the management of these risks through dose and schedule 
modifications are described in Sections 4.3.1 and 4.3.2.   
Refer also to the Investigator Brochure for complete and updated details. 
3.4.2.1 
Infusion-Related Events 
Some monoclonal antibodies may be associated with the development of allergic or 
anaphylactic reactions, to either the active protein or excipients.  True 
allergic/anaphylactic reactions are rare after the first dose of a product, as they require 
prior sensitization.  Patients with true allergic/anaphylactic reactions should not receive 
further doses of the product.  
Monoclonal antibodies may also be associated with reactions that are clinically 
indistinguishable from true allergic/anaphylactic reactions, but which are mediated 
through direct release of cytokines or other pro-inflammatory mediators.  Such reactions 
are often termed infusion-related reactions.  Infusion-related reactions typically occur 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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with the first infusion of a monoclonal antibody product and are generally less frequent 
and/or less severe with subsequent infusions.  They can often be managed by slowing 
the infusion rate and/or pre-treatment with various medications. 
Allergic/anaphylactic reactions and infusion-related reactions typically begin during or 
within several hours of completing the infusion.  The onset of symptoms may be rapid, 
and some reactions may be life threatening. 
Patients should be monitored for these types of reactions during and after receiving 
DCDT2908S and DCDS4501A.  DCDT2980S and DCDS4501A should be administered 
in an environment under close supervision of a physician and where full resuscitation 
facilities are immediately available.  Specific guidelines for additional precautions to be 
taken during and following DCDT2980S and DCDS4501A administration are provided in 
Sections 4.3.1.5. 
3.4.2.2 
Tumor Lysis Syndrome 
There is a potential risk of tumor lysis syndrome (TLS) if treatment with DCDT2980S or 
DCDS4501A results in the rapid destruction of a large number of tumor cells.  If any 
evidence of this occurs during the study, tumor lysis prophylaxis measures will be 
instituted.  Patients who are considered to have a high tumor burden (e.g., lymphocyte 
count ≥ 25 x 109/L) or bulky lymphadenopathy and who are considered to be at risk 
for tumor lysis by the investigator will receive tumor lysis prophylaxis 
(e.g., allopurinol ≥ 300 mg/day orally or a suitable alternative treatment according to 
institutional practice starting 12−24 hours prior to study treatment) and must be well 
hydrated prior to the initiation of study treatment at Cycle 1, Day 1.  These patients 
should continue to receive repeated prophylaxis with allopurinol and adequate hydration 
prior to each subsequent infusion as deemed appropriate by the investigator. 
3.4.2.3 
Bone Marrow Toxicity/Neutropenia 
Based on preclinical toxicity studies in rats and cynomolgus monkeys and clinical data 
from the ongoing Phase I studies DCT4862g and DCS4968g, neutropenia has been 
identified as a known risk (adverse drug reaction) of both DCDT2908S and 
DCDS4501A.  Neutropenia and neutropenia-associated events were reversible but in 
some cases resulted in protocol-mandated dose reductions and/or delays.   
Adequate hematologic function should be confirmed before initiation of study treatment.  
Patients receiving study treatment will be regularly monitored for evidence of marrow 
toxicity with complete blood counts.  Treatment for hematologic toxicities may be 
delayed or modified as described in Section 4.3.1.  
The use of G-CSF for neutropenia is described in Section 4.3.1.6.  Transfusion support 
for anemia and thrombocytopenia is also permitted at the discretion of the treating 
physician. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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3.4.2.4 
Immunogenicity 
As expected with any recombinant antibody, DCDT2980S and DCDS4501A may elicit 
an immune response and patients may develop antibodies against DCDT2980S and 
DCDS4501A.  Patients will be closely monitored for any potential immune response to 
DCDT2980S and DCDS4501A.  Appropriate screening and confirmatory assays will be 
employed to detect ATAs at multiple timepoints before, during, and after treatment with 
DCDT2980S or DCDS4501A.  Considering the historically low immunogenicity rate of 
rituximab in NHL patients, ATAs against rituximab will not be monitored in this study. 
3.4.2.5 
Peripheral Sensory Neuropathy 
Based on clinical data from the ongoing Phase I studies DCT4862g and DCS4968g and 
data from brentuximab vedotin, an anti-CD30-vc-MMAE ADC (see Section 3.4.2) 
peripheral sensory neuropathy has been identified as a known risk (adverse drug 
reaction) for both DCDT2980S and DCDS4501A. 
Patients should be monitored for signs of neuropathy or worsening neuropathy and 
appropriate action taken per protocol guidelines.  Study treatment dose and schedule 
modifications for significant and prolonged neuropathic toxicity and dose-reduction are 
described in Section 4.3.1.7.   
3.4.2.6 
Reproductive Toxicity 
Adverse effects on human reproduction and fertility are anticipated with the 
administration of DCDT2980S and DCDS4501A given the mechanism of action of 
MMAE.  Standard exclusion criteria will be used to ensure that patients of childbearing 
potential (male or female) are using adequate contraceptive methods.  
3.4.2.7 
Hyperglycemia 
Hyperglycemia has been observed in patients treated with DCDT2980S and 
DCDS4501A as well as with other antibody-drug conjugates using the same vc-MMAE 
platform.  Hyperglycemia has been reversible upon holding or discontinuing treatment 
of the ADCs and/or initiation or adjustment of anti-hyperglycemic medications. 
3.4.2.8 
Hepatotoxicity 
Hepatotoxicity is a potential risk of the ADCs.  Definitive attribution of hepatotoxicity 
to the ADCs has not been established.  Transient dose-related increases in hepatic 
enzyme levels were observed in rats treated with DCDT2980S and DCDS4501A.  
Elevations in transaminase and/or bilirubin levels requiring dose modifications have 
been reported in the ongoing clinical studies. 
3.4.3 
Risks Associated with Adcetris (Brentuximab vedotin) 
An ADC using the same MMAE drug and linker as that used in DCDT2980S and 
DCDS4501A, but coupled to an antibody targeting the CD30 antigen (brentuximab 
vedotin, ADCETRISTM, Seattle Genetics), was recently approved by the FDA for use in 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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the treatment of specific subsets of patients with relapsed Hodgkin lymphoma and 
systemic anaplastic large cell lymphoma.   
The most common adverse reactions observed in studies with brentuximab vedotin 
(occurring in at least 20% of patients) were neutropenia, peripheral sensory neuropathy, 
fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, 
thrombocytopenia, cough, and vomiting.   
Serious adverse reactions were reported in 31% of patients receiving Adcetris.  
The most common occurring in > 2% of patients included peripheral motor neuropathy, 
abdominal pain, septic shock, supraventricular arrhythmia, pain in extremity and urinary 
tract information.  In addition, JC virus infection resulting progressive multifocal 
leukoencephalopathy (PML) and death has been reported.   
Due to the use of the same MMAE drug, it is possible that the adverse events observed 
with the use of brentuximab vedotin can also be observed with the use of DCDT2980S 
and DCDS4501A.   
Refer to the current version of the ADCETRIS Prescribing Information for full and 
updated details. 
3.4.4 
Risks Associated with Rituximab Therapy and Their 
Management 
3.4.4.1 
Infusion Reactions 
In single-agent clinical trials of rituximab and in postmarketing surveillance studies, 
mild to moderate infusion reactions consisting of fever and chills/rigors occurred in the 
majority of patients during the first rituximab infusion.  Other frequent infusion reaction 
signs and symptoms included nausea, pruritus, angioedema, asthenia, hypotension, 
headache, bronchospasm, throat irritation, rhinitis, urticaria, rash, vomiting, myalgia, 
dizziness, and hypertension.  These reactions generally occurred within 30−120 minutes 
of beginning the first infusion, and they resolved with slowing or interruption of the 
rituximab infusion and with supportive care (diphenhydramine, acetaminophen/ 
paracetamol, IV saline, meperidine, and vasopressors).  The incidence of infusion 
reactions was highest during the first infusion and decreased with each subsequent 
infusion. 
Rituximab has caused severe infusion reactions.  In some cases, these reactions were 
fatal.  These severe reactions typically occurred during the first infusion with a time to 
onset of 30−120 minutes.  Signs and symptoms of severe infusion reactions may include 
urticaria, hypotension, angioedema, hypoxia, or bronchospasm and may require 
interruption of rituximab administration.  The most severe manifestations and sequelae 
include pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, 
ventricular fibrillation, cardiogenic shock, and anaphylactic and anaphylactoid events 
(see Appendix D).  Approximately 80% of fatal infusion reactions occurred in association 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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with the first infusion of rituximab.  Because of this, patients should receive 
premedication with acetaminophen/paracetamol, antihistamines, or corticosteroids, in 
accordance with standard clinical practice, prior to rituximab infusions. 
3.4.4.2 
Management of Severe Infusion Reactions 
Administration of rituximab will occur in a setting with emergency equipment 
and staff who are trained to monitor for and respond to medical emergencies.  
The rituximab infusion should be interrupted for severe reactions based on clinical 
judgment.   
Medications and supportive care measures⎯including, but not limited to, epinephrine, 
antihistamines, glucocorticoids, IV fluids, vasopressors, oxygen, bronchodilators 
and acetaminophen/paracetamol⎯should be available for immediate use and instituted 
as medically indicated for use in the event of a reaction during administration.   
In most cases, the infusion can be resumed at a 50% reduction in rate 
(e.g., from 100 mg/hr to 50 mg/hr) when symptoms have completely resolved.  
Patients requiring close monitoring during all rituximab infusions include those with 
preexisting cardiac and pulmonary conditions, those with prior clinically significant 
cardiopulmonary adverse events, and those with high numbers of circulating malignant 
cells (≥ 25,000/μL) with or without evidence of high tumor burden. 
3.4.4.3 
Tumor Lysis Syndrome 
Rapid reductions in tumor volume followed by acute renal failure, hyperkalemia, 
hypocalcemia, hyperuricemia, or hyperphosphatemia have been reported within 
12−24 hours after the first infusion of rituximab.  Rare instances of fatal outcome have 
been reported in the setting of TLS following treatment with rituximab.  The risks of TLS 
appear to be greater in patients with high tumor burden.  Patients deemed to be at high 
risk for TLS complications may at the investigator’s discretion receive their initial dose of 
rituximab over 2 consecutive days (see Section 4.3.2.3).  Correction of electrolyte 
abnormalities, monitoring of renal function and fluid balance, and administration of 
supportive care, including dialysis, should be initiated as indicated.  Following complete 
resolution of TLS complications, rituximab has been tolerated when re-administered 
in conjunction with prophylactic therapy for TLS in a limited number of cases. 
3.4.4.4 
Hepatitis B Reactivation with Related Fulminant Hepatitis and 
Other Viral Infections 
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death 
has been reported for some patients with hematologic malignancies treated with 
rituximab.  The majority of these patients received rituximab in combination with 
chemotherapy.  The median time to the diagnosis of hepatitis was approximately 
4 months after the initiation of rituximab and approximately 1 month after the last dose of 
rituximab.  Patients with serologic findings consistent with chronic HBV (Hepatitis B 
surface antigen [HBsAg] positivity) or hepatitis C virus (HCV) infection (HCV RNA or 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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antibody positivity) are ineligible for this study.  Patients who are not chronically infected 
with HBV but have serologic evidence of prior infection at baseline (IgG anti-HBc 
positive, but HBV DNA negative) may be eligible (if believed to be in the patient’s best 
interest by the investigator and Medical Monitor) and would be monitored closely for 
perturbations in liver function during the period of rituximab treatment and every 
2−4 weeks thereafter.  Such patients would also be required to receive prophylactic 
anti-viral therapy with lamivudine for at least 6 months after completion of rituximab 
therapy (Yeo et al. 2009). 
Additional serious viral infections, new, reactivated, or exacerbated (e.g., infections 
caused by cytomegalovirus, varicella zoster virus, herpes simplex virus, West Nile virus, 
parvovirus B19, JC virus, and HCV) have been reported with rituximab, mainly in 
patients who had received rituximab in combination with chemotherapy or as part of a 
hematopoietic stem cell transplant.  Particular attention should be given to patients who 
have had significant prior immunosuppressive treatment such as high-dose 
chemotherapy and stem cell transplant.  JC virus infection resulting in progressive 
multifocal leukencephalopathy (PML) and death has been observed in rituximab-treated 
patients with hematologic malignancies or with autoimmune diseases.  Most cases of 
PML were diagnosed within 12 months of the patient’s last infusion of rituximab.  
Physicians should consider the diagnosis of PML in any patient presenting with 
new-onset neurologic manifestations.  Evaluation of PML includes, but is not limited to, 
consultation with a neurologist, brain magnetic resonance imaging (MRI), and lumbar 
puncture.  Physicians should discontinue rituximab (and DCDT2980S and/or 
DCDS4501A) and consider discontinuation or reduction of any immunosuppressive 
therapy in patients who develop PML. 
3.4.4.5 
Cardiovascular Events 
Infusions should be discontinued in the event of serious or life-threatening cardiac 
arrhythmias.  Patients who develop clinically significant arrhythmias should 
undergo cardiac monitoring during and after subsequent infusions of rituximab.  
Patients with preexisting cardiac conditions, including arrhythmias and angina have had 
recurrences of these events during rituximab therapy should be monitored throughout 
the infusion and the immediate post-infusion period. 
3.4.4.6 
Bowel Obstruction and Perforation 
Abdominal pain, bowel obstruction, and perforation, in some cases leading to death, 
were observed in patients receiving rituximab in combination with chemotherapy for 
DLBCL.  In post-marketing reports, which include patients with low-grade or follicular 
NHL and patients with DLBCL, the mean time to onset of symptoms was 6 days 
(range, 1−77 days) in patients with documented gastrointestinal perforation.  Complaints 
of abdominal pain, especially early in the course of treatment, should prompt a thorough 
diagnostic evaluation and appropriate treatment.   
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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3.4.4.7 
Immunization 
The safety of immunization with live viral vaccines following rituximab therapy has not 
been studied.  Patients who participate in this study may not receive either primary or 
booster vaccination with live virus vaccines for at least 6 months prior to initiation of 
rituximab or at any time during study treatment.  Investigators should review the 
vaccination status of potential study patients being considered for this study and follow 
the U.S. Centers for Disease Control and Prevention guidelines for adult vaccination with 
non-live vaccines intended to prevent infectious diseases prior to study therapy. 
Refer to the Rituxan®/MabThera® (Rituximab) Package Insert/SmPC for additional safety 
information. 
3.5 
MINIMIZATION OF BIAS  
This is a randomized, non-comparative, open-label study.  Patients will be randomly 
allocated to two treatment arms in a 1:1 ratio through use of an Interactive Voice and 
Web Response System (IXRS).  A dynamic stratified randomization scheme will be 
employed to ensure balance in the stratification factors as specified in Section 3.1. 
3.6 
ADMINISTRATIVE STRUCTURE  
Genentech, Inc., a member of the Roche group, will Sponsor this study.  A Contract 
Research Organization (CRO) will be utilized to perform project management, study 
management and clinical monitoring.  Genentech will conduct CRO oversight, approve 
patient eligibility, perform dose escalation decision-making, medical monitoring, and 
statistical programming and analysis. An Internal Monitoring Committee 
(IMC; see Section 3.4) will provide an additional level of safety monitoring for the study.  
Approximately 40 study centers in the United States, Canada, and Europe will 
participate in the study to enroll approximately 120 patients.  Additional patients may be 
enrolled in order to obtain additional safety and/or efficacy data. 
Electronic data capture (EDC) will be utilized for this study.  An IXRS will be used to 
assign patient numbers.  A central laboratory will be used for sample management and 
storage until shipment to one of several specialty laboratories or GNE for analysis.  
An independent review facility (IRF) will be used for the collection and possible 
assessment of radiographic images from tumor assessments.  Additional vendors for 
ECG collection and possible analysis and for PRO collection and data entry will be used. 
3.7 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in accordance with the U.S. Food and Drug Administration 
(FDA) regulations, the International Conference on Harmonisation (ICH) E6 Guideline for 
Good Clinical Practice (GCP), and applicable local, state, and federal laws, as well as 
other applicable country laws. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria to be eligible for study entry: 
• 
Signed Informed Consent Form(s) 
• 
Age ≥ 18 years  
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 
• 
Life expectancy of at least 12 weeks 
• 
History of histologically documented relapsed or refractory Grades 1−3a FL, or 
relapsed or refractory DLBCL 
• 
Availability of an archival or freshly biopsied tumor tissue sample must be confirmed 
for study enrollment. 
• 
Have a clinical indication for treatment as determined by the investigator 
• 
Must have at least one bi-dimensionally measurable lesion (> 1.5 cm in its largest 
dimension by CT scan or MRI) 
• 
Laboratory values (including patients with hepatic or renal involvement), as follows: 
AST and ALT ≤ 2.5 × the upper limit of normal (ULN) 
Total bilirubin ≤ 1.5 × ULN 
Platelet count ≥ 75,000/mm3 (unless thrombocytopenia clearly due to marrow 
involvement of NHL, and/or disease-related immune thrombocytopenia) 
Absolute neutrophil count ≥ 1000/mm3 (without growth factor support, unless 
neutropenia clearly due to marrow involvement of NHL) 
Total hemoglobin ≥ 9 g/dL (without transfusion support >14 days prior to 
screening, unless anemia clearly due to marrow involvement of NHL) 
Serum creatinine ≤ 2.0 mg/dL or measured creatinine clearance ≥ 50 mL/min 
• 
For female patients of childbearing potential and male patients with female 
partners of childbearing potential, agreement to use one highly effective form of 
nonhormonal contraceptionor two effective forms of nonhormonal contraception, 
including at least one method with a failure rate of < 1% per year through the 
course of study treatment and for at least 3 months after the last dose of 
DCDT2980S or DCDS4501A or rituximab (whichever is later) in women and at 
least 5 months after the last dose of DCDT2980S or DCDS4501A or rituximab 
(whichever is later) in men. 
A woman is considered not to be of childbearing potential if she is 
postmenopausal, defined by amenorrhea of ≥ 12 months duration and age 
≥ 45 years, or has undergone hysterectomy and/or bilateral oophorectomy. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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The following are considered highly effective forms of contraception:  1) true 
abstinence; 2) male sterilization (with postprocedure documentation of absence 
of sperm in the ejaculate).  For female patients, the sterilized male partner 
should be the sole partner. 
The following are considered effective forms of contraception:  1) intrauterine 
device (copper IUD or hormonal IUDs only) or intrauterine system; 2) condom 
with spermicidal foam/gel/film/cream/suppository; 3) occlusive cap (diaphragm 
or cervical/vault cap) with spermicidal foam/gel/film/cream/suppository. 
Males must agree to abstain from sperm donation for at least 5 months after the 
last dose of DCDT2980S or DCDS4501A or rituximab (whichever is later). 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Prior use of any monoclonal antibody, radioimmunoconjugate or antibody-drug 
conjugate within 4 weeks before Cycle 1, Day 1 
• 
Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive 
therapy, or any investigational anti-cancer agent within 2 weeks prior to Cycle 1, 
Day 1 
Adverse events except for sensory neuropathy from any previous treatments 
must be resolved or stabilized to Grade ≤ 2 prior to Cycle 1, Day 1 
• 
Completion of autologous stem cell transplant within 100 days prior to Cycle 1, 
Day 1 
• 
Prior allogeneic stem cell transplant 
• 
Eligibility for autologous SCT (patients with relapsed or refractory DLBCL) 
• 
History of transformation of indolent disease to DLBCL 
• 
History of severe allergic or anaphylactic reactions to monoclonal antibody therapy 
(or recombinant antibody-related fusion proteins) 
• 
History of other malignancy that could affect compliance with the protocol or 
interpretation of results 
Patients with a history of curatively treated basal or squamous cell carcinoma of 
the skin or in situ carcinoma, e.g., of the cervix or breast, are allowed.  Patients 
with a malignancy that has been treated with curative intent will also be allowed if 
the malignancy has been in remission without treatment for ≥ 2 years prior 
to Cycle 1, Day 1. 
• 
Current or past history of CNS lymphoma 
• 
Current Grade > 1 peripheral neuropathy 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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• 
Evidence of significant, uncontrolled concomitant diseases which could affect 
compliance with the protocol or interpretation of results, including significant 
cardiovascular disease (such as New York Heart Association Class III or IV cardiac 
disease, myocardial infarction within the last 6 months, unstable arrhythmias, or 
unstable angina) or significant pulmonary disease (including obstructive pulmonary 
disease and history of bronchospasm) 
• 
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection 
(excluding fungal infections of nail beds) at study enrollment, or any major episode 
of infection requiring treatment with IV antibiotics or hospitalization (relating to the 
completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1 
• 
Recent major surgery within 6 weeks prior to Cycle 1, Day 1, other than 
for diagnosis 
• 
Presence of positive test results for Hepatitis B (HBsAg and/or total Hepatitis B core 
antibody [anti-HBc]) or Hepatitis C (HCV antibody) 
Patients who are positive for anti-HBc are eligible only if PCR is negative for HBV 
DNA and it is believed by both the investigator and Medical Monitor to be in the 
patient’s best interest to participate.  
Patients who are positive for HCV antibody must be negative by for HCV by PCR 
to be eligible for study participation 
• 
Known history of HIV seropositive status 
• 
Women who are pregnant or lactating 
• 
Ongoing corticosteroid use > 30 mg/day prednisone or equivalent 
Patients receiving corticosteroid treatment ≤ 30 mg/day prednisone or equivalent 
must be documented to be on a stable dose prior to study enrollment and 
initiation of therapy 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
This is an open-label study.  After written informed consent has been obtained and 
preliminary eligibility has been established, the study site will submit documentation 
supporting eligibility to the Sponsor via facsimile and obtain the Sponsor’s approval to 
enroll the patient.  Once the Sponsor reviews and approves the patient for enrollment, 
the patient number will be assigned via IXRS.  
As described in Section 3.1.2, only select investigator sites that have agreed to 
participate in the nonrandomized portion of the study will enroll patients into these 
cohorts.  Cohorts C and D will be opened sequentially following completion of the 
randomized portion of the study for follicular lymphoma patients. 
Personnel responsible for performing PK and ATA assays will be receive participants’ 
treatment assignments to identify appropriate PK and ATA samples to be analyzed in 
the appropriate corresponding assays.  
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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4.3 
STUDY TREATMENT  
4.3.1 
DCDT2980S and DCDS4501A 
4.3.1.1 
Formulation and Storage 
a. 
DCDT2980S 
DCDT2980S will be provided as a lyophilized powder in a single-use 20-cc vial.  
The solution for reconstitution is Sterile Water for Injection (SWFI) and the reconstitution 
volume is 2.6 mL to yield a final concentration of 20 mg/mL DCDT2980S in 40 mM 
L-histidine hydrochloride, 240 mM sucrose, and 0.02% polysorbate 20, pH 6.0. 
Reconstituted DCDT2980S should be further diluted with sterile 0.9% NaCl to a total 
volume of 250 mL. 
DCDT2980S vials must be refrigerated at 2°C–8°C (36°F−46°F) upon receipt until use.  
DCDT2980S should not be used beyond the expiration date provided by the 
manufacturer.  Vial contents should not be frozen or shaken and should be protected 
from direct sunlight.  After reconstitution, DCDT2980S vials may be stored at room 
temperatures (> 8°C−25°C [> 46°F−77°F]) for up to 4 hours, or at refrigerated 
temperatures (2°C−8°C [36°F−46°F]) for up to 8 hours prior to use.  Once DCDT2980S 
has been diluted with sterile 0.9% NaCl, the solution should be used within 4 hours at 
room temperature or within 8 hours at refrigerated temperature.  Vials are intended for 
single use only; therefore, any remaining solution should be discarded. 
For further details, refer to the DCDT2980S Investigator Brochure. 
b. 
DCDS4501A 
DCDS4501A is provided as a liquid formulation and contains no preservatives.  Each 
single-use, 20-cc vial is filled to deliver 100 mg of DCDS4501A.  The Drug Product is 
formulated as 10 mg/mL DCDS4501A in 20 mM L-histidine acetate, 240 mM sucrose, 
0.02% (w/v) polysorbate 20, pH 5.5.  
DCDS4501A will be administered to patients by IV via syringe pump with IV infusion 
set containing a 0.22 µm in-line filter with a final volume of DCDS4501A determined 
by the dose and patient weight.  
DCDS4501A vials must be refrigerated at 2−8°C (36−46°F) upon receipt until use.  
DCDS4501A vials may be stored at room temperature (> 8°C to 25°C [46°F−77°F]) for 
up to 8 hours.  DCDS4501A should not be used beyond the expiration date provided by 
the manufacturer.  Vial contents should not be frozen or shaken and should be protected 
from direct sunlight.  Vials are intended for single use only; therefore, any remaining 
solution should be discarded. 
Once the DCDS4501A dose solution has been prepared, the solution should be used 
within 4 hours at room temperature (> 8°C to 25°C [46°F−77°F]) or within 8 hours 
refrigerated at 2°C−8°C (36°F−46°F).  Because the Drug Product contains no 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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preservatives, the Sponsor recommends using DCDS4501A in a syringe and extension 
set as soon as possible to reduce the risk of microbial contamination.   
For further details, refer to the DCDS4501A Investigator Brochure. 
4.3.1.2 
Dosage and Administration 
a. 
DCDT2980S-Specific Information 
DCDT2980S will be administered to patients by IV infusion.  Compatibility testing has 
shown that DCDT2980S is stable when diluted in polyvinyl chloride (PVC) bags to a 
concentration at or above 0.04 mg/mL in 0.9% NaCl diluent.  The Drug Product will be 
delivered following dilution in 0.9% NaCl with a final DCDT2980S concentration 
determined based on dose and patient weight.  The study drug will be diluted in a PVC 
bag and delivered using a 0.22 µm in-line filter on the IV infusion set. 
Additional information/instructions regarding study drug administration will be provided in 
the Pharmacy Binder. 
b. 
DCDS4501A-Specific Information 
DCDS4501A will be administered to patients by IV via syringe pump with IV infusion 
set containing a 0.22 µm in-line filter with a final volume of DCDS4501A determined 
by the dose and patient weight.  Compatibility testing has shown that DCDS4501A is 
stable in both syringes made of polypropylene (PP) and in standard extension sets with 
0.22 µm in-line filter, when stored neat or diluted with 0.9% NaCl saline.   
Additional information/instructions regarding study drug administration will be provided in 
the Pharmacy Binder. 
c. 
General Information 
The total dose of DCDT2980S and DCDS4501A for each patient will depend on the 
patient’s weight within 96 hours prior to Day 1 of each cycle.  The patient weight 
obtained during screening may be used for dose determination at all treatment cycles; if 
the patient’s weight within 96 hours prior to Day 1 of a given treatment cycle differs by 
>10% from the weight obtained during screening, then the new weight should be used to 
calculate the dose.   
For both DCDT2980S and DCDS4501A, the initial dose will be administered 
to well-hydrated (based on clinical judgment) patients over 90 (± 10) minutes.  
Pre-medication with acetaminophen or paracetamol (e.g., 500–1000 mg) and 
diphenhydramine (e.g., 50–100 mg) per institutional standard practice may be 
administered prior to each infusion.  Administration of corticosteroids is permitted at the 
discretion of the treating physician.  For patients who do not receive pre-medications 
prior to the first dose of DCDT2980S and who develop an infusion related reaction 
during the first dose should receive pre-medications prior to subsequent doses 
(see Table 1). 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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The DCDT2980S/DCDS4501A infusion may be slowed or interrupted for patients 
experiencing infusion-associated symptoms.  Following the initial dose, patients will be 
observed for 90 minutes for fever, chills, rigors, hypotension, nausea, or other 
infusion-associated symptoms.  If the infusion is well-tolerated, subsequent doses of 
DCDT2980S/DCDS4501A may be administered over 30 (± 10) minutes, followed by a 
30-minute observation period post-infusion.   
For instructions on study drug preparation and administration, refer to the DCDT2980S 
and DCDS4501A Investigator Brochure. 
4.3.1.3 
Dosage Modification 
Patients should be assessed clinically for toxicity prior to each dose using the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
version 4.0 grading scale.  Dosing will occur only if a patient’s clinical assessment and 
laboratory test values are acceptable.  If scheduled dosing coincides with a holiday that 
precludes dosing, dosing should commence on the nearest following date, with 
subsequent dosing continuing on a 21-day schedule as applicable. 
Specific guidelines around dosage modifications for neutropenia and peripheral 
neuropathy are detailed below in Sections 4.3.1.6 and 4.3.1.7.  Patients who experience 
other treatment-related Grade 3 or 4 toxicity or laboratory abnormalities will be 
allowed to delay dosing of study treatment (both ADC and rituximab) for up to 2 weeks to 
allow for recovery.  Patients may continue to receive additional infusions of DCDT2980S 
or DCDS4501A per their treatment assignment provided that the toxicity has resolved to 
Grade ≤ 2 or ≥ 80% of the baseline value, whichever is lower within the 2 week delay 
period.  Upon resolution, the dose for subsequent infusions may be reduced to 
1.8 mg/kg.  If the toxicity that resulted in the dose reduction persists or recurs at the 
reduced dose, then the patient should be discontinued from study treatment.  The 
decision for dose modification will be made based on the investigator’s assessment of 
ongoing clinical benefit with continuing study treatment and in consultation with the 
Medical Monitor.   
Once dose reductions of DCDT2980S or DCDS4501A are made for toxicity, dose 
re-escalation will not be allowed.  Patients who are enrolled in the nonrandomized 
portion of the study (Cohorts C and D), are dosed at an ADC dose of 1.8 mg/kg, and 
have progressive disease in the absence of any drug-related toxicity may have their 
ADC dose increased to 2.4 mg/kg if it is felt that there is reasonable justification for 
ongoing clinical benefit.  The decision to increase the dose must be made in consultation 
with and approval of the Medical Monitor. 
If a patient develops unacceptable toxicity to DCDT2980S or DCDS4501A requiring its 
discontinuation, single-agent rituximab may be continued based on the investigator’s 
assessment of ongoing clinical benefit and with the approval of the Medical Monitor. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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4.3.1.4 
Schedule Modification 
Patients in whom toxicities have not resolved to Grade ≤ 2 or ≥ 80% of baseline value, 
whichever is lower, may have their study treatment delayed by up to 2 weeks.  Dosing of 
both DCDT2980S or DCDS4501A and rituximab should be held during this period.  If all 
study drug–related toxicities have resolved sufficiently, the patient may resume 
DCDT2980S or DCDS4501A and rituximab dosing on the regular every-21-day 
schedule.   
A patient’s dosing may be changed to a 28-day cycle if it is felt by the investigator that 
changing a patient’s dosing regimen from 21-day to 28-day cycles would provide 
sufficient time for recovery from a transient and reversible toxicity e.g., cytopenia without 
requiring repeated treatment delays.  Modifications to the dosing schedule in this fashion 
must be made in consultation with and with the approval of the Medical Monitor. 
Patients who do not fulfill the criteria for continuation of dosing after the 2-week delay 
may be discontinued from study treatment and be followed for safety outcomes (see 
Section 4.5.5).  Exceptions on the basis of ongoing clinical benefit may be allowed 
following a careful assessment and discussion of risk versus benefit with the patient by 
the investigator and approval from the Medical Monitor.  
Specific guidelines around schedule modifications for neutropenia and peripheral 
neuropathy are detailed below in Sections 4.3.1.6 and 4.3.1.7. 
4.3.1.5 
Infusion Reaction 
Patients will be monitored during and after each DCDT2980S/DCDS4501A infusion for 
90 minutes after the first infusion and for 30 minutes after subsequent infusions in the 
absence of infusion-related adverse events.  Patients who experience infusion-related 
symptoms should be managed as described in Table 1.  Precautions for suspected 
anaphylactic reaction during study drug infusions are provided in Appendix D. 
In the event of a life-threatening infusion-related reaction (IRR), which may include 
pulmonary or cardiac events, or an IgE-mediated anaphylactic reaction, administration of 
DCDT2980S/DCDS4501A should be immediately discontinued.  Patients who 
experience these reactions should receive aggressive symptomatic treatment and are 
not eligible to receive any additional study treatment. 
Premedication prior to DCDT2980S/DCDS4501A with acetaminophen/paracetamol, 
antihistamines, or corticosteroids per standard clinical practice is permitted, e.g., in 
patients with substantial tumor burden and where the risk of cytokine release syndrome 
is high.  In patients who do not receive premedication prior to any given dose of 
DCDT2980S/DCDS4501A and who develop any Grade ≥ 2 infusion-related toxicity, 
premedication should be administered prior to subsequent doses.  
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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4.3.1.6 
Neutropenia 
Because neutropenia is a known risk of DCDT2980S and DCDS4501A (see 
Section 3.4.2.3), the use of growth factor support (G-CSF) as prophylactic and 
therapeutic indications is permitted (see Appendix F) in order to allow continued dosing 
of DCDT2980S/DCDS4501A.  Dose modifications for patients who experience 
treatment-related Grade 3–4 neutropenia in the context of G-CSF usage are as follows: 
• 
Primary prophylaxis with G-CSF, i.e., prior to the first dose of 
DCDT2980S/DCDS4501A, is permitted for patients with clinical factors listed in 
Appendix F or who otherwise are considered at high risk for developing neutropenia 
on study treatment. 
• 
Patients who experience treatment-related Grade 3–4 neutropenia will be allowed to 
delay dosing of study treatment (both ADC and rituximab) for up to two weeks to 
allow for recovery.  Therapeutic G-CSF is permitted as clinically indicated (see 
Appendix F) and to facilitate neutrophil recovery to allow subsequent 
DCDT2980S/DCDS4501A dosing. 
• 
Subsequent dosing DCDT2980S/DCDS4501A is permitted provided that the 
neutropenia has resolved to Grade ≤ 2, or ≥ 80% of the baseline value, whichever is 
lower, within the 2-week period.   
• 
If prophylactic G-CSF was not administered prior to the cycle in which the 
Grade 3−4 neutropenia developed, then prophylactic G-CSF may be administered 
prior to subsequent cycles without DCDT2980S/DCDS4501A dose reduction.  The 
dose schedule may be changed from 21-day to 28-day cycles to provide sufficient 
time for neutrophil recovery in subsequent cycles.  In the absence of prophylactic 
G-CSF or dose schedule modification, the dose of DCDT2980S/DCDS4501A in 
subsequent cycles should be reduced to 1.8 mg/kg.   
• 
If Grade 3–4 neutropenia recurs with prophylactic G-CSF, the dose for subsequent 
DCDT2980S/DCDS4501A should be reduced to 1.8 mg/kg.  Prophylactic G-CSF 
and dose schedule modifications as described above are permitted in order to 
maintain the reduced DCDT2980S/DCDS4501A dose level and schedule. 
• 
If Grade 3–4 neutropenia recurs at the reduced dose despite the administration of 
prophylactic G-CSF, then the patient should be discontinued from study treatment.   
• 
For patients enrolled into the nonrandomized portion of the study (Cohorts C 
and D), dose modifications will not be allowed.  Administration of 
therapeutic/prophylactic G-CSF and dose-schedule modifications as described above 
are allowed.  Patients who have persistent or recurrent Grade 3−4 neutropenia as 
defined above should be discontinued from study treatment. 
 
The determination of the dose and schedule modifications will be made based on the 
investigator’s assessment of ongoing clinical benefit with continuing study treatment and 
with the approval of the Medical Monitor.   
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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4.3.1.7 
Peripheral Sensory Neuropathy 
Peripheral sensory neuropathy is a known risk of DCDT2980S and DCDS4501A 
(see Section 3.4.2.5).  For new or worsening drug-related Grade 2 or 3 peripheral 
sensory neuropathy, dosing should be held for up to 2 weeks until peripheral sensory 
neuropathy improves to Grade 1 or baseline grade.  Continuation of study treatment 
following dose delays beyond 2 weeks will require consultation with and approval of the 
Medical Monitor based on an assessment of the risk-benefit analysis of continuing to 
delay study treatment. 
Following resolution of peripheral sensory neuropathy, subsequent doses of 
DCDT2980S/DCDS4501A should be reduced to 1.8 mg/kg.  If worsening Grade 2 or 3 
peripheral sensory neuropathy recurs following dose reduction, study treatment should 
be discontinued.  For Grade 4 peripheral sensory neuropathy, study treatment should be 
discontinued.  
For patients enrolled into the nonrandomized portion of the study (Cohorts C and D), 
dose modifications will not be allowed.  Patients who have Grade 2 or 3 peripheral 
sensory neuropathy as defined above should be discontinued from study treatment. 
4.3.1.8 
Hyperglycemia 
Hyperglycemia has been observed in patients treated with DCDT2980S and 
DCDS4501A as well as with other antibody-drug conjugates using the same vc-MMAE 
platform.  Hyperglycemia has been reversible upon holding or discontinuing treatment 
of the ADCs and/or initiation of improved anti-hyperglycemic medications (see 
Section 3.4.2.7).   
For symptomatic fasting Grade 3 (> 250−500 mg/dL) or asymptomatic Grade 4 
(> 500 mg/dL) hyperglycemia, medical management should be initiated immediately and 
consultation with a specialist should be considered.  If the hyperglycemia persists for 
> 1 week after initiation of management, dose modification, schedule modification, or 
discontinuation of study treatment should be considered.  In these cases the study 
Medical Monitor should be consulted to assess the risk-benefit balance of continued 
study treatment. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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Table 1 
Management of Infusion-Related Symptoms 
Infusion-Related  
Symptoms a 
Guidance 
Grade 1−2 
• 
Slow or hold infusion 
• 
Give supportive treatment b 
• 
Upon symptom resolution, may resume/escalate infusion rate at the 
investigator’s discretion c. 
Note: For Grade 2 wheezing or bronchospasm, patient must be pre-medicated for 
subsequent doses.  If symptoms recur with the same or greater severity, the 
infusion must be stopped immediately and study treatment permanently 
discontinued. 
Grade 3 
• 
Discontinue infusion 
• 
Give supportive treatment b 
• 
Upon symptom resolution, may resume/escalate infusion rate at the 
investigator discretion c 
Note:  Patients must be pre-medicated prior to subsequent study treatment.  
If symptoms recur with the same or greater severity, the infusion must be stopped 
immediately and study treatment permanently discontinued. 
If patient has Grade 3 wheezing or bronchospasm at first occurrence, study 
treatment should be permanently discontinued.   
Grade 4 
• 
Discontinue infusion immediately, treat symptoms aggressively, and 
permanently discontinue patient from study treatment 
IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events. 
a Refer to the NCI CTCAE, v4.0 scale for the grading of symptoms.  Management of IgE-mediated 
allergic reactions should be as directed in the text following this table. 
b Supportive treatment:  Patients should be treated with acetaminophen/paracetamol and an 
antihistamine such as diphenhydramine if they have not been received in the last 4 hours.  
IV saline may be indicated.  For bronchospasm, urticaria, or dyspnea, patients may require 
antihistamines, oxygen, corticosteroids (e.g., 100 mg IV prednisolone or equivalent), 
and/or bronchodilators.  Patients with hypotension requiring vasopressor support must be 
permanently discontinued from study drug. 
c Infusion rate escalation after re-initiation:  Upon complete resolution of symptoms, the infusion 
may be resumed at 50% of the rate achieved prior to interruption.  In the absence of 
infusion-related symptoms, the rate of infusion may be escalated in increments of 50 mg/hr every 
30 minutes. 
  
4.3.2 
Rituximab 
4.3.2.1 
Formulation 
Rituximab (Rituxan®/MabThera®) is a sterile, clear, colorless, preservative-free liquid 
concentrate for IV administration.  Rituximab is supplied at a concentration of 10 mg/mL 
in 500-mg (50-mL) single-use vials.  A single-unit, 500-mg carton contains one 50-mL 
vial of rituximab (10 mg/mL).  The product is formulated for IV administration in 
9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, and 0.7 mg/mL 
polysorbate 80, after reconstitution with SWFI.  The pH is adjusted to 6.5.  Vials are for 
single use.  Each vial and carton will contain a label (either single-panel or booklet) 
affixed to the vial or carton.   
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4.3.2.2 
Dosage, Administration, and Storage 
Rituximab (Rituxan®, MabThera®) will be administered intravenously once per 3-week 
(or 4-week) cycle.  The infusion at 375 mg/m2 for each dose will be based on the 
patient’s body surface area at screening and will remain the same throughout the study.   
If a scheduled dose of rituximab falls outside of the ± 2-day window for reasons other 
than an adverse event, the site must notify and discuss with the Genentech Medical 
Monitor prior to rituximab administration.  Such dosing may not necessarily qualify as a 
protocol deviation, if deemed to be in the best interests of the patient, after consultation 
with the Medical Monitor and agreed to in advance by the Medical Monitor.  
Rituximab should not be administered as an IV push or bolus.  Infusion reactions may 
occur.  Premedication consisting of acetaminophen (or paracetamol), diphenhydramine 
(or other suitable antihistamine), and a single dose of hydrocortisone (e.g., up to 100 mg 
or an equivalent dose of methylprednisolone) may also be administered beginning with 
the first infusion, per standard clinical practice.  Premedication may attenuate infusion 
reactions.  Because transient hypotension may occur during rituximab infusion, 
consideration should be given to withholding antihypertensive medications for 12 hours 
prior to rituximab infusion.   
a. 
First Infusion 
The rituximab solution for infusion should be administered intravenously at an initial rate 
of 50 mg/hr.  Rituximab should not be mixed or diluted with other drugs.  If infusion 
reactions do not occur, the infusion rate should be escalated in 50 mg/hr increments 
every 30 minutes to a maximum of 400 mg/hr.  If an infusion reaction develops, 
the infusion should be temporarily slowed or interrupted.  The infusion can continue at 
one-half the previous rate upon improvement of patient symptoms.   
b. 
Subsequent Infusions 
If the patient tolerates the first infusion well, subsequent rituximab infusions may be 
administered at an initial rate of 100 mg/hr and increased in 100 mg/hr increments at 
30-minute intervals to a maximum of 400 mg/hr, as tolerated.  If the patient does not 
tolerate the first infusion well, the guidelines for the first infusion should be followed. 
If a patient tolerates the first three cycles of study treatment without significant infusion 
reactions, rituximab may be administered as “rapid infusion” in accordance with local 
institutional guidelines. 
c. 
Storage 
Rituximab vials must be stored at 2°C–8°C (36°C–46°F).  Rituximab vials should be 
stored in the outer carton in order to protect them from light.  Rituximab solution for 
infusion may be stored at 2°C–8°C (36°C–46°F) for 24 hours and has been shown to be 
stable for an additional 12 hours at room temperature.  However, since rituximab does 
not contain a preservative, diluted solutions should be stored refrigerated (2°C–8°C).  
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No incompatibilities between rituximab and PVC or polyethylene bags have 
been observed. 
See the Rituxan® (Rituximab) Package Insert or SmPC (in the E.U.) for additional 
information. 
4.3.2.3 
Dosage Modification 
There will be no rituximab dose modification in this study.  Patients at high risk for 
TLS complications (see Section 3.4.2.2) may, at the investigator’s discretion, receive 
their initial dose of rituximab over 2 consecutive days (e.g., 125 mg/m2 on Day 1, 
250 mg/m2 on Day 2; with DCDT2980S/DCDS4501A dose potentially delayed to Day 3). 
Any NCI CTCAE, v4.0, toxicity Grade ≥ 3 in severity that is deemed related to rituximab 
treatment will require interruption of study treatment (both ADC and rituximab) until 
resolution to Grade ≤ 2 or ≥ 80% of baseline, whichever is lower.  Resumption of 
rituximab treatment may be considered in patients with resolution of toxicities to 
Grade ≤ 1 within 2 weeks at the discretion of the investigator, after consultation with the 
Medical Monitor.  Failure of such toxicities to resolve after 2-week delay in study 
treatment will require permanent discontinuation of rituximab.  Continuation of rituximab 
treatment may be permitted on the basis of ongoing clinical benefit following a careful 
assessment and discussion of risk versus benefit with the patient by the investigator and 
approval from the Medical Monitor.   
If a patient develops unacceptable toxicity to rituximab requiring its discontinuation, 
single-agent DCDT2980S or DCDS4501A may be continued based on the investigator’s 
assessment of ongoing clinical benefit and with the approval of the Medical Monitor. 
4.3.2.4 
Schedule Modification 
Patients in whom toxicities have not resolved (i.e., to Grade ≤ 1 or ≥ 80% of baseline) 
may have their study treatment delayed by up to 2 weeks.  If after the up to 2-week 
delay all study drug–related toxicities have resolved sufficiently, the patient may receive 
the scheduled doses of rituximab.  In addition, a patient’s dosing may be changed to a 
28-day cycle if it is felt by the investigator and Medical Monitor that changing a patient’s 
dosing regimen from 21-day to 28-day cycles would provide sufficient time for recovery 
from transient cytopenias without requiring repeated treatment delays. 
Patients who do not fulfill the criteria for dosing after the additional 2 weeks have 
elapsed may be discontinued from study treatment and be followed for safety outcomes 
(see Section 4.5.5).  Exceptions on the basis of ongoing clinical benefit may be allowed 
following a careful assessment and discussion of risk versus benefit with the patient by 
the investigator and approval from the Medical Monitor.  In addition, delay of therapy 
because of toxicities not attributed to study drug may not require discontinuation and will 
be discussed with the Medical Monitor. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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4.3.2.5 
Infusion Reaction 
Patients will be monitored during and after each rituximab infusion for 90 minutes after 
the first infusion and for 30 minutes after subsequent infusions in the absence of 
infusion-related adverse events.  Patients who experience infusion-related symptoms 
should be managed as directed in Table 1 (see Section 4.3.1.5). 
In the event of a life-threatening IRR (which may include pulmonary or cardiac events) or 
IgE-mediated anaphylactic reaction to rituximab, rituximab should be discontinued and 
no additional rituximab should be administered.  Patients who experience these 
reactions should receive aggressive symptomatic treatment and should be discontinued 
from study treatment. 
4.4 
CONCOMITANT AND EXCLUDED THERAPIES  
4.4.1 
Concomitant Therapy  
Concomitant therapy includes any prescription medications or over-the-counter 
preparations used by a patient between the 7 days preceding the screening evaluation 
and the end of study visits.  All concomitant medications should be reported to the 
investigator and recorded on the appropriate electronic Case Report Form (eCRF). 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use.  Concomitant use of hematopoietic 
growth factors is allowed in accordance with instructions provided in the package inserts. 
Patients who experience infusion-related temperature elevations of > 38.5°C (> 101.3°F) 
or other minor infusion-related symptoms may be treated symptomatically with 
acetaminophen/paracetamol (≥ 500 mg) and/or H1 and H2 histamine-receptor 
antagonists (e.g., diphenhydramine, ranitidine).  Serious infusion-related events 
manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced 
oxygen saturation, or respiratory distress should be managed with additional supportive 
therapies (e.g., supplemental oxygen, β2-agonists, and/or corticosteroids) as clinically 
indicated according to standard clinical practice (see Table 1).   
Infusion reaction prophylaxis with medications (e.g., acetaminophen/paracetamol, 
antihistamines, and/or corticosteroids) may be instituted at any point in the study if it is 
determined to be in the best interest of the patient based on observation of IRRs in 
patients already enrolled in the study.  Patients with Grade 3 hypotension or fever must 
be pre-medicated prior to retreatment (see Section 4.3.1.5).  Patients with hypotension 
requiring vasopressor support, or with Grade 3 wheezing, hypoxia, or generalized 
urticaria, must be permanently discontinued from study treatment. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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4.4.2 
Excluded Therapy 
Use of the following therapies is prohibited during the study: 
• 
Cytotoxic chemotherapy 
• 
Radiotherapy 
• 
Immunotherapy including immunosuppressive therapy 
• 
Radioimmunotherapy 
• 
Hormone therapy (other than contraceptives, hormone-replacement therapy, or 
megestrol acetate) 
• 
Biologic agents (other than hematopoietic growth factors, which are allowed 
if clinically indicated and used in accordance with instructions provided in the 
package inserts); guidelines for the use of G-CSF are detailed in Section 4.3.1.6 
and Appendix F. 
• 
Any therapies intended for the treatment of lymphoma or leukemia, 
whether approved by local regulatory authorities or investigational 
 
Patients who require the use of any of these agents will be discontinued from all study 
treatment.  Patients who are discontinued from study treatment will be followed for safety 
outcomes for 30 days following the patient’s last dose of DCDT2980S or DCDS4501A or 
rituximab, whichever is later, or until the patient receives another anti-cancer therapy 
whichever occurs first. 
4.5 
STUDY ASSESSMENTS  
4.5.1 
Definitions of Study Assessments 
4.5.1.1 
Medical History and Demographics 
Medical history includes all clinically significant diseases, prior cancer history, prior 
cancer therapies and procedures, and all medications used by the patient within 7 days 
preceding the screening visit. 
4.5.1.2 
Vital Signs 
Vital signs will include measurements of systolic and diastolic blood pressure while the 
patient is in a sitting or semi-supine position, pulse oximetry, pulse rate, and body 
temperature.  Every effort will be made to ensure that vital signs are obtained from 
patients in a consistent manner and position.  The timing of vital sign collection on 
the days of study treatment administration is as follows: 
• 
For the administration of rituximab, vital signs should be assessed prior to the start 
of the infusion, every 15 (± 5) minutes during the first hour of the infusion, as 
clinically indicated during the remainder of the infusion, and following the completion 
of the infusion.  
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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• 
For the administration of DCDT2980S or DCDS4501A, vital signs should be assessed 
prior to the start of the infusion, every 15 (± 5) minutes during the infusion, at the end 
of the infusion, and every 30 (±10) minutes for 90 minutes post-infusion following 
dosing at Cycle 1 and 30 (±10) minutes following dosing in subsequent cycles.  
Additional monitoring of vital signs should be performed if clinically indicated. 
4.5.1.3 
Physical Examination 
A complete physical examination should include the evaluation of head, eye, ear, nose, 
and throat; cardiovascular; dermatological; musculoskeletal; respiratory; gastrointestinal; 
and neurological systems.   
Targeted physical examinations should be limited to systems of clinical relevance 
(i.e., cardiovascular, respiratory, and any system that might be associated with tumor 
assessment, such as lymph nodes, liver, and spleen) and those systems associated with 
symptoms. 
Changes from baseline should be recorded at each subsequent physical examination.  
New or worsened abnormalities should be recorded as adverse events if appropriate. 
4.5.1.4 
Laboratory Assessments 
On days of study drug administration, pre-infusion laboratory samples should be drawn 
within 4 hours prior to the start of infusion unless otherwise specified.   Local laboratory 
assessments may be obtained up to 72 hours prior to the start of study treatment 
administration (see below and Section 4.5.3).  Instruction manuals and supply kits will be 
provided for all central laboratory assessments. 
Central Laboratory Assessments 
Samples for flow cytometry, PK, bone marrow, and anti-DCDT2980S or 
anti-DCDS4501A antibody assessments will be sent to one or several laboratories or to 
Genentech for analyses (see Section 3.6): 
• 
Leukocyte immunophenotyping/flow cytometry (fluorescence-activated cell sorting 
[FACS] lymphocyte subsets) 
Whole-blood samples will be collected to analyze B-cell subsets (CD19+), T-cell 
counts (CD3+, CD4+, CD8+), and NK cell counts (CD16+, CD56+), by flow 
cytometry. 
• 
ATA assays 
ATAs to DCDT2980S or DCDS4501A will be determined at Genentech using a 
validated ELISAs (see Section 4.9).  
• 
PK assays (see Section 4.5.1.6) 
• 
A plasma sample will be collected from patients for exploratory research as 
indicated in Section 4.5.1.9.  
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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• 
For patients who sign the optional consent, a blood sample will be collected prior to 
the first dose of study treatment for exploratory research. 
• 
Tumor tissue sample (archival or fresh) will be collected from patients for central 
pathologic review as described in Sections 4.1.1 and 4.5.1.9. 
 
Local Laboratory Assessments 
Samples for hematology, serum chemistry, liver function, and pregnancy will be 
analyzed at the study site’s local laboratory.  Local laboratory assessments may be 
obtained up to 72 hours prior to start of study treatment administration on Day 1 of the 
treatment cycle.   
• 
Hematology:  Includes complete blood count (hemoglobin, hematocrit, red blood cell 
count, white blood cell count, platelet count, absolute neutrophil count, and percent 
or absolute differential counts [e.g., segmented neutrophils, bands, lymphocytes, 
eosinophils, monocytes, basophils, and other cells) 
• 
Coagulation:  aPTT, prothrombin time (PT), and INR 
• 
Quantitative immunoglobulins (IgA, IgG, and IgM) 
• 
Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen (BUN or local equivalent), creatinine, calcium, magnesium, phosphorus, 
total and direct bilirubin, total protein, albumin, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase 
(LDH) and uric acid 
Serum gamma-glutamyl transpeptidase (GGT) levels will be required at screening 
only 
• 
Hemoglobin A1c 
• 
Viral serology and detection (screening assessment only and if clinically indicated) 
Hepatitis B (HBsAg and HBcAb; also HBV DNA by PCR if the patient is HBcAb 
positive) 
HCV antibody 
• 
Pregnancy test 
For women of childbearing potential (see Section 4.1.2), a serum pregnancy test 
must be performed within 14 days prior to Cycle 1, Day 1.   
Urine pregnancy tests will be performed during the study treatment period.  If any 
urine test result is positive, patient dosing will be postponed until the result is 
confirmed by a serum pregnancy test.  Any patient with a positive serum test will 
not be allowed to receive any study treatment. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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4.5.1.5 
Electrocardiogram Assessments 
Twelve-lead digital ECG measurements will be obtained in triplicate, with immediately 
consecutive ECGs obtained until three evaluable ECGs are recorded, at the following 
timepoints: 
• 
Screening 
• 
30−60 minutes before the start of DCDT2980S or DCDS4501A infusion in Cycle 1 
• 
30−60 minutes after the completion of DCDT2980S or DCDS4501A infusion in 
Cycle 1 
• 
30−60 minutes after the completion of DCDT2980S or DCDS4501A infusion in 
Cycle 3 
• 
Day 8 (±1 day) of Cycle 3 time-matched, i.e., obtained at the same time of day, with 
post-DCDT2980s/DCDS4501A infusion ECGs for Cycle 3 
• 
Treatment completion/early termination visit 
 
Non-triplicate ECGs should also be performed when clinically indicated in any patient 
with evidence of, or suspicion for, clinically significant signs or symptoms of cardiac 
dysfunction.  
All ECGs as described above will be submitted to a Sponsor-designated ECG central 
laboratory for storage and potential analysis.  Detailed instructions on ECG acquisitions 
and transmissions to the ECG central laboratory will be provided in the ECG manual 
provided for this study. 
Representative ECGs at each timepoint should be reviewed by the investigator or a 
qualified designee.  Post-screening ECG measurements should be obtained as close as 
possible to scheduled serum and plasma PK samples (see Appendices B-1 and B-2) 
and should be no more than 30 minutes apart.  If QTc prolongation (> 500 msec and 
>60 msec longer than the pre-dose baseline value) is noted, ECGs should be repeated 
until the prolongation is reversed or stabilized.  If a PK sample is not scheduled at the 
timepoint where QTc prolongation is first observed, then an unscheduled sample should 
be obtained.  An evaluation for potential causes of QT prolongation e.g., electrolyte 
imbalances or concomitant medications, should be performed, study treatment dosing 
held, and the Medical Monitor notified.  Management of QT/QTc prolongation should be 
performed in accordance with institutional standard of care at the discretion of the 
treating physician. 
4.5.1.6 
Pharmacokinetic Assessments 
Pharmacokinetics of DCDT2980S and DCDS4501A will be characterized by measuring 
total antibody (conjugated and unconjugated antibody), antibody-conjugated MMAE 
(acMMAE), and free MMAE concentrations using validated methods (see Section 4.9).  
Plasma samples may also be analyzed for other potential MMAE containing catabolites, 
per sponsor’s discretion.  Pharmacokinetics of rituximab will be characterized by 
measuring rituximab concentrations using a validated method (see Section 4.9).  These 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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assessments will allow for further characterization of PK of DCDT2980S and 
DCDS4501A, the assessment of the drug interaction potential when they are given in 
combination with rituximab, and the investigation of potential correlations between 
PK parameters and safety and/or activity if data allow and at the sponsor’s discretion.   
4.5.1.7 
Immunogenicity Assessments 
The immunogenicity evaluation will utilize a risk-based strategy and tiered approach 
(Rosenberg and Worobec 2004a; 2004b, 2005, Koren et al. 2008) designed to detect 
and characterize all anti-therapeutic antibody (ATA) responses to DCDT2980S and 
DCDS4501A.  Patient samples will be first screened to detect all antibody responses 
toward DCDT2980S or DCDS4501A.  Samples that screen positive will be analyzed in a 
confirmatory assay (competitive binding with DCDT2980S or DCDS4501A) to assess the 
specificity of the positive response.  Titers will be determined for confirmed positive 
samples. Further characterization will be assessed by competitive binding with the 
monoclonal antibody (mAb) component of DCDT2980S or DCDS4501A to characterize if 
the ATA responses are primarily to the mAb or the linker-drug regions of the ADC.  
Positive ATA samples will be stored for further characterization of ATA responses, 
if necessary.   
The schedule of sample collection for ATA assessment is outlined in Appendices B-1 
and B-2, depending on the schedule of study treatment administration.  Samples for ATA 
will not be collected during the crossover treatment period. 
4.5.1.8 
Tumor Response Assessments 
All measurable disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Response assessments will be assessed by the 
investigator, based on physical examinations, CT and/or MRI scans, and bone marrow 
examinations, using standard response criteria for NHL (Cheson et al. 2007) 
(see Appendix C). 
a. 
Radiographic Assessments 
CT scans with contrast should include chest, abdomen, and pelvis scans; CT scans of 
the neck should be performed at screening and followed only if disease is present at 
screening.   Post-screening radiographic assessments may be limited to areas of prior 
involvement only if required by local health authorities. 
MRI scans may be used instead of CT scans in patients for whom CT scans with 
intravenous contrast are contraindicated.  Details regarding imaging procedures in these 
cases will be provided in the Imaging Manual. 
An 18F-FDG-PET (hereafter referred as PET) scan is required during screening for all 
patients with DLBCL.  An additional PET scan in DLBCL patients should be obtained at 
the 6-month tumor assessment to ensure consistency of response assessment 
methodology at this time point for all patients.  PET scans should additionally be 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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obtained to confirm disappearance of metabolically active disease during study 
treatment and to confirm a complete response (CR) upon discontinuation of study 
treatment.   
For patients with FL, PET scans are not required but may be obtained based on 
physician preference and if permitted by local health authorities.  Similar for DLBCL, 
PET scans on FL patients should be obtained during screening; for patients whose 
tumors are PET-positive during screening, an additional PET scan should be obtained at 
the 6-month tumor assessment.  PET scans should additionally be obtained to confirm 
disappearance of metabolically active disease during study treatment and to confirm a 
complete response (CR) upon discontinuation of study treatment.  
For all patients regardless of disease subtype, combined PET-CT scans may be used 
instead of CT alone if performed with contrast and if collected with resolution sufficient to 
allow accurate and consistent comparison of target lesion measurements with 
subsequent PET-CT scans.  If a PET-CT scan is to be used during screening, then 
PET-CT scans should be performed for all subsequent tumor assessments in order to 
ensure their consistency across different timepoints. 
All tumor assessments will be submitted to an independent review facility (IRF) for 
storage and possible independent centralized review.  Details related to submission of 
data to the IRF will be defined in a separate Imaging Manual. 
b. 
Bone Marrow Assessments 
A bone marrow biopsy for morphology is required at screening and should reflect 
disease status in the bone marrow following documented relapse on the last prior 
therapy or within 3 months of Day 1, whichever occurs later.  If the bone marrow biopsy 
at screening demonstrates presence of tumor cells, a subsequent bone marrow 
examination is required only to confirm a CR or if clinically indicated.  If the bone marrow 
biopsy at screening does not demonstrate presence of tumor cells, then subsequent 
bone marrow examination is required only if clinically indicated. 
c. 
Schedule of Tumor Response Assessments 
Tumor response assessments will be performed every three months (± 1 week) from the 
initiation of study treatment until study treatment completion or early termination, 
e.g., between Days 14 and 21 of Cycles 4 and 8 for those patients receiving at least 
eight 21-day cycles of treatment.   The schedule of tumor assessments should be 
independent of the study treatment dose schedule.  The schedule of tumor response 
assessments is detailed in Appendix A-1.  As stated above, for all DLBCL patients, 
PET scans are required during the screening period and at the 6-month tumor 
assessment timepoint. 
The schedule for tumor response assessments for patients who proceed to crossover 
treatment is detailed in Appendix A-2.   
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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Additional response assessments, after the final dose of study treatment, for patients 
who discontinue from study treatment (either initial or crossover treatment) for reasons 
other than progressive disease, will be performed as described in Appendix A-3.  
Tumor assessments should also be performed within 30 days after the last study drug 
infusion (both initial and crossover treatment) at the treatment completion/early 
termination visit.  Imaging scans are not required at the treatment completion/early 
termination visit if scans have been performed within the previous 8 weeks or if disease 
progression while receiving study treatment is documented.. 
If at any time during the study disease progression is suspected, a tumor assessment 
must be performed.   
4.5.1.9 
Exploratory Research 
a. 
Tumor Tissue Samples 
Required Tumor Tissue Samples 
Tumor tissue samples will be used for central pathologic laboratory review of CD20, 
CD22 and CD79b expression.  Additional studies to fulfill the exploratory objectives in 
Section 3.3.4 will be performed, including but not limited to the following: 
• 
Messenger RNA (mRNA) expression profiling for signatures of NHL biology, 
including prognostic subpopulations (Alizadeh et al. 2000; Wright et al. 2003), target 
expression (CD20, CD22 and CD79b) and apoptotic response  
• 
Tissue microarrays (TMAs) from cores taken from provided blocks for IHC and ISH 
assessments, including: 1) DLBCL classifiers in tissue obtained from patients with 
DLBCL (CD10; GCET, Mum1; FoxP1 LMO2 (Meyer P N et al. 2011); and 
2) biomarker endpoints involved in response to chemotherapy including quantitation 
of Bcl-2 protein and genetic alterations of bcl-2 including gene rearrangements, 
amplifications and t(14;18) translocations. Additional IHC markers may include 
those related to the tumor microenvironment. 
• 
Tumor DNA to assess mutations that have been shown to be associated with NHL 
biology and activation of the B-cell receptor, including mutations in CD79b 
(Pasqualucci et al. 2012) 
 
For patients who develop progressive disease and are eligible to receive crossover 
treatment (see Section 3.1.3) a biopsy of a safely accessible site of disease will be 
performed.  Tumor tissue samples obtained at this time point will be used to assess 
changes in biology, target expression and regulators of apoptosis as described above, 
which have occurred and may be linked to progression on initial study treatment. 
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Optional Tumor Tissue Samples (Requires Optional Research Informed Consent 
For patients who provide informed consent, an optional tumor biopsy will be collected at 
time of progression from the following patients: 
• 
Patients who develop disease progression following initial study treatment and do 
not proceed to receive crossover treatment 
• 
Patients who develop disease progression on crossover treatment 
 
Tumor tissue samples obtained at these time points will be used to assess changes in 
biology, target expression and regulators of apoptosis, as described above, that have 
occurred and may be linked to progression on treatment. 
b. 
Blood and Plasma Samples 
A plasma sample will be collected prior to treatment. 
For patients who sign the Optional Research Informed Consent, an additional blood 
sample will also be taken prior to treatment. 
The plasma and blood samples may be used for the assessment of specific tumor 
biologic markers, including proteins, circulating DNA, and microRNAs.  The information 
obtained from these samples will enable a better understanding of the biology of NHL 
and disease prognosis, identify potential predictors of response to treatment with 
DCDT2980S, DCDS4501A and/or rituximab, improve diagnostic assessments, and 
identify and characterize mechanisms of resistance to DCDT2980S or DCDS4501A and 
rituximab activity.   
As tumorigenesis is a multiple step process linked to somatic events, any DNA analysis 
will focus on sporadic mutations specifically found in tumor tissue and not on inherited 
changes found in the whole body.  For this purpose, some tumor-containing sections 
may be taken from the tissue block and used for the DNA extraction process.  Assays on 
stored tissue samples may be performed at Genentech or at a central specialty 
laboratory. 
4.5.1.10 
Patient Reported Outcome 
The M.D. Anderson Symptom Inventory (MDASI; Cleeland et al., 2000; Appendix E) is a 
multi-symptom patient-reported outcome (PRO) measure for clinical and research use. 
The MDASI’s 13 core symptom items, plus an additional four items for a total of 
17 symptom items, include those found to have the highest frequency and/or severity in 
patients with various cancers and treatment types.  These include pain, fatigue, nausea, 
disturbed sleep, emotional distress, shortness of breath, lack of appetite, drowsiness, 
dry mouth, sadness, vomiting, difficulty remembering and numbness or tingling.  
Six additional items focus on the degree of interference of the aforementioned symptoms 
for a total of 23 items in the questionnaire. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
92/P GO27834 A-1


Patient-reported outcome data will be elicited from all patients in this study to more fully 
characterize the clinical profile of study treatment.  The MDASI PRO instrument will be 
supplied in the local language of each participating country.  Electronic (hand held 
computers) will be used for the daily collection of symptoms derived from the MDASI.   
4.5.2 
Screening and Pretreatment Assessments 
All screening evaluations must be completed and reviewed by the Genentech Medical 
Monitor or designated CRO Medical Monitor to confirm that patients meet all eligibility 
criteria and are approved for enrollment before the first infusion of study treatment.  
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for patients who are not subsequently enrolled will be maintained at the study site. 
Screening and pretreatment tests and evaluations will be performed within 28 days 
preceding the day of the first dose of study treatment on Cycle 1 Day 1.  Results of 
standard-of-care tests or examinations performed prior to obtaining informed consent 
and within 28 days prior to Cycle 1 Day 1 may be used; such tests do not need to be 
repeated for screening. 
The availability of a patient’s tumor tissue sample for studies (see Sections 4.1.1 and 
4.5.1.i) should be confirmed prior to Cycle 1, Day 1.  Such specimens should consist of 
representative core biopsy in a paraffin block, which is the preferred method, or at least 
15 unstained slides.  Tumor specimens should be submitted with an accompanying 
pathology report and may be obtained at any time prior to entry to study.   
Bone marrow biopsy and aspirate specimens are required at screening (see 
Section 4.5.1.8).  Unsuccessful attempts at obtaining marrow aspirates will not be 
considered a protocol deviation or violation. 
Refer to the Study Flowchart provided in Appendix A-1 for the schedule of screening and 
pretreatment assessments. 
4.5.3 
Assessments during Treatment 
Study drug infusions (rituximab, DCDT2980S or DCDS4501A) should occur on the 
scheduled 21-day (or 28-day) cycle, but may be given up to ± 2 days from the date 
scheduled (i.e., with a minimum of 19 days between doses) if required for 
logistical/scheduling reasons.  All other study visits during Cycles 1 and 2 must occur 
within ± 1 day from the scheduled date, unless otherwise noted.  Study visits starting in 
Cycle 3 should occur within ± 2 days from the scheduled date, unless otherwise noted.  
All assessments will be performed on the day of the specified visit unless a time window 
is specified.  Assessments scheduled on the day of study drug administration (Day 1) of 
each cycle should be performed prior to study drug infusion unless otherwise noted.   
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
93/P GO27834 A-1


Local laboratory assessments may be performed within 72 hours preceding study drug 
administration on Day 1 of each cycle.  Otherwise, laboratory samples should be drawn 
0–4 hours pre-infusion.  Results must be reviewed and the review documented prior to 
study drug administration. 
Refer to the Study Flowchart provided in Appendix A-1 for the schedule of treatment 
period assessments. 
4.5.4 
Study treatment Completion Visit 
Patients who complete study treatment (approximately 1 year/17 cycles) or discontinue 
from study treatment early will be asked to return to the clinic within 30 days after the 
last DCDT2980S or DCDS4501A or rituximab infusion (whichever is later) for a study 
treatment completion visit.  The visit at which response assessment shows progressive 
disease may be used as the early termination visit. 
Refer to the Study Flowchart provided in Appendix A-1 for assessments to be performed 
at the treatment completion/early termination visit. 
Assessments conducted at the treatment completion/early termination visit may be used 
for the purposes of re-screening to determine eligibility to receive crossover treatment 
(see Section 3.1.3 and Section 4.5.5). 
4.5.5 
Crossover Treatment Completion Visit 
Patients who fulfill the criteria to receive crossover treatment (see Section 3.1.3) will 
have assessments during the crossover treatment period as described in Appendix A-2.  
The same guidelines regarding scheduling of assessments for treatment with initial study 
treatment as detailed in Section 4.5.3 will apply to crossover treatment.   
Patients who proceed to receive crossover treatment will have on-treatment 
assessments as described in Appendix A-2. 
Patients who complete the crossover treatment (approximately 1 year/17 cycles) or 
discontinue from crossover treatment early will be asked to return to the clinic within 
30 days after the last DCDT2980S, DCDS4501A or rituximab infusion (whichever is 
later) for a crossover treatment completion/early termination visit.  The visit at which 
response assessment shows disease progression on crossover treatment may be used 
as the early termination visit. 
Refer to Appendix A-2 for assessments to be performed at the treatment 
completion/early termination visit. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
94/P GO27834 A-1


4.5.6 
Follow-Up Assessments 
Ongoing adverse events thought to be related to DCDT2980S, DCS4501A, or rituximab 
will be followed until the event has resolved to baseline (pre-treatment) grade, the event 
is assessed by the investigator as stable, new anti-tumor treatment is initiated, the 
patient is lost to follow-up, the patient withdraws consent, or when it has been 
determined that the study treatment or participation is not the cause of the adverse 
event. 
Patients will be followed after the last dose of study treatment (either initial study 
treatment or crossover treatment) for safety outcomes.  Such follow-up will require an 
assessment (per verbal report, at minimum) of any adverse events and serious adverse 
events for 30 days after the last dose of study drug or until the patient receives another 
anti-cancer therapy, whichever occurs first. 
Patients who discontinue from study treatment (either initial study treatment or crossover 
treatment) for reasons other than progressive disease will be followed for response for 
up to 1 year after the last infusion of study treatment or until disease progression or 
initiation of another anti-lymphoma/leukemia therapy, whichever occurs first.  Response 
assessments should occur approximately every 2−3 months following the last infusions 
of DCDT2980S, DCDS4501A or rituximab.  Post-treatment assessments are described 
in Appendix A-3.  
Following discontinuation of study treatment, patients will be followed for survival 
approximately every three months until death, loss to follow-up, withdrawal of consent, 
or study termination. 
4.6 
PATIENT DISCONTINUATION 
4.6.1 
Discontinuation from Treatment 
Patients may discontinue study treatment early for reasons other than disease 
progression, such as patient/investigator choice or unacceptable toxicity.  The reasons 
for early discontinuation of treatment must be documented on the appropriate eCRF.  
Patients may continue treatment with either DCDT2980S/DCDS4501A or rituximab 
alone following a careful assessment and discussion of risk versus benefit with the 
patient by the investigator and approval from the Medical Monitor 
Patients who discontinue study treatment early due to toxicity should continue to be 
followed until resolution of toxicity as scheduled. 
Refer to Sections 4.5.4 and 4.5.5 for assessments that are to be performed for patients 
who discontinue from the study during the study treatment period. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
95/P GO27834 A-1


4.6.2 
Discontinuation from Study 
Patients must be discontinued from the study if they experience disease progression as 
defined using response and progression criteria in Appendix C.  Patients can continue 
crossover treatment following documentation of the first progressive disease event but 
must be discontinued from the study if they experience a second progressive disease 
event on the crossover treatment. 
The investigator has the right to discontinue a patient from the study for any medical 
condition that the investigator determines may jeopardize the patient’s safety if he or she 
continues in the study, for reasons of noncompliance (e.g., missed doses, visits), 
pregnancy, or if the investigator determines it is in the best interest of the patient. 
Refer to Section 4.5.4 and 4.5.5 for assessments that are to be performed for patients 
who prematurely discontinue from the study during the treatment period. 
4.7 
STUDY DISCONTINUATION 
Genentech has the right to terminate this study at any time.  Reasons for terminating the 
study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
• 
Data recording is inaccurate or incomplete. 
4.8 
POST-TRIAL ACCESS 
Genentech does not have any plans to provide DCDT2980S, DCDS4501A, rituximab or 
other study interventions to patients after the conclusion of the study or the study is 
terminated, or for patients who withdraw early from the study or complete their study 
treatment.  Genentech will evaluate the appropriateness of continuing to provide 
DCDT2980S, DCDS4501A, or rituximab to study patients after evaluating the safety and 
activity data from the study.   
4.9 
ASSAY METHODS  
4.9.1 
Total DCDT2980S/DCDS4501A Antibody ELISA 
Total DCDT2980S or DCDS4501A antibody (conjugated and unconjugated antibody) will 
be measured in serum samples using validated ELISAs. 
4.9.2 
Antibody-Conjugated MMAE (MMAE Affinity Capture 
Enzyme-Release LC/MS-MS) 
Antibody-conjugated MMAE (a measure of MMAE conjugated to 
DCDT2980S/DCDS4501A) will be measured in plasma samples using validated affinity 
capture enzyme-release LC-MS/MS assays. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
96/P GO27834 A-1


4.9.3 
Free MMAE LC-MS/MS 
Free MMAE will be measured in plasma samples using a validated electrospray 
LC-MS/MS method. 
4.9.4 
Rituximab ELISA 
Rituximab will be measured in serum samples using a validated ELISA.   
4.9.5 
Anti-Therapeutic Antibody 
ATAs against DCDT2980S and DCDS4501A in serum samples will be measured using 
validated bridging antibody ELISAs and characterized by competitive binding assays. 
4.9.6 
Biomarker Assays 
Tumor tissue assessment of biomarkers will be assayed using IHC; in situ hybridization 
(ISH), qPCR gene expression profiling using microarray, mutation detection assays and 
flow cytometry. 
4.10 
STATISTICAL METHODS 
The final analysis will be based on patient data collected through patient discontinuation 
or study discontinuation, whichever occurs first.  The analyses will be based on the 
safety evaluable population defined as patients who received at least one dose of study 
treatment.  All summaries will be presented according to the disease specific cohort, 
treatment group, and assigned dose level. 
4.10.1 
Analysis of the Conduct of the Study 
Enrollment, major protocol violations, and reasons for discontinuations from the study 
will be summarized. 
Demographic and baseline characteristics, such as age, sex, race/ethnicity, weight, 
duration of malignancy, and baseline ECOG Performance Status, will be summarized 
using means, standard deviations, medians, and ranges for continuous variables, and 
proportions for categorical variables.  All summaries will be presented overall and by 
treatment group, assigned dose level, and disease-specific cohort. 
Study drug administration data will be listed by the disease-specific cohorts described in 
Section 3.1.1 and 3.1.2.  Any dose modifications will be flagged.  Means and standard 
deviations will be used to summarize the total doses of DCDT2980S, DCDS4501A and 
rituximab received.  All summaries will be presented by treatment group, assigned dose 
level, and disease-specific cohort. 
4.10.2 
Safety Analysis 
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in physical findings on physical examinations, and changes in vital 
signs.  All patients who receive any amount of DCDT2980S, DCDS4501A or rituximab 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
97/P GO27834 A-1


will be included in the safety analysis and will be assigned to the treatment group based 
on the study treatment received.  Patients who have dose level changes from the initial 
assigned dose level will be summarized by the initial assigned dose level of DCDT2980S 
or DCDS4501A. 
All adverse event data will be listed by study site, patient number, treatment group, 
disease-specific cohort, and cycle.  All adverse events occurring on or after treatment on 
Day 1 of Cycle 1 will be summarized by mapped terms, appropriate thesaurus levels, 
and NCI CTCAE v4.0 toxicity grade.  In addition, all serious adverse events, including 
deaths will be listed separately and summarized.   
Selected laboratory data will be listed, with values outside of normal ranges identified.  
The incidence of antibodies to DCDT2980S and DCDS4501A will be summarized. 
4.10.3 
Pharmacokinetic and Pharmacodynamic Analyses 
Individual and mean serum concentrations of total DCDT2980S or DCDS4501A antibody 
(conjugated and unconjugated antibody) and rituximab, and plasma concentrations of 
antibody-conjugated MMAE and free MMAE versus time data will be tabulated and 
plotted by NHL disease subtype (relapsed/refractory follicular NHL or DLBCL).  The 
pharmacokinetics of the above analytes will be summarized by estimating the 
appropriate PK parameters (e.g., AUC, Cmax, CL, Vss, and t1/2).  Estimates for these 
parameters will be tabulated and summarized (mean, standard deviation, and range).  
Non-compartmental, compartmental and/or population methods will be used, as data 
allow.  
Exposure-response (safety and efficacy) analysis may be conducted using PK data and 
available drug effect (e.g., imaging, measures of tumor burden), and toxicity 
(e.g., clinical pathology) data, at the sponsor’s discretion. 
In addition, population PK methods may be employed to manage sparse data and to 
investigate the effects of certain covariates on the pharmacokinetics of DCDT2980S and 
DCDS4501A, as data allow, and at the sponsor’s discretion. 
4.10.4 
Activity Analyses 
Best overall response, duration of response, and PFS will be listed for all patients. 
Objective response rate from the initial study treatment will be calculated based on data 
from patients who received study treatment and had at least one post-baseline response 
assessment.  Objective response is defined as complete response (CR) or partial 
response (PR) as determined by the investigator, based on physical examinations, 
radiographic scans, and bone marrow examinations, using modified response criteria for 
NHL (Cheson et al. 2007; see Appendix C), and confirmed by repeat assessments 
≥ 4 weeks after initial documentation.  Any patient with insufficient data to determine 
response will be classified as a non-responder. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
98/P GO27834 A-1


For patients with DLBCL, primary assessment of tumor response will be based on 
diagnostic imaging scans, e.g., CT and/or MRI, and PET scans.  For patients with FL, 
primary assessment of response will be based on CT scans only; the assessment of 
response in FL based on PET scans will be performed for exploratory purposes only. 
Among patients with an objective response, duration of response will be defined as the 
time from the initial CR or PR to the time of disease progression or death.  If a patient 
does not experience death or disease progression before the end of the study, duration 
of response will be censored at the day of the last tumor assessment. 
For the randomized portion of the study (Arms A and B), PFS is defined as the time 
from the date of randomization to the date of disease progression or death from any 
cause, whichever occurs first.  If a patient has not experienced progressive disease or 
death, PFS will be censored at the day of the last tumor assessment.  Patients with no 
post-baseline tumor assessment will be censored on the date of randomization.  For the 
nonrandomized portion of the study (Cohorts C and D), PFS is defined as the time from 
the date of study enrollment to the date of disease progression or death from any cause, 
whichever occurs first. 
For the randomized portion of the study (Arms A and B), overall survival is defined as 
the time from the date of randomization to the date of death from any cause.  For the 
nonrandomized portion of the study (Cohorts C and D), overall survival is defined as 
the time from the date of study enrollment to date of death from any cause. 
4.10.5 
Exploratory Analyses  
Assay results of possible predictive markers will be listed by treatment group and 
response status. 
Summary statistics of the MDASI items, scales, and their changes from baseline will be 
calculated at each assessment timepoint.  The mean, standard error, and median of the 
absolute scores and the mean changes from baseline (and 95% CI) within and between 
study arms will be reported for the MDASI scales and single items, as well as the weekly 
averages of the worst symptom rating.  For change scores in the MDASI from baseline, 
patients without baseline scores will not be included in the analyses.  Line charts 
depicting the means and mean changes of subscales over time will be also provided.   
Frequencies and percentages of missing data for the patient-reported outcome 
endpoints will be reported.  Dropouts (defined as patients withdrawing from treatment for 
reasons other than documented disease progression or death) will be summarized. 
Repeated measures mixed-effects models will explore MDASI subscale scores with a 
baseline score and appropriate covariates added, as appropriate. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
99/P GO27834 A-1


4.10.6 
Handling of Missing Data 
For the endpoint of objective response, patients without a post-baseline tumor 
assessment will be considered non-responders in the all-treated population analysis.  
For duration of response and PFS, data from patients who are lost to follow-up will be 
included in the analysis as censored observations on the last date that the patient is 
known to be progression free, defined as the date of the last tumor assessment, or, if no 
tumor assessments were performed, as the date of last study treatment plus 1 day. 
Compliance to PRO data collection will be reported with summary statistics, including 
frequencies of reasons for non-compliance such as patient refusal to complete PRO 
data collection.   
4.10.7 
Determination of Sample Size 
For the randomized portion of the study (Arms A and B), a target of 120 patients will be 
enrolled in two separate cohorts of patients (40 in the follicular NHL cohort and 80 in the 
DLBCL cohort).  Genentech has judged this sample size to provide sufficient precision in 
estimating the anti-tumor activity of DCDT2980S combined with rituximab or DCDS4501A 
combined with rituximab as measured by objective response.  For example, with the 
assumption of an observed response rate of 40%, a 90% confidence interval for the 
response rate would be approximately 22%−58% (i.e., 40% ± 18%) for the follicular NHL 
cohort and approximately 27%−53% (i.e., 40% ± 13%) for the DLBCL cohort. 
This is a non-comparative hypothesis-generating study.  There is no formal hypothesis 
testing planned to compare the treatment arms.  Specifically, for the randomized 
portion of the study, there is insufficient power to detect minimum clinically meaningful 
differences between the two treatment arms. 
4.11 
DATA QUALITY ASSURANCE 
The data will be collected via Electronic Data Capture (EDC) using eCRFs.  The site will 
be responsible for data entry into the EDC system.  In the event of discrepant data, the 
CRO will request data clarification from the sites, which the sites will resolve electronically 
in the EDC system.  The CRO will be responsible for the data management of this trial, 
including quality checking of the data.   
Genentech will perform oversight of the data management of this trial.  Genentech will 
produce an EDC Study Specification document that describes the quality checking to be 
performed on the data.  Central Laboratory data and other electronic data will be sent 
directly to Genentech, using Genentech’s standard procedures to handle and process 
the electronic transfer of these data.  eCRFs and correction documentation will be 
maintained in the EDC system’s audit trail.  System backups for data stored at 
Genentech and records retention for the study data will be consistent with Genentech’s 
standard procedures. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
100/P GO27834 A-1


5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording protocol-defined adverse 
events (AEs) and serious adverse events (SAEs); measurement of protocol-specified 
hematology, clinical chemistry, and urinalysis variables; measurement of 
protocol-specified vital signs; physical examinations and other protocol-specified tests 
that are deemed critical to the safety evaluation of the study drug(s). 
Genentech or its designee is responsible for reporting relevant SAEs to the Competent 
Authority, other applicable regulatory authorities, and participating investigators, in 
accordance with ICH guidelines, FDA regulations, European Clinical Trials Directive 
(Directive 2001/20/EC), and/or local regulatory requirements. 
Genentech or its designee is responsible for reporting unexpected fatal or 
life-threatening events associated with the use of the study drug to the regulatory 
agencies and competent authorities by telephone or fax within 7 calendar days after 
being notified of the event.  Genentech or its designee will report other relevant SAEs 
associated with the use of the study medication to the appropriate competent authorities 
(according to local guidelines), investigators, and central IRBs/ECs (except in the United 
States where investigators are responsible for reporting to their IRBs per local 
requirements) by a written safety report within 15 calendar days of notification.   
5.1.1 
Adverse Event 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product (IMP) or other 
protocol-imposed intervention, regardless of attribution. 
This includes the following: 
• 
AEs not previously observed in the patient that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with the baseline 
hematologic malignancy (i.e., leukemia or lymphoma) that were not present prior to 
the AE reporting period (see Section 5.2.1) 
• 
Complications that occur as a result of protocol-mandated interventions 
(e.g., invasive procedures such as biopsies) 
• 
AEs that occur prior to assignment of study treatment that are related to a 
protocol-mandated intervention (e.g., medication washout, no treatment run-in, or 
invasive procedures such as biopsies) 
• 
Preexisting medical conditions other than the disease under study that are judged 
by the investigator to have worsened in severity or frequency or changed in 
character during the protocol-specified AE reporting period 
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
101/P GO27834 A-1


5.1.2 
Serious Adverse Event 
An SAE is any AE that is any of the following: 
• 
Fatal (i.e., the AE actually causes or leads to death) 
• 
Life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death) 
• 
Requires or prolongs inpatient hospitalization 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
• 
A congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
the investigational product(s) 
• 
Considered a significant medical event by the investigator (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
All AEs that do not meet any of the criteria for serious should be regarded as 
non-serious AEs. 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an AE (as in mild, moderate, or severe pain); the event itself may be of relatively minor 
medical significance (such as severe headache).  “Serious” is a regulatory definition and 
is based on patient or event outcome or action criteria usually associated with events 
that pose a threat to a patient’s life or vital functions.  Seriousness (not severity) serves 
as the guide for defining regulatory reporting obligations. 
Severity and seriousness should be independently assessed when recording AEs and 
SAEs on the eCRF.  
5.1.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious adverse events of special interest are required to be reported by the 
investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2 for reporting instructions), irrespective of regulatory 
seriousness criteria.  Adverse events of special interest for this study include the 
following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST 
in combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 5.3.1.6; treatment-emergent ALT or AST > 3 × baseline value 
in combination with total bilirubin > 2 × ULN [of which 35% is direct bilirubin]) 
• 
Suspected transmission of an infectious agent by the study drug 
• 
Grade ≥2 motor neuropathy 
• 
Grade ≥2 infusion reactions 
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
102/P GO27834 A-1


5.2 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all AEs and SAEs (as defined in 
Section 5.1) are recorded on the eCRF and reported to the Sponsor in accordance with 
protocol instructions.  
5.2.1 
Adverse Event Reporting Period 
After informed consent, but prior to initiation of study drug, only SAEs caused by a 
protocol-mandated intervention will be collected (e.g., SAEs related to invasive 
procedures such as biopsies, medication washout, or no treatment run-in). 
After initiation of study drug (the Genentech product(s) or other investigational medicinal 
product), all new AEs and SAEs regardless of attribution will be collected until 30 days 
following the last administration of study treatment or study discontinuation/termination, 
whichever is later.  After this period, investigators should report only SAEs that are felt to 
be related to prior study treatment (see Section 5.6).   
5.2.2 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting AEs at all patient 
evaluation time points should be adopted.  Examples of non-directive questions include: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?”  
 
5.2.3 
Assessment of Severity and Causality of Adverse Events 
Investigators will seek information on AEs and SAEs at each patient contact.  All AEs 
and SAEs, whether reported by the patient or noted by authorized study personnel, will 
be recorded in the patient’s medical record and on the Adverse Event eCRF. 
For each AE and SAE recorded on the applicable eCRF, the investigator will make an 
assessment of seriousness (see Section 5.1.2 for seriousness criteria), severity and 
causality.   
Table 2 provides guidance for grading AE severity and Table 3 provides guidance for 
assessing the causal relationship to the investigational product(s).  
The AE grading (severity) scale found in the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 will be used for AE 
reporting.   
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
103/P GO27834 A-1


Table 2 
Adverse Event Grading (Severity) Scale 
Grade 
Severity 
Alternate Description a 
1 
Mild (apply event-specific 
NCI CTCAE grading criteria) 
Transient or mild discomfort (< 48 hours); 
no interference with the patient’s daily 
activities; no medical intervention/therapy 
required 
2 
Moderate (apply event-specific 
NCI CTCAE grading criteria) 
Mild to moderate interference with the 
patient’s daily activities; no or minimal 
medical intervention/therapy required 
3 
Severe (apply event-specific 
NCI CTCAE grading criteria) 
Considerable interference with the 
patient’s daily activities; medical 
intervention/therapy required; 
hospitalization possible 
4 
Very severe, life threatening, 
or disabling (apply event-specific 
NCI CTCAE grading criteria) 
Extreme limitation in activity; significant 
medical intervention/therapy required, 
hospitalization probable 
5 
Death related to AE 
 
AE=adverse event; NCI CTCAE= National Cancer Institute Common Terminology Criteria 
for Adverse Events; SAE=serious adverse event. 
The NCI CTCAE v4.0 can be found: http://ctep.cancer.gov/reporting/ctc_v30.html  
Note:  Regardless of severity, some events may also meet regulatory serious criteria.  
Refer to definitions of an SAE (see Section 5.1.2). 
a Use these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or 
reported AE is not in the NCI CTCAE listing. 
  
To ensure consistency of causality assessments, investigators should apply the 
following general guidelines: 
Table 3 
Causal Attribution Guidance 
Is the AE/SAE suspected to be caused by the investigational product based on facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
The temporal relationship of the AE/SAE to investigational product administration 
makes a causal relationship possible, AND other drugs, therapeutic interventions 
or underlying conditions do not provide sufficient explanation for the AE/SAE.   
NO 
The temporal relationship of the AE/SAE to investigational product administration 
makes a causal relationship unlikely, OR other drugs, therapeutic interventions or 
underlying conditions provide a sufficient explanation for the AE/SAE.   
AE=adverse event; SAE=serious adverse event. 
  
The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the “Yes” or “No” causality assessment for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities.   
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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5.3 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
5.3.1 
Recording Adverse Events on the eCRF 
Investigators should use correct medical terminology/concepts when recording AEs or 
SAEs on the eCRF.  Avoid colloquialisms and abbreviations. 
There is one eCRF page for recording AEs or SAEs. 
Only one medical concept should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.1.1 
Diagnosis versus Signs and Symptoms 
If known, a diagnosis should be recorded on the eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded as an AE or SAE on the eCRF.  If a diagnosis 
is subsequently established, it should be reported as follow-up information. 
5.3.1.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause.  For example, if severe diarrhea is 
known to have resulted in dehydration, it is sufficient to record only diarrhea as an AE or 
SAE on the eCRF.  
However, medically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the eCRF.  For 
example, if a severe gastrointestinal hemorrhage leads to renal failure, both events 
should be recorded separately on the eCRF. 
5.3.1.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between patient 
evaluation time points.  Such events should only be recorded once in the eCRF unless 
their severity increases.  If a persistent AE becomes more severe, it should be recorded 
again on the Adverse Event eCRF.   
A recurrent AE is one that occurs and resolves between patient evaluation time points 
and subsequently recurs.  All recurrent AEs should be recorded on Adverse Event 
eCRF. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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5.3.1.4 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities that require active management, 
e.g., concomitant medication, will be recorded as AEs or SAEs on the eCRF 
(e.g., abnormalities that require study drug dose modification, discontinuation of study 
treatment, more frequent follow-up assessments, further diagnostic investigation, etc.) 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × the upper limit of normal associated with 
cholecystitis), only the diagnosis (e.g., cholecystitis) needs to be recorded on the 
Adverse Event eCRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded as an AE or SAE on the eCRF.  If the 
laboratory abnormality can be characterized by a precise clinical term, the clinical term 
should be recorded as the AE or SAE.  For example, an elevated serum potassium level 
of 7.0 mEq/L should be recorded as “hyperkalemia.” 
Specific to this study, lymphopenia and leukopenia due to lymphopenia of any grade are 
expected PD effects of study drug and therefore are not considered to be adverse 
events.  However, complications of lymphopenia (e.g., infections) will need to be 
reported as adverse events.  In addition, because monocytopenia is not reportable and 
neutropenia is already being monitored and reported as an adverse event, leukopenia 
does not need to be reported as a distinct adverse event. 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded as AEs or SAEs on the eCRF, unless their severity, 
seriousness, or etiology changes.  
5.3.1.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (including a diagnostic evaluation not mandated 
in this protocol) or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated vital sign 
abnormality should be classified as an adverse event. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
106/P GO27834 A-1


If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.1.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis 
or other causes of hyperbilirubinemia is considered to be an indicator of severe liver 
injury.  Therefore, investigators must report as an adverse event the occurrence of 
either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.1) and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2) 
5.3.1.7 
Deaths 
Deaths that occur during the protocol-specified AE reporting period (see Section 5.2.1) 
that are attributed by the investigator solely to progression of lymphoma will be recorded 
only on the Study Discontinuation eCRF.  All other on-study deaths, regardless of 
attribution, will be recorded on the Adverse Event eCRF and expeditiously reported to 
the Sponsor. 
When recording a death on an eCRF, the event or condition that caused or contributed 
to the fatal outcome should be recorded as the single medical concept on the eCRF.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
record “Unexplained Death” on the Adverse Event eCRF. 
5.3.1.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study.  Such 
conditions should be recorded on the Medical and Surgical History eCRF. 
A preexisting medical condition should be recorded as an AE or SAE only if the 
frequency, severity, or character of the condition worsens during the study.  When 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
107/P GO27834 A-1


recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
5.3.1.9 
Worsening of Baseline Hematologic Malignancy 
Worsening and/or progression of the baseline hematologic malignancy (e.g. leukemia or 
lymphoma) should not be recorded as an AE or SAE.  These data will be captured as 
efficacy assessment data only.   
5.3.1.10 
Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol.   
There are some hospitalization scenarios that do not require reporting as an SAE when 
there is no occurrence of an AE.  These scenarios include a planned hospitalization or 
prolonged hospitalization to: 
• 
Perform an efficacy measurement for the study 
• 
Undergo a diagnostic or elective surgical procedure for a preexisting medical 
condition that has not changed 
• 
Receive scheduled therapy for the target disease of the study 
 
5.3.1.11 
Pregnancy 
If a female patient becomes pregnant while receiving the study drug or within 6 months 
after the last dose of investigational product, a Pregnancy Report eCRF should be 
completed within 24 hours of learning of the pregnancy.  A pregnancy report will 
automatically be generated and sent to Genentech’s Drug Safety Department or its 
designee.  Pregnancy should not be recorded on the Adverse Event eCRF. 
Male patients must also be instructed to immediately inform the investigator if their 
partner becomes pregnant during the study or within 6 months after the last dose of 
study drug.  If such an event occurs, it should be reported as described below. 
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE 
(as the Sponsor considers these medically significant), recorded on an Adverse Event 
eCRF, and expeditiously reported to the Sponsor (see Section 5.4.2). 
Any congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to study drug should be classified as an SAE, recorded on the Adverse Event eCRF, and 
expeditiously reported to the Sponsor (see Section 5.4.2). 
After the study period, abortions, congenital anomalies/birth defects, and pregnancy 
outcomes should still be reported expeditiously to the Sponsor.   
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
108/P GO27834 A-1


In the event the EDC system is unavailable, a paper Pregnancy Report form and 
Pregnancy Fax Coversheet should be completed and faxed to Genentech’s Drug Safety 
Department or its designee within 24 hours of learning of the pregnancy, at the fax 
numbers listed in Section 5.4.2. 
a. 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
5 months after the last dose of study drug.  A Pregnancy Report eCRF should be 
completed by the investigator within 1 working day after learning of the pregnancy and 
submitted via the EDC system.  Attempts should be made to collect and report details of 
the course and outcome of any pregnancy in the partner of a male patient exposed to 
study drug.  The pregnant partner will need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
Once the authorization has been signed, the investigator will update the Pregnancy 
Report eCRF with additional information on the course and outcome of the pregnancy.  
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
In the event that the EDC system is unavailable, a paper Pregnancy Report form and 
Pregnancy Fax Coversheet should be completed and faxed to Genentech’s Drug Safety 
Department or its designee within 24 hours of learning of the pregnancy, at the fax 
numbers listed in Section 5.4.2. 
5.4 
EXPEDITED REPORTING REQUIREMENTS FOR SERIOUS 
ADVERSE EVENTS  
5.4.1 
Reporting Requirements for Fatal/Life-Threatening SAEs 
Related to Investigational Product 
Any life-threatening (i.e., imminent risk of death) or fatal AE that is attributed by the 
investigator to the investigational product will be telephoned to the Medical Monitor 
immediately, followed by submission of written case details on an eCRF within 24 hours 
as described in Section 5.4.2. 
Medical Monitor Contact Information for sites in North America: 
Medical Monitor: 
 M.D. 
Telephone No.: 
 
Alternate Telephone No.: 
+1 (888) 835-2555 (US sites only) 
For sites outside of North America, local contact details and numbers for safety issues 
and safety reporting will be provided in the study reference binder. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
109/P GO27834 A-1


5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
For reports of serious adverse events and non-serious adverse events of special interest, 
investigators should record all case details that can be gathered immediately 
(i.e., within 24 hours) on the Adverse Event eCRF and submit the report via the EDC 
system.  A report will be generated and sent to the Sponsor’s Safety Risk Management 
department by the EDC system. 
In the event that the EDC system is unavailable, a paper Serious Adverse 
Event/Non-serious Adverse Event of Special Interest CRF and Fax Coversheet should 
be completed and faxed to Safety Risk Management or its designee immediately (i.e., no 
more than 24 hours after learning of the event), using the fax numbers provided below.  
Once the EDC system is available, all information will need to be entered and 
submitted via the EDC system.   
Sites in North America: 
Fax No.: 
 
Alternate Fax No.: 
 
Sites outside of North America: Refer to the study reference binder for contact 
information. 
Relevant follow-up information should be submitted to Genentech’s Drug Safety 
Department or its designee as soon as it becomes available and/or upon request 
5.5 
TYPE AND DURATION OF FOLLOW-UP OF PATIENTS AFTER 
ADVERSE EVENTS 
The investigator should follow all unresolved AEs and SAEs until the events are resolved 
or stabilized, the patient is lost to follow up, or it has been determined that the study 
treatment or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs 
(with dates) should be documented on the Adverse Event eCRF and in the patient’s 
medical record to facilitate source data verification (SDV). 
For some SAEs, the Sponsor or its designee may follow up by telephone, fax, electronic 
mail, and/or a monitoring visit to obtain additional case details deemed necessary to 
appropriately evaluate the SAE report (e.g., hospital discharge summary, consultant 
report, or autopsy report). 
5.6 
POST-STUDY ADVERSE EVENTS 
At the last scheduled visit, the investigator should instruct each patient to report to the 
investigator any subsequent SAEs that the patient’s personal physician believes could 
be related to prior study treatment.   
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
110/P GO27834 A-1


The investigator should notify the study Sponsor of any death or other SAE occurring at 
any time after a patient has discontinued or terminated study participation if felt to be 
related to prior study treatment.  The Sponsor should also be notified if the investigator 
should become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a patient that participated in this study.  The 
investigator should report these events to Genentech Drug Safety on the study eCRF.  
If the study eCRF is no longer available, the investigator should report the event directly 
to Genentech Drug Safety via phone at 1-888-835-2555. 
6. 
INVESTIGATOR REQUIREMENTS 
6.1 
STUDY INITIATION 
Before the start of this study and any study-related procedures at a specific site, the 
following documents must be on file with Genentech or a Genentech representative: 
• 
U.S. FDA Form 1572 for each site (for all studies conducted under U.S. 
Investigational New Drug [IND] regulations), signed by the Principal Investigator 
The names of any subinvestigators must appear on this form.  Investigators must 
also complete all regulatory documentation as required by local and national 
regulations. 
• 
Current curricula vitae and evidence of licensure of the Principal Investigator and all 
subinvestigators 
• 
Complete financial disclosure forms for the Principal Investigator and all 
subinvestigators listed on the U.S. FDA Form 1572  
• 
Federalwide Assurance number or IRB statement of compliance 
• 
Written documentation of IRB/EC approval of the protocol (identified by protocol 
number or title and date of approval) and Informed Consent Form (identified by 
protocol number or title and date of approval) 
• 
A copy of the IRB/EC-approved Informed Consent Form 
Genentech or its designee must review any proposed deviations from the sample 
Informed Consent Form. 
• 
Current laboratory certification of the laboratory performing the analysis (if other 
than a Genentech-approved central laboratory), as well as current references 
ranges for all laboratory tests 
• 
A Clinical Research Agreement signed and dated by the study site 
• 
Investigator Brochure Receipt signed and dated by the Principal Investigator 
• 
Certified translations of an approved Informed Consent Form, and any other written 
information to be given to the patient (when applicable) , IRB/EC approval letters, 
and pertinent correspondence 
• 
A Protocol Acceptance Form signed and dated by the Principal Investigator 
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• 
Canada only when applicable:  original Qualified Investigator Undertaking Form, 
signed by each Canadian investigator involved in the study 
• 
For global studies, list documents as appropriate for additional countries. 
 
6.2 
STUDY COMPLETION 
The following data and materials are required by Genentech before a study can be 
considered complete or terminated: 
• 
Laboratory findings, clinical data, and all special test results from screening through 
the end of the study follow-up period 
• 
All laboratory certifications for laboratories performing the analysis (is other  than 
Genentech-approved central laboratory), as well as current normal laboratory 
ranges for all laboratory tests 
• 
eCRFs (including queries) properly completed by appropriate study personnel and 
electronically signed and dated by the investigator 
• 
Completed Drug Accountability Records (Retrieval Record, Drug Inventory Log, and 
Inventory of Returned Clinical Material forms) 
• 
Copies of protocol amendments and IRB/EC approval/notification, if appropriate 
• 
A summary of the study prepared by the Principal Investigator (IRB summary close 
letter is acceptable) 
• 
All essential documents (e.g., curriculum vitae for each Principal Investigator and 
subinvestigator, U.S. FDA Form 1572 for each site) 
• 
A signed and dated Protocol Amendment Acceptance Form(s) [if applicable] 
• 
Updated financial disclosure forms for the Principal Investigator and all 
subinvestigators listed on the U.S. FDA Form 1572 (applicable for 1 year after the 
last patient has completed the study) 
 
6.3 
INFORMED CONSENT FORM 
Genentech’s Sample Informed Consent Form will be provided to each site.  Genentech 
or its designee must review and approve any proposed deviations from the Sample 
Informed Consent Form or any alternate consent forms proposed by the site 
(collectively, the “Consent Forms”) before IRB/EC submission.  Patients must be 
re-consented to the most current version of the Consent Forms during their participation 
in the study.  The final IRB/EC-approved Consent Forms must be provided to Genentech 
for regulatory purposes. 
The Consent Forms must be signed by the patient or the patient’s legally authorized 
representative before his or her participation in the study.  The case history for each 
patient shall document the informed consent process and that written informed consent 
was obtained prior to participation in the study.  A copy of each signed Consent Form 
must be provided to the patient or the patient’s legally authorized representative.  
If applicable, it will be provided in a certified translation of the local language. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
112/P GO27834 A-1


All signed and dated Consent Forms must remain in each patient’s study file and must 
be available for verification by study monitors at any time. 
The Informed Consent Form should be revised whenever there are changes to 
procedures outlined in the informed consent or when new information becomes available 
that may affect the willingness of the patient to participate. 
For any updated or revised Consent Forms, the case history for each patient shall 
document the informed consent process and that written informed consent was obtained 
for the updated/revised Consent Form for continued participation in the study.  The final 
revised IRB/EC-approved Informed Consent Form must be provided to Genentech for 
regulatory purposes. 
If the site utilizes a separate Authorization Form for patient authorization to use and 
disclose personal health information under the U.S. Health Insurance Portability and 
Accountability Act (HIPAA) regulations, the review, approval, and other processes 
outlined above apply except that IRB/IEC review and approval may not be required per 
study site policies. 
Optional Research Informed Consent 
Informed consent for the collection and use of fresh tumor tissue at time of progression 
for optional research described in Section 4.5.1.10 will be documented in a section of the 
main Informed Consent Form.  This section provides patients with the option to authorize 
the collection and use of these samples and personal health information for additional 
research purposes.  Agreement to participate in the optional research (by checking the 
appropriate box in this section of the main Informed Consent Form) is not required for 
enrollment in the trial but is required prior to any optional research sample collection.  
Optional consent may be withdrawn at any time by the patient. 
6.4 
COMMUNICATION WITH THE INSTITUTIONAL REVIEW BOARD 
OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator for review and approval before the study is initiated.  In addition, any patient 
recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the regulatory 
requirements and policies and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol changes or 
amendments and of any unanticipated problems involving risk to human patients 
or others. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
113/P GO27834 A-1


In addition to the requirements to report protocol-defined AEs to the Sponsor, 
investigators are required to promptly report to their respective IRB/EC all unanticipated 
problems involving risk to human patients.  Some IRBs/ECs may want prompt 
notification of all SAEs, whereas others require notification only about events that are 
serious, assessed to be related to study treatment, and are unexpected.  Investigators 
may receive written IND safety reports or other safety-related communications from 
Genentech.  Investigators are responsible for ensuring that such reports are reviewed 
and processed in accordance with regulatory requirements and with the policies and 
procedures established by their IRB/EC and archived in the site’s Study File.  
6.5 
STUDY MONITORING REQUIREMENTS 
Site visits will be conducted by an authorized Genentech representative to inspect study 
data, patients’ medical records, and eCRFs.  The Principal Investigator will permit 
Genentech monitors/representatives and collaborators, the U.S. FDA, other regulatory 
agencies, Institutional Review Boards, and the respective national or local health 
authorities to inspect facilities and records relevant to this study. 
6.6 
ELECTRONIC CASE REPORT FORMS 
eCRFS are to be completed using the 
 EDC 
system.  Sites will receive training for appropriate eCRF completion.  eCRFs will be 
submitted electronically to Genentech and should be handled in accordance with 
instructions from Genentech. 
All eCRFs should be completed by designated, trained personnel or the study 
coordinator as appropriate.  The eCRF should be reviewed and electronically signed and 
dated by the investigator. 
In addition, at the end of the study, the investigator will receive patient data for his or her 
site in a readable format on a compact disc that must be kept with the study records. 
6.7 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing SDV to confirm that critical protocol data 
(i.e., source data) entered into the eCRFs by authorized site personnel are accurate, 
complete, and verifiable from source documents.  
Source documents are where patient data are recorded and documented for the first 
time.  They include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, patient diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, patient files, and records 
kept at the pharmacy, laboratories, and medico-technical departments involved in a 
clinical trial. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
114/P GO27834 A-1


Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must never be obliterated or destroyed. 
To facilitate SDV, the investigator(s) and institution(s) must provide the Sponsor direct 
access to applicable source documents and reports for trial-related monitoring, Sponsor 
audits, and IRB/EC review.  The investigational site must also allow inspection by 
applicable regulatory authorities. 
6.8 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), 
the electronic record can serve as the source document if the system has been validated 
in accordance with FDA requirements pertaining to computerized systems used in 
clinical research.  An acceptable computerized data collection system (for clinical 
research purposes) would be one that (1) allows data entry only by authorized 
individuals; (2) prevents the deletion or alteration of previously entered data and 
provides an audit trail for such data changes (e.g., modification of file); (3) protects the 
database from tampering; and (4) ensures data preservation. 
In collaboration with the study monitor, Genentech’s Quality Assurance group may assist 
in assessing whether electronic records generated from computerized medical record 
systems used at investigational sites can serve as source documents for the purposes of 
this protocol. 
If a site’s computerized medical record system is not adequately validated for the 
purposes of clinical research (as opposed to general clinical practice), applicable 
hardcopy source documents must be maintained to ensure that critical protocol data 
entered into the eCRFs can be verified. 
6.9 
STUDY MEDICATION ACCOUNTABILITY 
All study drug required for completion of this study will be provided by Genentech.  
The recipient will acknowledge receipt of the drug by returning the appropriate 
documentation form indicating shipment content and condition.  Damaged supplies will 
be replaced. 
Accurate records of all study drug received at, dispensed from, returned to and disposed 
of by the study site should be recorded by using the Drug Inventory Log. 
Study drug will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or returned to Genentech with the appropriate 
documentation, as determined by the study site.  If the study site chooses to destroy 
study drug, the method of destruction must be documented. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
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Genentech must evaluate and approve the study site’s drug destruction standard 
operating procedure prior to the initiation of drug destruction by the study site. 
6.10 
DISCLOSURE OF DATA 
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization to use and disclose personal health information) signed by the patient or 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other regulatory agencies, national and local health 
authorities, Genentech monitors/representatives and collaborators, and the IRB/EC for 
each study site, if appropriate. 
6.11 
RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP 
(see Section 4.9 of the guideline) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including eCRFs, 
consent forms, laboratory test results, and medication inventory records, must be 
retained by the Principal Investigator for 2 years after the last marketing application 
approval in an ICH region or after at least 2 years have elapsed since formal 
discontinuation of clinical development of the investigational product.  All state and local 
laws for retention of records also apply.  
No records should be disposed of without the written approval of Genentech.  Written 
notification should be provided to Genentech for transfer of any records to another party 
or moving them to another location. 
For studies conducted outside the United States under a U.S. IND, the Principal 
Investigator must comply with the record retention requirements set forth in the U.S. 
FDA IND regulations and the relevant national and local health authorities, whichever is 
longer. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
116/P GO27834 A-1


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Alizadeh et al, Nature 2000; Wright et al. PNAS, 2003; 100;17Cartron G, Watier H, 
Golay J, et al. From the bench to the bedside: ways to improve rituximab 
efficacy. Blood 2004;104:2635−42. 
Cartron G, Watier H, Golay J, et al. From the bench to the bedside: ways to improve 
rituximab efficacy. Blood 2004;104:2635−42. 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. J Clin Oncol 2007;25:579–86. 
Davis TA, Grillo-López AJ, White CA, et al. Rituximab anti-CD20 monoclonal antibody 
therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment. 
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Dornan D, Bennett F, Chen Y, et al. 2009. Therapeutic potential of an anti-CD79b 
antibody–drug conjugate, anti–CD79b-vc-MMAE, for the treatment of 
non-Hodgkin lymphoma. Blood September 24, 2009 vol. 114 no. 13 2721–9.  
Doronina SO, Toki BE, Torgov MY, et al. Development of potent monoclonal antibody 
auristatin conjugates for cancer therapy. Nat Biotechnol 2003;21(7):778−4. 
Freedman AS and Friedberg JW. Pathobiology and treatment of histologic 
transformation in the indolent non-Hodgkin lymphomas. UpToDate Online [article 
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detection and characterization of antibodies against biotechnology products. 
J Immunol Methods 2008;333:1−9. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
117/P GO27834 A-1


Luis F, Hemant P, Gregor V, et al. Clinical activity of the immunoconjugate CMC-544 in 
B-Cell malignancies: preliminary report of the expanded maximum tolerated dose 
(MTD) cohort of a Phase 1 study. [abstract] Blood (ASH Annual Meeting 
Abstracts) 2006;108:abstract 2711. Available from: 
http://abstracts.hematologylibrary.org/cgi/content/abstract/108/11/2711?maxtosh
ow=&hits=10&RESULTFORMAT=&fulltext=cd22&searchid=1&FIRSTINDEX=0&
volume=108&issue=11&resourcetype=HWCIT.  
McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, et al. 
Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent 
lymphoma: half of patients respond to a four-dose treatment program. 
J Clin Oncol 1998;16:2825–33. 
Meyer PN, Fu K, Greiner TC et al. Immunohistochemical methods for predicting cell of 
origin and survival in patients with diffuse large b-cell lymphoma treated with 
rituximab. J Clin Oncol 2011; v29,number 2. 
Nam HD, Mitchell RS, Fritz O, et al. Anti-CD22 Immunoconjugate inotuzumab 
ozogamicin (CMC-544) + Rituximab: clinical activity including survival in patients 
with recurrent/refractory follicular or ‘aggressive' lymphoma. [abstract] Blood 
(ASH Annual Meeting Abstracts) 2009;114:abstract 584. Available from: 
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w=&hits=10&RESULTFORMAT=&fulltext=inotuzumab&searchid=1&FIRSTINDE
X=0&volume=114&issue=22&resourcetype=HWCIT. 
Nina W-J, Andre G, Tatyana F, et al. Anti-CD22 Immunoconjugate Inotuzumab 
ozogamicin (CMC-544) + rituximab in relapsed DLBCL Patients followed by stem 
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Meeting Abstracts) 2010;116:abstract 2883. Available from: 
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ow=&hits=10&RESULTFORMAT=&fulltext=inotuzumab&searchid=1&FIRSTIND
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antibody-drug Conjugate (ADC) targeting CD79b, in relapsed or refractory 
B-cell non-Hodgkin’s lymphoma (NHL). [abstract] Blood (ASH Annual Meeting 
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w=&hits=10&RESULTFORMAT=&fulltext=of+DCDS4501A%2C+an+antibod
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or+refractory+B+cell+non&searchid=1&FIRSTINDEX=0&volume=120&issue=
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Pasqualucci L, Vladimir T, Fabri G, et al. Analysis of the coding genome of diffuse large 
b-cell lymphoma. Nat Genet. 2011 July 31; 43(9): 830–7.  
Piro LD, White CA, Grillo-López AJ, et al. Extended rituximab (anti-CD20 monoclonal 
antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's 
lymphoma. Ann Oncol 1999;10(6):655−61. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
118/P GO27834 A-1


Polson AG, Calemine-Fenaux J, Chan P, et al. Antibody-drug conjugates for the 
treatment of non-Hodgkin's lymphoma: target and linker-drug selection. Cancer 
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Polson AG, Yu SF, Elkins K, et al. Antibody-drug conjugates targeted to CD79 for the 
treatment of non-Hodgkin lymphoma. Blood 2007;110:616–23. 
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therapeutic protein products, part 1: considering consequences of the immune 
response to a protein. BioPharm International, November 2004a;22−6. 
Rosenberg AS, Worobec A. A risk-based approach to immunogenicity concerns of 
therapeutic protein products, part 2: considering hose-specific and 
product-specific factors impacting immunogenicity. BioPharm International, 
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therapeutic protein products. part 3: effects of manufacturing changes on 
immunogenicity and the utility of animal immunogenicity studies. BioPharm 
International, January 2005;32−36. 
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with prior resolved hepatitis B undergoing anticancer therapy with or without 
rituximab. J Clin Oncol 2009;27:605−11.  
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
119/P GO27834 A-1


Appendix A-1  
Study Flowchart:  Initial Study Treatment 
 
Treatment Period 
Cycle 
Screening
Cycle 1 
Cycles 2−4 
Cycles 5−17 
Day(s)a 
Assessment 
− 28 to − 1
1 b 
2 
8 
15 
1 b 
2 
8 
15 
1 b 
2 
15 
Treatment 
Completion/ Early 
Termination Visit c 
Safety and 
Survival 
Follow-Up d 
Written informed consent e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height (screening only) and weight 
x 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
Vital signs  
x 
x f 
x f 
x 
x 
x f 
(x) f 
x 
x 
x f 
(x) f 
x 
x 
 
ECOG Performance Status 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
 
x 
 
B symptoms g 
x 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
 
Complete physical examination h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical examination i 
 
x 
x 
x 
 
x 
(x) 
 
 
x 
(x) 
 
x 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
(x) 
x 
x 
x 
(x) 
x 
x 
 
Adverse events j 
x 
x  
x 
x 
x 
x  
(x) 
x 
x 
x  
(x) 
x 
x 
x 
MDASI PRO k 
 
Day 1–8 of Cycles 1–8 
 
 
12-lead electrocardiogram l 
x  
Refer to Footnote “l” 
x  
 
Tumor assessments m 
x 
Every 3 months 
x 
 
PET scan (required for DLBCL; optional 
for FL) m 
x 
6-month tumor assessment and as clinically indicated 
 
 
Rituximab infusion 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
DCDT2980S or DCDS4501A infusion n 
 
 
x 
 
 
x 
(x) 
 
 
x 
(x) 
 
 
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
120/P GO27834 A-1


Appendix A-1 (cont.)  
Study Flowchart: Initial Study Treatment 
 
Treatment Period 
Cycle 
Screening
Cycle 1 
Cycles 2−4 
Cycles 5−17 
Day(s)a 
Assessment 
− 28 to − 1
1 b 
2 
8 
15 
1 b 
2 
8 
15 
1 b 
2 
15 
Treatment 
Completion/ Early 
Termination Visit c 
Safety and 
Survival 
Follow-Up d 
Local Laboratory Assessments 
HBV and HCV screening o 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology p 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
Serum chemistry q 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
Hemoglobin A1c 
x 
 
 
 
 
 
 
 
 
Cycle 5 Day 1 
 
 
Total IgA, IgG, IgM 
x 
 
 
 
 
 
 
 
 
Cycle 8 Day 1 
x 
 
Coagulation (aPTT, PT, and INR) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test r 
x 
Within 10 days of Day 1 of Cycles 3, 6, 9, 12, and 15 
x 
 
Bone marrow biopsy s 
x 
Perform to confirm CR if positive for disease at screening or if clinically 
indicated 
 
 
Central Laboratory Assessments 
Leukocyte immunophenotyping (FACS) t 
 
Day 1 of Cycle1, Cycle 4, Cycle 8 and Cycle12 
x 
 
Tumor tissue sample u 
x 
 
 
 
 
 
 
 
 
 
 
 
x  
 
Exploratory plasma (required) and blood 
(optional) sample v 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
DCDT2980S or DCDS4501A and 
rituximab pharmacokinetic sampling w 
Serum sample for anti-DCDT2980S or 
anti-DCDS4501A antibody x 
Refer to Appendix B 
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
121/P GO27834 A-1


Appendix A-1 (cont.)  
Study Flowchart: Initial Study Treatment 
aPTT = activated partial thromboplastin time; AE = adverse event; CR = completed response; CT = computed tomography; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; FACS = fluorescent-activated cell sorter; HBV = hepatitis B virus; HCV = hepatitis C virus; 
Ig = immunoglobulin; INR = international normalized ratio; MDASI: MD Anderson Symptom Inventory; MRI = magnetic resonance imaging; 
NHL = non-Hodgkin’s lymphoma; PET = positron emission tomography; PT = prothrombin time; QLQ = Quality of Life Questionnaire; SAE = serious adverse 
event; (x) = Assessment or action to be performed only if study treatment is administered on Day 2 of the Cycle —refer to footnote ‘n’ for details. 
a Study drug infusions should occur on the scheduled 21-day cycle up to a maximum of 1 year (approximately 17 cycles on an every-21-day schedule) and 
may be given up to ± 2 days from the date scheduled (i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  
All other study visits during Cycles 1 and 2 must occur within ± 1 day from the scheduled date unless otherwise noted.  Study visits starting in Cycle 3 
should occur within ± 2 days from the scheduled date unless otherwise noted.  Treatment cycles may be extended to 28 days if needed to provide 
sufficient time for recovery from a transient and reversible toxicity (e.g., cytopenia) without reducing the dose of DCDT2980S or DSDA4501A.  Patients 
receiving study treatment on 28-day cycles should also follow the assessment schedule above up to a maximum of 1 year of total study treatment 
(approximately 13 cycles). 
b Local laboratory assessments and targeted physical examination may be performed within 72 hours preceding rituximab administration unless otherwise 
specified; pre-infusion laboratory samples should be drawn 0−4 hours prior to infusion. 
c Perform within 30 days after the last infusion of DCDT2980S, DCDS4501A, or rituximab.  The visit at which response assessment shows progressive 
disease may be used as the early termination visit.  Assessments during the treatment completion/early termination visit may be applied to assessments 
required to determine eligibility to receive crossover treatment.  Patients enrolled into Cohorts C and D are not eligible to receive crossover treatment. 
d Patients will be followed for safety for 30 days after the last infusions of DCDT2980S, DCDS4501A, or rituximab.  Such follow-up will require an 
assessment (per verbal report from the patient, at minimum) of any AEs and/or SAEs through 30 days after the last dose of study drug or until the patient 
receives another anti-cancer therapy including crossover treatment, whichever occurs first.  Patients who discontinue study treatment for reasons other 
than progressive disease will continue to be followed for response for up to 1 year after the last infusions of DCDT2980S or DCDS4501A and rituximab, 
or until disease progression or initiation of another anti-lymphoma/leukemia therapy, whichever occurs first.  Refer to Appendix A-3 for schedule of 
assessments during the post-treatment period.  Patients will also be followed for survival following study treatment discontinuation approximately 
every three months until death, loss to follow-up, withdrawal of consent, or study termination. 
e Informed consent form(s) must be signed by the patient before any study-specific procedures are performed. 
f Vital signs on days of study treatment administration should be recorded according to Section 4.5.1.2 of the protocol. 
g Defined as unexplained weight loss > 10% over previous 6 months, fever (> 38°C/100.4°F), and/or drenching night sweats. 
h Complete physical examination includes all systems described in Section 4.5.1.3.   
i Targeted physical examinations should be limited to systems of clinical relevance (see Section 4.5.1.3) and those systems associated with clinical 
signs/symptoms.  A targeted symptom directed examination is required prior to DCDT2980S or DCDS4501A dosing on Day 2 of each cycle if given on 
separate days from rituximab only if clinically indicated, e.g. to follow- up on signs or symptoms observed from the examinations performed on Day 1. 
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
122/P GO27834 A-1


Appendix A-1 (cont.)  
Study Flowchart: Initial Study Treatment 
j After informed consent is obtained but prior to initiation of study treatment, only SAEs caused by a protocol-mandated intervention should be reported.  
After initiation of study drug, all AEs and SAEs, regardless of attribution, must be reported until 30 days following the last administration of study drug or 
until the patient receives another anti-cancer therapy, whichever occurs first.  After this period, investigators should report only SAEs considered related 
to prior study treatment. 
k Treatment and disease associated symptoms using the MDASI questionnaire will be collected on hand-held computer devices (see Section 4.5.1.10).   
l Twelve-lead digital electrocardiogram (ECG) measurements must be obtained in triplicate (with immediately consecutive ECGs obtained until 
three evaluable ECGs are recorded) at the time points specified in Section 4.5.1.5.  Non-triplicate ECGs should also be performed when clinically 
indicated in any patient with evidence of, or suspicion for, clinically significant signs or symptoms of cardiac dysfunction.  The evaluating physician should 
determine the clinical significance of any abnormal ECGs. 
m Tumor assessments should be performed at screening and every 3 months while receiving study treatment regardless of study treatment dose schedule.  
Tumor assessments should also be performed within 30 days after the last study drug infusion as part of the treatment completion/early termination visit.  
Response should be assessed based on physical examination and imaged-based evaluation, using standard NHL criteria (Appendix C).  For DLBCL 
patients, a PET scan is required during screening, at the 6-month tumor assessment timepoint and as clinically indicated.  For FL patients, a PET scan is 
not required but may be obtained based on physician preference and if permitted by local health authorities.  Refer to Section 4.5.1.8 for complete 
details. 
n Administer DCDT2980S or DCDS4501A over 90 minutes for Cycle 1 and over 30 minutes in subsequent cycles if there are no infusion-related adverse 
events.  For Cycle 1 and Cycle 2, DCDT2980S or DCDS4501A should be administered on the day after rituximab is administered, e.g. Day 2 if rituximab 
is given on Day 1, or Day 3 if rituximab is given as a split dose on Days 1 and 2.  In the absence of any infusion-related adverse events, rituximab 
followed by DCDT2980S or DCDS4501A may be administered on the same day in each cycle starting with Cycle 3.  Study drug infusions should occur 
on the scheduled 21-day (or 28-day) cycle, but may be given up to ± 2 days from the date scheduled (i.e., with a minimum of 19 days between doses) if 
required for logistical/scheduling reasons.  Doses may also be delayed up to 2 weeks for recovery from reversible toxicity. 
o HBsAg, HBcAb, and Hep C Ab serology required.  If HBcAb or HCV antibody is positive, HBV / HCV DNA by PCR is required. 
p Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, absolute neutrophil count, and 
percent or absolute differential counts [e.g., segmented neutrophils, bands, lymphocytes, eosinophils, monocytes, basophils, and other cells]). 
q Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), creatinine, calcium, magnesium, phosphorus,  total 
and direct bilirubin, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactate 
dehydrogenase (LDH), and uric acid.  Serum gamma-glutamyl transpeptidase (GGT) levels will be required at screening only. 
r A serum pregnancy test should be performed for women of childbearing potential performed within 14 days prior to receiving first study treatment.  
In addition, a urine pregnancy test must also be performed within 10 days prior to Day 1 of Cycles 3, 6, 9, 12, and 15, and at the treatment 
completion/early termination visit unless patient receives crossover treatment, in which case follow the schedule of pregnancy testing outlined in 
Appendix A-2.  If any urine test result is positive, patient dosing will be postponed until the patient’s status is confirmed by a serum pregnancy test. 
 
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
123/P GO27834 A-1


Appendix A-1 (cont.)  
Study Flowchart: Initial Study Treatment 
s Bone marrow biopsy for morphology (aspirates for morphology and/or flow studies are optional) is required at screening.  Bone marrow biopsy 
for morphology are required at screening and should reflect disease status in the bone marrow following documented relapse on the last prior therapy 
or within 3 months of Day 1, whichever occurs later.  If the bone marrow biopsy at screening demonstrates presence of tumor cells, a subsequent 
bone marrow examination is required only to confirm a CR or if clinically indicated.  If the bone marrow biopsy at screening does not demonstrate 
presence of tumor cells, then subsequent bone marrow examination is required only if clinically indicated.  Unsuccessful attempts at marrow aspiration 
will not be considered a protocol violation. 
t A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.   
u Availability of archival or freshly biopsied tumor tissue samples should be confirmed at screening.  Tumor tissue samples should consist of representative 
tumor specimens in paraffin blocks (preferred) or at least 15 unstained slides, with an associated pathology report, obtained at any time prior to entry to 
study.  A biopsy of a safely accessible site of disease, defined as requiring only local anesthesia and in general excluding brain, lungs or any internal 
organs that may subject patients to significant risk, is required for patients who proceed to crossover treatment; if no such lesion exists then a biopsy is 
not required. 
v All patients who have successfully passed screening and are fully eligible for the study will have a 10-mL plasma sample taken for exploratory research.   
w Pharmacokinetic serum and plasma samples should be drawn according to the schedule provided in Appendices B-1 and B-2. 
x Whole blood samples for assessment of anti-DCDT2980S or anti-DCDS4501A antibodies in serum will be drawn according to the schedule provided in 
Appendices B-1 and B-2. 
 
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
124/P GO27834 A-1


 
Appendix A-2  
Study Flowchart:  Crossover Treatment (Patients Randomized to Arms A or B Only) 
 
 
Treatment Period 
Cycle 
Cycle 1b 
Cycles 2b−4b 
Cycles 5b−17b
Day(s) a 
Assessment  
1 b 
2 
8 
15 
1 b 
2 
8 
15 
1 b 
2 
15 
Crossover 
Treatment 
Completion/Early 
Termination Visit c
Safety  and 
Survival 
Follow-Up d 
Weight 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
Vital signs 
x e 
(x) e 
x 
x 
x e 
(x) e 
x 
x 
x e 
(x) e
x 
x 
 
ECOG Performance Status 
x 
 
x 
x 
x 
 
x 
x 
x 
 
 
x 
 
B symptoms f 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
 
Targeted physical examination g 
x 
(x) 
x 
 
x 
(x) 
 
 
x 
(x) 
 
x 
 
Concomitant medications 
x 
(x) 
x 
x 
x 
(x) 
x 
x 
x 
(x) 
x 
x 
 
Adverse events h 
x  
(x) 
x 
x 
x 
(x) 
x 
x 
x  
(x) 
x 
x 
x  
Tumor assessments i 
Every 3 months 
x 
 
Rituximab infusion 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
DCDT2980S or DCDS4501A infusion j 
x 
(x) 
 
 
x 
(x) 
 
 
x 
(x) 
 
 
 
Local Laboratory Assessments 
Hematology k 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
Serum chemistry l 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
Total IgA, IgG, IgM 
 
 
 
 
 
 
 
 
Cycle 8b Day 1
x 
 
Pregnancy test m 
Day 1 of Cycles 3b, 6b, 9b, 12b, and 15b 
x 
 
Bone marrow biopsy n 
Perform to confirm CR if positive for disease at screening or if clinically indicated
 
 
Central Laboratory Assessments 
Leukocyte immunophenotyping (FACS) o
Day 1 of Cycle 4, 8, and 12 
x 
 
Tumor biopsy/sample 
 
 
 
 
 
 
 
 
 
 
 
x p 
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
125/P GO27834 A-1


Appendix A-2 (cont.) 
Study Flowchart: Crossover Treatment (Patients Randomized to Arms A or B Only) 
 
(x) = Assessment or action to be performed only if study treatment is administered on Day 2 of the Cycle—refer to footnote ‘j’ for details. 
a Study drug infusions should occur on the scheduled 21-day cycle up to a maximum of 1 year (approximately 17 cycles) and may be given up to 
± 2 days from the date scheduled (i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  All other study visits 
during Cycles 1 and 2 must occur within ± 1 day from the scheduled date unless otherwise noted.  Study visits starting in Cycle 3 should occur within 
± 2 days from the scheduled date unless otherwise noted.  Treatment cycles may be extended to 28 days if needed to provide sufficient time for 
recovery from a transient and reversible toxicity (e.g., cytopenia) without reducing the dose of DCDT2980S or DSDA4501A.  Patients receiving study 
treatment on 28-day cycles should also follow the assessment schedule above up to a maximum of 1 year of total study treatment (approximately 
13 cycles). 
b Local laboratory assessments and targeted physical examination may be performed within 72 hours preceding rituximab administration unless 
otherwise specified; pre-infusion laboratory samples should be drawn 0−4 hours prior to infusion. 
c Perform within 30 days after the last infusion of DCDT2980S, DCDS4501A or rituximab.  The visit at which response assessment shows progressive 
disease may be used as the early termination visit. 
d Patients will be followed for safety for 30 days after the last infusions of DCDT2980S, DCDS4501A, or rituximab.  Such follow-up will require an 
assessment (per verbal report, at minimum) of any AEs and/or SAEs through 30 days after the last dose of study drug or until the patient receives 
another anti-cancer therapy including crossover treatment, whichever occurs first.  Patients who discontinue study treatment for reasons other than 
progressive disease will continue to be followed for response for up to 1 year after the last infusions of DCDT2980S or DCDS4501A and rituximab, or 
until disease progression or initiation of another anti-lymphoma/leukemia therapy, whichever occurs first.  Refer to Appendix A-3 for schedule of 
assessments during the post-treatment period.  Patients will also be followed for survival following study treatment discontinuation approximately 
every three months until death, loss to follow-up, withdrawal of consent, or study termination. 
e Vital signs on days of study treatment administration should be recorded according to Section 4.5.1.2 of the protocol. 
f Defined as unexplained weight loss > 10% over previous 6 months, fever (> 38°C/100.4°F), and/or drenching night sweats. 
g Targeted physical examinations should be limited to systems of clinical relevance and those systems associated with clinical signs/symptoms.  
A targeted symptom directed examination is required prior to DCDT2980S or DCDS4501A dosing on Day 2 of each cycle if given on separate days 
from rituximab only if clinically indicated, e.g. to follow -up on signs or symptoms observed from the examinations performed on Day 1. 
h Patients will be followed for safety for 30 days after the last infusions of DCDT2980S, DCDS4501A, or rituximab.  Such follow-up will require an 
assessment (per verbal report, at minimum) of any AEs and/or SAEs through 30 days after the last dose of study drug or until the patient receives 
another anti-cancer therapy including crossover treatment, whichever occurs first.  Patients who discontinue study treatment for reasons other than 
progressive disease will continue to be followed for response for up to 1 year after the last infusions of DCDT2980S or DCDS4501A and rituximab, or 
until disease progression or initiation of another anti-lymphoma/leukemia therapy, whichever occurs first.  Refer to Appendix A-3 for schedule of 
assessments during the post-treatment period.  
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
126/P GO27834 A-1


Appendix A-2 (cont.) 
Study Flowchart: Crossover Treatment (Patients Randomized to Arms A or B Only) 
i Tumor assessments should be performed at screening and every 3 months while receiving study treatment.  Tumor assessments should also be 
performed 28−56 days after the last study drug infusion as part of the crossover treatment completion/early termination visit.  Response should be 
assessed based on physical examination and imaged-based evaluation, using standard NHL criteria (Appendix C). 
j Administer DCDT2980S or DCDS4501A over 90 minutes for Cycle 1 and over 30 minutes in subsequent cycles if there are no infusion-related 
adverse events.  For Cycle 1b and Cycle 2b, DCDT2980S or DCDS4501A should be administered on the day after rituximab is administered, 
e.g., Day 2 if rituximab is given on Day 1, or Day 3 if rituximab is given as a split dose on Days 1 and 2.  In the absence of any infusion-related 
adverse events, rituximab followed by DCDT2980S or DCDS4501A may be administered on the same day in subsequent cycles starting with 
Cycle 3b.  Study drug infusions should occur on the scheduled 21-day (or 28-day) cycle, but may be given up to ± 2 days from the date scheduled 
(i.e., with a minimum of 19 days between doses) if required for logistical/scheduling reasons.  Doses may also be delayed up to 2 weeks for recovery 
from reversible toxicity. 
k Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, absolute neutrophil count, and 
percent or absolute differential counts [e.g., segmented neutrophils bands, lymphocytes, eosinophils, monocytes, basophils, and other cells]). 
l Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), creatinine, calcium, magnesium, phosphorus, 
total and direct bilirubin, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactate 
dehydrogenase (LDH), and uric acid. 
m A serum pregnancy test should be performed for women of childbearing potential performed within 14 days prior to receiving first study treatment.  
In addition, a serum or urine pregnancy test must also be performed within 10 days prior to Day 1 of Cycles 3, 6, 9, 12, and 15, and at the crossover 
treatment completion/early termination visit.  If any urine test result is positive, patient dosing will be postponed until the patient’s status is confirmed 
by a serum pregnancy test. 
n Bone marrow biopsy for morphology (aspirate for morphology and/or flow studies are optional) should be repeated only to confirm a CR where 
presence of tumor was documented at the screening bone marrow examination. 
o A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.   
p Optional tumor biopsy of a safely accessible site of disease, defined as requiring only local anesthesia and in general excluding brain, lungs or any 
internal organs that may subject patients to significant risk.  Tumor samples will be used for research purposes. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
127/P GO27834 A-1


 
Appendix A-3  
Study Flowchart: Post-Treatment Follow-Up 
Assessments/Procedures 
Post-treatment Follow-up 
Months after treatment completion visit
2 Months 
4 Months 
6 Months 
9 Months 
12 Months 
Targeted physical examination 
a 
x 
x 
x 
x 
x 
Vital signs (blood pressure, pulse rate, and 
body temperature) 
x 
x 
x 
x 
x 
ECOG Performance Status 
x 
x 
x 
x 
x 
B symptoms 
b 
x 
x 
x 
x 
x 
Tumor assessments 
c 
x 
x 
x 
x 
x 
Total IgA, IgG, IgM 
x 
x 
x 
x 
x 
Hematology
 d 
x 
x 
x 
x 
x 
Serum chemistry
 e 
x 
x 
x 
x 
x 
Bone marrow 
f 
Perform to confirm CR if positive for disease at screening or if 
clinically indicated 
Central Lab Assessments 
 
 
 
 
 
Leukocyte immunophenotyping (FACS) 
g 
x 
x 
x 
x 
x 
Pharmacokinetic sampling 
h 
x 
x 
x 
 
 
Serum sample for anti-DCDT2980S / 
anti-DCDS4501A ATA assay 
h 
x 
x 
x 
 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ATA = anti-therapeutic antibody; 
CR = completed response; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; 
FACS = fluorescent-activated cell sorter; Ig = immunoglobulin; MRI = magnetic resonance imaging; 
NHL = non-Hodgkin’s lymphoma; PET = positron emission tomography. 
NOTE: Post-treatment assessments apply to patients who discontinue from study treatment (initial or crossover 
treatment) for reasons other than disease progression.  The schedule corresponds to visits timed from 
treatment completion/early termination visit or crossover treatment completion/early termination visit until the 
time of disease progression, start of new anti-cancer therapy, or withdrawal from study participation.  
Two-month and 4-month follow-up visits should occur within ± 7 days from the scheduled date, while 
subsequent visits should occur within ± 14 days from the scheduled date. 
a Targeted physical examinations should be limited to systems of clinical relevance (see Section 4.5.1.3) and 
those systems associated with clinical signs/symptoms. 
b Defined as unexplained weight loss > 10% over previous 6 months, fever (> 38°C/100.4°F), and/or drenching 
night sweats. 
c Response should be assessed based on physical examination and imaged-based evaluation, using standard 
NHL criteria (Appendix C). 
d Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, 
platelet count, absolute neutrophil count, and percent or absolute differential counts [e.g., segmented 
neutrophils bands, lymphocytes, eosinophils, monocytes, basophils, and other cells]). 
e Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (or local equivalent), 
creatinine, calcium, magnesium, phosphorus, total and direct bilirubin, total protein, albumin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase 
(LDH), and uric acid. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
128/P GO27834 A-1


Appendix A-3 (cont.)  
Study Flowchart: Post-Treatment Follow-Up 
f Bone marrow biopsy for morphology (aspirate for morphology and/or flow studies are optional) should be 
repeated only to confirm a CR where presence of tumor was documented at the screening bone marrow 
examination. 
g A 5-mL whole-blood sample will be taken for the assessment of B cells, T cells, and NK cells.   
h Refer to Appendices B-1 or B-2. 
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
129/P GO27834 A-1


 
Appendix B–1  
Serum and Plasma Pharmacokinetic Schedule for 
DCDT2980S/DCDS4501A and Rituximab, and ATA Schedule for 
DCDT2980S/DCDS4501A (For Patients Receiving Rituximab on 
Day 1 and DCDT2980S/DCDS4501A on Day 2 of Every Cycle) 
Study Visit 
Sample Timepoint(s) 
a 
Samples 
e 
Cycle 1, Day 1 
Pre-rituximab infusion 
• 
Rituximab PK 
 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Pre-DCDT2980S/DCDS4501A 
infusion 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
DCDT2980S/DCDS4501A PK 
b 
Cycle 1, Day 2 
30 minutes (± 15 minutes)  
post- DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK 
Cycle 1, Day 8 (± 1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
Cycle 1, Day 15 (± 1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK  
Cycles 2−3, Day 1 
Pre-rituximab dose 
• 
Rituximab PK 
 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Pre- DCDT2980S/DCDS4501A 
infusion 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
c 
• 
DCDT2980S/DCDS4501A PK 
Cycles 2−3, Day 2 
30 minutes (± 15 minutes) 
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK 
Cycle 3, Day 8 (± 1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK  
Cycle 3, Day 15 (±1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
Pre-rituximab infusion 
• 
Rituximab PK 
Cycles 4, and 
every 4th cycle 
thereafter), Day 1 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Pre-DCDT2980S/DCDS4501A 
infusion 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
c 
• 
DCDT2980S/DCDS4501A PK 
Cycles 4, and 
every 4th cycle 
thereafter), Day 2 
30 minutes (± 15 minutes) 
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
130/P GO27834 A-1


Appendix B-1 (cont.)  
Serum and Plasma Pharmacokinetic Schedule for DCDT2980S/DCDS4501A 
and Rituximab, and ATA Schedule for DCDT2980S/DCDS4501A (For Patients 
Receiving Rituximab on Day 1 and DCDT2980S/DCDS4501A on Day 2 of 
Every Cycle) 
Study Visit 
Sample Timepoint(s) 
a 
Samples 
e 
Treatment 
Completion/ 
Early Termination 
Visit 
Approximately 15−30 days 
after last infusion  
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
Post-treatment 
Follow-Up Visits 
d 
2, 4, and 6 months after 
treatment completion visit 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
ATA = Anti-therapeutic antibody; MMAE = monomethyl auristatin E; PK = pharmacokinetic. 
NOTE: “Pre-infusion” means prior to the start of infusion; “Post-infusion” means after the infusion is 
completed. 
a A 3-mL whole-blood sample will be taken for each of the following at each specified timepoint: 
anti-DCDT2980S or anti-DCDS4501A antibody; rituximab PK; and/or DCDT2980S/DCDS4501A 
PK.  If rituximab dosing is split over two days, then PK will be obtained prior to the rituximab 
dose on the first day and 30 minutes (± 15 minutes) post-rituximab infusion on the second day. 
b DCDT2980S / DCDS4501A PK including serum PK samples for total DCDT2980S and 
DCDS4501A antibody and plasma PK samples for antibody-conjugated MMAE and free MMAE. 
c Cycles 2 and 4 only for anti-DCDT2980S or anti-DCDS4501A antibody.
  
d Post-treatment follow-up PK and ATA assessments only apply to patients who did not receive 
crossover treatment. 
e PK sampling will not be obtained from patients who cross-over to another treatment arm. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
131/P GO27834 A-1


 
Appendix B–2  
Serum and Plasma Pharmacokinetic Schedule for Rituximab and 
DCDT2980S/DCDS4501A, and ATA Schedule for 
DCDT2980S/DCDS4501A for Patients Receiving Rituximab and 
DCDT29808S/DCDS4501A on Day 1 of Every Cycle Beginning 
Cycle 3 
Study Visit 
Sample Timepoint(s) 
a 
Samples 
e 
For Cycle 1 and Cycle 2 PK assessments, refer to Appendix B-1 
Pre-rituximab infusion 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Cycle 3, Day 1 
 
30 minutes (± 15 minutes) 
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK  
Cycle 3, Day 8 (± 1 day) 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK  
Cycle 3, Day 15 (±1 day) 
• 
Rituximab  
• 
DCDT2980S/DCDS4501A PK 
Pre-rituximab infusion 
• 
Rituximab PK 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
c 
• 
DCDT2980S/DCDS4501A PK 
30 minutes (± 15 minutes) 
post-rituximab infusion 
• 
Rituximab PK 
Cycles 4, and 
every 4th cycle 
thereafter), Day 1 
30 minutes (± 15 minutes) 
post-DCDT2980S/DCDS4501A 
infusion 
• 
DCDT2980S/DCDS4501A PK 
Treatment 
Completion/ 
Early Termination 
Visit 
Approximately 15−30 days 
after last infusion  
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
Post-treatment 
Follow-Up Visits 
d 
2, 4, and 6 months after 
treatment completion visit 
• 
Anti-DCDT2980S/Anti-DCDS4501A 
antibody 
• 
Rituximab PK 
• 
DCDT2980S/DCDS4501A PK 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
132/P GO27834 A-1


Appendix B–2 (cont.) 
Serum and Plasma Pharmacokinetic Schedule for Rituximab and 
DCDT2980S/DCDS4501A, and ATA Schedule for DCDT2980S/DCDS4501A 
(For Patients Receiving Rituximab and DCDT29808S/DCDS4501A on Day 1 of 
Every Cycle Beginning Cycle 3) 
 
ATA = Anti-therapeutic antibody; MMAE = monomethyl auristatin E; PK = pharmacokinetic. 
NOTE: “Pre-infusion” means prior to the start of infusion; “Post-infusion” means after the infusion is 
completed. 
a A 3-mL whole-blood sample will be taken for each of the following at each specified timepoint: 
anti-DCDT2980S or anti-DCDS4501A antibody, rituximab PK, and/or DCDT2980S/DCDS4501A 
PK.  If rituximab dosing is split over two days, then PK will be obtained prior to the rituximab 
dose on the first day and 30 minutes (± 15 minutes) post-rituximab infusion on the second day. 
b DCDT2980S/DCDS4501A PK including serum PK samples for total DCDT2980S and 
DCDS4501A antibody and plasma PK samples for antibody-conjugated MMAE and free MMAE. 
c Cycles 4 only for anti-DCDT2980S or anti-DCDS4501A antibody.
  
d Post-treatment follow-up PK and ATA assessments only apply to patients who did not receive 
crossover treatment. 
e PK sampling will not be obtained from patients who cross-over to another treatment arm. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
133/P GO27834 A-1


Appendix C  
Modified Response and Progression Criteria for NHL 
Adapted from:  Cheson BD, Pfistner B, Juweid ME, et al. Revised Response Criteria for Malignant 
Lymphoma. J Clin Oncol 2007;25:579–86. 
Selection of Indicator (Target) Lesions 
Up to six of the largest dominant nodes or tumor masses selected according to all of the 
following: 
• 
Clearly measurable in at least two perpendicular dimensions 
Abnormal lymph nodes are those that are either 
>15 mm in the greatest transverse diameter (GTD) regardless of the short axis 
diameter, or 
> 10 mm in short axis diameter regardless of long axis 
• 
If possible, they should be from disparate regions of the body 
• 
Should include mediastinal and retroperitoneal areas of disease whenever these sites 
are involved 
• 
Extranodal lesions within the liver or spleen must be at least 1.0 cm in 
two perpendicular dimensions. 
PET Scans--Definition of a Positive PET scan 
Visual assessment currently is considered adequate for determining whether a PET scan is 
positive, and use of the standardized uptake value is not necessary.  In brief, a positive scan 
is defined as focal or diffuse FDG uptake above background in a location incompatible with 
normal anatomy or physiology, without a specific standardized uptake value cutoff.  Other 
causes of false-positive scans should be ruled out.  Exceptions include mild and diffusely 
increased FDG uptake at the site of moderate or large-sized masses with an intensity that is 
lower than or equal to the mediastinal blood pool, hepatic or splenic nodules 1.5 cm with 
FDG uptake lower than the surrounding liver/spleen uptake, and diffusely increased bone 
marrow uptake within weeks after treatment. 
Complete Remission (CR) 
1. Complete disappearance of all detectable clinical evidence of disease 
and disease-related symptoms if present prior to therapy.  
Typically FDG-avid lymphoma: in patients with no pre-treatment PET scan or when 
the PET scan was positive before therapy, a post-treatment residual mass of any 
size is permitted as long as it is PET negative. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
134/P GO27834 A-1


APPENDIX C (cont.) 
Modified Response and Progression Criteria for NHL 
Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, the designation 
of CR requires all nodal indicator lesions to regress to the size of normal lymph 
nodes.  Lymph nodes that were > 15 mm in GTD regardless of the short axis 
diameter at the screening tumor assessment must regress to ≤ 15 mm in GTD 
regardless of the short axis diameter.  Lymph nodes that were 11 to 15 mm in GTD 
and > 10 mm in the short axis diameter at the screening tumor assessment must 
regress to ≤ 10 mm in the short axis diameter. 
2. The spleen and/or liver, if considered enlarged prior to therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies, and nodules related to lymphoma should 
disappear.  However, determination of splenic involvement is not always reliable 
because a spleen considered normal in size may still contain lymphoma, whereas an 
enlarged spleen may reflect variations in anatomy, blood volume, the use of 
hematopoietic growth factors, or causes other than lymphoma. 
3. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have 
cleared on repeat bone marrow biopsy.  The biopsy sample on which this determination 
is made must be adequate (> 20 mm unilateral core).  If the sample is indeterminate by 
morphology, it should be negative by immunohistochemistry.  A sample that is negative 
by immunohistochemistry but demonstrating a small population of clonal lymphocytes by 
flow cytometry will be considered a CR until data become available demonstrating a 
clear difference in patient outcome.  
Partial Remission (PR) 
1. ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest 
dominant nodes or nodal masses.  These nodes or masses should be selected 
according to the following: (a) they should be clearly measurable in at least 2 
perpendicular dimensions; (b) if possible they should be from disparate regions of the 
body; (c) they should include mediastinal and retroperitoneal areas of disease whenever 
these sites are involved. 
2. No increase in the size of the other nodes, liver, or spleen. 
3. Splenic and hepatic nodules must regress by ≥ 50% in their SPD or, for single nodules, 
in the greatest transverse diameter. 
4. With the exception of splenic and hepatic nodules, involvement of other organs is usually 
assessable and no measurable disease should be present. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
135/P GO27834 A-1


APPENDIX C (cont.) 
Modified Response and Progression Criteria for NHL 
5. Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive prior to treatment.  However, if positive, the cell type should be specified 
(e.g., large-cell lymphoma or small neoplastic B cells).  Patients who achieve a complete 
remission by the above criteria, but who have persistent morphologic bone marrow 
involvement will be considered partial responders. 
6. No new sites of disease should be observed (e.g., nodes > 1.5 cm in any axis). 
7. Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the 
PET scan was positive before therapy, the post-treatment PET should be positive in at 
least one previously involved site. 
8. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, CT criteria should be used. 
9. In patients with follicular lymphoma, a PET scan is only indicated with one or at most two 
residual masses that have regressed by more than 50% on CT; those with more than 
two residual lesions are unlikely to be PET negative and should be considered partial 
responders. 
Stable Disease (SD) 
1. Failing to attain the criteria needed for a CR or PR, but not fulfilling those for progressive 
disease (see below). 
2. Typically FDG-avid lymphomas: the PET should be positive at prior sites of disease with 
no new areas of involvement on the post- treatment CT or PET. 
3. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment 
PET scan or if the pretreatment PET was negative, there must be no change in the size 
of the previous lesions on the post-treatment CT scan. 
Relapsed Disease (RD; after CR) or Progressive Disease (PD; for Patients 
with PR or SD) 
1. Lymph nodes should be considered abnormal if the long axis is > 1.5 cm, regardless of 
the short axis.  If a lymph node has a long axis of 1.1−1.5 cm, it should only be 
considered abnormal if its short axis is > 1.0.  Lymph nodes ≤ 1.0 cm by ≤ 1.0 cm will not 
be considered as abnormal for relapse or progressive disease. 
2. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size.  Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive disease 
after confirmation with other modalities. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
136/P GO27834 A-1


APPENDIX C (cont.) 
Modified Response and Progression Criteria for NHL 
3. At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a 
single involved node, or the size of other lesions (e.g., splenic or hepatic nodules).  
To be considered progressive disease, a lymph node with a diameter of the short axis of 
less than 1.0 cm must increase by ≥ 50% and to a size of 1.5 × 1.5 cm or more than 
1.5 cm in the long axis. 
4. At least a 50% increase in the longest diameter of any single previously identified node 
more than 1 cm in its short axis. 
5. Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected with 
current PET systems (< 15 mm in its long axis by CT). 
6. Measurable extranodal disease should be assessed in a manner similar to that 
for nodal disease.  For these recommendations, the spleen is considered nodal disease. 
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
137/P GO27834 A-1


Appendix D  
Anaphylaxis Management 
The following equipment is needed in the event of a suspected anaphylactic reaction 
during study drug infusion: 
• 
Appropriate monitors (electrocardiogram, blood pressure, pulse oximetry 
• 
Oxygen 
• 
Tourniquet 
• 
Epinephrine for intravenous, intramuscular, and/or endotracheal administration 
in accordance with institutional guidelines.   
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
 
The following are the procedures to follow in the event of a suspected anaphylactic 
reaction during study drug infusion: 
• 
Stop the study drug infusion. 
• 
Call for additional assistance! 
• 
Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
drug.  Do not obstruct arterial flow in the limb. 
• 
Maintain an adequate airway. 
• 
Ensure that appropriate monitoring is in place, with continuous electrocardiogram and 
pulse oximetry monitoring, if possible. 
• 
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge. 
• 
Continue to observe the patient and document observations. 
 
 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
138/P GO27834 A-1






Appendix F  
Recommendations for the Use of White Blood Cell Growth 
Factors 
Primary Prophylactic G-CSF Administration (First and Subsequent-Cycle Use) 
Primary prophylaxis with G-CSF is recommended if any of the following clinical factors 
are present: 
• 
Age >65 years 
• 
Poor performance status 
• 
Previous history of febrile neutropenia 
• 
Open wounds or active infections 
• 
More advanced cancer 
• 
Extensive prior treatment, including large radiation therapy ports 
• 
Cytopenias due to bone marrow involvement by tumor 
• 
Other serious comorbidities 
 
Secondary Prophylactic G-CSF Administration 
Prophylactic G-CSF administration is recommended for patients who fulfill each of the 
following circumstances: 
• 
Experienced a neutropenic complication from a prior cycle of study treatment 
• 
Primary prophylactic G-CSF was not received; and 
• 
The intent is to avoid dose reduction of the antibody−drug conjugate (ADC), where 
the effect of the reduced dose on disease-free, overall survival or treatment 
outcome is not known 
 
Therapeutic Use of G-CSF 
G-CSF administration should be considered for the following patients: 
• 
Patients with febrile neutropenia who are at high risk for infection-associated 
complications; or 
• 
Patients who have prognostic factors that are predictive of poor clinical outcome, 
e.g., prolonged (>10 days) and profound (<100/μL) neutropenia, age >65 years, 
uncontrolled primary disease, pneumonia, hypotension and multi-organ dysfunction 
(sepsis), invasive fungal infection, being hospitalized at the time of fever 
development 
 
 
 
Source:  Smith TJ et al. 2006 Update of Recommendations for the use of White Blood Cell 
Growth Factors: An Evidence-Based Clinical Practice Guideline. JCO 24:3187-3205. 2006. 
Protocol:  DCDT2980S and DCDS4501A—Genentech, Inc.
141/P GO27834 A-1