Clinical trial NCT01992653
Conditions: Lymphoma, Non Hodgkin
Sponsor: Genentech, Inc.
Start date: 2013-11-29; Completion date: 2018-12-19
Enrollment: 85 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multicenter, open-label, dose-escalation study will evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of polatuzumab vedotin in combination with rituximab or obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (CHP chemotherapy) in participants with non-Hodgkin's lymphoma (NHL). Participants will receive escalating doses of polatuzumab vedotin intravenously (IV) every 3 weeks in combination with standard doses of rituximab plus CHP chemotherapy (R-CHP) or obinutuzumab plus CHP chemotherapy (G-CHP). Participants will be treated for a total of six or eight cycles in accordance with local institutional practice. Two parallel treatment arms will explore doses of polatuzumab vedotin in combination with R-CHP or G-CHP. The maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of polatuzumab vedotin in combination with R-CHP will be identified before it is combined with G-CHP. Once the MTD or RP2D is determined, polatuzumab vedotin will be dosed at MTD or RP2D -1 in combination with G-CHP to start the dose escalation of this combination.

Detailed description:

Arms: arm 1: Dose Escalation: Participants will receive a total of six to eight 21-day cycles of polatuzumab vedotin in combination with G-CHP. arm 2: Dose Escalation: Participants will receive a total of six to eight 21-day cycles of polatuzumab vedotin in combination with R-CHP. arm 3: Dose Escalation: Participants will receive a total of six to eight 21-day cycles of polatuzumab vedotin in combination with G-CHP. arm 4: Dose Escalation: Participants will receive a total of six to eight 21-day cycles of polatuzumab vedotin in combination with R-CHP. arm 5: Dose Escalation: Participants will receive a total of six to eight 21-day cycles of polatuzumab vedotin in combination with R-CHP. arm 6: Dose Escalation: Participants will receive a total of six to eight 21-day cycles of polatuzumab vedotin in combination with R-CHP. arm 7: Dose Expansion: Participants will receive a total of six to eight 21-day cycles of polatuzumab vedotin in combination with R-CHP. arm 8: Dose Expansion: Participants will receive a total of six to eight 21-day cycles of polatuzumab vedotin in combination with G-CHP.
Interventions: intervention 1: Cyclophosphamide intervention 2: Doxorubicin intervention 3: Obinutuzumab intervention 4: Polatuzumab Vedotin intervention 5: Prednisolone intervention 6: Prednisone intervention 7: Rituximab
Intervention descriptions: intervention 1: Cyclophosphamide will be administered at 750 milligrams per square meter (mg/m\^2) IV every 3 weeks (starting from Cycle 1 Day 1), for 6 or 8 cycles. intervention 2: Doxorubicin will be administered at 50 mg/m\^2 IV every 3 weeks (starting from Cycle 1 Day 1), for 6 or 8 cycles. intervention 3: Obinutuzumab will be administered at 1000 milligrams (mg) IV on Cycle 1 Days 1, 8, and 15 and on Day 1 of Cycles 3-8. intervention 4: Polatuzumab vedotin will be administered at escalating doses (at a starting dose of 1 mg/kg) IV every 3 weeks, for 6 or 8 cycles. intervention 5: Prednisolone will be administered at 100 mg orally daily for 5 days every 3 weeks (starting from Cycle 1 Day 1), for 6 or 8 cycles. Prednisone at 100 mg orally from Day -7 to Day -1 may be given at the discretion of the treating investigator physician. intervention 6: Prednisone will be administered at 100 mg orally daily for 5 days every 3 weeks (starting from Cycle 1 Day 1), for 6 or 8 cycles. Prednisone at 100 mg orally from Day -7 to Day -1 may be given at the discretion of the treating investigator physician. intervention 7: Rituximab will be administered at 375 mg/m\^2 IV every 3 weeks (starting from Cycle 1 Day 1), for 6 or 8 cycles.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
A PHASE IB/II STUDY EVALUATING THE SAFETY, 
TOLERABILITY AND ANTI-TUMOR ACTIVITY OF POLATUZUMAB 
VEDOTIN (DCDS4501A) IN COMBINATION WITH RITUXIMAB OR 
OBINUTUZUMAB, CYCLOPHOSPHAMIDE, DOXORUBICIN, AND 
PREDNISONE IN PATIENTS WITH B-CELL NON-HODGKIN’S 
LYMPHOMA 
NCT Number: 
NCT01992653 
Document Date:  Protocol Version 9: 26-July-2017 
 
 
 
 


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. 
 
Polatuzumab Vedotin—Genentech, Inc. 
Protocol GO29044, Version 9 
PROTOCOL 
TITLE: 
A PHASE IB/II STUDY EVALUATING THE SAFETY, 
TOLERABILITY AND ANTI-TUMOR ACTIVITY OF 
POLATUZUMAB VEDOTIN (DCDS4501A) IN 
COMBINATION WITH RITUXIMAB OR 
OBINUTUZUMAB, CYCLOPHOSPHAMIDE, 
DOXORUBICIN, AND PREDNISONE IN PATIENTS 
WITH B-CELL NON-HODGKIN’S LYMPHOMA 
PROTOCOL NUMBER: GO29044 
VERSION NUMBER: 
9 
EUDRACT NUMBER: 
2013-003541-42 
IND NUMBER: 
109409 
TEST PRODUCT: 
Polatuzumab Vedotin (DCDS4501A) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
Version 1:  13 August 2013 
DATES AMENDED: 
Version 2:  21 February 2014 
Version 3:  28 March 2014 
Version 4 (France Only):  17 April 2014 
Version 5:  18 July 2014 
Version 6:  24 September 2015 
Version 7 (France Only):  5 April 2016 
Version 8:  23 September 2016 
Version 9:  See electronic date stamp below. 
 
26-Jul-2017 14:27:03
Title
Approver's Name
Company Signatory (Clinical)
Date and Time (UTC)


Polatuzumab Vedotin—Genentech, Inc. 
2/Protocol GO29044, Version 9 
PROTOCOL AMENDMENT, VERSION 9: 
RATIONALE 
Protocol GO29044 has been amended to introduce second malignancies as an adverse 
event of special interest (AESI) for patients who have received obinutuzumab.  The 
classification of second malignancies has been changed from a selected adverse event 
to AESI to more closely monitor this adverse event.  Changes to the protocol, along with 
a rationale for each change, are summarized below: 
x 
Second malignancies have been added as an AESI in Section 5.2.3.  The duration 
of AE reporting for second malignancies has been changed to indefinitely in 
Section 5.3.1 and Section 5.7.  
x 
The reporting of the term “sudden death” has been updated to also require the 
presumed cause of death (Section 5.4.7). 
x 
Event reporting for hospitalization has been clarified (Section 5.4.10). 
x 
The process for reviewing and handling protocol deviations has been updated per 
internal standard operating procedures (Section 9.2). 
x 
A section on the publication of data and protection of trade secrets was added per 
internal standard operating procedures (Section 9.5). 
 
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. 


 
Polatuzumab Vedotin—Genentech, Inc. 
3/Protocol GO29044, Version 9 
PROTOCOL AMENDMENT, VERSION 9: 
SUMMARY OF CHANGES 
SECTION 5.2.3:  Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Adverse events of special interest for this study include the following: 
[}] 
x 
Second malignancies 
 
SECTION 5.3.1:  Adverse Event Reporting Period 
Second malignancies will be reported indefinitely for patients who received 
obinutuzumab, regardless of relationship to study treatment (even if the study has been 
closed and even after initiation of new anti-lymphoma therapy; see Section 5.7). 
SECTION 5.4.7:  Deaths 
The term "sudden death" should be used only for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour after the onset of acute symptoms or, in the case 
of an unwitnessed death, within 24 hours after the patient was last seen alive and stable.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be 
replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
SECTION 5.4.10:  Hospitalization and Prolonged Hospitalization 
The following An event that leads to hospitalization scenarios are under the following 
circumstances should not considered to be reported as an adverse events event or a 
serious adverse event: 
x 
Hospitalization for respite care 
x 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration, perform an efficacy 
measurement for the study) 
x 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease. 
The patient has not experienced an adverse event. 
x 
Hospitalization due solely to progression of the underlying cancer 
 


 
Polatuzumab Vedotin—Genentech, Inc. 
4/Protocol GO29044, Version 9 
The following An event that leads to hospitalization scenarios are under the following 
circumstances is not considered to be a serious adverse events event, but should be 
reported as an adverse events event instead: 
Hospitalization that was necessary because of patient requirement for outpatient care 
outside of normal outpatient clinic operating hours 
SECTION 5.7:  POST-STUDY ADVERSE EVENTS 
The Sponsor should also be notified of events of second malignancies indefinitely for 
patients who received obinutuzumab. 
SECTION 9.2:  PROTOCOL DEVIATIONS 
The Sponsor will review all protocol deviations and assess whether any represent a 
serious breach of Good Clinical Practice guidelines and require reporting to health 
authorities.  As per the Sponsor's standard operating procedures, prospective requests 
to deviate from the protocol, including requests to waive protocol eligibility criteria, are 
not allowed. 
SECTION 9.5:  PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
This section has been added. 
 


Polatuzumab Vedotin—Genentech, Inc. 
5/ Protocol GO29044, Version 9 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13 
PROTOCOL SYNOPSIS .................................................................................... 14 
1. 
BACKGROUND .......................................................................................... 26 
1.1 
Non-Hodgkin’s Lymphoma .................................................... 26 
1.2 
Background on Polatuzumab Vedotin ................................... 27 
1.2.1 
Background on Nonclinical Data ............................................ 27 
1.2.2 
Polatuzumab Vedotin Clinical Data ....................................... 28 
1.2.2.1 Patient Enrollment ................................................................ 28 
1.2.2.2 Safety ................................................................................... 28 
1.2.3 
Pharmacokinetic and Pharmacodynamic 
Properties of Polatuzumab Vedotin ........................................ 31 
1.3 
Rationale for Doing this Study ............................................... 32 
2. 
OBJECTIVES .............................................................................................. 35 
2.1 
Primary Objectives ................................................................ 35 
2.2 
Secondary Objectives ............................................................ 35 
2.3 
Exploratory Objectives ........................................................... 36 
3. 
STUDY DESIGN ......................................................................................... 36 
3.1 
Description of the Study......................................................... 36 
3.1.1 
Dose Escalation, Dose-Limiting Toxicity, and 
Determination of the Maximum Tolerated Dose ..................... 37 
3.1.1.1 Definition of Dose-Limiting Toxicity ...................................... 38 
3.1.1.2 Dose Escalation after Dose-Limiting Toxicity and 
Determination of the Maximum Tolerated Dose .................... 40 
3.1.2 
Phase II:  Expansion Stage ................................................... 41 
3.1.3 
Internal Monitoring Committee ............................................... 42 
3.1.4 
Independent Review Committee ............................................ 43 
3.2 
End of Study .......................................................................... 43 
3.3 
Rationale for Study Design .................................................... 43 
3.3.1 
Rationale for Obinutuzumab Dosing and 
Schedule ................................................................................ 44 
3.3.2 
Rationale for Exploratory Biomarker Research 
Samples ................................................................................. 44 


 
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3.3.3 
Rationale for Pharmacokinetic Sampling ............................... 45 
3.3.4 
Rationale for Patient-Reported Outcomes ............................. 45 
3.4 
Outcome Measures ............................................................... 45 
3.4.1 
Safety Outcome Measures .................................................... 45 
3.4.2 
Pharmacokinetic and Pharmacodynamic 
Outcome Measures ................................................................ 46 
3.4.3 
Activity and Dose Exposure Outcome Measures ................... 46 
3.4.4 
Immunogenicity Outcome Measures ..................................... 47 
3.4.5 
Patient-Reported Outcome Measures ................................... 47 
3.4.6 
Biomarker Outcome Measures .............................................. 47 
4. 
MATERIALS AND METHODS .................................................................... 47 
4.1 
Patients .................................................................................. 47 
4.1.1 
Patient Selection .................................................................... 47 
4.1.2 
Inclusion Criteria .................................................................... 48 
4.1.3 
Exclusion Criteria ................................................................... 49 
4.2 
Method of Treatment Assignment .......................................... 51 
4.3 
Study Treatment .................................................................... 51 
4.3.1 
Formulation, Packaging, and Handling .................................. 51 
4.3.1.1 Polatuzumab Vedotin ........................................................... 51 
4.3.1.2 Rituximab ............................................................................. 51 
4.3.1.3 Obinituzumab ....................................................................... 51 
4.3.1.4 Cyclophosphamide, Doxorubicin, and 
Prednisone ............................................................................ 51 
4.3.2 
Dosage, Administration, and Compliance .............................. 52 
4.3.2.1 Polatuzumab Vedotin ........................................................... 53 
4.3.2.2 Rituximab ............................................................................. 54 
4.3.2.3 Obinutuzumab ...................................................................... 56 
4.3.2.4 CHP Chemotherapy Dosage and Administration ................. 58 
4.3.3 
Investigational Medicinal Product Accountability ................... 58 
4.3.4 
Post-Trial Access to Polatuzumab Vedotin ............................ 59 
4.4 
Concomitant Therapy ............................................................ 59 
4.4.1 
Permitted Therapy ................................................................. 59 
4.4.1.1 CNS Prophylaxis .................................................................. 60 


 
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4.4.1.2 Prophylaxis for Hemorrhagic Cystitis .................................... 60 
4.4.1.3 Treatment and Prophylaxis of Neutropenia .......................... 60 
4.4.1.4  Premedication before Rituximab and 
Obinutuzumab ....................................................................... 60 
4.4.1.5 Infection Prophylaxis ............................................................ 61 
4.4.2 
Prohibited Therapy ................................................................ 61 
4.4.2.1 Immunizations ...................................................................... 61 
4.5 
Study Assessments ............................................................... 61 
4.5.1 
Informed Consent Forms and Screening Log ........................ 62 
4.5.2 
Medical History and Demographic Characteristics ................ 62 
4.5.3 
Physical Examinations ........................................................... 62 
4.5.4 
Clinical Total Neuropathy Score Assessment ........................ 63 
4.5.5 
Vital Signs .............................................................................. 63 
4.5.6 
Tumor and Response Evaluation .......................................... 63 
4.5.7 
Laboratory, Biomarker, and Other Biological 
Assessments .......................................................................... 64 
4.5.8 
Electrocardiogram and Echocardiogram or MUGA ................ 66 
4.5.9 
Patient-Reported Outcomes (PRO) ....................................... 66 
4.5.10 
Pharmacokinetic Assessment ................................................ 67 
4.5.11 
Immunogenicity Assessments ............................................... 67 
4.5.12 
Samples for Roche Clinical Repository.................................. 68 
4.5.13 
Timing of Study Assessments ............................................... 71 
4.5.13.1 Screening and Pretreatment Assessments ........................ 71 
4.5.13.2 Assessments during Treatment .......................................... 71 
4.5.13.3 Study Treatment Completion Visit ...................................... 72 
4.5.13.4 Follow-Up Assessments ..................................................... 72 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation ...................................................................... 73 
4.6.1 
Patient Discontinuation .......................................................... 73 
4.6.2 
Study Treatment Discontinuation ........................................... 73 
4.6.3 
Study and Site Discontinuation .............................................. 74 
4.7 
Assay Methods ...................................................................... 74 
4.7.1 
Total Polatuzumab Vedotin Antibody ELISA .......................... 74 


 
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4.7.2 
Conjugated (Evaluated as Antibody-Conjugated 
MMAE) Affinity Capture Enzyme-Release 
LC/MS/MS .............................................................................. 74 
4.7.3 
Unconjugated MMAE LC/MS/MS .......................................... 74 
4.7.4 
Rituximab ELISA ................................................................... 74 
4.7.5 
Obinutuzumab ELISA ............................................................ 75 
4.7.6 
Cyclophosphamide LC/MS/MS .............................................. 75 
4.7.7 
Doxorubicin LC/MS/MS ......................................................... 75 
4.7.8 
Polatuzumab Vedotin Anti-Therapeutic Antibody .................. 75 
4.7.9 
Obinutuzumab Anti-Therapeutic Antibody ............................. 75 
5. 
ASSESSMENT OF SAFETY ....................................................................... 75 
5.1 
Safety Plan ............................................................................ 75 
5.1.1 
Risks Associated with Polatuzumab Vedotin ......................... 76 
5.1.1.1 Known Risks:  Neutropenia and Peripheral 
Neuropathy .......................................................................... 76 
5.1.2 
Potential Risks ....................................................................... 76 
5.1.2.1 Effects on the Relative Dose Intensity of R-CHP 
or G-CHP ............................................................................. 76 
5.1.2.2 Potential Risks Associated with Polatuzumab 
Vedotin ................................................................................ 77 
5.1.3 
Risks Associated with Cyclophosphamide, 
Doxorubicin, and Prednisone ................................................ 81 
5.1.4 
Risks Associated with Rituximab Therapy ............................. 81 
5.1.5 
Risks Associated with Obinutuzumab .................................... 84 
5.1.5.1 Infusion-Related Reactions and Hypersensitivity 
Reactions (Including Anaphylaxis) ....................................... 84 
5.1.5.2 Tumor Lysis Syndrome ........................................................ 84 
5.1.5.3 Neutropenia .......................................................................... 85 
5.1.5.4 Thrombocytopenia ................................................................ 85 
5.1.5.5 Infection ................................................................................ 85 
5.1.5.6 Worsening of Cardiac Conditions ......................................... 86 
5.1.5.7 Gastro-Intestinal (GI) Perforation ......................................... 86 
5.1.6 
Management of Specific Adverse Events .............................. 86 
5.1.6.1 Dose Delays and Dose Modifications ................................... 86 
5.1.6.2 Dose Modifications ............................................................... 87 


 
Polatuzumab Vedotin—Genentech, Inc. 
9/Protocol GO29044, Version 9 
5.1.6.3 Schedule Modification .......................................................... 87 
5.1.7 
Management of Toxicities R-CHP or G-CHP and 
Polatuzumab Vedotin ............................................................. 87 
5.1.7.1 Tumor Lysis Syndrome ........................................................ 87 
5.1.7.2 Infusion-Related Reactions and Anaphylaxis ....................... 88 
5.1.7.3 Neutropenia .......................................................................... 89 
5.1.7.4 Dose Delays and Dose Modifications ................................... 90 
5.1.7.5 Dose Discontinuation ........................................................... 97 
5.2 
Safety Parameters and Definitions ........................................ 97 
5.2.1 
Adverse Events ..................................................................... 97 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ..................................................................... 98 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 98 
5.2.4 
Dose-Limiting Toxicities (Immediately Reportable 
to the Sponsor) ....................................................................... 99 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 99 
5.3.1 
Adverse Event Reporting Period ........................................... 99 
5.3.2 
Eliciting Adverse Events ...................................................... 100 
5.3.3 
Assessment of Severity of Adverse Events ......................... 100 
5.3.4 
Assessment of Causality of Adverse Events ....................... 101 
5.4 
Procedures for Recording Adverse Events .......................... 102 
5.4.1 
Diagnosis versus Signs and Symptoms............................... 102 
5.4.2 
Adverse Events Occurring Secondary to Other 
Events ................................................................................. 103 
5.4.3 
Persistent or Recurrent Adverse Events .............................. 103 
5.4.4 
Abnormal Laboratory Values ............................................... 103 
5.4.5 
Abnormal Vital Sign Values ................................................. 104 
5.4.6 
Abnormal Liver Function Tests ............................................ 105 
5.4.7 
Deaths ................................................................................. 105 
5.4.8 
Preexisting Medical Conditions ............................................ 106 
5.4.9 
Lack of Efficacy or Worsening of Lymphoma ....................... 106 
5.4.10 
Hospitalization or Prolonged Hospitalization ........................ 106 


 
Polatuzumab Vedotin—Genentech, Inc. 
10/Protocol GO29044, Version 9 
5.4.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 107 
5.4.12 
Patient-Reported Outcome Data ......................................... 107 
5.5 
Immediate Reporting Requirements from 
Investigator to Sponsor ........................................................ 107 
5.5.1 
Emergency Medical Contacts .............................................. 108 
5.5.2 
Reporting Requirements for All Serious Adverse 
Events, Adverse Events of Special Interest, and 
Dose-Limiting Toxicities ...................................................... 108 
5.5.2.1 Events That Occur prior to Study Drug Initiation ................ 108 
5.5.2.2 Events That Occur after Study Drug Initiation .................... 109 
5.5.3 
Reporting Requirements for Pregnancies ............................ 109 
5.5.3.1 Pregnancies in Female Patients ......................................... 109 
5.5.3.2 Pregnancies in Female Partners of Male 
Patients .............................................................................. 109 
5.5.3.3 Abortions ............................................................................ 110 
5.5.3.4 Congenital Anomalies/Birth Defects and 
Abortions ........................................................................... 110 
5.6 
Follow-Up of Patients after Adverse Events ........................ 110 
5.6.1 
Investigator Follow-Up ......................................................... 110 
5.6.2 
Sponsor Follow-Up .............................................................. 110 
5.7 
Post-Study Adverse Events ................................................. 111 
5.8 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ............................................................... 111 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ..................... 112 
6.1 
Determination of Sample Size ............................................. 112 
6.2 
Summaries of Conduct of the Study .................................... 112 
6.3 
Safety Analyses ................................................................... 112 
6.4 
Pharmacokinetic Analyses ................................................... 113 
6.5 
Activity Analyses .................................................................. 113 
6.6 
Patient-Reported Outcome Analyses .................................. 114 
6.7 
Handling Rf Missing Data .................................................... 114 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 114 
7.1 
Data Quality Assurance ....................................................... 114 


 
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7.2 
Electronic Case Report Forms ............................................. 115 
7.3 
Electronic Patient-Reported Outcome Data ......................... 115 
7.4 
Source Data Documentation ................................................ 116 
7.5 
Use of Computerized Systems ............................................ 116 
7.6 
Retention of Records ........................................................... 116 
8. 
ETHICAL CONSIDERATIONS .................................................................. 117 
8.1 
Compliance with Laws and Regulations .............................. 117 
8.2 
Informed Consent ................................................................ 117 
8.3 
Institutional Review Board or Ethics Committee .................. 118 
8.4 
Confidentiality ...................................................................... 119 
8.5 
Financial Disclosure ............................................................ 119 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 119 
9.1 
Study Documentation .......................................................... 119 
9.2 
Protocol Deviations .............................................................. 119 
9.3 
Site Inspections ................................................................... 120 
9.4 
Administrative Structure....................................................... 120 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................. 120 
9.6 
Protocol Amendments ......................................................... 121 
10. REFERENCES ......................................................................................... 122 
 


 
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LIST OF TABLES 
Table 1 
GA101  CHOP for the Treatment of Lymphoma ....................... 34 
Table 2 
Administration of First and Subsequent Infusions of 
Rituximab .................................................................................... 56 
Table 3 
Administration of First and Subsequent Infusions of 
Obinutuzumab ............................................................................. 57 
Table 4 
Management of Infusion-Related Symptoms .............................. 89 
Table 5 
Dose Interruptions, Reductions, and Discontinuations of 
Polatuzumab Vedotin and R-CHP or G-CHP .............................. 91 
Table 6 
Guidelines for Dose Delay for Obinutuzumab on Cycle 1 Day 
8 and Cycle 1 Day 15 .................................................................. 96 
Table 7 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 101 
Table 8 
Causal Attribution Guidance ..................................................... 102 
 
 
LIST OF FIGURES 
Figure 1 
Nonclinical Data in WSU-DLCL2 ................................................. 33 
Figure 2 
Overview of Study Design ........................................................... 42 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments ......................................................... 126 
Appendix 2 
Modified Revised Response Criteria for Malignant 
Lymphoma ................................................................................ 131 
Appendix 3 
Modified Criteria for Response Assessment:  The Lugano 
Classification ............................................................................. 139 
Appendix 4 
R-CHP Plus Polatuzumab Vedotin Pharmacokinetic and 
Anti-Therapeutic Antibody Sampling Schedule ......................... 147 
Appendix 5 
G-CHP Plus Polatuzumab Vedotin Pharmacokinetic and 
Anti-Therapeutic Antibody Schedule ......................................... 153 
Appendix 6 
Recommendations for the Use of White Blood Cell Growth 
Factors ...................................................................................... 160 
Appendix 7 
Recommended Anaphylaxis Management ............................... 161 
Appendix 8 
International Prognostic Index for Non-Hodgkin’s Lymphoma .. 162 
Appendix 9 
Total Neuropathy Score Clinical Assessment ........................... 163 
Appendix 10 Therapy-Induced Neuropathy Assessment Scale (TINAS) ....... 164 


 
Polatuzumab Vedotin—Genentech, Inc. 
13/Protocol GO29044, Version 9 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE Ib/II STUDY EVALUATING THE SAFETY, 
TOLERABILITY AND ANTI-TUMOR ACTIVITY OF 
POLATUZUMAB VEDOTIN (DCDS4501A) IN 
COMBINATION WITH RITUXIMAB OR 
OBINUTUZUMAB, CYCLOPHOSPHAMIDE, 
DOXORUBICIN, AND PREDNISONE IN PATIENTS 
WITH B-CELL NON-HODGKIN’S LYMPHOMA 
PROTOCOL NUMBER: GO29044 
VERSION NUMBER: 
9 
EUDRACT NUMBER: 
2013-003541-42 
IND NUMBER: 
109409 
TEST PRODUCT: 
Polatuzumab Vedotin (DCDS4501A) 
MEDICAL MONITOR: 
, 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 retain the signed original of this form for your study files.  Please return a copy to 
the CRO Monitor at your site. 
 


 
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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE Ib/II STUDY EVALUATING THE SAFETY, 
TOLERABILITY AND ANTI-TUMOR ACTIVITY OF POLATUZUMAB 
VEDOTIN (DCDS4501A) IN COMBINATION WITH RITUXIMAB OR 
OBINUTUZUMAB, CYCLOPHOSPHAMIDE, DOXORUBICIN, AND 
PREDNISONE IN PATIENTS WITH B-CELL NON-HODGKIN’S 
LYMPHOMA 
PROTOCOL NUMBER: 
GO29044 
VERSION NUMBER: 
9 
EUDRACT NUMBER: 
2013-003541-42 
IND NUMBER: 
109409 
TEST PRODUCT: 
Polatuzumab Vedotin (DCDS4501A) 
PHASE: 
Ib/II 
INDICATION: 
B-Cell Non-Hodgkin’s Lymphoma 
SPONSOR: 
Genentech, Inc. 
 
OBJECTIVES 
Primary Objectives 
The primary objectives of this study are the following: 
x 
To assess the safety and tolerability of the combination of polatuzumab vedotin with 
rituximab in combination with cyclophosphamide, doxorubicin, and prednisolone or 
prednisone (R-CHP) or obinutuzumab in combination with cyclophosphamide, doxorubicin, 
and prednisolone or prednisone (G-CHP) administered to patients with B-cell non-Hodgkin’s 
lymphoma (NHL) 
x 
To determine the maximum tolerated dose (MTD) and schedule for polatuzumab vedotin 
given in combination with R-CHP or G-CHP to patients with B-cell NHL 
 
Secondary Objectives 
The secondary objectives of this study are the following: 
x 
To characterize the pharmacokinetics of polatuzumab vedotin, cyclophosphamide, 
doxorubicin, and rituximab or obinutuzumab in patients when polatuzumab vedotin is given 
in combination with R-CHP or G-CHP 
x 
To make a preliminary assessment of efficacy as measured by complete response (CR) 
rate determined by positron emission tomography (PET)-computed tomography (CT) scan 
of polatuzumab vedotin and R-CHP or G-CHP administered to patients with previously 
untreated diffuse large B-cell lymphoma (DLBCL) in the expansion phase of the study 
x 
To make a preliminary assessment of efficacy when polatuzumab vedotin and R-CHP or 
G-CHP are administered in combination to patients with previously untreated DLBCL, as 
measured by: 
Objective response (OR) rate 
CR rate as determined by CT scan 
Duration of response (DOR) 
Progression-free survival (PFS) 


 
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Event-free survival (EFS) 
Overall survival (OS) 
x 
To assess the immunogenicity of polatuzumab vedotin and obinutuzumab, as measured by 
the formation of anti-therapeutic antibodies (ATAs) 
x 
To assess the potential relationships of such ATA (anti-polatuzumab vedotin or anti-
obinutuzumab) formation with other outcome measures (e.g., pharmacokinetics, efficacy, 
safety) 
x 
To evaluate peripheral neuropathy symptom severity and interference on daily functioning 
and to better understand treatment impact, tolerability, and reversibility, as measured by the 
Therapy-Induced Neuropathy Assessment Scale (TINAS) 
 
Exploratory Objectives 
The exploratory objectives of this study are the following: 
x 
To assess the efficacy of therapy in different potential prognostic subgroups, including 
DLBCL genotypic subtypes (e.g., activated B cell–like, germinal-center B cell–like) and high 
Bcl-2 (Bcl-2positive) expression 
x 
To assess tumor expression of CD79b 
x 
To assess prevalence and the correlation of lymphoma associated mutations with outcome 
x 
To assess minimal residual disease as quantified by measurements of lymphoma-specific 
markers in peripheral blood 
x 
To evaluate the prognostic significance of interim PET assessment 
x 
Response, by Independent Review Committee (IRC), will be determined through use of the 
PET-CT scans based on a modified version of the Lugano Response Criteria for Malignant 
Lymphoma, hereinafter referred to as Modified Lugano 2014 criteria: 
To assess CR by PET at end of induction (EOI) by IRC  
To assess CR by CT at EOI by IRC 
To assess OR (defined as a CR or partial response [PR]) at EOI 
To assess best response of CR or PR during the study 
To evaluate patients who have positive PET scans at EOI:  CR at 12 months 
 
STUDY DESIGN 
This is a Phase Ib/II, multicenter, open-label, dose-escalation study of polatuzumab vedotin 
administered by intravenous (IV) infusion in combination with standard doses of rituximab or 
obinutuzumab, cyclophosphamide, doxorubicin, and oral prednisone in patients with NHL 
whose disease is expected to express CD79b.  Two parallel treatment arms will explore doses 
of polatuzumab vedotin in combination with R-CHP and G-CHP.  The MTD or RP2D of 
polatuzumab vedotin in combination with R-CHP will be identified before it is combined with 
G-CHP.  Once the MTD or RP2D is determined, polatuzumab vedotin will be dosed at MTD or 
RP2D -1 in combination with G-CHP to start the dose escalation of this combination.  Study 
treatment will be given in every-21-day cycles, with the first day of treatment constituting Day 1 
of the cycle.  Patients will be treated for a total of six or eight cycles in accordance with local 
institutional practice. 
Sites cannot enroll patients in rituximab-containing and obinutuzumab-containing phases 
simultaneously.  Sites do not need to have prior experience with the rituximab-containing 
combination before enrolling patients with the obinutuzumab combination. 
Patients will be evaluated for safety, tolerability, and pharmacokinetics of study treatment.  
Assessments for anti-tumor activity will be performed by the investigator using the Revised 
Response Criteria for Malignant Lymphoma at screening and at the following timepoints: 
x 
Interim response assessment following four cycles of study treatment (i.e., at Cycle 4, 
between Days 15 and 21) 
x 
Primary response assessment at the completion of study treatment 


 
Polatuzumab Vedotin—Genentech, Inc. 
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Patients with no evidence of OR (CR or PR) at the postCycle 4 tumor assessment may be 
discontinued from study treatment, at the discretion of the investigator. 
Imaging at these timepoints must include 18F-fluorodeoxyglucose (FDG)-PET and a diagnostic-
quality CT scan with both oral and IV contrast.  A combined PET-CT scan is encouraged if 
feasible.  An independent review of the responses of all patients will also be conducted to 
confirm the primary CR endpoint.  Patients will also be evaluated every 3 months thereafter until 
disease progression, death, withdrawal of consent, or initiation of another anti-cancer therapy.  
Tumor assessments should also be performed to confirm clinical suspicion of relapse or 
disease progression for documentation. 
Number of Patients 
The study will enroll approximately 2430 patients during the dose-escalation stage and 
approximately 60 patients in the expansion stage, at approximately 612 investigative sites in 
the United States and Europe. 
Target Population 
Inclusion Criteria 
Dose-Escalation Portion of the Study 
x 
Histologically confirmed B-cell NHL:  Patients with newly diagnosed B-cell NHL or 
relapsed/refractory B-cell NHL are eligible. 
Note that patients in France with newly diagnosed B-cell NHL are not eligible. 
x 
No more than one prior systemic treatment regimen for B-cell NHL (single agent 
anti-CD20 MAb therapy will not be counted as a prior treatment regimen) 
x 
No prior treatment with anthracyclines 
 
Expansion Portion of the Study 
x 
Previously untreated patients with DLBCL 
x 
International Prognostic Index score of 25 
 
All Patients 
x 
Age  t  18 years  
x 
Signed informed consent form(s) 
x 
At least one bi-dimensionally measurable lesion, defined as ! 1.5 cm in its longest 
dimension  
x 
Ability and willingness to comply with the study protocol procedures 
x 
Confirmed availability of archival or freshly collected tumor tissue before study enrollment 
x 
Life expectancy of at least 24 weeks   
x 
Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2 
x 
Adequate hematologic function (unless inadequate function is due to underlying disease, as 
established by extensive bone marrow involvement or is due to hypersplenism secondary 
to the involvement of the spleen by lymphoma per the investigator) defined as follows: 
Hemoglobin t  9 g/dL 
ANC t  1.5 u 109/L 
Platelet count t 75 u 109/L 
x 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of  1% 
per year during the treatment period and for at least 12 months for R-CHP arm or 
t 18 months for the G-CHP arm after the last dose of study drug.  


 
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A woman is considered to be of childbearing potential if she is post-menarcheal, has 
not reached a postmenopausal state (t 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal 
are not acceptable methods of contraception. 
x 
For women of childbearing potential, a negative serum pregnancy test result within 7 days 
prior to commencement of dosing.  Women who are considered not to be of childbearing 
potential are not required to have a pregnancy test. 
x 
For men, agreement to remain abstinent (refrain from heterosexual intercourse) or to use a 
condom plus an additional contraceptive method that together result in a failure rate of   1% 
per year during the treatment period and for at least 5 months after the last dose of study 
drug and agreement to refrain from donating sperm during this same period. 
Men with a pregnant partner must agree to remain abstinent or to use a condom during 
the treatment period and for at least 6 months after the last dose of study drug to avoid 
exposing the embryo for the duration of the pregnancy. 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not acceptable methods of contraception. 
Male patients considering preservation of fertility should bank sperm before treatment 
with polatuzumab vedotin. 
 
Exclusion Criteria 
Exclusion Criteria for Dose-Escalation Portion of the Study 
x 
Diagnosis of primary mediastinal DLBCL 
 
Exclusion Criteria for Expansion Portion of the Study 
x 
Patients with transformed lymphoma 
x 
Prior therapy for NHL 
 
All Patients 
x 
Prior stem cell transplant 
x 
History of severe allergic or anaphylactic reactions to humanized or murine monoclonal 
antibodies or known sensitivity or allergy to murine products 
x 
Contraindication to receive any of the individual components of R-CHP or G-CHP   
x 
Current Grade ! 1 peripheral neuropathy 
x 
Ongoing corticosteroid use of ! 30 mg/day of prednisone/prednisolone or equivalent.  
Patients receiving corticosteroid treatment with d 30 mg/day of prednisone//prednisolone or 
equivalent must be documented to be on a stable dose of at least 4 weeks’ duration before 
Cycle 1 Day 1 
Note:  If corticosteroid treatment is urgently required for lymphoma symptom control 
prior to the start of study treatment, up to 100 mg/day prednisone or equivalent can be 
given for a maximum of 7 days, but all tumor assessments must be completed prior to 
start of corticosteroid treatment. 
x 
Primary CNS lymphoma 
x 
Vaccination with live vaccines within 6 months before Cycle 1 Day 1 


 
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x 
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 or 
melanoma of the skin or in situ carcinoma of the cervix are eligible. 
Patients with a malignancy that has been treated with surgery alone with curative 
intent will also be excluded unless the malignancy has been in documented remission 
without treatment for t 5 years before enrollment. 
x 
Evidence of significant, uncontrolled concomitant diseases that could affect compliance with 
the protocol or interpretation of results or that could increase risk to the patient, including 
renal disease that would preclude chemotherapy administration, or pulmonary disease 
(including obstructive pulmonary disease and history of bronchospasm) 
x 
Significant cardiovascular disease (such as New York Heart Association Class III or IV 
cardiac disease, congestive heart failure, myocardial infarction within the previous 6 months, 
unstable arrhythmias, or unstable angina) or significant pulmonary disease 
(including obstructive pulmonary disease and history of bronchospasm) 
x 
Left ventricular ejection fraction defined by multiple-gated acquisition 
(MUGA)/echocardiogram (ECHO) below the institutional lower limit of normal 
x 
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 before Cycle 1 Day 1 
x 
Clinically significant history of liver disease, including viral or other hepatitis, current alcohol 
abuse, or cirrhosis 
x 
Presence of positive test results for hepatitis B (hepatitis B surface antigen and/or total 
hepatitis B core antibody) or hepatitis C (hepatitis C virus [HCV] antibody) 
Patients who are positive for HCV antibody must be negative for HCV by polymerase 
chain reaction to be eligible for study participation. 
x 
Prior radiotherapy to the mediastinal/pericardial region 
x 
Women who are pregnant, lactating, or who intend to become pregnant within a year after 
the last dose of study treatment in the rituximab cohort or within 18 months after the last 
dose of study treatment in the obinutuzumab cohort 
x 
Recent major surgery within 6 weeks before the start of Cycle 1 Day 1, other than 
superficial lymph node biopsies for diagnosis. 
x 
Any of the following abnormal laboratory values: 
Creatinine ! 1.5 u upper limit of normal (ULN) or a measured creatinine clearance 
 50 mL/min   
AST or ALT ! 2.5 u ULN 
Total bilirubin t 1.5 u ULN:  
INR ! 1.5 u ULN in the absence of therapeutic anticoagulation 
PTT or aPTT ! 1.5 u ULN in the absence of a lupus anticoagulant 
 
End of Study 
The end of the study is defined as the time point at which all patients enrolled into the study 
have either had at least 2 years of follow-up from the time of the Treatment Completion/Early 
Termination visit or have discontinued from the study.  The Sponsor has the right to terminate 
the study at any time. 
 
OUTCOME MEASURES 
Safety Outcome Measures 
The following safety outcome measures will be assessed: 
x 
Incidence, nature, and severity of adverse events and serious adverse events 


 
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x 
Changes in vital signs, physical findings, ECGs, and clinical laboratory results during and 
following study treatment administration 
x 
Incidence of anti-polatuzumab vedotin antibodies and anti-obinutuzumab antibodies 
 
Pharmacokinetic/Pharmacodynamic Outcome Measures 
The following pharmacokinetic (PK) parameters will be derived from the serum 
concentrationtime profiles of total antibody (the sum of fully conjugated antibody, partially 
deconjugated antibody, and fully deconjugated antibody concentrations), plasma 
concentrationtime profiles of conjugate (evaluated as antibody-conjugated mono-methyl 
auristatin E [acMMAE]) and unconjugated mono-methyl auristatin E (MMAE), following 
administration of polatuzumab vedotin, when appropriate as data allow. 
x 
Total exposure (area under the concentration-time curve [AUC]) 
x 
Maximum plasma and serum concentration observed (Cmax) 
x 
Total clearance of drug (CL) 
x 
Terminal half-life (t1/2,terminal) 
x 
Volume of distribution under steady-state conditions (Vss) 
 
Compartmental, non-compartmental, and/or population methods may be used.  Other 
parameters, such as accumulation ratio and minimum concentration under steady-state 
conditions within a dosing interval (Cmin), may also be calculated, when appropriate as data 
allow. 
Limited sampling of serum concentrations of rituximab/obinutuzumab will be assessed and 
compared with historical data to evaluate potential PK interactions with polatuzumab vedotin.  
Plasma levels of cyclophosphamide and doxorubicin will be assessed and compared at the 
same timepoints of Cycle 1 (in the absence of polatuzumab vedotin) and Cycle 3 (in the 
presence of polatuzumab vedotin), and compared with historical data to evaluate potential PK 
interactions with polatuzumab vedotin.   
Activity Outcome Measures 
Response assessment will be determined using the modified version of the Revised Response 
Criteria for Malignant Lymphoma (Cheson et al. 2007) and the modified version of the Lugano 
Response Criteria (Cheson et al. 2014). 
The following activity outcome measures will be assessed: 
x 
CR rate as defined as the percentage of patients with CR at the end of treatment, as 
assessed by the investigator, with and without FDG-PET. 
x 
OR at the end of treatment, as assessed by the investigator, with and without FDG-PET.  
The overall response rate is defined as the percentage of patients with CR or PR at the end 
of treatment.  All other cases are designated non-responders. 
x 
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 (PFS), as assessed by 
the investigator for the subgroup of patients with a best overall response of CR or PR.  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.  
x 
PFS, defined as the time from date of first dose of study drug to the first occurrence 
of progression or relapse, or death from any cause while in the study 
x 
EFS is defined as the time from randomization to disease progression or relapse, as 
assessed by the investigator, death from any cause, or initiation of any new anti-lymphoma 
therapy (NALT).  If the specified event (disease progression or relapse, death, initiation of 
an NALT does not occur, EFS will be censored at the date of last tumor assessment. For 
patients without an event who have not had post-baseline tumor assessments, EFS will be 
censored at the time of randomization. 
x 
Relative dose intensity (DI) is defined as the ratio of the amount of a drug actually 
administered (actual DI) to the amount planned (planned DI) for a fixed time period 


 
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x 
OS, defined as the time from the date of randomization to the date of death from any cause. 
Immunogenicity Outcome Measures 
ATA responses to polatuzumab vedotin and obinutuzumab will be characterized at 
predetermined timepoints. 
Patient-Reported Outcome Measures 
The patient-reported outcome (PRO) measures for this study are as follows: 
x 
PRO of peripheral neuropathy symptom severity and symptom interference, as measured 
by the TINAS. 
 
Biomarker Outcome Measures 
x 
Gene expression profiles in tumor relating to:  
DLBCL prognostic subgroups 
Target (CD79b) biology 
Expression of apoptotic regulators (including but not limited to Bcl-2) 
Drug efflux transporters and other potential mediators of antibody-drug conjugate 
resistance 
x 
Tumor immunohistochemistry of target (CD79b) expression and apoptotic regulators 
(including but not limited to Bcl-2) 
 
INVESTIGATIONAL MEDICINAL PRODUCTS 
Patients will receive treatment with one of two immunochemotherapy regimens in combination 
with polatuzumab vedotin: 
R-CHP:  rituximab plus CHP chemotherapy 
G-CHP:  obinutuzumab plus CHP chemotherapy  
 
Patients will receive a total of six to eight cycles of polatuzumab vedotin in combination with 
R-CHP or G-CHP.  A cycle is typically 21 days in duration. 
See the protocol for details on dosage and administration of each product. 
CONCOMITANT THERAPIES 
Permitted Therapy 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by a patient from 7 days before 
screening to the study completion/discontinuation visit.  All such medications should be reported 
to the investigator and recorded on the Concomitant Medications electronic Case Report Form. 
Patients who are receiving oral contraceptives, stable doses of hormone-replacement therapy, 
or other maintenance therapy should continue their use. 
Other than prednisone/prednisolone that may be given as pre-phase treatment at the discretion 
of the treating investigator physician, corticosteroids may be used only for the treatment of 
conditions other than lymphoma (e.g., asthma). 
The use of any calcium channel entry blockers given concomitantly with an anthracycline drug 
may potentially increase the risk of cardiac toxicity associated with anthracycline administration.  
It is recommended that calcium channel blockers be avoided within 30 days of the 
administration of an anthracycline drug when possible and clinically appropriate.  
See the protocol for guidelines on prophylaxis. 
Prohibited Therapy 
Treatment with other concomitant anti-tumor agents not defined in this protocol as study 
treatment, radiotherapy, or other concurrent investigational agents of any type will result in 
withdrawal of patients from study treatment; however, patients will be followed. 
Use of the following therapies is prohibited during the study: 


 
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x 
Cytotoxic chemotherapy other than cyclophosphamide, doxorubicin, and prednisolone or 
prednisone and intrathecal chemotherapy for CNS prophylaxis 
x 
Immunotherapy or immunosuppressive therapy other than study treatments 
x 
Radioimmunotherapy 
x 
Hormone therapy other than contraceptives, hormone-replacement therapy, or megestrol 
acetate 
x 
Biologic agents other than hematopoietic growth factors, which are allowed if clinically 
indicated and used in accordance with instructions provided in the package inserts 
x 
Any therapies (other than intrathecal CNS prophylaxis) intended for the treatment of 
lymphoma whether European Medicines Agencies or U.S. Food and Drug Administration 
approved or experimental 
x 
Radiotherapy 
Immunizations 
Patients who participate in this study may not receive either primary or booster vaccination with 
live virus vaccines for at least 6 months before initiation of rituximab or 28 days prior to 
obinutuzumab 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 before study therapy. 
Patients who require the use of any of these agents will be discontinued from study treatment. 
 
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, changes in ECGs, ECHO/MUGA 
scans, and changes in vital signs.  All patients who receive any amount of any drug that was 
part of the combination study treatment will be included in the safety analysis.  
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 study treatment 
administration on Day 1 of Cycle 1 will be summarized by mapped terms, appropriate thesaurus 
levels, and toxicity grade per National Cancer Institute Common Terminology Criteria for 
Adverse Events Version 4.0.  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 polatuzumab vedotin will be summarized. 
Pharmacokinetic Analysis 
Selected laboratory data will be listed, with values outside of normal ranges identified.  The 
incidence of antibodies to polatuzumab vedotin will be summarized. 
Individual and mean serum concentrations of total polatuzumab vedotin antibody (fully 
conjugated, partially deconjugated and fully deconjugated antibody) and rituximab and plasma 
concentrations of polatuzumab vedotin conjugate (evaluated as acMMAE), unconjugated 
MMAE, cyclophosphamide, and doxorubicin versus time data will be tabulated and plotted.  The 
pharmacokinetics of the above analytes will be summarized by estimating the appropriate PK 
parameters (e.g., AUC, Cmax, CL, Vss, and t1/2,terminal), as data allow.  Estimates for these 
parameters will be tabulated and summarized (mean, standard deviation, and range), as data 
allow.  Non-compartmental, compartmental and/or population methods will be used, as data 
allow. 
To assess PK drug interactions, PK parameters for each analyte of polatuzumab vedotin, 
rituximab, and obinutuzumab will be compared with historical single-agent data, as data allow.  
PK data of cyclophosphamide, and doxorubicin will be compared between Cycle 1 (in the 
absence of polatuzumab vedotin) and Cycle 3 (in the presence of polatuzumab vedotin), and 
compared to historical data, as data allow. 


 
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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, per the Sponsor’s discretion and as data allow. 
In addition, population PK methods may be employed to manage sparse data and to investigate 
the effects of certain covariates on the pharmacokinetics of polatuzumab vedotin, as data allow 
and at the Sponsor’s discretion. 
Activity Analyses 
OR is defined as a CR or PR, as determined by investigator assessment with use of standard 
criteria.  OR rate will be summarized.  Patients with missing or no response assessments will be 
classified as non-responders.  Among patients with an OR, DOR will be defined as the time 
from documentation of the first CR or PR to the time of disease progression, relapse, or death 
from any cause, as assessed by the investigator.  If a patient does not experience death or 
disease progression before the end of the study, DOR will be censored on the day of the 
last tumor assessment.  OS is defined as the period from the date of randomization until the 
date of death from any cause.  For patients who have not died at the time of the analyses, OS 
will be censored on the last date when the patients are known to be alive.   
PFS is defined as the time from the first day of study treatment (Day 1) to disease progression, 
relapse, or death from any cause, as assessed by the investigator.  If a patient has not 
experienced progressive disease or death, PFS will be censored on the day of the last tumor 
assessment.  If a post-baseline assessment is not available, PFS will be censored on Day 1.   
The Kaplan-Meier approach will be used to estimate the distribution of DOR, PFS, and OS in all 
patients.  Results will also be summarized separately among those patients in the dose-
escalation part of the study and among those patients in the dose-expansion part of the study. 
Patient-Reported Outcome Analyses 
The TINAS will be scored using a corresponding user manual.  Summary statistics of the TINAS 
total and individual items with their changes from baseline will be calculated at each 
assessment timepoint. 
Missing Data 
For PFS, patients who do not have documented disease progression or have died will be 
treated as censored observations on the date of the last tumor assessment.  If no tumor 
assessments were performed after the baseline visit, PFS will be censored at the time of 
randomization. 
For the response endpoints, patients with no response assessments (for any reason) will be 
considered non-responders. 
Determination of Sample Size 
The sample size required estimating the MTD is based on the dose-escalation rules.  In addition, 
approximately 17 and 40 patients will be enrolled into expansion cohorts G-CHP and R-CHP 
respectively, in combination with the MTD of polatuzumab vedotin identified during dose 
escalation.  With 40 patients, the 95% exact Clopper-Pearson CIs for the true CR rate would 
have a margin of error not exceeding 17%.  The planned enrollment for this study is 
approximately 2430 patients for dose-escalation cohorts and 60 patients for expansion cohorts 
for a total planned enrollment of 84–90 patients. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ABC 
activated B cell-like (subgroup) 
acMMAE 
antibody-conjugated mono-methyl auristatin E 
ADC 
antibody-drug conjugate 
ADR 
adverse drug reaction 
ATA 
anti-therapeutic antibody 
AUC 
area under the concentration-time curve 
AUCinf 
area under the concentration-time curve from Time 0 to infinity 
BSA 
body surface area 
CHOP 
cyclophosphamide, doxorubicin, vincristine, and prednisolone or 
prednisone 
CHP 
cyclophosphamide, doxorubicin, and prednisolone or prednisone 
CL 
total clearance of drug 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum plasma and serum concentration observed 
Cmin 
minimum concentration under steady-state conditions within a dosing 
interval 
CR 
complete response 
CRO 
contract research organization 
CT 
computed tomography 
DI 
dose intensity 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EC 
Ethics Committee 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EFS 
event-free survival 
EOI 
end of induction 
ePRO 
electronic patient-reported outcome 
FDA 
U.S. Food and Drug Administration 
FDG 
18F-fluorodeoxyglucose 
FL 
follicular lymphoma 
GCB 
germinal-center B cell–like (subgroup) 
GCP 
Good Clinical Practice 


 
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Abbreviation 
Definition 
G-CHP 
Obinutuzumab in combination with cyclophosphamide, doxorubicin, and 
prednisolone or prednisone 
G-CSF 
granulocyte colony-stimulating factor 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
ICH 
International Council for Harmonisation 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
iNHL 
indolent non-Hodgkin’s lymphoma 
IPI 
International Prognostic Index 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRR 
infusion-related reaction 
IV 
intravenous 
IXRS 
Interactive Voice and Web Response System 
LC/MS/MS 
liquid chromatography tandem mass spectrometry 
MAb 
monoclonal antibody 
MMAE 
mono-methyl auristatin E 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition 
NALT 
new anti-lymphoma therapy 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NHL 
non-Hodgkin’s lymphoma 
OR 
objective response 
OS 
overall survival 
PCR 
polymerase chain reaction 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PO 
by mouth (orally) 
PR 
partial response 


 
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Abbreviation 
Definition 
PRO 
patient-reported outcome 
R-CHOP 
rituximab in combination with cyclophosphamide, doxorubicin, vincristine, 
and prednisolone or prednisone 
R-CHP 
rituximab in combination with cyclophosphamide, doxorubicin, and 
prednisolone or prednisone 
RP2D 
recommended Phase II dose 
t1/2,terminal 
terminal half-life 
TINAS 
Therapy-Induced Neuropathy Assessment Scale 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
Vss 
volume of distribution under steady-state conditions 


 
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1. 
BACKGROUND 
1.1 
NON-HODGKIN’S LYMPHOMA 
Non-Hodgkin’s lymphoma (NHL) is the most common hematologic malignancy in adults.  
It is estimated that in 2010 there were 93,172 new cases of NHL in Europe and 
65,540 new cases of NHL in the United States (American Cancer Society 2010; 
GLOBOCAN 2010).  The majority of NHL is of B-cell origin with multiple histologic 
subtypes that confer different clinical outcomes.  Generally, NHL can be divided into 
aggressive and indolent lymphomas.  Diffuse large B-cell lymphoma (DLBCL) is the 
most common aggressive NHL, accounting for approximately 30% of all cases of NHL 
(Armitage and Weisenburger 1998).  Follicular lymphoma (FL) is the most common form 
of indolent NHL (iNHL) and accounts for approximately 20%25% of all cases of newly 
diagnosed NHL.  If left untreated, patients with aggressive lymphomas have a median 
survival of approximately 6 months, whereas patients with indolent lymphomas may live 
as long as 810 years. 
Standard-of-care therapies for NHL involve multi-agent chemotherapy with non-cross 
resistant mechanisms of action combined with immunotherapy.  In DLBCL, the addition 
of the CD20-directed monoclonal antibody (MAb) rituximab to CHOP (cyclophosphamide, 
doxorubicin, vincristine, and prednisolone or prednisone)-based chemotherapy results in 
significantly improved survival, as demonstrated by three randomized prospective 
studies, comprising a total of approximately 2000 patients with newly diagnosed 
advanced DLBCL (Coiffier et al. 2002; Pfreundschuh et al. 2006, 2008).  On the basis of 
the above studies, up to 8 cycles of rituximab combined with 6 or 8 cycles of CHOP 
or CHOP-like chemotherapy (R-CHOP) is considered to be the standard of care 
for patients with previously untreated DLBCL (Tilly et al. 2012; 
National Comprehensive Cancer Network£ 2013), with approximately 60%70% of 
patients being cured of their disease.  In addition to newly diagnosed and 
relapsed/refractory DLBCL, R-CHOP is also used in other NHL indications, including 
relapsed FL and mantle-cell lymphoma (Hauptrock and Hess 2008).  
Clinical factors at the time of initial diagnosis of NHL have been identified that influence 
the prognosis of patients with initial therapy.  In DLBCL, an International Prognostic 
Index (IPI) for aggressive NHL (i.e., DLBCL) identified risk factors based on performance 
status and extent of disease that are prognostic of response to therapy and overall 
survival (OS).  Patients with a higher number of risk factors have lower rates of complete 
response (CR) to therapy, as well as lower rates of 5-year survival (Ziepert et al. 2010). 
Despite improvements in clinical outcomes of patients with NHL due to advances in 
treatments such as rituximab, indolent B-cell malignancies remain incurable, as do 
approximately half of aggressive NHLs, especially those with intermediate/high IPI.  
Thus, there is still a need for treatments that can significantly extend disease-free 
survival and OS in these patients, with at least acceptable, if not superior, safety and 
tolerability profiles. 


 
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1.2 
BACKGROUND ON POLATUZUMAB VEDOTIN 
1.2.1 
Background on Nonclinical 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 chronic lymphocytic leukemia (CLL) samples tested 
(Dornan et al. 2009).  Antibodies bound to CD79b are rapidly internalized, which makes 
CD79b ideally suited for targeted delivery of cytotoxic agents (Polson et al. 2007, 2009). 
Polatuzumab vedotin (DCDS4501A) is an antibody-drug conjugate (ADC) that contains a 
humanized immunoglobulin-G1 (IgG1) antihuman CD79b MAb (MCDS4409A) and a 
potent anti-mitotic agent, mono-methyl auristatin E (MMAE), linked through a 
protease-labile linker, maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl 
(MC-VC-PABC).  MMAE has a mode of action similar to that of vincristine, which is 
a component of standard chemotherapy, R-CHOP, used for treatment of lymphoma.  
Following internalization, MMAE is released following cleavage of the linker by 
lysosomal enzymes.  MMAE then binds to tubulin and disrupts the microtubule network, 
resulting in inhibition of cell division and cell growth (Doronina et al. 2003).  
This therapeutic approach takes advantage of the specific targeting capability of the 
antibody and the cytotoxic activity of MMAE and the increased potency of MMAE 
compared to vincristine.  Given that vincristine is commonly used in the treatment of 
NHL, it is hypothesized that the replacement of vincristine with polatuzumab vedotin in 
an anti-CD20 antibody  chemotherapy regimen will provide better efficacy and safety to 
patients with NHL. 
Comprehensive pharmacologic, pharmacokinetic (PK), pharmacodynamic, 
and toxicological studies were done to support the entry of polatuzumab vedotin into 
clinical trials.  Because polatuzumab vedotin specifically recognizes CD79b on B cells of 
human but not on those of the cynomolgus monkey, rat, or mouse, a surrogate ADC 
(DCDS5017A) that binds to cynomolgus monkey CD79b was generated to assess the 
antigen-dependent activities in cynomolgus monkeys.  The structure, binding epitope, 
and binding affinity of the surrogate ADC are similar to that of polatuzumab vedotin.  
Polatuzumab vedotin has demonstrated efficacy in nonclinical mouse xenograft models 
of human CD79b-positive NHL.  Additionally, polatuzumab vedotin when combined with 
R-CHP (rituximab in combination with cyclophosphamide, doxorubicin, and prednisolone 
or prednisone) demonstrated better anti-tumor activity compared with polatuzumab 
vedotin as single agent or compared with a current standard-of-care regimen (R-CHOP) 
in xenograft models of NHL.  The pharmacokinetics and safety of polatuzumab vedotin 
and/or the surrogate ADC was characterized in repeat-dose toxicity studies in rats and 
cynomolgus monkeys.  Polatuzumab vedotin and the surrogate ADC were well tolerated 
in both species at the tested doses.  The predominant antigen-independent findings 
associated with polatuzumab vedotin or surrogate ADC exposure were reversible bone 
marrow toxicity and associated peripheral blood cell effects in both monkeys and rats.  
The PK profiles of polatuzumab vedotin and the surrogate ADC suggested that the 


 
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pharmacokinetics of the ADC was driven mainly by the antibody component (similar 
serum concentrationtime profile between ADC and total MAb). 
Refer to the Investigator’s Brochure for complete details of the biochemical composition 
and nonclinical studies of polatuzumab vedotin. 
1.2.2 
Polatuzumab Vedotin Clinical Data 
On the basis of nonclinical data, polatuzumab vedotin is currently being evaluated in 
Phase I and Phase II studies in relapsed/refractory NHL.  Complete and updated details 
of this data are provided in the Polatuzumab Vedotin Investigator’s Brochure. 
Study DCS4968g is a Phase I study to evaluate the safety and tolerability and anti-tumor 
activity of polatuzumab vedotin and to determine the maximum tolerated dose 
(MTD)/recommended Phase II dose (RP2D) as a single agent and in combination with 
rituximab in relapsed/refractory NHL.  Study GO27834 is a randomized study to evaluate 
the safety and anti-tumor activity of polatuzumab vedotin in combination with rituximab in 
patients with relapsed/refractory DLBCL and FL.  A second vc-MMAE ADC targeting 
CD22 (DCDT2980S) combined with rituximab is also being evaluated in this study.  
Patients are randomized to receive either polatuzumab vedotin or DCDT2980S in 
combination with rituximab. 
1.2.2.1 
Patient Enrollment 
A total of 95 patients have been enrolled into the Phase I study (Study DCS4968g), of 
whom 32 patients with NHL (iNHL or DLBCL) were enrolled in single-agent dose 
escalation, 11 were enrolled in iNHL single-agent expansion cohort, 23 were enrolled in 
the DLBCL single-agent expansion cohort, and 9 patients were enrolled in the Phase Ib 
polatuzumab vedotin  rituximab combination treatment cohort.  Enrollment into the study 
of patients with NHL has been completed. 
Twenty patients with CLL were enrolled into single-agent dose-escalation cohorts of 
Study DCS4968g.  Refer to the Polatuzumab Vedotin Investigator’s Brochure for details 
regarding clinical data in patients with CLL. 
As of 28 February 2013, preliminary safety data were available for all 95 patients 
enrolled in the dose-escalation and expansion cohorts. 
1.2.2.2 
Safety 
Dose-Limiting Toxicities in NHL 
In the Phase I Study DCS4968g, a dose-limiting toxicity (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 polatuzumab vedotin ! 2.4 mg/kg as monotherapy or in combination with 
rituximab were not assessed.  Consequently, polatuzumab vedotin at 2.4 mg/kg was 
determined to be the RP2D as both monotherapy and in combination with rituximab. 


 
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Treatment Discontinuations for Adverse Events 
In Study DCS4968g as of 28 February 2013 (the clinical data cutoff date), study 
treatment discontinuation because of adverse events not due to the disease under study 
was reported in 19 of 95 patients (20.0%), with study treatmentrelated adverse events 
leading to treatment discontinuation in 17 of 95 patients (17.9%).  The treatment-related 
events included Grade 2 peripheral neuropathy (9 patients), Grade 3 peripheral 
neuropathy (3 patients), Grade 4 peripheral neuropathy (1 patient), Grade 3 diarrhea 
(1 patient), and Grade 2 hyperesthesia, Grade 2 asthenia, Grade 3 anemia, and 
Grade 4 thrombocytopenia (all four events occurring in 1 patient).  Two adverse events 
resulting in treatment discontinuation were reported as not related to study treatment:  
Grade 3 worsening hyponatremia (1 patient) and Grade 4 invasive fungal infection 
(1 patient). 
Adverse events that led to study treatment discontinuation and that were not due to the 
disease under study were reported in 5 patients with DLBCL:  Grade 2 peripheral 
neuropathy (3 patients), Grade 3 peripheral neuropathy (1 patient), and 
Grade 3 diarrhea (1 patient).  The only adverse event that led to treatment 
discontinuation and that was not due to the disease under study among the patients with 
CLL was Grade 4 invasive fungal infection (1 patient).  All remaining events occurred in 
patients with iNHL, including a single event (Grade 2 peripheral neuropathy) reported 
among the 9 patients treated with the combination of polatuzumab vedotin  rituximab. 
In Phase II Study GO27834, as of the clinical data cutoff (28 February 2013), treatment 
discontinuation due to adverse events had not been reported for any patient. 
Adverse Events with Single-Agent Polatuzumab Vedotin 
Adverse events regardless of relationship to study drug were reported in 66 of 
66 patients (100%) with NHL (iNHL  DLBCL) who were treated with polatuzumab 
vedotin as a single agent.  Treatment-emergent adverse events in ! 20% of patients 
included neutropenia (44%), diarrhea (38%), pyrexia (32%), nausea (32%), neuropathy 
peripheral (30%), fatigue (23%), and cough (21%). 
Grade t 3 adverse events regardless of relationship to study drug were reported in 48 of 
66 patients (72.7%) with NHL (iNHL or DLBCL).  Neutropenia was the most common 
adverse event experienced by more than 35% of the 66 NHL patients.  Thirty-one of 
45 patients (68.8%) treated at the RP2D of 2.4 mg/kg experienced a Grade 35 adverse 
event.  Grade 3-4 adverse event of neutropenia were experience by more than 10% of 
the patients.  Three Grade 5 events were reported:  1 patient died of sepsis, 1 patient 
died of pulmonary vascular disorder, and 1 patient died of unknown cause.  None of the 
deaths was assessed by the investigator to be related to study treatment. 
Adverse Events with Polatuzumab Vedotin Combined with Rituximab 
In the Phase Ib cohort of Study DCS4968g, adverse events regardless of relationship 
to study drug were reported in 9 of 9 patients (100%) who received polatuzumab vedotin 


 
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(2.4 mg/kg) plus rituximab (375 mg/m²).  The most common adverse events that 
occurred in t 2 patients were neutropenia, pyrexia, nausea, diarrhea, hyperuricemia, 
bone pain, fatigue, peripheral neuropathy, decreased appetite, chills, pain in extremity, 
pruritus, arthralgia, night sweats, hypokalemia, dysgeusia, increased blood creatinine, 
infusion-related reactions (IRRs), cough, constipation, thrombocytopenia, anemia, 
hyperglycemia, rash, alopecia, hypomagnesemia, upper abdominal pain, hyperhidrosis, 
myalgia, peripheral motor neuropathy, febrile neutropenia, hyperbilirubinemia, and tooth 
fracture. 
Grade t 3 adverse events regardless of relationship to study drug were reported in 
7 of 9 patients (77.8%) receiving polatuzumab vedotin in combination with rituximab in 
the Phase Ib cohort of Study DCS4968g.  Grade 34 neutropenia was reported in 
5 patients, Grade 34 anemia in 2 patients, Grade 34 febrile neutropenia in 2 patients, 
and Grade 34 hyperglycemia in 2 patients.  No Grade 5 adverse events were reported.   
In the ongoing Phase II Study GO27834, adverse events regardless of relationship to 
study drug were reported in 15 of 15 patients (100%) who received polatuzumab vedotin 
(2.4 mg/kg) plus rituximab (375 mg/m²).  The most common adverse events of all grades 
in t 2 patients were fatigue, nausea, diarrhea, neutropenia, vomiting, dry mouth, 
asthenia, arthralgia, back pain, and headache. 
In the Phase II study, Grade t 3 adverse events regardless of relationship to study drug 
were reported in 4 of 15 patients (26.7%) receiving polatuzumab vedotin in combination 
with rituximab.  Grade 34 neutropenia was reported in 2 patients, Grade 3 diarrhea in 
1 patient, Grade 3 chest pain in 1 patient, Grade 3 decreased neutrophil count in 
1 patient, and Grade 3 hypophosphatemia in 1 patient. 
Serious Adverse Events 
From ongoing Phase I Study DCS4968g, a total of 44 serious adverse events were 
reported among 22 patients in the single-agent NHL (iNHL  DLBCL) cohorts, 19 serious 
adverse events in 11 patients in the CLL cohort, and 15 serious adverse events in 
4 patients treated with polatuzumab vedotin  rituximab.  Among all patients, the most 
common serious adverse events (occurring in t 2% of patients) were Grades 12 pyrexia 
(6 patients), Grade 34 febrile neutropenia (4 patients), Grade 45 lung infection 
(3 patients), Grade 34 diarrhea (3 patients), Grade 34 hyperglycemia (2 patients), 
Grade 34 hyponatremia (2 patients), Grade 23 mental status changes (2 patients), 
Grade 34 peripheral neuropathy (2 patients), Grade 34 neutropenia (2 patients), 
Grade 45 pneumonia (2 patients), and acute renal failure (Grade 1 in 1 patient and 
Grade 4 in 1 patient). 
In the Phase II Study GO27834, a total of 2 serious adverse events were reported in 
2 patients treated with polatuzumab vedotin  rituximab:  Grade 2 pyrexia and 
Grade 2 chest tightness.  Both serious adverse events were reported as not related to 
study drug treatment. 


 
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Refer to the Polatuzumab Vedotin Investigator’s Brochure for complete and updated 
details related to safety. 
Anti-Tumor Activity 
In ongoing Phase I Study DCS4968g, preliminary anti-tumor activity data for best overall 
response were available for 88 of 95 patients (92.6%) as of the clinical data cutoff date. 
86 of the 88 patients had relapsed/refractory iNHL, DLBCL, or CLL.  Data regarding 
duration of response (DOR), progression-free survival (PFS), and OS were insufficiently 
mature for reporting.  Most evidence of anti-tumor activity was observed at ADC doses 
t 1.8 mg/kg.  Among patients with relapsed/refractory iNHL, 13 of 22 (59%) patients 
treated with single-agent polatuzumab vedotin and 6 of 8 (75%) patients treated with 
polatuzumab vedotin  rituximab had an investigator-assessed objective response (OR).  
Among patients with relapsed/refractory DLBCL, 14 of 26 (54%) patients treated with 
single-agent polatuzumab vedotin and 1 of 1 patient treated with polatuzumab 
vedotin  rituximab had an investigator-assessed OR. 
In the Phase II Study GO27834, anti-tumor activity data were not sufficiently mature to 
report as of the clinical data cutoff date, because most patients had not yet undergone 
on-treatment tumor assessments to evaluate response. 
1.2.3 
Pharmacokinetic and Pharmacodynamic Properties of 
Polatuzumab Vedotin 
The PK properties of polatuzumab vedotin conjugate (evaluated as antibody-conjugated 
mono-methyl auristatin E [acMMAE]), total antibody, and unconjugated MMAE after the 
first dose of polatuzumab vedotin in patients with NHL, either as a single agent or in 
combination with rituximab, are summarized below.  The PK properties after repeated 
doses of polatuzumab vedotin have not yet been characterized at the time of the current 
version of the protocol.   
In patients with NHL, polatuzumab vedotin demonstrated a trend of linear 
pharmacokinetics for each measurement across the dose range from 0.1 to 2.4 mg/kg.  
At the RP2D of 2.4 mg/kg in patients with NHL, serum concentrations of total antibody 
and conjugate (evaluated as acMMAE) reached peak values at the end of infusion.  The 
distribution of total antibody and acMMAE appears to be restricted to the serum 
compartment, with median volume of distribution under steady-state conditions (Vss) 
values of 112 mL/kg and 73.3 mL/kg for total antibody and acMMAE, respectively.  
Median total clearance of drug (CL) of acMMAE was approximately similar to CL of total 
antibody.  Median terminal half-life (t1/2,terminal) values for total antibody and acMMAE 
were 5.85 and 6.22 days, respectively.  The disposition of the MMAE component of the 
ADC (represented by acMMAE) appears to be dictated by its antibody component.  
In single-agent dose escalation in patients with NHL, maximum plasma and serum 
concentration observed (Cmax) and area under the concentration-time curve from Time 0 
to infinity (AUCinf) of unconjugated MMAE appear increased with dose across the dose 


 
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levels tested.  At the RP2D of 2.4 mg/kg in patients with NHL, maximum concentrations 
of free MMAE occur 23 days after dosing.  At all timepoints, MMAE concentrations 
were at least 100 times lower than acMMAE concentrations.  The median t1/2,terminal value 
for unconjugated MMAE was 3.57 days, which is relatively long for a small molecule and 
more similar to the half-life of acMMAE, suggesting that the rate of elimination of MMAE 
may be limited by its release from the ADC.  On the basis of its half-life, no accumulation 
of unconjugated MMAE is expected when polatuzumab vedotin is administered every 21 
days. 
The co-administration of rituximab did not affect the pharmacokinetics of polatuzumab 
vedotin in patients with NHL.  Given the various mechanisms of action, an interaction 
with chemotherapy is not expected with polatuzumab vedotin. 
Refer to the Polatuzumab Vedotin Investigator’s Brochure for complete and updated 
details. 
1.3 
RATIONALE FOR DOING THIS STUDY 
The addition of rituximab to standard CHOP chemotherapy has resulted in 
significantly improved outcomes and has demonstrated the importance of an anti-CD20 
antibody combined with standard chemotherapy as an effective treatment for patients 
with newly diagnosed DLBCL.  On the basis of the available clinical data 
(Coiffier et al. 2002; Habermann et al. 2006; Pfreundschuh et al. 2008), the 3-year PFS 
rate of patients with newly diagnosed DLBCL treated with R-CHOP had a range of 
53%76%, with a corresponding OS rate between 65% and 84%.  Despite this progress, 
a significant number of patients are still not cured of the disease, especially those who 
present with one or more clinical risk factors at diagnosis as assessed by the IPI.  
Following progression on or relapse after first-line treatment, salvage regimens can 
induce a second remission, but less than half of patients experience prolonged PFS with 
second-line regimens without autologous stem-cell transplant.  Even if patients are 
eligible for high-dose chemotherapy and autologous stem-cell transplant, less than half 
will be cured (Seyfarth et al. 2006).  Therefore, obtaining the best outcome for patients 
with newly diagnosed disease is critically important for patients because this still offers 
the best chance for long-term survival. 
Polatuzumab vedotin is an ADC designed for the targeted delivery of the potent 
microtubule inhibitor MMAE to lymphoma cells expressing CD79b.  MMAE has a 
mechanism of action that is similar to that of vincristine.  Phase I data to date suggest 
that polatuzumab vedotin has activity in relapsed/refractory DLBCL with a generally 
acceptable safety and tolerability profile.  Because ADCs are believed to have a 
therapeutic index superior to that of systemically administered chemotherapy, 
polatuzumab vedotin has the potential to replace vincristine as part of the standard 
treatment regimen for DLBCL.  Nonclinical data from murine xenograft models support 
the combination of R-CHP and polatuzumab vedotin and demonstrate significantly 
improved anti-lymphoma activity of the combination over R-CHP alone (see Figure 1; 


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Genentech data on file).  Data from these xenograft models also suggest that it is 
reasonable to assume that vincristine (‘O’ in CHOP) can be replaced with polatuzumab 
vedotin as the additional contribution of vincristine (at least in this model) appears to be 
minimal. 
Figure 1 Nonclinical Data in WSU-DLCL2 
Fitted tumor volume
Days
 
In addition to the potential of ADCs to replace systemic chemotherapy, development of 
next-generation anti-CD20 directed therapy may further enhance the efficacy of current 
standard immunochemotherapy regimens.  Obinutuzumab ([G] 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 polatuzumab vedotin with obinutuzumab-
containing regimens. 
The combination of obinutuzumab with CHOP (G-CHOP) has been evaluated in several 
ongoing studies (see Table 1).  Safety was acceptable, with no new or unexpected 


 
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adverse events observed.  The most common adverse event was neutropenia.  In 
patients with either previously untreated or relapsed/refractory FL response rates of ! 95% 
were observed (Dyer et al. 2012; Radford et al. 2013).  The overall response rate in 
patients with previously untreated DLBCL treated with G-CHOP was 83% (Zelenetz et al. 
2013).  Study BO21005 is an ongoing Phase III study that randomized patients with 
DLBCL to either receive R-CHOP vs G-CHOP. 
Table 1 
GA101  CHOP for the Treatment of Lymphoma 
Study 
GAUDI  
Study BO21000 
(Dyer et al. 2012) 
GAUDI  
Study BO21000 
(Radford et al. 
2013) 
GATHER  
Study 
GAO4915g 
(Zelenetz et al. 
2013) 
GOYA 
Study 
BO21005 
N 
40 
28 
80 
1400 
Patient population 
1L FL 
R/R FL 
1L DLBCL 
1L DLBCL 
GA101 dose 
1000 mg 
1600/800 mg 
(n   14) 
1000 mg 
1000 mg 
Chemotherapy 
CHOP 
CHOP 
CHOP 
CHOP 
Efficacy 
ORR 95% 
CR 35% 
PR 60% 
ORR 100% 
CR 64% 
PR 36% 
ORR 83% 
CR 55% 
PR 28% 
Detailed 
results not 
available 
Neutropenia 
45% (all grades) 
43% 
(Grades 3/4) 
57% (all grades) 
50% 
(Grades 3/4) 
7.5% (Grade 3) 
22% (Grade 4) 
Detailed 
results not 
available 
Febrile neutropenia 
10% (all 
Grades 3/4) 
7% (all 
Grades 3/4) 
6% (Grade 3) 
7.5% (Grade 4) 
Detailed 
results not 
available 
1L   first line; CHOP   cyclophosphamide, doxorubicin, vincristine, prednisolone or prednisone; 
CR   complete response; DLBCL   diffuse large B-cell lymphoma; FL   follicular lymphoma; 
GA101   Gazyva/Gazyvaro (obinutuzumab); ORR   overall response rate; PR   partial 
response; R/R   relapsed/refractory. 
 
The goals of this Phase Ib/II study are to assess the safety, tolerability, and potential 
biologic and clinical activity of escalating doses of polatuzumab vedotin in combination 
with a standard regimen of an anti-CD20 antibody  chemotherapy without vincristine 
(R-CHP or obinutuzumab in combination with cyclophosphamide, doxorubicin, and 
prednisolone or prednisone [G-CHP]) in patients with B-cell NHL.  In the dose-finding 
portion of the study, the MTD of polatuzumab vedotin in combination with R-CHP or 
G-CHP will be determined.  Following identification of the MTD, the dose-expansion 
portion of the study will further evaluate the safety and tolerability and clinical activity of 
R-CHP or G-CHP plus polatuzumab vedotin in patients with newly diagnosed DLBCL. 


 
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2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
The primary objectives of this study are the following: 
x 
To assess the safety and tolerability of the combination of polatuzumab vedotin with 
R-CHP or G-CHP administered to patients with B-cell NHL 
x 
To determine the MTD and schedule for polatuzumab vedotin given in combination 
with R-CHP or G-CHP to patients with B-cell NHL 
 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of this study are the following: 
x 
To characterize the pharmacokinetics of polatuzumab vedotin, cyclophosphamide, 
doxorubicin, and rituximab or obinutuzumab in patients when polatuzumab vedotin 
is given in combination with R-CHP or G-CHP 
x 
To make a preliminary assessment of efficacy as measured by CR rate determined 
by positron emission tomography (PET)-computed tomography (CT) scan (see 
Appendix 2 and Section 4.5.6) of polatuzumab vedotin and R-CHP or G-CHP 
administered to patients with previously untreated DLBCL in the expansion phase of 
the study  
x 
To make a preliminary assessment of efficacy when polatuzumab vedotin and 
R-CHP or G-CHP are administered in combination to patients with previously 
untreated DLBCL (see Appendix 2 and Section 4.5.6), as measured by: 
OR rate 
CR rate as determined by CT scan 
DOR 
PFS 
Event-free survival (EFS) 
OS 
x 
To assess the immunogenicity of polatuzumab vedotin and obinutuzumab, as 
measured by the formation of anti-therapeutic antibodies (ATAs) 
x 
To assess the potential relationships of such ATA (anti-polatuzumab vedotin or 
anti-obinutuzumab) formation with other outcome measures (e.g., pharmacokinetics, 
efficacy, safety) 
x 
To evaluate peripheral neuropathy symptom severity and interference on daily 
functioning and to better understand treatment impact, tolerability, and reversibility, 
as measured by the Therapy-Induced Neuropathy Assessment Scale (TINAS) 
 


 
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2.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives of this study are the following: 
x 
To assess the efficacy of therapy in different potential prognostic subgroups, 
including DLBCL genotypic subtypes (e.g., activated B cell–like [ABC], 
germinal-center B cell–like [GCB]) and high Bcl-2 (Bcl-2positive) expression 
x 
To assess tumor expression of CD79b 
x 
To assess prevalence and the correlation of lymphoma associated mutations with 
outcome 
x 
To assess minimal residual disease (MRD) as quantified by measurements of 
lymphoma-specific markers in peripheral blood 
x 
To evaluate the prognostic significance of interim PET assessment 
x 
Response, by Independent Review Committee (IRC), will be determined through 
use of the PET-CT scans based on a modified version of the Lugano Response 
Criteria for Malignant Lymphoma (Cheson et al. 2014; see Appendix 3), hereinafter 
referred to as Modified Lugano 2014 criteria: 
To assess CR by PET at end of induction (EOI) by IRC  
To assess CR by CT at EOI by IRC 
To assess OR (defined as a CR or partial response [PR]) at EOI 
To assess best response of CR or PR during the study 
To evaluate patients who have positive PET scans at EOI: CR at 12 months 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a Phase Ib/II, multicenter, open-label, dose-escalation study of polatuzumab 
vedotin administered by intravenous (IV) infusion in combination with standard doses of 
rituximab or obinutuzumab, cyclophosphamide, doxorubicin, and oral prednisone in 
patients with NHL whose disease is expected to express CD79b.  Two parallel treatment 
arms will explore doses of polatuzumab vedotin in combination with R-CHP and G-CHP.  
The MTD or RP2D of polatuzumab vedotin in combination with R-CHP will be identified 
before it is combined with G-CHP.  Once the MTD or RP2D is determined, polatuzumab 
vedotin will be dosed at MTD or RP2D -1 in combination with G-CHP to start the dose 
escalation of this combination.  Study treatment will be given in every-21-day cycles, 
with the first day of treatment constituting Day 1 of the cycle (see Section 4.3 for specific 
treatment scheduling).  Patients will be treated for a total of six or eight cycles in 
accordance with local institutional practice. 
Sites cannot enroll patients in rituximab-containing and obinutuzumab-containing phases 
simultaneously.  Sites do not need to have prior experience with the rituximab-containing 
combination before enrolling patients with the obinutuzumab combination. 


 
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Patients will be evaluated for safety, tolerability, and pharmacokinetics of study 
treatment.  Assessments for anti-tumor activity will be performed by the investigator 
using the Revised Response Criteria for Malignant Lymphoma (Cheson et al. 2007) at 
screening and at the following timepoints: 
x 
Interim response assessment following four cycles of study treatment (i.e., at 
Cycle 4, between Days 15 and 21)  
x 
Primary response assessment at the completion of study treatment 
 
Patients with no evidence of OR (CR or PR) at the post-Cycle 4 tumor assessment may 
be discontinued from study treatment, at the discretion of the investigator. 
Imaging at these timepoints must include 18F-fluorodeoxyglucose (FDG)-PET and a 
diagnostic-quality CT scan with both oral and IV contrast.  A combined PET-CT scan is 
encouraged if feasible.  An independent review of the responses of all patients will also 
be conducted to confirm the primary CR endpoint (see Section 3.1.4).  Patients will also 
be evaluated every 3 months thereafter until disease progression, death, withdrawal of 
consent, or initiation of another anti-cancer therapy.  Tumor assessments should also be 
performed to confirm clinical suspicion of relapse or disease progression for 
documentation. 
The study will enroll approximately 2430 patients during the dose-escalation stage and 
approximately 60 patients in the expansion stage, at approximately 612 investigative 
sites in the United States and Europe.  The study schema is illustrated in Figure 2. 
3.1.1 
Dose Escalation, Dose-Limiting Toxicity, and Determination of 
the Maximum Tolerated Dose 
The dose-escalation stage of the study will assess the safety, tolerability, 
and pharmacokinetics of polatuzumab vedotin administered in combination with R-CHP 
or G-CHP.  Patients must have histologically documented B-cell NHL with no restriction 
on the histologic subtype.  Patients with newly diagnosed or relapsed/refractory NHL 
may be enrolled (note that patients in France with newly diagnosed B-cell NHL are not 
eligible for enrollment in the dose-escalation portion of the study).  Patients with 
relapsed/refractory disease should have received only one prior treatment regimen and 
must be eligible for an anthracycline-containing therapy (i.e., must not have received 
prior CHOP therapy, or variants of CHOP).  Prior vinca-alkaloid therapy is allowed if any 
resulting neuropathy does not exceed Grade 1 at enrollment. 
The starting dose level for polatuzumab vedotin will be 1.0 mg/kg.  The selection of the 
starting dose level is based on the absence of DLTs observed at this dose level when 
administered as a single agent in the Phase I study.  R-CHP or G-CHP will be given at 
standard doses, with modifications for toxicity (see Section 5.1.7).  In those instances 
where individual toxicities are attributed to polatuzumab vedotin, R-CHP or G-CHP 
dosing may be maintained, per the guidelines in Section 5.1.7. 


 
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Patients will be monitored for DLTs from Cycle 1 Day 1 to Cycle 2 Day 1 (minimum of 
21 days).  Any patient who does not complete the full DLT observation period for any 
reason other than DLT will be considered non-evaluable for dose-escalation decisions 
and/or MTD assessment and will be replaced by an additional patient at that same 
dose level. 
All dose-escalation cohorts will consist of at least 3 patients.  If a DLT is observed in 
1 patient at a given dose level during the DLT observation period before dose escalation, 
additional patients will be enrolled at that dose level for a total of at least 6 patients. 
At each dose level during escalation, the first patient treated at each dose level will 
receive the first infusion of polatuzumab vedotin at least 1 day before any subsequent 
patients in that cohort being treated in order to assess for any severe and unexpected 
acute drug or infusion-related toxicities. 
Decisions regarding dose escalations will be made by the Sponsor Medical Monitor in 
consultation with the Safety Science Leader, and Biostatistician.  All relevant safety data 
including but not limited to adverse event and laboratory data will be reviewed.  
Decisions will be made on the basis of this review and in consultation with the 
participating investigators on whether dose escalation should proceed and if so, to what 
dose level. 
3.1.1.1 
Definition of Dose-Limiting Toxicity 
All adverse events, including DLTs, are to be reported according to instructions 
in Section 5.3 and graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0 unless otherwise 
indicated.  If a patient experiences a DLT, he or she will be treated according to clinical 
practice and will be monitored for resolution of the toxicity (see Section 5.6 for 
description of adverse event follow-up).  All adverse events should be considered to be 
related to study treatment unless such events are clearly attributed by the investigator to 
another clearly identifiable cause (e.g., documented tumor progression).  Decreases in 
B cells, lymphopenia, and leukopenia due to lymphopenia will not be considered DLTs 
because they are expected pharmacodynamic outcomes of rituximab and polatuzumab 
vedotin treatment.  Granulocyte colony-stimulating factor (G-CSF) may be provided to 
patients for the management of neutropenia.   
For dose-escalation purposes, a DLT will be defined as any of the following adverse 
events occurring during the DLT period that are attributed to study treatment and not 
attributable to another clearly identifiable cause: 
x 
Any adverse event regardless of grade that leads to a delay of at least 7 days to the 
start of the next cycle  


 
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x 
Grade t 3 non-hematologic toxicity that is not attributable to disease progression or 
another clearly identifiable cause, excluding the following: 
Grade 3 diarrhea that responds to standard-of-care therapy within 72 hours 
Grade 3 nausea or vomiting, in the absence of premedication, that responds to 
standard-of-care therapy within 72 hours 
Grade 3 laboratory abnormality that is asymptomatic and deemed by the 
investigator not to be clinically significant 
Reversible Grade 3 non-allergic infusion toxicities (including symptoms such as 
fever, chills/rigors, nausea, vomiting, pruritus, headache, rhinitis, rash, asthenia, 
and/or hypoxia in the absence of signs/symptoms of respiratory distress) 
occurring during or within 24 hours after completing an infusion and resolving 
within 24 hours 
Grade t 3 allergic toxicities such as wheezing, bronchospasm, shortness 
of breath, and/or stridor in the presence or absence of hypoxia, and/or urticaria 
are not excluded and should be considered DLTs.  (Patients with 
infusion-related Grade t 3 wheezing, hypoxia, or generalized urticaria must be 
permanently discontinued from study drug on the first occurrence.) 
Grade 3 elevation in ALT or AST, provided the following criteria are met: 
ALT or AST level is no greater than 8 u the upper limit of normal (ULN) 
ALT or AST elevation resolves to Grade  2 ( 5 u ULN) within 7 days 
Total and direct bilirubin and other laboratory parameters of liver synthetic 
function (e.g., prothrombin time) are normal 
There are no clinical signs or symptoms of hepatic injury 
Any case involving an increase in hepatic transaminase ! 3 u baseline AND 
an increase in direct bilirubin ! 2 u ULN, WITHOUT any findings of 
cholestasis or jaundice or signs of hepatic dysfunction AND in the absence 
of other contributory factors (e.g., worsening of metastatic disease or 
concomitant exposure to known hepatotoxic agent or of a documented 
infectious etiology) is suggestive of potential drug-induced liver injury (DILI) 
(according to Hy’s Law) and will be considered a DLT. 
x 
All Grade 3 or 4 hematological toxicity considered by the investigator to be related to 
polatuzumab vedotin and not attributable to another clearly identifiable cause with 
the exception of the following: 
Lymphopenia, which is an expected outcome of therapy 
Grade 4 neutropenia (in the absence of G-CSF) that is not accompanied by 
temperature elevation (oral or tympanic temperature of t 100.4qF [38qC]) and 
improves to Grade 3 within 1 week and further improves to Grade d 2 (or to t 80% 
of the baseline value, whichever is lower) within another week 
Grade 3 neutropenia (in the absence of G-CSF) that is not accompanied by 
temperature elevation (oral or tympanic temperature of t 100.4qF (38qC) and 


 
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improves to Grade  2 (or to ! 80% of the baseline value, whichever is lower) 
within 1 week 
Grade 3 or 4 leukopenia 
Grade 4 thrombocytopenia that does not result in bleeding and improves 
to Grade 3 within 1 week and further improves to Grade d 2 (or to t 80% of the 
baseline value, whichever is lower) within another week without 
platelet transfusion 
Grade 3 thrombocytopenia that does not result in bleeding and improves 
to Grade  2 (or to t 80% of the baseline value, whichever is lower) within 
1 week without platelet transfusion 
Grade 3 or 4 anemia that does not require an emergent transfusion 
 
If a patient experiences a DLT as described above, the patient will be observed for 
resolution of the toxicity.  If the DLT resolves to Grade d 2 (or t 80% of the baseline 
value) and it is determined to be in the patient’s best interest to continue study treatment 
(after discussion between the treating investigator and the Medical Monitor), the patient 
may continue to receive polatuzumab vedotin.  The dose of polatuzumab vedotin may be 
reduced to the dose level tested in the previous cohort, with minimum dose level of 
1.0 mg/kg.  For details regarding dose reductions and interruptions, refer to 
Section 5.1.6. 
3.1.1.2 
Dose Escalation after Dose-Limiting Toxicity and 
Determination of the Maximum Tolerated Dose 
The following dose-escalation rules will apply: 
x 
At least 3 patients will be enrolled at each dose level of polatuzumab vedotin.  If a 
DLT is observed in 1 patient at a given dose level during the DLT observation period, 
additional patients will be enrolled at that dose level for a total of at least 6 patients. 
All patients will be evaluated for DLTs before any dose-escalation decision. 
x 
The dose of polatuzumab vedotin will be increased by no more than 50% for 
subsequent cohorts.  For example, in the absence of establishing the MTD at the 
1.0-mg/kg dose level, the next dose level will not exceed 1.5 mg/kg. 
x 
Due to additional information regarding the risk/benefit profile of polatuzumab 
vedotin at the 2.4-mg/kg dose, the Sponsor is no longer pursuing the 2.4-mg/kg 
dose of polatuzumab vedotin at this time.  The maximum polatuzumab vedotin dose 
was 2.4 m/kg as determined in the Phase I study (Study DCS4968g) and had been 
the RP2D. 
x 
If DLTs are observed in ! 33% of the patients enrolled in a given cohort, further 
enrollment at that dose level and dose escalation will be halted, and that dose will 
be declared as exceeding the MTD.  Dose levels intermediate between the two 
highest dose levels may be evaluated after consultation with the study investigators. 
 
The highest dose level resulting in DLTs in less than one-third of a minimum of 
6 patients will be declared the MTD.  Additional patients may be enrolled at a given dose 


 
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level in the absence of DLTs to acquire additional safety data to inform the appropriate 
dose level for the expansion stage of the study. 
G-CSF may be provided to patients for the management of neutropenia.   
3.1.2 
Phase II:  Expansion Stage 
The expansion stage will include approximately 60 patients aged t 18 years old at the 
time of study registration who have previously untreated DLBCL and with 
high-intermediate to high risk as defined by IPI score of 25 (see Appendix 8).  Forty 
patients will receive R-CHP in combination with polatuzumab vedotin at a dose less than 
or equal to the MTD identified during escalation and an additional 17 patients will receive 
G-CHP in combination with polatuzumab vedotin at a dose less than or equal to the 
MTD identified during escalation.  The purpose of the expansion stage is to evaluate the 
safety and preliminary efficacy of the selected dose and schedule for the combination 
therapy, determined from the dose-escalation portion of the study. 
In the event that the observed toxicities during the expansion stage are different from 
what was predicted on the basis of the escalation portion of the study, additional 
expansion cohorts of approximately 40 patients may be enrolled to evaluate lower doses 
of polatuzumab vedotin.  Additional patients may be enrolled in the expansion cohort in 
order to obtain additional safety, tolerability, and PK data, as well as data in specific 
biologic risk groups. 
Patients in both the dose-escalation and expansion cohorts will be evaluated for safety 
and efficacy according to the schedules of assessments outlined in Appendix 1. 
Tumor assessments, including CT and PET scans will be performed at screening, 
following Cycle 4 of treatment (i.e., at Cycle 4 Days 15-21), and at the Treatment 
Completion/Early Termination visit (obtained at 6-8 weeks after study treatment 
completion).  CT scans (PET scans not required) will be performed every 6 months 
thereafter until approximately 2 years after the Treatment Completion/Early Termination 
visit or until progression or the start of an alternate lymphoma treatment regimen.  Tumor 
assessments should also be performed to confirm clinical suspicion of 
relapse/progression, for documentation of disease progression or relapse, following the 
completion of study treatment. 
 
 




 
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to the ongoing assessment of the incidence and nature of DLTs, adverse events 
(particularly Grades t 3), serious adverse events, deaths, and laboratory abnormalities 
by the investigator and the Medical Monitor, the IMC will review all necessary cumulative 
data at regular intervals during the study.  At the time of each review, the IMC will make 
one of the following recommendations:  the trial continues as planned, a study arm stops, 
the protocol is amended, additional analyses need to be performed, or enrollment will be 
held pending further safety evaluations.  Decisions will be made in consideration of the 
totality of the available data.  Ad hoc meetings may be called in addition to scheduled 
meetings, as necessary, to provide recommendations on management of any new safety 
issues.  Specific operational details such as the committee’s composition, frequency, 
and timing of meetings, and members’ roles and responsibilities will be detailed in an 
IMC Charter. 
3.1.4 
Independent Review Committee 
An IRC composed of board-certified radiologists and an oncologist with experience in 
malignant lymphoma will assess all patients for response (see Appendix 2 and 
Appendix 3) on the basis of imaging results, bone marrow biopsy results, and relevant 
clinical data during the Phase II portion of the study.  Decisions will be guided by a 
Charter specific to the independent review. 
3.2 
END OF STUDY 
The end of the study is defined as the time point at which all patients enrolled into the 
study have either had at least 2 years of follow-up from the time of the Treatment 
Completion/Early Termination visit or have discontinued from the study.  The Sponsor 
has the right to terminate the study at any time. 
3.3 
RATIONALE FOR STUDY DESIGN 
Because R-CHOP is the standard of care for first-line treatment of patients with DLBCL 
(and other types of B-cell NHL) and the preliminary efficacy and safety profile of 
polatuzumab vedotin demonstrates promising efficacy and a tolerable safety profile, this 
study was designed to assess the combinability of polatuzumab vedotin with R-CHP in 
patients with newly diagnosed DLBCL and other types of B cell NHL.  Because the 
mechanism of action of polatuzumab vedotin involves the targeted delivery of MMAE, a 
potent microtubule inhibitor that has the same binding site as the vinca alkaloids 
(vincristine), it is hypothesized that replacement of vincristine with a targeted microtubule 
inhibitor will result in an improved efficacy profile (given the increased potency of MMAE 
vs. vincristine).  The dose-finding part of the study is open to all patients with B-cell 
lymphoma for whom R-CHOP or G-CHOP is considered a reasonable treatment option 
and who fulfill inclusion and exclusion criteria.  Once a dose has been identified for 
Stage 2, the study will restrict enrollment to a group of patients with high medical need 
(newly diagnosed DLBCL patients who are aged t 18 years and who have an IPI of 2–5) 
to further assess safety and efficacy of the combination.  Patients with these 
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front-line therapy (Shipp et al. 1993; Ziepert et al. 2010).  Administration of polatuzumab 
vedotin combined with R-CHP or G-CHP in these patients would increase the possibility 
of observing increased clinical benefit over patients with similar clinical characteristics 
historically treated with R-CHOP or G-CHOP. 
The dose escalation of polatuzumab vedotin combined with R-CHP will begin at a dose 
level of 1.0 mg/kg, because this was the highest dose level at which no DLTs or clinically 
significant adverse events were observed during the Phase I study.  The MTD of 
polatuzumab vedotin in combination with R-CHP will be identified before it is combined 
with G-CHP.  Once the MTD is determined, polatuzumab vedotin will be dosed at MTD-1 
in combination with G-CHP to start the dose escalation of this combination.  Rules for 
dose escalation and final dose selection are outlined in Section 3.1.1.2. 
3.3.1 
Rationale for Obinutuzumab Dosing and Schedule 
The combination of obinutuzumab with CHOP is being evaluated in several ongoing 
studies (see Table 1), including a Phase Ib trial in patients with previously untreated and 
relapsed/refractory FL (Study BO21000), a Phase II (Study GAO4915g, single arm 
G-CHOP) and a Phase III (Study BO21005, randomized R-CHOP vs G-CHOP) trials 
both in patients with previously untreated DLBCL. 
The recommended dose and schedule for obinutuzumab in this regimen is 1000 mg on 
Days 1, 8, and 15 of Cycle 1 and Day 1 of each subsequent cycle (Cycles 26 or 8). 
3.3.2 
Rationale for Exploratory Biomarker Research Samples 
Biomarkers associated with drug target, mechanism of action, and DLBCL biology may 
correlate with outcome in several ways.  First, the activity of ADCs is dependent on a 
number of factors including but not necessarily limited to the presence of the antibody 
target, internalization of the ADC, and sensitivity of the tumor cell to the payload drug.  
Second, therapeutic approaches in DLBCL may result in differential activity in DLBCL 
prognostic subpopulations based on gene profile expressionthat is, ABC versus GCB.  
Finally, resistance to cytotoxic treatment may be a result of high expression of 
anti-apoptotic regulators such as Bcl-2. 
To assess target expression, DLBCL prognostic subpopulation, and levels of apoptotic 
regulators, archival or fresh tumor samples whose availability are required for study 
enrollment will be retrospectively analyzed for expression of CD79b; members of the 
Bcl-2 family; mutations associated with DLBCL biology including but not limited to 
CD79b, Myd88, CARD11 and A20; and genotypic classification of the DLBCL 
subpopulationfor example, ABC versus GCB.  Results from these assays will be used 
to assess correlation with outcome. 
Tumor-associated biomarkers may also be detected in blood.  Since tumor tissue is 
often limited and difficult to acquire, assessment of blood-borne markers that are 
representative of the current disease state is of high interest.  


 
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3.3.3 
Rationale for Pharmacokinetic Sampling 
The PK sampling schedule following polatuzumab vedotin administration at Cycle 1 
based on a 21-day cycle is designed to describe a detailed profile of the distribution and 
elimination of polatuzumab vedotin.  The limited PK sampling schedule following 
polatuzumab vedotin at later cycles are obtained to assess pharmacokinetics after 
repeated dosing, given the likely changing effect of peripheral B-cell counts, tumor 
burden, and target antigen expression on target-mediated CL over multiple doses 
of polatuzumab vedotin. 
Polatuzumab vedotin related analyte (total antibody, conjugate [evaluated as acMMAE] 
or unconjugated MMAE) concentration results will also contribute to future population PK 
analysis to investigate the effects of physiologic and disease-related covariates on 
polatuzumab vedotin disposition, if data allow, per Sponsor’s decision. 
Limited sampling for rituximab serum concentration measurements from this study will 
be obtained and compared with PK data from historical rituximab clinical studies.  
Pharmacokinetic data from these assessments will be used to inform potential future 
trials of this combination. 
Limited PK sampling will be obtained for plasma concentrations of cyclophosphamide 
and doxorubicin.  A comparison of the plasma concentration of cyclophosphamide, and 
doxorubicin between Cycle 1 (in the absence of polatuzumab vedotin) and Cycle 3 (in 
the presence of polatuzumab vedotin), and comparison with historical data will assess 
potential PK interactions when they are given in combination with polatuzumab vedotin. 
3.3.4 
Rationale for Patient-Reported Outcomes 
Peripheral sensory neuropathy is an adverse drug reaction (ADR) of polatuzumab 
vedotin.  Peripheral neuropathy in several forms, including sensory and/or motor 
neuropathy, is experienced by a majority of patients treated with polatuzumab vedotin.  It 
is known that a discrepancy exists between healthcare provider interpretation and 
reporting of these events and a patient’s self-assessment of their experience with 
peripheral neuropathy.  This discrepancy is due, in part, to the lack of an adequate 
patient-reported measure of symptomatic burden of peripheral neuropathy on daily 
functioning.  The primary objective of the patient-reported outcome (PRO) assessment in 
the Phase Ib/II study is to comprehensively assess and quantify the symptomatic burden 
and personal tolerability of this adverse event.  The objective is to provide a better 
understanding of the clinical profile of polatuzumab vedotin from a patient perspective 
using a novel validated measure known as TINAS (Thomas et al. 2012). 
3.4 
OUTCOME MEASURES 
3.4.1 
Safety Outcome Measures 
x 
Incidence, nature, and severity of adverse events and serious adverse events  


 
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x 
Changes in vital signs, physical findings, ECGs, and clinical laboratory results 
during and following study treatment administration 
x 
Incidence of anti-polatuzumab vedotin antibodies and anti-obinutuzumab antibodies 
 
3.4.2 
Pharmacokinetic and Pharmacodynamic Outcome Measures 
The following PK parameters will be derived from the serum concentration–time profiles 
of total antibody (the sum of fully conjugated antibody, partially deconjugated antibody, 
and fully deconjugated antibody concentrations), plasma concentration-time profiles of 
conjugate (evaluated as acMMAE) and unconjugated MMAE, following administration of 
polatuzumab vedotin, when appropriate as data allow: 
x 
Total exposure (area under the concentration-time curve [AUC]) 
x 
Cmax 
x 
CL 
x 
t1/2,terminal 
x 
Vss 
 
Compartmental, non-compartmental, and/or population methods may be used.  Other 
parameters, such as accumulation ratio and minimum concentration under steady-state 
conditions within a dosing interval (Cmin), may also be calculated, when appropriate as 
data allow. 
Limited sampling of serum concentrations of rituximab/obinutuzumab will be assessed 
and compared with historical data to evaluate potential PK interactions with polatuzumab 
vedotin.  Plasma levels of cyclophosphamide and doxorubicin will be assessed and 
compared at the same timepoints of Cycle 1 (in the absence of polatuzumab vedotin) 
and Cycle 3 (in the presence of polatuzumab vedotin), and compared with historical data 
to evaluate potential PK interactions with polatuzumab vedotin. 
3.4.3 
Activity and Dose Exposure Outcome Measures 
Response assessment will be determined using the modified version of the Revised 
Response Criteria for Malignant Lymphoma (Cheson et al. 2007; see Appendix 2) and 
the modified version of the Lugano Response Criteria (Cheson et al. 2014; see 
Appendix 3). 
The following activity outcome measures will be assessed: 
x 
CR rate as defined as the percentage of patients with CR at the end of treatment, as 
assessed by the investigator, with and without FDG-PET. 
x 
OR at the end of treatment, as assessed by the investigator, with and without FDG-
PET.  The overall response rate is defined as the percentage of patients with CR or 
PR at the end of treatment.  All other cases are designated non-responders. 
x 
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 (PFS), as 


 
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assessed by the investigator for the subgroup of patients with a best overall 
response of CR or PR.  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.  
x 
PFS, defined as the time from date of first dose of study drug to the first occurrence 
of progression or relapse, or death from any cause while in the study 
x 
EFS is defined as the time from randomization to disease progression or relapse, as 
assessed by the investigator, death from any cause, or initiation of any new anti-
lymphoma therapy (NALT).  If the specified event (disease progression or relapse, 
death, initiation of a NALT does not occur, EFS will be censored at the date of last 
tumor assessment.  For patients without an event who have not had post-baseline 
tumor assessments, EFS will be censored at the time of randomization. 
x 
Relative dose intensity (DI) is defined as the ratio of the amount of a drug actually 
administered (actual DI) to the amount planned (planned DI) for a fixed time period 
x 
OS, defined as the time from the date of randomization to the date of death from 
any cause. 
 
3.4.4 
Immunogenicity Outcome Measures 
ATA responses to polatuzumab vedotin and obinutuzumab will be characterized at 
predetermined timepoints (see Appendix 4 and Appendix 5). 
3.4.5 
Patient-Reported Outcome Measures 
The PRO measures for this study are as follows: 
x 
PRO of peripheral neuropathy symptom severity and symptom interference, as 
measured by the TINAS (Thomas et al. 2012; see Appendix 10) 
 
3.4.6 
Biomarker Outcome Measures 
x 
Gene expression profiles in tumor relating to:  
DLBCL prognostic subgroups 
Target (CD79b) biology 
Expression of apoptotic regulators (including but not limited to Bcl-2) 
Drug efflux transporters and other potential mediators of ADC resistance 
x 
Tumor immunohistochemistry of target (CD79b) expression and apoptotic regulators 
(including but not limited to Bcl-2) 
 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
4.1.1 
Patient Selection 
Eligible patients who are in conformance with the following inclusion and exclusion 
criteria may enroll in this study. 


 
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4.1.2 
Inclusion Criteria 
Dose-Escalation Portion of the Study 
x 
Histologically confirmed B-cell NHL:  Patients with newly diagnosed B-cell NHL or 
relapsed/refractory B-cell NHL are eligible. 
Note that patients in France with newly diagnosed B-cell NHL are not eligible. 
x 
No more than one prior systemic treatment regimen for B-cell NHL (single agent 
anti-CD20 MAb therapy will not be counted as a prior treatment regimen) 
x 
No prior treatment with anthracyclines 
 
Expansion Portion of the Study 
x 
Previously untreated patients with DLBCL 
x 
IPI score of 25 (see Appendix 8). 
 
All Patients 
x 
Age t 18 years  
x 
Signed informed consent form(s) 
x 
At least one bi-dimensionally measurable lesion, defined as ! 1.5 cm in its longest 
dimension  
x 
Ability and willingness to comply with the study protocol procedures 
x 
Confirmed availability of archival or freshly collected tumor tissue before study 
enrollment 
x 
Life expectancy of at least 24 weeks 
x 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 
x 
Adequate hematologic function (unless inadequate function is due to underlying 
disease, as established by extensive bone marrow involvement or is due to 
hypersplenism secondary to the involvement of the spleen by lymphoma per the 
investigator) defined as follows: 
Hemoglobin t 9 g/dL 
ANC t 1.5 u 109/L 
Platelet count t 75 u 109/L 
x 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of  1% per year during the treatment period and for at least 12 months for R-CHP 
arm or t 18 months for the G-CHP arm after the last dose of study drug.  
A woman is considered to be of childbearing potential if she is post-menarcheal, 
has not reached a postmenopausal state (t 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, and copper intrauterine devices. 


 
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The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
x 
For women of childbearing potential, a negative serum pregnancy test result within 
7 days prior to commencement of dosing.  Women who are considered not to be of 
childbearing potential are not required to have a pregnancy test. 
x 
For men, agreement to remain abstinent (refrain from heterosexual intercourse) or 
to use a condom plus an additional contraceptive method that together result in a 
failure rate of 1 % per year during the treatment period and for at least 5 months 
after the last dose of study drug and agreement to refrain from donating sperm 
during this same period. 
Men with a pregnant partner must agree to remain abstinent or to use a 
condom during the treatment period and for at least 6 months after the last 
dose of study drug to avoid exposing the embryo for the duration of the 
pregnancy. 
Abstinence is only acceptable if it is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
Male patients considering preservation of fertility should bank sperm before 
treatment with polatuzumab vedotin. 
 
4.1.3 
Exclusion Criteria 
Exclusion Criteria for Dose-Escalation Portion of the Study 
x 
Diagnosis of primary mediastinal DLBCL 
 
Exclusion Criteria for Expansion Portion of the Study 
x 
Patients with transformed lymphoma 
x 
Prior therapy for NHL 
 
All Patients 
x 
Prior stem cell transplant 
x 
History of severe allergic or anaphylactic reactions to humanized or murine 
monoclonal antibodies or known sensitivity or allergy to murine products 
x 
Contraindication to receive any of the individual components of R-CHP or G-CHP 
x 
Current Grade ! 1 peripheral neuropathy 
x 
Ongoing corticosteroid use of ! 30 mg/day of prednisone/prednisolone or equivalent.  
Patients receiving corticosteroid treatment with d 30 mg/day of 
prednisone/prednisolone or equivalent must be documented to be on a stable dose 
of at least 4 weeks’ duration before Cycle 1 Day 1 
Note:  If corticosteroid treatment is urgently required for lymphoma symptom 
control prior to the start of study treatment, up to 100 mg/day prednisone or 


 
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equivalent can be given for a maximum of 7 days, but all tumor assessments 
must be completed prior to start of corticosteroid treatment. 
x 
Primary CNS lymphoma 
x 
Vaccination with live vaccines within 6 months before Cycle 1 Day 1 
x 
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 or 
melanoma of the skin or in situ carcinoma of the cervix are eligible. 
Patients with a malignancy that has been treated with surgery alone with 
curative intent will also be excluded unless the malignancy has been in 
documented remission without treatment for t 5 years before enrollment. 
x 
Evidence of significant, uncontrolled concomitant diseases that could affect 
compliance with the protocol or interpretation of results or that could increase risk 
to the patient, including renal disease that would preclude chemotherapy 
administration, or pulmonary disease (including obstructive pulmonary disease and 
history of bronchospasm) 
x 
Significant cardiovascular disease (such as New York Heart Association Class III 
or IV cardiac disease, congestive heart failure, myocardial infarction within the 
previous 6 months, unstable arrhythmias, or unstable angina) or significant 
pulmonary disease (including obstructive pulmonary disease and history of 
bronchospasm) 
x 
Left ventricular ejection fraction defined by multiple-gated acquisition 
(MUGA)/echocardiogram (ECHO) below the institutional lower limit of normal 
x 
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 before Cycle 1 Day 1 
x 
Clinically significant history of liver disease, including viral or other hepatitis, current 
alcohol abuse, or cirrhosis 
x 
Presence of positive test results for hepatitis B (hepatitis B surface antigen [HBsAg] 
and/or total hepatitis B core antibody [HBcAb]) or hepatitis C (hepatitis C virus [HCV] 
antibody) 
Patients who are positive for HCV antibody must be negative for HCV by 
polymerase chain reaction (PCR) to be eligible for study participation. 
x 
Prior radiotherapy to the mediastinal/pericardial region 
x 
Women who are pregnant, lactating, or who intend to become pregnant within a 
year after the last dose of study treatment in the rituximab cohort or within 
18 months after the last dose of study treatment in the obinutuzumab cohort 
x 
Recent major surgery within 6 weeks before the start of Cycle 1 Day 1, other than 
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x 
Any of the following abnormal laboratory values: 
Creatinine ! 1.5 u ULN or a measured creatinine clearance  50 mL/min   
AST or ALT ! 2.5 u ULN 
Total bilirubin t 1.5 u ULN:  
INR ! 1.5 u ULN in the absence of therapeutic anticoagulation 
PTT or aPTT ! 1.5 u ULN in the absence of a lupus anticoagulant 
 
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 and obtain the Sponsor’s approval to enroll the 
patient.  Once the Sponsor reviews and approves the patient for enrollment, the Sponsor 
will provide the dose group assignment and the patient number will be assigned via the 
Interactive Voice and Web Response System (IXRS). 
4.3 
STUDY TREATMENT 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Polatuzumab Vedotin 
Polatuzumab vedotin will be supplied by the Sponsor.  For information on the formulation, 
packaging, and handling of polatuzumab vedotin, see the pharmacy manual and the 
Polatuzumab Vedotin Investigator’s Brochure. 
4.3.1.2 
Rituximab 
Rituximab (MabThera£/Rituxan£) will be supplied by the Sponsor where required by 
local health authority regulations.  For information on the formulation, packaging and 
handling of rituximab, see the pharmacy manual, the local prescribing information 
(Rituxan£ U.S. Package Insert; MabThera£ SmPC 2016) and investigator’s brochure for 
rituximab (MabThera£/Rituxan£). 
4.3.1.3 
Obinituzumab 
Obinutuzumab (Gazyva¥/Gazyvaro¥), will be supplied by the Sponsor.  For information 
on the formulation, packaging and handling of obinutuzumab, see the pharmacy manual, 
local prescribing information, and investigator’s brochure for obinutuzumab 
(Gazyva¥/Gazyvaro¥). 
4.3.1.4 
Cyclophosphamide, Doxorubicin, and Prednisone 
Cyclophosphamide, doxorubicin, and prednisolone or prednisone (CHP) will be supplied 
by the Sponsor where required by local health authority regulations.  For information on 
the formulation, packaging and handling of CHP, see the local prescribing information for 
CHP. 


 
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4.3.2 
Dosage, Administration, and Compliance 
Patients will receive treatment with one of two immunochemotherapy regimens in 
combination with polatuzumab vedotin:  
x 
R-CHP:  rituximab plus CHP chemotherapy 
x 
G-CHP:  obinutuzumab plus CHP chemotherapy 
 
Patients will receive a total of six to eight cycles of polatuzumab vedotin in combination 
with R-CHP or GCHP.  A cycle is typically 21 days in duration. 
For the purposes of ensuring consistent PK measurements, treatments will be 
administered in the order specified below. 
Pre-Phase Treatment:  Day7 to Day1 (1 day prior to Cycle 1 Day 1) 
x 
Prednisone/prednisolone 100 mg by mouth (orally; PO) every day 
 
Administration of an approximately 7-day course of pre-phase treatment may be given at 
the discretion of the treating investigator physician.  The purpose of pre-phase treatment 
is to prevent tumor lysis syndrome (TLS) in patients with extensive disease and to 
reduce toxicity of the first cycle of study treatment, e.g., cytokine release syndrome. 
Cycles 12 
Cycles 12 Day 1 
x 
First treatment administered:  prednisone/prednisolone 100 mg PO 
x 
Second treatment administered:  rituximab 375 mg/m2 IV or obinutuzumab 1000 mg 
IV 
x 
Third and fourth treatment administered:  cyclophosphamide 750 mg/m2 IV and 
doxorubicin 50 mg/m2 IV.  The order of administration will be based on institutional 
practice.  The order of administration of cyclophosphamide and doxorubicin used in 
Cycle 1 should be maintained for Cycles 26 (or 28).  A PK analysis will be 
conducted to evaluate potential drug interactions.  Because this is an important 
objective of this study, the length of infusions for cyclophosphamide and doxorubicin 
should be approximately the same for all cycles, as allowed by the observed safety 
profile of the infusions. 
 
Cycles 12 Day 2 
x 
First treatment administered:  prednisone/prednisolone 100 mg PO 
x 
Second treatment administered:  polatuzumab vedotin administered IV.  Refer to 
Section 3.1 for information regarding planned doses of polatuzumab vedotin to be 
tested. 
 
Cycle 1 Only Day 8 and Day 15 (G-CHP only)  
x 
Obinutuzumab 1000 mg IV 
 


 
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Cycles 36 (or 8) 
As long as the observed individual patient safety profile of R-CHP or G-CHP and 
polatuzumab vedotin allows all study treatment infusions to be given on the same day, 
then the R-CHP or G-CHP and polatuzumab vedotin infusions will be given on a single 
day for Cycles 36 (or 8). 
Cycles 36 (or 8) Day 1 
x 
First treatment administered:  prednisone/prednisolone 100 mg PO 
x 
Second treatment administered:  rituximab 375 mg/m2 IV or obinutuzumab 1000 mg 
IV 
x 
Third and fourth treatments administered:  cyclophosphamide 750 mg/m2 IV and 
doxorubicin 50 mg/m2 IV.  The order of administration of cyclophosphamide and 
doxorubicin used in Cycle 1 should be maintained for Cycles 26 (or 28).  Because 
PK analysis to evaluate potential drug interactions is an important objective of this 
study, the length of infusions for cyclophosphamide and doxorubicin should be 
approximately the same for all cycles, as allowed by the observed safety profile of 
the infusions. 
x 
Fifth treatment administered:  polatuzumab vedotin administered IV.  Refer to 
Section 3.1 for information regarding planned doses of polatuzumab vedotin to be 
tested. 
 
The doses of the rituximab, polatuzumab vedotin, cyclophosphamide, and doxorubicin 
should be calculated on the basis of a patient’s body weight at the screening 
assessment (Day14 to Day1).  For changes ! 10% in body weight from screening, all 
subsequent doses should be modified accordingly.  The weight that triggered a dose 
adjustment will be taken as the new reference weight for future dose adjustments. 
4.3.2.1 
Polatuzumab Vedotin 
The total dose of polatuzumab vedotin for each patient will depend on dose level 
assignment and the patient’s weight on Day 1 of Cycle 1 (or within 96 hours before 
Cycle 1 Day 1).  The total dose of polatuzumab vedotin should be adjusted for 
subsequent doses only if the patient’s weight has changed by ! 10% from baseline. 
Polatuzumab vedotin will be administered to patients by IV infusion with use of syringes 
and syringe pumps.  Compatibility testing has shown that polatuzumab vedotin is stable 
in extension sets and polypropylene syringes.  Extension sets and syringes used to 
deliver polatuzumab vedotin must be comprised of specific materials, please refer to the 
study team for a list of approved materials.  Polatuzumab vedotin 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 polatuzumab vedotin determined by the dose and patient weight. 
The initial dose will be administered to well-hydrated patients over 90 (r 10) minutes.  
Premedication (e.g., 5001000 mg of oral acetaminophen or paracetamol and 
50100 mg diphenhydramine as per institutional standard practice) may be administered 


 
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to an individual patient before administration of polatuzumab vedotin.  If IRRs are 
observed with the first infusion in the absence of premedication, premedication must be 
administered before subsequent doses.  Note that the prednisone/prednisolone 
component of R-CHP infusion will be administered before polatuzumab vedotin infusion 
for all treatment cycles. 
The polatuzumab vedotin 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 prior infusions have been well tolerated, subsequent doses of 
polatuzumab vedotin may be administered over 30 (r 10) minutes, followed by a 
30-minute observation period after the infusion.   
For additional instructions on study drug preparation and administration, refer to the 
Investigator’s Brochure. 
4.3.2.2 
Rituximab 
Six to eight cycles of rituximab at 375 mg/m2 will be administered IV to patients every 
21 days (or over 28 days for those patients who experienced toxicity that necessitates 
an extended cycle duration).  No dose modifications of rituximab are allowed. 
Rituximab Preparation 
All transfer procedures require strict adherence to aseptic techniques, preferably in a 
laminar flow hood.  Prepare the rituximab solution as follows 
x 
Refrigerate 2qC8qC all materials and solutions before use.  Do not freeze or store 
at room temperature. 
x 
Use sterile, non-pyrogenic disposable containers, syringes, needles, stopcocks, and 
transfer tubing, etc. 
x 
Transfer of rituximab from the glass vial should be made by using a suitable sterile 
graduated syringe and large-gauge needle. 
x 
Transfer the appropriate amount of rituximab from the graduated syringe into a 
partially filled IV pack containing sterile pyrogen-free 0.9% NaCl solution saline 
solution.  Discard any unused portion left in the vial. 
x 
Mix by inverting the bag gently.  Do not use a vacuum apparatus to transfer the 
product from syringe to the plastic bag.  Handle gently and avoid foaming, because 
this may lead to the denaturing of the product proteins. 
 
It is recommended that rituximab be given at a dilution of 2 mg/mL for ease in calculating 
the dose. 
Rituximab Administration 
Rituximab will be administered after the prednisone/prednisolone dosing and before the 
cyclophosphamide, doxorubicin, and polatuzumab vedotin infusions.  Once the rituximab 


 
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infusion is completed, patients are to be observed for 30 minutes before the start of CHP 
administration.  For patients who experience an adverse event during a rituximab 
infusion, administration of rituximab and CHP chemotherapy may be continued on the 
following day if required.  Empiric dose adjustment for obese patients (defined as a body 
mass index of t 30, as measured in kilograms per meter squared) may be implemented 
per institutional guidelines.  There will be no dose modification for changes in weight 
unless a patient’s weight increases or decreases by ! 10% from baseline weight. 
The rituximab administration should be completed at least 30 minutes before 
administration of other study treatments.  The infusion of rituximab may be split over 
2 days if the patient is at increased risk for an IRR (high tumor burden, high peripheral 
lymphocyte count).  Also, in patients who experience an adverse event during the 
rituximab infusion, administration of rituximab may be continued on the following day if 
needed.  If a dose of rituximab is split over 2 days, both infusions must occur with 
appropriate premedication and at the first infusion rate (see Table 2). 
All rituximab infusions should be administered to patients after premedication with oral 
acetaminophen (e.g., 6501000 mg) and an antihistamine such as diphenhydramine 
hydrochloride (50100 mg) 3060 minutes before starting each infusion (unless 
contraindicated).  An additional glucocorticoid (e.g., 100 mg IV prednisone or 
prednisolone or equivalent) is 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.  
Note Do not use the evacuated glass containers that require vented administration sets, 
because this causes foaming as air bubbles pass through the solution.  
The administration of rituximab will be accomplished by slow IV infusion.  Do not infuse 
concomitantly with another IV solution or IV medications. 
Rituximab infusions will be administered according to the instructions outlined in Table 2.  
Please note:  A rapid infusion is not allowed. 


 
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Table 2 
Administration of First and Subsequent Infusions of Rituximab 
First Infusion (Day 1) 
Subsequent Infusions 
x Begin infusion at and initial rate of 
50 mg/hour. 
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/hour. 
If an infusion reaction develops, stop or 
slow the infusion.  Administer 
infusion-reaction medications and 
supportive care in accordance with 
institutional guidelines.  If the reaction 
resolves, resume the infusion at a 50% 
reduction in rate (i.e., 50% of rate being 
used at the time that the reaction 
occurred).  
x If the patient experienced an infusion-related or 
hypersensitivity reaction during the prior 
infusion, begin infusion at an initial rate of 
50 mg/hour and follow instructions for the first 
infusion. 
If the patient tolerated the prior infusion well 
(defined as an absence of Grade 2 reactions 
during a final infusion rate of t 100 mg/hour), 
begin the infusion at a rate of 100 mg/hour. 
If no infusion reaction occurs, increase the 
infusion rate in 100-mg/hour increments every 
30 minutes, to a maximum of 400 mg/hour. 
If an infusion reaction develops, stop or slow 
the infusion.  Administer infusion-reaction 
medications and supportive care in accordance 
with institutional guidelines.  If the reaction 
resolves, resume the infusion at a 
50% reduction in rate (i.e., 50% of rate being 
used at the time that the reaction occurred). 
Note:  A fast infusion is not allowed. 
 
During the treatment period, rituximab must be administered to patients in a setting 
where full emergency resuscitation facilities are immediately available.  Patients should 
be under close supervision of the investigator at all times.  For the management of IRRs 
and anaphylaxis, see Section 5.1.7.2. 
Rituximab should be administered as a slow IV infusion through a dedicated line.  
IV infusion pumps (such as the Braun Infusomat Space) should be used to control the 
infusion rate of rituximab.  Administration sets with PVC, PUR, or PE as a product 
contact surface and IV bags with polyolefin, PP, PVC, or PE as a product contact 
surface are compatible and can be used.  Additional in-line filters should not be used 
because of potential adsorption. 
After the end of the first infusion, the IV line or central venous catheter should remain in 
place for t 2 hours in order to administer IV drugs if necessary.  If no adverse events 
occur after 2 hours, the IV line may be removed or the central venous catheter may be 
de-accessed.  For subsequent infusions, the IV line or central venous catheter should 
remain in place for at least 1 hour after the end of the infusion.  If no adverse events 
occur after 1 hour, the IV line may be removed or the central venous catheter may be 
de-accessed. 
4.3.2.3 
Obinutuzumab 
Obinutuzumab will be administered by IV infusion as an absolute (flat) dose of 1000 mg 
in combination with polatuzumab vedotin and CHP, as outlined in Section 4.3.2.1.  


 
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Obinutuzumab will be administered on Days 1, 8, and 15 of Cycle 1 and on Day 1 of 
Cycles 2-6 or 2-8 (see Table 3).  No dose modifications of obinutuzumab are allowed. 
All obinutuzumab infusions should be administered after premedication with oral 
acetaminophen and an antihistamine (see Section 4.4.1.4).  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.  Premedication with 
prednisone/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 Section 5.1.7.2. 
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 prior studies of obinutuzumab, 100 mg was administered on the first day, with the 
balance (900 mg) administered on the second day. 
Table 3 
Administration of First and Subsequent Infusions of 
Obinutuzumab 
First Infusion (Cycle 1 Day 1) 
Subsequent Infusions 
x 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). 
x 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 infusion-related reaction 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 t 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). 
 
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 Section 5.1.7.2. 


 
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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, PUR, or PE as a 
product contact surface and IV bags with polyolefin, 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.  
After the end of the first infusion, the IV line or central venous catheter should remain in 
place for greater than or equal to 2 hours in order to be able to administer IV drugs if 
necessary.  If no adverse events occur after 2 hours, the IV line may be removed or the 
central venous catheter may be de-accessed.  For subsequent infusions, access (either 
through an IV line or central venous catheter) should remain in place for at least 1 hour 
from the end of the infusion, and if no adverse events occur after 1 hour, the IV access 
may be removed. 
4.3.2.4 
CHP Chemotherapy Dosage and Administration 
CHP chemotherapy consists of cyclophosphamide and doxorubicin administered by IV 
push and oral prednisone or prednisolone.  For information on the order of 
administration, please see Section 4.3.1. 
x 
Cyclophosphamide 750 mg/m2 administered IV on Day 1 
x 
Doxorubicin 50 mg/m2 administered IV on Day 1 
x 
Prednisone 100 mg/day PO on Days 15 
Note:  Prednisone may be replaced with prednisolone (100 mg/day) at sites 
where prednisone is not available or is not the therapy of choice. 
 
Refer to the specific package inserts for preparation, administration, and storage 
guidelines.  Body surface area (BSA) may be capped at 2 m2 per institutional standards. 
The rituximab or obinutuzumab administration should be completed at least 30 minutes 
before administration of other study treatments. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(polatuzumab vedotin, rituximab, obinutuzumab, CHP) will be provided by the Sponsor 
where required by local health authority regulations.  The study site will acknowledge 
receipt of IMPs by returning the appropriate documentation form to confirm the shipment 
condition and content.  Any damaged shipments will be replaced. 
IMPs will either be 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, 
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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. 
4.3.4 
Post-Trial Access to Polatuzumab Vedotin 
The Sponsor (Genentech) is a member of the Roche group and is subject to Roche’s 
global policies.  The Sponsor will offer post-trial access to the study drug polatuzumab 
vedotin free of charge to eligible patients in accordance with the Roche Global Policy on 
Continued Access to IMP, as outlined below. 
A patient will be eligible to receive study drug after the end of the study if all of the 
following conditions are met: 
x 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
x 
There are no appropriate alternative treatments available to the patient 
x 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive study drug after the end of the study if any of the 
following conditions are met:   
x 
The study drug is commercially marketed in the patient’s country and is reasonably 
accessible to the patient (e.g., is covered by the patient’s insurance or wouldn’t 
otherwise create a financial hardship for the patient). 
x 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for DLBCL. 
x 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for DLBCL. 
x 
Provision of study drug is not permitted under the laws and regulations of the 
patient’s country. 
 
The Roche Global Policy on Continued Access to IMP is available at the following Web 
site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days before screening to the study completion/discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications electronic Case Report Form (eCRF). 


 
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Patients who are receiving oral contraceptives, stable doses of hormone-replacement 
therapy, or other maintenance therapy should continue their use. 
Other than prednisone/prednisolone that may be given as pre-phase treatment at the 
discretion of the treating investigator physician (see Section 4.3.1), corticosteroids may 
be used only for the treatment of conditions other than lymphoma (e.g., asthma). 
The use of any calcium channel entry blockers given concomitantly with an anthracycline 
drug may potentially increase the risk of cardiac toxicity associated with anthracycline 
administration.  It is recommended that calcium channel blockers be avoided within 
30 days of the administration of an anthracycline drug when possible and clinically 
appropriate. 
4.4.1.1 
CNS Prophylaxis 
CNS prophylaxis with intrathecal chemotherapy should only be given according to 
institutional practice and its use documented in the eCRF. 
4.4.1.2 
Prophylaxis for Hemorrhagic Cystitis 
Patients should be adequately hydrated before and after cyclophosphamide 
administration and should be instructed to void frequently.  Mesna may be used as 
prophylaxis according to institutional practice. 
4.4.1.3 
Treatment and Prophylaxis of Neutropenia 
The use of G-CSF is allowed for treatment of neutropenia.  G-CSF is strongly 
encouraged, especially in the obinutuzumab-containing cohorts as primary prophylaxis 
in each cycle of therapy (see Appendix 6) per the ASCO guidelines (Smith et al. 2006) or 
following each site’s institutional standards. 
4.4.1.4 
Premedication before Rituximab and Obinutuzumab 
All rituximab and obinutuzumab infusions should be administered to patients after 
premedication.  The following premedication is required before rituximab and 
obinutuzumab therapy:   
x 
Acetaminophen/paracetamol (6501000 mg) PO at least 3060 minutes before the 
start of all infusions 
x 
Antihistamine, such as diphenhydramine (2550 mg), approximately 3060 minutes 
before the start of each infusion (unless contraindicated) 
 
On Cycle 1 Day 1, it is recommended that oral prednisone, prednisolone, or 
methylprednisolone be given within 12 hours as pre-medication, but at least 60 minutes 
prior to the obinutuzumab infusion.  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. 


 
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4.4.1.5 
Infection Prophylaxis 
If clinically indicated, anti-infective prophylaxis for viral, fungal, bacterial or Pneumocystis 
infections is permitted and should be instituted per institutional practice.  Patients in 
countries where prophylactic anti-viral medications for hepatitis B reactivation are the 
standard of care may be treated prophylactically. 
4.4.2 
Prohibited Therapy 
Treatment with other concomitant anti-tumor agents not defined in this protocol as study 
treatment, radiotherapy, or other concurrent investigational agents of any type will result 
in withdrawal of patients from study treatment; however, patients will be followed as 
described in Section 4.5.13.4. 
Use of the following therapies is prohibited during the study: 
x 
Cytotoxic chemotherapy other than CHP and intrathecal chemotherapy for CNS 
prophylaxis 
x 
Immunotherapy or immunosuppressive therapy other than study treatments 
x 
Radioimmunotherapy 
x 
Hormone therapy other than contraceptives, hormone-replacement therapy, or 
megestrol acetate 
x 
Biologic agents other than hematopoietic growth factors, which are allowed if 
clinically indicated and used in accordance with instructions provided in the package 
inserts 
x 
Any therapies (other than intrathecal CNS prophylaxis) intended for the treatment of 
lymphoma whether European Medicines Agencies or U.S. Food and Drug 
Administration (FDA) approved or experimental 
x 
Radiotherapy 
 
4.4.2.1 
Immunizations 
Patients who participate in this study may not receive either primary or booster 
vaccination with live virus vaccines for at least 6 months before initiation of rituximab or 
28 days prior to obinutuzumab 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 before 
study therapy. 
Patients who require the use of any of these agents will be discontinued from study 
treatment. 
4.5 
STUDY ASSESSMENTS  
See Appendix 1 for the schedule of assessments performed during the study. 


 
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4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
Tests that are performed as standard of care before obtaining informed consent may be 
used for screening and baseline assessments, provided that they have been performed 
within the allowable timeframe as described in the schedule of assessments. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.2 
Medical History and Demographic Characteristics 
Medical history includes all clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, and all 
medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 7 days prior to the 
screening visit. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
A complete physical examination should include the evaluation of the head, eyes, ears, 
nose, and throat and cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems.  Any abnormality identified at baseline should 
be recorded on the General Medical History and Baseline Conditions eCRF. 
As part of tumor assessment, physical examinations should also include the evaluation 
of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly.  
These will be recorded into the appropriate eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Targeted physical examinations should be limited to 
systems of clinical relevance (i.e., cardiovascular, respiratory, those associated with 
symptoms, and those associated with tumor assessment [lymph nodes, liver, and 
spleen]).  Changes from baseline abnormalities should be recorded in patient notes.  
New or worsened clinically significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF. 
Formal assessments of peripheral neuropathy, including the use of the Total Neuropathy 
Score (TNS), should also be performed at Day 1 of each cycle. 


 
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4.5.4 
Clinical Total Neuropathy Score Assessment 
Patients may undergo a Clinical Total Neuropathy Assessment 
(Cavaletti et al. 2006, 2007) as shown in the schedule of assessments (see Appendix 1).  
The neuropathy assessments include subjective sensory symptoms, motor symptoms, 
autonomic symptoms and objective pinprick sensitivity and vibration sensitivity) to 
determine their total neuropathy score (see Appendix 9). 
4.5.5 
Vital Signs 
Vital signs include systolic and diastolic blood pressure, heart rate, respiratory rate, 
oxygen saturation as measured by pulse oximetry, and body temperature while the 
patient is in a seated or supine position.  Weight, height, and BSA will also be recorded.  
Height and BSA are required at screening only, unless there has been ! 10% change in 
body weight since the last BSA assessment, in which case BSA should be recalculated 
and documented in the eCRF. 
During rituximab or obinutuzumab administration visits, vital signs are to be obtained 
before infusion of rituximab or obinutuzumab, then after the start of the infusion 
approximately every 15 (r 5) minutes for 90 minutes, then every 30 (r 10) minutes until 
1 hour after the end of the infusion.  
During the administration of polatuzumab vedotin, vital signs should be assessed before 
the start of the infusion, every 15 (r 5) minutes during the infusion, at the end of the 
infusion and every 30 (r 10) minutes for 90 minutes following completion of dosing at 
Cycle 1 and 30 (r 10) minutes following completion of dosing in subsequent cycles. 
Additional monitoring of vital signs should be performed if clinically indicated. 
4.5.6 
Tumor and Response Evaluation 
All evaluable or 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, PET, and/or magnetic 
resonance imaging (MRI) scans, and bone marrow examinations, through use of the 
Revised Response Criteria for Malignant Lymphoma (Juweid and Cheson 2006; Cheson 
et al. 2007; Juweid et al. 2007; see Appendix 2). 
The response criteria for NHL have been updated in Appendix 3.  The Modified Lugano 
Response Criteria (Cheson et al. 2014) will be used to evaluate CR by PET scan at the 
Primary Response Assessment by IRC as stated in the exploratory objective sections.  
The Modified Lugano Response Criteria will also be used to evaluate OR by PET as 
assessed by IRC. 
Radiographic Assessments 
CT and MRI are currently the best available and most reproducible methods for 
measuring target lesions selected for response assessment; conventional CT and MRI 


 
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should be performed with contiguous cuts of d 10 mm in slice thickness.  CT scans (with 
IV and oral contrast) should include the chest, abdomen, and pelvis; 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 regulatory authorities. 
In patients for whom contrast is contraindicated, e.g. patients with contrast allergy or 
impaired renal clearance, CT or combined PET-CT scans without contrast or MRI scans 
are permitted so long as they permit consistent and precise measurement of target 
lesions during the study treatment period.  Details regarding imaging procedures in 
these cases will be provided in the Imaging Manual. 
The same radiographic assessment modality should be used for all response 
evaluations, in order to ensure consistency across different timepoints. 
FDG-PET (hereafter referred as “PET”) scans in conjunction with CT scans will be 
obtained in this study.  CT and PET scans are required at screening, following Cycle 4 of 
study treatment (i.e., at Cycle 4 Days 1521), and at the Treatment Completion/Early 
Termination visit.  End-of-treatment PET scan should be obtained 68 weeks after the 
last dose of study treatment.  However, for patients with suspicion of progressive 
disease at the end of treatment, it is permissible to obtain the PET scan at 4 weeks after 
the last dose of study treatment.  CT scans without PET scans will be obtained every 
6 months thereafter until approximately 2 years following the Treatment 
Completion/Early Termination visit.  Modified Revised Response Criteria for 
Malignant Lymphoma (see Appendix 2) will be used to assess overall response to study 
treatment.  Patients who are assessed to have stable disease or progressive disease at 
the postCycle 4 tumor assessment may be discontinued from study treatment. 
A full tumor assessment including radiographic assessment must be performed any time 
disease progression or relapse is suspected.   
Bone Marrow Assessments 
Bone marrow examinations are required at screening and should include biopsy for 
morphology.  Repeat bone marrow examinations are required only in two circumstances: 
x 
If involved with tumor at screening, a repeat bone marrow examination is required to 
confirm a radiological assessment of CR  
x 
As evidence of relapse (if bone marrow assessment was negative at baseline) and 
there is no radiographic evidence of progression 
 
4.5.7 
Laboratory, Biomarker, and Other Biological Assessments 
Local Laboratory Assessments 
The procedures for the collection, handling, and shipping of laboratory samples are 
specified in the laboratory manuals. 


 
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Samples for hematology, serum chemistry, pregnancy, and hepatitis B and C serology 
and quantitative immunoglobulin assessments will be analyzed at the study site’s local 
laboratory.  Laboratory samples may be obtained up to 72 hours before start of study 
treatment administration on Day 1 of the treatment cycle. 
Samples for the following laboratory tests will be sent to the study site’s local laboratory 
for analysis: 
x 
Hematology:  hemoglobin, platelet count, white blood cell count, and ANC 
x 
Chemistry:  glucose, sodium, potassium, chloride, bicarbonate, urea nitrogen, 
creatinine, calcium, phosphorous, total bilirubin, direct bilirubin, total protein, 
albumin, ALT, AST, LDH, alkaline phosphatase, amylase, lipase, uric acid and 
hemoglobin A1c.  At screening, all samples for laboratory tests will be obtained in a 
fasting state for all patients.  
x 
Pregnancy test 
All women of childbearing potential who are sexually active (including those 
who have had a tubal ligation) will have a serum pregnancy test within 7 days 
before Cycle 1 Day 1 of study treatment.  Women of childbearing potential who 
are not sexually active will have a serum pregnancy test within 28 days before 
Cycle 1 Day 1 of study treatment.  An additional serum pregnancy test will be 
performed at the Treatment Completion/Early Termination visit. 
x 
Coagulation:  aPTT or PTT, PT, and INR 
x 
Viral serology and detection 
Hepatitis B (HBsAg and HBcAb) 
HCV antibody; HCV RNA by PCR if the patient is HCV-antibody positive 
x 
Quantitative immunoglobulins:  IgG, IgA, and IgM 
 
Central Laboratory Assessments 
Samples for the following laboratory test will be sent to one or several central 
laboratories for analysis: 
x 
PK sample assessments (see Appendix 2) 
x 
Immunogenicity assessment (see Appendix 2) 
Serum samples for anti-polatuzumab vedotin antibody 
Serum samples for anti-obinutuzumab antibody 
x 
Flow cytometry (CD19+, CD3+, T cells) 
x 
Analysis of biomarker testing, gene expression, genetic mutations, and epigenetic 
assessment of blood and tissue samples will be performed at Genentech or other 
central laboratories.   
x 
A peripheral blood sample for MRD analysis is required for all patients at C1D1, 
between Cycle 3 Day 15 and Cycle 4 Day 1 and at Treatment Completion Visit. 


 
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x 
Samples collected for PK and immunogenicity analyses may be used for assay 
development, validation and additional characterization, and additional safety and 
immunogenicity assessments, as appropriate. 
x 
Biological samples, if not used up, will be destroyed within 5 years after the final 
clinical study report has been completed, unless the patient gives specific consent 
for the leftover samples to be stored for optional exploratory research (see 
Section 4.5.12). 
 
4.5.8 
Electrocardiogram and Echocardiogram or MUGA 
A 12-lead ECG is required at screening and study treatment termination and as clinically 
indicated.  ECGs for each patient should be obtained using the same machine wherever 
possible.  Representative ECGs at each timepoint should be reviewed by the 
investigator or a qualified designee. 
For assessment of cardiac function (left ventricular ejection fraction), an ECHO or MUGA 
scan is required for all patients at screening and Early Termination visit or Study 
Completion visit.  An ECG, ECHO, or MUGA scan may also be done as clinically 
indicated by an adverse event, including cardiac or cardiovascular adverse events; 
consultation regarding the adverse event should occur with the Medical Monitor.  During 
infusion of doxorubicin, ECG monitoring should be performed per clinical practice. 
4.5.9 
Patient-Reported Outcomes (PRO) 
The TINAS is an 11-item questionnaire scored on a 0 to 10 scale, with 0 being the 
symptom is not present to 10 being the symptom is as bad as the patient can imagine.  
The questionnaire will be analyzed for the individual neuropathy symptoms experienced 
by a patient as well as the calculation of an overall neuropathy severity score.  
Additionally, a single item that asks patients to rate when numbness and tingling was at 
the worst will be used to predict the onset of peripheral neuropathy.  The measure takes 
less than 5 minutes to complete.  See Appendix 10 for a full description of the TINAS. 
The TINAS scale will be completed weekly, preferably on the same day each week over 
the course of study treatment.  Additionally, to collect information about the reversibility 
of peripheral neuropathy, following completion of treatment the TINAS will be completed 
once a week for the first 2 months, then once a month for 10 months. 
The PRO instrument, translated as required into the local language, will be completed by 
the patient on his or her own electronic devices (i.e., mobile phone, tablet, or home 
computer) after the software is distributed by the investigator staff.  If the patient does 
not own their own device, one will be provided by the electronic PRO (ePRO) vendor.  
All measures are to be completed in their entirety by the patient.  To ensure instrument 
validity and that data standards meet health authority requirements, PRO questionnaires 
should be completed prior to the completion of other study assessments and the 
administration of study treatment. 


 
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Patients will use an ePRO device to capture PRO data.  The device will be the patient’s 
own (i.e., mobile phone, tablet, or home computer) with specialized software installed to 
allow for the secure access and transmission of the questionnaire.  The ePRO software 
and instructions for completing the PRO questionnaires electronically will be provided by 
the investigator staff.  The data will be transmitted automatically via Web or wireless to a 
centralized database at the ePRO vendor.  The data can be accessed securely by 
appropriate study personnel securely via the Internet. 
Adverse event reports will not be derived from PRO data by the Sponsor.  However, any 
PRO responses suggestive of a possible adverse event that are identified during site 
review of the PRO data should be reported as outlined in Section 5.4.12. 
4.5.10 
Pharmacokinetic Assessment 
Pharmacokinetics of polatuzumab vedotin will be characterized by measuring total 
antibody (fully conjugated, partially deconjugated and fully deconjugated antibody), 
conjugate (evaluated as acMMAE), and unconjugated MMAE concentrations through 
use of validated methods (see Section 4.7).  Plasma samples may also be analyzed for 
other potential MMAE-containing catabolites, per the Sponsor’s discretion.  
Pharmacokinetics of rituximab will be characterized by measuring rituximab 
concentrations with use of a validated method (see Section 4.7).  Pharmacokinetics of 
obinutuzumab will be characterized by measuring obinutuzumab concentrations with use 
of a validated method (see Section 4.7).  Pharmacokinetics of cyclophosphamide and 
doxorubicin will be assessed at the same time points of Cycle 1 (in the absence of 
polatuzumab vedotin) and Cycle 3 (in the presence of polatuzumab vedotin) to evaluate 
for any potential PK interactions with polatuzumab vedotin.  These assessments will 
allow for further characterization of the pharmacokinetics of polatuzumab vedotin, the 
assessment of the drug interaction potential when they are given in combination with 
rituximab, cyclophosphamide, and doxorubicin, and the investigation of potential 
correlations between PK parameters and safety and/or activity, if data allow and per the 
Sponsor’s discretion. 
4.5.11 
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 polatuzumab vedotin.  Patient samples will be 
first screened to detect all antibody responses to polatuzumab vedotin.  Samples that 
screen positive will be analyzed in a confirmatory assay (competitive binding with 
polatuzumab vedotin) to assess the specificity of the positive response.  Confirmed 
positive samples will be further characterized by competitive binding with the MAb 
component of polatuzumab vedotin to characterize whether the ATA responses are 
primarily to the MAb or the linker-drug regions of the ADC.  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. 


 
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ATA responses to obinutuzumab will be detected and confirmed using a similar tiered 
approach.  Patient samples will be first 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. 
4.5.12 
Samples for Roche Clinical Repository 
Genentech is a member of the Roche group and participates in the collection and/or 
submission of biological samples to the Roche Clinical Repository (RCR).  Collection 
and submission of biological samples to the RCR is contingent upon the review and 
approval of the RCR portion of the Informed Consent Form by each site’s Institutional 
Review Board or Ethics Committee (IRB/EC) and, if applicable, an appropriate 
regulatory body.  If a site is not granted the necessary approval for RCR sampling, this 
section of the protocol will not be applicable at that site. 
Overview of the Roche Clinical Repository 
The RCR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients in the future. 
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives: 
x 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
x 
To increase knowledge and understanding of disease biology 
x 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
x 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
Approval by the Institutional Review Board or Ethics Committee 
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's IRB or EC and, if applicable, an appropriate regulatory 
body.  If a site has not been granted approval for RCR sampling, this section of the 
protocol (Section 4.5.12) will not be applicable at that site. 


 
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Sample Collection 
The following samples will be collected for research purposes, including but not limited 
to research on dynamic (non-inherited) biomarkers: 
x 
Residual tumor sample from lymph node biopsy may be submitted at the screening 
visit for DNA, RNA, or protein extraction 
x 
Residual samples of peripheral blood and bone marrow aspirates from MRD 
analysis 
 
The following samples will be collected for research purposes, including but not limited 
to research on genetic (inherited) biomarkers: 
x 
Whole blood samples for DNA, RNA, or protein extraction will be drawn at the 
screening visit and at the end of treatment 
 
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the laboratory manual.   
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.   
Confidentiality 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is “double-coded” by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A “linking key” between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche’s Legal Department, as applicable. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 


 
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Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient’s agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant’s death or loss of competence, the participant’s 
specimens and data will continue to be used as part of the RCR research. 
 
Withdrawal from the Roche Clinical Repository 
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient’s wishes through use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient’s withdrawal 
from Study GO29044 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient’s withdrawal from the RCR does not constitute withdrawal 
from Study GO29044. 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice (GCP) 
by a quality-controlled, auditable, and appropriately validated laboratory information 


 
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management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples. 
4.5.13 
Timing of Study Assessments 
4.5.13.1 
Screening and Pretreatment Assessments 
All screening evaluations must be completed and reviewed by the investigator to confirm 
that patients meet all eligibility criteria and are approved for enrollment before the first 
study treatment infusion.  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 the time 
frame specified in Appendix 1 relative to Cycle 1 Day 1.  Results of standard-of-care 
tests or examinations performed before obtaining informed consent and within the 
timelines specified by Appendix 1 may be used; such tests do not need to be repeated 
for screening. 
An Eligibility Screening Form documenting the investigator’s assessment of each 
screened patient with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator. 
Refer to the Study Flowchart provided in Appendix 1 for the schedule of screening and 
pretreatment assessments. 
4.5.13.2 
Assessments during Treatment 
Adverse events, serious adverse events, and concomitant medication information should 
be recorded throughout the study.   
Study visits for Cycle 1 through the Treatment Completion/Early Termination Visit should 
occur within r 2 days from the scheduled date unless otherwise noted.  That is, the 
Treatment Completion/Early Termination Visit and all subsequent follow-up visits should 
occur within r 1 week of 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 before study drug infusion unless otherwise noted. 


 
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Local laboratory assessments may be performed within 72 hours preceding study drug 
administration on Day 1 of each cycle.  Results must be reviewed and the review 
documented before study drug administration. 
If a visit is scheduled on a holiday that precludes protocol-specified procedure, the 
procedure should be performed on the nearest following date.  Subsequent 
protocol-specified procedures should remain synchronized with Day 1 of the most recent 
cycle. 
Refer to the Study Flowchart provided in Appendix 1 for the schedule of treatment period 
assessments. 
4.5.13.3 
Study Treatment Completion Visit 
Patients who complete the study treatment or discontinue from study treatment early will 
return 30 days after the last dose of study treatment for the study Treatment Completion 
visit or Early Termination visit. 
For patients who have progressive disease during the treatment period, the visit at which 
a response assessment shows disease progression may be used as the Treatment 
Completion/Early Termination visit.  Assessment of disease progression based on 
clinical examination must be confirmed by radiographic assessment as soon as 
practicable. 
Refer to the Study Flowchart in Appendix 1 for assessments to be performed at the 
Treatment Completion/Early Termination visit. 
4.5.13.4 
Follow-Up Assessments 
After completion of study treatment (Section 4.5.13.3), all patients will continue to be 
followed according to the schedule outlined in Appendix 1. 
If response assessment shows PD during the follow-up period, assessments at 
subsequent visits will be limited (see Appendix 1).  Diagnosis of disease progression 
based on clinical examination must be confirmed by CT scan as soon as possible 
(maximum, within 4 weeks) and prior to any NALT. 
After a patient has PD during follow-up and starts a NALT, contact will be made with 
patients by telephone on an annual basis for survival. 
Patients who discontinue study treatment early because of adverse event, and start a 
NALT in the absence of PD should be followed according to Appendix 1 unless they 
withdraw consent. 
Ongoing adverse events related to study treatment will be followed until the event has 
resolved to baseline (pretreatment) grade or better, the event is assessed by the 
investigator as stable, the patient is lost to follow-up, the patient withdraws consent, or 


 
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when it has been determined that the study treatment or participation is not the cause of 
the adverse event.  Such follow-up will require an assessment (per verbal report, at 
minimum) of any adverse events and serious adverse events for 90 days after the last 
dose of study drug or until the patient receives another anti-cancer therapy, whichever 
occurs first. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
x 
Patient withdrawal of consent at any time 
x 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
x 
Investigator or Sponsor determines it is in the best interest of the patient 
x 
Patient non-compliance (i.e., consistent failure to show up for scheduled visits, 
consistent missed treatment, etc.) 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
x 
Pregnancy 
x 
Documented disease progression/relapse or in the absence of OR (PR or CR) at the 
tumor assessment following Cycle 4 of treatment (i.e., at Cycle 4 Days 1521). 
x 
Unacceptable toxicity (as described in Section 3.1.1) 
x 
Patient/investigator decision.  In these cases, patients should continue to be 
followed for both resolution of toxicity and disease progression as described in 
Section 4.5.13.4 and Appendix 1. 
 
The reasons for early discontinuation of treatment must be documented on the 
appropriate eCRF. 
In the event that a patient discontinues from study treatment early for reasons other than 
documented disease progression/relapse, he or she will proceed into the follow-up 
period until progression. 


 
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The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
x 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
x 
Patient enrollment is unsatisfactory. 
x 
Data recording is inaccurate or incomplete 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
The Sponsor has the right to close or replace a site at any time.  Reasons for closing or 
replacing a site may include, but are not limited to, the following: 
x 
Excessively slow recruitment 
x 
Poor protocol adherence 
x 
Inaccurate or incomplete data recording 
x 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
GCP 
x 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
 
4.7 
ASSAY METHODS 
4.7.1 
Total Polatuzumab Vedotin Antibody ELISA 
Total polatuzumab vedotin antibody (fully conjugated, partially deconjugated and fully 
deconjugated antibody) will be measured in serum samples with use of validated ELISAs. 
4.7.2 
Conjugated (Evaluated as Antibody-Conjugated MMAE) Affinity 
Capture Enzyme-Release LC/MS/MS 
acMMAE (a measure of MMAE conjugated to polatuzumab vedotin) will be measured in 
plasma samples with use of a validated affinity-capture enzyme-release liquid 
chromatography tandem mass spectrometry (LC/MS/MS) assay. 
4.7.3 
Unconjugated MMAE LC/MS/MS 
Unconjugated MMAE will be measured in plasma samples using a validated LC/MS/MS 
method. 
4.7.4 
Rituximab ELISA 
Rituximab will be measured in serum samples using a validated ELISA.   


 
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4.7.5 
Obinutuzumab ELISA 
Obinutuzumab will be measured in serum samples using a validated ELISA. 
4.7.6 
Cyclophosphamide LC/MS/MS 
Cyclophosphamide will be measured in plasma samples with use of a validated 
LC/MS/MS method. 
4.7.7 
Doxorubicin LC/MS/MS 
Doxorubicin will be measured in plasma samples with use of a validated LC/MS/MS 
method. 
4.7.8 
Polatuzumab Vedotin Anti-Therapeutic Antibody 
ATAs against polatuzumab vedotin in serum samples will be measured using validated 
bridging antibody ELISA and characterized by competitive binding assays. 
4.7.9 
Obinutuzumab Anti-Therapeutic Antibody 
ATAs against obinutuzumab in serum samples will be measured using a validated 
bridging antibody ELISA. 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
Polatuzumab vedotin is not approved and is currently in clinical development; the entire 
safety profile is not known at this time.  The safety plan for this study is designed to 
ensure patient safety and will include specific eligibility criteria and monitoring 
assessments as detailed below. 
Safety will be evaluated through the monitoring of the following: 
x 
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 
x 
All adverse events, including serious and non-serious adverse events, from Cycle 1 
Day 1 until 90 days after the last dose of study treatment. 
x 
Measurements of protocol-specified hematology and clinical chemistry laboratory 
values 
x 
Measurements of protocol-specified vital signs 
x 
Assessment of ECGs and ECHOs or MUGA scans 
x 
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 or better, the event is assessed by the investigator 
as stable, the patient is lost to follow-up, the patient withdraws consent, when it has 


 
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been determined that the study treatment or participation is not the cause of the adverse 
event, or when the study is terminated (see Section 4.5.13.4 for details of follow-up). 
5.1.1 
Risks Associated with Polatuzumab Vedotin 
The clinical safety profile of polatuzumab vedotin based on clinical data obtained in the 
ongoing Phase I and Phase II studies is summarized in Section 1.2.1.  On the basis of 
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 Section 4.3.  Refer also to the Investigator’s Brochure for 
complete and updated details. 
5.1.1.1 
Known Risks:  Neutropenia and Peripheral Neuropathy 
Based on clinical experience with polatuzumab vedotin in patients treated in the current 
Phase I and Phase II studies, neutropenia including febrile neutropenia and peripheral 
neuropathy are identified risks of polatuzumab vedotin.  
Neutropenia including Febrile Neutropenia 
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 may be delayed or modified for hematologic toxicities as 
described in Table 5.  The use of G-CSF for neutropenia is described in Section 4.4.1.3. 
Peripheral Neuropathy (Sensory and/or Motor) 
Patients receiving polatuzumab vedotin may develop peripheral neuropathy (sensory 
and/or motor).  Patients in clinical trials with polatuzumab vedotin should be monitored 
for symptoms of neuropathy, including hypoesthesia, hyperesthesia, paresthesia, 
dysesthesia, discomfort, a burning sensation, weakness, gait disturbance, or 
neuropathic pain.  Patients experiencing new or worsening peripheral neuropathy may 
require a dose delay, change in dose, or discontinuation of treatment and should be 
managed according to the protocol. 
Study treatment dose and schedule modifications for peripheral neuropathy are 
described in Table 5. 
5.1.2 
Potential Risks 
5.1.2.1 
Effects on the Relative Dose Intensity of R-CHP or G-CHP 
Depending upon the toxicity profile observed with the addition of polatuzumab vedotin to 
R-CHP or G-CHP there may be a reduction in the relative DI of R-CHP or G-CHP that is 
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5.1.2.2 
Potential Risks Associated with Polatuzumab Vedotin 
Infections 
There are several factors in the patient population under study that influence their 
vulnerability to a higher risk of infections, particularly serious and opportunistic infections, 
including a single report of PML (see Polatuzumab vedotin IB version 7).  The risk 
factors include pre-disposition of the indication disease to infections, elderly population, 
comorbidity, impaired capacity of bone marrow recovery with multiple lines of prior anti-
cancer therapies. 
In addition, neutropenia is an ADR for polatuzumab vedotin.  Reports in the literature 
state that granulocytopenia, is a major predisposing factor to infections in patients with 
B-cell lymphoma.  The reported incidence of infection in chemotherapy courses for B-cell 
lymphoma associated with  500 granulocytes /μL was higher than those with 
t 500 granulocytes /μL.  Neutropenia events should be monitored closely and any signs 
of infection should be treated as appropriate. 
Infections of all grades have been reported in phase I and II clinical trials for 
polatuzumab vedotin.  Fatal outcome has been reported in 5 patients, all in the Phase I 
study. 
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, because 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 that are mediated through 
direct release of cytokines or other pro-inflammatory mediators.  Such reactions are 
often termed “infusion-related reactions.”  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 pretreatment 
with various medications. 
Allergic/anaphylactic reactions and IRRs typically begin during or within several hours 
after completing the infusion.  The onset of symptoms may be rapid, and some reactions 
may be life threatening. 
Because of the potential for infusion reactions with protein drugs, administration of 
polatuzumab vedotin will be performed in a setting with access to emergency equipment 
and staff who are trained to monitor and respond to medical emergencies.  All patients 
will be monitored for infusion reactions during the infusion and immediately afterward (for 
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Section 4.3.2.2).  Precautions for suspected anaphylactic reaction during study drug 
infusions are provided in Appendix 7.  The initial dose of polatuzumab vedotin may be 
administered with premedication with acetaminophen, antihistamines, or corticosteroids 
per institutional standard practice at the discretion of the Investigator.  Premedication 
should be instituted for subsequent doses if IRRs are observed in patients who receive 
their first dose of polatuzumab vedotin without premedications (see Section 4.3.2.2).  
Significant issues with polatuzumab vedotin IRRs have not been observed. 
Similar considerations regarding infusion reactions are applicable for rituximab and 
obinutuzumab.  Refer to Section 5.1.4 and Section 5.1.5.1 for additional information. 
Tumor Lysis Syndrome 
There is a potential risk of TLS if treatment with polatuzumab vedotin 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 t 25 u 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 t 300 mg/day PO or a 
suitable alternative treatment [according to institutional practice] starting before study 
treatment, refer to Section 5.1.7.1) and must be well hydrated before the initiation of 
study treatment at Cycle 1 Day 1.  These patients should continue to receive repeated 
prophylaxis with allopurinol and adequate hydration before each subsequent infusion, 
as deemed appropriate by the investigator. 
Bone Marrow Toxicity 
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 may be delayed or modified for 
hematologic toxicities as described in Table 5. 
Transfusion support for anemia and thrombocytopenia is also permitted at the discretion 
of the treating physician. 
Immunogenicity (anti-therapeutic antibodies) 
As with any recombinant antibody, polatuzumab vedotin may elicit an immune response 
and patients may develop antibodies against polatuzumab vedotin.  Patients will be 
closely monitored for any potential immune response to polatuzumab vedotin.  
Appropriate screening, confirmatory, and characterization assays will be employed to 
assess ATAs before, during, and after the treatment with polatuzumab vedotin.  Given 
the historically low immunogenicity rate of rituximab in NHL patients, ATAs against 
rituximab will not be monitored in this study. 


 
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Reproductive Toxicity 
Adverse effects on human reproduction and fertility are anticipated with the 
administration of polatuzumab vedotin given the mechanism of action of MMAE.  
Standard exclusion criteria are used to ensure that patients with reproductive potential 
(male or female) are using adequate contraceptive methods.  
Hyperglycemia 
Hyperglycemia has been observed in patients treated with polatuzumab vedotin as well 
as with other ADCs that use 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. 
GI Toxicity (diarrhea, nausea, vomiting, constipation, anorexia) 
Diarrhea, constipation, anorexia, nausea and vomiting are reported frequently with 
diarrhea and nausea being the most common (t 30 %) treatment-emergent AEs in 
Phase I and II clinical studies using polatuzumab vedotin.  With the exception of one 
event (Grade 4 diarrhea), all events were of Grade 13 severity.  Diarrhea has been 
responsible for study drug modification and discontinuation.  Most cases were low grade 
with more serious cases being confounded by poly pharmacy and comorbidity and 
disease under study 
Hepatotoxicity 
Hepatotoxicity has been observed in patients treated with polatuzumab vedotin in both 
the Phase I and Phase II trials.  Although the relationship between hepatotoxicity and 
polatuzumab vedotin has not been definitively determined, transient, dose-related 
increases in hepatic enzymes were noted in nonclinical rat studies.  No hepatotoxicity 
was noted following administration of the surrogate ADC in cynomolgus monkeys.  
Elevations of transaminases have been reported in several patients receiving 
polatuzumab vedotin and have ranged in intensity from Grade 14.  These have been 
reversible with and without dose modification/discontinuation.  One event each of 
hepatomegaly/hepatic steatosis, cholecystitis acute, or hepatocellular injury has also 
been reported.  For additional information please refer to the current version of the IB. 
Pulmonary toxicity (Interstitial lung diseases) 
Pulmonary toxicities have been reported from the ongoing clinical trials of similar ADCs 
with the same linker and cytotoxic agent MMAE. As there is no identified antibody 
antigen binding in the lung, this is considered to be possibly due to MMAE. 
No events of pulmonary toxicities (interstitial lung disease) were reported in the Phase I 
study and three patients reported events of pulmonary toxicity(Pneumonitis, Pulmonary 
fibrosis and ILD) in Study GO27834 (Grade12).  None of them were considered related 
to study drug by the investigator.  


 
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Joint pain/arthralgia/skeletal pain 
Musculoskeletal pain, back pain and/or arthralgia have been reported as Grade 13 
treatment-emergent adverse events in clinical studies using polatuzumab vedotin. 
Cardiac Arrythmia 
Serious and non-serious cardiac arrhythmia events have been observed in clinical trials 
using polatuzumab vedotin.  The highest grade event reported was Grade 4.  No 
clinically significant QTc prolongations were reported.  For additional information, please 
refer to the latest IB.  
Renal Toxicity 
Preliminary safety observations in clinical trials with ADCs using the same linker and 
MMAE have suggested that some patients experience reduction of renal function during 
clinical trials. 
Three patients experienced acute renal failure events. In all three, the events occurred in 
patients who received combination treatment of 2.4 mg/kg polatuzumab vedotin and 
rituximab.  For additional information, please refer to the latest IB.  
Ocular Toxicity 
Treatment-emergent non-serious low grade severity ocular AEs were reported in 
Phase I/II clinical trials using polatuzumab vedotin.  The broad spectrum of the reported 
terms of individual AEs did not suggest a pattern of a specific ophthalmologic toxicity.  
There was no evidence of permanent disabilities or treatment discontinuations reported.  
Most events were reversible as far as information was available. 
Alopecia 
Alopecia (Grades 12) has been reported as treatment-emergent adverse events in 
patients receiving polatuzumab vedotin as single-agent or in combination in clinical 
studies. 
Dysgeusia 
Treatment-emergent AEs of dysgeusia or alteration of taste have been experienced by 
patients receiving ADC-vc-MMAEs which are in the same class as polatuzumab vedotin. 
Non-serious Grade 12 AEs of dysgeusia or taste alteration were reported in Phase I/II 
clinical studies using polatuzumab vedotin. 
Genotoxicity/carcinogenicity (myelodysplastic syndrome) 
MMAE, the cytotoxic component of polatuzumab vedotin, is a microtubule inhibitor 
targeting rapidly dividing cells and is expected to be carcinogenic.  Patients who 
received chemotherapy with vincristine sulfate in combination with anticancer drugs 
known to be carcinogenic have developed second malignancies, although the 
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Two cases of Grade 4 myelodysplastic syndrome have been reported in patients with r/r 
FL in Phase I and II clinical trials using polatuzumab vedotin.  Both SAEs led to study 
treatment discontinuation. 
5.1.3 
Risks Associated with Cyclophosphamide, Doxorubicin, and 
Prednisone 
The toxicity profile of CHP in the absence of vincristine is not well characterized; the side 
effects noted in this section are largely taken from the risks associated with the CHOP 
regimen. 
The administration of CHP can be associated with nausea, vomiting, hair loss, 
leukopenia, anemia, thrombocytopenia, headache, elevated liver function tests, and 
dizziness.  All patients who receive CHP are at risk for developing infections.  
Cyclophosphamide has been associated with hemorrhagic cystitis. 
Doxorubicin has been associated with myocardial toxicity, manifested as congestive 
heart failure, which may occur either during therapy or months to years after termination 
of drug use.  
Prednisone may cause fluid retention, depression, and glucose intolerance and, upon 
withdrawal, has been associated with adrenal insufficiency. 
For CHP dose delay, modification, and discontinuation instructions, see Table 5. 
Please see the prescribing information for cyclophosphamide, doxorubicin, and 
prednisone for full information. 
5.1.4 
Risks Associated with Rituximab Therapy 
Please see the prescribing information and IB for rituximab for full information. 
a. Infusion-Related Reactions 
Patients treated with rituximab in combination with chemotherapy are at risk for IRRs.  
Fatal infusion reactions within 24 hours of rituximab infusion can occur; approximately 80% 
of fatal reactions occurred with the first infusion.  Severe reactions to rituximab typically 
occurred during the first infusion with time to onset of 30120 minutes.  Rituximab-
induced infusion reactions and sequelae include urticaria, hypotension, angioedema, 
hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, 
myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or 
death. 
Because of the potential for severe infusion reactions with rituximab, rituximab 
administration will occur in a setting with emergency equipment and staff who are trained 
to monitor for and respond to medical emergencies.  Medications and supportive care 
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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. 
Patients should receive premedication with acetaminophen/paracetamol, antihistamines, 
or corticosteroids, in accordance with standard clinical practice, before rituximab 
infusions. 
The rituximab infusion should be interrupted for severe reactions on the basis of clinical 
judgment.  In most cases, the infusion can be resumed at a 50% reduction in rate (e.g., 
from 100 mg/hour to 50 mg/hour.) 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 (t 25,000/μL) 
with or without evidence of high tumor burden. 
Additional details of anaphylaxis management are provided in Appendix 7. 
b. Tumor Lysis Syndrome 
Patients may be at risk for TLS.  With rituximab treatment, acute renal failure, 
hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, 
some fatal, can occur within 1224 hours after the first infusion of rituximab in patients 
with NHL.  A high number of circulating malignant cells (t 25,000/mm3) or high tumor 
burden confers a greater risk of TLS.  For patients with evidence of TLS, rituximab 
should be interrupted and the patient treated through a correction of electrolyte 
abnormalities, monitoring of renal function and fluid balance, and administration of 
supportive care, including dialysis, as clinically 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. 
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 4.3.2.2). 
c. Hepatitis B Exposure 
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and 
death can occur in patients with hematologic malignancies treated with rituximab.  The 
median time to the diagnosis of hepatitis was approximately 4 months after the initiation 
of rituximab treatment and approximately 1 month after the last dose. 
Patients with evidence of prior hepatitis B exposure or who are carriers (defined as 
HBsAg negative and HBcAb positive) are at a lower risk for reactivation.  In a study of 
51 hepatitis B carriers with DLBCL who received rituximab, 12% of patients developed 
evidence of reactivation (Niitsu et al. 2010). 


 
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Patients with serologic findings consistent with chronic HBV (HBsAg positivity and/or 
total HBcAb) or HCV infection (HCV RNA) are ineligible for this study. 
Patients who demonstrate evidence of reactivation of hepatitis will discontinue study 
treatment.   
d. Progressive Multifocal Leukoencephalopathy 
Rare cases of progressive multifocal leukoencephalopathy (PML) have also been 
reported in patients treated with rituximab alone or in combination with other 
immunosuppressive medications (Goldberg et al. 2002; Calabrese et al. 2007; Carson et 
al. 2009).  In a review of 57 patients who developed PML after rituximab administration, 
all patients had received prior therapies with alkylating agents, corticosteroids, purine 
analogs, or drugs to prevent allogeneic stem-cell or solid-organ graft rejection.  The 
diagnosis of PML in any patient treated with rituximab is extremely rare but should be 
suspected in any patient who develops new-onset neurologic manifestations.  The 
majority of patients with hematologic malignancies diagnosed with PML received 
rituximab in combination with chemotherapy or as part of a hematopoietic stem-cell 
transplant.  Most cases of PML were diagnosed within 12 months of the patients’ 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 MRI, and lumbar puncture.  Physicians should 
discontinue rituximab (and polatuzumab vedotin) and consider discontinuation or 
reduction of any immunosuppressive therapy in patients who develop PML. 
e. Cardiac Toxicity 
Angina and cardiac arrhythmias have occurred with rituximab treatment and can be life 
threatening.  Treatment with CHP chemotherapy is a known risk factor for cardiotoxicity, 
and to mitigate this risk, patients will be required to undergo assessments of left 
ventricular ejection fraction at baseline and at the Treatment Completion Visit/Early 
Termination Visit. 
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. 
f. 
Infection 
Serious infections, including fatal bacterial, fungal, and new or reactivated viral infections, 
can occur during and up to 1 year following the completion of rituximab-based therapy.  


 
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New or reactivated viral infections include cytomegalovirus, herpes simplex virus, 
parvovirus B19, Varicella zoster virus, West Nile virus, and hepatitis B and C. 
g. Severe Mucocutaneous Reactions 
Severe reactions, including fatal mucocutaneous reactions, can occur in patients 
receiving rituximab.  These reactions include paraneoplastic pemphigus, 
StevensJohnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic 
epidermal necrolysis.  The onset of these reactions in patients treated with rituximab has 
varied from 1 to 13 weeks following rituximab exposure.  Stevens-Johnson syndrome 
and toxic epidermal necrolysis are considered mandatory as SAEs regardless of their 
clinical grade. 
h. Bowel Obstruction and Perforation 
Abdominal pain, bowel obstruction, and perforation, in some cases leading to death, can 
occur in patients receiving rituximab in combination with chemotherapy.  In 
post-marketing reports of rituximab, the mean time to documented gastrointestinal 
perforation was 6 days (range, 177) in patients with NHL. 
5.1.5 
Risks Associated with Obinutuzumab 
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. 
5.1.5.1 
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, 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. 
5.1.5.2 
Tumor Lysis Syndrome 
TLS has been reported with obinutuzumab administration.  To date, no patient has 
required hemodialysis for renal failure.  Patients with a high tumor burden, including 


 
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patients with a lymphocyte count t 25 u 109/L, particularly patients with B-cell CLL and 
mantle cell lymphoma, are at increased risk for TLS and severe IRRs. 
5.1.5.3 
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 
of neutropenia in this study.  Primary prophylaxis with G-CSF is strongly recommended, 
especially in the obinutuzumab-containing cohort, according to the ASCO, EORTC, and 
European Society for Medical Oncology (ESMO) guidelines (see Appendix 6). 
5.1.5.4 
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. 
5.1.5.5 
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. 
Reactivation of hepatitis B as well as other serious viral infections (e.g., infections 
caused by cytomegalovirus, Varicella zoster virus, herpes simplex virus, John 
Cunningham [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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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. 
5.1.5.6 
Worsening of Cardiac Conditions 
In patients with underlying cardiac disease, arrhythmias (such as atrial fibrillation and 
tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and 
heart failure have occurred when treated with obinutuzumab. 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 
in order to prevent a potential fluid overload. 
5.1.5.7 
Gastro-Intestinal (GI) Perforation 
GI perforation has been reported in patients treated with obinutuzumab including fatal 
events. Patients with GI involvement should be monitored for signs of GI perforation. 
5.1.6 
Management of Specific Adverse Events 
Guidelines for management of specific adverse events are outlined in Table 5.  
Additional guidelines are provided in the subsections below. 
5.1.6.1 
Dose Delays and Dose Modifications 
Patients should be assessed clinically for toxicity before each dose using 
NCI CTCAE v4.0 unless otherwise stated.  These guidelines pertain to dose delays and 
modifications based on physical examination findings, observed toxicities, and laboratory 
results obtained within 72 hours before study treatment administration.  Dosing will occur 
only if a patient’s clinical assessment and laboratory test values are acceptable.  Dosing 
of polatuzumab vedotin beyond Cycle 1 (i.e., at Cycle 2 and beyond) may be delayed, 
depending on the rapidity for reversal of toxicity as discussed in Table 5.  Dose delays 


 
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beyond 2 weeks will require Medical Monitor approval.  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 Cycles 26 (or 8) are detailed below.  
Patients who are receiving study treatment and experience toxicities should undergo 
dose interruptions and reductions, per instructions in Table 5.  All considerations of dose 
and schedule modifications should be discussed with and approved by the Medical 
Monitor.  Any patient in whom similar toxicity recurs at the reduced dose should be 
discontinued from further polatuzumab vedotin treatment. 
5.1.6.2 
Dose Modifications 
No dose modifications of rituximab (375 mg/m2) or obinutuzumab (1000 mg) are allowed. 
CHP and polatuzumab vedotin doses may be reduced (per the guidelines outlined in 
Table 5 with the approval of the Medical Monitor.  Doses of polatuzumab vedotin will not 
be reduced to  1.0 mg/kg. 
5.1.6.3 
Schedule Modification 
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. 
5.1.7 
Management of Toxicities R-CHP or G-CHP and Polatuzumab 
Vedotin 
5.1.7.1 
Tumor Lysis Syndrome 
Patients with high tumor burden and who are considered by the investigator to be at risk 
for tumor lysis should also receive tumor lysis prophylaxis before the initiation of 
treatment.  Patients should be well hydrated.  Starting 1 or 2 days before the first dose of 
study treatment, it is desirable to maintain a fluid intake of approximately 3 L/day.  In 
addition, all patients with high tumor burden and who are considered to be at risk for 
tumor lysis should be treated with 300 mg/day of allopurinol PO or a suitable alternative 
treatment starting 4872 hours before Cycle 1 Day 1 of treatment and hydration.  
Patients should continue to receive repeated prophylaxis with allopurinol and adequate 
hydration before each subsequent infusion, if deemed appropriate by the investigator. 
For patients with evidence of TLS, all study treatment should be interrupted and the 
patient should be treated as clinically indicated.  Following the complete resolution 
of TLS complications, treatment with R-CHP or G-CHP and polatuzumab vedotin may be 
resumed at the full dose at the next scheduled infusion in conjunction with prophylactic 
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5.1.7.2 
Infusion-Related Reactions and Anaphylaxis 
Medications including epinephrine for subcutaneous injections, corticosteroids, 
diphenhydramine hydrochloride for IV injection and resuscitation equipment should be 
available for immediate use.  Management of infusion-related symptoms for rituximab is 
summarized in Table 4 according to the administration rates in Section 4.3.2.2. 
In the event of a life-threatening IRR (which may include pulmonary or cardiac events) or 
IgE-mediated anaphylactic reaction, study treatment should be discontinued and no 
additional drug should be administered.  Patients who experience any of these reactions 
should receive aggressive symptomatic treatment and will be discontinued from study 
treatment.  See Section 5.1.7.2 for recommended management of anaphylaxis. 
Patients who experience rituximab-associated infusion-related temperature elevations of 
! 38.5°C or other minor infusion-related symptoms may be treated symptomatically with 
acetaminophen (t 500 mg) and/or H1- and H2-histamine–receptor antagonists (e.g., 
diphenhydramine hydrochloride) and 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, E2-agonists, epinephrine, and/or corticosteroids) 
as clinically indicated according to standard clinical practice.  See Section 5.1.7.2 for 
recommended management of anaphylaxis.  Guidelines for the management of IRRs 
and anaphylaxis are detailed in Table 4.  Dose reductions are detailed in Table 5 and 
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Table 4 
Management of Infusion-Related Symptoms 
Infusion-Related Symptoms 
Guidance 
Grade 12 
x 
Slow or hold infusion. 
Give supportive treatment a. 
Upon symptom resolution, may resume infusion-rate 
escalation at the investigator’s discretion. 
Note:  For Grade 2 wheezing or urticaria, patient must be 
premedicated for any subsequent doses.  If symptoms recur, 
the infusion must be stopped immediately and patient 
permanently discontinued from study drug. 
Grade 3 
x 
Discontinue infusion. 
Give supportive treatment a. 
Upon symptom resolution, may resume infusion-rate 
escalation, at investigator discretion b. 
Note:  If the same adverse event recurs with same severity, 
treatment must be permanently discontinued. 
Note:  For Grade 3 hypotension or fever, patient must be 
premedicated before re-treatment.  If symptoms recur, then 
patient must be permanently discontinued from study drug. 
Note:  If patient has Grade 3 wheezing, bronchospasm, or 
generalized urticaria at first occurrence, patient must be 
permanently discontinued from study drug. 
Grade 4 
x 
Discontinue infusion immediately, treat symptoms 
aggressively, and permanently discontinue study drug. 
Note:  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. 
a Supportive treatment:  Patients should be treated with acetaminophen/paracetamol and an 
antihistamine such as diphenhydramine if they have not been received in the previous 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 who require vasopressor support must be 
permanently discontinued from study drug. 
b 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/hour every 30 minutes. 
 
5.1.7.3 
Neutropenia 
Because neutropenia is a known risk of polatuzumab vedotin (see Section 5.1.1.1), the 
use of growth factor support (G-CSF) as prophylactic and therapeutic indications should 
be implemented (see Appendix 6) in order to allow continued dosing of polatuzumab 
vedotin. 
Dose and schedule modifications for neutropenia are detailed in Table 5 and Table 6.  
These guidelines pertain to dose delays and modifications based on physical 
examination findings, observed toxicities, and laboratory results obtained within 72 hours 
before study treatment administration.  Dose delays and dose modifications due to 
adverse events not specified in Table 5 should proceed on the basis of the principle of 
maintaining the DI of R-CHP or G-CHP.  The determination of all dose and schedule 


 
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modifications will be made on the basis of the investigator’s assessment of ongoing 
clinical benefit with continuing study treatment in consultation with and with the approval 
of the Medical Monitor. 
No dose modifications of rituximab are allowed.  Cyclophosphamide, doxorubicin, and 
polatuzumab vedotin doses may be re-escalated (even to the full dose) with the approval 
of the Medical Monitor. 
If administration of chemotherapy is delayed, the administration of rituximab or 
obinutuzumab and CHP should be delayed for the same time frame; for example, if CHP 
therapy is delayed, administration of rituximab or obinutuzumab should also be delayed 
so that they are given together beginning on Day 1 of the same cycle. 
5.1.7.4 
Dose Delays and Dose Modifications 
Guidelines for dose delay and modification of R-CHP or G-CHP and polatuzumab 
vedotin are shown in Table 5 and Table 6.  These guidelines pertain to dose delays and 
modifications based on physical examination findings, observed toxicities, and laboratory 
results obtained within 72 hours before study treatment administration.  Dose delays and 
dose modifications due to adverse events not specified in Table 5 should proceed on the 
basis of the principle of maintaining the DI of R-CHP or G-CHP.  The determination of all 
dose and schedule modifications will be made on the basis of the investigator’s 
assessment of ongoing clinical benefit with continuing study treatment in consultation 
with and with the approval of the Medical Monitor. 
No dose modifications of rituximab are allowed.  Cyclophosphamide, doxorubicin, and 
polatuzumab vedotin doses may be re-escalated (even to the full dose) with the approval 
of the Medical Monitor. 
If administration of chemotherapy is delayed, the administration of rituximab or 
obinutuzumab and CHP should be delayed for the same time frame; for example, if CHP 
therapy is delayed, administration of rituximab or obinutuzumab should also be delayed 
so that they are given together beginning on Day 1 of the same cycle. 
 


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Table 5
Dose Interruptions, Reductions, and Discontinuations of Polatuzumab Vedotin and R-CHP or G-CHP
Event(s)
Dose Delay or Modification
Grade 3 or 4 neutropenia with or 
without infection or fever, first delay a
!
Delay all study treatment.
!
Administer growth factors, e.g., G-CSF for neutropenia as indicated and for all subsequent cycles
!
If ANC recovers to &1000/uL )7 days after the scheduled date for the next cycle, administer full dose of 
polatuzumab vedotin and R-CHP or G-CHP
!
If ANC recovers to &1000/uL %8 days after the scheduled date for the next cycle, reduce the dose of 
polatuzumab vedotin to the previously tested (lower) dose level.  The minimum dose level of 
polatuzumab vedotin is 1.0 mg/kg.
!
If the primary cause of neutropenia is thought to be lymphoma infiltration into the bone marrow, the 
investigator may elect not to reduce the dose of polatuzumab vedotin.
For guidelines for dose delay for obinutuzumab on Cycle 1 Day 8 and Cycle 1 day 15, see Table 6.
Recurrent Grade 3 neutropenia
!
Delay all study treatment.
!
If ANC recovers to &1000/uL )7 days after the scheduled date for the next cycle, administer full dose of 
polatuzumab vedotin and R-CHP or G-CHP.
!
If ANC recovers to &1000/uL %8 days after the scheduled date for the next cycle, then:
If no prior dose reduction of polatuzumab vedotin:  reduce the dose of polatuzumab vedotin to the 
previously tested (lower) dose level.  Minimum dose level of polatuzumab vedotin allowed is 1.0 
mg/kg.
If there was a prior dose reduction of polatuzumab vedotin:  the polatuzumab vedotin dose 
reduction should be maintained, and the doses of cyclophosphamide and doxorubicin should be 
reduced to 50% of the original dose.
!
If Grade 3 neutropenia persists despite growth factor support and following polatuzumab vedotin, 
cyclophosphamide, and doxorubicin dose reductions, in the absence of fever, patient may continue 
study treatment.
!
If patient develops Grade 3 febrile neutropenia or infection despite growth factor support and following 
polatuzumab vedotin, cyclophosphamide, and doxorubicin dose reductions, discontinue all study 
treatment permanently.


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Event(s)
Dose Delay or Modification
Recurrent Grade 4 neutropenia
!
Delay all study treatment.
!
If ANC recovers to &1000/4L ) 7 days after the scheduled date for the next cycle, administer full dose of 
polatuzumab vedotin and R-CHP or G-CHP.
!
If ANC recovers to &1000/uL %8 days after the scheduled date for the next cycle, then:
If no prior dose reduction of polatuzumab vedotin:  reduce the dose of polatuzumab vedotin to the 
previously tested (lower) dose level.  Minimum dose level of polatuzumab vedotin is 1.0 mg/kg.
If there was a prior dose reduction of polatuzumab vedotin:  the polatuzumab vedotin dose 
reduction should be maintained, and the doses of cyclophosphamide and doxorubicin should be 
reduced to 50% of the original dose.
!
If patient develops Grade 4 neutropenia despite growth factor support and following polatuzumab 
vedotin, cyclophosphamide, and doxorubicin dose reductions, discontinue all study treatment 
permanently.
Severe thrombocytopenia (platelets 
( 10,000/µL) and/or symptomatic 
bleeding in patients not receiving 
concomitant anticoagulants or platelet 
inhibitors
!
Hold obinutuzumab in case of severe thrombocytopenia (platelets ( 10,000/µL) or symptomatic 
bleeding (irrespective of platelet count) until it resolves, but do not skip any doses of obinutuzumab for 
sake of maintaining the chemo schedule.
Thrombocytopenia (platelets 
( 20,000/µL and/or symptomatic 
bleeding in patients receiving 
concomitant anticoagulants or platelet 
inhibitors b,c)
!
Hold obinutuzumab in case of platelets ( 20.000/µL or symptomatic bleeding (irrespective of platelet 
count) until it resolves, but do not skip any doses of obinutuzumab for sake of maintaining the chemo 
schedule.
!
For patients who are on LMWH, when thrombocytopenia with platelets ( 20,000/µL develops, reduce 
the dose of LMWH used.b
!
For patients who are on platelet inhibitors, when thrombocytopenia with platelets ( 20,000/µL develops, 
consideration should be given to temporarily pause their use.b
!
For guidelines for dose delay for obinutuzumab on Cycle 1 Day 8 and Cycle 1 Day 15, see Table 6.


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Event(s)
Dose Delay or Modification
Grade 3 or 4 thrombocytopenia, first 
episode
!
Delay all study treatment.
!
If platelet count recovers to &75∋109/L by Day 7 of the scheduled date of the next cycle, administer full 
dose of polatuzumab vedotin and R-CHP or G-CHP.
!
If platelet count recovers to &75∋109/L on or after Day 8 of the scheduled date of the next cycle, 
reduce the dose of cyclophosphamide and doxorubicin to 50% of the original dose.  Full-dose 
polatuzumab vedotin may be given.
!
If the primary cause of thrombocytopenia is thought to be lymphoma infiltration into the bone marrow, 
the investigator may elect not to reduce the dose of cyclophosphamide and doxorubicin.  
Recurrent Grade 3 or 4 
thrombocytopenia
!
If patient develops Grade 3-4 thrombocytopenia following cyclophosphamide and doxorubicin dose 
reductions, discontinue all study treatment permanently.
Hemorrhagic cystitis
!
Patients should be adequately hydrated before and after cyclophosphamide administration and should 
be instructed to void frequently.  If gross hematuria develops, cyclophosphamide should be withheld 
until resolution of cystitis.  A dose reduction of 50% for cyclophosphamide may be considered at the 
next cycle.  Re-escalation of cyclophosphamide to the initial full dose is recommended if symptoms do 
not recur.
Grade 2-4 heart failure or Grade 3 or 
4 LVSD
!
Discontinue all study treatment permanently.
Bilirubin &3.0 mg/dL
!
Delay all study treatment until resolution to Grade )1.  Evaluate for causality.
Bilirubin between 1.5 and 3.0 mg/dL
!
Reduce doxorubicin dose by at least 25% of baseline.  With subsequent courses of treatment if bilirubin 
has returned to ) 1 mg/dL, full doses may be given.  Evaluate for causality.
Grade 4 neurotoxicity (including 
peripheral neuropathy)
!
Discontinue polatuzumab vedotin treatment permanently.
!
Patients should be evaluated regarding the continuation of R-CHP or G-CHP on the basis of their 
risk/benefit.


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Event(s)
Dose Delay or Modification
Grade 2 or 3 neurotoxicity (including 
peripheral neuropathy)
!
Delay all study treatment.
!
If recovered to Grade )1 within 14 days:
If no prior dose reduction of polatuzumab vedotin for any reason:  Reduce polatuzumab vedotin to 
the previously tested (lower) dose level (permanent dose reduction).  Minimum dose level of 
polatuzumab vedotin is 1.0 mg/kg.  R-CHP or G-CHP may be administered at their full doses.
If there was a prior dose reduction of polatuzumab vedotin:  Polatuzumab vedotin must be 
permanently discontinued.  R-CHP or G-CHP administration at full doses should continue. 
!
If not recovered to Grade ) 1 until 14 days or more after the scheduled date for the next cycle, 
polatuzumab vedotin treatment must be permanently discontinued.  R-CHP or G-CHP may be 
administered at their full doses.  
Grade 3 or 4 tumor lysis syndrome
!
Following complete resolution of tumor lysis syndrome, study treatment may be re-administered at the 
full dose during next scheduled infusion in conjunction with prophylactic therapy.  
Anaphylaxis or Grade 4 IRR
!
Discontinue rituximab or obinutuzumab or polatuzumab vedotin permanently.
!
If anaphylaxis is attributed to rituximab or obinutuzumab, continue polatuzumab vedotin and CHP.
!
If anaphylaxis is attributed to polatuzumab vedotin, continue rituximab or obinutuzumab and CHP.
Grade 3 IRR, second episode
!
Discontinue rituximab or polatuzumab vedotin permanently.
!
If IRR is attributed to rituximab or obinutuzumab, continue polatuzumab vedotin and CHP.
!
If IRR is attributed to polatuzumab vedotin, continue rituximab or obinutuzumab and CHP.
Grade 3 or 4 non-hematologic toxicity 
not otherwise specified
!
Delay all study treatment for a maximum of 2 weeks.
!
Subsequent episodes:  Decrease polatuzumab vedotin to the previously tested (lower) dose level.  
Once polatuzumab vedotin has been dose reduced to 1.0 mg/kg, then for subsequent episodes the 
polatuzumab vedotin dose reduction (to 1.0 mg/kg) should be maintained and the dose of 
cyclophosphamide should be reduced to 375 mg/m2 and doxorubicin to 25 mg/m2.
!
Final episode:  discontinue all study treatment permanently.
Grade 2 non-hematologic toxicity not 
otherwise specified
!
Delay all study treatment for a maximum of 2 weeks.
!
If improvement to Grade )1 or baseline, administer study treatment without modification.


 
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Event(s) 
Dose Delay or Modification 
Hepatitis B reactivation (as evidenced 
by new detectable HBV DNA) 
x 
HBV DNA between WHO-recommended range of 10 and 100 IU/mL:  retest within 2 weeks.  If still 
positive, patient should be treated with an appropriate nucleoside analogue and immediately referred to 
a gastroenterologist or hepatologist. 
x 
HBV DNA WHO-recommended cutoff of ! 100 IU/mL:  the patient should be treated with an appropriate 
nucleoside analogue and immediately referred to a gastroenterologist or hepatologist. 
x 
Increasing HBV DNA viral load while on an appropriate anti-viral therapy:  discontinue all study 
treatment immediately. 
CHP   cyclophosphamide, doxorubicin, and prednisone or prednisolone; G-CSF   granulocyte colonystimulating factor; HBV   hepatitis B virus; 
IRR   infusion-related reaction; LVSD   left ventricular systolic dysfunction; R   rituximab; WHO   World Health Organisation.  
Note:  All decisions regarding dose delays, modifications and discontinuations should be done in consultation with and the approval of the Medical 
Monitor. 
a Based on laboratory results obtained within 72 hours before study treatment administration on Cycle 1 Day 1. 
b If the clinical condition of patient requires the use of concomitant anticoagulants, the patients are at increased risk of bleeding when 
thrombocytopenia with platelets  20,000/μL develops.  When possible, replace prior therapy with vitamin K antagonists with LMWH before 
Cycle 1 Day 1.  
c Clinical decision making may be adjusted depending on the patient-specific assessment of benefit and risk. 
 


 
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Table 6 
Guidelines for Dose Delay for Obinutuzumab on Cycle 1 Day 8 and Cycle 1 Day 15 
Event(s) 
Dose Delay or Modification 
Febrile neutropenia or neutropenia with 
infection 
x 
Hold obinutuzumab dose until fever or infection resolves. 
x 
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). 
x 
If Cycle 1 Day 15 is delayed long enough that the patient is approaching Cycle 2, then skip Day 15 
dosing and administer Cycle 2 Day 1 of obinutuzumab  CHP and polatuzumab vedotin as 
scheduled (if infection or fever has resolved). 
x 
Note:  Obinutuzumab should not be held for neutropenia without infection or fever. 
Thrombocytopenia with platelet count 
 20,000/ȝL and/or symptomatic bleeding 
x 
Hold obinutuzumab dose if platelet count  20,000/ȝL and/or symptomatic bleeding. 
x 
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 symptomatic bleeding has resolved). 
x 
If Cycle 1 Day 15 is delayed long enough that the patient is approaching Cycle 2, then skip Day 15 
dosing and administer Cycle 2 Day 1 of obinutuzumab  CHP and polatuzumab vedotin as 
scheduled (if symptomatic bleeding has resolved). 
 


 
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5.1.7.5 
Dose Discontinuation 
Dosing delay exceeding 14 days in the initiation of the next planned cycle of R-CHP or 
G-CHP and polatuzumab vedotin will require study treatment discontinuation unless 
Medical Monitor approval is obtained to continue on study treatment. 
Patients discontinuing rituximab or obinutuzumab should continue with CHP and 
polatuzumab vedotin and remain in the study and continue with all protocol-defined 
assessments. 
Patients who discontinue all study treatment for adverse events should remain in the 
study and continue to have disease assessments until progression and standard follow-up 
per Section 4.5. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest; measurement of 
protocol-specified laboratory assessments; measurement of protocol-specified vital signs; 
and other protocol-specified tests that are deemed critical to the safety evaluation of the 
study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guidelines for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can therefore be any of the following: 
x 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
x 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.4.9 
x 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
x 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
x 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 


 
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5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following: 
x 
Fatal (i.e., the adverse event actually causes or leads to death) 
x 
Life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death. 
x 
Requires or prolongs inpatient hospitalization (see Section 5.4.10) 
x 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
x 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
x 
Significant medical event in the investigator’s judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness should be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events 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 5.5.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
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 5.5.2 for reporting instructions).  Adverse events of special interest for this study 
include the following: 
x 
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 5.4.6) 
x 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
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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. 
x 
TLS of any grade (irrespective of regulatory seriousness criteria or causality) 
x 
Second malignancies 
 
Real-time safety monitoring will be employed for DLT assessment and dose-escalation 
decisions. 
5.2.4 
Dose-Limiting Toxicities (Immediately Reportable to the 
Sponsor) 
Adverse events that meet the definition of a DLT during the DLT observation period 
(see Section 3.1) will be recorded on the Adverse Event eCRF and reported immediately 
to the Medical Monitor as described in Section 5.4.  If a DLT also meets the definition of 
a severe adverse event, the event will also qualify for expedited reporting to the Sponsor 
(see Section 5.2.2 and Section 5.5.2 for reporting instructions). 
During the DLT assessment window, adverse events identified as DLTs, as defined in 
Section 3.1.1.1, 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 5.5.2 for 
reporting instructions). 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4, Section 5.5, and 
Section 5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.5.2 for instructions for reporting serious adverse events). 


 
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After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until 90 days after the last dose of study drug.  After this period, 
the investigator should report any serious adverse events that are believed to be related 
to prior study drug treatment (see Section 5.7).  
Second malignancies will be reported indefinitely for patients who received 
obinutuzumab, regardless of relationship to study treatment (even if the study has been 
closed and even after initiation of new anti-lymphoma therapy; see Section 5.7). 
5.3.2 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE v4.0 will be used for 
assessing adverse event severity.  Table 7 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


 
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Table 7 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE   National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.5.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.5.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration (see also 
Table 8): 
x 
Temporal relationship of event onset to the initiation of study drug 
x 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
x 
Known association of the event with the study drug or with similar treatments 
x 
Known association of the event with the disease under study 
x 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
x 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 


 
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Table 8 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.4 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.4.1 
Diagnosis versus Signs and Symptoms 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study drug infusion should be 
captured as individual signs and symptoms rather than a diagnosis of allergic reaction or 
infusion reaction (e.g., record dyspnea and hypotension as separate events rather than 
as a diagnosis of IRR). 
Other Adverse Events 
For adverse events other than IRRs, a diagnosis (if known) should be recorded on the 
Adverse Event 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 on the Adverse Event eCRF.  If a diagnosis is subsequently established, all 
previously reported adverse events based on signs and symptoms should be nullified 
and replaced by one adverse event report based on the single diagnosis, with a starting 
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5.4.2 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
x 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
x 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
x 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
recorded separately on the eCRF. 
x 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
x 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.4.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF, unless the severity increases.   The initial severity (intensity or 
grade) of the event will be recorded at the time the event is first reported.  If a persistent 
adverse event becomes more severe, the most extreme severity should also be 
recorded on the Adverse Event eCRF.   If a persistent adverse event becomes serious, it 
should be recorded as a separate event on the Adverse Event eCRF and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning that the event became 
serious; see Section 5.5.2 for reporting instructions).  The initial (non-serious) adverse 
event report should be updated to indicate that the event resolved on the date just prior 
to the day the event became serious. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.4.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
x 
Accompanied by clinical symptoms 


 
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x 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
x 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
x 
Clinically significant in the investigator’s judgment  
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 u ULN associated with cholestasis), only the 
diagnosis (e.g., cholestasis) needs to be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia”. 
Observations of the same clinically significant laboratory 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 (see Section 5.4.3). 
5.4.5 
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: 
x 
Accompanied by clinical symptoms 
x 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
x 
Results in a medical intervention (including a diagnostic evaluation not mandated 
in this protocol) or a change in concomitant therapy 
x 
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. 


 
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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 (see Section 5.4.3). 
5.4.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (! 3 u baseline value) in combination with either 
an elevated total bilirubin (! 2 u ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy’s law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
x 
Treatment-emergent ALT or AST ! 3 u baseline value in combination with total 
bilirubin ! 2 u ULN (of which t 35% is direct bilirubin) 
x 
Treatment-emergent ALT or AST ! 3 u 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 5.6) 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 adverse event of special interest (see 
Section 5.5.2). 
5.4.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol-
specified adverse event reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of lymphoma should be recorded only on the Study 
Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.6.2). 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not 
be used unless combined with the presumed cause of death (e.g., "sudden cardiac 
death"). 


 
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During survival follow-up, deaths attributed to progression of lymphoma should be 
recorded only on the Survival eCRF. 
5.4.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event 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”). 
5.4.9 
Lack of Efficacy or Worsening of Lymphoma 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on the Revised Response Criteria for Malignant Lymphoma 
(see Appendix 2).  In rare cases, the determination of clinical progression will be based 
on symptomatic deterioration.  However, every effort should be made to document 
progression through use of objective criteria.  If there is any uncertainty as to whether an 
event is due to disease progression, it should be reported as an adverse event. 
5.4.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
x 
Hospitalization for respite care 
x 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration, perform an efficacy 
measurement for the study) 
x 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease. 
The patient has not experienced an adverse event. 


 
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x 
Hospitalization due solely to progression of the underlying cancer 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
x 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.4.11 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills serious 
criteria, the event should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.5.2). 
No safety data related to overdosing of polatuzumab vedotin are available. 
5.4.12 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF. 
5.5 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
x 
Serious adverse events 
x 
Adverse events of special interest 
x 
Pregnancies 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
x 
New signs or symptoms or a change in the diagnosis 


 
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x 
Significant new diagnostic test results 
x 
Change in causality based on new information 
x 
Change in the event’s outcome, including recovery 
x 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.5.1 
Emergency Medical Contacts 
Medical Monitor Contact Information 
Genentech Medical Monitor contact information for sites in the United States: 
Medical Monitor:  
, M.D. 
Telephone No.:  
 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators.  
5.5.2 
Reporting Requirements for All Serious Adverse Events, 
Adverse Events of Special Interest, and Dose-Limiting 
Toxicities 
5.5.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
A paper Serious Adverse Event/Adverse Event of Special Interest Reporting Form and 
fax cover sheet should be completed and faxed or scanned and emailed to sponsor or 
its designee using the fax number or email address provided to investigators 
immediately (i.e., no more than 24 hours after learning of the event). 
Sites in the United States: 
Fax No.:  
 
 
Sites in France: 
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.   


 
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5.5.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and non-serious adverse events of 
special interest will be reported until 90 days after the last dose of study drug.  DLTs will 
be reported during the DLT assessment window.  Investigators should record all case 
details that can be gathered immediately (i.e., within 24 hours after learning of the event) 
on the Adverse Event eCRF and submit the report via the electronic data capture (EDC) 
system.  A report will be generated and sent to Safety Risk Management by the EDC 
system. 
In the event that the EDC system is unavailable, a paper Serious Adverse Event/ 
Adverse Event of Special Interest Reporting Form and fax cover sheet 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 to 
investigators (see fax numbers provided in Section 5.5.2.1).  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting post study adverse events are provided in Section 5.7. 
5.5.3 
Reporting Requirements for Pregnancies 
5.5.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 90 days after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Pregnancy should not be 
recorded on the Adverse Event eCRF. 
The investigator should discontinue study drug and counsel the patient, discussing the 
risks of the pregnancy and the possible effects on the fetus.  Monitoring of the patient 
should continue until conclusion of the pregnancy.  Any serious adverse events 
associated with the pregnancy (e.g., an event in the fetus, an event in the mother during 
or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.  
5.5.3.2 
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 Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy) either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.  


 
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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.   After the authorization has been 
signed, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available.  
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. 
5.5.3.3 
Abortions 
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 
5.5.3.4 
Congenital Anomalies/Birth Defects and Abortions 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed study drug should be classified as 
a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.5.2).  Any abortion should be reported in the same fashion (as the Sponsor 
considers abortions to be medically significant). 
5.6 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.6.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions in Section 5.5.3.1. 
5.6.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 


 
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monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, or autopsy report) in order to perform 
an independent medical assessment of the reported case. 
5.7 
POST-STUDY ADVERSE EVENTS 
The investigator is not required to actively monitor patients for adverse events after the 
end of the adverse event reporting period (defined as 90 days after the last dose of 
study drug).  However, the Sponsor should be notified if the investigator becomes aware 
of any death or other serious adverse event that occurs after the end of the adverse 
event reporting period if the event is believed to be related to prior study drug treatment.  
The Sponsor should also be notified of events of second malignancies indefinitely for 
patients who received obinutuzumab. 
The investigator should report these events directly to the Sponsor or its designee by 
completing and faxing or emailing a paper Serious Adverse Event Reporting 
Form/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators using the fax numbers provided below. 
Sites in the United States:  
Fax: 650-225-4682 
Sites in France: 
Fax: 
 
 
5.8 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
x 
Polatuzumab vedotin Investigator's Brochure 
x 
Rituximab Investigator’s Brochure 
x 
Obinutuzumab Investigator’s Brochure  
x 
Local prescribing information for CHP medications 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
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Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
6.1 
DETERMINATION OF SAMPLE SIZE 
The sample size required for estimating the MTD is based on the dose-escalation rules 
described in Section 3.1.1.2.  In addition, approximately 17 and 40 patients will be 
enrolled into the expansion cohorts for G-CHP and R-CHP, respectively, in combination 
with the MTD of polatuzumab vedotin identified during dose escalation.  With 40 patients 
the 95% exact Clopper-Pearson CIs for the true CR rate would have a margin of error 
not exceeding 17%.  The planned enrollment for this study is approximately 2430 
patients for dose-escalation cohorts and 60 patients for expansion cohorts for a total 
planned enrollment of 8490 patients. 
6.2 
SUMMARIES OF CONDUCT OF THE STUDY 
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 of 
polatuzumab vedotin. 
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. 
Any dose modifications will be flagged.  Means and standard deviations will be used to 
summarize the total doses of each study medication received.  All summaries will be 
presented by treatment group and disease specific cohort. 
6.3 
SAFETY ANALYSES 
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in physical findings on physical examinations, changes in ECGs, 
ECHO/MUGA scans, and changes in vital signs.  All patients who receive any amount of 
any drug that was part of the combination study treatment will be included in the safety 
analysis.  
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 study 


 
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treatment administration on Day 1 of Cycle 1 will be summarized by mapped terms, 
appropriate thesaurus levels, and toxicity grade per NCI CTCAE v4.0.  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 polatuzumab vedotin will be summarized. 
6.4 
PHARMACOKINETIC ANALYSES 
Selected laboratory data will be listed, with values outside of normal ranges identified.  
The incidence of antibodies to polatuzumab vedotin will be summarized. 
Individual and mean serum concentrations of total polatuzumab vedotin antibody (fully 
conjugated, partially deconjugated and fully deconjugated antibody) and rituximab and 
plasma concentrations of polatuzumab vedotin conjugate (evaluated as acMMAE), 
unconjugated MMAE, cyclophosphamide, and doxorubicin versus time data will be 
tabulated and plotted.  The pharmacokinetics of the above analytes will be summarized 
by estimating the appropriate PK parameters (e.g., AUC, Cmax, CL, Vss, and t1/2,terminal), as 
data allow.  Estimates for these parameters will be tabulated and summarized (mean, 
standard deviation, and range), as data allow.  Non-compartmental, compartmental 
and/or population methods will be used, as data allow. 
To assess PK drug interactions, PK parameters for each analyte of polatuzumab vedotin, 
rituximab, and obinutuzumab will be compared with historical single-agent data, as data 
allow.  PK data of cyclophosphamide, and doxorubicin will be compared between 
Cycle 1 (in the absence of polatuzumab vedotin) and Cycle 3 (in the presence of 
polatuzumab vedotin), and compared to historical data, 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, per the Sponsor’s discretion and as data allow. 
In addition, population PK methods may be employed to manage sparse data and to 
investigate the effects of certain covariates on the pharmacokinetics of polatuzumab 
vedotin, as data allow and at the Sponsor’s discretion. 
6.5 
ACTIVITY ANALYSES 
OR is defined as a CR or PR, as determined by investigator assessment with use of 
standard criteria (Cheson et al. 2007).  OR rate will be summarized.  Patients with 
missing or no response assessments will be classified as non-responders.  Among 
patients with an OR, DOR will be defined as the time from documentation of the first CR 
or PR to the time of disease progression, relapse, or death from any cause, as assessed 
by the investigator.  If a patient does not experience death or disease progression before 
the end of the study, DOR will be censored on the day of the last tumor assessment.  
OS is defined as the period from the date of randomization until the date of death from 


 
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any cause.  For patients who have not died at the time of the analyses, OS will be 
censored on the last date when the patients are known to be alive. 
PFS is defined as the time from the first day of study treatment (Day 1) to disease 
progression, relapse, or death from any cause, as assessed by the investigator.  If a 
patient has not experienced progressive disease or death, PFS will be censored on the 
day of the last tumor assessment.  If a post-baseline assessment is not available, PFS 
will be censored on Day 1. 
The Kaplan-Meier approach will be used to estimate the distribution of DOR, PFS, and 
OS in all patients.  Results will also be summarized separately among those patients in 
the dose-escalation part of the study and among those patients in the dose-expansion 
part of the study. 
6.6 
PATIENT-REPORTED OUTCOME ANALYSES 
The TINAS will be scored using a corresponding user manual.  Summary statistics of the 
TINAS total and individual items with their changes from baseline will be calculated at 
each assessment timepoint. 
6.7 
HANDLING OF MISSING DATA 
For PFS, patients who do not have documented disease progression or have died will be 
treated as censored observations on the date of the last tumor assessment.  If no tumor 
assessments were performed after the baseline visit, PFS will be censored at the time of 
randomization. 
For the response endpoints, patients with no response assessments (for any reason) will 
be considered non-responders. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor 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 the Sponsor, using the Sponsor’s standard 
procedures to handle and process the electronic transfer of these data. 


 
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eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
ePRO data will be collected through use of an electronic device.  This device will be the 
patient’s own electronic devices (i.e., mobile phone, tablet, or home computer) with 
specialized software installed to ensure the secure collection and transmission of the 
data.  If the patient does not own their own device, one will be provided by the ePRO 
vendor.  The software is designed for entry of data in a way that is attributable, secure, 
accurate, and in compliance with U.S. FDA regulations for electronic records (21 Code 
of Federal Regulations [CFR] Part 11).  The ePRO device data are available for view 
access only via secure access to a Web server.  Only identified and trained users may 
view the data, and their actions become part of the audit trail.  The Sponsor will have 
view access only.  System backups for data stored by the Sponsor and records retention 
for the study data will be consistent with the Sponsor’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
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.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
Patients will use an electronic patient-reported outcome (ePRO) device to capture PRO 
data.  This device will be the patient’s own electronic devices (i.e., mobile phone, tablet, 
or home computer) with specialized software installed to ensure the secure collection 
and transmission of the data.  If the patient does not own their own device, one will be 
provided by the ePRO vendor.  The data will be transmitted via Web or wireless 
automatically to a centralized database at the ePRO vendor.  The data can be reviewed 
by site staff via secure access to a Web server. 
Once the study is complete, the ePRO data, audit trail, and trial and system 
documentation will be archived.  The investigator will receive patient data for the site in 
both human- and machine-readable formats on an archival-quality compact disc that 
must be kept with the study records as source data.  Acknowledgement of receipt of the 
compact disc is required.  In addition, the Sponsor will receive all patient data in a 
machine-readable format on a compact disc. 


 
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7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification 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 (paper or electronic) 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-reported outcomes, 
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. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable regulatory authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study 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 health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of original entry of 
data.  If original data are modified, the system should maintain a viewable audit trail that 
shows the original data as well as the reason for the change, name of the person making 
the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 


 
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the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations. 
No records should be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP, and 
the principles of the Declaration of Helsinki, or the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the 
individual.  The study will comply with the requirements of the ICH E2A guideline 
(Clinical Safety Data Management:  Definitions and Standards for Expedited Reporting).  
Studies conducted in the United States or under a U.S. Investigational New Drug (IND) 
application will comply with U.S. FDA regulations and applicable local, state, and federal 
laws.  Studies conducted in the European Union (E.U.) or European Economic Area will 
comply with the E.U. Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor’s sample Informed Consent Form or any alternate consent 
forms proposed by the site (collectively, the “Consent Forms”) before IRB/EC 
submission.  The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a patient's agreement to allow 
any remaining specimens to be used for exploratory research.  Patients who decline to 
participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained before participation in the study. 


 
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The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Form for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  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. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
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 and reviewed and approved by the IRB/EC 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 requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.5). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 


 
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8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only 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 national and local health authorities, Sponsor 
monitors, representatives and collaborators, and the IRB/EC for each study site, if 
appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 


 
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prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
Genentech, Inc., a member of the Roche group, is the sponsor of this study.  A contract 
research organization (CRO) may provide clinical monitoring, data management, and 
medical monitoring support.  Genentech will conduct CRO oversight, approve patient 
eligibility, make decisions regarding dosing levels and schedules, provide primary 
medical monitoring, and conduct statistical programming and analysis.  
EDC will be utilized for this study.  An IXRS will be used to assign patient numbers.  A 
central laboratory will be used for a subset of laboratory assessments as specified in 
Section 4.5.7; otherwise, local laboratories will be used.  A central independent review 
facility will be used to collect radiographic and nuclear medicine scans, which may be 
analyzed at a later time. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript reporting primary clinical trial results within 6 months after the 
availability of the respective Clinical Study Report.  In addition, for all clinical trials in 
patients involving an IMP for which a marketing authorization application has been 
filed or approved in any country, the Sponsor aims to publish results from analyses of 
additional endpoints and exploratory data that are clinically meaningful and 
statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 


 
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proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual 
center data.  In this case, a coordinating investigator will be designated by mutual 
agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal 
publication of the study in which contribution of Sponsor personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator 
and the appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating 
from the use of data from this study will become and remain the exclusive and 
unburdened property of the Sponsor, except where agreed otherwise. 
 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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Appendix 1  
Schedule of Assessments 
Assessment 
Screening  
Treatment Period 
TCV/ 
ETV a P-T b 
Days  28 
to  1 
 14 
to  1 
C1 
D1 
C1 
D2 
C1 
D8 
C1 
D15 
C2 
D1 
C2 
D2 
C2 
D8 
C3 
D1 
C3 
D8 
C4 
D1 
C4 
D8 
C5 
D1 
C5 
D8 
C6 
D1 
C6 
D8 
C7 
D1 c 
C7 
D8 c 
C8 
D1 c 
C8 
D8 c 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and medical 
history d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical exam f 
 
 
x 
 
(x) 
(x) 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
Height (at screening only), 
weight, BSA  
 
x 
x 
 
 
 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
 
Vital signs g 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
ECOG PS 
x 
 
x 
 
 
 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
Hematology and serum 
chemistry h 
 
x 
x 
 
x 
x 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
Serum pregnancy test i 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
B-symptoms j 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
(q6m) 
Coagulation (PT, aPTT, 
and INR) 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Viral serology k 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum IgA, IgG, and IgM 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Bone marrow exam l 
x 
 
 
 
 
 
 
 
 
 
 
 
 
[l] 
 
 
 
 
 
 
 
[l] 
[l]x k 
CT scan m 
Please see footnote m. 
PET scan m 
Please see footnote m. 
Tumor assessment 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Appendix 1  
Schedule of Assessments (cont.) 
 
Polatuzumab Vedotin—Genentech, Inc. 
127/Protocol GO29044, Version 9 
Assessment 
Screening  
Treatment Period 
TCV/ 
ETV a P-T b 
Days  28 
to  1 
 14 
to  1 
C1 
D1 
C1 
D2 
C1 
D8 
C1 
D15 
C2 
D1 
C2 
D2 
C2 
D8 
C3 
D1 
C3 
D8 
C4 
D1 
C4 
D8 
C5 
D1 
C5 
D8 
C6 
D1 
C6 
D8 
C7 
D1 c 
C7 
D8 c 
C8 
D1 c 
C8 
D8 c 
Adverse event n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Echocardiogram or MUGA 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
12-lead ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Rituximab o 
 
 
x 
 
 
 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
 
Obinutuzumab o 
 
 
x 
 
x 
x 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
 
Doxorubicino 
 
 
x 
 
 
 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
 
Cyclophosphamide o 
 
 
x 
 
 
 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
 
Prednisone (Days 15 of 
each cycle) o 
 
 
xn 
xn 
 
 
xn 
xn 
 
xn 
 
xn 
 
xn 
 
xn 
 
xn 
 
xn 
 
 
 
Polatuzumab vedotin p 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
 
Pharmacokinetic samples 
See Appendix 4 and Appendix 5  
Archival (or fresh) tumor 
tissue sample q 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukocyte 
immunophenotyping r 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
MRD biomarker studies 
(whole blood) s 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
Exploratory biomarker 
studies t 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Pre-phase treatment u 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral neuropathy 
assessments v 
 
 
x 
 
 
 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
Patient-reported outcomes 
(TINAS) w 
 
 
Weekly on the same day each week during study treatment period. 
Weekly for 2 
months, then 
monthly for 
10 months 


Appendix 1  
Schedule of Assessments (cont.) 
 
Polatuzumab Vedotin—Genentech, Inc. 
128/Protocol GO29044, Version 9 
Assessment 
Screening  
Treatment Period 
TCV/ 
ETV a P-T b 
Days  28 
to  1 
 14 
to  1 
C1 
D1 
C1 
D2 
C1 
D8 
C1 
D15 
C2 
D1 
C2 
D2 
C2 
D8 
C3 
D1 
C3 
D8 
C4 
D1 
C4 
D8 
C5 
D1 
C5 
D8 
C6 
D1 
C6 
D8 
C7 
D1 c 
C7 
D8 c 
C8 
D1 c 
C8 
D8 c 
Optional residual tumor 
tissue  
 
 
(x) 
 
 
 
 
 
 
 
 
(x) 
 
 
 
 
 
 
 
 
 
(x) 
 
Optional RCR blood 
sample y 
(x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(x) 
 
BSA   body surface area; C   cycle; CHP   cyclophosphamide, doxorubicin, and prednisolone or prednisone; CT   computed tomography; D   day; ECOG   Eastern 
Cooperative Oncology Group; eCRF   electronic Case Report Form; ETV   Early Termination Visit; HCV   hepatitis C virus; MRD   minimal residual disease; 
MRI   magnetic resonance imaging; MUGA   multigated acquisition; PS   Performance Status; P-T   post-treatment; PT   prothrombin time; PET   positron 
emission tomography; q6m   every 6 months; R   rituximab; RCR   Roche Clinical Repository; TINAS   Therapy-Induced Neuropathy Assessment Scale; 
TCV   Treatment Completion Visit; (x)   conditional/optional (refer to footnote). 
Notes:  The visit window during each cycle of study treatment is r 2 days.  The window for the treatment discontinuation/early termination and post-treatment study 
visits is r 1 week (unless otherwise specified).  Please refer to Appendix 4 and Appendix 5 for the schedule of PK assessments (Cycle 3, Day 2 PK sampling 
also required in the expansion portion of the study per Appendix 5). 
a Patients should return for this study visit within 30 days after receiving their last dose of study drug, including all patients who withdraw/discontinue because of 
progression of disease or for any other reason, anytime during the study treatment period. 
b Post treatment study visits will occur 3, 6, 9, 12 months after the last dose of study treatment and every 6 months thereafter until the close of the study (after at 
least 2 years of follow-up after the end of study treatment for all of the enrolled patients. 
c These visits will be conducted only at those sites that choose eight cycles of R-CHP or G-CHP and polatuzumab vedotin. 
d At screening, obtain demographic data and complete medical history.  On Day 1, obtain medical history since the screening visit. 
e Complete physical examination includes all systems described in the body of the protocol, including assessment of lymph nodes, hepatomegaly, and 
splenomegaly. 
f The targeted physical examination should include only systems of most clinical relevance (i.e., cardiovascular, respiratory, those associated with clinical 
signs/symptoms, and lymph nodes, liver, and spleen).  On Cycle 1 Day 8 and Cycle 1 Day 15, a physical examination can be performed at the discretion of the 
investigator if clinically indicated. 
g Vital signs include systolic and diastolic blood pressure, heart rate, respiratory rate, pulse oximetry, and temperature while patient is seated or supine.  On 
polatuzumab vedotin infusion days, vital signs should be assessed before the start of the infusion, every 15 (r 5) minutes during the infusion, at the end of the 
infusion and every 30 (r 10) minutes for 90 minutes following completion of dosing at Cycle 1 and 30 (r 10) minutes following completion of dosing in subsequent 
cycles.  On rituximab and obinutuzumab infusion days, obtain vital signs before the infusion of rituximab or obinutuzumab, then after the start of the infusion 
approximately every 15 (r 5) minutes for 90 minutes, then approximately every 30 (r 10) minutes until the 1 hour after the end of infusion. 
h Hematology includes hemoglobin, platelet count, white blood cell count, and ANC.  Results should be obtained within 3 days before the study treatment.  Serum 
chemistry includes glucose, sodium, potassium, chloride, bicarbonate, urea nitrogen, creatinine, calcium, phosphorous, total bilirubin, direct bilirubin, total protein, 


Appendix 1  
Schedule of Assessments (cont.) 
 
Polatuzumab Vedotin—Genentech, Inc. 
129/Protocol GO29044, Version 9 
albumin, ALT, AST, LDH, alkaline phosphatase, uric acid, amylase and lipase.  At screening, a fasting blood glucose should be obtained for all patients.  HbA1c 
will be measured at Cycle 4 Day 1. 
i All women who are not postmenopausal (t 12 months of non-therapy-induced amenorrhea) or surgically sterile will have a serum pregnancy test at screening 
within 28 days before Cycle 1 Day 1 of study treatment if not sexually active and within 7 days of Cycle 1 Day 1 if sexually active.   
j B-symptoms include weight loss, night sweats, and fever. 
k Hepatitis B (HBsAg and total HB core antibody), and hepatitis C antibody serology required.  PCR testing will be required in those patients who are HCV 
antibody positive to determine eligibility.  HTLV-1 screening also required in patients from endemic countries. 
l A bone marrow biopsy and aspirate are mandatory at screening and should include biopsy for morphology.  The bone marrow assessment must be performed 
within 4 months of the Cycle 1 Day 1 as long as it was for the purpose of diagnosis and staging of diffuse large B-cell lymphoma.  For patients with bone marrow 
involvement at screening, a repeat biopsy at the end of therapy is mandatory only to confirm a complete response.  [l]:  Perform bone marrow biopsy to confirm 
complete response if bone marrow biopsy at screening shows presence of lymphoma or there is clinical suspicion of progressive disease in the bone marrow in 
the absence of progressive disease as demonstrated by radiographic imaging. 
m CT and PET scans are required at screening, following Cycle 4 of study treatment (i.e., at Cycle 4 Days 1521),and at the Treatment Completion/Early 
Termination visit (68 weeks after the last dose of study treatment).  CT scans will be obtained every 6 months thereafter for an additional four radiographic 
assessments (last radiographic assessment will be performed approximately 2 years following the Treatment Completion/Early Termination visit).  CT scan (with 
IV and oral contrast) of the chest, abdomen, pelvis (including inguinal/femoral regions), and neck, if clinically indicated.  Any time the investigator suspects 
disease progression, a full tumor assessment including anatomic scans must be performed.  MRIs may be used instead of CT scans with contrast in patients for 
whom CT scans with contrast are contraindicated.  The results of PET scans that are performed as part of the routine clinical care at the institution should be 
recorded on the CRF. 
n Patients will be evaluated for new adverse events at each study visit until 90 days after completing or discontinuing study treatment.  Unresolved adverse events 
will be followed from Cycle 1 Day 1 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.  
o Rituximab 375 mg/m2 will be administered on Day 1 of each cycle.  Obinutuzumab will be administered as 1000 mg on Day 1, 8, and 15 of Cycle 1, then Day 1 of 
each subsequent cycle.  CHP consists of cyclophosphamide 750 mg/m2 IV on Day 1 of each cycle, doxorubicin 50 mg/m2 IV on Day 1 of each cycle, and 
prednisone (prednisolone) 100 mg orally on Days 15 of each cycle.  When rituximab or obinutuzumab is administered on the same day as prednisone 
(prednisolone), it is recommended that prednisone (prednisolone) be given before the rituximab or obinutuzumab infusion.  The order of administration of study 
treatment will be determined by local institutional practice.  Empiric dose adjustment in obese patients (defined as a body mass index t 30, as measured in 
kg/m2) may be implemented per institutional guidelines.  There will be no dose modification for changes in patients’ weight unless the weight increases or 
decreases by ! 10% from weight on Cycle 1 Day 1.  Rituximab or obinutuzumab should be administered after premedication with oral 
acetaminophen/paracetamol and an antihistamine such as diphenhydramine hydrochloride (unless contraindicated).  Allopurinol should be administered for 
patients with high tumor burden, if pretreatment with allopurinol is deemed appropriate.  Please see Section 4.3.1 for information regarding the order of 
administration of study treatments.  During infusion of doxorubicin, continuous ECG monitoring should be performed per clinical practice. 
p Polatuzumab vedotin will be administered on Day 2 of Cycles 1 and 2.  If well tolerated, then all study treatments may be administered on the same day during 
subsequent cycles. 


Appendix 1  
Schedule of Assessments (cont.) 
 
Polatuzumab Vedotin—Genentech, Inc. 
130/Protocol GO29044, Version 9 
q 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 before study entry. 
r CD3+, CD19+, etc. 
s Peripheral blood sample (10-mL per sample) for MRD analysis in all patients at Cycle 1 Day 1 (prior to dosing), between Cycle 3 Day 15 and Cycle 4 Day 1, and 
at the Treatment Completion Visit. 
t 
5-mL each of whole blood and plasma prior to treatment and treatment completion. 
u Day -7 to -1.  Administration of an approximate 7 day of pre-phase treatment (consisting of prednisone/prednisolone 100 mg PO daily) between Days -7 to -1 
may be given at the discretion of the treating investigator physician.   
v Patients may undergo a Clinical Total Neuropathy Assessment (to include subjective sensory symptoms, motor symptoms, autonomic symptoms; to include 
objective  pinprick sensitivity, vibration sensitivity, strength testing and deep tendon reflex testing). 
w The TINAS is the patient reported outcomes instrument.  TINAS should be completed weekly, preferably on the same day each week during the course of study 
treatment.  On study visit days, TINAS should be completed before all other assessments during the study visit.  Following the study treatment period, the TINAS 
will be completed once a week for the first 2 months, then once per month for the next 10 months.   
x With consent to optional research, residual tumor specimens are requested at screening and optional blood samples are requested at screening and at the end 
of multi-agent therapy visit or end of treatment/early termination visit for collection and storage at the RCR. 
y With consent to optional research, a blood sample will be requested at screening and at the end of treatment/early termination visit for collection and storage at 
the Roche Clinical Repository. 


 
Polatuzumab Vedotin—Genentech, Inc. 
131/Protocol GO29044, Version 9 
Appendix 2  
Modified Revised Response Criteria for Malignant Lymphoma 
SELECTION OF TARGET LESIONS 
Up to six of the largest dominant nodes or tumor masses selected according to all of the 
following: 
x 
Clearly measurable in at least two perpendicular dimensions at baseline 
All nodal lesions must measure: 
! 1.5 cm in greatest transverse diameter (GTD) regardless of short axis 
measurement, or 
! 1.0 cm in short axis regardless of the GTD measurement 
x 
All extranodal lesions must measure t 10 mm in the GTD and twice the 
reconstruction interval of the scan. 
x 
If possible, they should be from disparate regions of the body. 
x 
Should include mediastinal and retroperitoneal areas of disease whenever these 
sites are involved. 
x 
Extranodal lesions within the liver or spleen must be at least 1.0 cm in two 
perpendicular dimensions. 
 
Measurable extranodal disease should be assessed in a manner similar to that used 
for nodal disease.  For these recommendations, the spleen is considered nodal disease.  
SELECTION OF NON-TARGET LESIONS 
Non-target lesions will be qualitatively assessed at each subsequent time point.  All of 
the sites of disease present at baseline and not classified as target lesions will be 
classified as non-target lesions, including any measurable lesions that were not chosen 
as target lesions.  Examples of non-target lesions include: 
x 
All bone lesions, irrespective of the modality used to assess them 
x 
Lymphangitis of the skin or lung 
x 
Cystic lesions 
x 
Splenomegaly and hepatomegaly 
x 
Measurable lesions beyond the maximum number of six 
x 
Groups of lesions that are small and numerous 
x 
Pleural/pericardial effusions and/or ascites 
x 
For this study, a significant increase in existing pleural effusions, ascites, or other 
fluid collections will be considered sufficient evidence of progression and will not 
require cytological proof of malignancy.  Effusions, ascites or other fluid collections 
will be followed as non-target lesions. 


 
 
Appendix 2 
Modified Revised Response Criteria for Malignant Lymphoma 
(cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
132/Protocol GO29044, Version 9 
Existing effusions/ascites:  Effusions, ascites or other fluid collections will be 
followed as non-target lesions.  At each time point, radiologists will check for the 
presence or absence of effusions/ascites.  If there is a significant volume increase in 
the absence of a benign etiology, progression can be assessed. 
New effusions/ascites:  Significant new effusions, ascites or other fluid collections, 
which are radiographically suggestive of malignancy should be recorded as new 
lesions. 
 
REPORTING CONVENTIONS 
UNABLE TO EVALUATE (UE) LESION CATEGORY 
This category is reserved for target and non-target lesions that are deemed unevaluable 
because 1) subsequent (post-baseline) examinations had not been performed, 2) lesions 
could not be evaluated because of poor radiographic technique or poorly defined 
margins, or 3) lesions identified at baseline were not at a subsequent time point. 
Examples of UE lesions are a lung lesion in the hilum obstructing the bronchus and 
causing atelectasis of the lobe or a hypodense liver lesion that becomes surrounded by 
fatty infiltration.  In both examples the boundaries of the lesion can be difficult to 
distinguish.  Every effort should be made to assign measurements to lesions that 
develop less distinct margins because they become much smaller.  Another example is 
the instance when lesions identified at baseline were not imaged at a subsequent time 
point unless the lesions are not imaged because of complete resolution.  Lesions that 
cannot be measured or evaluated will be classified for that time point as UE. 
If a target lesion is classified as UE after baseline, the SPD/area (whichever applies) of 
the target lesions cannot accurately be determined for that time point a response of CR, 
PR, or SD cannot be assigned for that time point and the response assessment will be UE 
unless unequivocal progression is determined on the basis of non-target or new lesions, 
or the evaluable target lesions. 
PD can be determined without evaluation of all sites of disease based on the GTD, area 
or SPD for target lesions, evaluation of unequivocal progression in non-target lesions or 
observation of a new lesion within the available radiographic or clinical assessments. 
TOO SMALL TO MEASURE (TSTM) /BELOW MEASURABLE LIMIT (BML) 
LESION CATEGORY 
Any target lesion findings identified on baseline images, which at a subsequent time 
point decreases in size to  5 mm in any dimension, should be categorized as TSTM.  
The lesion, node or mass should be assigned measurements of 5 mm u 5 mm (for the  


 
 
Appendix 2 
Modified Revised Response Criteria for Malignant Lymphoma 
(cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
133/Protocol GO29044, Version 9 
GTD and the short axis) on the Source Document for the purpose of calculating the area.  
If that lesion increases in size to t 5 mm in any dimension afterward, its true size (GTD 
and short axis) should be recorded.  The purpose of the assigned value for the 
measurement is the acknowledgment that small findings are not accurately measured.  
Table 1 
Timepoint Response 
Target Lesions 
Non-Target Lesions 
New Lesions1 
Time Point Response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
CR 
UE 
No 
UE 
PR 
UE 
No 
UE 
PR 
CR 
No 
PR 
PR 
SD 
No 
PR 
SD 
UE 
No 
UE 
SD 
CR 
No 
SD 
SD 
SD 
No 
SD 
PD 
ANY 
Yes/No 
PD 
ANY 
PD 
Yes/No 
PD 
ANY 
ANY 
Yes 
PD 
UE 
Non-PD 
No 
UE 
UE 
UE 
No 
UE 
CR 
NA 3 
No 
CR 
PR 
NA 3 
No 
PR 
SD 
NA 3 
No 
SD 
NA 2 
SD 
No 
SD 
NA 2 
CR 
No 
CR 
NA 2 
UE 
No 
UE 
NA 2 
NA 3 
No 
UE 
Modified version of Cheson et al. 2007. 
1 Identification of new lesions at a post-baseline time point will result in a response 
assessment of PD.  If an identified new lesion subsequently becomes UE, the time point 
response will be recorded as PD unless the new lesion has proven to have resolved.   
2 No target lesions identified at baseline. 
3 No non-target lesions identified at baseline. 
 


 
 
Appendix 2 
Modified Revised Response Criteria for Malignant Lymphoma 
(cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
134/Protocol GO29044, Version 9 
Response should be determined on the basis of radiographic and clinical evidence of 
disease using the modified Cheson et al. (2007) criteria below.  For the end-of-treatment 
response assessment, an FDG-PET scan will be performed approximately 68 weeks 
after completion of after last dose of antibody immunochemotherapy.  Assessment of 
PET should follow the criteria described by Juweid et al. (2007), which is presented in 
the table, Response Definitions for Clinical Trials. 
COMPLETE REMISSION (CR) 
To assess response using CT only, the designation of CR requires the following: 
x 
Complete disappearance of all detectable clinical evidence of disease 
and disease-related symptoms if present before therapy.  
x 
The spleen and/or liver, if considered enlarged before 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. 
x 
If the bone marrow was involved by lymphoma before 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.  
x 
A second response assessment should be made with incorporation of PET imaging 
results as follows:  
x 
The designation of CR requires the following:  All CR requirements as described 
above with use of a CT onlydetermined CR.   
x 
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.  
x 
Variably FDG-avid lymphomas/FDG avidity unknown:  In patients without a pre-
treatment PET scan, or if a pre-treatment PET scan was negative, all lymph nodes 
and nodal masses must have regressed on CT to normal size (d 1.5 cm in their 
greatest transverse diameter for nodes ! 1.5 cm before therapy).  Previously 
involved nodes that were 1.1 to 1.5 cm in their long axis and ! 1.0 cm in their short 
axis before treatment must have decreased to d 1.0 cm in their short axis after 
treatment. 
 


 
 
Appendix 2 
Modified Revised Response Criteria for Malignant Lymphoma 
(cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
135/Protocol GO29044, Version 9 
PARTIAL REMISSION (PR) 
The first response should be based on CT criteria only: 
A t 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:  1) they should be clearly measurable in 
at least 2 perpendicular dimensions; 2) if possible, they should be from disparate 
regions of the body; 3) they should include mediastinal and retroperitoneal areas of 
disease whenever these sites are involved. 
x 
No increase in the size of the other nodes, liver, or spleen 
x 
Splenic and hepatic nodules must regress by t 50% in their SPD or, for single 
nodules, in the greatest transverse diameter. 
x 
With the exception of splenic and hepatic nodules, involvement of other organs 
is usually assessable and no measurable disease should be present. 
x 
Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive before 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. 
x 
No new sites of disease should be observed (e.g., nodes ! 1.5 cm in any axis). 
 
A second response assessment should be made with PET imaging.   
x 
Typically FDG-avid lymphoma:  For patients with no pretreatment PET scan or 
whose PET scan was positive before therapy, the post-treatment PET scan should 
be positive in at least one previously involved site.   
x 
Variably FDG-avid lymphomas/FDG-avidity unknown:  For patients without a pre-
treatment PET scan, or if a pre-treatment PET scan was negative, CT criteria should 
be used. 
 
In patients with follicular lymphoma or mantle-cell 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) 
x 
A patient is considered to have stable disease when that patient fails to attain the 
criteria needed for a CR or PR, but not fulfilling those for progressive disease (see 
Relapsed Disease [after Complete Remission] or PD [after Partial Remission or 
Stable Disease]). 


 
 
Appendix 2 
Modified Revised Response Criteria for Malignant Lymphoma 
(cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
136/Protocol GO29044, Version 9 
x 
Typically FDG-avid lymphoma:  PET imaging should be positive at prior sites of 
disease with no new areas of involvement on the post-treatment CT or PET scan. 
x 
Variably FDG-avid lymphomas/FDG-avidity unknown:  for patients without a 
pre-treatment PET scan or if the pre-treatment 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; 
AFTER PR OR SD) 
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 d 1.0 cm u d 1.0 cm will not 
be considered as abnormal for relapse or progressive disease. 
x 
Appearance of any new lesion ! 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 PD after confirmation with 
other modalities.  In patients with no prior history of pulmonary lymphoma, new lung 
nodules identified by CT are mostly benign.  Thus, a therapeutic decision should not 
be made solely on the basis of the PET without histologic confirmation. 
x 
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  1.0 cm must increase by t 50% and to a size of 1.5 u 1.5 cm or 
! 1.5 cm in the long axis. 
x 
At least a 50% increase in the longest diameter of any single previously identified 
node ! 1 cm in its short axis 
x 
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 ( 1.5 cm in its long axis by CT). 
x 
Measurable extranodal disease should be assessed in a manner similar to that for 
nodal disease.  For these recommendations, the spleen is considered nodal disease.  
Disease that is only assessable (e.g., pleural effusions, bone lesions) will be 
recorded as present or absent only, unless, while an abnormality is still noted by 
imaging studies or physical examination, it is found to be histologically negative. 
x 
In clinical trials where PET is unavailable to the vast majority of participants, or 
where PET is not deemed necessary or appropriate for use (e.g., a study in patients 
with mucosa-associated lymphoid tissue lymphoma), response should be assessed 
as above but only using CT scans.  However, residual masses should not be 
assigned unconfirmed CR status but should be considered PRs. 


 
 
Appendix 2 
Modified Revised Response Criteria for Malignant Lymphoma 
(cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
137/Protocol GO29044, Version 9 
Table 2 
Response Definitions for Clinical Trials (Revised International 
Working Group Criteria 2007) 
Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance 
of all evidence 
of disease 
a) FDG-avid or PET 
positive before therapy; 
mass of any size 
permitted if PET negative
b) Variably FDG-avid or 
PET negative; regression 
to normal size on CT 
No palpable, 
nodules; 
nodules 
disappeared 
Infiltrate cleared on 
repeat biopsy; if 
indeterminate on 
morphology and 
immunohistochemistry; 
bone marrow should 
be negative 
PR 
Regression of 
measurable 
disease and 
no new sites 
A t 50% decrease in SPD 
of up to six largest 
dominant masses; no 
increase in size of other 
nodes 
a) FDG-avid or PET 
positive before therapy; 
one or more PET positive 
at previously involved site
b) Variably FDG-avid or 
PET negative; regression 
on CT 
A t 50% 
decrease in 
SPD of 
nodules 
(for single 
nodule in the 
greatest 
transverse 
diameter); 
no increase 
in size of 
liver or 
spleen 
Irrelevant if positive 
before therapy; cell 
type should be 
specified 
SD 
Failure to 
attain CR/PR 
or PD 
a) FDG-avid or PET 
positive before therapy; 
PET positive at prior sites 
of disease and no new 
sites on CT or PET 
b) Variably FDG-avid or 
PET negative; no change 
in size of previous lesions 
on CT 
 
 
Relapsed 
disease 
or PD 
Any new lesion 
or increase by 
t 50% of 
previously 
involved sites 
from nadir 
Appearance of a new 
lesion(s) ! 1.5 cm in any 
axis, t 50% increase in 
SPD of more than one 
node, or t 50% increase 
in longest diameter of 
previously identified node 
! 1 cm in short axis 
Lesions PET positive if 
FDG-avid lymphoma or 
PET positive before 
therapy 
50% 
increase 
from nadir in 
the SPD of 
any previous 
lesions 
New or recurrent 
involvement 
CR   complete response; CT   computed tomography; FDG   18F-fluorodeoxyglucose; 
PD   progressive disease; PET   positron-emission tomography; PR   partial response; SPD   sum 
of the product of the diameters. 
Excerpted from:  Juweid et al. 2007. 
 


 
 
Appendix 2 
Modified Revised Response Criteria for Malignant Lymphoma 
(cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
138/Protocol GO29044, Version 9 
In this study, for purposes described in the exploratory objective, only positron emission 
tomography and computed tomography (PET and CT) based response criteria will be 
used. Additionally, if the bone marrow was involved by lymphoma before treatment, the 
designation of a CR requires normal bone marrow by morphology. If indeterminate by 
morphology, immunohistochemistry should be negative. 
REFERENCES 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. J Clin Oncol 2007;25:57986. 
Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for 
response assessment of lymphoma: consensus of the Imaging Subcommittee of 
International Harmonization Project in Lymphoma. J Clin Oncol 2007;25:5718. 
 


 
Polatuzumab Vedotin—Genentech, Inc. 
139/Protocol GO29044, Version 9 
Appendix 3  
Modified Criteria for Response Assessment:  The Lugano 
Classification 
Response should be determined on the basis of radiographic and clinical evidence of 
disease.  For the Primary Response Assessment, an FDG-PET 
(18F-fluorodeoxyglucose-positron emission tomography) scan will be performed 
68 weeks after Cycle 6 Day 1 as assessed by IRC and by investigator.  Assessment of 
the PET scan should follow the criteria described by Cheson et al. (2014) presented 
below. 
Selection of measured dominant (indicator) lesions: 
x 
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. 
x 
Nodes should preferably be from disparate regions of the body and should include, 
where applicable, mediastinal and retroperitoneal areas.  
x 
Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, and 
lungs), GI involvement, cutaneous lesions, or those noted on palpation.  
x 
If possible, they should be from disparate regions of the body. 
x 
Should include mediastinal and retroperitoneal areas of disease whenever these 
sites are involved 
 
Selection of non-measured (non-indicator) lesions: 
x 
Any disease not selected as measured, dominant disease and truly assessable 
disease should be considered not measured.   
x 
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.  
x 
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). 
 


 
 
Appendix 3 
Modified Criteria for Response Assessment:  The Lugano 
Classification (cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
140/Protocol GO29044, Version 9 
Modifications to the Lugano Criteria: 
x 
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.   
x 
For PET/CT-based PR, criteria for both PET/CT and CT response must be met, 
defined in table Appendix 3.


Appendix 3 
Modified Criteria for Response Assessment:  The Lugano Classification (cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
141/Protocol GO29044, Version 9 
Table 1 
The Modified Lugano Classification 
Response 
Site 
PET-CTbased Response 
CT-based Response 
Complete 
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  d 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 


Appendix 3 
Modified Criteria for Response Assessment:  The Lugano Classification (cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
142/Protocol GO29044, Version 9 
Table 1 
The Modified Lugano Classification (cont.)  
Response 
Site 
PET-CTbased Response 
CT-based Response 
Partial 
 
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 
t 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 u 5 mm as the default value 
When no longer visible, 0 u 0 mm 
For a node ! 5 mm u 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 


Appendix 3 
Modified Criteria for Response Assessment:  The Lugano Classification (cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
143/Protocol GO29044, Version 9 
Table 1 
The Modified Lugano Classification (cont.)  
Response 
Site 
PET-CTbased Response 
CT-based Response 
Partial (cont). 
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 
None / Stable 
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 
Bone marrow 
No change from baseline 
Not applicable 


Appendix 3 
Modified Criteria for Response Assessment:  The Lugano Classification (cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
144/Protocol GO29044, Version 9 
Table 1 
The Modified Lugano Classification (cont.)  
Response 
Site 
PET-CTbased Response 
CT-based Response 
Progressive 
Individual target nodes/nodal 
lesions 
Score 4 or 5** with an increase in intensity of 
uptake from baseline and/or 
PPD progression: 
An individual node/lesion must be abnormal with at least 
one of the following:  
x 
LDi ! 1.5 cm AND  
x 
Increase by t 50% from PPD nadir AND  
An increase in LDi or SDi from nadir 
x 
0.5 cm for lesions d 2 cm 
x 
1.0 cm for lesions ! 2 cms 
Nonmeasured lesions 
None 
New or clear progression of preexisting  
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 3 
Modified Criteria for Response Assessment:  The Lugano Classification (cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
145/Protocol GO29044, Version 9 
Table 1 
The Modified Lugano Classification (cont.)  
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 under treatment) 
**PET 5PS:  1, no uptake above background; 2, uptake  d  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. 
 


 
 
Appendix 3 
Modified Criteria for Response Assessment:  The Lugano 
Classification (cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
146/Protocol GO29044, Version 9 
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. 
 


 
Polatuzumab Vedotin—Genentech, Inc. 
147/Protocol GO29044, Version 9 
Appendix 4  
R-CHP Plus Polatuzumab Vedotin Pharmacokinetic and 
Anti-Therapeutic Antibody Sampling Schedule 
Ideally, all pharmacokinetic (PK) samples and anti-therapeutic antibody (ATA) samples 
will be drawn from the arm opposite from the infusion arm.  In patients with indwelling 
catheters, a PK sample may be drawn from the catheter after ample flushing. 
PHASE IB DOSE ESCALATION (R-CHP PLUS POLATUZUMAB VEDOTIN) 
The PK sampling schedule below is applicable to patients who receive the 
rituximab-containing regimen in the dose escalation portion of the study.  A total of 16 
samples will be collected from each patient treated with R-CHP plus polatuzumab 
vedotin. 
 


Appendix 4  
R-CHP Plus Polatuzumab Vedotin Pharmacokinetic and Anti-Therapeutic Antibody Sampling 
Schedule (cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
148/Protocol GO29044, Version 9 
Table 1 
PK Sampling Schedule (Phase 1b Dose-Escalation:  R-CHP Plus Polatuzumab Vedotin) 
Study Visit 
Sample Time point(s) a 
Samples  
Cycle 1 Day 2 
Pre-polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b 
Polatuzumab vedotin ATA (serum) 
30 minutes (r 15 minutes) after the end of the polatuzumab vedotin 
infusion 
Polatuzumab vedotin PK (serum and plasma) b 
Cycle 1 Day 8 
6 days (r 1 day) after Day 2 infusion  
Polatuzumab vedotin PK (serum and plasma) b 
Cycle 1 Day 15 
13 days (r 1 day) after Day 2 infusion 
Polatuzumab vedotin PK (serum and plasma) b 
Cycle 2 Day 2 
Pre-polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b  
Polatuzumab vedotin ATA (serum) 
30 minutes (r 15 minutes) after end of polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b 
Cycle 3 Day 1 
Pre-polatuzumab vedotin dose 
Polatuzumab vedotin PK (serum and plasma) b 
30 minutes (r 15 minutes) post end of polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b 
Cycle 3 Day 8 
7 days (r 1 day) post- Day 1 infusion 
Polatuzumab vedotin PK (serum and plasma)  b  
Cycle 4 Day 1 
Pre-polatuzumab vedotin dose 
Polatuzumab vedotin PK (serum and plasma) b 
Polatuzumab vedotin ATA (serum) 
30 minutes (r 15 minutes) post end of polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b 
Post-treatment follow-up  
(Month 3) 
Random sample 
Polatuzumab vedotin ATA (serum),  
Polatuzumab vedotin PK (serum and plasma) b 
ATA   anti-therapeutic antibody; MMAE   monomethyl auristatin E; PK   pharmacokinetic. 
a Up to 5-mL whole-blood samples will be taken for polatuzumab vedotin PK (polatuzumab vedotin total antibody, unconjugated MMAE and conjugate [evaluated 
as antibody conjugated MMAE], and polatuzumab vedotin ATA at each specified time point, with separate tubes for plasma or serum samples. 
b 
Polatuzumab vedotin PK, including serum PK samples for conjugate antibody and conjugate (evaluated as antibody conjugated MMAE) and unconjugated 
MMAE. 
 


 
 
Appendix 4 
R-CHP Plus Polatuzumab Vedotin Pharmacokinetic and 
Anti-Therapeutic Antibody Sampling Schedule (cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
149/Protocol GO29044, Version 9 
PHASE II DOSE EXPANSION (R-CHP PLUS POLATUZUMAB VEDOTIN) 
The PK sampling schedule below is applicable to the first 20 patients who receive the 
rituximab-containing regimen in the dose expansion portion of the study.  The remaining 
20 patients will follow only the polatuzumab vedotin PK and ATA sampling schedule.  
Per the sampling schedule (see below), a total of 31 samples will be collected from the 
first 20 patients treated with R-CHP plus polatuzumab vedotin and a total of 17 samples 
(for only polatuzumab vedotin PK and ATA) will be collected for the remaining 
20 patients. 
 


Appendix 4 
R-CHP Plus Polatuzumab Vedotin Pharmacokinetic and Anti-Therapeutic Antibody Sampling 
Schedule (cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
150/Protocol GO29044, Version 9 
Table 2 
PK Sampling Schedule (Dose-Expansion) 
Study Visit 
Sample Time point(s) a 
Samples  
Cycle 1 Day 1 
Pre-rituximab infusion 
Rituximab PK (serum) 
30 minutes (r 15 minutes) post end of rituximab 
infusion 
Rituximab PK (serum) 
End (r 2 minutes) of cyclophosphamide infusion 
Cyclophosphamide PK (plasma) 
3 hours (r 5 minutes) post end of cyclophosphamide 
infusion 
Cyclophosphamide PK (plasma) 
2 hours (r 5 minutes) post end of doxorubicin 
administration 
Doxorubicin PK (plasma) 
Cycle 1 Day 2 
Pre-polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b 
Polatuzumab vedotin ATA (serum) 
30 minutes (r 15 minutes) after the end of the 
polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b 
23 hours (r 15 minutes) post end of 
cyclophosphamide infusion on Cycle 1 Day 1 
Cyclophosphamide PK (plasma) 
24 hours (r 15 minutes) post end of doxorubicin 
administration on Cycle 1 Day 1 
Doxorubicin PK (plasma) 
Cycle 1 Day 8 
6 days (r 1 day) after Day 2 infusion  
Polatuzumab vedotin PK (serum and plasma) b 
Cycle 1 Day 15 
13 days (r 1 day) after Day 2 infusion 
Polatuzumab vedotin PK (serum and plasma) b 


Appendix 4 
R-CHP Plus Polatuzumab Vedotin Pharmacokinetic and Anti-Therapeutic Antibody Sampling 
Schedule (cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
151/Protocol GO29044, Version 9 
Table 2 
PK Sampling Schedule (Dose-Expansion) (cont.)  
Study Visit 
Sample Time point(s) a 
Samples  
Cycle 2 Day 2 
Pre-polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b 
Polatuzumab vedotin ATA (serum) 
30 minutes (r 15 minutes) after end of polatuzumab 
vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b 
Cycle 3, Day 1 
Pre-polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b  
30 minutes (r 15 minutes) after end of polatuzumab 
vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b  
End (r 2 minutes) of cyclophosphamide infusion 
Cyclophosphamide PK (plasma) 
3 hours (r 5 minutes) post end of cyclophosphamide 
infusion 
Cyclophosphamide PK (plasma) 
2 hours (r 5 minutes) post end of doxorubicin 
administration 
Doxorubicin PK (plasma) 
Cycle 3 Day 2 
23 hours (r 15 minutes) post end of 
cyclophosphamide infusion on Cycle 3 Day 1 
Cyclophosphamide PK (plasma) 
24 hours (r 15 minutes) post end of doxorubicin 
administration on Cycle 3 Day 1 
Doxorubicin PK (plasma) 
Cycle 4, Day 1  
Pre-rituximab dose 
Rituximab PK (serum) 
30 minutes (r 15 minutes) post end of rituximab 
infusion 
Rituximab PK (serum) 
Pre-polatuzumab vedotin dose 
Polatuzumab vedotin ATA (serum),  
Polatuzumab vedotin PK (serum and plasma) b 
30 minutes (r 15 minutes) post end of polatuzumab 
vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b 


Appendix 4 
R-CHP Plus Polatuzumab Vedotin Pharmacokinetic and Anti-Therapeutic Antibody Sampling 
Schedule (cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
152/Protocol GO29044, Version 9 
Table 2 
PK Sampling Schedule (Dose-Expansion) (cont.)  
Study Visit 
Sample Time point(s) a 
Samples  
Treatment Completion/ 
Early Termination 
Approximately 1530 days after last infusion  
Polatuzumab vedotin ATA (serum),  
Polatuzumab vedotin PK (serum and plasma) b 
Post-treatment follow-up 
(Month 3) 
Random sample 
Polatuzumab vedotin ATA (serum),  
Polatuzumab vedotin PK (serum and plasma) b 
ATA   anti-therapeutic antibody; MMAE   monomethyl auristatin E; PK   pharmacokinetic. 
a Up to 5-mL whole-blood samples will be taken for rituximab PK, polatuzumab vedotin PK (polatuzumab vedotin total antibody, free MMAE and 
antibody conjugated MMAE), polatuzumab vedotin ATA, polatuzumab vedotin concentration, cyclophosphamide and doxorubicin PK at each 
specified time point, with separate tubes. 
b Polatuzumab vedotin PK, including serum PK samples for total antibody and plasma PK samples for antibody-conjugated MMAE and free 
MMAE. 
 


 
Polatuzumab Vedotin—Genentech, Inc. 
153/Protocol GO29044, Version 9 
Appendix 5  
G-CHP Plus Polatuzumab Vedotin Pharmacokinetic and 
Anti-Therapeutic Antibody Schedule 
PHASE IB DOSE ESCALATION (G-CHP PLUS POLATUZUMAB VEDOTIN)  
The PK sampling schedule below is applicable to patients who receive the 
obinutuzumab-containing regimen in the dose escalation portion of the study.  Per the 
sampling schedule (see below), 21 samples will be collected from each patient treated 
with G-CHP plus polatuzumab vedotin. 
 


Appendix 5  
G-CHP Plus Polatuzumab Vedotin Pharmacokinetic and Anti-Therapeutic Antibody Schedule 
(cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
154/Protocol GO29044, Version 9 
Table 1 
Phase Ib Dose Escalation (G-CHP plus Polatuzumab Vedotin) 
Study Visit 
Sample Time point(s) a 
Samples  
Cycle 1 Day 1 
Pre-obinutuzumab infusion 
Obinutuzumab ATA (serum),  
Obinutuzumab PK (serum) 
Cycle 1 Day 2 
Pre-polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b 
Polatuzumab vedotin ATA (serum) 
30 minutes (r 15 minutes) after the end of the polatuzumab vedotin 
infusion 
Polatuzumab vedotin PK (serum and plasma) b 
Cycle 1 Day 8 
6 days (r 1 day) after Day 2 infusion  
Polatuzumab vedotin PK (serum and plasma) b 
Cycle 1 Day 15 
13 days (r 1 day) after Day 2 infusion 
Polatuzumab vedotin PK (serum and plasma) b 
Cycle 2 Day 1 
Pre-obinutuzumab infusion 
Obinutuzumab ATA (serum),  
Obinutuzumab PK (serum) 
Cycle 2 Day 2 
Pre- polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b  
Polatuzumab vedotin ATA (serum) 
30 minutes (r 15 minutes) after end of polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b 
Cycle 4, Day 1  
Pre-obinutuzumab infusion 
Obinutuzumab ATA (serum),  
Obinutuzumab PK (serum) 
Pre-polatuzumab vedotin dose 
Polatuzumab vedotin PK (serum and plasma) b 
Polatuzumab vedotin ATA (serum) 
30 minutes (r 15 minutes) post end of polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b 


Appendix 5  
G-CHP Plus Polatuzumab Vedotin Pharmacokinetic and Anti-Therapeutic Antibody Schedule 
(cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
155/Protocol GO29044, Version 9 
Table 1 
Phase Ib Dose Escalation (G-CHP plus Polatuzumab Vedotin) (cont.)  
Study Visit 
Sample Time point(s) a 
Samples  
Post-treatment 
follow-up 
(Month 3) 
Random sample 
Obinutuzumab ATA (serum),  
Obinutuzumab PK (serum),  
Polatuzumab vedotin ATA (serum),  
Polatuzumab vedotin PK (serum and plasma) b 
ATA   anti-therapeutic antibody; MMAE   monomethyl auristatin E; PK   pharmacokinetic. 
a Up to 5-mL whole-blood samples will be taken for polatuzumab vedotin PK (polatuzumab vedotin total antibody, unconjugated MMAE and 
conjugate [evaluated as antibody conjugated MMAE], polatuzumab vedotin ATA, obinutuzumab PK, and obinutuzumab ATA at each specified 
time point, with separate tubes for plasma or serum samples. 
b Polatuzumab vedotin PK, including serum PK samples for conjugate antibody and conjugate (evaluated as antibody conjugated MMAE) and 
unconjugated MMAE. 


 
 
Appendix 5  
G-CHP Plus Polatuzumab Vedotin Pharmacokinetic and 
Anti-Therapeutic Antibody Schedule (cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
156/Protocol GO29044, Version 9 
PHASE II DOSE EXPANSION (G-CHP PLUS POLATUZUMAB VEDOTIN)  
The PK sampling schedule below is applicable to the first 20 patients who receive the 
obinutuzumab-containing regimen in the dose expansion portion of the study.  The 
remaining 20 patients will follow only the polatuzumab vedotin and obinutuzumab PK 
and ATA sampling schedule.  Per the sampling schedule (see below), a total of 38 
samples will be collected from the first 20 patients treated with G-CHP plus polatuzumab 
vedotin and a total of 28 samples (for only polatuzumab vedotin and obinutuzumab PK 
and ATA) will be collected from the remaining 20 patients. 
 


Appendix 5  
G-CHP Plus Polatuzumab Vedotin Pharmacokinetic and Anti-Therapeutic Antibody Schedule 
(cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
157/Protocol GO29044, Version 9 
Table 2 
Phase II Dose Expansion (G-CHP plus Polatuzumab Vedotin) 
Study Visit 
Sample Timepoint(s) a 
Samples  
Cycle 1 Day 1 
Pre-obinutuzumab infusion 
Obinutuzumab ATA (serum),  
Obinutuzumab PK (serum) 
End of obinutuzumab infusion 
Obinutuzumab PK (serum) b 
End (r 2 minutes) of cyclophosphamide infusion 
Cyclophosphamide PK (plasma) 
3 hours (r 5 minutes) post end of cyclophosphamide infusion 
Cyclophosphamide PK (plasma) 
2 hours (r 5 minutes) post end of doxorubicin administration 
Doxorubicin PK (plasma) 
Cycle 1 Day 2 
Pre-polatuzumab vedotin infusion 
Polatuzumab vedotin ATA (serum); 
Polatuzumab vedotin PK (serum and plasma) b  
30 minutes (r 15 minutes) after the end of the polatuzumab vedotin 
infusion 
Polatuzumab vedotin PK (serum and plasma) b  
23 hours (r 15 minutes) post end of cyclophosphamide infusion on 
Cycle 1 Day 1 
Cyclophosphamide PK (plasma) 
24 hours (r 15 minutes) post end of doxorubicin administration on 
Cycle 1 Day 1 
Doxorubicin PK (plasma) 
Cycle 1 Day 8 
6 days (r 1 day) after Day 2 infusion  
Polatuzumab vedotin PK (serum and plasma) b  
Cycle 1 Day 15 
13 days (r 1 day) after Day 2 infusion 
Polatuzumab vedotin PK (serum and plasma) b  
Cycle 2 Day 1 
Pre-obinutuzumab infusion 
Obinutuzumab ATA (serum),  
Obinutuzumab PK (serum) 
End of obinutuzumab infusion 
Obinutuzumab PK (serum) b 
Cycle 2 Day 2 
Pre-polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b  
Polatuzumab vedotin ATA (serum) 
30 minutes (r 15 minutes) after end of polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b 


Appendix 5  
G-CHP Plus Polatuzumab Vedotin Pharmacokinetic and Anti-Therapeutic Antibody Schedule 
(cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
158/Protocol GO29044, Version 9 
Table 2 
Phase II Dose Expansion (G-CHP plus Polatuzumab Vedotin) (cont.)  
Study Visit 
Sample Timepoint(s) a 
Samples  
Cycle 3, Day 1 
Pre-polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b  
30 minutes (r 15 minutes) after end of polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b 
End (r 2 minutes) of cyclophosphamide infusion 
Cyclophosphamide PK (plasma) 
3 hours (r 5 minutes) post end of cyclophosphamide infusion 
Cyclophosphamide PK (plasma) 
2 hours (r 5 minutes) post end of doxorubicin administration 
Doxorubicin PK (plasma) 
Cycle 3 Day 2 
23 hours (r 15 minutes) post end of cyclophosphamide infusion on 
Cycle 3 Day 1 
Cyclophosphamide PK (plasma) 
24 hours (r 15 minutes) post end of doxorubicin administration on 
Cycle 3 Day 1 
Doxorubicin PK (plasma) 
Cycle 4, Day 1  
Pre-obinutuzumab infusion 
Obinutuzumab ATA (serum),  
Obinutuzumab PK (serum) 
End of obinutuzumab infusion 
Obinutuzumab PK (serum) b 
Pre-polatuzumab vedotin dose 
Polatuzumab vedotin ATA (serum); 
Polatuzumab vedotin PK (serum and plasma) b  
30 minutes (r 15 minutes) post end of polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b  


Appendix 5  
G-CHP Plus Polatuzumab Vedotin Pharmacokinetic and Anti-Therapeutic Antibody Schedule 
(cont.) 
Polatuzumab Vedotin—Genentech, Inc. 
159/Protocol GO29044, Version 9 
Table 2 
Phase II Dose Expansion (G-CHP plus Polatuzumab Vedotin) (cont.)  
Study Visit 
Sample Timepoint(s) a 
Samples  
Treatment 
Completion/ 
Early 
Termination  
Approximately 1530 days after last infusion  
Polatuzumab vedotin ATA (serum); 
Polatuzumab vedotin PK (serum and plasma) b  
Post-treatment 
follow-up  
(Month 3) 
Random sample 
Obinutuzumab ATA (serum),  
Obinutuzumab PK (serum),  
Polatuzumab vedotin ATA (serum), 
Polatuzumab vedotin PK (serum and plasma) 
ATA   anti-therapeutic antibody; MMAE   monomethyl auristatin E; PK   pharmacokinetic. 
a Up to 5-mL whole-blood samples will be collected for rituximab PK, polatuzumab vedotin PK (polatuzumab vedotin total antibody, free MMAE 
and antibody conjugated MMAE), polatuzumab vedotin ATA, obinutuzumab PK, obinutuzumab ATA, and cyclophosphamide and doxorubicin 
PK at each specified time point, in separate tubes. 
b Polatuzumab vedotin PK, including serum PK samples for total antibody and plasma PK samples for antibody-conjugated MMAE and free 
MMAE. 
 


 
Polatuzumab Vedotin—Genentech, Inc. 
160/Protocol GO29044, Version 9 
Appendix 6  
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: 
x 
Age ! 65 years 
x 
Poor Performance Status 
x 
Previous history of febrile neutropenia 
x 
Open wounds or active infections 
x 
More advanced cancer 
x 
Extensive prior treatment, including large radiation therapy ports 
x 
Cytopenias due to bone marrow involvement by tumor 
x 
Other serious comorbidities 
 
SECONDARY PROPHYLACTIC G-CSF ADMINISTRATION 
Prophylactic G-CSF administration is recommended for patients who fulfill each of the 
following circumstances: 
x 
Experienced a neutropenic complication from a prior cycle of study treatment 
x 
Primary prophylactic G-CSF was not received; and 
x 
The intent is to avoid dose reduction of the ADC, where the effect of the reduced 
dose on disease-free or treatment outcome is not known 
 
THERAPEUTIC USE OF G-CSF 
G-CSF administration should be considered for the following patients: 
x 
Patients with febrile neutropenia who are at high risk for infection-associated 
complications; or 
x 
Patients who have prognostic factors that are predictive of poor clinical outcome, 
e.g., prolonged (! 10 days) and profound ( 100/PL) 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 
 
REFERENCES 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the 
use of white blood cell growth factors: an evidence-based clinical practice 
guideline. J Clin Oncol 2006;24:3187205. 


 
Polatuzumab Vedotin—Genentech, Inc. 
161/Protocol GO29044, Version 9 
Appendix 7  
Recommended Anaphylaxis Management 
The following equipment is needed in the event of a suspected anaphylactic 
reaction during study drug infusion: 
x 
Appropriate monitors (ECG, blood pressure, pulse oximetry 
x 
Oxygen and masks for oxygen delivery 
x 
Airway management devices per standard of care 
x 
Epinephrine for intravenous, intramuscular, and/or endotracheal administration 
in accordance with institutional guidelines  
x 
Salbutamol (or albuterol or equivalent) 
x 
Antihistamines (H1 and H2 blockers) 
x 
Corticosteroids 
x 
IV 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: 
x 
Stop the study drug infusion. 
x 
Call for additional assistance! 
x 
Maintain an adequate airway 
x 
Provide oxygen. 
x 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring, if possible. 
x 
Administer epinephrine first, followed by antihistamines, albuterol, or other 
medications as required by patient status and directed by the physician in charge. 
x 
Continue to observe the patient and document observations. 
 
 


 
Polatuzumab Vedotin—Genentech, Inc. 
162/Protocol GO29044, Version 9 
Appendix 8  
International Prognostic Index for Non-Hodgkin’s Lymphoma 
Table 1 
International Prognostic Index (IPI) 
International Prognostic Index (IPI) 
Risk Factors 
Ann-Arbor Stage III or IV 
Age ! 60 years 
Serum LDH ! 1 u ULN 
ECOG Performance Status t 2 
Extranodal involvement t 2 
IPI Risk Group 
Number of IPI Risk Factors 
Low 
0 or 1 
Low-intermediate 
2 
High-intermediate 
3 
High 
4 or 5 
ECOG   Eastern Cooperative Oncology Group; IPI   International Prognostic Index; ULN   upper 
limit of normal. 
The results of FDG-PET should not be taken into account for calculation of IPI as this 
prognostic score was established without FDG-PET. 
Adapted from:  Shipp et al. 1993. 
 
REFERENCES 
Shipp MA, Harrington DP, Anderson JR, et al. A predictive model for aggressive Non-
Hodgkin’s Lymphoma. N Engl J Med 1993;329:98794. 
 


 
Polatuzumab Vedotin—Genentech, Inc. 
163/Protocol GO29044, Version 9 
Appendix 9  
Total Neuropathy Score Clinical Assessment 
Table 1 
 Total Neuropathy Score – Nurse (TNSn) 
TNSn 
0 
1 
2 
3 
4 
Sensory 
symptoms 
None 
Symptoms 
limited to 
fingers or toes 
Symptoms 
extend to 
ankle or wrist 
Symptoms 
extend to knee 
or elbow 
Symptoms 
extend above 
knees or 
elbows 
Motor 
symptoms 
None 
Slight difficulty 
Moderate 
difficulty 
Require help/ 
assistance 
Paralysis 
Autonomic 
symptoms 
None 
1 yes 
2 yes 
3 yes 
4 or 5 yes 
Pin sensibility 
Normal 
Reduced in 
fingers/toes 
Reduced up to 
wrist/ankle 
Reduced up to 
elbow/knee 
Reduced to 
above 
elbow/knee 
Vibration 
sensibility 
Normal 
Reduced in 
fingers/toes 
Reduced up to 
wrist/ankle 
Reduced up to 
elbow/knee 
Reduced to 
above 
elbow/knee 
Copyright Johns Hopkins University 2008, all rights reserved. 
Sources:  Cavaletti et al. 2006, 2007. 
 
REFERENCES 
Cavaletti G, Frigeni B, Lanzani F, et al. The total neuropathy score as assessment tool 
for grading the course of chemotherapy-induced peripheral neurotoxicity: 
comparison with the National Cancer Institute-Common Toxicity Scale. J Peripher 
Nerv Syst 2007;12:2105. 
Cavaletti G, Jann S, Pace A, et al. Multi-center assessment of the total neuropathy score 
for chemotherapy-induced peripheral neurotoxicity. J Peripher Nerv Syst 
2006;11:13541. 
 


 
Polatuzumab Vedotin—Genentech, Inc. 
164/Protocol GO29044, Version 9 
Appendix 10  
Therapy-Induced Neuropathy Assessment Scale (TINAS) 
 
 
 
Source:  Thomas et al. 2012. 
 
REFERENCES 
Thomas SK, Mendoza TR, Vichaya EG, et al. Validation of the chemotherapy-induced 
neuropathy scale. J Clin Oncol 2012;30(Suppl 15):9140.