Conditions: Non-Hodgkin's Lymphoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1401
Healthy volunteers: no

Brief summary:
This open-label, randomized study will assess the efficacy and safety of obinutuzumab (RO5072759) in combination with chemotherapy compared to rituximab (MabThera/Rituxan) with chemotherapy followed by obinutuzumab or rituximab maintenance in participants with untreated advanced indolent non-Hodgkin's lymphoma. After the end of the induction period, participants achieving response (Complete response \[CR\] or partial response \[PR\]) will undergo a maintenance period continuing on the randomized antibody treatment alone every 2 months until disease progression for a total of 2 years. Anticipated time on study treatment is up to approximately 2.5 years. After maintenance or observation, participants will be followed for 5 years until progression. After progression, participants will be followed for new anti-lymphoma therapy and overall survival until the end of the study.

Detailed description:

Arms:
arm 1: Participants will receive either 8 cycles of rituximab along with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (21-day cycle) or 8 cycles of rituximab along with 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) (21-day cycles) or 6 cycles of rituximab along with 6 cycles of bendamustine (28-day cycle) during the induction period. The induction period will be followed by either a maintenance or observation period for responders or non-responders, respectively. Responders will receive rituximab monotherapy every 2 months for 2 years during the maintenance period. Non-responders will receive no protocol specified treatment during the 2-year observation period. Finally, participants will be followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual participant will be chosen by the site prior to initiation of the study. arm 2: Participants will receive either 8 cycles of obinutuzumab along with 6 cycles of CHOP (21-day cycle) or 8 cycles of obinutuzumab along with 8 cycles of CVP (21-day cycles) or 6 cycles of obinutuzumab along with 6 cycles of bendamustine (28-day cycle) during induction period. The induction period will be followed by either a maintenance or observation period for responders or non-responders, respectively. Responders will receive obinutuzumab monotherapy every 2 months for 2 years during the maintenance period. Non-responders will receive no protocol specified treatment during the 2-year observation period. Finally, participants will be followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual participant will be chosen by the site prior to initiation of the study.

Interventions: intervention 1: Obinutuzumab intervention 2: Cyclophosphamide intervention 3: Doxorubicin intervention 4: Vincristine intervention 5: Prednisone intervention 6: Bendamustine intervention 7: Rituximab
Intervention descriptions: intervention 1: Obinutuzumab 1000 milligrams (mg) intravenous (IV) infusion will be administered on Day 1, 8, and 15 of Cycle 1 and then on Day 1 of each subsequent cycle during induction period and obinutuzumab 1000 mg IV infusion every 2 months during maintenance period. intervention 2: Cyclophosphamide 750 mg/m\^2 IV will be administered on Day 1 of each cycle during induction period. intervention 3: Doxorubicin 50 mg/m\^2 IV will be administered on Day 1 of each cycle during induction period. intervention 4: Vincristine 1.4 mg/m\^2 (maximum 2 mg) IV will be administered on Day 1 of each cycle during induction period. intervention 5: Prednisone 100 mg (or equivalent prednisolone or methylprednisolone) will be administered orally on Days 1-5 of each cycle during induction period. intervention 6: Bendamustine 90 mg/m\^2 IV infusion will be administered on Days 1 and 2 of each cycle during induction period. intervention 7: Rituximab 375 milligrams per square meter (mg/m\^2) IV infusion will be administered on Day 1 of each cycle during induction period and rituximab 375 mg/m\^2 every 2 months during maintenance period.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
A Multicenter, Phase III, Open-Label, Randomized Study in 
Previously Untreated Patients With Advanced, Indolent Non-
Hodgkin's Lymphoma Evaluating The Benefit of Obinutuzumab 
(RO5072759) Plus Chemotherapy Compared With Rituximab Plus 
Chemotherapy Followed By Obinutuzumab or Rituximab 
Maintenance Therapy in Responders 
NCT Number: 
NCT01332968 
Document Date: 
Protocol Version A7: 15-February-2020 
 
 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL STATEMENT
The information contained in this document, especially any unpublished data, is the property of 
F. HoffmannLa Roche, Ltd (or under its control) and therefore is provided to you in confidence as 
an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board.  It is understood that this information 
will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered.  
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
P BO21223A7
PROTOCOL
TITLE:
A MULTICENTER, PHASE III, OPENLABEL, RANDOMIZED STUDY IN 
PREVIOUSLY UNTREATED PATIENTS WITH ADVANCED INDOLENT 
NONHODGKIN'S LYMPHOMA EVALUATING THE BENEFIT OF 
GA101 (RO5072759) PLUS CHEMOTHERAPY COMPARED WITH 
RITUXIMAB PLUS CHEMOTHERAPY FOLLOWED BY GA101 OR 
RITUXIMAB MAINTENANCE THERAPY IN RESPONDERS
PROTOCOL NUMBER:
BO21223
VERSION NUMBER:
A7
EUDRACT NUMBER:
201002413241
IND NUMBER:
104405
TEST PRODUCT:
Obinutuzumab (GA101, RO5072759)
MEDICAL MONITOR:
, Ph.D.
SPONSOR:
F. HoffmannLa Roche, Ltd
DATE FINAL:
Version 1:  14 January 2011
DATES AMENDED
Version A1:  26 July 2011
Version A2:  16 July 2012
Version A3:  18 November 2012 (France only)
Version A4:  28 May 2013
Version A5:  22 Mar 2014
Version A6:  9 June 2017
Version A7:  See electronic date stamp below
IN COOPERATION
WITH:
German Low Grade Lymphoma Study Group (GLSG) and 
East German Study Group for Hematology and Oncology 
(OSHO), LudwigMaximilians University Grosshadern 
Hospital, Marchioninistr. 15, 81377 Munich, Germany
and
National Cancer Research Institute (NCRI), 90 Tottenham 
Court Road, London W1T 4TJ, United Kingdom
 
15-Feb-2020 04:14:34
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
2/P BO21223A7
PROTOCOL AMENDMENT, VERSION A7:  
RATIONALE
Study BO21223 has been amended in part to collect response after progression and 
administration of NALT (Sections 3.1.1, 4.5.7, and 4.6, and Appendices A1-A5).
Additional changes are listed below:

The Medical Monitor for the study has been changed to 
, Ph.D.  

Reference Safety Information has been added (Section 5.7).
Additional minor changes have been made to improve clarity and consistency. New 
information appears in italics. This amendment represents cumulative changes to the 
original protocol. 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
3/P BO21223A7
TABLE OF CONTENTS
PROTOCOL SYNOPSIS ...................................................................................... 9
1.
BACKGROUND .......................................................................................... 24
1.1
Background on Disease......................................................... 24
1.1.1
NonHodgkin’s Lymphoma.................................................... 24
1.1.2
Natural History and Current Management of 
Indolent Non-Hodgkin's Lymphoma....................................... 24
1.2
Background on the Molecule ................................................. 28
1.2.1
Obinutuzumab (RO5072759, GA101) Structure 
and Mechanism of Action ...................................................... 28
1.2.2
Nonclinical Efficacy with Obinutuzumab ................................ 29
1.2.3
Clinical Experience with Obinutuzumab in
NonHodgkin's Lymphoma.................................................... 29
1.2.4
Pharmacokinetic and Pharmacodynamic Data for 
Obinutuzumab ....................................................................... 33
1.3
Study Rationale and BenefitRisk Assessment..................... 33
2.
OBJECTIVES.............................................................................................. 35
2.1
Primary Objective .................................................................. 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
Study Overview ..................................................................... 36
3.1.2
Patient-Reported Outcomes .................................................. 42
3.1.3
Medical Resource Utilization ................................................. 42
3.2
Rationale for Study Design.................................................... 42
3.2.1
Rationale for Study Drug Dosing ........................................... 42
3.2.2
Rationale for Required Biomarker Research 
Samples................................................................................. 49
3.2.3
Rationale for Optional Biomarker Samples 
(Stored in the Roche Clinical Repository).............................. 52
3.3
Outcome Measures ............................................................... 53
3.3.1
Primary Efficacy Outcome Measure ...................................... 53


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
4/P BO21223A7
3.3.2
Secondary Efficacy Outcome Measures................................ 53
3.3.3
Safety Outcome Measures .................................................... 54
3.3.4
Exploratory Outcome Measures ............................................ 55
3.4
Safety Plan ............................................................................ 56
3.4.1
Risks Associated with Obinutuzumab Therapy...................... 56
3.4.2
Risks Associated with Rituximab Therapy............................. 59
3.4.3
Risks Associated with CHOP Chemotherapy ........................ 61
3.4.4
Risks Associated with CVP Chemotherapy ........................... 61
3.4.5
Risks Associated with Bendamustine 
Chemotherapy....................................................................... 61
3.5
Study Patients and Analysis Groups ..................................... 63
3.6
Control Groups ...................................................................... 63
3.7
Minimization of Bias............................................................... 64
3.8
End of Study.......................................................................... 65
3.9
Ethical Considerations........................................................... 65
3.10
Administrative Structure......................................................... 66
3.11
Compliance with Laws and Regulations ................................ 67
4.
MATERIALS AND METHODS .................................................................... 67
4.1
Patient Selection.................................................................... 67
4.1.1
Inclusion Criteria.................................................................... 67
4.1.2
Exclusion Criteria................................................................... 69
4.2
Method of Treatment Assignment and Blinding..................... 71
4.3
Study Treatment.................................................................... 72
4.3.1
Formulation............................................................................ 72
4.3.2
Dosage, Administration, and Storage .................................... 73
4.3.3
Premedication........................................................................ 87
4.3.4
Dosage Modification Guidelines ............................................ 87
4.3.5
Management of Toxicities.................................................... 108
4.3.6
Treatment Discontinuation Criteria ...................................... 112
4.4
Concomitant and Excluded Therapies................................. 113
4.4.1
Concomitant Therapy .......................................................... 113
4.4.2
Excluded Therapy................................................................ 114
4.5
Study Assessments ............................................................. 115


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
5/P BO21223A7
4.5.1
Definitions of Study Assessments ....................................... 115
4.5.2
Screening and Pretreatment Assessments.......................... 123
4.5.3
Assessments During Induction Treatment........................... 123
4.5.4
Induction Completion/Early Termination Visit ...................... 123
4.5.5
Assessments During Maintenance Treatment or 
Observation ......................................................................... 124
4.5.6
Maintenance or Observation Completion/Early 
Termination Visit.................................................................. 125
4.5.7
FollowUp Assessments ..................................................... 126
4.6
Patient Discontinuation........................................................ 126
4.6.1
Discontinuation from Study Treatment ................................ 127
4.6.2
Discontinuation from Study.................................................. 127
4.6.3
Withdrawal of Patients from the Roche Clinical 
Repository ........................................................................... 127
4.7
Study or Site Discontinuation............................................... 128
4.8
PostTrial Access................................................................ 128
4.9
Assay Methods.................................................................... 128
4.10
Statistical Methods .............................................................. 128
4.10.1
Analysis of the Conduct of the Study................................... 128
4.10.2
Analysis of Treatment Group Comparability ........................ 128
4.10.3
Efficacy Analyses ................................................................ 129
4.10.4
Safety Analysis.................................................................... 132
4.10.5
PatientReport Outcomes ................................................... 133
4.10.6
Pharmacokinetic and Pharmacodynamic 
Analyses.............................................................................. 133
4.10.7
Exploratory Analyses........................................................... 134
4.10.8
Handling of Missing Data..................................................... 135
4.10.9
Determination of Sample Size ............................................. 135
4.10.10
Interim and Final Analyses .................................................. 137
4.11
Data Quality Assurance....................................................... 138
5.
ASSESSMENT OF SAFETY..................................................................... 138
5.1
Safety Parameters and Definitions ...................................... 138
5.1.1
Adverse Event ..................................................................... 139
5.1.2
Serious Adverse Event ........................................................ 139


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
6/P BO21223A7
5.1.3
ProtocolDefined Events of Special 
Interest/Non-Serious Expedited Adverse Events................. 140
5.2
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 140
5.2.1
Adverse Event Reporting Period ......................................... 140
5.2.2
Eliciting Adverse Events ...................................................... 141
5.2.3
Assessment of Severity and Causality of Adverse 
Events.................................................................................. 141
5.3
Procedures for Recording Adverse Events.......................... 143
5.4
Expedited Reporting Requirements for Serious 
Adverse Events and ProtocolDefined Events 
of Special Interest................................................................ 147
5.4.1
Reporting Requirements for 
Fatal/LifeThreatening SAEs Related to 
Investigational Product ........................................................ 147
5.4.2
Reporting Requirements for All SAEs and 
ProtocolDefined Events of Special Interest........................ 147
5.5
Type and Duration of FollowUp of Patients 
After Adverse Events ........................................................... 148
5.6
PostStudy Adverse Events ................................................ 148
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees........................................................ 149
6.
INVESTIGATOR REQUIREMENTS.......................................................... 149
6.1
Study Initiation..................................................................... 149
6.2
Study Completion ................................................................ 150
6.3
Informed Consent Forms..................................................... 151
6.3.1
Pregnant Partner Consent................................................... 152
6.3.2
Roche Clinical Repository Informed Consent ...................... 152
6.4
Death or Loss of Competence of Participant Who 
Has Donated a Specimen That Is Stored in the 
Roche Clinical Repository.................................................... 152
6.5
Communication with the Institutional Review 
Board or Ethics Committee.................................................. 152
6.6
Study Monitoring Requirements .......................................... 153
6.7
Electronic Case Report Forms............................................. 153
6.8
Source Data Documentation................................................ 153


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
7/P BO21223A7
6.9
Use of Computerized Systems ............................................ 154
6.10
Study Medication Accountability.......................................... 154
6.11
Disclosure of Data ............................................................... 155
6.12
Retention of Records........................................................... 155
6.13
Financial Disclosure ............................................................ 156
7.
CLINICAL STUDY REPORT..................................................................... 156
8.
REFERENCES ......................................................................................... 157
LIST OF TABLES
Table 1
Phase III Trials of Rituximab plus Chemotherapy in 
Previously Untreated Patients with Follicular Lymphoma ........... 26
Table 2
Administration of First and Subsequent Infusions 
of Rituximab................................................................................ 74
Table 3
Administration of First and Subsequent Infusions of 
Obinutuzumab............................................................................. 76
Table 4
Dosing with Rituximab plus CHOP.............................................. 79
Table 5
Dosing with Obinutuzumab plus CHOP ...................................... 80
Table 6
Dosing with Rituximab plus CVP................................................. 82
Table 7
Dosing with Obinutuzumab plus CVP ......................................... 83
Table 8
Dosing with Rituximab plus Bendamustine ................................. 85
Table 9
Dosing with Obinutuzumab plus Bendamustine.......................... 86
Table 10
Guidelines for Dose Delay or Modification of Obinutuzumab, 
Rituximab, or CHOP during Induction Therapy........................... 92
Table 11
Guidelines for Dose Delay or Modification of Obinutuzumab, 
Rituximab, or CVP during Induction Therapy.............................. 97
Table 12
Guidelines for Dose Delay or Modification of Obinutuzumab, 
Rituximab, or Bendamustine during Induction Therapy ............ 102
Table 13
Guidelines for Dose Delay or Modification of Obinutuzumab 
or Rituximab during Maintenance Therapy ............................... 107
Table 14
Guidelines for Management of Symptoms Related to 
Rituximab or Obinutuzumab Infusion........................................ 109
Table 15
Adverse Event Grading (Severity) Scale................................... 142
Table 16
Causal Attribution Guidance ..................................................... 142


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
8/P BO21223A7
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 37
Figure 2
Sequence of Study Phases in Study BO21223 (GALLIUM)........ 39
Figure 3
Schema of Returning to Original Schedule after a Visit Delay 
in Maintenance.......................................................................... 125
                         LIST OF APPENDICES
APPENDIX A1 Study Flowchart:  Induction Treatment with CHOP plus                  
Rituximab/Obinutuzumab (21Day Cycles) .............................. 165
APPENDIX A2 Study Flowchart:  Induction Treatment with CVP plus 
Rituximab/Obinutuzumab (21Day Cycles) .............................. 174
APPENDIX A3 Study Flowchart:  Induction Treatment with Bendamustine 
plus Rituximab/Obinutuzumab (28Day Cycles)....................... 182
APPENDIX A4 Study Flowchart:  Maintenance Treatment and Observation . 190
APPENDIX A5 Study Flowchart:  FollowUp.................................................. 195
APPENDIX B  Pharmacokinetic Assessments ................................................. 199
APPENDIX C  Modified Version of the Revised Response Criteria 
for Malignant Lymphoma .......................................................... 201
APPENDIX D  Functional Assessment of Cancer Therapy for Lymphoma     
(FACT-Lym) (Version 4)............................................................ 210
APPENDIX E  EuroQol's EQ5D Questionnaire ............................................. 213
APPENDIX F  Commonly Used CYP1A2 Inhibitors and Inducers................... 214
APPENDIX G  Inclusion Criteria for Patients with Gastric 
Extranodal Marginal Zone Lymphoma ...................................... 216
APPENDIX H  ECOG Performance Status Scale and Ann Arbor Staging........ 217
APPENDIX I  Calculation of Creatinine Clearance 
Using the Cockcroft-Gault Formula........................................... 219
APPENDIX J   Rituximab Preparation Instructions........................................... 220
APPENDIX K Obinutuzumab Preparation Instructions.................................... 221
APPENDIX L   Bendamustine Preparation Instructions.................................... 222
APPENDIX M Follicular Lymphoma International Prognostic Index 
and International Prognostic Index............................................ 223
APPENDIX N Activities of Daily Living Scale and 
Instrumental Activities of Daily Living Scale.............................. 227


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
9/P BO21223A7
PROTOCOL SYNOPSIS
TITLE:
A MULTICENTER, PHASE III, OPENLABEL, 
RANDOMIZED STUDY IN PREVIOUSLY UNTREATED 
PATIENTS WITH ADVANCED INDOLENT 
NONHODGKIN'S LYMPHOMA EVALUATING THE 
BENEFIT OF GA101 (RO5072759) PLUS CHEMOTHERAPY 
COMPARED WITH RITUXIMAB PLUS CHEMOTHERAPY 
FOLLOWED BY GA101 OR RITUXIMAB MAINTENANCE 
THERAPY IN RESPONDERS 
PROTOCOL NUMBER:
BO21223
Eudract Number:
201002413241
STUDY DRUG:
RO5072759 (GA101, obinutuzumab)
PHASE:
III
INDICATION:
Indolent nonHodgkin's lymphoma
IND:
104,405
SPONSOR:
F. HoffmannLa Roche, Ltd (exU.S.)
Grenzacherstrasse 124
4070 Basel, Switzerland 
Objectives
Primary Objective
The primary objective for this study is as follows:  

To evaluate the efficacy of obinutuzumab (GA101, RO5072759) plus chemotherapy followed 
by obinutuzumab maintenance therapy compared with rituximab plus chemotherapy followed 
by rituximab maintenance therapy in patients with previously untreated advanced follicular 
lymphoma, as measured by investigatorassessed progressionfree survival (PFS)
Secondary Objectives
The following secondary objective applies to patients with previously untreated advanced 
indolent nonHodgkin’s lymphoma (NHL) (i.e., overall population):  

To evaluate and compare investigatorassessed PFS between the two arms
The following secondary objectives apply to patients with previously untreated advanced 
indolent NHL (i.e., overall population) and to the subset of patients with previously untreated 
advanced follicular lymphoma (i.e., follicular population):  

To evaluate and compare Independent Review Committee (IRC)assessed PFS between 
the two arms

To evaluate and compare overall response and complete response (CR) after the end of 
induction treatment, as assessed by the investigator, between the two arms, with and 
without fluorodeoxyglucose positron emission tomography (FDGPET)

To evaluate and compare overall response and CR after the end of induction treatment, 
as assessed by the IRC, between the two arms, with and without 18FFDGPET


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
10/P BO21223A7

To evaluate and compare overall survival, event-free survival (EFS), diseasefree survival 
(DFS), duration of response, and time to next antilymphoma treatment between the two 
arms
EFS, DFS, and duration of response will be based on investigator assessment.  

To evaluate and compare the safety profiles between the two arms during induction and 
maintenance

To assess patientreported outcomes (PROs) in both arms
Study Design
This is an openlabel, international, multicenter, randomized, Phase III study to investigate the 
efficacy and safety of obinutuzumab plus chemotherapy followed by obinutuzumab 
maintenance therapy for responders CR or partial response (PR) compared with rituximab plus 
chemotherapy followed by rituximab maintenance therapy for responders in patients with 
previously untreated advanced indolent NHL.  Prior to the initiation of the study, each site will 
choose one of three chemotherapy regimens cyclophosphamide, doxorubicin, vincristine, and 
prednisone (CHOP), cyclophosphamide, vincristine, and prednisone (CVP) or bendamustine) 
that is considered to be the standard of care for follicular lymphoma; all patients with follicular 
lymphoma at that site will receive the chosen chemotherapy regimen for the duration of the 
study (a site may switch to another regimen if new scientific data become available and after 
Sponsor approval).  For nonfollicular NHL, the investigator will have the option of choosing one 
of the three chemotherapy regimens (CHOP, CVP, or bendamustine) for each patient.  All 
patients will then be randomized to either rituximab plus chemotherapy or obinutuzumab plus 
chemotherapy.  
Approximately 1200 patients with follicular lymphoma will be recruited and randomly assigned in 
a 1:1 ratio to either obinutuzumab plus chemotherapy followed by obinutuzumab maintenance 
in responders or rituximab plus chemotherapy followed by rituximab maintenance in responders.  
In addition, approximately 200 patients with marginal zone lymphoma (MZL) will be recruited 
and randomly assigned in a 1:1 ratio to the two treatment arms.  
The schedule for administration of rituximab or obinutuzumab will be dependent upon the 
accompanying chemotherapy regimen.  In the control arm of the study (Arm A), six to eight 
doses of rituximab at 375 mg/m2 will be administered by IV infusion with the accompanying 
chemotherapy regimen.  In the experimental arm of the study (Arm B), eight to ten doses of 
obinutuzumab (including two additional doses of obinutuzumab on Days 8 and 15 of Cycle 1) at 
an absolute (flat) dose of 1000 mg will be administered by IV infusion with the accompanying 
chemotherapy regimen.  Patients who demonstrate a CR or PR at the end of induction therapy 
will continue to receive rituximab at 375 mg/m2 (Arm A) or obinutuzumab at a flat dose of 
1000 mg (Arm B) every 2 months until disease progression for up to 2 years.  Patients who 
demonstrate stable disease (SD) at the end of induction therapy will be followed for progression 
for up to 2 years according to the same followup schedule as responding patients (CR or PR) 
receiving maintenance (observation).  If induction therapy was stopped for toxicity or any reason 
other than toxicity, then patients are discontinued from study treatment and go into followup 
directly.  
All patients will be assessed for disease response by the investigator through use of regular 
clinical and laboratory examinations and computed tomography (CT) scans according to a 
modified version of the Revised Response Criteria for Malignant Lymphoma.  Additional 
response criteria based on paraprotein assessment are in effect for the MZL population and 
based on hematological parameters and spleen size for the subset of splenic MZL patients.  
During induction treatment, tumor assessment is performed after three cycles for patients 
receiving bendamustine, after four cycles for patients receiving CVP or CHOP, and at the 
completion of induction therapy.  
Following the completion of induction therapy, patients receiving maintenance therapy 
(CR or PR) or undergoing observation (SD) will be followed clinically every 2 months for 2 years 
(with CT scans every 4 months for the first year and then every 6 months for the second year).  
For patients who have not progressed at the maintenance or observation completion visit 
(25 months from Day 1 of Cycle 8 [CHOP/CVP arms] or Cycle 6 [bendamustine arm]), disease 
assessments will continue every 3 months for 3 years (with CT scans every 6 months) and then 
every 6 months for 2 years (with CT scans every year) (followup for disease progression).  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
11/P BO21223A7
After 5 years of followup or disease progression (whichever comes first), patients will still be 
followed every 6 months for overall survival and new antilymphoma treatment (NALT), or for 
disease progression if applicable,  until the end of the study, which will be approximately 
10.2 years after inclusion of the first patient.  Patients who terminate induction early without 
progressive disease (PD) will be followed for PD, as per Appendix A5, and in the extended 
followup for PD, NALT and overall survival.  Patients who terminate induction early because of 
PD will go directly into the extended followup for NALT and overall survival.  Patients who 
discontinue the protocoldefined treatment path and need to start an NALT in the absence of 
disease progression (e.g., if wrong diagnosis at screening and new diagnosis requires a change 
of treatment) will be followed for disease progression and overall survival. For patients who 
progressed and received NALT, response after NALT will be collected.  
An independent radiologic and oncologic review of the responses of all patients by an IRC will 
also be conducted for the futility and efficacy analyses with and without PET.  
Patients who discontinue all components of study therapy prior to disease progression 
(e.g., for toxicity) will enter the followup phase of the study and will continue to be followed for 
PD and overall survival (regardless of whether they subsequently receive NALT).  
A retrospective quality assurance pathology review will be conducted on pathology samples to 
evaluate histology and CD20 status in addition to other prognostic features.  
An IDMC will conduct periodic interim reviews of safety summaries, starting approximately 
1 month after enrollment of the first patient and then approximately every 2 months until 
100 patients have completed two cycles of study treatment.  Afterward, the IDMC will conduct 
reviews of safety summaries approximately every 6 months.  All summaries and analyses 
reviewed by the IDMC will be prepared by an Independent Data Coordinating Center (IDCC).  
Safety will be evaluated by monitoring dose delays and dose intensity, adverse events, 
serious adverse events, and deaths.  These will be graded using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0.  Laboratory 
safety assessments will include regular monitoring of hematology, blood chemistry, and tests of 
immunologic parameters.  In addition, tests for the presence of human antihuman antibodies 
(HAHAs) will be performed only in all patients receiving obinutuzumab.  
Outcome Measures
Primary Efficacy Outcome Measure
The primary efficacy endpoint, PFS in patients with follicular lymphoma, is defined as the time 
from randomization to the first occurrence of progression or relapse as assessed by the 
investigator according to the Revised Response Criteria for Malignant Lymphoma, or death from 
any cause.  
Secondary Efficacy Outcome Measures
For the endpoints below that specify disease response, response will be assessed by the 
investigator according to the Revised Response Criteria for Malignant Lymphoma and additional 
response criteria for MZL.  
The following secondary outcome measure applies to patients with previously untreated 
advanced indolent NHL (i.e., overall population):  

Investigatorassessed PFS
The following secondary outcome measures apply to patients with previously untreated 
advanced indolent NHL (i.e., overall population) and to the subset of patients with previously 
untreated advanced follicular lymphoma (i.e., follicular population):  

IRCassessed PFS

CR and overall response (CR or PR) at the end of induction, as assessed by the investigator 
with and without FDGPET

CR and overall response (CR or PR) at the end of induction, as assessed by the IRC 
with and without FDGPET

Overall survival, defined as the time from randomization to death from any cause

EFS, defined as the time from randomization to disease progression/relapse as assessed by 
the investigator, death from any cause, or start of an NALT


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
12/P BO21223A7

DFS, defined for patients with a best overall response (BOR) of CR as the time from first 
occurrence of a documented CR to PD as assessed by the investigator or death from any 
cause.  Patients who have had no documented disease progression or have not died after CR 
will be censored at the last disease assessment date.  

Duration of response, defined for patients with a BOR of CR or PR as the time from first 
occurrence of a documented CR or PR to disease progression/relapse as assessed by the 
investigator or death from any cause.  For patients achieving a response who have not 
progressed, relapsed, or died at the time of the analysis, duration of response will be censored 
on the date of last disease assessment.  

Time to next antilymphoma treatment, defined as the time from randomization to start of 
new nonprotocol antilymphoma therapy or death from any cause

Change from baseline to the end of study in PROs based on the FACTLym instrument, 
as outlined below.  
Change from baseline in all domains of the FACTG
Change from baseline in the total outcome index (TOI) (range, 0116):  sum of physical 
wellbeing (7 items), functional wellbeing (7 items), and Lym subscale (15 items) 
scores
Change from baseline in the FACTLym subscale score (range, 060):  
15 lymphomaspecific items
Change from baseline in the FACTLym total score (range, 0168):  sum of physical 
wellbeing (7 items), social/family wellbeing (7 items), emotional wellbeing (6 items), 
functional wellbeing (7 items), and Lym subscale (15 items) scores

EQ5D summary scores at baseline, during treatment, after treatment, at the last 
assessment prior to progression, and at the first assessment after progression
Analysis of medical resource utilization data will be provided if required.  
Safety Plan
This trial is designed to allow for early termination or a modification of the protocol (in particular, 
the dosing regimens) for safety concerns, based on the advice of an IDMC.  The IDMC will be 
incorporated into the study to review safety data on a regular basis, including adverse events of 
special interest.  The IDMC will meet 1 month after enrollment of the first patient and then 
approximately every 2 months until 100 patients have completed two cycles of study treatment.  
Afterward, the IDMC will meet approximately every 6 months.  Both the Sponsor and the IDMC 
can request ad hoc IDMC meetings if potential safety concerns arise.  Following each meeting, 
the IDMC will recommend to the Sponsor whether the study should continue according to the 
protocol or may suggest changes to the protocol based on the outcome of the data review.  
In exceptional cases, the IDMC may recommend stopping the study or closing a treatment arm 
as a result of safety reasons.  The IDMC will also perform a safety review at the preplanned 
interim analyses for futility and efficacy.  
Risks Associated with Obinutuzumab Therapy
The commonly experienced IRRs have been characterized by fever, chills, flushing, nausea, 
vomiting, hypotension, hypertension, and fatigue, as well as 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, Version 3.0, 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 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.  
Cases of tumor lysis syndrome have been reported with obinutuzumab administration.  To date, 
no patient has required hemodialysis for renal failure.  Patients with a high tumor burden, 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
13/P BO21223A7
including patients with a lymphocyte count of 25 109/L (particularly, patients with Bcell CLL 
and MCL), are at increased risk for tumor lysis syndrome and severe IRRs.  
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 granulocyte colony stimulating factors 
(GCSF) has been found to result in a rapid normalization of neutrophils, similar to what has 
been observed in patients treated with rituximab.  The use of GCSF is allowed for treatment of
neutropenia in this study.  Primary prophylaxis with GCSF is recommended according to the 
American Society of Clinical Oncology (ASCO), European Organisation for Research and 
Treatment of Cancer (EORTC), and European Society for Medical Oncology (ESMO) guidelines, 
namely for patients who are 60 years old and/or with comorbidities.  The use of GCSF is 
strongly recommended in Cycle 1 for all patients treated with obinutuzumab plus CHOP 
(GCHOP).  
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.  
Based on the available evidence to date the greatest risk of hemorrhage in 
obinutuzumabtreated patients are observed in the first cycle.  A clear relationship between 
thrombocytopenia and hemorrhagic events has not been established.  Patients treated with 
concomitant medication, which could possibly worsen thrombocytopeniarelated events, such 
as 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.  
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.  
Serious infections, including fatal, bacterial, fungal, and new or reactivated viral infections 
(e.g., cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile 
virus, and hepatitis B and C) 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 stemcell transplant.  The risk of such infections with obinutuzumab is unknown.  
Physicians should be aware of symptoms suggestive of progressive multifocal 
leukoencephalopathy (PML) and consider the diagnosis of PML in any patient presenting with 
newonset neurologic manifestations.  Evaluation of PML includes but is not limited to 
consultation with a neurologist, brain magnetic resonance imaging (MRI), and lumbar puncture.  
To date, there have been no reports of patients experiencing PML while or after receiving 
obinutuzumab.  
Cases (including fatal) of John Cunningham virus (JCV) infection resulting in PML 
(destructive infection of oligodendrocytes of the central nervous system 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 to quantify DNA of JCV in the cerebrospinal fluid.  
Therapy with obinutuzumab and rituximab should be withheld during the investigation of 
potential PML and permanently discontinued in the 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 treatment of PML.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
14/P BO21223A7
Risks Associated with Rituximab Therapy
Patients treated with rituximab in combination with chemotherapy are at risk for IRRs.  Fatal 
infusion reactions within 24 hours after 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, adult respiratory distress syndrome, myocardial infarction, ventricular 
fibrillation, cardiogenic shock, anaphylactoid events, or death.  
Patients may be at risk for tumor lysis syndrome.  A high number of circulating malignant cells 
(25,000/mm3) or high tumor burden confers a greater risk of tumor lysis syndrome.  For 
patients with evidence of tumor lysis syndrome, rituximab should be discontinued and the 
patient treated as clinically indicated.  
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 diagnosis 
of hepatitis was approximately 4 months after the initiation of rituximab and approximately 
1 month after the last dose.  
Patients with chronic hepatitis B viral infection (i.e., hepatitis B surface antigen [HBsAg] positive) 
are at risk for reactivation and will be excluded from the study.  Patients with evidence of prior 
hepatitis B exposure or who are carriers (defined as HBsAg negative and hepatitis B core 
antibody [HBcAb] positive) are at a lower risk for reactivation.  In a study of 51 HBV carriers with 
diffuse large Bcell lymphoma who received rituximab, 12% of patients developed evidence of 
reactivation (Niitsu et al. 2010).  Patients who demonstrate evidence of reactivation while 
receiving an appropriate antiviral therapy will discontinue study treatment.  
Rare cases of PML have been reported in patients treated with rituximab alone or in 
combination with other immunosuppressive medications.  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 after the patient's last infusion 
of rituximab.  
Angina and cardiac arrhythmias have occurred with rituximab treatment and can be life 
threatening.  Patients in the CHOP arm who have been treated with doxorubicin, an 
anthracyclinebased chemotherapy, are at risk for cardiotoxicity and will be required to have 
assessments of left ventricular ejection fraction (LVEF) at baseline and at the end of induction 
treatment.  
Serious infections, including fatal, bacterial, fungal, and new or reactivated viral infections 
(e.g., cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile 
virus, and hepatitis B and C), can occur during and up to 1 year following the completion of 
rituximabbased therapy.  
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 (TEN).  The 
onset of these reactions in patients treated with rituximab has varied from 1 to 13 weeks 
following rituximab exposure.  
Abdominal pain, bowel obstruction, and perforation, in some cases leading to death, can occur 
in patients receiving rituximab in combination with chemotherapy.  In postmarketing reports of 
rituximab, the mean time to documented gastrointestinal perforation was 6 days 
(range, 177 days) in patients with NHL.  
Risks Associated with CHOP or CVP Chemotherapy
Please refer to prescribing information for doxorubicin, cyclophosphamide, vincristine, and 
prednisone/prednisolone/methylprednisolone for risks related to CHOP or CVP chemotherapy.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
15/P BO21223A7
Risks Associated with Bendamustine Chemotherapy
Patients treated with bendamustine are likely to experience myelosuppression.  Blood counts 
will be monitored weekly during the first cycle and then frequently throughout subsequent cycles 
of treatment.  Patients who experience Grade 3 or 4 neutropenia or thrombocytopenia should 
be monitored until neutrophil and platelet values return to at least Grade 2.  The use of myeloid 
growth factors for the primary and secondary prevention of febrile neutropenia is permitted.  
Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in 
postmarketing reports.  Infection has been associated with hospitalization, septic shock, and 
death.  Patients with myelosuppression following treatment with bendamustine are more 
susceptible to infections.  
Infusion reactions to bendamustine have occurred commonly in clinical trials.  Symptoms 
include fever, chills, pruritis, and rash.  In rare instances, severe anaphylaxis and anaphylactoid 
reactions have occurred, particularly in the second and subsequent cycles of therapy.  Patients 
should be monitored clinically and discontinue drug for every reaction.  
Tumor lysis syndrome has been reported in association with bendamustine treatment in clinical 
trials and in postmarketing reports.  The onset tends to be within the first treatment cycle of 
bendamustine and without intervention may lead to acute renal failure and death.  Preventive 
measures include maintaining adequate volume status and close monitoring of blood chemistry, 
particularly potassium and uric acid levels.  Allopurinol has also been used during the beginning 
of bendamustine therapy.  However, there may be an increased risk of severe skin toxicity when 
bendamustine and allopurinol are administered concomitantly.  
A number of skin reactions have been reported in clinical trials and postmarketing safety reports.  
These events have included rash, toxic skin reactions, and bullous exanthema.  Some events 
occurred when bendamustine was given in combination with other anticancer agents, so the 
precise relationship to bendamustine is uncertain.  
In a study of bendamustine in combination with rituximab, one case of TEN occurred.  TEN has 
been reported for rituximab.  Cases of StevensJohnson syndrome and TEN, some fatal, have 
been reported when bendamustine was administered concomitantly with allopurinol and other 
medications known to cause these syndromes.  Allopurinol must not be given on days of 
bendamustine administration.  Patients with skin reactions should be monitored closely.  
If skin reactions are severe or progressive, bendamustine should be withheld.  
Premalignant and malignant diseases, including myelodysplastic syndrome, myeloproliferative 
disorders, acute myeloid leukemia, and bronchial carcinoma, have developed in patients treated 
with bendamustine.  The association with bendamustine has not been determined.  
There are postmarketing reports of bendamustine extravasation resulting in hospitalization from 
erythema, marked swelling, and pain.  Precautions should be taken to avoid extravasation, 
including monitoring of the IV infusion site for redness, swelling, pain, infections, and necrosis 
during and after administration of bendamustine.  
Rare cases of transfusionassociated graft versus host disease have been reported following 
treatment of lowgrade Bcell malignancies with the purine analogues fludarabine.  The 
situation with newer purine antagonists such as bendamustine is unclear.  Transfusions, if 
required, should be performed according to national guidelines.  
Certain medications may interact with bendamustine.  Caution should be used or alternative 
treatments considered if concomitant treatment with CYP1A2 inhibitors or inducers is needed.  
CYP1A2 inhibitors and inducers are not contraindicated.  During treatment with bendamustine, 
patients will be provided with a card to keep with them that provides notification to other health 
care providers that the patient is taking bendamustine as a participant in a clinical study
(see Appendix F).  
Study Treatment
In the control arm (Arm A), six to eight doses of rituximab at 375 mg/m2 will be administered by 
IV infusion with the accompanying chemotherapy regimen during induction, as outlined below:  

RCHOP:  Rituximab will be administered on Day 1 of Cycles 18 (21day cycles).  CHOP 
will be administered on Day 1, with prednisone/prednisolone/methylprednisolone also 
administered on Days 25, of Cycles 16.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
16/P BO21223A7

RCVP:  Rituximab will be administered on Day 1 of Cycles 18 (21day cycles).  CVP will 
be administered on Day 1, with prednisone/prednisolone/methylprednisolone also 
administered on Days 25, of Cycles 18.  

Rbendamustine:  Rituximab will be administered on Day 1 of Cycles 16 (28day cycles).  
Bendamustine will be administered on Days 1 and 2 of Cycles 16, with 
prednisone/prednisolone/methylprednisolone also administered on Day 1 of Cycle 1.  
If it is the strong preference of the investigator or of the site (e.g., for logistical or safety reasons), 
the administration of rituximab on the day prior to CHOP or CVP or bendamustine with 
premedication is allowed.  It is also allowed to split the antibody infusion over 2 days if the 
patient is at increased risk for an IRR (high tumor burden, high peripheral lymphocyte count). 
However, both optional changes to the administration schedule have to be done equally in both 
study arms (RChemo and GChemo) in order to avoid any bias.  Premedication before 
antibody administration in Cycle 1 is recommended and may include 100 mg 
prednisone/prednisolone or 80 mg methylprednisolone orally (within 12 hours but at least 
60 minutes prior to start of antibody infusion) or IV (if less than 60 minutes prior to start of 
antibody infusion) in order to minimize cytokine release syndrome or allergic reactions.  
Premedication with prednisone/prednisolone/methylprednisolone is mandatory in patients who 
had an IRR until no IRRs occur anymore during antibody infusion.  Withhold antihypertensive 
medication 12 hours prior to start of antibody infusion and during the infusion.  
Patients randomized to receive rituximab plus chemotherapy who achieve a CR or PR at the 
end of induction therapy will continue to receive rituximab at 375 mg/m2 every 2 months until 
disease progression for up to 2 years.  
In the experimental arm (Arm B), eight to ten doses of obinutuzumab at 1000 mg will be 
administered by IV infusion with the accompanying chemotherapy regimen during induction, as 
outlined below.  

GCHOP:  Obinutuzumab will be administered on Days 1, 8, and 15 of Cycle 1 and on 
Day 1 of Cycles 28 (21day cycles).  CHOP will be administered on Day 1, with 
prednisone/prednisolone/methylprednisolone also administered on Days 25, of Cycles 16

GCVP:  Obinutuzumab will be administered on Days 1, 8, and 15 of Cycle 1 and on Day 1 
of Cycles 28 (21day cycles).  CVP will be administered on Day 1, with 
prednisone/prednisolone/methylprednisolone also administered on Days 25, of Cycles 18

Gbendamustine:  Obinutuzumab will be administered on Days 1, 8, and 15 of Cycle 1 and 
on Day 1 of Cycles 26 (28 day cycles).  Bendamustine will be administered on Days 1 and 
2 of Cycles 16, with prednisone/prednisolone/methylprednisolone administered on Day 1 
of Cycle 1
If it is the strong preference of the investigator or of the site (e.g., for logistical or safety reasons), 
the administration of obinutuzumab is allowed on the day prior to CHOP or CVP or 
bendamustine.  It is also allowed to split the antibody infusion over 2 days if the patient is at 
increased risk for an IRR (high tumor burden, high peripheral lymphocyte count).  However, 
both optional changes to the administration schedule have to be done equally in both study 
arms (RChemo and GChemo) in order to avoid any bias.  Premedication before antibody 
administration in Cycle 1 is recommended and may include 100 mg prednisone/prednisolone or 
80 mg methylprednisolone orally (within 12 hours but at least 60 minutes prior to start of 
antibody infusion) or IV (if less than 60 minutes prior to start of antibody infusion) in order to 
minimize cytokine release syndrome or allergic reactions.  Premedication with 
prednisone/prednisolone/methylprednisolone is mandatory in patients who had an IRR until no 
IRRs occur anymore during antibody infusion.  Withhold antihypertensive medication 12 hours 
prior to start of antibody infusion and during the infusion.  
Patients randomized to receive obinutuzumab plus chemotherapy who achieve a CR or PR at 
the end of induction therapy will continue to receive obinutuzumab at 1000 mg every 2 months 
until disease progression for up to 2 years.  
Concomitant Therapy and Clinical Practice
Patients who use oral contraceptives, hormonereplacement therapy, or other maintenance 
therapy should continue their use.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
17/P BO21223A7
Patients may receive prophylactic antiviral medication to prevent hepatitis B reactivation in 
countries where they are administered as part of the standard of care or national guidelines.  
The use of rasburicase for the treatment of tumor lysis syndrome and the prevention of 
hyperuricemia is allowed according to institutional guidelines.  
The use of antibiotic and/or antiviral prophylaxis according to institutional guidelines is also 
allowed.  
Primary prophylaxis with granulocyte colony stimulating factors (GCSF) is recommended as 
per the American Society of Clinical Oncology (ASCO), European Organisation for Research 
and Treatment of Cancer (EORTC), and European Society for Medical Oncology (ESMO) 
guidelinesnamely, in patients who are 60 years of age and/or with comorbidities.  The use 
of GCSF prophylaxis is strongly recommended in Cycle 1 for all patients treated with 
GA101CHOP.  
Harvesting of stem cells by GCSF alone (no additional chemotherapeutic agent) is allowed 
only if it is done between Cycle 5 Day 1 and Cycle 8 Day 1 (R/GCHOP or R/GCVP) or 
Cycle 4 Day 1 and Cycle 6 Day 1 (R/GBendamustine).  
Patients who experience obinutuzumab infusionrelated temperature elevations of 38.5C 
or other minor infusionrelated symptoms may be treated symptomatically with 
acetaminophen/paracetamol (500 mg) and/or H1and H2receptor antagonists 
(e.g., diphenhydramine, ranitidine).  Serious infusionrelated events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory 
distress should be managed with additional supportive therapies (e.g., supplemental oxygen, 2
agonists/epinephrine, and/or corticosteroids) as clinically indicated according to standard clinical 
practice.  
It is mandatory to follow the ASCO/EORTC/ESMO guidelines about the use of myeloid growth 
factors for the primary prevention of febrile neutropenia throughout the trial.  
Mesna (2mercaptoethane sulfonate sodium) may be administered as prophylaxis per 
institutional guidelines for patients treated with CHOP or CVP.  
Use of the following therapies is prohibited during the study:  

Cytotoxic chemotherapy (other than bendamustine, cyclophosphamide, doxorubicin, 
or vincristine)
Although MTX is a chemotherapeutic agent, due to the low doses used in treating 
rheumatoid arthritis (typically 7.5 to a maximum of 20 mg/week) it is not considered 
chemotherapy for lymphoma.  Therefore, patients treated before or during study conduct 
with MTX for rheumatoid arthritis are still eligible to participate in the study.  It is 
recommended to stop MTX 23 weeks prior to starting immunochemotherapy since the 
combination of MTX and immunochemotherapy increases the risk of 
immunosuppression and the risk of infection, but MTX may be resumed during 
maintenance/observation/followup, if clinically indicated

Radiotherapy

Immunotherapy (other than rituximab and obinutuzumab)

Hormone therapy (other than contraceptives, hormonereplacement therapy, or megestrol 
acetate)
Hormonal therapy (e.g., GmRHagonists) for egg cell harvest/fertility preservation prior 
to randomization is allowed in women of childbearing age

Any therapies intended for the treatment of NHL whether U.S. Food and Drug Administration 
approved or experimental (outside of this study)
Statistical Methods
Primary Efficacy Analysis
The primary analysis population for efficacy is the intenttotreat follicular population, defined 
as all randomized patients with follicular histology, according to local diagnosis provided in 
interactive voice or Webbased response system (IxRS).  Patients will be analyzed according to 
the treatment arm to which they were randomized.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
18/P BO21223A7
The primary efficacy endpoint, PFS in patients with follicular lymphoma, is defined as the time 
from randomization to the first occurrence of progression or relapse as assessed by the 
investigator according to the Revised Response Criteria for Malignant Lymphoma or death from 
any cause.  PFS for patients without disease progression, relapse, or death will be censored at 
the time of the last tumor assessment or, if no tumor assessments were performed after the 
baseline visit, at the time of randomization.  
Although the primary efficacy endpoint is the investigatorassessed PFS, PFS based on IRC 
assessments will also be analyzed to support the primary analysis.  In the United States, 
IRCassessed PFS will be the basis for regulatory decisions.  
The primary analysis of the study will test the equality of PFS distributions in the obinutuzumab 
plus chemotherapy (GChemo) and rituximab plus chemotherapy (RChemo) arms, as follows:  
H0: PFSG-Chemo = PFSR-Chemo versus
H1: PFSG-Chemo ≠ PFSR-Chemo
Treatment comparison will be made using a twosided stratified logrank test (0.05 significance 
level) stratified by chemotherapy regimen (CHOP, CVP, or bendamustine) and FLIPI risk group 
(low, intermediate, or high).  KaplanMeier methodology will be used to estimate PFS 
distribution for each treatment arm.  The KaplanMeier curve will provide a visual description of 
the differences across treatment arms.  Estimates of the treatment effect will be expressed as 
hazard ratios through use of a stratified Cox proportionalhazards analysis, including 
95% confidence limits.  
Median PFS is not expected to be reached in this study; hence, the 3year and 4year rates will 
be used to describe PFS in addition to the hazard ratio.  
Missing Data  
For PFS, patients who do not have documented disease progression or death will be treated as 
censored observations on the date of the last tumor assessment.  
For overall survival, patients who do not have documented deaths will be censored on the last 
date they were known to be alive.  
For response endpoints, patients with no response assessments (for whatever reason) will be 
considered nonresponders.  
Determination of Sample Size
Estimates of the number of events required to demonstrate efficacy with regard to PFS are 
based on the following assumptions:  

Twosided logrank test at the 0.05 level of significance

Powered for follicular lymphoma patient subset

Eighty percent power to detect a hazard ratio for GChemo versus RChemo of 0.74, 
corresponding to an improvement in 3year PFS from 70.7% to 77.4% or in median PFS 
from 6 years to 8.1 years (35%)
Note that estimates of median PFS are not likely to be reached in either study arm.  

Exponential distribution of PFS

An annual dropout rate of 2.5%

Performance of interim analyses on PFS: one for futility when approximately 30% of the 
total (investigatorassessed) PFS events have occurred and one for efficacy when 
approximately 67% of the total PFS events have occurred.  Efficacy and (nonbinding) futility 
boundaries will be computed using the LanDeMets approximation to the O’BrienFleming 
boundary shape.  
The futility boundary will be nonbinding.  
In addition, a futility analysis based on CR rates at the end of induction determined by CT (or 
MRI, but not PET) will be performed on the first 170 follicular lymphoma patients randomized.  
With these assumptions, 370 PFS events are required to achieve 80% power for the primary 
analysis.  Recruitment will be staggered in order to recruit the first 170 patients in a smaller 
number of sites (approximately 125 sites), followed by the activation of all 
(approximately 200250) sites after the IDMC meeting for futility based on CR rates.  It 
is expected that during the first stage, after a 6-month ramp up, 18 patients per month will be 
recruited, and after the IDMC meeting and another 4month ramp up, an accrual rate of 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
19/P BO21223A7
37 patients per month is expected.  The 1200 follicular patients enrolled over 49 months 
and followed for an additional 29 months will be required to provide 370 PFS events, with a total 
duration for PFS followup of approximately 78 months (6.5 years). 
Approximately 200 additional patients with nonfollicular lymphoma will be enrolled.  This number 
was based on a study of enrollment feasibility, which indicated that 200 patients would likely be 
enrolled in 49 months, in addition to the planned follicular enrollment.  Although the study would 
not be powered to detect statistically significant differences in this 200patient cohort, there would 
be a reasonable chance of detecting a trend.  
The pharmacokinetic assessments will apply to a subpopulation of approximately 460 patients 
receiving obinutuzumab.  This is the minimum number of patients needed to accurately construct 
a population pharmacokinetic model and will allow for the evaluation of the relationship between 
exposure and pharmacodynamic markers of response.  Approximately 120 follicular patients will 
undergo pharmacokinetic sampling from each of the three chemotherapy groups (GCHOP, 
GCVP, and Gbendamustine), and 100 additional patients with nonfollicular lymphoma will also 
undergo sampling.  This sample size is believed to be sufficient to characterize with confidence 
the pharmacokinetics of obinutuzumab in the target population as well as the relationships 
between exposure to obinutuzumab and response.  The pharmacokinetic sampling schedule in 
this study was determined using an optimal sampling strategy with the software PFIM and should 
result in a precision of parameter estimates lower than 20% for the main pharmacokinetic 
parameters.  
Interim and Final Analyses  
Although the study is open label, Sponsor personnel will not have access to byarm efficacy 
and safety summaries prior to the formal reporting of study results.  In order to monitor safety, 
Sponsor drug safety and medical monitoring staff will have access to the treatment assignments 
of particular patients.  An IDMC will evaluate interim analysis results and determine whether the 
trial will be stopped early.  
Three interim analyses are planned:  two for futility and one for efficacy.  The first interim 
analysis will be based on differences in end of induction CR rates in the first 170 enrolled 
follicular lymphoma patients.  The analysis will be conducted once the 170 follicular lymphoma 
patients have reached their endofinduction response assessment or have withdrawn 
prematurely.  The IDMC may recommend to stop the study for futility if the observed difference 
in CR rate based on CT (or MRI, but not PET) is 3% in favor of GChemo (i.e., CR rate needs 
to be 3% higher on GChemo vs. RChemo).  
The second interim analysis (futility on PFS) will be conducted when 30% of the required PFS 
events (i.e., approximately 111 events) will have occurred.  The IDMC may recommend to stop 
the study for futility if the observed hazard ratio of obinutuzumab over rituximab is 1 
(futility boundary based on nonbinding O´BrienFleming betaspending function).  
At the time of the third interim analysis (efficacy on PFS) that will be conducted when 67% of 
the events have occurred (i.e., approximately 248 events), all patients will have been enrolled 
and followed for an estimated minimum of 11 months.  PFS will be tested at the significance 
level determined using the O´BrienFleming alphaspending function so the overall Type I error 
rate will be maintained at the 0.05 level.  With 67% information, the alpha spending is 0.012.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
20/P BO21223A7
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
ADCC
antibodydependent cellular cytotoxicity
ADLs
activities of daily living
AE
adverse event
aPTT
activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
B
bendamustine
BOR
best overall response
BSA
body surface area
CDC
complementdependent cytotoxicity
CHOP
cyclophosphamide, doxorubicin, vincristine, and 
prednisone (or prednisolone/methylprednisolone)
CI
confidence interval
CLL
chronic lymphocytic leukemia
CMH
CochranMantelHaenszel
CR
complete response
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CVP
cyclophosphamide, vincristine, and prednisone 
(or prednisolone/methylprednisolone)
DFS
diseasefree survival
DLBCL
diffuse large Bcell lymphoma
DLT
doselimiting toxicity
EC
Ethics Committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EFS
eventfree survival
EORTC
European Organisation for Research and 
Treatment of Cancer
ESMO
European Society for Medical Oncology
EuroQol
European Quality of Life
FACS
fluorescenceactivated cell sorting
FACTG
functional assessment instrument
FACTLym
Functional Assessment of Cancer Therapy for 
Lymphoma
FC
fludarabine and cyclophosphamide
FCM
fludarabine, cyclophosphamide, and mitoxantrone
FDA
Food and Drug Administration


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
21/P BO21223A7
Abbreviation
Definition
FDG
18Ffluorodeoxyglucose
FLIPI
Follicular Lymphoma International Prognostic 
Index
FU
followup
G
GA101
GCHOP
obinutuzumab plus CHOP
GCSF
granulocyte colony stimulating factor
GClb
obinutuzumab plus chlorambucil
GCP
Good Clinical Practice
GFC
obinutuzumab plus fludarabine and 
cyclophosphamide
GTD
greatest transverse diameter
HAHA
human antihuman antibody
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HRQoL
healthrelated quality of life
HTLV
human Tlymphotropic virus
IADLs
instrumental activities of daily living
ICH
International Conference on Harmonisation
IDCC
Independent Data Coordinating Center
IDMC
Independent Data Monitoring Committee
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug
INR
international normalized ratio
IPI
International Prognostic Index
IRB
Institutional Review Board
IRC
Independent Review Committee
IRR
infusionrelated reaction
IV
intravenous
IxRS
interactive voice or Webbased response system
JCV
John Cunningham Virus
LMWH
low molecular weight heparins
LVEF
left ventricular ejection fraction
MALT
mucosaassociated lymphoid tissue


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
22/P BO21223A7
Abbreviation
Definition
MCL
mantle cell lymphoma
MP
methylprednisolone
MRD
minimum residual disease
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MTX
methotrexate
MUGA
multiplegated acquisition
MZL
marginal zone lymphoma
NALT
new antilymphoma treatment
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NHL
nonHodgkin’s lymphoma
NK 
natural killer [cell]
ORR
overall response rate
PCR
polymerase chain reaction
PD
progressive disease
PE
polyethylene
PET
positron emission tomography
PFS
progressionfree survival
PML
progressive multifocal leukoencephalopathy
PR
partial response
PRIMA
Primary Rituximab and Maintenance (trial)
PRO
patientreported outcome
PT
prothrombin time
PTT
partial thromboplastin time
PVC
polyvinyl chloride
R
rituximab
RBC
red blood cell
RClb
rituximab plus chlorambucil
RCR
Roche Clinical Repository
RCHOP
rituximab plus CHOP
RCVP
rituximab plus CVP
SAE
serious adverse event
SD
stable disease
SDV
source data verification
SLL
small lymphocytic lymphoma
SPD
sum of the product of the diameters


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
23/P BO21223A7
Abbreviation
Definition
SUSAR
suspected unexpected serious adverse reaction
TEN
toxic epidermal necrolysis
TMA
tissue microarray
TOI
total outcome index
TTNLT
time to next antilymphoma treatment
ULN
upper limit of normal
US
United States
WM
Waldenström's macroglobulinemia


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
24/P BO21223A7
1.
BACKGROUND
1.1
BACKGROUND ON DISEASE
1.1.1
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 (US; American Cancer Society 2010; 
GLOBOCAN 2010).  The majority of NHLs (also known as malignant lymphoma) are 
of Bcell origin and are characterized by the expression of a membrane antigen, CD20, 
which is important in cell cycle initiation and differentiation (Anderson et al. 1984).  NHL 
can be divided into aggressive and indolent NHL.  Indolent NHLs are a heterogeneous 
group of malignant lymphomas and account for about onethird of all NHLs.  Follicular 
lymphoma is the most common subtype of indolent NHL in the Western hemisphere and 
is associated with follicle center Bcells that typically contain the BCL2 chromosome 
translocation t(14:18), which leads to overexpression of the intracellular antiapoptotic 
protein Bcl2.  Although follicular lymphoma is the most common subtype of indolent 
NHL, there are also many histological nonfollicular subtypes, including marginal zone 
lymphoma (MZL), Waldenström's macroglobulinemia (WM; also known as 
lymphoplasmacytic lymphoma), mucosaassociated lymphoid tissue (MALT) lymphoma, 
and small lymphocytic lymphoma (SLL).  Earlystage indolent NHL may be effectively 
treated with radiation therapy, but advanced stages remain incurable.  
1.1.2
Natural History and Current Management of Indolent 
Non-Hodgkin's Lymphoma
The clinical course of indolent NHL is characterized by remission and relapse 
(Gallagher et al. 1986).  The disease initially responds to radiation and/or 
immunochemotherapy with conventional agents, but patients eventually suffer multiple 
relapses distinguished by increasing refractoriness and decreasing duration of response 
in subsequent lines of therapy.  Patients with advancestage disease are not usually 
cured with conventional treatment and ultimately die from recurrent disease or 
treatmentrelated toxicity.  
a.
Immunochemotherapy in Follicular Lymphoma
There is no standard treatment for the management of advanced follicular lymphoma, 
and data from the National LymphoCare registry demonstrate that practice varies widely 
among physicians (Friedberg et al. 2009).  For follicular lymphoma patients requiring 
treatment, immunochemotherapy with rituximab (MabThera, Rituxan), a monoclonal 
antibody directed against CD20, plus chemotherapy has demonstrated improvements in 
response rates, progressionfree survival (PFS), and overall survival compared with 
chemotherapy alone in four studies (Hiddemann et al. 2005; Herold et al. 2007; 
Marcus et al. 2008; Salles et al. 2008) (see Table 1).  Rituximab in combination with 
chemotherapy (e.g., CHOP [cyclophosphamide, doxorubicin, vincristine, 
and prednisone], CVP [cyclophosphamide, vincristine, and prednisone], or purine 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
25/P BO21223A7
analoguebased schemes such as those with fludarabine or bendamustine) for newly 
diagnosed patients with advanced Stage III and IV disease requiring treatment is 
strongly supported by both the 2009 European Society for Medical Oncology (ESMO) 
Guidelines Working Group recommendations (level of evidence:  I; grade of 
recommendation:  B) and the 2010 National Comprehensive Cancer Network (NCCN) 
guidelines (Category 1 recommendation based on highlevel evidence, with a uniform 
NCCN consensus) (Dreyling 2009; Zelenetz et al. 2010).  


Protocol:  Obinutuzumab—F. Hoffmann–La Roche, Ltd
26/P BO21223A7
Table 1
Phase III Trials of Rituximab plus Chemotherapy in Previously Untreated Patients with Follicular 
Lymphoma
Reference
Treatment
n
Median 
FollowUp
Primary Endpoint
ORR and CR Rates
Overall Survival
Marcus et al. 2008
RCVP vs. CVP for 
8 cycles
321
53 months
Median TTF: 
27 vs. 7 months
ORR81% vs. 57%
CR41% vs. 10%
4year OS:  
83% vs. 77%
Hiddemann et al. 2005
RCHOP vs. CHOP 
for 68 cycles
428
18 months
Treatment failure:  
28/223 vs. 61/205
ORR96% vs. 90%
CR20% vs. 17%
2year OS:  
95% vs. 90%
Herold et al. 2007
RMCP vs. MCP for 
6 cycles
201
47 months
PFS:  not reached 
vs. 29 months
ORR92% vs. 75%
CR50% vs. 25%
4year OS:  87% 
vs. 74%
Salles et al. 2008
RCHVP for 6 cycles 
vs. CHVP for 
12 cycles; both with 
IFN
358
5 years
EFS:  
53% vs. 37%
ORR94% vs. 85%
CR63% vs. 34%
5year OS:  
84% vs. 79%
CHOPcyclophosphamide, doxorubicin, vincristine, and prednisone (or prednisolone/methylprednisolone); CHVP cyclophosphamide, 
doxorubicin, etoposide, and prednisone; CR complete response; CVP cyclophosphamide, vincristine, and prednisone (or 
prednisolone/methylprednisolone); EFS eventfree survival; IFNinterferon; MCPmitoxantrone, chlorambucil, and prednisolone; 
ORRoverall response rate (complete response plus partial response); OSoverall survival; PFSprogressionfree survival; Rrituximab; 
TTFtime to treatment failure.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
27/P BO21223A7
b.
Immunochemotherapy in NonFollicular Indolent Lymphoma
Rituximab has also demonstrated efficacy in patients with nonfollicular indolent 
lymphoma, including MZL, WM, and SLL (Foran et al. 2000; Treon et al. 2001; 
Hainsworth et al. 2003).  A Phase II trial conducted in 39 patients with MZL (Brown et al. 
2009) showed high response rates (overall response rate [ORR] of 85%; complete 
response [CR] rate of 54%) with durable responses (79.5% PFS after 3.1 years) 
following treatment with rituximab and chemotherapy.  
The uncommon nature of MZL with an incidence of about 2/100,000 has limited 
the number of dedicated studies on the optimal therapeutic approach.  Historically,this 
subtype of indolent NHL has been studied in smaller nonrandomized trials or in 
conjunction with other more prevalent types of indolent NHL, such as follicular 
lymphoma.  As a result, treatment of MZL is approached in a fashion similar to treatment 
of follicular lymphoma, with similar results for rituximab monotherapy and rituximab plus 
chemotherapy.  A randomized study comparing chemotherapy with chemotherapy plus 
rituximab in patients with extranodal MZL at a median followup time of 60 months 
showed an improvement in 5year eventfree survival (EFS) from 50% (95% confidence 
interval [CI], 40%, 9%) in those receiving chlorambucil to 68% (95% CI, 58%, 76%) in 
those receiving chlorambucil plus rituximab (Zucca and Dreyling 2010).  
Rituximab is listed as an option for the treatment of advanced MZL in the recent ESMO 
and NCCN Clinical Practice Guidelines (Zelenetz et al. 2010; Zucca et al. 2010).  
c.
Maintenance Therapy after Induction Treatment
In addition to immunochemotherapy induction, two recent randomized clinical trials 
have demonstrated the benefit of maintenance rituximab in responding patients with 
both previously untreated and relapsed follicular lymphoma.  In a clinical trial of patients 
with relapsed follicular lymphoma, responders to rituximab plus CHOP (RCHOP) 
or CHOP underwent a second randomization to maintenance rituximab or observation.  
Patients who received maintenance rituximab demonstrated a superior median PFS 
(52 vs. 15 months) and 3 year overall survival (85% vs. 77%) compared with patients 
who underwent observation (van Oers et al. 2006).  This benefit for maintenance 
rituximab was evident even for patients who received rituximab during induction therapy.  
Updated results from this study, with a median followup of 6 years, continued to 
demonstrate a significant improvement in PFS with rituximab maintenance versus 
observation (median PFS:  3.7 years vs. 1.3 years; p0.001; hazard ratio, 0.55) and in 
5 year overall survival (74% vs. 64%) after either RCHOP or CHOP induction 
(van Oers et al. 2010).  Most recently, a study of patients with previously untreated 
follicular lymphoma that responded to rituximab in combination with CVP, CHOP, or 
FCM (fludarabine, cyclophosphamide, and mitoxantrone) who were later randomized to 
observation or 2 years of maintenance rituximab (the Primary Rituximab and 
Maintenance [PRIMA] trial) demonstrated an improvement in PFS with the addition of 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
28/P BO21223A7
maintenance rituximab.  Patients who received 2 years of rituximab maintenance 
demonstrated a 2year PFS of 82%, compared with 66% for the observation group 
(p0.001; hazard ratio, 0.50; overall survival data are still immature) (Salles et al. 2011).  
These studies have set a new standard for the treatment of patients with follicular 
lymphoma.  
Despite these encouraging results, therapy for indolent NHL is not curative.  
The majority of patients will ultimately die from progressive disease (PD). It is important 
to introduce new agents that may potentially alter the natural history of indolent NHL.  
One such candidate is obinutuzumab (RO5072759, GA101), a novel glycoengineered 
antiCD20 monoclonal antibody that has shown efficacy with an acceptable toxicity 
profile in Phase I and Phase II trials.  
This trial will test whether obinutuzumab combined with chemotherapy followed by 
maintenance obinutuzumab can improve the outcome over rituximab combined with 
chemotherapy followed by maintenance rituximab in patients with previously untreated 
indolent NHL.  The study aims to obtain an improvement of 25 months for obinutuzumab 
plus chemotherapy versus rituximab plus chemotherapy, corresponding to a hazard ratio 
of 0.74 for an improvement in median PFS from 6 to 8.1 years.  
1.2
BACKGROUND ON THE MOLECULE
1.2.1
Obinutuzumab (RO5072759, GA101) Structure and Mechanism 
of Action
Obinutuzumab is a humanized and glycoengineered monoclonal antibody, derived by 
humanization of the parental BLy1 mouse antibody and subsequent glycoengineering 
leading to the following characteristics (Beers et al. 2010; Mössner et al. 2010):  

Highaffinity binding to CD20

Type II binding to the CD20 epitope, leading to low complementdependent 
cytotoxicity (CDC) related to the recognition of the CD20 epitope and the lack of 
CD20 localization into lipid rafts after binding of the monoclonal antibody to CD20

Compared with the chimeric Type I antiCD20 antibody rituximab, increased 
antibodydependent cellular cytotoxicity (ADCC) related to an improved binding of 
obinutuzumab to the different allotypes of FcRIIIa expressed by natural killer (NK) 
cells and monocytes

Compared with rituximab, increased direct celldeath induction related to an elbow 
hinge amino exchange of the Fab region and Type II binding of the CD20 epitope
Given the significantly greater ADCC and direct celldeath induction, it is possible that 
obinutuzumab may have greater efficacy than rituximab, particularly in the 80%85% of 
patients who are carriers of the FcRIIIa lowaffinity receptor polymorphism (FF/FV 
genotype; see Section 3.2.2.b), since such patients may have decreased overall survival 
compared with patients with the highaffinity (V/V) polymorphism who demonstrate 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
29/P BO21223A7
improved survival following therapy with chemotherapy plus either rituximab or I131 
tositumomab (Persky et al. 2009).  
1.2.2
Nonclinical Efficacy with Obinutuzumab
Obinutuzumab has demonstrated in vivo efficacy superior to that of rituximab in various 
human lymphoma xenograft models.  Both antibodies have been compared in human 
SUDHL4 cells (a diffuse large Bcell lymphoma [DLBCL] model) that were 
subcutaneously injected into severe combined immunodeficient beige mice.  Therapy 
began when tumors were established and rapidly growing.  
It was shown that rituximab at 10 mg/kg inhibited tumor growth more than rituximab at 
1 mg/kg; however, increasing the dose to 30 mg/kg did not result in increased efficacy 
of rituximab.  In contrast, obinutuzumab showed a dosedependent increase in efficacy 
in the range of 130 mg/kg and resulted in complete tumor regression in all animals and 
in lasting tumor eradication in 9 of 10 animals at the highest dose of 30 mg/kg and in 
1 of 10 animals at a dose of 10 mg/kg.  
Additional studies have also shown similar results, because obinutuzumab treatment 
was able to control tumor growth when vehicleand rituximabtreated tumors were not 
controlled (Mössner et al. 2010).  
For more detailed nonclinical information on obinutuzumab, please refer to the current 
version of the obinutuzumab Investigator’s Brochure.  
1.2.3
Clinical Experience with Obinutuzumab in NonHodgkin's 
Lymphoma
As of June 2010, clinical data on obinutuzumab are available from four Phase I or II 
studies (Studies BO20999, BO21003, BO21000, and JO21900) and two Phase III 
studies (Studies GAO4753g and BO21004/CLL11).  More than 350 patients with 
CD20positive malignant disease have been treated with obinutuzumab.  
Results from the aggressive and indolent NHL cohorts in ongoing studies are described 
below.  For more detailed clinical information on obinutuzumab and for information 
regarding chronic lymphocytic leukemia (CLL) cohorts and all Phase I studies, please 
refer to the obinutuzumab Investigator’s Brochure.  
a)
Study BO20999 (Phase I/II):  Obinutuzumab Monotherapy
The results from the Phase II part of the study are presented below.  
Patients with Indolent NonHodgkin's Lymphoma
Forty patients with relapsed or refractory indolent NHL were randomized to receive 
obinutuzumab in a lowdose cohort (n18) or a highdose cohort (n22).  Patients 
were pretreated with a median of four prior regimens (range, 113), and the majority 
(39 of 40) had received prior rituximab treatment.  More than half of these patients (24 of 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
30/P BO21223A7
40) were considered to be rituximab refractory, and 25% (10 of 40) of all patients   had 
previously received an autologous stem-cell transplant.  The lowdose cohort received 
obinutuzumab 400 mg on Days 1 and 8 of Cycle 1 followed by obinutuzumab 400 mg on 
Day 1 of Cycles 2-8 (21day cycles), and the highdose cohort received obinutuzumab 
1600 mg on Days 1 and 8 of Cycle 1 followed by obinutuzumab 800 mg on Day 1 of 
Cycles 28 (21day cycles).  The end-of-treatment response rate (response evaluation 
4 weeks after the end of treatment) was 17% in the lowdose cohort (3 with partial 
response [PR], 6 with stable disease [SD], 7 with PD, and 2 unevaluable) and 55% in the 
highdose cohort (2 with CR, 10 with PR, 6 with SD, and 4 with PD).  
Obinutuzumab was well tolerated in both cohorts.  During the treatment period, 
9 patients experienced a total of 12 serious adverse events, with 4 (all in the highdose 
cohort) assessed by the investigator as related to obinutuzumab (herpes zoster, 
neutropenia, febrile neutropenia, and pancreatitis).  During the additional followup 
period, 2 patients reported serious adverse events of pyrexia (lowdose cohort) and 
bacteremia (highdose cohort).  The most common adverse events (all grades), 
occurring with an incidence of 10%, were infusionrelated reaction (IRR; 73%), 
asthenia (33%), nasopharyngitis (13%), peripheral edema (10%), pyrexia (10%), 
abdominal pain (10%), bronchitis (10%), and nausea (10%).  Thirtythree percent of 
patients had Grade 3 or 4 adverse events; the three most common were lymphopenia 
(8%), neutropenia (8%), and infections (10%).  
Patients with Aggressive NonHodgkin's Lymphoma
Forty patients with aggressive NHL were enrolled into the Phase II part of the study.  
Of these patients with aggressive NHL (25 with DLBCL and 15 with mantlecell 
lymphoma [MCL]), 19 were treated in the highdose cohort (15 with DLBCL and 4 with 
MCL) and 21 were treated in the lowdose cohort (10 with DLBCL and 11 with MCL).  
Preliminary safety and efficacy data are available (data on file).  The primary endpoint 
was endoftreatment response, assessed 4 weeks after the last infusion (25 weeks 
after treatment start).  Patients were heavily pretreated (median of three prior therapies), 
with 63% of patients having not responded to or relapsed within 6 months after a 
previous rituximab-containing regimen (rituximab refractory); 45% of patients completed 
all nine infusions.  The endoftreatment response rate was 24% in the lowdose cohort 
(DLBCL: 2 with PR, 1 with CR unconfirmed); MCL: 2 with CR) and 32% in the 
highdose cohort (DLBCL:  4 with PR; MCL:  2 with PR).  
The five most common adverse events were IRR (75%), infection (25%), asthenia (18%), 
anemia (15%), and lymphopenia (15%).  Fifty percent of patients had Grade 3 or 4 
adverse events; the five most common were lymphopenia (15%), anemia (10%), 
thrombocytopenia (8%), IRR (8%), and tumor lysis syndrome (5%).  Serious adverse 
events occurring in 2 or more patients included cardiac failure (n2), IRR (n3), tumor 
lysis syndrome (n2), and anemia (n2).  There was one Grade 5 adverse event, 
cardiorespiratory arrest that was thought to be secondary to ventricular arrhythmia.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
31/P BO21223A7
b)
Study BO21003 (Phase II):  Obinutuzumab Monotherapy plus Maintenance
Study BO21003 is an ongoing, openlabel, multicenter, randomized, Phase I/II study 
to investigate the efficacy and safety of obinutuzumab monotherapy compared with that 
of rituximab monotherapy in patients with relapsed indolent NHL.  The Phase II portion 
of the study began in July 2009, and approximately 176 patients have been enrolled.  
An interim analysis for safety and a futility analysis for efficacy were performed in 
July 2010 with use of data from 78 patients.  Per the protocol, futility stopping rules 
recommended a halt to the trial if the rituximab arm had 2 more patients with a response 
at the end of treatment than did the obinutuzumab arm (Δ3.14%).  The internal 
monitoring committee’s recommendation was to continue the study as planned.  No new 
safety issues were identified.  
c)
Study BO21000 (Phase Ib):  Obinutuzumab in Combination with 
Chemotherapy
Study BO21000 is an ongoing, openlabel, randomized Phase I/II trial investigating two 
doses of obinutuzumab (400 mg and 1600/800 mg) in combination with chemotherapy 
given every 4 weeks for a maximum of six cycles (obinutuzumab plus fludarabine and 
cyclophosphamide [GFC]) or a maximum of eight cycles (obinutuzumab plus CHOP 
[G-CHOP]) in patients with relapsed or refractory follicular lymphoma.  In the 
1600/800 mg GCHOP arm, patients receive a cumulative dose of 7200-8000 mg of 
obinutuzumab, depending on the standard number of cycles delivered.  Patients with a 
PR or CR who complete a minimum of four cycles of GFC or six cycles of GCHOP 
have the option of receiving maintenance therapy with obinutuzumab alone every 
3 months for up to 2 years.  Currently, safety data from the induction period are 
available.  Of 56 patients enrolled with relapsed/refractory disease, all 28 patients 
treated with GCHOP have completed the induction treatment, whereas 6 of the
28 patients who started GFC withdrew early from induction treatment.  Reasons for 
withdrawal from study treatment for the 6 patients who withdrew from the GFC arm 
were PD for 1 patient and adverse events reported in 5 patients:  neutropenia 
(3 patients) and rash and infection (1 patient each).  
Overall, between the lowdose and highdose arms, the rate of adverse events by 
system organ class did not differ greatly, and given the small numbers of patients, 
definitive conclusions cannot be drawn about differences between lowdose and 
high-dose obinutuzumab adverse event rates.  All 56 patients experienced at least one 
adverse event.  The most commonly reported events were classified under the system 
organ class “general disorders and administrationsite conditions,” with the highest rate 
for IRR events, regardless of the chemotherapy backbone and dose level group 
considered.  
The rate of IRRs was 68% of patients in the GCHOP arm and 82% of patients in the 
G-FC arm; 7% of events were Grade 3 or 4 events in both chemotherapy arms.  Events 
in the gastrointestinal disorders system organ class were the second most common 


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reported adverse events and were reported in 86% and 71% of patients in the G-CHOP 
and GFC arms, respectively.  Infection and infestation events were experienced by 
79% (93% high dose; 64% low dose) of the patients in the GCHOP arm and 57% 
(57% high dose; 57% low dose) of the patients in the GFC arm.  Grade 3 and 4 
infection and infestation events were reported in 21% of patients in the GCHOP arm 
and 29% of patients in the G-FC arm.  
Blood and lymphatic system events, with neutropenia being the most common event, 
were observed for 57% and 64% of the patients in the GCHOP and GFC arms, 
respectively.  Of these events, 46% and 61% were considered Grade 3 or 4 events.  
Neutropenic events (i.e., neutropenia, febrile neutropenia, neutropenic sepsis, and 
neutropenic infections) were reported in 14 patients (50%) and 17 patients (61%) in 
the GCHOP and GFC arms, respectively.  Serious adverse events were reported in 
8 patients (29%) and 7 patients (25%) receiving G-CHOP and GFC induction, 
respectively.  Infections were the most commonly reported events.  No deaths have 
been reported during the induction treatment period (Davies et al. 2011).  
The protocol was amended to include obinutuzumab at a flat dose of 1000 mg plus 
bendamustine (G-bendamustine) or CHOP in previously untreated patients with follicular 
lymphoma.  Again, patients with a PR or CR who complete a minimum of six cycles of 
G-CHOP or four cycles of G-bendamustine have the option of receiving maintenance 
therapy with obinutuzumab alone every 3 months for up to 2 years.  For the patient 
cohort with untreated follicular lymphoma, 80 treatmentnaive patients will be enrolled, 
with 40 patients in each cohort.  Enrollment has meanwhile been completed, with 
40 patients recruited into the G-CHOP cohort and 41 patients in the G-bendamustine 
cohort.  The Data and Safety Monitoring Board evaluated safety of the patients 
throughout the study without requesting modifications to the protocol.  
d)
Study GAO4753g (Phase III):  Obinutuzumab in Combination with 
Chemotherapy
Study GAO4753g is an ongoing, openlabel, multicenter, randomized, Phase III study 
to investigate the efficacy and safety of bendamustine compared with that for 
bendamustine plus obinutuzumab in patients with rituximabrefractory indolent NHL.  
Approximately 360 patients will be enrolled.  The first patient was enrolled in April 2010, 
and approximately 60 patients have been enrolled through May 2011.  No safety data 
are available yet.  The Data and Safety Monitoring Board evaluated safety of the first 
20 patients without requesting modifications to the protocol.  
e)
Summary of Safety and Efficacy Results
With consideration of all the available obinutuzumab Phase I and II data, the data 
strongly suggest that obinutuzumab could represent a more effective treatment than the 
wellestablished anti-CD20 antibody rituximab, offering improved outcomes for patients 
without significantly compromising safety.  


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For more information relating to safety and efficacy in the NHL indication, refer to the 
obinutuzumab Investigator's Brochure.  
1.2.4
Pharmacokinetic and Pharmacodynamic Data for 
Obinutuzumab
A population pharmacokinetic model has been developed for Studies BO20999 and 
BO21003 to characterize the pharmacokinetics of obinutuzumab and its variability.  
A two-compartment model, comprising both a linear clearance pathway and a nonlinear 
timevarying clearance pathway, was fitted to the data.  Data are available for a total 
of 134 patients following intravenous (IV) administration of obinutuzumab in 
Studies BO20999 (n114) and BO21003 (n20).  
Following infusion of obinutuzumab, the elimination appears to be characterized by a 
clearance that is dependent on time; that is, starting at a typical value of 594 mL/day and 
then gradually decreasing to an asymptote of 112 mL/day at steady state.  Tumor 
burden potentially contributes significantly to the clearance of obinutuzumab, especially 
at the beginning of treatment when there is an excess of CD20 cells.  As tumor burden 
decreases, the clearance reaches an asymptote, which is thought to be primarily a 
function of the proteolytic metabolic clearance.  Consequently, some patients with a high 
tumor burden appear to clear the drug from the plasma faster than patients with a low 
tumor burden because obinutuzumab binds to the CD20positive tumor cells and is 
effectively removed from the plasma.  Therefore, the clearance of the drug will vary with 
time since repeated treatments with obinutuzumab will reduce the quantity of 
CD20positive tumor cells.  
Treatment with obinutuzumab resulted in extensive Bcell depletion, with all patients 
showing a reduction in cell count to absolute zero at some stage of their treatment cycle.  
Overall, there has been no notable increase in complement levels before or after 
infusion, but changes have been observed in the levels of interleukin6 and 
interleukin8 before and after infusion.  
1.3
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
Indolent NHL is characterized by a pattern of remission and relapses and is incurable 
with standard treatment options.  In spite of the progress made in the treatment of 
patients with indolent NHL based on the addition of rituximab to chemotherapy, a 
significant number of patients will relapse and ultimately die of PD or treatmentrelated 
toxicity.  Therefore, obtaining better outcomes for previously untreated patients is of 
critical importance.  
Phase II and III trials have confirmed the safety and efficacy of combining rituximab, an 
antiCD20 monoclonal antibody, with various chemotherapy regimens such as CVP, 
CHOP, and bendamustine in previously untreated patients with indolent NHL.  The 
addition of an antiCD20 monoclonal antibody to conventional chemotherapy improves 
efficacy without adding significant toxicity (Czuczman et al. 2005; Rummel et al. 2005, 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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2009; Marcus et al. 2008; Salles et al. 2008).  Several additional Phase III trials have 
demonstrated the benefit of adding anti-CD20 maintenance therapy following induction 
treatment with singleagent rituximab, chemotherapy, or immunochemotherapy 
(Ghielmini et al. 2004; van Oers et al. 2006; Hochster et al. 2009; Martinelli et al. 2010; 
Salles et al. 2011).  
Nonclinical data have demonstrated that the novel humanized glyco-engineered, Type II 
monoclonal antiCD20 antibody obinutuzumab may have activity against 
rituximab-resistant cell lines and that the combination of obinutuzumab and 
chemotherapy has, at a minimum, an additive effect in relation to efficacy (see the 
obinutuzumab Investigator’s Brochure; Mössner et al. 2010).  This is consistent with the 
hypothesis that rituximab therapy may potentially sensitize tumor cells to 
chemotherapyinduced cell death when combined with chemotherapy (Plosker and 
Figgitt 2003).  Compared with the chimeric Type I antiCD20 antibody rituximab, 
obinutuzumab demonstrates increased ADCC related to an improved binding of 
obinutuzumab to the different allotypes of FcRIIIa expressed by NK cells and 
monocytes (Mössner et al. 2010).   Improved ADCC with obinutuzumab may therefore 
be particularly important in the 80%85% of patients who are carriers of the lowaffinity 
FcRIIIa allele, because such patients have a decreased overall survival compared 
with carriers of the highaffinity FcRIIIa allele who demonstrate improved survival 
following therapy with chemotherapy plus either rituximab or I-131 tositumomab 
(Persky et al. 2009).  
In clinical trials (see Section 1.2.3), obinutuzumab demonstrated activity in patients with 
relapsed or refractory indolent lymphoma with an acceptable toxicity profile 
(Morschhauser et al. 2009; Salles et al. 2009; Sehn et al. 2009).  In these trials, the 
majority of patients had been previously treated with multiple lines of therapy and many 
were rituximab refractory.  Phase I/II data indicate that obinutuzumab may offer an 
improved treatment option over the wellestablished antiCD20 antibody rituximab.  
Moreover, preliminary data suggest that the safety profile of obinutuzumab is similar to 
that of rituximab.  
In terms of safety, differences in the molecular structure and mode of action between 
obinutuzumab and rituximab may result in different safety profiles.  In particular, adverse 
events relating to more rapid and extensive CD20positive–cell depletion, both 
malignant and normal, may be more common with obinutuzumab.  The safety data 
available to date, with more than 470 patients treated at doses of up to 2000 mg, show 
that obinutuzumab is well tolerated and has a safety profile similar to that of 
rituximab.  So far, no maximum tolerated dose, no dose-limiting toxicities (DLTs), and 
no doserelated trends in the incidence of adverse events have been observed.  
Given the nonclinical data demonstrating superior direct celldeath induction with 
obinutuzumab when compared with rituximab and clinical data showing efficacy 
and a favorable safety profile, it is hypothesized that the addition of obinutuzumab to 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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chemotherapy followed by maintenance obinutuzumab may provide additional clinical 
benefit over rituximab plus chemotherapy followed by maintenance rituximab in 
previously untreated patients with indolent NHL.  
The headtohead design of the study, precautionary safety measures, and regular 
monitoring of safety by an Independent Data Monitoring Committee (IDMC) and the 
Sponsor enables early identification of safety signals in the study and minimizes the risk 
to enrolled patients.  In conclusion, it is considered that the benefitrisk ratio for this 
study is favorable.  
2.
OBJECTIVES
2.1
PRIMARY OBJECTIVE
The primary objective for this study is as follows:  

To evaluate the efficacy of obinutuzumab plus chemotherapy followed by 
obinutuzumab maintenance therapy compared with rituximab plus chemotherapy 
followed by rituximab maintenance therapy in patients with previously untreated 
advanced follicular lymphoma, as measured by investigatorassessed PFS
2.2
SECONDARY OBJECTIVES
The following secondary objective applies to patients with previously untreated 
advanced indolent NHL (i.e., overall population):  

To evaluate and compare investigatorassessed PFS between the two arms
The following secondary objectives apply to patients with previously untreated advanced 
indolent NHL (i.e., overall population) and to the subset of patients with previously 
untreated advanced follicular lymphoma (i.e., follicular population):  

To evaluate and compare Independent Review Committee (IRC)assessed PFS 
between the two arms

To evaluate and compare overall response and CR after the end of induction 
treatment, as assessed by the investigator, between the two arms, with and without 
18Ffluorodeoxyglucose positron emission tomography (FDGPET)

To evaluate and compare overall response and CR after the end of induction 
treatment, as assessed by the IRC, between the two arms, with and without 
FDG-PET

To evaluate and compare overall survival, EFS, diseasefree survival (DFS), 
duration of response, and time to next antilymphoma treatment between the two 
arms
EFS, DFS, and duration of response will be based on investigator assessment.  

To evaluate and compare the safety profiles between the two arms during induction 
and maintenance

To assess patientreported outcomes (PROs) in both arms


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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2.3
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:  

To evaluate and compare the proportion of patients who transform to aggressive 
histology at first relapse between the two arms

To evaluate the proportion of patients with a PR or SD at the end of induction 
treatment who convert to CR or to PR/CR, respectively, during maintenance 
treatment or postinduction observation, as assessed by the investigator

To characterize the pharmacokinetics and pharmacodynamics of obinutuzumab in 
combination with chemotherapy

To compare the efficacy of obinutuzumab versus rituximab within each 
chemotherapy subset

To assess the prognostic and predictive ability of baseline clinical factors, which 
may include activities of daily living (ADLs), instrumental activities of daily living 
(IADLs), Follicular Lymphoma International Prognostic Index 2 (FLIPI2) score, 
International Prognostic Index (IPI) score, and FDGPET imaging

To assess the prognostic and predictive ability of biomarkers (such as FcReceptor 
polymorphisms) pertaining to the biology of follicular lymphoma and factors relating 
to the host immune system (may include immunohistochemistry [IHC] and gene 
expression assessment of specific targets or gene profiles)

To assess the prognostic and predictive value of BCL2/IgH rearrangement and 
other markers of minimum residual disease (MRD) in patients with follicular 
lymphoma at baseline, during induction, at the completion of induction therapy, 
during maintenance therapy or observation, and during followup (IgH clonality may 
be used as a marker of MRD in patients without an identifiable BCL2/IgH
translocation at baseline)

To correlate FDGPET results with efficacy parameters

A dedicated analysis to adequately assess PFS in the MZL subcohort will be 
performed

To identify and characterize changes in tumor gene expression and cell surface 
markers that occur in patients who have relapsed and/or transformed after initial 
treatment with a rituximabor obinutuzumabcontaining regimen 
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Study Overview
This is an openlabel, international, multicenter, randomized, Phase III study to 
investigate the efficacy and safety of obinutuzumab plus chemotherapy followed by 
obinutuzumab maintenance therapy for responders (CR or PR) compared with rituximab 
plus chemotherapy followed by rituximab maintenance therapy for responders in patients 
with previously untreated advanced indolent NHL.  Prior to the initiation of the study, 
each site will choose one of three chemotherapy regimens (CHOP, CVP, or 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
37/P BO21223A7
bendamustine) that is considered to be the standard of care for follicular lymphoma; all 
patients with follicular lymphoma at that site will receive the chosen chemotherapy 
regimen for the duration of the study (a site may switch to another regimen if new 
scientific data become available and after Sponsor approval).  For nonfollicular NHL, 
the investigator will have the option of choosing one of the three chemotherapy regimens 
(CHOP, CVP, or bendamustine) for each patient.  All patients will then be randomized to 
either rituximab plus chemotherapy or obinutuzumab plus chemotherapy.  A study 
schema is provided in Figure 1.  
Figure 1
Study Schema
Bendabendamustine; CHOPcyclophosphamide, doxorubicin, vincristine, and 
prednisone/prednisolone/methylprednisolone; CR complete response; CVP cyclophosphamide, 
vincristine, and prednisone/prednisolone/methylprednisolone; FU follow up; G GA101; 
PDprogressive disease; PRpartial response; Rrituximab; SDstable disease.  
Approximately 1200 patients with follicular lymphoma will be recruited and randomly 
assigned in a 1:1 ratio to either obinutuzumab plus chemotherapy followed by 
obinutuzumab maintenance in responders or rituximab plus chemotherapy followed by 
rituximab maintenance in responders.  In addition, approximately 200 patients with MZL 
will be recruited and randomly assigned in a 1:1 ratio to the two treatment arms.  


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Randomization will be performed separately for follicular and nonfollicular patients.  
The randomization scheme will ensure approximately equal samples sizes in the 
two treatment arms for the following stratification factors:  

Chemotherapy regimen (CHOP, CVP, or bendamustine)

Follicular Lymphoma International Prognostic Index (FLIPI) risk group (low, 
intermediate, or high according to FLIPI) in patients with follicular lymphoma or IPI 
risk group (low/lowintermediate vs. highintermediate/high) in patients with 
non-follicular lymphoma

Geographic region (Western Europe, Eastern Europe, South and Central America, 
North America, Asia, and "Other")
Randomization will be conducted with the aid of an interactive voice or Web-based 
response system (IxRS).  Study treatment must begin within 7 days after randomization.  
The schedule for administration of rituximab or obinutuzumab will be dependent upon 
the accompanying chemotherapy regimen.  In the control arm of the study (Arm A), 
six to eight doses of rituximab at 375 mg/m2 will be administered by IV infusion with the 
accompanying chemotherapy regimen.  In the experimental arm of the study (Arm B), 
eight to ten doses of obinutuzumab (including two additional doses of obinutuzumab on 
Days 8 and 15 of Cycle 1) at an absolute (flat) dose of 1000 mg will be administered by 
IV infusion with the accompanying chemotherapy regimen.  It is mandatory that the full 
number of cycles be given for each immunochemotherapy regimen during induction.  
Patients who demonstrate a CR or PR at the end of induction therapy will continue to 
receive rituximab at 375 mg/m2 (Arm A) or obinutuzumab at a flat dose of 1000 mg 
(Arm B) every 2 months until disease progression for up to 2 years.  Patients who 
demonstrate SD at the end of induction therapy will be followed for progression for up to 
2 years according to the same followup schedule as responding patients (CR or PR) 
receiving maintenance (observation).  If induction therapy was stopped for toxicity or any 
reason other than toxicity, then patients are discontinued from study treatment and go 
into followup directly.  
All patients will be assessed for disease response by the investigator through use of 
regular clinical and laboratory examinations and computed tomography (CT) scans 
according to a modified version of the Revised Response Criteria for Malignant 
Lymphoma (Cheson et al. 2007; see Appendix C).  Additional response criteria based on 
paraprotein assessment are in effect for the MZL population and based on hematological 
parameters and spleen size for the subset of splenic MZL patients.  During induction 
treatment, tumor assessment is performed after three cycles for patients receiving 
bendamustine, after four cycles for patients receiving CVP or CHOP, and at the 
completion of induction therapy.  
Following the completion of induction therapy, patients receiving maintenance therapy 
(CR or PR) or undergoing observation (SD) will be followed clinically every 2 months for 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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2 years (with CT scans every 4 months for the first year and then every 6 months for the 
second year).  For patients who have not progressed at the maintenance or observation 
completion visit (25 months from Day 1 of Cycle 8 [CHOP/CVP arms] or Cycle 6 
[bendamustine arm]), disease assessments will continue every 3 months for 3 years 
(with CT scans every 6 months) and then every 6 months for 2 years (with CT scans 
every year) (followup for disease progression).  After 5 years of followup or disease 
progression (whichever comes first), patients will still be followed every 6 months for 
overall survival and new antilymphoma treatment (NALT), or for disease progression if 
applicable, until the end of the study, which will be approximately 10.2 years after 
inclusion of the first patient.  Patients who terminate induction early without PD will be 
followed for PD, as per Appendix A-5, and in the extended followup for PD, NALT, and 
overall survival.  Patients who terminate induction early because of PD will go directly 
into the extended followup for NALT and overall survival.  Patients who discontinue the 
protocoldefined treatment path and need to start an NALT in the absence of disease 
progression (e.g., if wrong diagnosis at screening and new diagnosis requires a change 
of treatment) will be followed for disease progression and overall survival (Figure 2).  For 
patients who progressed and received NALT, response after NALT will be collected.  
Figure 2
Sequence of Study Phases in Study BO21223 (GALLIUM)


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
40/P BO21223A7
CR = complete response; eCRF = electronic Case Report Form; ET early termination; 
FU follow up; Ind. induction treatment; Maint = maintenance; NALT new antilymphoma 
therapy, Obs. = observation; OS overall survival, PD progressive disease; PR = partial 
response; SD stable disease; w/o = without.  
Note: Following the completion of induction therapy, patients receiving maintenance therapy (CR 
or PR) or undergoing observation (SD) will be followed as per Appendix A-5.  After 5 years of 
followup or disease progression (whichever comes first), patients will enter the extended 
followup for overall survival and NALT until the end of the study.  Patients who terminate 
induction early without PD will be followed for PD as per Appendix A-5, and in the extended 
followup for PD, NALT, and overall survival.  Patients who terminate induction early because of 
PD will go directly into the extended follow-up for NALT and overall survival.  Patients who 
discontinue the protocol-defined treatment path and need to start an NALT in the absence of 
disease progression (e.g., if wrong diagnosis at screening and new diagnosis requires a change 
of treatment) will be followed for disease progression and overall survival.  For patients who 
progressed and received NALT, response after NALT will be collected.  
For the first futility analysis based on CR rates at the induction 
completion/end-of-treatment visit in 170 patients with follicular lymphoma, the response 
assessment by investigator and IRC based on CT (magnetic resonance imaging [MRI]) 
will be complemented in an exploratory analysis with data from two other methods of 
response assessment:  

Evaluation of response by FDG-PET is mandatory at induction 
completion/endoftherapy visit (only if screening PET was positive) 68 weeks 
after Day 1 of the last cycle of induction for the first 170 patients with follicular 
lymphoma at those sites that have a PET scanner available.  This may require 
specific approval in some countries.  In such instances, PET becomes mandatory 
only after necessary approvals have been obtained.  

The depth of response will be assessed by determination of MRD via polymerase 
chain reaction (PCR)based detection of BCL2/IgH rearrangements in the first 
170 patients with follicular lymphoma at screening, midterm induction (i.e., before 
Cycle 4 Day 1 for R/Gbendamustine, before Cycle 5 Day 1 for R/GCHOP 
or -CVP), induction completion/end of therapy and during maintenance/observation 
at Month 4.  MRD detection will be based on peripheral blood and bone marrow 
aspirate samples.  MRD peripheral blood samples are mandatory and are required 
at all time points in all patients with follicular lymphoma.  MRD bone marrow aspirate 
samples are mandatory at screening in all patients with follicular lymphoma.  At 
induction completion/end of therapy, MRD bone marrow aspirate samples are 
mandatory in responders (CRPR) in whom bone marrow involvement was 
diagnosed by morphology at screening and are optional but strongly recommended 
in responders (CRPR) in whom no bone marrow involvement was diagnosed by 
morphology at screening.  This recommendation is based on the observation that, at 
screening, bone marrow involvement is detectable on the level of minimal residual 
disease in the large majority of patients even if it appears to be negative by 
morphology.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
41/P BO21223A7
After passing the first futility analysis, PET and MRD will be integrated into additional 
exploratory analyses in the following manner for the full study:  

Additional optional FDGPET scans (e.g., in all other lymphoma patients beyond 
the first 170 patients with follicular lymphoma) are permitted if the investigator 
chooses to perform them.  

Assessment of MRD is mandatory via PCRbased detection of BCL2/IgH
rearrangements in all patients with follicular lymphoma at screening; midterm 
induction (i.e., before Cycle 4 Day 1 for R/Gbendamustine, before Cycle 5 Day 1 
for R/G-CHOP or CVP); induction completion/end of therapy; during 
maintenance/observation at Months 4, 8, 12, and 18 and at maintenance or 
observation completion/end of therapy; and during follow-up at Months 30, 36, 42, 
48, 54, 60, 72, and 84.  MRD detection will be based on peripheral blood and bone 
marrow aspirate samples.  MRD peripheral blood samples are mandatory and are 
required at all time points in all patients with follicular lymphoma.  MRD bone 
marrow aspirate samples are mandatory at screening in all patients with follicular 
lymphoma.  At induction completion/end of therapy, MRD bone marrow aspirate 
samples are mandatory in responders (CRPR) in whom bone marrow involvement 
was diagnosed by morphology at screening and are optional but strongly 
recommended in responders (CRPR) in whom no bone marrow involvement was 
diagnosed by morphology at screening.  This recommendation is based on the 
observation that, at screening, bone marrow involvement is detectable on the level 
of minimal residual disease in the large majority of patients even if it appears to be 
negative by morphology.  
An independent radiologic and oncologic review of the responses of all patients by an 
IRC will also be conducted for the futiliy and efficacy analyses with and without PET.  
Patients who discontinue all components of study therapy prior to disease progression 
(e.g., for toxicity) will enter the followup phase of the study and will continue to be 
followed for PD and overall survival (regardless of whether they subsequently receive 
NALT).  
A retrospective quality assurance pathology review will be conducted on pathology 
samples to evaluate histology and CD20 status in addition to other prognostic features.  
An IDMC will conduct periodic interim reviews of safety summaries, 
starting approximately 1 month after enrollment of the first patient and then 
approximately every 2 months until 100 patients have completed two cycles of study 
treatment.  Afterward, the IDMC will conduct reviews of safety summaries approximately 
every 6 months.  All summaries and analyses reviewed by the IDMC will be prepared by 
an Independent Data Coordinating Center (IDCC).  Safety will be evaluated by 
monitoring dose delays and dose intensity, adverse events, serious adverse events, and 
deaths.  These will be graded using the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.0.  Laboratory safety assessments 
will include regular monitoring of hematology, blood chemistry, and tests of immunologic 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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parameters.  In addition, tests for the presence of human antihuman antibodies 
(HAHAs) will be performed only in all patients receiving obinutuzumab.  
Study assessments are listed in the flowcharts provided in Appendix A.  
3.1.2
Patient-Reported Outcomes
Patients will assess their healthrelated quality of life (HRQoL) using two validated 
questionnaires:  the Functional Assessment of Cancer Therapy for Lymphoma 
(FACT-Lym) (see Appendix D) and European Quality of Life (EuroQol) EQ5D 
(see Appendix E).  The FACT-Lym and EQ-5D will enable assessment of the differences 
between treatment arms with respect to overall HRQoL and changes in HRQoL brought 
about by symptom worsening/alleviation and treatment toxicity.  The PRO 
questionnaires will be selfadministered at the investigational site prior to administration 
of study drug and prior to any other study assessments, to ensure that the validity of the 
instruments is not compromised and to ensure that data quality meets regulatory 
requirements.  
The FACTLym questionnaire (Webster et al. 2005) consists of the four domains 
(physical, social/family, emotional, and functional wellbeing) found in the general 
functional assessment instrument (FACTG) plus a 15-item lymphoma-specific subscale 
that assesses Bsymptoms and changes in HRQoL.  Cella and colleagues developed 
and scientifically validated the instrument in a general lymphoma population, including 
patients with either aggressive or indolent disease (Cella et al. 2005).  Items for inclusion 
in the lymphoma subscale were selected on the basis of symptom relevance, disease 
specificity, and clinical relevance.  
The EQ5D is a generic preference-based health utility measure that provides a single 
index value for health status. The EQ5D consists of two parts.  The first part, 
health-state classification, contains five dimensions of health:  mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression.  The second part, consisting of a 
visual analogue scale, will not be used.  
3.1.3
Medical Resource Utilization
Analysis of medical resource utilization will be provided if required.  
3.2
RATIONALE FOR STUDY DESIGN
3.2.1
Rationale for Study Drug Dosing
a.
Rationale for Obinutuzumab Dose
A unit dose of 1000 mg of obinutuzumab was chosen after data from completed Phase I 
studies were reviewed by participating investigators and the Sponsor.  This unit dose of 
obinutuzumab was based on the following findings:  

No DLTs were observed, and no maximum tolerated dose was reached in Phase I 
(doses of 502000 mg were tested).  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
43/P BO21223A7

Clinical activity (responses) was observed at all dose levels tested.  

Pharmacokinetic analyses suggested that a decreased variability of drug exposure 
related to tumor burden was achieved at doses above 800 mg given on Days 1, 8, 
and 22 and then every 3 weeks thereafter, for a total of nine doses.  

Obinutuzumab was well tolerated, with a preliminary safety profile similar to that of 
rituximab in NHL patients (i.e., mainly Grade 1 or 2 toxicities, with more frequent 
IRRs around the time of the first infusion and a decreased frequency with 
subsequent infusions).  
After a comprehensive review of all safety, efficacy, and pharmacokinetic data obtained 
in Phase I studies, an obinutuzumab dose of 1000 mg for all infusions was chosen for 
use in future Phase II and Phase III NHL studies, because this dose is most likely to be 
well tolerated and efficacious in a majority of NHL patients regardless of their initial 
tumor burden.  To coordinate the dosing of study drugs during the first 6 months of 
treatment, obinutuzumab will be administered for six 28day cycles or for eight 21day 
cycles, depending on the accompanying chemotherapy regimen.  Pharmacokinetic 
modeling suggests that giving additional doses of obinutuzumab on Days 8 and 15 of 
Cycle 1 will be needed to saturate targetmediated clearance and achieve and maintain 
a steady state of drug early and for as long as possible during treatment.  
In Phase I studies, obinutuzumab given as monotherapy to patients with CD20positive 
Bcell malignancies was well tolerated up to and including a single dose of 2000 mg and 
cumulative doses per treatment regimen of 17,200 mg.  Responses were observed in all 
cohorts, with Bcell depletion observed even at the lowest dose.  No DLTs were 
observed.  A high intraindividual and interindividual degree of antibody clearance was 
observed.  
As for most modern monoclonal antibodies, a flat dose (not adapted to body weight or 
body surface area [BSA]) was chosen since antibody clearance is determined mostly by 
the target (i.e., for antiCD20 antibodies accessibility to normal or malignant tumor cells 
in various compartments, such as blood, bone marrow, nodal or extranodal sites of 
disease, or lymphatic organs).  This flat dose is in contrast to the first monoclonal 
antibody licensed for the treatment of Bcell malignancies, for which dosing was based 
on BSA.  In the 1990s, when little was known about the toxicity of monoclonal antibodies, 
development of these agents followed an approach typical for cytotoxic drugs, which 
usually had DLTs.  DLTs were usually a function of the capacity to eliminate the drug by 
organs such as the liver and spleen.  This narrows the therapeutic window and 
necessitates the adaptation of the dose according to body weight or BSA.  It is widely 
accepted that for most monoclonal antibodies, including antiCD20 antibodies, there is 
a wide therapeutic window that does not need to rely on dosing by body weight or BSA.  
Because quantifying the target and individual dosing according to target has been 
notoriously difficult, the currently accepted approach for most monoclonal antibodies, 
including nearly all anti-CD20 antibodies in various stages of development, is flat dosing.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
44/P BO21223A7
Pharmacokinetic analyses in the Phase I studies, together with published data on 
rituximab, showed that patients with higher disease burden have faster clearance of the 
antibody and thus may require higher doses to saturate this target population.  In recent 
studies of rituximab, a similar concept is the basis for a dosedense RCHOP regimen, 
used for example by the German High Grade NonHodgkin's Lymphoma Study Group, 
where dose densification of rituximab resulted in higher serum levels and in higher CR 
and EFS rates in a study in elderly patients with poorprognosis DLBCL (Reiser et 
al. 2006).  This finding was further substantiated by a modeling and simulation 
experiment, suggesting an even higher degree of variability at lower obinutuzumab 
doses.  
Thus, to further understand a potential dose effect, patients were randomized to two 
different doses of GA10 in the Phase II part of Study BO20999:  a lowdose regimen 
consisting of obinutuzumab 400 mg on Days 1 and 8 of Cycle 1 followed by 
obinutuzumab 400 mg on Day 1 of Cycles 28 and a highdose regimen consisting of 
obinutuzumab 1600 mg on Days 1 and 8 of Cycle 1 followed by obinutuzumab 800 mg 
on Day 1 of Cycles 28.  The cumulative dose was 3600 mg for the lowdose cohort and 
8800 mg for the highdose cohort.  A typical dose for the reference antibody, rituximab, 
is about 50006000 mg (375 mg/m2 for eight doses), which would fall between the low 
and high doses tested for obinutuzumab.  Pharmacokinetic simulations show that the 95% 
confidence limits for exposure are between the low and high doses and are not 
overlapping.  
No DLTs were observed across the two doses.  Although there was a slight increase in 
IRRs and neutropenia rates for the highdose cohort, the regimen was generally well 
tolerated.  As expected, a decreased pharmacokinetic variability was observed at the 
higher dose.  Most importantly, improved efficacy was observed with the higher dose in 
the indolent cohort, with an ORR of 55% compared with an ORR of 13% in the lowdose 
cohort.  Findings in the aggressive cohort did not show a marked difference in response 
rates between the high and low doses, yet this cohort was further subdivided by the 
inclusion of patients with relapsed DLBCL and relapsed MCL, and small numbers might 
have prevented a more compelling result.  
Overall, it was concluded that a higher dose of obinutuzumab can be delivered and that 
the available evidence from nonclinical studies, pharmacokinetic studies, modeling and 
simulation, and clinical trials in patients with NHL (Phase I and Phase II) are suggestive 
of a higher dose being more appropriate to saturate the target in the majority of patients 
with NHL and, thus, being more efficacious than a lower dose.  
In the highdose cohort of Study BO20999, the first two doses of obinutuzumab were set 
at 1600 mg.  This dose was well tolerated but resulted in application times for patients 
up to and exceeding 5 hours.  To maintain the loading dose concept and provide a 
significant amount of antibody early during the treatment course, it was therefore 
decided to change the application time and dose during the first 2 weeks of future 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
45/P BO21223A7
studies from a 1600 mg dose on Days 1 and 8 to a 1000 mg dose on Days 1, 8, and 15, 
thus providing comparably fast rising pharmacokinetic exposure and early target 
saturation, while avoiding the practical challenges of delivering 1600 mg on 1 day 
together with chemotherapy.  All other doses were also set at 1000 mg, and this schema 
(i.e., Days 1, 8, and 15 of Cycle 1 followed by subsequent doses given in 3or 4-week 
intervals) has been selected as the obinutuzumab dosing regimen for use in all future 
obinutuzumab Phase III studies.  This schema results in an exposure to obinutuzumab 
during the first 2 weeks of 3000 mg and a cumulative exposure of 10,000 mg and is 
therefore very close to the regimen that has delivered thus far the best results for 
obinutuzumab in both indolent and aggressive NHL.  
b.
Rationale for Chemotherapy in Combination with Rituximab or 
Obinutuzumab
Rituximab in combination with chemotherapy (e.g., CHOP, CVP, or purine 
analoguebased schemes such as those with fludarabine or bendamustine) for newly 
diagnosed patients with advanced Stage III and IV disease requiring treatment is 
strongly supported by several clinical trials and both the ESMO and NCCN guidelines.  
However, there is no universally accepted standard of care for the accompanying 
chemotherapy regimen administered for the firstline treatment of indolent NHL.  
Therefore, sites will be able to choose among three different chemotherapy regimens 
(i.e., CHOP, CVP, or bendamustine) that are widely accepted for the firstline treatment 
of follicular lymphoma.  Allocation by site was chosen in order to possibly achieve a 
better understanding of the optimal firstline chemotherapy regimen for patients with 
follicular lymphoma.  For nonfollicular lymphoma, investigators will choose among three 
different chemotherapy regimens because patients with MZL may respond to less toxic 
chemotherapies.  This will allow sites that choose CHOP for the treatment of follicular 
lymphoma to use CVP or bendamustine for the treatment of non-follicular lymphoma.  
Combination Therapy with CHOP
RCHOP is one of the standard induction regimens for previously untreated patients 
with indolent NHL (Czuczman et al. 1999; Zinzani et al. 2004; Hiddemann et al. 2005; 
Salles et al. 2011).  The CHOP dosing regimen consists of IV cyclophosphamide 
750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (maximum dose, 2 mg) on 
Day 1 and oral prednisone 100 mg on Days 15 of each 21day cycle.  Six cycles were 
administered in most studies, but in some studies, the number of cycles was dependent 
on the response to the first four courses.  Patients achieving a CR after four cycles are 
treated with a total of six cycles only, whereas all other patients are treated with eight 
cycles.  Rituximab 375 mg/m2 IV was administered on a variable schedule during earlier 
studies.  In a trial by Czuczman et al. (1999), the first and second rituximab infusions 
were given on Days 1 and 6 of Cycle 1 (prior to the first CHOP cycle on Day 8), the third 
and fourth rituximab infusions were given 2 days prior to the third and fifth CHOP cycles, 
respectively, and the fifth and sixth rituximab infusions were given on Days 134 and 141, 
respectively, after the sixth CHOP cycle.  In other trials, rituximab 375 mg/m2 was 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
46/P BO21223A7
administered the day before each CHOP cycle (Hiddemann et al. 2005).  Most recently, 
in the PRIMA study, rituximab 375 mg/m2 was administered on Day 1 of each of six 
CHOP cycles.  A seventh and eighth dose of rituximab were administered 21 and 
42 days, respectively, after the sixth CHOP cycle.  
In Study BO21000, two different obinutuzumab dosing regimens were administered with 
a standard CHOP regimen to relapsed or refractory patients.  The lowdose cohort 
received obinutuzumab 400 mg on Days 1 and 8 of Cycle 1 followed by obinutuzumab 
400 mg on Day 1 of Cycles 28 (21day cycles), and the highdose cohort received 
obinutuzumab 1600 mg on Days 1 and 8 of Cycle 1 followed by obinutuzumab 800 mg 
on Day 1 of Cycles 28 (21 day cycles).  In addition, obinutuzumab at a flat dose of 
1000 mg was administered with CHOP on Days 1 and 8 of Cycle 1 and on Day 1 of 
Cycles 28 to previously untreated patients.  
Given this experience, the CHOP regimen in this study will consist of the following 
agents:  

Cyclophosphamide 750 mg/m2 IV on Day 1 of each of six 21day cycles

Doxorubicin 50 mg/m2 IV on Day 1 of each of six 21day cycles

Vincristine 1.4 mg/m2 IV (maximum dose, 2 mg) on Day 1 of each of six 21-day 
cycles

Prednisone 100 mg orally on Days 1–5 of each of six 21day cycles (or 100 mg 
prednisolone in countries or sites without availability of prednisone or with strong 
preference for prednisolone or 80 mg methylprednisolone in countries or sites 
without availability of prednisone/prednisolone)
Rituximab will be administered at 375 mg/m2 IV on Day 1 of each of eight 21day cycles.  
Obinutuzumab will be administered at a flat dose of 1000 mg on Day 1 of each of eight 
21day cycles and on Days 8 and 15 of Cycle 1 to achieve appropriate levels of drug.  If 
it is the strong preference of the investigator or of the site (e.g., for logistical or safety 
reasons), the administration of rituximab or obinutuzumab is allowed on the day prior to 
administration of CHOP with premedication.  It is also allowed to split the antibody 
infusion over 2 days if the patient is at increased risk for an IRR (high tumor burden, high 
peripheral lymphocyte count).  
This dosing regimen provides a total dose of RCHOP and GCHOP that is consistent 
with that used in prior studies in previously untreated patients with indolent NHL.  
Combination Therapy with CVP
CVP is a standard induction regimen for patients with indolent NHL.  The addition of 
eight doses of rituximab to eight cycles of CVP (RCVP) has been shown to significantly 
improve the clinical outcome of previously untreated patients with follicular lymphoma 
(Marcus et al. 2005, 2008; Salles et al. 2011).  In these trials, patients treated with 
R-CVP received IV cyclophosphamide 750 mg/m2 and vincristine 1.4 mg/m2 on Day 1 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
47/P BO21223A7
(maximum dose, 2 mg) and oral prednisone 40 mg/m2 on Days 15 of each of eight 
21-day cycles.  Patients treated with R-CVP also received IV rituximab 375 mg/m2 on 
Day 1 of each cycle.  
Given this experience, the CVP regimen in this study will consist of the following agents:  

Cyclophosphamide 750 mg/m2 IV on Day 1 of each of eight 21day cycles

Vincristine 1.4 mg/m2 IV (maximum dose, 2 mg) on Day 1 of each of eight 21day 
cycles

Prednisone 100 mg orally on Days 15 of each of eight 21day cycles (or 100 mg 
prednisolone in countries or sites without availability of prednisone or with strong 
preference of prednisolone or 80 mg methylprednisolone in countries or sites 
without availability of prednisone/prednisolone)
Rituximab will be administered at 375 mg/m2 IV on Day 1 of each of eight 21day cycles.  
Obinutuzumab will be administered at a flat dose of 1000 mg on Day 1 of each of eight 
21day cycles and on Days 8 and 15 of Cycle 1 to achieve appropriate levels of drug.  If 
it is the strong preference of the investigator or of the site (e.g., for logistical or safety 
reasons), the administration of rituximab or obinutuzumab is allowed on the day prior to 
administration of CVP with premedication.  It is also allowed to split the antibody infusion 
over 2 days if the patient is at increased risk for an IRR (high tumor burden, high 
peripheral lymphocyte count).  
This dosing regimen provides a total dose of RCVP and GCVP that is consistent with 
that used in prior studies in previously untreated patients with indolent NHL.  
Combination Therapy with Bendamustine
Bendamustine with and without rituximab has demonstrated efficacy in patients 
with relapsed or refractory indolent NHL (Rummel et al. 2005; Friedberg et al. 2008; 
Robinson et al. 2008; Kahl et al. 2010).  A recent Phase III trial also demonstrated the 
efficacy of bendamustine plus rituximab in previously untreated patients with indolent 
NHL (Rummel et al. 2009).  Bendamustine when administered as firstline therapy for 
patients with indolent NHL and MCL demonstrated an improvement in PFS from 
34.8 months to 54.8 months and an improvement in the CR rate from 30.8% to 40.1% 
with less toxicity when compared with RCHOP.  
Clinical studies testing the combination of bendamustine plus rituximab have 
administered bendamustine 90 mg/m2 on Days 2 and 3 of each 28-day cycle and 
rituximab on Day 1 of each 28-day cycle because of concerns of additive toxicity 
(Rummel et al. 2005, 2007; Robinson et al. 2008).  Importantly,in the study of previously 
untreated patients with indolent NHL (Rummel et al. 2009), a dose of 90 mg/m2 was 
given every 28 days in combination with rituximab.  Ninety-six percent of patients 
received the full six cycles (average of 5.58 cycles administered).  In addition, 
90 mg/m2 is the dose of bendamustine recommended for use in combination with 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
48/P BO21223A7
rituximab at a consensus conference of hematologists who had extensive experience 
with bendamustine (Cheson et al. 2010).  
Given this experience, the bendamustine regimen in this study will consist of 
IV bendamustine 90 mg/m2 given on Days 1 and 2 of each of six 28day cycles, 
with oral prednisone (or prednisolone) 100 mg (or 80 mg of methylprednisolone) also 
administered on Day 1 of Cycle 1.  Rituximab will be administered at 375 mg/m2 IV on 
Day 1 of each of six 28day cycles.  Obinutuzumab will be administered at a flat dose of 
1000 mg on Day 1 of each of six 28-day cycles and on Days 8 and 15 of Cycle 1 to 
achieve appropriate levels of drug.  If it is the strong preference of the investigator or of 
the site (e.g., for logistical or safety reasons), the administration of rituximab or 
obinutuzumab is allowed on the day prior to administration of bendamustine with 
premedication.  It is also allowed to split the antibody infusion over 2 days if the patient is 
at increased risk for an infusionrelated reaction (high tumor burden, high peripheral 
lymphocyte count).  
This dosing regimen provides a total dose of bendamustine that is consistent with the 
recommendations of the consensus conference for patients with relapsed or refractory 
indolent NHL.  
c.
Rationale for Maintenance Treatment
Rituximab has been studied as a maintenance therapy in a variety of settings.  
A Phase II trial of rituximab monotherapy (once weekly for 4 weeks) followed by 
rituximab maintenance therapy, consisting of additional courses (once weekly for 
4 weeks) every 6 months, for patients with previously untreated indolent NHL was the 
first to demonstrate the benefits of maintenance with an antiCD20 monoclonal antibody 
(Hainsworth et al. 2002).  The ORR at 6 weeks following induction was 47%.  With 
continued rituximab, the final ORR increased to 73%, with 37% having a CR.  
Among patients with previously untreated hightumorburden follicular lymphoma who 
have a response to prior immunochemotherapy (RFC, RCHOP, or R-CVP), treatment 
with 2 years of maintenance rituximab significantly improves PFS with little additional 
toxicity (Salles et al. 2011).  In that trial, responding patients who received rituximab 
375 mg/m2 IV every 8 weeks for 2 years following induction immunochemotherapy 
demonstrated a 2-year PFS of 82%, compared with 66% in the observation group 
(p0.001; hazard ratio, 0.5; no difference in overall survival).  
Additional supporting evidence for rituximab maintenance is provided by trials in the 
relapsed or refractory setting that randomized patients to rituximab maintenance or 
observation following induction with immunochemotherapy or immunotherapy alone 
(van Oers et al. 2006, 2010; Martinelli et al. 2010).  Taken together, these trials support 
the administration of antiCD20 maintenance therapy to responding patients in this trial.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
49/P BO21223A7
3.2.2
Rationale for Required Biomarker Research Samples
a.
Minimum Residual Disease Assessment
The t(14;18)(q32;q21) translocation found in 80%–90% of patients with follicular 
lymphoma results in the overexpression of BCL2 and may have prognostic value as a 
surrogate endpoint in clinical trials of follicular lymphoma.  Randomized studies have 
demonstrated that molecular remission is the most predictive factor of outcome in terms 
of PFS, DFS, and duration of response (Ladetto et al. 2007; Hirt et al. 2008).  A study by 
Rambaldi et al. (2004) demonstrated that lower baseline levels of BCL2/IgHpositive 
cells (i.e., those with the translocation) in the bone marrow prior to treatment correlated 
with the achievement of a complete clinical and molecular response following the 
sequential administration of CHOP and rituximab.  Patients who achieve a CR or PR 
following induction chemotherapy and whose disease remains undetectable for the 
BCL2 translocation by PCR following treatment with rituximab or Yttrium-90 ibritumomab 
tiuxetan have significantly improved median PFS.  
In this study, BCL2/IgH rearrangement will be measured at baseline, during induction, at 
the end of induction therapy, and at Month 4 of maintenance or observation to determine 
whether changes after one cycle of therapy or after completion of induction therapy are 
predictive of PFS.  In patients without an identifiable BCL2/IgH rearrangement, clonal 
IgH rearrangements may be used as a marker of MRD.  Additionally, BCL2/IgH
rearrangement will be measured during maintenance therapy or observation to 
determine the ability of rituximab or obinutuzumab to convert patients from MRD positive 
to MRD negative with the addition of maintenance treatment.  Reappearance of the 
BCL2/IgH rearrangement after achievement of MRD negativity may also be assessed as 
an early marker of relapse or progression during treatment or followup.  
b.
FcReceptor Gene Polymorphism
The actual causes of rituximab treatment failure remain largely unknown.  In vitro studies 
suggested that rituximab induces lymphoma cell lysis in vitro through ADCC, CDC, or 
direct signaling leading to apoptosis.  ADCC requires leukocyte receptors for the 
Fc portion of IgG (FcR).  The implication of FcR in the anti-tumor effects of 
anti-CD20 antibodies against human lymphoma cell lines has been demonstrated in 
murine models, and rituximab has significantly reduced antitumor effects in 
FcR-deficient mice.  There are three classes of FcR (FcRI, FcRII, and FcRIII), and 
their subclasses are encoded by eight genes in humans.  Some of those genes display 
a functional allelic polymorphism generating allotypes with different receptor properties.  
One of those genetic factors is a gene dimorphism in FCGR3A, which encodes FcRIIIa 
with either a phenylalanine (F) or a valine (V) at amino acid position 158.  It has been 
clearly demonstrated that human IgG1 binds more strongly to homozygous 
FcRIIIa-158V/V NK cells than to homozygous FcRIIIa158F/F or heterozygous 
FcRIIIa158F/V NK cells.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
50/P BO21223A7
Cartron et al. (2002) and Weng and Levy (2003) have shown an association between 
the FCGR3A genotype and clinical and molecular responses to rituximab.  The 
FCGR3A-158V/V genotype is associated with a higher response rate to rituximab 
treatment in follicular lymphoma (Weng et al. 2010).  Kim et al. (2006) also evaluated 
the impact of FcR polymorphism on the response to R-CHOP therapy for patients with 
DLBCL.  In patients treated with RCHOP, the FCGR3A-158V allele was significantly 
correlated with a higher CR rate compared with the FCGR3A158F allele, whereas no 
difference was found between FCGR2A polymorphisms.  
FCGRIIB/IIC is the only inhibitory low affinity Fcreceptor and therefore is critical for 
maintaining the balance of activatory and inhibitory signaling.  A polymorphism in 
FCGR2B that alters an isoleucine to a threonine in the transmembrane region in exon 5 
(I232T) is associated with the presence and severity of autoimmune disease (Niederer et 
al. 2010a, 2010b).  
The optimization of the interaction between antibodies and FcR has emerged as a 
promising technology to enhance the activity of therapeutic antibodies for cancer 
treatment.  Given the significantly greater ADCC and direct cell-death induction 
associated with obinutuzumab, it is possible that obinutuzumab may have greater 
efficacy than rituximab, particularly in the 80%85% of patients who are carriers of the 
FcRIIIa low-affinity receptor polymorphism.  Given the enhanced ADCC, it is necessary 
to observe the outcome of patients on the basis of FcR to select a therapy for patients 
who are most likely to derive maximum clinical benefit from it.  Further studies may 
provide an increased understanding of the relationship between FcR polymorphisms 
and response to monoclonal antibodies.  
c.
Gene Expression Profiling
Prognostic markers that predict the clinical behavior of follicular lymphomas with greater 
accuracy are needed to guide treatment management decisions.  It has been shown that 
the length of survival among patients with follicular lymphoma correlates with the 
molecular features of the nonmalignant immune cells present in the tumor at 
diagnosis (Dave et al. 2004).  More recently, expression levels of 35 candidate genes 
have identified an immune signature associated with shorter survival intervals 
(Byers et al. 2007), and this information may be used in the future to optimize therapy.  
d.
Analysis of Biopsy at Relapse or Transformation
Treatment with rituximab has dramatically improved the outcome of patients with 
indolent and aggressive Bcell NHL (Cheson and Leonard 2008).  
Typically, NHL patients respond to several lines of rituximabbased therapies.  However, 
approximately 50% of patients with relapsed or refractory CD20positive follicular 
lymphoma do not respond to initial therapy with rituximab (innate resistance) and are 
primary refractory (McLaughlin et al. 1998).  Furthermore, NHL patients who do respond 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
51/P BO21223A7
to standard chemotherapy or rituximabbased treatment regimens eventually relapse 
and acquire rituximab resistance.  Acquired resistance to rituximab may be explained 
only in part by the loss of CD20 expression (Kennedy et al. 2002).  Because of the more 
widespread use of rituximab maintenance therapy for indolent NHL, increased selection 
for antibody resistance can be expected (Stolz et al. 2007).  In addition, patients with 
CD20positive Bcell NHL with adverse prognostic features still exhibit less favorable 
outcomes, despite rituximab-based firstline therapies.  
The mechanisms responsible for primary and acquired resistance to rituximab therapy 
are not well understood.  Nonclinical data derived primarily from culture cell lines and
xenograft mouse models have not revealed any unifying mechanisms of resistance.  
However, the following are some of the possible mechanisms that may contribute to 
development of rituximab resistance:  

Upregulation of antiapoptotic factors and downregulation of proapoptotic factors 
(Stolz et al. 2007)

Downregulation of CD20 on the cell surface (Davis et al. 1999; 
Czuczman et al. 2008)

Decreased complement activation (Klepfish et al. 2009)

Upregulation of complement inhibitors CD55 and CD59 (Cruz et al. 2007)

Membrane/lipid raft abnormality (Smith 2003)
The clinical significance of these mechanisms remains unclear.  Identifying and 
characterizing changes in tumor gene expression that occur with disease progression or 
transformation in follicular lymphoma, which is one of the exploratory objectives of the 
current clinical study, may provide a better understanding of genetic mechanisms 
contributing to development of resistance to rituximab or obinutuzumab in these 
disorders.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
52/P BO21223A7
3.2.3
Rationale for Optional Biomarker Samples (Stored in the 
Roche Clinical Repository)
The Sponsor is committed to the collection of biomarker samples in all clinical studies.  
The objective of biomarker profiling is to enable development of treatments specifically 
targeted for optimal patient benefit (personalized health care).  If a patient consents, the 
following material will be collected and stored in the Roche Clinical Repository (RCR) for 
up to 15 years:  
Sample Material
Time Point
Serum and plasma

At screening only
Unstained sections, tissue microarrays, and 
tumor RNA and tumor DNA extracted from the 
residual tissue biopsy 

At baseline

At progression/transformation
DNA extracted from a sample of peripheral 
blood (leftover DNA after analysis for 
FcReceptor gene singlenucleotide 
polymorphism) a

At screening only
DNA extracted from samples of peripheral 
blood and bone marrow aspirates (leftover 
DNA after analysis of BCL2/IgH [minimum 
residual disease]) a

At screening (peripheral blood and bone 
marrow aspirate)

Before Cycle 5 Day 1 (CHOP/CVP) or 
Cycle 4 Day 1 (bendamustine) (peripheral 
blood only)

At end of induction/early termination 
(peripheral blood and bone marrow 
aspirate)

During maintenance/observation at 
Months 4, 8, 12, and 18 and at 
maintenance/observation completion 
(peripheral blood only)

During followup at Months 30, 36, 42, 48, 
54, 60, 72, and 84 (peripheral blood only)
CHOPcyclophosphamide, doxorubicin, vincristine, and prednisone (or prednisolone or 
methylprednisolone); CVPcyclophosphamide, vincristine, and prednisone (or 
prednisolone or methylprednisolone).  
a See additional DNA substudy protocol for further details. 
The RCR is a centrally administered facility for the longterm storage of human biologic 
specimens, including body fluids, solid tissues, and derivatives thereof (e.g., RNA, DNA, 
proteins, peptides).  Specimens will be used for research purposes related to NHL to 
identify biomarkers that are predictive of response to rituximab or obinutuzumab
treatment in terms of dose, safety, and tolerability and will help to better understand the 
pathogenesis, course, and outcome of indolent NHL only.  The tissue blocks will be 


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returned to the local pathology laboratories according to country-specific procedures
after the requisite material is obtained. 
For more details on DNA collection in the RCR, please see the Study BO21223 DNA 
substudy protocol.  
Specimens will be collected for storage in the RCR and may be used to achieve the 
following exploratory objectives:  

To study the association of biomarkers with efficacy and/or adverse events 
associated with medicinal products

To increase knowledge and understanding of disease biology

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
3.3
OUTCOME MEASURES
3.3.1
Primary Efficacy Outcome Measure
The primary efficacy endpoint, PFS in patients with follicular lymphoma, is defined as the 
time from randomization to the first occurrence of progression or relapse as assessed by 
the investigator according to the Revised Response Criteria for Malignant Lymphoma 
(Cheson et al. 2007; see Appendix C) or death from any cause.  
3.3.2
Secondary Efficacy Outcome Measures
For the endpoints below that specify disease response, response will be assessed by 
the investigator according to the Revised Response Criteria for Malignant Lymphoma 
and additional response criteria for MZL (see Appendix C).  
The following secondary outcome measure applies to patients with previously untreated 
advanced indolent NHL (i.e., overall population):  

Investigatorassessed PFS
The following secondary outcome measures apply to patients with previously untreated 
advanced indolent NHL (i.e., overall population) and to the subset of patients with 
previously untreated advanced follicular lymphoma (i.e., follicular population):  

IRCassessed PFS

CR and overall response (CR or PR) at the end of induction, as assessed by the 
investigator with and without FDGPET

CR and overall response (CR or PR) at the end of induction, as assessed by the 
IRC with and without FDGPET

Overall survival, defined as the time from randomization to death from any cause

EFS, defined as the time from randomization to disease progression/relapse as 
assessed by the investigator, death from any cause, or start of an NALT


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
DFS, defined for patients with a best overall response (BOR) of CR as the time from 
first occurrence of a documented CR to PD as assessed by the investigator or death 
from any cause.  Patients who have had no documented disease progression or 
have not died after CR will be censored at the last disease assessment date.  

Duration of response, defined for patients with a BOR of CR or PR as the time from 
first occurrence of a documented CR or PR to disease progression/relapse as 
assessed by the investigator or death from any cause.  For patients achieving a 
response who have not progressed, relapsed, or died at the time of the analysis, 
duration of response will be censored on the date of last disease assessment.  

Time to next antilymphoma treatment, defined as the time from randomization to 
start of new nonprotocol antilymphoma therapy or death from any cause

Change from baseline to the end of study in PROs based on the FACTLym 
instrument, as outlined below
Change from baseline in all domains of the FACTG
Change from baseline in the total outcome index (TOI) (range, 0116):  sum of 
physical wellbeing (7 items), functional wellbeing (7 items), and Lym subscale 
(15 items) scores
Change from baseline in the FACTLym subscale score (range, 060):  
15 lymphomaspecific items
Change from baseline in the FACTLym total score (range, 0168):  sum of 
physical wellbeing (7 items), social/family wellbeing (7 items), emotional 
well-being (6 items), functional wellbeing (7 items), and Lym subscale (15 items) 
scores

EQ5D summary scores at baseline, during treatment, after treatment, at the last 
assessment prior to progression, and at the first assessment after progression
Analysis of medical resource utilization data will be provided if required.  
3.3.3
Safety Outcome Measures
The safety outcome measures are as follows:  

Incidence, nature, and severity of adverse events with obinutuzumab plus 
chemotherapy followed by obinutuzumab versus rituximab plus chemotherapy 
followed by rituximab

Changes in vital signs, physical findings, and clinical laboratory results during and 
following study treatment administration

Incidence of hepatitis B reactivation
Hepatitis B reactivation will be defined as an elevation in serum hepatitis B virus 
(HBV) DNA to more than 29 IU/L.  


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3.3.4
Exploratory Outcome Measures
a.
Pharmacokinetic/Pharmacodynamic Outcome Measures
The pharmacokinetic and pharmacodynamic outcome measures are as follows:  

Pharmacokinetic profile (i.e., plasma concentration–time profile, predose trough 
concentrations, and clearance rates) of obinutuzumab in induction and maintenance 
settings among a subset of patients receiving obinutuzumab.  
b.
Clinical and Biomarker Exploratory Outcome Measures
The following outcome measures apply only to patients with previously untreated 
advanced follicular lymphoma (i.e., follicular population), unless otherwise specified:  

Histologic transformation rate from an indolent to a more aggressive NHL at first 
progression, as assessed by the investigator, defined as the appearance of diffuse 
areas of large lymphoma cells within a tumor site in patients with a repeat biopsy at 
the time of disease progression/relapse (overall population, follicular population and 
MZL population)

Conversion rate, defined as the proportion of patients with a PR or SD at the end of 
induction therapy who convert to a CR or to a PR/CR, respectively, at any time 
during maintenance therapy or postinduction observation, as assessed by the 
investigator (overall population, follicular population, and MZL population)

MRD negativity, defined as the absence of BCL2/IgH rearrangement or IgH clonality 
in whole blood and/or bone marrow in follicular lymphoma patients with evidence of 
BCL2/IgH rearrangement or IgH clonality at baseline (follicular population only)

Risk of progression as a function of baseline levels of BCL2/IgH rearrangement or 
other markers of MRD (follicular population only)

Risk of progression as a function of the absence of BCL2/IgH rearrangement and 
other markers of MRD at the end of induction and maintenance therapy (follicular 
population only)

Risk of progression as a function of a decrease in BCL2/IgH rearrangement and 
other markers of MRD during therapy (follicular population only)

Relationship between FDGPET values at baseline and changes at the end of 
induction treatment and clinical outcome (i.e., CR rate, DFS, PFS, etc.)

Relationship between chemotherapy regimen and efficacy outcomes (overall 
population,  follicular population, and MZL population)

Incidence of HAHAs among patients receiving obinutuzumab

Relationship between various clinical factors (e.g., FLIPI2 score, IPI score, 
ADLs/IADLs) or baseline markers (e.g., Fcreceptor status, IHC, and tumor gene 
profiling) and clinical outcome parameters in patients from both arms of the study 
(overall population, follicular population, and MZL population)

To assess the prognostic ability of a geneexpression profile of tumor biopsy 
specimens obtained from all patients at diagnosis to predict risk of progression


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
Changes in tumor gene expression profiles and cell surface markers between the 
time of initial biopsy and the time when progressive and/or transformed disease is 
diagnosed

Change in B cell populations defined by 
CD19/CD22/CD79b/CD5/CD10/kappa/lambda in 60 patients of each 
antibody-chemotherpy combination group (RCHOP, GCHOP, RCVP, GCVP, 
R-bendamustine, Gbendamustine) and in all patients with splenic MZL

Change in B(CD19+), T(CD3+, CD4+, CD8+), and NK cell (CD56+) counts over 
time in all patients
3.4
SAFETY PLAN
This trial is designed to allow for early termination or a modification of the protocol 
(in particular, the dosing regimens) for safety concerns, on the basis of the advice of an 
IDMC.  The IDMC will be incorporated into the study to review safety data on a regular 
basis, including adverse events of special interest (see Section 5.1.3).  The IDMC will 
meet 1 month after enrollment of the first patient and then approximately every 2 months 
until 100 patients have completed two cycles of study treatment.  Afterward, the IDMC 
will meet approximately every 6 months.  Both the Sponsor and the IDMC can request 
ad hoc IDMC meetings if potential safety concerns arise.  Following each meeting, the 
IDMC will recommend to the Sponsor whether the study should continue according to 
the protocol or may suggest changes to the protocol based on the outcome of the data 
review.  In exceptional cases, the IDMC may recommend stopping the study or closing a 
treatment arm as a result of safety reasons.  The IDMC will also perform a safety review 
at the preplanned interim analyses for futility and efficacy (see Section 4.10.10 and the 
Statistical Analysis Plan for details).  
For dose delay, dose modification, and treatment discontinuation instructions, see 
Section 4.3.  
3.4.1
Risks Associated with Obinutuzumab Therapy
No evidence available at the time of the approval of this protocol indicates that special 
warnings or precautions are appropriate, other than those noted in the obinutuzumab 
Investigator’s Brochure and as described in the following sections.  
a.
InfusionRelated Reactions and Hypersensitivity Reactions 
(Including Anaphylaxis)
The commonly experienced IRRs have been characterized by fever, chills, flushing, 
nausea, vomiting, hypotension, hypertension, and fatigue, as well as 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, Version 3.0, Grade 1 and 2 events), and 
10% of the events were severe (Grade 3 events), occurring predominantly during the 


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first hour of the infusion or shortly after the first infusion had finished; the events resolved 
with 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.  
b.
Tumor Lysis Syndrome
Cases of tumor lysis syndrome have been reported with obinutuzumab administration.  
To date, no patient has required hemodialysis for renal failure.  Patients with a high 
tumor burden, including patients with a lymphocyte count of 25109/L (particularly, 
patients with B-cell CLL and MCL), are at increased risk for tumor lysis syndrome and 
severe IRRs.  
c.
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 
granulocyte colony stimulating factors (GCSF) has been found to result in a rapid 
normalization of neutrophils, similar to what has been observed in patients treated with 
rituximab.  The use of GCSF is allowed for treatment of neutropenia in this study.  
Primary prophylaxis with GCSF is recommended according to the American Society of 
Clinical Oncology (ASCO), European Organisation for Research and Treatment of 
Cancer (EORTC), and ESMO guidelines, namely for patients who are 60 years old 
and/or with comorbidities (Lyman et al. 2004).  The use of GCSF is strongly 
recommended in Cycle 1 for all patients treated with GCHOP.  
d.
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.  Based on the available evidence to date the greatest risk of 
hemorrhage in obinutuzumab-treated patients is observed in the first cycle.  A clear 
relationship between thrombocytopenia and hemorrhagic events has not been 
established.  Patients treated with concomitant medication, which could possibly worsen 
thrombocytopeniarelated events, such as 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 


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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. 
e.
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.  
Serious infections, including fatal, bacterial, fungal, and new or reactivated viral 
infections (e.g., cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster 
virus, West Nile virus, and hepatitis B and C) 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 stem-cell transplant.  The 
risk of such infections with obinutuzumab is unknown.  Physicians should be aware of 
symptoms suggestive of progressive multifocal leukoencephalopathy (PML) and 
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.  To date, there have been no reports of 
patients experiencing PML while or after receiving obinutuzumab.  
Cases (including fatal) of John Cunningham virus (JCV) infection resulting in PML 
(destructive infection of oligodendrocytes of the central nervous system 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 to quantify DNA of JCV in the cerebrospinal fluid.  
Therapy with obinutuzumab and rituximab should be withheld during the investigation of 
potential PML and permanently discontinued in the 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 treatment of PML.  


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There may be additional potential health risks, including hitherto unknown risks, derived 
from exposure to obinutuzumab.  
3.4.2
Risks Associated with Rituximab Therapy
See the prescribing information 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 after 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, adult respiratory distress 
syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid 
events, or death.  
b.
Tumor Lysis Syndrome
Patients may be at risk for tumor lysis syndrome.  With rituximab treatment, acute renal 
failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor 
lysis, sometimes fatal, can occur within 1224 hours after the first infusion of rituximab in 
patients with NHL.  A high number of circulating malignant cells (25,000/mm3) or high 
tumor burden confers a greater risk of tumor lysis syndrome.  For patients with evidence 
of tumor lysis syndrome, rituximab should be discontinued and the patient treated as 
clinically indicated.  
c.
Hepatitis B Virus Reactivation
HBV reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients 
with hematologic malignancies treated with rituximab.  The median time to diagnosis of 
hepatitis was approximately 4 months after the initiation of rituximab and approximately 
1 month after the last dose.  
Patients with chronic hepatitis B viral infection (i.e., hepatitis B surface antigen [HBsAg] 
positive) are at risk for reactivation and will be excluded from the study.  Patients with 
evidence of prior hepatitis B exposure or who are carriers (defined as HBsAg negative 
and hepatitis B core antibody [HBcAb] positive) are at a lower risk for reactivation.  In a 
study of 51 HBV carriers with DLBCL who received rituximab, 12% of patients developed 
evidence of reactivation (Niitsu et al. 2010).  Patients who demonstrate evidence of 
reactivation while receiving an appropriate antiviral therapy will discontinue study 
treatment.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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d.
Progressive Multifocal Leukoencephalopathy
Rare cases of PML have 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 after the patient's last infusion of rituximab (please also refer to 
Section 3.4.1.e).  
e.
Cardiac Toxicity
Angina and cardiac arrhythmias have occurred with rituximab treatment and can be life 
threatening.  Patients in the CHOP arm who have been treated with doxorubicin, an 
anthracyclinebased chemotherapy, are at risk for cardiotoxicity and will be required to 
have assessments of left ventricular ejection fraction (LVEF) at baseline and at the end 
of induction treatment.  
f.
Infection
Serious infections, including fatal, bacterial, fungal, and new or reactivated viral 
infections (e.g., cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster 
virus, West Nile virus, and hepatitis B and C), can occur during and up to 1 year 
following the completion of rituximabbased therapy.  
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 (TEN).  The onset of these reactions in patients treated with 
rituximab has varied from 1 to 13 weeks following rituximab exposure.  
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 
postmarketing reports of rituximab, the mean time to documented gastrointestinal 
perforation was 6 days (range, 177 days) in patients with NHL.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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3.4.3
Risks Associated with CHOP Chemotherapy
Please refer to prescribing information for doxorubicin, cyclophosphamide, vincristine, 
and prednisone/prednisolone/methylprednisolone for risks related to CHOP 
chemotherapy.  
Patients in the CHOP arm treated with doxorubicin, an anthracyclinebased 
chemotherapy, are at risk for cardiotoxicity.  Although the risk increases with cumulative 
dose, irreversible cardiotoxicity may occur at any dose level.  Patients with preexisting 
heart disease, hypertension, concurrent administration of other antineoplastic agents, 
prior or concurrent chest irradiation, and advanced age are at increased risk.  Baseline 
and periodic monitoring of ECGs and LVEF, as determined by echocardiogram or 
multiplegated acquisition (MUGA) scan, will be required.  The evaluation of LVEF is 
required at baseline and after 300 mg/m2 of doxorubicin (Schwartz et al. 1987).  Patients 
who receive doxorubicin and develop evidence of impaired cardiac function (LVEF of 
50% in the presence of an absolute decrease in LVEF of 10%) will be given the 
option of switching to a non-cardiotoxic regimen (i.e., CVP) or discontinuing from trial 
participation.  
3.4.4
Risks Associated with CVP Chemotherapy
Please refer to prescribing information for cyclophosphamide, vincristine, 
and prednisone/prednisolone/methylprednisolone for risks related to CVP chemotherapy.  
3.4.5
Risks Associated with Bendamustine Chemotherapy
a.
Myelosuppression
Patients treated with bendamustine are likely to experience myelosuppression.  Blood 
counts will be monitored weekly during the first cycle and then frequently throughout 
subsequent cycles of treatment.  Patients who experience Grade 3 or 4 neutropenia or 
thrombocytopenia should be monitored until neutrophil and platelet values return to at 
least Grade 2.  The use of myeloid growth factors for the primary and secondary 
prevention of febrile neutropenia is permitted.  
b.
Infections
Infection, including pneumonia and sepsis, has been reported in patients in clinical trials 
and in postmarketing reports.  Infection has been associated with hospitalization, septic 
shock, and death.  Patients with myelosuppression following treatment with 
bendamustine are more susceptible to infections.  
c.
InfusionRelated Reactions and Anaphylaxis
Infusion reactions to bendamustine have occurred commonly in clinical trials.  Symptoms 
include fever, chills, pruritus, and rash.  In rare instances, severe anaphylaxis and 
anaphylactoid reactions have occurred, particularly in the second and subsequent cycles 


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of therapy.  Patients should be monitored clinically and discontinue drug for every 
reaction.  
d.
Tumor Lysis Syndrome
Tumor lysis syndrome has been reported in association with bendamustine treatment in 
clinical trials and in postmarketing reports.  The onset tends to be within the first 
treatment cycle of bendamustine and without intervention may lead to acute renal failure 
and death.  Preventive measures include maintaining adequate volume status and close 
monitoring of blood chemistry, particularly potassium and uric acid levels.  Allopurinol 
has also been used during the beginning of bendamustine therapy.  However, there may 
be an increased risk of severe skin toxicity when bendamustine and allopurinol are 
administered concomitantly.  
e.
Skin Reactions
A number of skin reactions have been reported in clinical trials and postmarketing safety 
reports.  These events have included rash, toxic skin reactions, and bullous exanthema.  
Some events occurred when bendamustine was given in combination with other 
anti-cancer agents, so the precise relationship to bendamustine is uncertain.  
In a study of bendamustine in combination with rituximab, one case of TEN occurred.  
TEN has been reported for rituximab.  Cases of StevensJohnson syndrome and TEN, 
some fatal, have been reported when bendamustine was administered concomitantly 
with allopurinol and other medications known to cause these syndromes.  Allopurinol 
must not be given on days of bendamustine administration.  Patients with skin reactions 
should be monitored closely.  If skin reactions are severe or progressive, bendamustine 
should be withheld.  
f.
Other Malignancies
Premalignant and malignant diseases, including myelodysplastic syndrome, 
myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma, have 
developed in patients treated with bendamustine.  The association with bendamustine 
has not been determined.  
g.
Extravasation
There are postmarketing reports of bendamustine extravasation resulting in 
hospitalization to treat erythema, marked swelling, and pain.  Precautions should be 
taken to avoid extravasation, including monitoring of the IV infusion site for redness, 
swelling, pain, infections, and necrosis during and after administration of bendamustine.  


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h.
TransfusionAssociated Graft versus Host Disease
Rare cases of transfusionassociated graft versus host disease have been reported 
following treatment of lowgrade B cell malignancies with the purine analogues 
fludarabine (Hutchinson et al. 2002; Leitman et al. 2003) and cladribine (Zulian et 
al. 1995).  The situation with newer purine antagonists such as bendamustine is unclear.  
Transfusions, if required, should be performed according to national guidelines.  
i.
Possible Interactions with CYP1A2 Inhibitors and Inducers
Certain medications may interact with bendamustine.  Caution should be used or 
alternative treatments considered if concomitant treatment with CYP1A2 inhibitors or 
inducers is needed.  CYP1A2 inhibitors and inducers are not contraindicated.  During 
treatment with bendamustine, patients will be provided with a card to keep with them that 
provides notification to other health care providers that the patient is taking 
bendamustine as a participant in a clinical study (see Appendix F).  
3.5
STUDY PATIENTS AND ANALYSIS GROUPS
Different etiologic, genetic, or environmental factors may influence the development of 
follicular lymphoma (Biagi and Seymour 2002).  There is evidence to suggest a 
decreased incidence of follicular lymphoma in Asian countries relative to Western 
countries, which may be reflective of underlying differences in molecular pathways.  
Since this is an international study, the study population will allow the evaluation of 
obinutuzumab in populations with potentially heterogeneous disease pathways and 
treatment settings.  
The primary endpoint analysis (PFS) will be performed for the follicular lymphoma patient 
population.  
3.6
CONTROL GROUPS
Patients will be randomized in a 1:1 ratio to either rituximab plus chemotherapy followed 
by rituximab maintenance in responders (Arm A) or obinutuzumab plus chemotherapy 
followed by obinutuzumab maintenance in responders (Arm B), with chemotherapy 
consisting of CHOP, CVP, or bendamustine.  The control (or comparator) arm of the 
study will be rituximab plus chemotherapy followed by rituximab maintenance in 
responders.  No crossover between the obinutuzumab and rituximab arms will be 
allowed.  
Immunotherapy with rituximab is a key component of the treatment of patients with 
follicular lymphoma.  In the control arm, rituximab at 375 mg/m2 will be administered by 
IV infusion on Day 1 of each 21day or 28-day cycle for up to eight cycles.  There is no 
standard chemotherapy in combination with rituximab.  Prior to study initiation, each site 
will choose one of three chemotherapy regimens (CHOP, CVP, or bendamustine), and 
all patients with follicular lymphoma at that site will receive the chosen chemotherapy 


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regimen for the duration of the study (a site may switch to another regimen if new 
scientific data become available and after Sponsor approval).  For nonfollicular 
lymphoma, the investigator will have the option of choosing one of the three 
chemotherapy regimens (CHOP, CVP, or bendamustine) for each patient.  
Rituximab, as the first monoclonal antibody, was developed with dosing that is based on 
BSA.  The dose of 375 mg/m2 results in an average dose of 650 mg for a patient with a 
BSA of 1.73 m2, which is consistent with MabTheraand RITUXANprescribing 
information and with current medical practice.  
In contrast, obinutuzumab is administered as a flat dose of 1000 mg on the basis of 
Phase I–II trials supporting this dose.  Although this may result in an obvious 
discrepancy in dose between the two agents, obinutuzumab is being tested against 
the dose of rituximab that is approved by the European Medicines Agency, 
the U.S. Food and Drug Administration (FDA), and other global regulatory authorities.  
See Section 3.2.1 for a rationale supporting the control arm treatment regimen.  
3.7
MINIMIZATION OF BIAS
Because of the use of weightbased versus flat dosing and the use of different dosing 
schedules for obinutuzumab, rituximab, and chemotherapy, this will be an open-label 
study.  To minimize the potential biases, the following procedures will be incorporated in 
the study.  
Patients will be randomized to the two treatment arms through use of an IxRS.  
Drug assignment will be performed by the IxRS.  
For study treatment decisions, response and progression will be assessed by the 
investigator on the basis of physical examinations, radiography, hematology, 
serum chemistry, and bone marrow examinations, through use of Revised Response 
Criteria for Malignant Lymphoma (Cheson et al. 2007; see Appendix C).  
PET results should be treated as exploratory data and should not be used for study 
treatment decisions.  The decision for maintenance or observation should rely solely on 
the results obtained by all other methods, but not PET.  
PET should also not be used to diagnose relapse or disease progression.  Every finding 
of relapse or progression by PET needs to be confirmed by CT (MRI).  
An independent assessment of response and progression, based on CT (MRI) scans 
plus pertinent clinical data with or without PET, will be provided by an IRC 
with appropriate expertise in reading radiology and oncology examinations.  The IRC 
assessment will be blinded with respect to treatment arm and investigator assessment.  
Instructions to sites for processing and submitting imaging scans will be provided by the 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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IRC.  IRC membership and procedures to be followed for the study will be detailed in an 
IRC charter.  
An IDMC will be incorporated to monitor patient safety and efficacy.  All analyses for the 
IDMC's reviews will be prepared by an IDCC.  Sponsor personnel will not have access to 
byarm efficacy and safety summaries prior to the formal reporting of study results.  
A guidance document detailing the procedures to be followed for keeping blinding will be 
observed by the study operations team.  Treating clinical staff at investigator sites and 
Sponsor drug safety and medical monitoring staff will have access to the treatment 
assignments of particular patients to allow for safety monitoring.  IDMC membership and 
procedures to be followed for the study will be detailed in an IDMC charter.  
3.8
END OF STUDY
The end of the study is defined as the date of the last followup visit (to occur 5 years 
after the last study treatment) of the last patient entered, or sooner, if all patients have 
progressed, died, or withdrawn from the study.  With consideration of a recruitment 
period of approximately 2.5 years, the overall duration of the study is planned to be 
approximately 10.2 years (or shorter, if all patients have progressed, died, or withdrawn 
from the study).  The Sponsor has the right to terminate the study at any time.  
3.9
ETHICAL CONSIDERATIONS
Any information obtained from this research will be treated as confidential.  
The information collected will not be provided to any third parties, such as insurers or 
employers (other than those required by law), but will be provided to health authorities 
(e.g., European Medicines Agency or FDA), the Sponsor (Genentech, South San 
Francisco, U.S.A.; F. HoffmannLa Roche Ltd, Basel, Switzerland), and the Sponsor's 
collaborators.  The results of these analyses will be treated with the same level of 
confidentiality as the rest of the data arising from this study.  
Patients will provide a blood sample for FcRIIIa, FcRIIa, and FcRIIb/c polymorphism 
analysis.  After completion of this analysis, any DNA material used to determine 
polymorphisms will be destroyed.  The disposal of remaining DNA material will be 
documented according to standard operating procedures, and no other assessments or 
analyses of the DNA samples will be performed.  Samples will not be identified with 
patients’ names, pictures, or any governmentissued identification numbers (e.g., Social 
Security number).  A unique sample identification number will be used to identify 
samples (these are considered patient identifiers under the Heath Insurance Portability 
and Accountability Act).  Samples will be linked with clinical data from the Sponsor's 
clinical database (including outcome data) with use of the study identification number.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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3.10
ADMINISTRATIVE STRUCTURE
In the United States, this trial will be sponsored and managed by Genentech.  
F. Hoffmann–La Roche will sponsor this trial outside of the United States, 
with management responsibilities being shared by Genentech and Roche.  Genentech 
and Roche have authorized Roche Registrations, a company formed under the laws of 
England, to act as their legally authorized representative for the purposes of Article 19 of 
Directive 2001/20/EC relating to the implementation of Good Clinical Practice (GCP) in 
the conduct of clinical trials on medicinal products for human use.  Reference to 
“Sponsor” in this protocol will mean Genentech for the United States and 
F. HoffmannLa Roche for all countries outside of the United States.  
Approximately 250 sites from 3040 countries, including the United States, Canada, 
Europe, and potentially South and Central America, Japan, China, Australia, and 
Southeast Asia, will enroll up to 1400 patients.  
Randomization and drug assignment will be performed by an IxRS.  The IxRS will also 
manage obinutuzumab, bendamustine, and rituximab inventory for all sites globally.  
Electronic data capture (EDC) will be utilized for this study.  
A central laboratory will be used for a subset of laboratory assessments, as specified in 
Section 4.5.1.c; otherwise, local laboratories will be used.  
An IRC will perform independent assessments of response and progression for all 
patients enrolled in the study.  
An external IDMC will be mandated for the purpose of evaluating interim safety, 
tolerability, and efficacy, according to policies and procedures detailed in the 
IDMC charter.  
An independent Science and Ethics Advisory Group, consisting of experts in the fields 
of biology, ethics, sociology, and law, will advise the Sponsor regarding the use of 
specimens stored in the RCR and on the scientific and ethical aspects of handling 
genetic information.  
A Protocol Steering Committee consisting of a panel of hematologists/oncologists has 
been consulted for this study.  The Protocol Steering Committee provided scientific input 
into the design of the study and the development of the study protocol.  In addition, the 
committee will supervise the overall execution of the trial, generate and approve study 
policies, consider modifications of the protocol and operations, and plan and draft 
study-related publications.  Additionally, the committee will provide scientific input for the 
analysis of samples collected for future scientific research.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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3.11
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in accordance with the principles of the Declaration of 
Helsinki, U.S. FDA regulations, the International Conference on Harmonisation (ICH) 
E6 Guideline for GCP, and applicable local, state, and federal laws, as well as other 
applicable country laws.  
4.
MATERIALS AND METHODS
4.1
PATIENT SELECTION
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:  

Histologically documented, CD20positive, indolent Bcell NHL consisting of one 
of the following:  follicular lymphoma (Grades 13a) splenic MZL, nodal MZL, or 
extranodal MZL
Tissue diagnostic procedures must be performed within 12 months prior to 
randomization.  Biopsy material from an excisional or core biopsy must be 
submitted for retrospective central confirmation.  Tissue samples dated 
12 months prior to randomization can be accepted only if tissue material is 
available for retrospective confirmation, if there is no clinical indication for 
transformation of disease, and if the request for additional biopsy would be 
unethical treatment of the patient.  Bone marrow alone is not suited to make 
the diagnosis of follicular lymphoma.  
Approximately 200 patients with MZL (splenic, nodal, or extranodal) can be 
randomized.  After reaching the cap of 200, recruitment of patients with MZL will 
be stopped.  
In patients with splenic MZL without splenic tissue available for histologic review, 
the diagnosis may be confirmed by the presence of splenomegaly and typical 
morphologic and immunophenotypic findings in the blood and bone marrow.  
Bone marrow must be submitted for retrospective central confirmation.  

Stage III or IV disease or Stage II bulky disease
Bulky disease is defined as a tumor diameter of 7 cm.  

For patients with follicular lymphoma:  requirement for treatment, defined as meeting 
at least one of the following criteria:  
Bulky disease, defined as a nodal or extranodal (except spleen) mass 7 cm in 
the greatest diameter
Local symptoms or compromise of normal organ function due to progressive 
nodal disease or extranodal tumor mass
Presence of B symptoms (fever, drenching night sweats, or unintentional weight 
loss of 10% of normal body weight over a period of 6 months or less)
Presence of symptomatic extranodal disease (e.g., pleural effusions, 
peritoneal ascites)


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Cytopenias due to underlying lymphoma (i.e., absolute neutrophil count 
1.0109/L, hemoglobin 10 g/dL, and/or platelet count 100109/L)
Involvement of 3 nodal sites, each with a diameter of 3 cm
Symptomatic splenic enlargement

For patients with symptomatic splenic, nodal, or nongastric extranodal MZL:  
disease that is de novo or has relapsed following local therapy (i.e., surgery or 
radiotherapy) and requires therapy, as assessed by the investigator

For patients with symptomatic gastric extranodal MZL:  Helicobacter pylorinegative 
disease that is de novo or has relapsed following local therapy (i.e., surgery or 
radiotherapy) and requires therapy, as assessed by the investigator, or 
H. pyloripositive disease that has remained stable, progressed, or relapsed 
following antibiotic therapy and requires therapy, as assessed by the investigator 
(see Appendix G for additional details regarding gastric extranodal MZL)

At least one bidimensionally measurable lesion (2 cm in its largest dimension by 
CT scan or MRI)
In patients with splenic MZL, an enlarged spleen on CT scan or extending at 
least 2 cm below the costal margin by physical examination will constitute 
measurable disease providing that no explanation other than lymphomatous 
involvement is likely.  For an enlarged liver to constitute the only measurable 
disease parameter, a liver biopsy showing proof of NHL in the liver is required.  

Able and willing to provide written informed consent and to comply with the 
study protocol

Age 18 years

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 
(see Appendix H)

Adequate hematologic function (unless abnormalities are related to NHL), defined 
as follows:
Hemoglobin 9.0 g/dL
Absolute neutrophil count 1.5109/L
Platelet count 75109/L

For men who are not surgically sterile:  agreement to use a barrier method of 
contraception during the treatment phase and for at least 3 months after the last 
dose of obinutuzumab and rituximab or bendamustine or according to institutional 
guidelines for CHOP or CVP chemotherapy, whichever is longer.  In addition, male 
patients must agree to request that their partners use an additional method of 
contraception, such as oral contraceptives, intrauterine device, barrier method of 
contraception, or spermicidal jelly.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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
For women of reproductive potential who are not surgically sterile:  agreement to 
use two adequate methods of contraception, such as oral contraceptives, 
intrauterine device, or barrier method of contraception in conjunction with 
spermicidal jelly during the treatment period and for at least 12 months after the last 
dose of obinutuzumab or rituximab, for at least 3 months after the last dose of 
bendamustine or according to institutional guidelines for CHOP or CVP 
chemotherapy, whichever is longer.  
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:  

History of severe allergic or anaphylactic reactions to monoclonal antibody therapy 
(e.g., patients in whom dosing with rituximab would be contraindicated for safety 
reasons)

Known hypersensitivity to any of the study drugs

Known sensitivity to murine products

History of sensitivity to mannitol

Central nervous system lymphoma, leptomeningeal lymphoma, or histologic 
evidence of transformation to a highgrade or diffuse large B-cell lymphoma

Grade 3b follicular lymphoma, SLL, or WM

Ann Arbor Stage I disease (see Appendix H)

For patients with follicular lymphoma:  prior treatment for NHL by chemotherapy, 
immunotherapy, or radiotherapy
Lowdose methotrexate (MTX) in rheumatoid arthritis (typically 7.5 to a 
maximum of 20 mg/week) is not considered chemotherapy for lymphoma.  It is 
recommended to stop MTX 2-3 weeks prior to starting immunochemotherapy 
since the combination of MTX and immunochemotherapy increases the risk of 
immunosuppression and of infection

For patients with nonfollicular lymphoma:  prior treatment with chemotherapy 
or immunotherapy

Regular treatment with corticosteroids during the 4 weeks prior to the start of 
Cycle 1, unless administered for indications other than NHL at a dose equivalent 
to 30 mg/day prednisone
Patients receiving corticosteroid treatment with 30 mg/day of prednisone or 
equivalent must be documented to be on a stable dose of at least 4 weeks’ 
duration prior to randomization.  
If glucocorticoid treatment is urgently required for medical reasons (e.g., 
complications imminent if not treated at least with glucocorticoids; strong 
discomfort/pain of the patient due to lymphoma), prednisone 100 mg or 
equivalent can be given for a maximum of 5 sequential days, but all tumor 
assessments must be completed prior to the start of glucocorticoid treatment.  
Glucocorticoid treatment must be stopped prior to randomization.  


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In cases when a glucocorticoid pretreatment/prephase was done externally 
prior to considering the patient for study inclusion, glucocorticoids must be 
stopped for at least 7 days before screening assessments can begin.  

Patients with a history of confirmed PML

History of prior other malignancy with the exception of:  
Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix at any time prior to study
Other cancers not specified above which have been curatively treated by surgery 
alone and from which subject is diseasefree for 5 years without further 
treatment

Evidence of significant, uncontrolled concomitant diseases that could affect 
compliance with the protocol or interpretation of results, including significant 
cardiovascular disease (such as New York Heart Association Class III or IV cardiac 
disease, severe arrhythmia, myocardial infarction within the previous 6 months, 
unstable arrhythmias, or unstable angina) or pulmonary disease 
(including obstructive pulmonary disease and history of bronchospasm)

For patients who will be receiving CHOP:  LVEF 50% by MUGA scan or 
echocardiogram

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection 
(excluding fungal infections of nail beds) or any major episode of infection requiring 
treatment with IV antibiotics or hospitalization (relating to the completion of the 
course of antibiotics, except if for tumor fever) within 4 weeks prior to the start 
of Cycle 1
Patients with suspected active or latent tuberculosis (latent tuberculosis needs to 
be confirmed by positive Interferongamma release assay)

Vaccination with a live vaccine within 28 days prior to randomization

Recent major surgery (within 4 weeks prior to the start of Cycle 1), other than for 
diagnosis

Any of the following abnormal laboratory values (unless any of these abnormalities 
are due to underlying lymphoma):  
Creatinine 1.5 times the upper limit of normal (ULN) (unless creatinine 
clearance normal) or calculated creatinine clearance 40 mL/min 
(using CockcroftGault formula; see Appendix I)
AST or ALT 2.5ULN
Total bilirubin 1.5ULN (or 3ULN for patients with documented 
Gilbert syndrome)
International normalized ratio (INR) or prothrombin time (PT) 1.5 ULN in the 
absence of therapeutic anticoagulation
Partial thromboplastin time (PTT) or activated PTT (aPTT) 1.5ULN in the 
absence of a lupus anticoagulant


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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
Positive test results for chronic HBV infection (defined as positive HBsAg serology)
Patients with occult or prior HBV infection (defined as negative HBsAg and 
positive total HBcAb) may be included if HBV DNA is undetectable, provided that 
they are willing to undergo monthly DNA testing.  Patients who have protective 
titers of hepatitis B surface antibody (HBSAb) after vaccination or prior but cured 
hepatitis B are eligible.  

Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing)
Patients positive for HCV antibody are eligible only if PCR is negative for 
HCV RNA.  

Known history of HIV seropositive status.  
In countries where mandatory testing by health authorities is required, HIV 
testing will be performed.  

Positive test results for human Tlymphotropic 1 (HTLV 1) virus
HTLV testing is required in patients from endemic countries (Japan, countries 
in the Caribbean basin, South America, Central America, sub-Saharan Africa, 
and Melanesia).  

Pregnant or lactating

Life expectancy 12 months

Participation in another clinical trial with drug intervention within 28 days prior to 
start of Cycle 1 and during the study
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
After written informed consent has been obtained and eligibility has been established, 
the study site will obtain the patient’s unique identification number and treatment 
assignment from the IxRS.  Randomization will be performed separately for follicular and 
nonfollicular patients through the IxRS with use of a hierarchical dynamic 
randomization scheme.  The scheme is designed with three levels.  The first level 
ensures approximately equal numbers of patients between the two treatment arms 
overall.  If the first level is balanced, the second level ensures treatment balance within 
the strata defined by 1) chemotherapy regimen (CHOP, CVP, bendamustine) and 2) 
either FLIPI risk group (low, intermediate, high) in follicular lymphoma patients or IPI risk 
group (low/low-intermediate risk versus intermediatehigh/high risk) in nonfollicular 
lymphoma patients.  If the first two levels are balanced, the third level ensures treatment 
balance within geographic region (Western Europe, Eastern Europe, South and Central 
America, North America, Asia, and Other).  Since geographic region is not expected to 
be strongly prognostic, in order to avoid loss of efficiency, the region factor will be 
included in the randomization but not in the primary or secondary stratified analyses.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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Because of the two different study arms with different administration schedules, it is very 
difficult to keep blinding for the investigators.  Therefore, this study will be conducted in 
an openlabel manner.  However, the IRC will remain blinded to treatment assignment.  
Approximately 200 patients with MZL (splenic, nodal, or extranodal) can be randomized.  
After reaching the cap of 200, recruitment of patients with MZL will be stopped.  All 
patients who are randomized into IxRS on the day the cap is reached will be allowed to 
enter the trial provided they meet all other eligibility criteria.  
4.3
STUDY TREATMENT
4.3.1
Formulation
a.
Rituximab
Rituximab is packaged in 10 mL 100 mgand 50 mL 500 mgsingledose, 
pharmaceuticalgrade glass vials at a concentration of 10 mg/mL of protein.  The 
antibody is formulated for IV injection as a sterile product in a solution of sodium chloride 
pH 6.5containing polysorbate 80 and sodium citrate.  The Sponsor will provide 
rituximab to investigational sites as an investigational medicinal product (IMP).  
For further details, see the MabTheraor RITUXANprescribing information.  
b.
Obinutuzumab
Obinutuzumab is provided as a single-dose, sterile liquid formulation in 50 mL 
pharmaceutical-grade glass vials containing a nominal 1000 mg of obinutuzumab.  The 
formulated drug product consists of 25 mg/mL drug substance (G3 material) formulated 
in histidine, trehalose, and poloxamer 188.  The vials contain 41 mL (with 2.5% overfill).  
The Sponsor will provide obinutuzumab to investigational sites as an IMP.  
For further details, see the obinutuzumab Investigator's Brochure.  
c.
CHOP Chemotherapy
For details on drug formulations, see the cyclophosphamide, vincristine, doxorubicin, or 
prednisone/prednisolone/methylprednisolone prescribing information.  
d.
CVP Chemotherapy
For details on drug formulations, see the cyclophosphamide, vincristine, 
or prednisone/prednisolone/methylprednisolone prescribing information.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
73/P BO21223A7
e.
Bendamustine
Bendamustine is provided as a singleuse vial containing 220 mg of powder for the 
preparation of an infusion solution that contains 100 mg of bendamustine hydrochloride.  
The Sponsor will provide bendamustine to investigational sites as an IMP.  
For further details, see the Levact® prescribing information.  
4.3.2
Dosage, Administration, and Storage
a.
Rituximab
In the control arm (Arm A), six to eight doses of rituximab at 375 mg/m2 will be 
administered by IV infusion with the accompanying chemotherapy regimen during 
induction, as outlined below and described in more detail in Sections 4.3.2.c 
through 4.3.2.e.  

RCHOP:  Rituximab will be administered on Day 1 of Cycles 18 (21-day cycles).  
CHOP will be administered on Day 1, with 
prednisone/prednisolone/methylprednisolone also administered on Days 25, of 
Cycles 16.  

RCVP:  Rituximab will be administered on Day 1 of Cycles 18 (21 day cycles).  
CVP will be administered on Day 1, with 
prednisone/prednisolone/methylprednisolone also administered on Days 25, of 
Cycles 1 8.  

Rbendamustine:  Rituximab will be administered on Day 1 of Cycles 1 6 
(28-day cycles).  Bendamustine will be administered on Days 1 and 2 of Cycles 1 6, 
with prednisone/prednisolone/methylprednisolone also administered on Day 1 of 
Cycle 1.  
If it is the strong preference of the investigator or of the site (e.g., for logistical or safety 
reasons), the administration of rituximab on the day prior to CHOP or CVP or 
bendamustine with premedication is allowed.  It is also allowed to split the antibody 
infusion over 2 days if the patient is at increased risk for an IRR (high tumor burden, high 
peripheral lymphocyte count).  However, both optional changes to the administration 
schedule have to be done equally in both study arms (RChemo and GChemo) in order 
to avoid any bias.  Premedication before antibody administration in Cycle 1 is 
recommended and may include 100 mg prednisone/prednisolone or 80 mg 
methylprednisolone orally (within 12 hours but at least 60 minutes prior to start of 
antibody infusion) or IV (if less than 60 minutes prior to start of antibody infusion) in 
order to minimize cytokine release syndrome or allergic reactions.  Premedication with 
prednisone/prednisolone/methylprednisolone is mandatory in patients who had an IRR 
until no IRRs occur anymore during antibody infusion.  Withhold antihypertensive 
medication 12 hours prior to start of antibody infusion and during the infusion.  For the 
management of IRRs and anaphylaxis, see Section 4.3.5.a.  


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Patients randomized to receive rituximab plus chemotherapy who achieve a CR or PR 
at the end of induction therapy will continue to receive rituximab at 375 mg/m2 every 
2 months until disease progression for up to 2 years.  
See Appendix J for rituximab preparation instructions.  For patients in Arm A, rituximab 
infusions will be administered per institutional guidelines or per the instructions outlined 
in Table 2.  
Table 2
Administration of First and Subsequent Infusions of Rituximab
First Infusion (Day 1 of Cycle 1)
Subsequent Infusions
Begin infusion at an 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 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 
being used at the time that the reaction 
occurred).  
If the patient experienced an infusion-related or 
hypersensitivity reaction during the prior infusion, 
use full premedication including 100 mg 
prednisone/prednisolone or 
80 methylprednisolone or equivalent (until no 
further IRR occurs), begin infusion at an initial rate 
of 50 mg/hour and follow instructions for first 
infusion.  
If the patient tolerated the prior infusion well 
(defined by an absence of Grade 2 reactions 
during a final infusion rate of 100 mg/hour), 
begin infusion at a rate of 100 mg/hour.  
If no reaction occurs, increase the infusion rate in 
100 mg/hour increments every 30 minutes, to a 
maximum of 400 mg/hour.  
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 being used 
at the time that the reaction occurred).  
In all parts of the study, rituximab must be administered in a clinical (inpatient or 
outpatient) setting.  Full emergency resuscitation facilities should be immediately 
available, and patients should be under close supervision of the investigator at all times.  
For the management of IRRs and anaphylaxis, see Section 4.3.5.a.  
Rituximab should be administered as a slow IV infusion through a dedicated line.  
IV infusion pumps should be used to control the infusion rate of rituximab.  Do not 
administer as an IV push or bolus.  Administration sets with polyvinyl chloride (PVC) or 
polyethylene (PE) as a product contact surface and IV bags with 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 2 hours 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 


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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.  During maintenance, for those patients who tolerate the antibody infusion 
well without IRR, the IV line may be removed or the central venous catheter may be    
deaccessed immediately after the end of antibody infusion.  
For this study, rituximab produced by Roche (MabThera) or Genentech (Rituxan) is 
used.  For specifications on stability and storage of rituximab, please refer to the 
instruction provided with the respective product information.  
The prepared infusion solution of rituximab is physically and chemically stable for 
24 hours at 2°C-8°C and subsequently 12 hours at room temperature.  The product 
should be used immediately.  If not used immediately, inuse storage times and 
conditions prior to use are the responsibility of the user and would normally not be longer 
than 24 hours at 2°C-8°C, unless dilution has taken place in controlled and validated 
aseptic conditions.  Rituximab should not be frozen or shaken.  Mix gently.  Do not use 
rituximab beyond the expiration date stamped on the carton.  
b.
Obinutuzumab
In the experimental arm (Arm B), eight to ten doses of obinutuzumab at 1000 mg will be 
administered by IV infusion with the accompanying chemotherapy regimen during 
induction, as outlined below and described in more detail in Sections 4.3.2.c through 
Section 4.3.2.e.  

GCHOP:  Obinutuzumab will be administered on Days 1, 8, and 15 of Cycle 1 and 
on Day 1 of Cycles 28 (21day cycles).  CHOP will be administered on Day 1, with 
prednisone/prednisolone/methylprednisolone also administered on Days 25 of 
Cycles 16.  

GCVP:  Obinutuzumab will be administered on Days 1, 8, and 15 of Cycle 1 and 
on Day 1 of Cycles 28 (21day cycles).  CVP will be administered on Day 1, with 
prednisone/prednisolone/methylprednisolone also administered on Days 25 of 
Cycles 18.  

Gbendamustine:  Obinutuzumab will be administered on Days 1, 8, and 15 of 
Cycle 1 and on Day 1 of Cycles 26 (28-day cycles).  Bendamustine will be 
administered on Days 1 and 2 of Cycles 16, with 
prednisone/prednisolone/methylprednisolone administered on Day 1 of Cycle 1.  
If it is the strong preference of the investigator or of the site (e.g., for logistical or safety 
reasons), the administration of obinutuzumab is allowed on the day prior to CHOP or 
CVP or bendamustine.  It is also allowed to split the antibody infusion over 2 days if the 
patient is at increased risk for an IRR (high tumor burden, high peripheral lymphocyte 
count).  However, both optional changes to the administration schedule have to be done 
equally in both study arms (RChemo and G-Chemo) in order to avoid any bias.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
76/P BO21223A7
Premedication before antibody administration in Cycle 1 is recommended and may 
include 100 mg prednisone/prednisolone or 80 mg methylprednisolone orally (within 12 
hours but at least 60 minutes prior to start of antibody infusion) or IV (if less than 
60 minutes prior to start of antibody infusion) in order to minimize cytokine release 
syndrome or allergic reactions.  Premedication with 
prednisone/prednisolone/methylprednisolone is mandatory in patients who had an IRR 
until no IRRs occur anymore during antibody infusion.  Withhold antihypertensive 
medication 12 hours prior to start of antibody infusion and during the infusion.  For the 
management of IRRs and anaphylaxis, see Section 4.3.5.a.  
Patients randomized to receive obinutuzumab plus chemotherapy who achieve a CR or 
PR at the end of induction therapy will continue to receive obinutuzumab at 1000 mg 
every 2 months until disease progression for up to 2 years.  
See Appendix K for obinutuzumab preparation instructions.  For patients in Arm B, 
obinutuzumab infusions will be administered per the instructions outlined in Table 3.  
Table 3
Administration of First and Subsequent Infusions of 
Obinutuzumab
First Infusion (Day 1 of Cycle 1)
Subsequent Infusions
Begin infusion at an 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 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 being used 
at the time that the reaction occurred).  
If the patient experienced an 
infusion-related or hypersensitivity reaction 
during the prior infusion, use full 
premedication including 100 mg 
prednisone/prednisolone or 80 mg 
methylprednisolone (until no further IRR 
occurs), begin infusion at an initial rate of 
50 mg/hour and follow instructions for 
first infusion.  
If the patient tolerated the prior infusion well 
(defined by an absence of Grade 2 
reactions during a final infusion rate of 
100 mg/hour), begin infusion at a rate of 
100 mg/hour.  
If no reaction occurs, increase the infusion 
rate in 100 mg/hour increments every 
30 minutes, to a maximum of 400 mg/hour.  
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 being 
used at the time that 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 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
77/P BO21223A7
available, and patients should be under close supervision of the investigator at all times.  
For the management of IRRs and anaphylaxis, see Section 4.3.5.a.  
Obinutuzumab should be administered as a slow IV infusion through a dedicated line.  
IV infusion pumps should be used to control the infusion rate of obinutuzumab.  Do not 
administer as an IV push or bolus.  Administration sets with PVC, polyurethane, or PE as 
a product contact surface and IV bags with polyolefin, polypropylene, PVC, or PE as a 
product contact surface are compatible and can be used.  In addition, inlinefilters with 
poly ethersulphone as product contact surface, stopcocks with polycarbonate, and 
catheters with polyether urethane can be used.  
After the end of the first infusion, the IV line or central venous catheter should remain in 
place for 2 hours 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, 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.  During maintenance, for those patients, who tolerate the antibody infusion 
well without IRR, the IV line may be removed or the central venous catheter may be 
de-accessed immediately after the end of antibody infusion.  
Obinutuzumab drug product should be stored at 2C8C and protected from light.  
Chemical and physical inuse stability for obinutuzumab dilutions in 0.9% sodium 
chloride in the concentration range of 0.4 to 20 mg/mL have been demonstrated for up to 
24 hours at 2C8C followed by 24 hours at ambient temperature and ambient room 
lighting.  The product should be used immediately.  If not used immediately, inuse 
storage times and conditions prior to use are the responsibility of the user and would 
normally not be longer than indicated above.  Obinutuzumab should not be frozen 
or shaken.  Mix gently.  All transfer procedures require strict adherence to aseptic 
techniques.  Do not use obinutuzumab beyond the expiration date stamped on the 
carton.  
c.
CHOP plus Rituximab (RCHOP) or Obinutuzumab (GCHOP)
It is mandatory to administer a total of six 21day cycles of CHOP.  If CHOP is 
discontinued for any reason other than toxicity, patients will be discontinued from study 
treatment and proceed to followup directly without maintenance.  
CHOP will be administered according to the standard preparation and infusion 
procedures of each investigational site.  Prednisone can be replaced by prednisolone or 
an equivalent dose of methylprednisolone in countries or sites where prednisone is not 
available or where it is not the therapy of choice.  When rituximab or obinutuzumab is 
administered on the same day as prednisone/prednisolone/methylprednisolone, 
it is recommended that prednisone/prednisolone/methylprednisolone be given within 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
78/P BO21223A7
12 hours but at least 60 minutes prior to the rituximab or obinutuzumab infusion.  If there 
are 60 minutes before start of antibody, IV application of 
prednisone/prednisolone/methylprednisolone is preferred.  The order of administration of
cyclophosphamide, doxorubicin, and vincristine will be determined by local institutional 
practice, but these agents should be administered at least 30 minutes after rituximab or 
obinutuzumab.  
If it is the strong preference of the investigator or of the site (e.g., for logistical or safety 
reasons), the administration of rituximab or obinutuzumab on the day prior to CHOP with 
premedication is allowed.  It is also allowed to split the antibody infusion over 2 days if 
the patient is at increased risk for an IRR (high tumor burden, high peripheral 
lymphocyte count).  However, both optional changes to the administration schedule have 
to be done equally in both study arms (R-CHOP and GCHOP) in order to avoid any 
bias.  
Doses will be administered for RCHOP recipients as shown in Table 4 and for 
G -CHOP recipients as shown in Table 5.  For the purposes of this study, Day 1 is the 
day when the first cycle of R/GCHOP is initiated.  In patients who experience an 
adverse event during antibody infusion, administration of rituximab or obinutuzumab and 
application of chemotherapy may be continued on the following day if clinically required.  
If the chemotherapy component is started later than Day 1 of the cycle, then planned 
Day 1 of the next cycle should be calculated from the day when chemotherapy was 
actually initiated, in order to maintain the regular chemotherapy interval of 21 days.  
Empiric dose adjustment in obese patients (defined as a body mass index 30, as 
measured in kg/m2) 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 weight at screening.  The weight that triggered a dose adjustment will be 
taken as the new reference weight for future dose adjustments.  Capping the dose of 
cyclophosphamide and doxorubicin according to BSA is not recommended but may be 
done if required by institutional guidelines.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
79/P BO21223A7
Table 4
Dosing with Rituximab plus CHOP
Treatment
Dose
Mode
Cycles 1–6 a
Cycles 7 
and 8 a
Day 1 b
Days 2–5
Day 1 b
Prednisone (or 
prednisolone/ 
methylprednisolonec)
100 (80c) mg
Oral
x
x
Rituximab
375 mg/m2
IV
x
x
Cyclophosphamide
750 mg/m2
IV
x
Doxorubicin
50 mg/m2
IV
x
Vincristine
1.4 mg/m2 (2 mg max)
IV
x
CHOP cyclophosphamide, doxorubicin, vincristine, and 
prednisone/prednisolone/methylprednisolone; IV intravenous; max maximum; Rrituximab.  
Note:  Oral prednisone/prednisolone/methylprednisolone should be given at least 60 minutes 
prior to rituximab (when applicable).  If there are 60 minutes before start of rituximab, IV 
application of prednisone/prednisolone/methylprednisolone is preferred.  The order of 
administration of cyclophosphamide, doxorubicin, and vincristine will be determined by local 
institutional practice, but these agents should be administered at least 30 minutes after rituximab.  
a Treatment administered in 21day cycles.  
b If it is the strong preference of the investigator or of the site (e.g., for logistical or safety 
reasons), the administration of rituximab on the day prior to CHOP with premedication is 
allowed.  It is also allowed to split the antibody infusion over 2 days if the patient is at 
increased risk for an IRR (high tumor burden, high peripheral lymphocyte count).  However, 
both optional changes to the administration schedule have to be done equally in both study 
arms (RCHOP and G-CHOP) in order to avoid any bias.  In patients who experience an 
adverse event during rituximab infusion, administration of rituximab may be continued on the 
following day if clinically required.  If the chemotherapy component is started later than Day 1 
of the cycle, then planned Day 1 of the next cycle should be calculated from the day when 
chemotherapy was actually initiated, in order to maintain the regular chemotherapy interval of 
21 days.  
c Methylprednisolone can be used at sites/countries in which IV prednisone/prednisolone is not 
available.  It should be administered at an equivalent dose of 80 mg to 100 mg 
prednisone/prednisolone.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
80/P BO21223A7
Table 5
Dosing with Obinutuzumab plus CHOP
Treatment
Dose
Mode
Cycle 1 a
Cycles 2–6 a
Cycles 7 
and 8 a
Day 1 b Days 2–5
Day 8 Day 15 Day 1 b Days 2–5
Day 1
Prednisone (or 
prednisolone/ 
methylpredniso
lonec)
100 
(80c) mg
Oral
x
x
x
x
Obinutuzumab
1000 mg
IV
x
x
x
x
x
Cyclophospha
mide
750 mg/m2
IV
x
x
Doxorubicin
50 mg/m2
IV
x
x
Vincristine
1.4 mg/m2
(2 mg 
max)
IV
x
x
CHOP cyclophosphamide, doxorubicin, vincristine, and 
prednisone/prednisolone/methylprednisolone; IV intravenous; max maximum.  
Note:  Oral prednisone/prednisolone/methylprednisolone should be given within 12 hours but at 
least 60 minutes prior to obinutuzumab (when applicable).  If there are 60 minutes before start 
of obinutuzumab, IV application of prednisone/prednisolone/methylprednisolone is preferred.  
The order of administration of cyclophosphamide, doxorubicin, and vincristine will be determined 
by local institutional practice, but these agents should be administered at least 30 minutes after 
obinutuzumab.  
a Treatment administered in 21day cycles.  
b If it is the strong preference of the investigator or of the site (e.g., for logistical or safety 
reasons), the administration of obinutuzumab is allowed on the day prior to CHOP with 
premedication.  It is also allowed to split the antibody infusion over 2 days if the patient is at 
increased risk for an IRR (high tumor burden, high peripheral lymphocyte count).  However, 
both optional changes to the administration schedule have to be done equally in both study 
arms (RCHOP and GCHOP) in order to avoid any bias.  In patients who experience an 
adverse event during obinutuzumab infusion, administration of obinutuzumab may be 
continued on the following day if clinically required.  If the chemotherapy component is started 
later than Day 1 of the cycle, then planned Day 1 of the next cycle should be calculated from 
the day when chemotherapy was actually initiated, in order to maintain the regular 
chemotherapy interval of 21 days.  
c Methylprednisolone can be used at sites/countries in which IV prednisone/prednisolone is not 
available.  It should be administered at an equivalent dose of 80 mg to 100 mg 
prednisone/prednisolone.
d.
CVP plus Rituximab (RCVP) or Obinutuzumab (GCVP)
It is mandatory to administer a total of eight 21day cycles of CVP.  If CVP is 
discontinued for any reason other than toxicity, patients will be discontinued from study 
treatment and proceed to followup directly without maintenance.  
CVP will be administered according to the standard preparation and infusion procedures 
of each investigational site.  Prednisone can be replaced by prednisolone or an 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
81/P BO21223A7
equivalent dose of methylprednisolone in countries or sites where prednisone is not 
available or where it is not the therapy of choice.  When rituximab or obinutuzumab is 
administered on the same day as prednisone/prednisolone/methylprednisolone, it is 
recommended that prednisone/prednisolone/methylprednisolone be given at least 
60 minutes prior to the rituximab or obinutuzumab infusion.  If there are 60 minutes 
before start of antibody, IV application of prednisone/prednisolone/methylprednisolone is 
preferred.  The order of administration of cyclophosphamide and vincristine will be 
determined by local institutional practice, but these agents should be administered at 
least 30 minutes after rituximab or obinutuzumab.  
If it is the strong preference of the investigator or of the site (e.g., for logistical or safety 
reasons), the administration of rituximab or obinutuzumab on the day prior to CVP with 
premedication is allowed.  It is also allowed to split the antibody infusion over 2 days if 
the patient is at increased risk for an IRR (high tumor burden, high peripheral 
lymphocyte count).  However, both optional changes to the administration schedule have 
to be done equally in both study arms (R-CVP and GCVP) in order to avoid any bias.  
Doses will be administered for RCVP recipients as shown in Table 6 and for G-CVP 
recipients as shown in Table 7.  For this study, Day 1 is the day when the first cycle of 
R/GCVP is initiated.  In patients who experience an adverse event during antibody 
infusion, administration of rituximab or obinutuzumab and application of chemotherapy 
may be continued on the following day if clinically required.  
If the chemotherapy component is started later than Day 1 of the cycle, then planned 
Day 1 of the next cycle should be calculated from the day when chemotherapy was 
actually initiated, in order to maintain the regular chemotherapy interval of 21 days.  
Empiric dose adjustment in obese patients (defined as a body mass index 30, as 
measured in kg/m2) may be implemented per institutional guidelines.  There will be 
no dose modification for changes in weight unless the patient's weight increases or 
decreases by 10% from weight at screening.  The weight that triggered a dose 
adjustment will be taken as the new reference weight for future dose adjustments.  
Capping the dose of cyclophosphamide according to BSA is not recommended but may 
be done if required by institutional guidelines.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
82/P BO21223A7
Table 6
Dosing with Rituximab plus CVP
Treatment
Dose
Mode
Cycles 1–8 a
Day 1 b
Days 2–5
Prednisone (or prednisolone
/methylprednisolonec)
100 
(80c) mg
Oral
x
x
Rituximab
375 mg/m2
IV
x
Cyclophosphamide
750 mg/m2
IV
x
Vincristine
1.4 mg/m2
(2 mg max)
IV
x
CVPcyclophosphamide, vincristine, and 
prednisone/prednisolone/methylprednisolone; IVintravenous; 
max maximum; Rrituximab.  
Note:  Oral prednisone/prednisolone/methylprednisolone should be given 
within 12 hours but at least 60 minutes prior to rituximab (when applicable).  If 
there are 60 minutes before start of rituximab, IV application of 
prednisone/prednisolone/methylprednisolone is preferred.  The order of 
administration of cyclophosphamide and vincristine will be determined by 
local institutional practice, but these agents should be administered at least 
30 minutes after rituximab.  
a Treatment administered in 21day cycles.  
b If it is the strong preference of the investigator or of the site (e.g., for 
logistical or safety reasons), the administration of rituximab is allowed on 
the day prior to CVP with premedication.  It is also allowed to split the 
antibody infusion over 2 days if the patient is at increased risk for an IRR 
(high tumor burden, high peripheral lymphocyte count).  However, both 
optional changes to the administration schedule have to be done equally in 
both study arms (R-CVP and GCVP) in order to avoid any bias. In patients 
who experience an adverse event during rituximab infusion, administration 
of rituximab may be continued on the following day if clinically required.  If 
the chemotherapy component is started later than Day 1 of the cycle, then 
planned Day 1 of the next cycle should be calculated from the day when 
chemotherapy was actually initiated, in order to maintain the regular 
chemotherapy interval of 21 days.  
c Methylprednisolone can be used at sites/countries in which IV 
prednisone/prednisolone is not available.  It should be administered at an 
equivalent dose of 80 mg to 100 mg prednisone/prednisolone.


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
83/P BO21223A7
Table 7
Dosing with Obinutuzumab plus CVP
Treatment
Dose
Mode
Cycle 1 a
Cycles 2–8 a
Day 1 b Days 2–5
Day 8
Day 15 Day 1 b Days 2–
5
Prednisone (or 
prednisolone/ 
methylprednisolonec)
100 
(80c) mg
Oral
x
x
x
x
Obinutuzumab
1000 mg
IV
x
x
x
x
Cyclophosphamide
750 mg/m2
IV
x
x
Vincristine
1.4 mg/m2
(2 mg max)
IV
x
x
CVP cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone; 
G GA101; IV intravenous; max maximum.  
Note:  Oral prednisone/prednisolone/methylprednisolone should be given within 12 hours but at 
least 60 minutes prior to obinutuzumab (when applicable).   If there are 60 minutes before start 
of obinutuzumab, IV application of prednisone/prednisolone/methylprednisolone is preferred.  
The order of administration of cyclophosphamide and vincristine will be determined by local 
institutional practice, but these agents should be administered at least 30 minutes after 
obinutuzumab.  
a Treatment administered in 21day cycles.  
b If it is the strong preference of the investigator or of the site (e.g., for logistical or safety 
reasons), the administration of obinutuzumab is allowed on the day prior to CVP with 
premedication.  It is also allowed to split the antibody infusion over 2 days if the patient is at 
increased risk for an IRR (high tumor burden, high peripheral lymphocyte count).  However, 
both optional changes to the administration schedule have to be done equally in both study 
arms (RCVP and GCVP) in order to avoid any bias.  In patients who experience an adverse 
event during obinutuzumab infusion, administration of obinutuzumab may be continued on the 
following day if clinically required.  If the chemotherapy component is started later than Day 1 
of the cycle, then planned Day 1 of the next cycle should be calculated from the day when 
chemotherapy was actually initiated, in order to maintain the regular chemotherapy interval of 
21 days.  
c Methylprednisolone can be used at sites/countries in which IV prednisone/prednisolone is not 
available. It should be administered at an equivalent dose of 80 mg to 100 mg 
prednisone/prednisolone.
e.
Bendamustine plus Rituximab (RBendamustine) or Obinutuzumab 
(G-Bendamustine)
It is mandatory to administer a total of six 28day cycles of bendamustine.  If 
bendamustine is discontinued for any reason other than toxicity, patients will be 
discontinued from study treatment and proceed to followup directly without 
maintenance.  
On Day 1 of Cycle 1, it is recommended that oral 
prednisone/prednisolone/methylprednisolone be given within 12 hours but at least 
60 minutes prior to the rituximab or obinutuzumab infusion as premedication.  If there 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
84/P BO21223A7
are 60 minutes before start of antibody, IV application of 
prednisone/prednisolone/methylprednisolone is preferred.  Bendamustine at a dose of 
90 mg/m2 will be administered by IV infusion over 60 minutes on Days 1 and 2 of each 
cycle.  There must be a minimum of 12 hours between each bendamustine 
administration.  Bendamustine should be administered at least 30 minutes after 
rituximab or obinutuzumab.  Doses will be administered for R-bendamustine recipients 
as shown in Table 8 and for G-bendamustine recipients as shown in Table 9.  For the 
purposes of this study, Day 1 is the day when the first cycle of R/Gbendamustine is 
initiated.  
If it is the strong preference of the investigator or of the site (e.g., for logistical or safety 
reasons), the administration of rituximab on the day prior to bendamustine with 
premedication is allowed.  It is also allowed to split the antibody infusion over 2 days if 
the patient is at increased risk for an IRR (high tumor burden, high peripheral 
lymphocyte count).  However, both optional changes to the administration schedule have 
to be done equally in both study arms (R-bendamustine and Gbendamustine) in order 
to avoid any bias.  
In patients who experience an adverse event during antibody infusion, administration of 
rituximab or obinutuzumab and application of chemotherapy may be continued on the 
following day if clinically required.  If the chemotherapy component is started later than 
Day 1 of the cycle, then planned Day 1 of the next cycle should be calculated from the 
day when chemotherapy was actually initiated, in order to maintain the regular
chemotherapy interval of 28 days.  
Empiric dose adjustment in obese patients (defined as a body mass index 30, as 
measured in kg/m2) may be implemented per institutional guidelines.  There will be no 
dose modification for changes in weight unless the patient's weight increases or 
decreases by 10% from weight at screening.  The weight that triggered a dose 
adjustment will be taken as the new reference weight for future dose adjustments.  
Capping the dose of bendamustine according to BSA is not recommended but may be 
done if required by institutional guidelines.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
85/P BO21223A7
Table 8
Dosing with Rituximab plus Bendamustine
Treatment
Dose
Mode
Cycle 1–6 a
Day 1 b
Day 2
Prednisone
100 (80c) mg
Oral
xc
Rituximab
375 mg/m2
IV
x
Bendamustine
90 mg/m2
IV
x
x
IV intravenous; R rituximab.
Note:  Bendamustine is to be administered at least 30 minutes 
after rituximab.  
a Treatment is administered in 28day cycles.  
b If it is the strong preference of the investigator or of the site 
(e.g., for logistical or safety reasons), the administration of 
rituximab on the day prior to bendamustine with premedication is 
allowed.  It is also allowed to split the antibody infusion over 2 days 
if the patient is at increased risk for an infusionrelated reaction 
(high tumor burden, high peripheral lymphocyte count).  However, 
both optional changes to the administration schedule have to be 
done equally in both study arms (R-bendamustine and 
G-bendamustine) in order to avoid any bias.  In patients who 
experience an adverse event during rituximab infusion, 
administration of rituximab and application of chemotherapy may 
be continued on the following day if clinically required.  If the 
chemotherapy component is started later than Day 1 of the cycle, 
then planned Day 1 of the next cycle should be calculated from the 
day when chemotherapy was actually initiated, in order to maintain 
the regular chemotherapy interval of 28 days.  
c Oral prednisone/prednisolone/methylprednisolone is given only on 
Cycle 1 Day 1 within 12 hours but at least 60 minutes prior to 
administration of rituximab.  If there are 60 minutes before start 
of rituximab, IV application of 
prednisone/prednisolone/methylprednisolone is preferred.  
Methylprednisolone can be used at sites/countries in which IV 
prednisone/prednisolone is not available.  It should be 
administered at an equivalent dose of 80 mg to 100 mg 
prednisone/prednisolone.


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
86/P BO21223A7
Table 9
Dosing with Obinutuzumab plus Bendamustine
Cycle 1 a
Cycles 2–6 a
Treatment
Dose
Mode
Day 1 b
Day 2
Day 8
Day 15 Day 1 b
Day 2
Prednisone
100 
(80c) mg
Oral
xc
Obinutuzumab
1000 mg
IV
x
x
x
x
Bendamustine
90 mg/m2
IV
x
x
x
x
IVintravenous.  
Note:  Bendamustine is to be administered at least 30 minutes after obinutuzumab.  
a Treatment is administered in 28day cycles.  
b If it is the strong preference of the investigator or of the site (e.g., for logistical or safety 
reasons), the administration of rituximab is allowed on the day prior to bendamustine with 
premedication.  It is also allowed to split the antibody infusion over 2 days if the patient is at 
increased risk for an infusionrelated reaction (high tumor burden, high peripheral lymphocyte 
count).  In patients who experience an adverse event during obinutuzumab infusion, 
administration of obinutuzumab and application of chemotherapy may be continued on the 
   following day if clinically required.  If the chemotherapy component is started later than Day 1 of 
the cycle, then planned Day 1 of the next cycle should be calculated from the day when 
chemotherapy was actually initiated, in order to maintain the regular chemotherapy interval of 
28 days.  
c Oral prednisone/prednisolone/methylprednisolone is given only on Cycle 1 Day 1 within 
12 hours but at least 60 minutes prior to administration of obinutuzumab.  If there are 60 
minutes before start of obinutuzumab, IV application of 
prednisone/prednisolone/methylprednisolone is preferred.  Methylprednisolone can be used at 
sites/countries in which IV prednisone/prednisolone is not available.  It should be administered 
at an equivalent dose of 80 mg to 100 mg prednisone/prednisolone.
See Appendix L for full bendamustine preparation instructions.  Unreconstituted 
bendamustine should be stored at ambient temperature (up to 25°C [77°F] with deviations 
permitted up to 30°C [86°F]).  
After reconstitution and dilution, the final preparation is stable for 3.5 hours at 25ºC and 
2 days at 2°C to 8°C in polyethylene bags.  
From a microbiological perspective, the readyforuse preparation should be used 
immediately unless the dilution method precludes a risk of microbial infection.  If the 
readyforuse preparation is not used immediately, the user is responsible for the 
duration and conditions of storage.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
87/P BO21223A7
4.3.3
Premedication
a.
Rituximab and Obinutuzumab
General Guidelines
All rituximab or obinutuzumab infusions should be administered after premedication with 
oral acetaminophen/paracetamol (e.g., 6501000 mg) and an antihistamine such as 
diphenhydramine (e.g., 50100 mg) 3060 minutes prior to starting each infusion 
(unless contraindicated).  If the chemotherapy regimen contains oral 
prednisone/prednisolone/methylprednisolone or if premedication with glucocorticoids is 
done orally, these tablets should be taken within 12 hours but at least 60 minutes prior to 
start of antibody infusion.  If there are 60 minutes before start of antibody, IV 
application of prednisone/prednisolone/methylprednisolone is preferred.  For patients 
who did not experience infusion-related symptoms with their previous infusion, 
premedication for subsequent infusions may be omitted at the investigator’s discretion.  
Premedication for Patients at High Risk for Tumor Lysis Syndrome
Patients who are considered to have a high tumor burden and who are considered to be 
at risk for tumor lysis by the investigator should additionally receive tumor 
lysis prophylaxis prior to the initiation of treatment.  These patients should be well 
hydrated.  Starting 12 days before the first dose of rituximab, it is desirable to maintain 
a fluid intake of approximately 3 L/day.  In addition, it is recommended that all patients 
considered to have high tumor burden and who are considered to be at risk for tumor 
lysis be treated with allopurinol 300 mg/day orally or a suitable alternative treatment 
starting 23 days prior to treatment on Day 1 of Cycle 1.  These patients may continue 
to receive repeated prophylaxis with allopurinol and adequate hydration prior to each 
subsequent infusion, if deemed appropriate by the investigator.  Allopurinol should be 
administered with caution in patients receiving bendamustine because of the potential 
for skin reactions.  Allopurinol must not be given on days of bendamustine administration 
(see Section 4.3.4.c).  
b.
CHOP, CVP, and Bendamustine
Cyclophosphamide, doxorubicin, and bendamustine have a moderate risk of emesis.  It 
is recommended that infusions be administered following premedication with a serotonin 
(5HT3) antagonist (e.g., dolasetron, ondansetron) or per institutional practice.  
4.3.4
Dosage Modification Guidelines
a.
Dosage Modification during Induction Therapy with RCHOP or 
G-CHOP
Dose modifications are based on all laboratory values obtained within 72 hours prior to a 
study treatment infusion.  The recommended dose modifications are in effect only for 
toxicities that are present within 72 hours prior to Day 1 of the next cycle.  Toxicities that 
occur during the cycle and that subside prior to the next cycle should not trigger the 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
88/P BO21223A7
suggested dose modifications.  Dose delays apply to all adverse events; dose 
modifications are applied only for adverse events that are considered drug related.  
Nonhematologic Toxicity
Cardiotoxicity.  A cumulative dose of 300 mg/m2 of doxorubicin in this study should not 
be exceeded.  Doxorubicin should be discontinued if evidence of left ventricular 
dysfunction or congestive heart failure develops.  
Hepatic Toxicity.  If bilirubin level is abnormal, the doxorubicin dose should be reduced 
to avoid myelotoxicity as outlined below.  
Serum bilirubin 
1.53.0 mg/dL

Decrease doxorubicin dose to 25 mg/m2.  

If improvement to 1.5 mg/dL, resume doxorubicin at 
50 mg/m2.  
Serum bilirubin 3.0 mg/dL 
or severe hepatic 
impairment

Delay doxorubicin for a maximum of 3 weeks.  

If improvement to 1.53.0 mg/dL, resume 
doxorubicin at 25 mg/m2.  If improvement to 
1.5 mg/dL, resume doxorubicin at 50 mg/m2.  

If no improvement, discontinue doxorubicin.  
Neurotoxicity.  Dosing should be modified for neurotoxicity as outlined below.  
Grade 4 neurotoxicity

Hold RCHOP or GCHOP for a maximum of 
3 weeks.  

If improvement to Grade 2 within 3 weeks, continue 
full dose of RCHOP or GCHOP, but without 
vincristine.  

If improvement to Grade 3 only within 3 weeks, 
administer R or G without CHOP in the next cycle.  If 
improvement to Grade 2 within 6 weeks, continue 
full dose of RCHOP or G-CHOP, but without 
vincristin.  If still Grade 3 after 6 weeks, continue 
therapy with R or G alone for all subsequent cycles.  
Grade 13 neurotoxicity

Reduce vincristine for all subsequent cycles to 1 mg 
absolute; do not delay RCHOP or GCHOP.  

If worsening despite dose reduction to 1 mg, 
eliminate vincristin for all subsequent cycles; do not 
delay R-CHOP or GCHOP.
Tumor Lysis Syndrome.  For patients with evidence of tumor lysis syndrome, treatment 
with RCHOP or GCHOP should be discontinued and the patient should be treated as 
clinically indicated.  Following the complete resolution of tumor lysis syndrome 
complications, treatment with RCHOP or GCHOP may be resumed at the full dose at 
the next scheduled infusion in conjunction with prophylactic therapy.  
Hepatitis B Virus Reactivation.  For the subset of patients who are HBsAg negative 
and HBcAb positive and have undetectable HBV DNA levels at screening, HBV DNA 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
89/P BO21223A7
levels must be followed approximately every 34 weeks during induction and then 
approximately every 4 weeks (see Section 4.3.5.c).  Treatment with R-chemo or 
G-chemo will be held for patients with a serum HBV DNA level of 29 IU/mL.  Patients 
should begin treatment with antiviral medication immediately after the first report 
showing HBV DNA 29 IU/mL.  Retest HBV DNA level as soon as possible to rule out a 
falsepositive report and to confirm HBV reactivation (29 IU/mL) (best prior to 
treatment; e.g., when prescribing the antiviral treatment).  If HBV reactivation is 
confirmed in a second test, continue to treat for at least 1 year after the last dose of 
rituximab or obinutuzumab and immediately refer the patient to a gastroenterologist or 
hepatologist for additional management.  If a second test does not confirm HBV 
reactivation and was taken prior to start of antiviral therapy, then antiviral therapy may 
be stopped again, and Rchemo/Gchemo may be resumed.  If a second test does not 
confirm HBV reactivation but was potentially confounded because it was taken only after 
the start of antiviral therapy, then continue to treat for at least 1 year after the last dose 
of rituximab or obinutuzumab and refer the patient to a gastroenterologist or hepatologist 
for additional management.  Patients may resume R-chemo or G-chemo once HBV DNA 
levels decrease to undetectable levels (10 IU/mL) or if retest does not confirm HBV 
reactivation.  If the HBV DNA level exceeds 100 IU/mL and are increasing while a 
patient is receiving antiviral medication, treatment with Rchemo or G-chemo will be 
discontinued.  
If HBV DNA level is detectable but 29 IU/mL, then continue with Rchemo/Gchemo, 
but retest at close intervals (e.g., every 34 weeks).  If HBV DNA is still detectable but 
29 IU/mL on retest, then continue to administer treatment and retest at close intervals 
(e.g., every 34 weeks).  If HBV DNA is 29 IU/mL on retest, then follow the instructions 
for HBV DNA levels 29 IU/mL (see above).  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
90/P BO21223A7
HBV DNA level of 29 IU/mL

Hold Rchemo/Gchemo.

Begin antiviral medication immediately 
after the first report showing HBV DNA 
29 IU/mL

Retest HBV DNA level as soon as possible 
to rule out a falsepositive report and to 
confirm HBVreactivation (29 IU/mL) (best 
prior to treatment; e.g., when prescribing 
the antiviral treatment).  

If HBV reactivation is confirmed in second 
test, continue to treat for at least 1 year 
after the last dose of rituximab or 
obinutuzumab and refer the patient to a 
gastroenterologist or hepatologist for 
additional management.  

If a second test does not confirm HBV 
reactivation and was taken prior to start of 
anti-viral therapy, then antiviral therapy 
may be stopped again, and R-
chemo/Gchemo may be resumed.  Retest 
the patient at close intervals (every 34 
weeks).  

If a second test does not confirm HBV 
reactivation but was potentially confounded 
because it was taken only after the start of 
ant-viral therapy, then continue to treat for 
at least 1 year after the last dose of 
rituximab or obinutuzumab and refer the 
patient to a gastroenterologist or 
hepatologist for additional management.  

Resume Rchemo or Gchemo once HBV 
DNA levels decrease to undetectable levels 
(10 IU/mL) or if retest does not confirm 
hepatitis B reactivation.  
HBV DNA level of 100 IU/mL and
increasing while on appropriate 
anti-viral medication
Discontinue Rchemo/Gchemo.  

HBV DNA level detectable  but 
<29 IU/mL

Continue with Rchemo/Gchemo, but 
retest at close intervals (e.g., every 
34 weeks).  
If HBV DNA still detectable, but 29 IU/mL on 
retest

Continue to administer treatment and retest 
at close intervals (e.g., every 34 weeks).  
If HBV DNA 29 IU/mL on retest

Follow instructions for HBV DNA level of 
29 IU/mL (see above).  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
91/P BO21223A7
Progressive Multifocal Leukoencephalopathy (PML).  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 to quantify DNA of JCV in the cerebrospinal fluid.  
Therapy with obinutuzumab or rituximab should be withheld during the investigation of 
potential PML and permanently discontinued in the 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 treatment of PML.  
Other Nonhematologic Toxicities.  For nausea or vomiting of all grades, optimize 
anti-emetic therapy.  
For Grade 2 nonhematologic toxicities (excluding alopecia, nausea, and vomiting), 
treatment with RCHOP or GCHOP will be delayed for a maximum of 3 weeks until 
resolution to Grade 1 (or baseline for all except hemorrhagic cystitis); for Grade 3 or 4 
toxicities, dosing will be modified or discontinued as outlined in Table 10.  Resumption of 
dosing without complete resolution of toxicity may be considered only upon careful 
weighing of the risks and benefits to the patient and agreement between the investigator 
and the Sponsor.  It is recommended that cycles be delayed in 1-week increments.  If 
treatment is delayed for more than 3 weeks, study treatment will be discontinued.  
If surgery is required as a result of a lifethreatening condition unrelated to treatment, 
Day 1 of the next cycle may be delayed up to a total of 8 weeks.  
There will be no dose reductions of rituximab (375 mg/m2) or obinutuzumab (1000 mg).  
If toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15, these doses will not be 
skipped but given after resolution of toxicity.  In such instances, all subsequent visits and 
the start of Cycle 2 will be shifted to accommodate for the delay in Cycle 1.  For Grade 3 
or 4 nonhematologic toxicities, doses of cyclophosphamide and doxorubicin should be 
decreased as outlined in Table 10.  
Hematologic Toxicity
Note that lymphopenia is not considered to be a hematologic toxicity, because it is 
an expected outcome of therapy.  
For Grade 3 hematologic toxicities (defined as neutropenia, anemia, 
or thrombocytopenia), treatment with RCHOP or GCHOP will be delayed for a 
maximum of 3 weeks until resolution to Grade 2.  In case of recurring Grade 3 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
92/P BO21223A7
hematological toxicity, dosing of cyclophosphamide, doxorubicin, rituximab, or 
obinutuzumab will be modified or discontinued as outlined in Table 10.  For Grade 4 
toxicities, dosing will be modified or discontinued as outlined in Table 10.  Resumption of 
dosing without complete resolution of toxicity may be considered only upon careful 
weighing of the risks and benefits to the patient and agreement between the investigator 
and the Sponsor.  It is recommended that cycles be delayed in 1-week increments.  If 
treatment is delayed for more than 3 weeks, study treatment will be discontinued.  
There will be no dose reduction of rituximab (375 mg/m2) or obinutuzumab (1000 mg).  If 
toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15, these doses will not be skipped 
but given after resolution of toxicity.  In such instances, all subsequent visits and the 
start of Cycle 2 will be shifted to accommodate for the delay in Cycle 1.  If cytopenia is 
thought to be caused mainly by NHL infiltration of the bone marrow, the investigator may 
decide not to reduce the cyclophosphamide and doxorubicin doses, for the first cycle 
only.  Even in the absence of bone marrow infiltration, cytopenias occurring on Cycle 1 
Day 8 and/or Cycle 1 Day 15 may be handled by delaying drug administration for a 
maximum of 3 weeks but do not necessarily trigger a dose reduction of 
cyclophosphamide and doxorubicin in Cycle 2.  
Table 10 Guidelines for Dose Delay or Modification of Obinutuzumab, 
Rituximab, or CHOP during Induction Therapy
Event
Dose Delay or Modification
Grade 3 or 4 
nonhematologic 
toxicity a, b

Delay doses of RCHOP or GCHOP for a maximum of 3 weeks.  

First episode:  If improvement to Grade 1 or baseline, decrease 
cyclophosphamide dose to 500 mg/m2 and doxorubicin dose to 
35 mg/m2 for subsequent cycles.  

Second episode:  If improvement to Grade 1 or baseline, decrease 
cyclophosphamide dose to 375 mg/m2 and doxorubicin dose to 
25 mg/m2 for subsequent cycles.   

Third episode:  Discontinue CHOP. c  If improvement to Grade 1 
or baseline, continue full dose of rituximab or obinutuzumab.  

Fourth episode:  Discontinue all study treatment. c
Grade 2 
nonhematologic 
toxicity a, b

Delay doses of RCHOP or GCHOP for a maximum of 3 weeks.  

If improvement to Grade 1 or baseline, administer previous dose 
of CHOP with full dose of rituximab or obinutuzumab.
Grade 1
nonhematologic 
toxicity a

No dose reduction or delay.
Grade 24 
hemorrhagic cystitis

Delay doses of RCHOP or GCHOP for a maximum of 3 weeks.  

If improvement to Grade 1, decrease cyclophosphamide dose to 
500 mg/m2 for next cycle.  Mesna and hydration during the next 
administration of cyclophosphamide is recommended.  

If symptoms do not recur, cyclophosphamide dose may be again 
increased to 750 mg/m2 for subsequent cycles.


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
93/P BO21223A7
Table 10 Guidelines for Dose Delay or Modification of Obinutuzumab, 
Rituximab, or CHOP during Induction Therapy (cont.)
Event
Dose Delay or Modification
Grade 4 
hematologic 
toxicity b, c, d, e, f

Delay doses of RCHOP or GCHOP for a maximum of 3 weeks.  

Administer myeloid growth factors for neutropenia as allowed per 
institutional guidelines.  

Administer RBCs or platelets as required.  

First episode:  If improvement to Grade 2, decrease 
cyclophosphamide dose to 500 mg/m2 and doxorubicin dose to 
35 mg/m2 for subsequent cycles. c, f  

In patients who are not receiving concomitant anticoagulants or platelet 
inhibitors, hold obinutuzumab in cases of severe thrombocytopenia 
(platelet count 10,000/µL) or symptomatic bleeding (irrespective of 
platelet count) until it resolves, but do not skip doses of obinutuzumab 
for the sake of maintaining the chemotherapy schedule.  

In patients who are receiving concomitant anticoagulants or platelet 
inhibitors, hold obinutuzumab in cases of platelets 20,000/µL or 
symptomatic bleeding (irrespective of platelet count) until it resolves, 
but do not skip any doses of obinutuzumab for the 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. d   For patients who are on platelet inhibitors when 
thrombocytopenia with platelet < 20,000/µL develops, consideration 
should be given to temporarily pause their use. d, e  

Second episode:  If improvement to Grade 2, decrease 
cyclophosphamide dose to 375 mg/m2 and doxorubicin dose to 
25 mg/m2 for subsequent cycles. c  

Third episode:  Discontinue CHOP. c  If improvement to Grade 2, 
continue full dose of rituximab or obinutuzumab.  

Fourth episode:  Discontinue all study treatment.c


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
94/P BO21223A7
Table 10 Guidelines for Dose Delay or Modification of Obinutuzumab, 
Rituximab, or CHOP during Induction Therapy (cont.)
Event
Dose Delay or Modification
Grade 3 
hematologic 
toxicity b,c, f

Delay doses of RCHOP or GCHOP for a maximum of 3 weeks.  

Administer myeloid growth factors for neutropenia as allowed per 
institutional guidelines.  

Administer RBCs or platelets as required.  

First episode:  If improvement to Grade 2, administer previous dose of 
CHOP with full dose of rituximab or obinutuzumab. c, f  

Second episode:  If improvement to Grade 2, decrease 
cyclophosphamide dose to 500 mg/m2 and doxorubicin dose to 
35 mg/m2 for subsequent cycles. c  

Third episode:  If improvement to Grade 2, decrease 
cyclophosphamide dose to 375 mg/m2 and doxorubicin dose to 
25 mg/m2 for subsequent cycles. c  

Fourth episode: Discontinue CHOP. c  If improvement to Grade 2, 
continue full dose of rituximab or obinutuzumab.  

Fifth episode: Discontinue all study treatment. c
Grade 1 or 2 
hematologic toxicity

No dose reduction or delay.
CHOPcyclophosphamide, doxorubicin, vincristine, and 
prednisone/prednisolone/methylprednisolone; GGA101; LMWHlow molecular weight 
heparins; NHLnon-Hodgkin's lymphoma; Rrituximab; RBCred blood cell  .
a Alopecia, nausea, and vomiting excluded.  In case of nausea or vomiting of all grades, 
optimize anti-emetic therapy; for cardiotoxicity, hepatic toxicity, neurotoxicity, tumor lysis 
syndrome, or hepatitis B virus reactivation, see guidelines above this table.  
b Dose delays apply to all adverse events; dose modifications are applied for only adverse 
events that are considered drug related.  
c Dose modifications are based on all laboratory values obtained within 72 hours prior to Day 1 
of the next cycle.  The recommended dose modifications are in effect only for toxicities that are 
present within 72 hours prior to Day 1 of the next cycle.  Toxicities that occur during the cycle 
and that subside prior to the next cycle should not trigger the suggested dose modifications.  
d If the clinical condition of patient requires the use of concomitant anticoagulants, the patients 
are at increased risk of bleeding when thrombocytopenia with platelets 20,000µL develops.  
When possible, replace prior therapy with vitamin K antagonists with LMWH before Cycle 1 
Day 1.  
e Clinical decision making may be adjusted depending on the patientspecific assessment of 
benefit and risk.  
f
If cytopenia is thought to be caused mainly by NHL infiltration of the bone marrow, 
the investigator may decide not to reduce the cyclophosphamide and doxorubicin doses, 
for the first cycle only.  Even in the absence of bone marrow infiltration, cytopenias occurring 
on Cycle 1 Day 8 and/or Cycle 1 Day 15 may be handled by delaying drug administration for a 
maximum of 3 weeks but do not necessarily trigger a dose reduction of cyclophosphamide and 
doxorubicin in Cycle 2.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
95/P BO21223A7
b.
Dosage Modification during Induction Therapy with RCVP or G-CVP
Dose modifications are based on all laboratory values obtained within 72 hours prior to a 
study treatment infusion.  The recommended dose modifications are in effect for only 
toxicities that are present within 72 hours prior to Day 1 of the next cycle.  Toxicities that 
occur during the cycle and that subside prior to the next cycle should not trigger the 
suggested dose modifications.  Dose delays apply to all adverse events; dose 
modifications are applied only for adverse events that are considered drug related.  
Nonhematologic Toxicity
Neurotoxicity.  Dosing should be modified for neurotoxicity as outlined below.  
Grade 4 neurotoxicity

Hold RCVPor GCVP for a maximum of 3 weeks.  

If improvement to Grade2 within 3 weeks, continue 
full dose of RCVP or GCVP but without vincristine. 

If improvement to Grade 3 only within 3 weeks, 
administer R or G without CVP in the next cycle.  If 
improvement to Grade 2 within 6 weeks, continue 
full dose of RCVP or G-CVP but without vincristine.  
If still Grade 3 after 6 weeks, continue therapy with R 
or G alone for all subsequent cycles. 
Grade 13 neurotoxicity

Reduce vincristine for all subsequent cycles to 1 mg 
absolute; do not delay RCVP or GCVP.  

If worsening despite dose reduction to 1 mg, 
eliminate vincristine for all subsequent cycles; do not 
delay R-CVP or GCVP.
Tumor Lysis Syndrome.  For patients with evidence of tumor lysis syndrome, treatment 
with RCVP or GCVP should be discontinued and the patient should be treated as 
clinically indicated.  Following the complete resolution of tumor lysis syndrome 
complications, treatment with RCVP or GCVP may be resumed at the full dose at the 
next scheduled infusion in conjunction with prophylactic therapy.  
Hepatitis B Virus Reactivation.  Refer to Section 4.3.4.a.  
Progressive Multifocal Leukoencephalopathy (PML). Refer to Section 4.3.4.a.  
Other Nonhematologic Toxicities.  For nausea or vomiting of all grades, 
optimize anti-emetic therapy.  
For Grade 2 nonhematologic toxicities (excluding alopecia, nausea, and vomiting), 
treatment with RCVP or GCVP will be delayed for a maximum of 3 weeks until 
resolution to Grade 1 (or baseline for all except hemorrhagic cystitis); for Grade 3 or 4 
toxicities, dosing will be modified or discontinued as outlined in Table 11.  Resumption of 
dosing without complete resolution of toxicity may be considered only upon careful 
weighing of the risks and benefits to the patient and agreement between the investigator 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
96/P BO21223A7
and the Sponsor.  It is recommended that cycles be delayed in 1-week increments.  
If treatment is delayed for more than 3 weeks, study treatment will be discontinued.  
There will be no dose reductions of rituximab (375 mg/m2) or obinutuzumab (1000 mg).  
If toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15, these doses will not be 
skipped but given after resolution of toxicity.  In such instances, all subsequent visits and 
the start of Cycle 2 will be shifted to accommodate for the delay in Cycle 1.  For Grade 3 
or 4 nonhematologic toxicities, the cyclophosphamide dose should be decreased as 
outlined in Table 11.  
Hematologic Toxicity
Note that lymphopenia is not considered to be a hematologic toxicity, because it is an 
expected outcome of therapy.  
For Grade 3 hematologic toxicities (defined as neutropenia, anemia, 
or thrombocytopenia), treatment with RCVP or GCVP will be delayed for a maximum 
of 3 weeks until resolution to Grade 2.  In case of recurring Grade 3 hematological 
toxicity, dosing of cyclophosphamide, rituximab, or obinutuzumab will be modified or 
discontinued as outlined in Table 11.  For Grade 4 toxicities, dosing will be modified or 
discontinued as outlined in Table 11.  Resumption of dosing without complete resolution 
of toxicity may be considered only upon careful weighing of the risks and benefits to the 
patient and agreement between the investigator and the Sponsor.  It is recommended 
that cycles be delayed in 1-week increments.  If treatment is delayed for more than 
3 weeks, study treatment will be discontinued.  
If surgery is required as a result of a lifethreatening condition unrelated to treatment, 
Day 1 of the next cycle may be delayed up to a total of 8 weeks.  
There will be no dose reductions of rituximab (375 mg/m2) or obinutuzumab (1000 mg).  
If toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15, these doses will not be 
skipped but given after resolution of toxicity.  In such instances, all subsequent visits and 
the start of Cycle 2 will be shifted to accommodate for the delay in Cycle 1.  If cytopenia 
is thought to be caused mainly by NHL infiltration of the bone marrow, the investigator 
may decide not to reduce the cyclophosphamide dose, for the first cycle only.  Even in 
the absence of bone marrow infiltration, cytopenias occurring on Cycle 1 Day 8 and/or 
Cycle 1 Day 15 may be handled by delaying drug administration for a maximum of 
3 weeks but do not necessarily trigger a dose reduction of cyclophosphamide in Cycle 2.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
97/P BO21223A7
Table 11 Guidelines for Dose Delay or Modification of Obinutuzumab, 
Rituximab, or CVP during Induction Therapy
Event
Dose Delay or Modification
Grade 3 or 4 
nonhematologic 
toxicity a, b

Delay doses of RCVP or GCVP for a maximum of 3 weeks.  

First episode:  If improvement to Grade 1 or baseline, decrease 
cyclophosphamide dose to 500 mg/m2 for subsequent cycles.  c

Second episode:  If improvement to Grade 1 or baseline, decrease 
cyclophosphamide dose to 375 mg/m2 for subsequent cycles.  c

Third episode:  Discontinue CVP. c  If improvement to Grade 1 or
baseline, continue full dose of rituximab or obinutuzumab.  

Fourth episode:  Discontinue all study treatment. c
Grade 2 
nonhematologic 
toxicity a, b

Delay doses of RCVP or GCVP for a maximum of 3 weeks.  

If improvement to Grade 1 or baseline, administer previous dose of 
CVP with full dose of rituximab or obinutuzumab.
Grade 1
nonhematologic 
toxicity a

No dose reduction or delay.
Grade 2–4 
hemorrhagic cystitis

Delay doses of RCVP or GCVP for a maximum of 3 weeks.  

If improvement to Grade 1, decrease cyclophosphamide dose to 
500 mg/m2 for next cycle.  Mesna and hydration during the next 
administrations of cyclophosphamide is recommended.  

If symptoms do not recur, cyclophosphamide dose may be again 
increased to 750 mg/m2 for subsequent cycles.


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
98/P BO21223A7
Table 11 Guidelines for Dose Delay or Modification of Obinutuzumab, 
Rituximab, or CVP during Induction Therapy (cont.)
Event
Dose Delay or Modification
Grade 4 
hematologic 
toxicity b, c, d, e, f

Delay doses of RCVP or GCVP for a maximum of 3 weeks.  

Administer myeloid growth factors for neutropenia as allowed per 
institutional guidelines.  

Administer RBCs or platelets as required.  

First episode:  If improvement to Grade 2, decrease 
cyclophosphamide dose to 500 mg/m2 for subsequent cycles.  c, f

In patients who are 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 doses of obinutuzumab for the 
sake of maintaining the chemotherapy schedule.  

In patients who are receiving concomitant anticoagulants or platelet 
inhibitors, 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 the sake of maintaining 
the chemotherapy schedule.  For patients who are on LMWH, when 
thrombocytopenia with platelets 20,000/µL develops, reduce the dose 
of LMWH used. d  For patients who are on platelet inhibitors when 
thrombocytopenia with platelets 20,000/µL develops, consideration 
should be given to temporarily pause their use. d, e  

Second episode:  If improvement to Grade 2, decrease 
cyclophosphamide dose to 375 mg/m2 for subsequent cycles. c  

Third episode:  Discontinue CVP. c  If improvement to Grade 2, 
continue full dose of rituximab or obinutuzumab.  

Fourth episode:  Discontinue all study treatment. c  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
99/P BO21223A7
Table 11 Guidelines for Dose Delay or Modification of Obinutuzumab, 
Rituximab, or CVP during Induction Therapy (cont.)
Event
Dose Delay or Modification
Grade 3 
hematologic 
toxicity b,c, f

Delay doses of RCVP or GCVP for a maximum of 3 weeks.  

Administer myeloid growth factors for neutropenia as allowed per 
institutional guidelines.  

Administer RBCs or platelets as required.  

First episode:  If improvement to Grade 2, administer previous dose 
of CVP with full dose of rituximab or obinutuzumab.  

Second episode:  If improvement to Grade 2, decrease 
cyclophosphamide dose to 500 mg/m2 for subsequent cycles.  c

Third episode:  If improvement to Grade 2, decrease 
cyclophosphamide dose to 375 mg/m2 for subsequent cycles.  c

Fourth episode:  Discontinue CVP. c  If improvement to Grade 2, 
continue full dose of rituximab or obinutuzumab.  

Fifth episode: Discontinue all study treatment. c
Grade 1 or 2 
hematologic toxicity

No dose reduction or delay.
CVPcyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone; 
GGA101; LMWHlow molecular weight heparins; NHLnon-Hodgkin's lymphoma;
Rrituximab; RBCred blood cell.  
a Alopecia, nausea, and vomiting excluded; for nausea or vomiting of all grades, optimize 
anti-emetic therapy; for neurotoxicity, tumor lysis syndrome, or hepatitis B virus reactivation, 
see guidelines above this table.  
b Dose delays apply to all adverse events; dose modifications are applied for only adverse 
events that are considered drug related.  
c Dose modifications are based on all laboratory values obtained within 72 hours prior to Day 1 
of the next cycle.  The recommended dose modifications are in effect only for toxicities that are 
present within 72 hours prior to Day 1 of the next cycle.  Toxicities that occur during the cycle 
and that subside prior to the next cycle should not trigger the suggested dose modifications.  
d 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.  
e Clinical decision making may be adjusted depending on the patientspecific assessment of 
benefit and risk.  
f
If cytopenia is thought to be caused mainly by NHL infiltration of the bone marrow, the 
investigator may decide not to reduce the cyclophosphamide and doxorubicin doses for the
first cycle only.  Even in the absence of bone marrow infiltration, cytopenias occurring on Cycle 
1 Day 8 and/or Cycle 1 Day 15 may be handled by delaying drug administration for a 
maximum of 3 weeks but do not necessarily trigger a dose reduction of cyclophosphamide and 
doxorubicin in Cycle 2.


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
100/P BO21223A7
c.
Dosage Modification during Induction Therapy with RBendamustine 
or G-Bendamustine
Dose modifications are based on all laboratory values obtained within 72 hours prior to a 
study treatment infusion.  The recommended dose modifications are in effect only for 
toxicities that are present within 72 hours prior to Day 1 of the next cycle.  Toxicities that 
occur during the cycle and that subside prior to the next cycle should not trigger the 
suggested dose modifications.  Dose delays apply to all adverse events; dose 
modifications are applied only for adverse events that are considered drug related.  
Nonhematologic Toxicity
Tumor Lysis Syndrome.  For patients with evidence of tumor lysis syndrome, treatment 
with Rbendamustine or Gbendamustine should be discontinued and the patient 
should be treated as clinically indicated.  Following the complete resolution of tumor lysis 
syndrome complications, treatment with Rbendamustine or Gbendamustine may be 
resumed at the full dose at the next scheduled infusion in conjunction with prophylactic 
therapy.  
Patients receiving prophylactic allopurinol should be monitored for skin reactions.  Skin 
reactions reported in clinical trials and postmarketing experience have included rash, 
toxic skin reactions, and bullous exanthema.  Cases of StevensJohnson syndrome and 
TEN have been reported when bendamustine was administered concomitantly with 
allopurinol and other agents known to cause these syndromes.  Skin reactions should be 
monitored closely.  In order to avoid such interaction, allopurinol must not be given on 
the days of bendamustine administration.  Bendamustine therapy should be withheld or 
discontinued for conditions that are severe or progressive.  
Hepatitis B Virus Reactivation.  Please refer to Section 4.3.4.a.  
Progressive Multifocal Leukoencephalopathy (PML). Please refer to Section 4.3.4.a.  
Other Nonhematologic Toxicities.  For nausea or vomiting of all grades, optimize 
anti-emetic therapy.  
For Grade 2 nonhematologic toxicities (excluding alopecia, nausea, and vomiting), 
treatment with Rbendamustine or G-bendamustine will be delayed for a maximum of 
3 weeks until resolution to Grade 1 (or baseline for all except hemorrhagic cystitis); for 
Grade 3 or 4 toxicities, dosing will be modified or discontinued as outlined in Table 12.  
Resumption of dosing without complete resolution of toxicity may be considered only 
upon careful weighing of the risks and benefits to the patient and agreement between 
the investigator and the Sponsor.  It is recommended that cycles be delayed in 1-week 
increments.  If treatment is delayed for more than 3 weeks, study treatment will be 
discontinued.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
101/P BO21223A7
There will be no dose reductions of rituximab (375 mg/m2) or obinutuzumab (1000 mg).  
If toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15, these doses will not be 
skipped but given after resolution of toxicity.  In such instances, all subsequent visits and 
the start of Cycle 2 will be shifted to accommodate for the delay in Cycle 1.  For Grade 3 
or 4 nonhematologic toxicities, the bendamustine dose should be decreased as outlined 
in Table 12.  
Hematologic Toxicity
Note that lymphopenia is not considered to be a hematologic toxicity, because it is an 
expected outcome of therapy.  
For Grade 3 hematologic toxicities (defined as neutropenia, anemia, 
or thrombocytopenia), treatment with Rbendamustine or Gbendamustine will be 
delayed for a maximum of 3 weeks until resolution to Grade 2.  In case of recurring 
Grade 3 hematological toxicity, dosing of bendamustine, rituximab, or obinutuzumab will 
be modified or discontinued as outlined in Table 12.  For Grade 4 toxicities, dosing will 
be modified or discontinued as outlined in Table 12.  Resumption of dosing without 
complete resolution of toxicity may be considered only upon careful weighing of the risks 
and benefits to the patient and agreement between the investigator and the Sponsor.  
It is recommended that cycles be delayed in 1-week increments.  If treatment is delayed 
for more than 3 weeks, study treatment will be discontinued.  
If surgery is required as a result of a lifethreatening condition unrelated to treatment,
Day 1 of the next cycle may be delayed up to a total of 8 weeks.  
There will be no dose reductions of rituximab (375 mg/m2) or obinutuzumab (1000 mg).  
If toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15, these doses will not be 
skipped but given after resolution of toxicity.  In such instances, all subsequent visits and 
the start of Cycle 2 will be shifted to accommodate for the delay in Cycle 1.  If cytopenia 
is thought to be caused mainly by NHL infiltration of the bone marrow, the investigator 
may decide not to reduce the bendamustine dose, for the first cycle only.  Even in the 
absence of bone marrow infiltration, cytopenias occurring on Cycle 1 Day 8 and/or 
Cycle 1 Day 15 may be handled by delaying drug administration for a maximum of 3 
weeks but do not necessarily trigger a dose reduction of bendamustine in Cycle 2.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
102/P BO21223A7
Table 12 Guidelines for Dose Delay or Modification of Obinutuzumab, 
Rituximab, or Bendamustine during Induction Therapy
Event
Dose Delay or Modification
Grade 3 or 4 
nonhematologic 
toxicity a,b

Delay doses of Rbendamustine or Gbendamustine for a maximum of 
3 weeks.  

First episode:  If improvement to Grade 1 or baseline, decrease 
bendamustine dose to 60 mg/m2 for subsequent cycles.c

Second episode:  Discontinue bendamustine.  If improvement to 
Grade 1 or baseline, continue full dose of rituximab or obinutuzumab. c

Third episode:  Discontinue all study treatment. c
Grade 2 
nonhematologic 
toxicity a,b

Delay doses of Rbendamustine or Gbendamustine for a maximum of 
3 weeks  

If improvement to Grade 1 or baseline, administer previous dose of 
bendamustine with full dose of rituximab or obinutuzumab.
Grade 1
nonhematologic 
toxicity a

No dose reduction or delay.
Grade 4 
hematologic 
toxicity b, c, d, e, f

Delay doses of Rbendamustine or Gbendamustine for a maximum 
of 3 weeks.  

Administer myeloid growth factors for neutropenia as allowed per 
institutional guidelines.  

Administer RBCs or platelets as required.  

First episode:  If improvement to Grade 2, decrease bendamustine 
dose to 60 mg/m2 for subsequent cycles.  c, f

In patients who are 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 doses of obinutuzumab for the 
sake of maintaining the chemotherapy schedule.  

In patients who are receving concomitant anticoagulants or platelet 
inhibitors, 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 the sake of maintaining the 
chemotherapy schedule.  For patients who are on LMWH, when 
thrombocytopenia with platelets 20,000/µL develop, reduce the dose of 
LMWH used. d  For patients who are on platelet inhibitors when 
thrombocytopenia with platelet 20,000/µL develops, consideration 
should be given to temporarily pause their use.  d, e

Second episode:  If improvement to Grade 2, decrease dose of 
bendamustine to 50 mg/m2 for subsequent cycles.  c

Third episode:  Discontinue bendamustine.  If improvement to Grade 2, 
continue full dose of rituximab or obinutuzumab.  

Fourth episode:  Discontinue all study treatment. c  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
103/P BO21223A7
Table 12 Guidelines for Dose Delay or Modification of Obinutuzumab, 
Rituximab, or Bendamustine during Induction Therapy (cont.)
Event
Dose Delay or Modification
Grade 3 
hematologic 
toxicity b,c, f 

Delay doses of Rbendamustine or Gbendamustine for a maximum of 
3 weeks.  

Administer myeloid growth factors for neutropenia as allowed per 
institutional guidelines.  

Administer RBCs or platelets as required.  

First episode:  If improvement to Grade 2, decrease dose of 
bendamustine to 70 mg/m2 with full dose of rituximab or obinutuzumab 
for subsequent cycles.  b, c

Second episode:  If improvement to Grade 2, decrease dose of 
bendamustine to 60 mg/m2 with full dose of rituximab or obinutuzumab 
for subsequent cycles.  c

Third episode:  If improvement Grade 2, decrease dose of 
bendamustine to 50 mg/m2 with full dose of rituximab or obinutuzumab 
for subsequent cycles.  c

Fourth episode:  Discontinue bendamustine. c  If improvement to 
Grade 2, continue full dose of rituximab or obinutuzumab.  

Fifth episode: Discontinue all study treatment. c
Grade 1 or 2 
hematologic 
toxicity

No dose reduction or delay.
GGA101; LMWHlow molecular weight heparins; NHLnon-Hodgkin's lymphoma;
Rrituximab; RBCred blood cell.  
a For tumor lysis syndrome or hepatitis B virus reactivation, see guidelines above this table.  
b Dose delays apply to all adverse events; dose modifications are applied for only adverse 
events that are considered drug related.  
c Dose modifications are based on all laboratory values obtained within 72 hours prior to Day 1 
of the next cycle.  The recommended dose modifications are in effect only for toxicities that 
are present within 72 hours prior to Day 1 of the next cycle.  Toxicities that occur during the 
cycle and that subside prior to the next cycle should not trigger the suggested dose 
modifications.  
d 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.  
e Clinical decision making may be adjusted depending on the patientspecific assessment of 
benefit and risk.  
f
If cytopenia is thought to be caused mainly by NHL infiltration of the bone marrow, the
investigator may decide not to reduce the cyclophosphamide and doxorubicin doses for the
first cycle only.  Even in the absence of bone marrow infiltration, cytopenias occurring on 
Cycle 1 Day 8 and/or Cycle 1 Day 15 may be handled by delaying drug administration for a 
maximum of 3 weeks but do not necessarily trigger a dose reduction of cyclophosphamide 
and doxorubicin in Cycle 2.


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
104/P BO21223A7
d.
Dosage Modification during Maintenance Therapy with Rituximab or 
Obinutuzumab
Nonhematologic Toxicity
Hepatitis B Virus Reactivation.  For the subset of patients who are HBsAg negative 
and HBcAb positive and have undetectable HBV DNA levels at screening, HBV DNA 
levels must be followed approximately every 4 weeks during maintenance 
(see Section 4.3.5.c).  Treatment with rituximab or obinutuzumab will be held for patients 
with a serum HBV DNA level of 29 IU/mL.  Patients should begin treatment with 
anti-viral medication immediately after the first report showing HBV DNA 29 IU/mL.  
Retest HBV DNA level as soon as possible to rule out a falsepositive report and to 
confirm HBV reactivation (29 IU/mL) (best prior to treatment; e.g., when prescribing the 
antiviral treatment).  If HBV reactivation is confirmed in a second test, continue to treat 
for at least 1 year after the last dose of rituximab or obinutuzumab and immediately refer 
the patient to a gastroenterologist or hepatologist for additional management.  If a 
second test does not confirm HBV reactivation and was taken prior to start of antiviral 
therapy, then antiviral therapy may be stopped again, and rituximab or obinutuzumab 
may be resumed.  If a second test does not confirm HBV reactivation but was potentially 
confounded because it was taken only after the start of antiviral therapy, then continue 
to treat for at least 1 year after the last dose of rituximab or obinutuzumab and refer the 
patient to a gastroenterologist or hepatologist for additional management.  Patients may 
resume rituximab or obinutuzumab once HBV DNA levels decrease to undetectable 
levels (10 IU/mL) or if retest does not confirm HBV reactivation.  If the HBV DNA level 
exceeds 100 IU/mL and are increasing while a patient is receiving antiviral medication,
treatment with rituximab or obinutuzumab will be discontinued.  
If HBV DNA level is detectable but 29 IU/mL, then continue with rituximab or 
obinutuzumab, but retest at close intervals (e.g., every 34 weeks).  If HBV DNA is still 
detectable but 29 IU/mL on retest, then continue to administer treatment and retest at 
close intervals (e.g., every 34 weeks).  If HBV DNA is 29 IU/mL on retest, then follow 
the instructions for HBV DNA levels 29 IU/mL (see above).  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
105/P BO21223A7
HBV DNA level of 29 IU/mL

Hold rituximab or obinutuzumab

Begin antiviral medication immediately 
after the first report showing HBV DNA 
29 IU/mL.  

Retest HBV DNA level as soon as 
possible to rule out a false-positive report 
and to confirm HBV reactivation 
(29 IU/mL) (best prior to treatment; e.g., 
when prescribing the anti-viral treatment).

If HBV reactivation is confirmed in a 
second test, continue to treat for at least 
1 year after the last dose of rituximab or 
obinutuzumab and immediately refer the 
patient to a gastroenterologist or 
hepatologist for additional management.  

If a second test does not confirm HBV 
reactivation and was taken prior to start of 
antiviral therapy, then antiviral therapy 
may be stopped again, and rituximab or 
obinutuzumab may be resumed.  Retest 
the patient at close intervals (every 
34 weeks).  

If a second test does not confirm HBV 
reactivation but was potentially 
confounded because it was taken only the 
after start of anti-viral therapy, then 
continue to treat for at least 1 year after 
the last dose of rituximab or 
obinutuzumab and refer the patient to a 
gastroenterologist or hepatologist for 
additional management.  

Resume rituximab or obinutuzumab once 
HBV DNA levels decrease to 
undetectable levels (10 IU/mL) or if 
retest does not confirm hepatitis B 
reactivation.
HBV DNA level of 100 IU/mL and 
increasing while on appropriate 
antiviral medication
Discontinue rituximab or obinutuzumab.
HBV DNA level detectable but 
29 IU/mL
Continue with rituximab or obinutuzumab, but 
retest at close intervals (e.g., every 
34 weeks).  
If HBV DNA still detectable but 29 IU/mL on 
retest

Continue to administer treatment and 
retest at close intervals (e.g., every 
34 weeks).  
If HBV DNA 29 IU/mL on retest

Follow instructions for HBV DNA level of 
29 IU/mL (see above).


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
106/P BO21223A7
For the subset of patients who are HBsAg negative and HBcAb positive and have 
undetectable HBV DNA levels at screening, HBV DNA levels must be followed 
approximately every 4 weeks (see Section 4.3.5.c).  Treatment with rituximab or 
obinutuzumab will be held for patients with a serum HBV DNA level of 100 IU/mL.  
Patients will begin treatment with antiviral medication (treatment will continue for at 
least 1 year after the last dose of rituximab or obinutuzumab) and will be immediately 
referred to a gastroenterologist or hepatologist for management.  Patients may resume 
rituximab or obinutuzumab once HBV DNA levels decrease to undetectable levels.  If the 
HBV DNA level exceeds 100 IU/mL while a patient is receiving antiviral medication, 
treatment with rituximab or obinutuzumab will be discontinued.  
If the HBV DNA assay becomes positive and is within the range of 29100 IU/mL, the 
patient should be retested within 2 weeks.  If the HBV DNA assay is still positive, 
treatment with Rituximab or obinutuzumab will be held and the patient should be treated 
with an appropriate nucleoside analogue (for at least 1 year after the last dose of 
rituximab or obinutuzumab) and immediately referred to a gastroenterologist or 
hepatologist for management.  Patients may resume treatment once the HBV DNA 
levels decrease to undetectable levels.  
Progressive Multifocal Leukoencephalopathy (PML).  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 to quantify DNA of JCV in the cerebrospinal fluid.  
Therapy with obinutuzumab or rituximab should be withheld during the investigation of 
potential PML and permanently discontinued in case of confirmed PML.  Discontinuation 
or reduction of any immunosuppressive therapy should also be considered.  The patient 
should be referred to a neurologist for the treatment of PML.  
Other Nonhematologic Toxicities.  For Grade 2 nonhematologic toxicities, treatment 
with rituximab or obinutuzumab will be delayed for a maximum of 42 days until resolution 
to Grade 1 or baseline (see Table 13).  Resumption of dosing without complete 
resolution of toxicity may be considered only upon careful weighing of the risks and 
benefits to the patient and agreement between the investigator and the Sponsor.  It is 
recommended that cycles be delayed in 1-week increments.  If treatment is delayed for 
more than 42 days, study treatment will be discontinued.  Any delay should be caught up 
within the next few subsequent visits to keep the treatment period of the maintenance 
phase within 2 years.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
107/P BO21223A7
There will be no dose reductions or skipping of rituximab (375 mg/m2) or obinutuzumab 
(1000 mg).  
Hematologic Toxicity
Note that lymphopenia is not considered to be a hematologic toxicity, because it is an 
expected outcome of therapy.  
For Grade 3 hematologic toxicities (defined as neutropenia, anemia, 
or thrombocytopenia), treatment with rituximab or obinutuzumab will be delayed for a 
maximum of 42 days until resolution to Grade 2 (see Table 13).  Resumption of dosing 
without complete resolution of toxicity may be considered only upon careful weighing of 
the risks and benefits to the patient and agreement between the investigator and the 
Sponsor.  It is recommended that cycles be delayed in 1-week increments.  If treatment 
is delayed for more than 42 days, study treatment will be discontinued.  Any delay 
should be caught up within the next few subsequent visits to keep the treatment period 
of the maintenance phase within 2 years.  
There will be no dose reductions of rituximab (375 mg/m2) or obinutuzumab (1000 mg).  
Table 13 Guidelines for Dose Delay or Modification of Obinutuzumab or 
Rituximab during Maintenance Therapy
Event
Dose Delay or Modification
Grade 2, 3, or 4 
nonhematologic 
toxicity a

Delay doses of rituximab or obinutuzumab for a maximum of 42 days.b

If improvement to Grade 1 or baseline, administer full dose of 
rituximab or obinutuzumab.
Grade 1
nonhematologic 
toxicity a

No dose reduction or delay.
Grade 3 or 4 
hematologic toxicity 

Delay doses of rituximab or obinutuzumab for a maximum of 42 days.b

Administer myeloid growth factors for neutropenia as allowed per 
institutional guidelines.  

Administer RBCs or platelets as required.  

If improvement to Grade 2, administer full dose of rituximab or 
obinutuzumab.
Grade 1 or 2 
hematologic toxicity

No dose reduction or delay.
RBC red blood cell.  
a For tumor lysis syndrome or hepatitis B virus reactivation, see guidelines above this table.  
b Any delay should be caught up within the next few subsequent visits to keep the treatment 
period of the maintenance phase within 2 years.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
108/P BO21223A7
4.3.5
Management of Toxicities
a.
Infusion-Related Reactions and Anaphylaxis
Please refer to Section 4.4 for information relating to concomitant medications.  
Medications (including epinephrine for subcutaneous injections and corticosteroids and 
diphenhydramine for IV injection) and resuscitation equipment should be available for 
immediate use.  Patients will receive premedication prior to infusion to decrease the risk 
of IRRs and will have regular monitoring of their vital signs during and after infusions.  
LifeThreatening Infusion-Related Reactions and IgEMediated 
Anaphylaxis
In the event of a life-threatening IRR (which may include pulmonary or cardiac events) 
or IgEmediated anaphylactic reaction, rituximab or obinutuzumab should be 
discontinued and no additional rituximab or obinutuzumab should be administered.  
Patients who experience any of these reactions should receive aggressive symptomatic 
treatment and will be discontinued from R/G chemotherapy and R/G maintenance.  
Management of Symptoms Related to Rituximab or Obinutuzumab Infusion
Symptoms related to rituximab or obinutuzumab infusion should be managed as outlined 
in Table 14.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
109/P BO21223A7
Table 14 Guidelines for Management of Symptoms Related to Rituximab 
or Obinutuzumab Infusion
Infusion-Related Symptoms a
Guidance
Grade 4

Discontinue infusion immediately, treat symptoms 
aggressively, and do not resume treatment.
Grade 3

Hold infusion.  

Give supportive treatment. b  

Upon symptom resolution, may resume infusion rate 
escalation at the investigator's discretion. c  

If the same adverse event recurs with the same severity, 
treatment must be permanently discontinued.
Grade 12

Slow or hold infusion.  

Give supportive treatment. b  

Upon symptom resolution, may resume infusion rate 
escalation at the investigator’s discretion. c
Note:  This table is for infusionrelated reactions (IRRs) according to investigator’s judgment, not 
for IRRs according to the IRR definition for reporting purposes.  Also, this table does not refer to 
management of IgEmediated anaphylactic reactions, which should be managed as directed 
above (see Section 4.3.5.a, "LifeThreatening Infusion-Related Reactions and IgEMediated 
Anaphylaxis").  
a Refer to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 
4.0, for the grading of symptoms.  
b Patients should be treated with acetaminophen/paracetamol and an antihistamine such as 
diphenhydramine if they have not received such treatment in the previous 4 hours.  
Intravenous saline may be indicated.  For bronchospasm, urticaria, or dyspnea, patients may 
require antihistamines, oxygen, corticosteroids (e.g., 100 mg of IV prednisolone or equivalent), 
and/or bronchodilators.  For hypotension, patients may require vasopressors.  
c 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 to a maximum rate of 
400 mg/hour.
b.
Cardiotoxicity
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 infusion of rituximab or obinutuzumab.  
Patients with preexisting cardiac conditions, including arrhythmias and angina, who have 
had recurrences of these events during rituximab or obinutuzumab therapy should be 
monitored throughout the infusion and immediate postinfusion period.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
110/P BO21223A7
c.
Hepatitis B Virus Reactivation
For the subset of patients who are HBsAg negative and HBcAb positive and have 
undetectable HBV DNA levels at screening, HBV DNA levels must be followed 
approximately every 34 weeks (depending on chemotherapy regimen) by real-time PCR 
through use of an assay with a limit of quantification of at least 10 IU/mL for at least 
1 year after the last cycle of therapy.  
Patients with a serum HBV DNA level of 100 IU/mL should immediately be started on 
treatment with an appropriate antiviral medication and should be referred to a 
hepatologist/gastroenterologist for further management.  Patients with a serum HBV 
DNA level in the range of 29100 IU/mL should have their HBV DNA test repeated within 
2 weeks.  If the level is rising, patients should immediately be started on treatment with 
an appropriate antiviral medication.  Antiviral treatment should continue for at least 
1 year after the last cycle of therapy.  
For the subset of patients who are HBsAg negative and HBcAb positive and have 
undetectable HBV DNA levels at screening, HBV DNA levels must be followed 
approximately every 34 weeks (depending on chemotherapy regimen and study phase) 
by realtime PCR through use of an assay with a limit of quantification of at least 
29 IU/mL for at least 1 year after the last cycle of therapy.  
Study treatment will be held for patients with a serum HBV DNA level of 29 IU/mL.  
Patients should begin treatment with anti-viral medication immediately after the first 
report showing HBV DNA 29 IU/mL.  HBV DNA level is retested as soon as possible 
to rule out a false-positive report and to confirm HBV reactivation (29 IU/mL) (best prior 
to (treatment; e.g., when prescribing the antiviral treatment).  If HBV reactivation is 
confirmed in a second test, antiviral treatment will continue for at least 1 year after the 
last dose of rituximab or obinutuzumab) and patient will be immediately referred to a 
gastroenterologist or hepatologist for additional management.  If a second test does not 
confirm HBV reactivation and was taken prior to start of antiviral therapy, then antiviral 
therapy may be stopped again, and study treatment may be resumed.  If a second test 
does not confirm HBV reactivation but was potentially confounded because it was taken 
only after the start of antiviral therapy, then antiviral treatment should continue for at 
least 1 year after the last dose of rituximab or obinutuzumab and the patient should be 
referred to a gastroenterologist or hepatologist for additional management.  Patients may 
resume study treatment once HBV DNA levels decrease to undetectable levels 
(10 IU/mL) or if retest does not confirm HBV reactivation.  If the HBV DNA level 
exceeds 100 IU/mL and are increasing while a patient is receiving antiviral medication, 
study treatment will be discontinued.  
If HBV DNA level is detectable but 29 IU/mL, then study treatment may continue, but 
patient should be retested at close intervals (e.g., every 34 weeks).  If HBV DNA is still 
detectable but 29 IU/mL on retest, then study treatment should be continued and 


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patient should be retested at close intervals (e.g., every 34 weeks).  If HBV DNA is 
29 IU/mL on retest, the instructions for HBV DNA levels 29 IU/m should be followed.  
d.
Progressive Multifocal Leukoencephalopathy (PML)
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 to quantify DNA of JCV in the cerebrospinal 
fluid.  
Therapy with obinutuzumab or rituximab 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 treatment of 
PML.  
e.
Febrile Neutropenia
It is mandatory to follow the ASCO/EORTC/ESMO guidelines about the use of myeloid 
growth factors for the primary prevention and treatment of febrile neutropenia throughout 
the trial (Smith et al. 2006; Crawford et al. 2009; Aapro et al. 2011).  
f.
Hemorrhagic Cystitis
Patients should be adequately hydrated prior to and after cyclophosphamide 
administration and should be instructed to void frequently.  Mesna (2-mercaptoethane 
sulfonate sodium) may be administered as prophylaxis per institutional guidelines.  
If gross hematuria develops, the cyclophosphamide dose should be decreased 
(see Table 10 and Table 11).  
g.
Gastrointestinal Toxicity
CHOP and CVP are associated with chemotherapyinduced nausea and vomiting.  
Anti-emetics should be administered per institutional guidelines.  


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4.3.6
Treatment Discontinuation Criteria
A patient should discontinue rituximab, obinutuzumab, or chemotherapy if any of the 
following occurs.  If it is unclear as to which drug caused the toxicity, all agents should 
be discontinued.  

Grade 4 infusionrelated symptom or anaphylaxis as per investigator’s judgment; 
the patient should be withdrawn from study treatment (R/G chemotherapy and R/G 
maintenance) immediately.  

Recurrence of Grade 3 infusionrelated symptom at rechallenge as per 
investigator’s judgment despite adequate preventive measures 
(i.e., acetaminophen/paracetamol plus antihistamine plus corticosteroid), regardless 
of timing (e.g., within the same session or at a subsequent session)

Fourth recurrence of Grade 4 hematologic toxicity (each episode of which delayed 
the start of the next treatment cycle) despite adequate dose reductions

Fifth recurrence of Grade 3 hematological toxicity (each episode of which delayed 
the start of the next treatment cycle) despite adequate dose reductions

Diagnosis of confirmed PML

Grade 2 nonhematologic toxicity that does not resolve to Grade 1 or baseline 
despite delaying treatment for at least 3 weeks during induction treatment

Grade ≥2 nonhematologic toxicity that does not resolve to Grade ≤1 or baseline 
despite delaying treatment for at least 6 weeks during the maintenance phase

For R/GCHOP/CVP:  Fourth episode of Grade 2 nonhematologic toxicity 
(each episode of which delayed the start of the next treatment cycle) despite 
adequate dose reductions in R/GCHOP/CVP

For R/Gbendamustine:  Third episode of Grade 2 nonhematologic toxicity 
(each episode of which delayed the start of the next treatment cycle) despite 
adequate dose reductions in R/Gbendamustine

Grade 1–4 heart failure or Grade 34 left ventricular systolic dysfunction

Hepatitis B exacerbation despite the initiation of the appropriate antiviral therapy

Disease progression
A patient should discontinue rituximab or obinutuzumab if any of the following occurs:  

Recurrent Grade 4 hematologic toxicity or Grade 3 or 4 nonhematologic toxicity 
despite discontinuation of CHOP, CVP, or bendamustine (as described in 
Table 10Table 12).  
Patients who discontinue rituximab or obinutuzumab treatment because of 
infusionrelated symptoms may continue to receive chemotherapy alone and should 
continue to have disease assessments per the protocol.  Patients who discontinue 
rituximab may not cross over to obinutuzumab.  


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Patients who discontinue chemotherapy prior to the completion of induction treatment 
because they have experienced a chemotherapy-specific toxicity should continue to 
receive rituximab or obinutuzumab alone as previously scheduled until disease 
progression.  
Patients who discontinue chemotherapy prior to the completion of the full number of 
induction cycles for any reason other than toxicity should discontinue study treatment 
and go into followup directly without maintenance (see Appendix A-5).  
It is mandatory that the full number of cycles will be given for each 
immunochemotherapy regimen during induction.  If induction therapy was stopped for 
toxicity or any reason other than toxicity, then patients are discontinued from study 
treatment and go into followup directly without maintenance (see Appendix A-5).  
4.4
CONCOMITANT AND EXCLUDED THERAPIES
4.4.1
Concomitant Therapy
Concomitant therapy includes any prescription medications or over-the-counter 
preparations used by a patient between the 7 days preceding the study entry evaluation 
and the end of study visits.  All concomitant medications should be reported to the 
investigator and recorded on the appropriate electronic Case Report Form (eCRF).  
Patients who use oral contraceptives, hormonereplacement therapy, 
or other maintenance therapy should continue their use.  
Patients may receive prophylactic antiviral medication to prevent hepatitis B 
reactivation in countries where they are administered as part of the standard of care or 
national guidelines.  
The use of rasburicase for the treatment of tumor lysis syndrome and the prevention of 
hyperuricemia is allowed according to institutional guidelines. 
The use of antibiotic and/or antiviral prophylaxis according to institutional guidelines is 
also allowed. 
Primary prophylaxis with granulocyte colony stimulating factors (GCSFs) is 
recommended as per the ASCO, EORTC, and ESMO guidelinesnamely, in patients 
who are 60 years of age and/or with comorbidities (Lyman et al.2004). The use of 
G-CSF prophylaxis is strongly recommended in Cycle 1 for all patients treated with 
GA101 CHOP.  
Harvesting of stem cells by GCSF alone (no additional chemotherapeutic agent) is 
allowed only if it is done between Cycle 5 Day 1 and Cycle 8 Day 1 (R/GCHOP or 
R/GCVP) or Cycle 4 Day 1 and Cycle 6 Day 1 (R/GBendamustine).  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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Patients who experience obinutuzumab infusionrelated temperature elevations 
of 38.5C or other minor infusion-related symptoms may be treated symptomatically 
with acetaminophen/paracetamol (500 mg) and/or H1and H2receptor antagonists 
(e.g., diphenhydramine, ranitidine).  Serious infusion-related events manifested by 
dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen 
saturation, or respiratory distress should be managed with additional supportive 
therapies (e.g., supplemental oxygen, 2 agonists/epinephrine, and/or corticosteroids) 
as clinically indicated according to standard clinical practice.  
a.
Therapy for Febrile Neutropenia
It is mandatory to follow the ASCO/EORTC/ESMO guidelines about the use of myeloid 
growth factors for the primary prevention and treatment of febrile neutropenia throughout 
the trial (Smith et al. 2006; Crawford et al. 2009; Aapro et al. 2011).  
b.
Hemorrhagic Cystitis
Mesna may be administered as prophylaxis per institutional guidelines for patients treated 
with CHOP or CVP.  
4.4.2
Excluded Therapy
Use of the following therapies is prohibited during the study:  

Cytotoxic chemotherapy (other than bendamustine, cyclophosphamide, doxorubicin, 
or vincristine)
Although MTX is a chemotherapeutic agent, due to the low doses used in 
treating rheumatoid arthritis (typically 7.5 to a maximum of 20 mg/week) it is not 
considered chemotherapy for lymphoma.  Therefore, patients treated before or 
during study conduct with MTX for rheumatoid arthritis are still eligible to 
participate in the study.  It is recommended to stop MTX 2-3 weeks prior to 
starting immunochemotherapy since the combination of MTX and 
immunochemotherapy increases the risk of immunosuppression and the risk of 
infection, but MTX may be resumed during maintenance/observation/followup, if 
clinically indicated

Radiotherapy

Immunotherapy (other than rituximab and obinutuzumab)

Hormone therapy (other than contraceptives, hormone-replacement therapy, or 
megestrol acetate)
Hormonal therapy (e.g., GnRHagonists) for egg cell harvest/fertility preservation 
prior to randomization is allowed in women of childbearing age

Any therapies intended for the treatment of NHL, whether FDA approved or 
experimental (outside of this study)


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Patients who require the use of any of these agents will be discontinued from 
study treatment but followed for PD and overall survival.  
4.5
STUDY ASSESSMENTS
Signed informed consent will be obtained from the patient or patient’s legally acceptable 
representative before any studyspecific procedures are performed or any prohibited 
medications are withheld for purposes of study participation.  
Test results or examinations that are performed as standard of care prior to obtaining 
informed consent and appropriately within 35 days prior to randomization may be used 
to satisfy screening requirements rather than repeating required tests.  A separate 
optional informed consent is required for collection of optional research samples 
(see Section 4.5.1.h).  
See Appendix A for the Study Flowcharts.  
4.5.1
Definitions of Study Assessments
a.
Physical Examination
A complete physical examination should include an evaluation of head, eye, ear, nose, 
and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems.  Changes from baseline abnormalities should 
be recorded at each subsequent physical examination.  New or worsened abnormalities 
should be recorded as adverse events if appropriate.  
As part of tumor assessment, physical examinations should also include the evaluation 
of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly.  
A targeted physical examination should be limited to systems of primary relevancethat 
is, cardiovascular, respiratory, those associated with symptoms, and those associated 
with tumor assessment (lymph nodes, liver, and spleen).  
b.
Tumor and Response Evaluation
All measurable disease must be documented at baseline and re-assessed within 
14 days prior to each subsequent study visit.  Response assessments will be performed 
by the investigator, based on physical examinations, CT/MRI scans, hematology, 
laboratory results, and bone marrow examinations, through use of Revised Response 
Criteria for Malignant Lymphoma (Cheson et al. 2007; see Appendix C).  Response 
evaluation by the investigator shall be done with and without FDGPET results or the 
PET portion of a combined PETCT in the eCRF.  
CT scans (with contrast) should include chest, abdomen, and pelvis scans; CT scans of 
the neck should be included if clinically indicated (i.e., if evidence of disease on physical 


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examination) and must be followed throughout the trial if there is disease involvement at 
baseline.  MRIs of the chest, abdomen, and pelvis with a noncontrast CT scan of the 
chest may be used in patients for whom CT scans with contrast are contraindicated 
(i.e., patients with contrast allergy or impaired renal clearance).  If MRI is used at 
screening, then MRI should be used throughout the study (same method during the 
entire study).  In addition, the CT portion of a combined FDGPET/CT scan may be 
used only if performed with contrast and collected with resolution sufficient to allow 
accurate and consistent comparison of target lesion measurements with subsequent CT 
scans.  Any time the investigator suspects disease progression, a full tumor assessment 
must be performed, including a CT scan (limited to areas of prior involvement if required 
by local authorities).  

In the first 170 patients with follicular lymphoma, an FDGPET is mandatory where 
a PET scanner is available.  This may require specific approval in some countries.  
In such instances, FDGPET becomes manadatory only after necessary approvals 
have been obtained.  
PET scans are to be performed at screening and at induction completion/end of 
treatment visit (only if screening PET was positive) within 68 weeks after Day 1 of the 
last cycle, within 48 weeks (in case of early termination due to adverse event), 
or within 28 weeks after last dose (in case of early termination due to clinical 
disease progression).  
In the overall study population, FDGPET remains optional upon investigator’s discretion.  
If the screening PET scan is negative, subsequent FDGPET scans need not be 
performed.  Any time the investigator suspects disease progression on the basis of PET 
scan results, a full tumor assessment must be performed, including a CT scan (or MRI 
scan if CT scan is contraindicated), limited to areas of prior involvement (if required by 
local authorities to limit scans).  FDGPET standardized uptake values will be collected.  
FDGPET scan results will be incorporated in an exploratory analysis in a separate 
response assessment based on physical examinations, relevant clinical information, 
CT or MRI scans, and bone marrow examinations by the investigator and the IRC.  
Bone marrow examinations should include a biopsy for morphology, an aspirate for local 
hematology (optional, if part of standard of care at site), and an aspirate for 
BCL2/IgH (MRD) determination.  Bone marrow examinations are required at screening 
for staging purposes in all patients (CR definition requires clearing of a previously 
infiltrated bone marrow) and in all patients with follicular lymphoma also for 
determination of BCL2/IgH (MRD) baseline levels.  BCL2/IgH based MRD 
determination will not be performed in patients with MZL.  
If there was bone marrow infiltration at screening, then a subsequent bone marrow 
biopsy (trephine) at the induction completion visit is required for clinical response 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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evaluation for all patients who may have achieved a CR.  In patients with a PR and 
continued bone marrow involvement, a subsequent bone marrow examination may be 
required to confirm a CR at a later time point.  An additional bone marrow aspirate may 
be done if that is standard of care at the site.  
If bone marrow involvement was diagnosed by morphology at screening, a subsequent 
bone marrow aspirate for BCL2/IgH (MRD) is required at the induction 
completion/end-of-treatment visit for all patients with follicular lymphoma who achieve 
a CR or PR (all responders).  If bone marrow was free of lymphoma by morphology at 
screening, a subsequent bone marrow aspirate for BCL2/IgH (MRD) at the induction 
completion/end-of-treatment visit is optional but strongly recommended in responders 
(CRPR).  This recommendation is based on the observation that, at screening, 
bone marrow involvement is detectable on the level of minimal residual disease in the 
large majority of patients even if it appears to be negative by morphology.  
Any additional (unscheduled) bone marrow examinations performed during the study will 
be at the discretion of the investigator.  
In patients with gastric extranodal MZL, the initial staging should include a 
gastroduodenal endoscopy with multiple biopsies from the stomach, duodenum, 
gastroesophageal junction, and any site that seems abnormal.  If any disease sites are 
identified in this manner at screening, a subsequent gastroduodenal endoscopy and 
biopsy are required to confirm a CR.  In addition, if other sites are involved at baseline, 
they should be appropriately staged at baseline and re-evaluated during followup.  The 
diagnosis of CR in splenic MZL also requires the normalization of the blood counts 
(hemoglobin 12g/dL; platelets 100109/L; neutrophils 1.5109/L) and no evidence 
of circulating clonal B cells.  
In patients with splenic MZL, the spleen is considered a target lesion, and its size should 
be determined by ultrasound, CT/MRI, or by physical examination.  Local guidelines for 
determining normal organ size are acceptable.  
c.
Laboratory Assessments
Samples for the following laboratory assessments will be analyzed at the study site’s 
local laboratory:  hematology, serum chemistry, urinalysis, serum electrophoresis and 
M protein, serum immunofixation, pregnancy test, HTLV testing, hepatitis B serology, 
hepatitis C serology and RNA, coagulation, and quantitative immunoglobulins.  Samples 
for the following laboratory assessments will be sent to the Sponsor or designees for 
analysis:  HBV DNA, flow cytometry (leukocyte immunophenotyping), biologic markers, 
pharmacokinetics, BCL2/IgH rearrangement, and HAHAs.  Instruction manuals and 
supply kits will be provided for all central laboratory assessments. Flow cytometric 
determination of T, B, and NK cells (TBNKPanel) will be performed in all patients of the 
trial (both rituximaband obinutuzumabtreated patients).  Flow cytometric 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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determination of B cell subsets (B cell panel) will be performed in 60 patients of each 
treatment group (R-CHOP, GCHOP, RCVP.  GCVP, Rbendamustine, 
Gbendamustine) and in all patients with splenic MZL.  Pharmacokinetic assessments 
will be performed in a subset of approximately 460 patients receiving obinutuzumab.  
HAHA will be performed in all patients receiving obinutuzumab.  
On days of study drug administration, pre-infusion laboratory samples should be drawn 
04 hours before the start of infusion, and post-infusion laboratory samples should be 
drawn 030 minutes after the end of infusion, unless otherwise specified.  
Protection of patient confidentiality will extend to any data generated from the assaying 
of these samples.  
Laboratory assessments will include the following:  

Hematology includes hemoglobin, hematocrit, platelet count, red blood cell (RBC) 
count, white blood cell count, and absolute neutrophil count as routine components.  
Percent or absolute differential count [segmented neutrophils, banded neutrophils, 
eosinophils, lymphocytes, monocytes, basophils, malignant lymphocytes are done if 
clinically indicated {e.g., for differential diagnosis of any kind of clinically relevant 
cytopenia/cytophilia, or, e.g., if other undefined cells are present in the peripheral 
blood}]).  In case of splenic MZL, the percent or absolute number of malignant 
lymphocytes (“villous lymphocytes”) in peripheral blood should be assessed.  

Serum chemistries (sodium, potassium, chloride, bicarbonate [if clinically indicated], 
BUN, creatinine, calcium, phosphorus, total bilirubin, total protein, albumin, ALT, 
AST, LDH, alkaline phosphatase, uric acid, and 2 microglobulin [2 microglobulin 
required only at screening]).  Urinalysis: In a fresh sample of midstream urine, a 
dipstick testing for proteinuria is required.  

Creatinine clearance (glomerular filtration rate) according to Cockroft Gault during 
screening and approximately 1 year after last treatment.  

For MZL patients, serum electrophoresis (% albumin, alpha 1, alpha 2, beta, 
gamma), relative and absolute determination of M protein if present.  If M protein is 
present, immunofixation for detection of Ig subtype (IgG, IgA, IgM, IgD, lightchain 
kappa or lambda) should be performed.  

Coagulation (PTT or aPTT, prothrombin time or INR)

Pregnancy test:  All women of childbearing potential (including those who have had 
a tubal ligation) will have a serum pregnancy test at screening.  Urine pregnancy 
tests will be performed at specified subsequent visits and may be performed more 
frequently if required by local legislation.  If a urine pregnancy test result is positive, 
dosing will be delayed until the patient’s status is determined by a serum pregnancy 
test.  


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
Viral serology and detection
Hepatitis B (HBsAg and total HBcAb and hepatitis B surface antibody [HBsAb])
HBV DNA should be monitored centrally every 3 to 4 weeks (depending on 
chemotherapy regimen) by real-time PCR with a limit of quantification of at 
least 29 IU/mL until at least 1 year after the last treatment cycle in patients 
who are HBsAg negative and HBcAb positive.  
If a patient is HBsAg negative and HBcAb positive during screening, 
additional serology for HBsAb is required prior to Day 1 of Cycle 1.  
HCV antibody (also HCV RNA by PCR in a local laboratory if the patient is 
HCV antibody positive)
HTLV1 serology (for patients from endemic countries only; endemic countries 
include Japan, the Caribbean basin, South America, sub-Saharan Africa, and 
Melanesia)

Quantitative immunoglobulins (IgG, IgA, and IgM)

Flow cytometry (fluorescence-activated cell sorting [FACS] subsets)
Whole-blood samples will be collected to determine
In all patients:  TBNKPanel. The duration of B-cell depletion and recovery 
(CD19+), Tcell counts (CD3+, CD4+, CD8+), and NKcell counts (CD56+)
B cell panel:  In 60 patients of each therapeutic group (RCHOP, GCHOP, 
R-CVP, G-CVP, Rbendamustine, Gbendamustine) and in all splenic MZL 
patients:  Bcell subsets defined by a combination of Bcell markers.  

HAHAs (patients receiving obinutuzumab only)
Although obinutuzumab is a humanized antibody, there is a risk that HAHAs 
could develop, thus reducing efficacy and/or resulting in symptomatic 
hypersensitivity reactions.  Experience with similar humanized antibodies (e.g., 
trastuzumab) suggests that the incidence and titer of such antibodies will be low 
and that they will be unlikely to affect efficacy or cause unwanted 
immunological reactions (Genentech data on file).  Nevertheless, samples will 
be collected to assess the possible induction of HAHAs in patients receiving 
obinutuzumab.  

Pharmacokinetic measurements (subset of patients receiving obinutuzumab only) 
(see Appendix B)

Tumor tissue samples at screening and at time of progression/transformation will be 
collected from patients for central pathologic review and confirmation of CD20 
positivity.  Tissue should be collected within 12 months prior to randomization.  
Tissue samples dated 12 months prior to randomization can be accepted only 
if tissue material is available for retrospective confirmation, if there is no clinical 
indication for transformation of disease, and if the request for additional biopsy 
would be unethical treatment of the patient.  Bone marrow alone is not suited to 
make the diagnosis of follicular lymphoma.  In patients with splenic MZL without 
splenic tissue available for histologic review, the bone marrow must be submitted 


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for retrospective central confirmation.  All tissue samples should be sent for quality 
assurance pathology review within 4 months after randomization.  A formalinfixed, 
paraffinembedded tissue sample is preferred over 1520 sections on coated slides.  
If the tissue sample is small, fewer sections (minimum, within range of 612) can be 
accepted.  Remainders of the tissue blocks will be returned to local pathology 
according to countryspecific procedures.  
d.
Electrocardiograms
A 12lead ECG is required at screening and when clinically indicated.  ECGs for each 
patient should be obtained from the same machine whenever possible.  
e.
Cardiac Function Evaluation
Patients randomized to RCHOP or GCHOP are required to have an evaluation of their 
cardiac function by MUGA scan or echocardiogram within 6 months prior to screening 
and after receipt of 300 mg/m2 of doxorubicin (end of induction therapy).  
f.
PatientReported Outcomes
The PRO questionnaires (FACTLym and EQ5D) should be selfadministered at the 
investigational site.  Study personnel should review all questionnaires for completeness 
before the patient leaves the investigational site.  It is important that the questionnaires 
be administered before any other study procedure is performed during that study visit.  
g.
ECOG Performance Status, Ann Arbor Staging, IPI and FLIPI Index, 
ADLs/IADLs
The ECOG Performance Status scale and Ann Arbor staging classifications are provided 
in Appendix H.  Appendix M provides a description of the IPI, FLIPI, and FLIPI2 indices 
and FLIPI nodal areas.  Appendix N provides a description of ADLs/IADLs scoring scale.  
h.
Exploratory Biomarker Research (Required and Optional Components)
Samples will be collected from all patients to enable differentiation of predictive factors 
from prognostic factors.  Samples will be collected to identify biomarkers that are 
predictive of response to obinutuzumab treatment (in terms of dose, safety, 
and tolerability) and will help to better understand the pathogenesis, course, 
and outcome of advanced follicular lymphoma and related diseases.  In countries where 
DNA collection is restricted, local laws and regulations will apply and a separate consent 
may be issued to comply with local legislation.  
All specimens for exploratory biomarker analyses (both required and optional) will be 
single coded like any other clinical sample (labeled and tracked using the patient’s study 
identification number).  


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Required Exploratory Biomarkers
Required samples for exploratory biomarker research are as follows:  

Fcreceptor polymorphisms (only in fully eligible patients)

Tumor tissue sample at time of progression/transformation
A tumor sample will be collected at time of progression from patients who 
undergo such a biopsy as part of the standard of care at their institution for 
central pathology review.  A biopsy at the time of progression is not mandatory.  

Bone marrow aspirate for BCL2/IgH (MRD) analysis at screening 
(follicular lymphoma patients only) and at induction completion/early termination 
(only responders [CR and PR] in whom bone marrow involvement was diagnosed 
by morphology at screening)
For each required bone marrow examination, a bone marrow aspirate is 
required for the analysis of clonal BCL2/IgH rearrangement (as a potential 
marker of tumor burden).  
Peripheral blood sample for BCL2/IgH (MRD) analysis in all patients with 
follicular lymphoma at screening, before Cycle 4 Day 1 bendamustine) or Cycle 5 
Day 1 (CHOP/CVP), at induction completion/end of treatment, maintenance or 
observation Month 4, 8, 12, 18, at maintenance or observation 
completion/end-of-treatment visit, and during followup at Months 30, 36, 42, 48, 
60, and 72.  
Required exploratory biomarker samples will be stored for up to 5 years after completion 
of the study.  
Optional Exploratory Biomarkers
Optional samples for exploratory biomarker research are as follows:  

Baseline serum and plasma samples to enable future analyses of protein 
expression (e.g., cytokine profiles)

Leftover DNA from Fcreceptor polymorphism samples (see DNA Substudy 
protocol)

Leftover DNA from peripheral blood samples for for BCL2/IgH (MRD) analysis in all 
patients with follicular lymphoma at screening, before Cycle 4 Day 1 bendamustine) 
or Cycle 5 Day 1 (CHOP/CVP), at induction completion/end of treatment, 
maintenance or observation Month 4, 8, 12, 18, at maintenance or observation 
completion/endoftreatment visit, and during followup at Months 30, 36, 42, 48, 
60, and 72 (see DNA Substudy protocol)

Bone marrow aspirate samples for MRD analysis at the induction 
completion/endoftreatment visit from responding (CRPR) patients with follicular 
lymphoma in whom no bone marrow involvement was diagnosed by morphology at 
screening


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
122/P BO21223A7

Leftover DNA from bone marrow aspirate samples for MRD analysis at the induction 
completion/endoftreatment visit from responding (CRPR) patients with follicular 
lymphoma in whom no bone marrow involvement was diagnosed by morphology at 
screening (see DNA Substudy protocol).  

Residual tumor tissue sample from baseline biopsy sample
In addition to central pathology review (see the Required Exploratory Biomarkers 
section), representative tumor sections from the original biopsy sample will be cut 
for generation of tissue microarrays (TMAs), extraction of tumor messenger 
ribonucleic acid (mRNA), microRNA, and DNA.  If possible, two tissue cores will 
be punched for construction of a TMA.  These samples may be used for the 
assessment of specific tumor biologic markers, including proteins, mRNA, 
microRNA, and DNA, in order to better understand the biology of NHL and 
disease prognosis to predict response to treatment with obinutuzumab 
(see DNA Substudy protocol).  
Assays on stored tissue samples may be performed by the Sponsor or at a 
central specialty laboratory.  
Any remaining tissue in the tissue block will be returned to the site according to 
countryspecific procedures.  Unused slides will not be returned.  

Residual tumor tissue from sample at time of progression/transformation
In addition to central pathology review (see the Required Exploratory Biomarkers 
section), representative tumor sections from the sample at time of 
progression/transformation will be used for the assessment of specific tumor 
biologic markers, including proteins, mRNA, microRNA, and DNA, in order to 
better understand possible changes in tumor biology (e.g., histological 
transformation, gene expression, expression of surface markers) that may have 
occurred (see DNA Substudy protocol).  
If patients consent to participate in the optional exploratory biomarker research, serum, 
plasma, leftover DNA from FcReceptor polymorphism, peripheral blood and bone 
marrow BCL2/IgH (MRD) samples, and unstained sections, TMAs, as well as mRNA, 
microRNA, and DNA extracted from the residual tumor tissue specimens from the biopsy 
sample at baseline and at progression/transformation will be stored in the RCR for up to 
15 years after database freeze to enable future research.  
The RCR specimens will be destroyed no later than 15 years after the final freeze of the 
respective clinical database unless regulatory authorities require that specimens be 
maintained for a longer period.  The implementation and use of the RCR specimens is 
governed by the RCR policy to ensure the appropriate use of the RCR specimens.  
Specimens in the RCR will be used for research purposes to identify biomarkers that are 
predictive of response to obinutuzumab treatment (in terms of dose, safety, 
and tolerability) and will help to better understand the pathogenesis, course, 
and outcome of advanced follicular lymphoma and related diseases.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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i.
Medical Resource Utilization
Where possible, medical resource utilization data will be collected from the clinical 
eCRFs completed by site staff (e.g., adverse events associated with hospitalization, 
concomitant therapy).  Where necessary, patients will be asked whether they have 
received additional medical care and will be asked to identify the type of resource 
(e.g., primary care physician).  
4.5.2
Screening and Pretreatment Assessments
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.  A 
separate, optional informed consent is required for the optional research described in 
Section 4.5.1.h.  
Screening tests and evaluations will be performed within 35 days prior to randomization.  
Results of standardofcare tests or examinations performed prior to obtaining informed 
consent and within 14 days prior to study entry may be used; such tests do not need to 
be repeated for screening.  All screening evaluations must be completed and reviewed 
to confirm that patients meet all eligibility criteria before initiation of study treatment.  
Please see the Study Flowcharts provided in Appendix A for schedules of screening and 
pretreatment assessments.  
4.5.3
Assessments during Induction Treatment
Local laboratory assessments may be performed within 72 hours prior to study drug 
administration on Day 1 of each cycle.  Results must be reviewed and the review 
documented prior to study drug administration.  
During induction treatment, all visits must occur within 4 days from the scheduled date, 
unless otherwise noted.  Assessments scheduled on the day of study drug 
administration should be performed prior to study drug infusion, unless otherwise noted.  
Please see the Study Flowcharts provided in Appendix A for schedules of assessments 
to be performed during induction treatment.  
4.5.4
Induction Completion/Early Termination Visit
Patients who complete the induction treatment period or discontinue early will be asked 
to return to the clinic within 68 weeks after Cycle 8 Day 1 (CHOP or CVP) or Cycle 6 
Day 1 (bendamustine) for a followup visit.  The visit at which a response assessment 
showed disease progression may be used as the early termination visit.  An early 
termination visit should occur within 48 weeks after last dose (in case of early 
termination due to adverse event) or within 28 weeks after last dose (in case of early 
termination due to clinical disease progression).  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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See the Study Flowcharts provided in Appendix A for schedules of assessments to be 
performed at the induction completion/early termination visit.  
4.5.5
Assessments during Maintenance Treatment or Observation
Patients who demonstrate a CR or PR at the end of induction therapy will be eligible 
to receive maintenance therapy with rituximab or obinutuzumab based upon the initial 
randomization.  Patients should start treatment with rituximab or obinutuzumab 
2 months 14 days after the last dose of immunochemotherapy and will continue to 
receive treatment every 2 months 14 days until disease progression for up to 2 years.  
If the end of induction/early termination visit was done 8 weeks after the last dose of 
immunochemotherapy, the first maintenance visit should be scheduled 714 days later
in order to keep an interval between end of induction/early termination and maintenance 
Month 2.  
Patients who demonstrate SD at the end of induction therapy will undergo observation 
for up to 2 years.  
The schedule of 2month visits should be maintained.  During maintenance a month will 
be calculated as 28 days.   
Patients receiving maintenance therapy or undergoing observation will be followed 
clinically every 2 months 14 days for 2 years (with CT scans every 4 months for the first 
year and then every 6 months for the second year) or until disease progression or patient 
discontinuation from the study, whichever comes first.  
Tumor assessment (CT scan or MRI) may be performed within 14 days prior to study 
drug administration.  If a dose of study drug is delayed, tumor assessment should be 
performed 14 days prior to the new planned visit (for Months 4, 8, 12, and 18).  
Local laboratory assessments may be performed within 72 hours prior to study drug 
administration on Day 1 of each cycle.  Results must be reviewed and the review 
documented prior to study drug administration.  
See the Study Flowcharts provided in Appendix A-4 for schedules of assessments to be 
performed during maintenance treatment or observation.  
Any delay in maintenance or observation visits should be reverted to the original 
schedule within the next few subsequent visits.  No study drug infusion should be 
skipped due to a visit delay (see Figure 3).  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
125/P BO21223A7
Figure 3
Schema of Returning to Original Schedule after a Visit Delay in 
Maintenance
Note: This schema shows only two catchup visits.  More visits could be necessary in order to 
return to the original schedule.  
Maint.maintenance; Discont.discontinuation
4.5.6
Maintenance or Observation Completion/Early Termination 
Visit
Patients who complete the maintenance treatment or observation period or who 
discontinue early will be asked to return to the clinic within 2135 days after the last 
immunotherapy dose or the date of the decision to discontinuation for a maintenance or 
observation completion/ET visit.  
The visit at which a response assessment showed disease progression may be used as 
the early termination visit.  
Please see the Study Flowcharts provided in Appendix A for schedules of assessments 
to be performed at the maintenance or observation completion/early termination visit.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
126/P BO21223A7
4.5.7
FollowUp Assessments
a.
Patients with a Response or Stable Disease
For patients who have a CR, a PR, or SD at the maintenance or observation completion 
visit, disease assessments will continue every 3 months 14 days for 3 years (with CT 
scans every 6 months) and then every 6 months 14 days for 2 years (with CT scans 
every year) until the end of the study (at approximately 10.2 years) or until disease 
progression, whichever occurs first.  This assessment is consistent with both NCCN and 
ESMO guidelines.  Patients will then be followed twice per year, starting 6 months after 
the last clinical visit, until the end of the study for the following:  

Disease progression

NALT

Survival
Patients who start an NALT or discontinue study drug in the absence of disease 
progression should be followed according to the above schedule.  
b.
Patients with Disease Progression
Patients with disease progression will be followed twice per year, starting 6 months after 
the last clinical visit, until the end of the study (at approximately 10.2 years) for the 
following:  

NALT

Survival

Response after NALT
c.
Ongoing Adverse Events
Ongoing adverse events thought to be related to study drug treatment will be followed 
until the event has resolved to baseline grade, the event is assessed by the investigator 
as stable, NALT is initiated, the patient is lost to followup, the patient withdraws consent, 
or it has been determined that the study treatment or participation is not the cause of the 
adverse event.  
See the Study Flowcharts provided in Appendix A for schedules of followup 
assessments.  
4.6
PATIENT DISCONTINUATION
The investigator has the right to discontinue a patient from the study for any medical 
condition that the investigator determines may jeopardize the patient’s safety if he or she 
continues in the study; for reasons of noncompliance (e.g., missed doses, visits); if the 
patient becomes pregnant; or if the investigator determines it is in the best interest of the 
patient.  Patients who are discontinued because of investigators decision will be followed 
up for disease progession, NALT, response after NALT, and survival.  


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See Sections 4.5.4 and 4.5.6 for assessments that are to be performed for patients who 
prematurely withdraw from the study during the treatment period.  
4.6.1
Discontinuation from Study Treatment
Patients may discontinue chemotherapy treatment (i.e., CHOP, CVP, or bendamustine) 
early if they experience unacceptable toxicity as described in Section 4.3.4.  Patients 
may also discontinue obinutuzumab or rituximab treatment early because of 
unacceptable toxicity as described in Section 4.3.6.  The reasons for early 
discontinuation of treatment must be documented on the appropriate eCRF.  
Patients who discontinue study treatment early because of an unacceptable toxicity 
should continue to be followed for both resolution of toxicity and disease progression as 
scheduled in Appendix A-5.  
Patients must discontinue study treatment if they experience disease progression.  After 
disease progression, patients will be followed until the next treatment and then for 
survival until study completion, starting 6 months after the last clinical visit (see 
Section 4.5.7 a).  
The investigator has the right to discontinue a patient from study treatment for any 
medical condition that the investigator determines may jeopardize the patient’s safety if 
he or she continues in the study, for reasons of noncompliance (e.g., missed doses, 
visits), if the patient becomes pregnant, or if the investigator determines it is in the best 
interest of the patient.  
See Sections 4.5.4 and 4.5.6 for assessments that are to be performed for patients who 
prematurely discontinue treatment during the primary study treatment period.  
4.6.2
Discontinuation from Study
Patients have the right to voluntarily withdraw or discontinue from the study at any time 
for any reason.  The investigator also has the right to withdraw a patient from the study 
at any time for any reason.  Those patients who are withdrawn or withdraw from study 
participation (and not just study treatment) will not be followed up for any reason after 
consent has been withdrawn.  
4.6.3
Withdrawal of Patients from the Roche Clinical Repository
Patients who give consent to allow collection of exploratory biomarker specimens for 
storage in the RCR have the right to withdraw their specimens at any time for any 
reason.  If a patient wishes to withdraw his or her specimens, the investigator must 
inform the Medical Monitor in writing of the patient’s wishes using the RCR Patient 
Withdrawal Form and enter the date of withdrawal in the patient’s eCRF.  A patient 
withdrawal from the study does not, by itself, constitute withdrawal of the specimen from 
the RCR; likewise, withdrawal of a patient’s specimens from the RCR does not constitute 
a withdrawal from the study.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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4.7
STUDY OR 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:  

The incidence or severity of adverse events in this or other studies indicates 
a potential health hazard to patients.  

Patient enrollment is unsatisfactory.  

Data recording is inaccurate or incomplete.  
The Sponsor has the right to replace a site at any time.  Reasons for replacing a site 
may include but are not limited to the following:  

Excessively slow recruitment

Poor protocol adherence
4.8
POSTTRIAL ACCESS
Currently, the Sponsor does not have any plans to provide obinutuzumab or other study 
interventions to patients after the conclusion of the study or any earlier withdrawal.  
Patients in the control arm are not allowed to cross over to receive obinutuzumab.  The 
Sponsor will evaluate the appropriateness of continuing to provide obinutuzumab to 
study patients after evaluating the primary efficacy outcome measure and safety data 
gathered in the study.  
4.9
ASSAY METHODS
Obinutuzumab concentration will be determined in serum through use of a sandwich 
ELISA method.  Assay sensitivity was determined to be 4.05 ng/mL obinutuzumab in 
human serum.  
A sandwich bridging ELISA was developed using conjugated obinutuzumab as a capture 
agent to detect antiobinutuzumab antibodies in human serum.  
4.10
STATISTICAL METHODS
All analyses will be performed for the follicular population and for the overall population 
unless otherwise specified.  
4.10.1
Analysis of the Conduct of the Study
Enrollment, eligibility violations, study drug administration, and patient disposition will be 
summarized by treatment arm in all randomized patients and by histology (follicular and 
nonfollicular).  A summary of patient disposition will include whether treatment was 
completed or discontinued early and the reason for early treatment discontinuation. 
4.10.2
Analysis of Treatment Group Comparability
Demographic and baseline characteristics, such as age, sex, race/ethnicity, 
and baseline ECOG Performance Status, will be summarized by treatment arm in all 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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randomized patients and by histology (follicular vs. nonfollicular).  Descriptive baseline 
summaries of continuous data will present the group mean, standard deviation, median, 
minimum, maximum, and sample size.  Descriptive summaries of discrete data will 
include frequencies and percentages.  
4.10.3
Efficacy Analyses
The primary analysis population for efficacy is the intenttotreat follicular population, 
defined as all randomized patients with follicular histology, according to local diagnosis 
provided in IxRS.  Patients will be analyzed according to the treatment arm to which they 
were randomized.  
a.
Primary Efficacy Endpoint
The primary efficacy endpoint, PFS in patients with follicular lymphoma, is defined as the 
time from randomization to the first occurrence of progression or relapse as assessed by 
the investigator according to the Revised Response Criteria for Malignant Lymphoma 
(Cheson et al. 2007; see Appendix C) or death from any cause.  PFS for patients without 
disease progression, relapse, or death will be censored at the time of the last tumor 
assessment or, if no tumor assessments were performed after the baseline visit, at the 
time of randomization.  
Although the primary efficacy endpoint is the investigatorassessed PFS, PFS based on 
IRC assessments will also be analyzed to support the primary analysis.   In the United 
States, IRCassessed PFS will be the basis for regulatory decisions.  
The primary analysis of the study will test the equality of PFS distributions in the 
obinutuzumab plus chemotherapy (GChemo) and rituximab plus chemotherapy 
(R-Chemo) arms, as follows:  
H0: PFSG-Chemo = PFSR-Chemo
versus
H1: PFSG-Chemo ≠ PFSR-Chemo
Treatment comparison will be made using a twosided stratified logrank test 
(0.05 significance level) stratified by chemotherapy regimen (CHOP, CVP, 
or bendamustine) and FLIPI risk group (low, intermediate, or high).  KaplanMeier 
methodology will be used to estimate PFS distribution for each treatment arm.  The 
KaplanMeier curve will provide a visual description of the differences across treatment 
arms.  Estimates of the treatment effect will be expressed as hazard ratios through use 
of a stratified Cox proportionalhazards analysis, including 95% confidence limits.  
Median PFS is not expected to be reached in this study; hence, the 3year and 4year 
rates will be used to describe PFS in addition to the hazard ratio.  
The following sensitivity analyses for PFS will also be performed:

An unstratified logrank test will be performed.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
130/P BO21223A7

A rerandomization test of the primary endpoint will be performed to assess the 
sensitivity of the stratified logrank test to the dynamic randomization procedure.  

The impact of loss to followup will be assessed by a worstcase analysis 
that assigns event outcomes to patients who were lost prior to disease progression 
in the obinutuzumab arm at the next scheduled disease assessment date and 
censored outcomes to patients in the rituximab arm at the last disease assessment 
date.  

PFS analyses will be performed with censoring at the initiation of 
nonprotocolspecified antilymphoma therapy to assess potential confounding of 
the treatment effect estimates by subsequent therapy.  

PFS analyses will be performed with censoring of patients who died more than 
6 months after their last tumor assessment and showed no sign of progression 
(i.e., at the last available tumor assessment).  

A multivariate sensitivity analysis of PFS will be performed using Cox 
proportionalhazards regression to assess the treatment effect after adjustment for 
potential prognostic factors.  
b.
Secondary Efficacy Endpoints
All analyses of secondary efficacy endpoints will be performed for all randomized 
patients (i.e., overall population) and for the follicular subset of randomized patients 
(i.e., follicular population), with the exception of PFS, which will be performed for the 
overall population as a secondary efficacy endpoint (PFS for the follicular population is 
the primary efficacy endpoint).  Patients will be analyzed according to the treatment arm 
to which they were randomized.  
To adjust for multiple statistical testing of the primary and key secondary efficacy 
endpoints, thereby controlling the overall Type I error rate at a twosided 0.05 level of 
significance, the fixed sequence testing procedure (Westfall and Krishen 2001) will be 
used.  These endpoints will be tested in the following order:  

PFS in all randomized patients (i.e., the overall population)

CR rate at the end of induction therapy in the follicular population of randomized 
patients (i.e., the follicular population) based on tumor assessment without PET

CR rate at the end of induction therapy in the overall population based on tumor 
assessment without PET

Overall survival in the follicular population

Overall survival in the overall population

ORR at the end of induction therapy in the follicular subset of randomized patients 
(i.e., the follicular population) based on tumor assessment without PET

ORR at the end of induction therapy in the overall population based on tumor 
assessment without PET


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
131/P BO21223A7
All analyses will be based on the investigator’s assessment.  For U.S. registration 
purposes, the key secondary analyses of PFS, CR rate, and ORR will be based on 
IRC assessments.  
CR rate and ORR (CR or PR) at the end of induction are defined according to 
the Revised Response Criteria for Malignant Lymphoma (Cheson et al. 2007; 
see Appendix C).  
Overall survival is defined as the time from the date of randomization to the date of 
death from any cause.  Patients who were not reported as having died at the time of the 
analysis will be censored at the date when they were last known to be alive as 
documented by the investigator.  
EFS is defined as the time from the date of randomization to the date to disease 
progression/relapse, death from any cause, or start of a NALT.  If the specified event 
(disease progression/relapse, death, start of an NALT) does not occur, patients will be 
censored at the date of last tumor assessment.  For patients who do not have 
postbaseline tumor assessments or documentation of NALT, EFS will be censored at 
the time of randomization.  
DFS is defined for all patients with a CR as the time from the date the CR was first 
recorded to the date on which PD was first noted or the date of death from any cause.  
Patients with no documented disease progression or death after CR will be censored at 
the last disease assessment date.  
BOR is defined as the best response assigned to a patient at any time point during the 
treatment or followup, prior to NALT.  
Duration of response is defined for patients with a CR or PR as the time from the date 
of the initial response (CR or PR) to the date of progression/relapse or death from any 
cause.  For patients achieving a response who have not progressed, relapsed, or died 
at the time of analysis, duration of response will be censored on the date of last disease 
assessment.  
Time to next antilymphoma treatment (TTNLT) is defined as the time from the date of 
randomization to the start date of the next antilymphoma treatment or death from any 
cause.  For patients who have not received the next anti-lymphoma treatment or died 
at the time of analysis, TTNLT will be censored at the date when the patient was last 
known to be alive without having received additional antilymphoma treatment.  
Timetoevent endpoints such as overall survival, EFS, DFS, duration of response, and 
TTNLT will be analyzed using the same statistical methods described for the primary 
analysis of PFS (see Section 4.10.3.a).  Indolent histology (follicular or nonfollicular) will 
also be included as a stratification factor in the stratified analyses of the overall 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
132/P BO21223A7
population.  Formal statistical comparison will not be performed for DFS and duration of 
response.  
Response rates in the treatment groups will be compared using stratified 
Cochran-MantelHaenszel (CMH) tests.  Stratification factors are chemotherapy 
regimen (CHOP, CVP, or bendamustine) and FLIPI risk group (low, intermediate, or high) 
in follicular lymphoma patients or IPI risk group (low/lowintermediate risk vs. 
intermediate-high/high risk) in nonfollicular lymphoma patients.  Indolent histology 
(follicular or nonfollicular) will be included as a stratification factor in the stratified 
analyses of the overall population.  In addition, rates and 95% confidence limits will be 
reported for each treatment group.  The effect of prognostic factors will be assessed in 
an exploratory analysis with use of logistic regression.  Patients with no response 
assessments (for whatever reason) will be considered nonresponders.  
Analysis of medical resource utilization data will be provided if required.  
4.10.4
Safety Analysis
The safety analysis population will include all patients who receive any amount of study 
drug (obinutuzumab, rituximab, or chemotherapy [CHOP, CVP, or bendamustine]), and 
patients will be analyzed according to the treatment received.  Key treatment exposure 
and adverse event tables will also be generated for follicular patients.  
Treatment exposure will be summarized, including the number of cycles received by 
each patient, and the cumulative dose will be summarized by treatment arm.  
Verbatim descriptions of adverse events will be mapped to Medical Dictionary for 
Regulatory Activities thesaurus terms and graded according to NCI CTCAE, Version 4.0.  
All adverse events occurring during or after the first treatment will be summarized by 
treatment arm and NCI CTCAE grade.  In addition, all serious adverse events will be 
summarized.  
Deaths reported during the study treatment period and those reported after treatment 
completion/discontinuation will be summarized by treatment arm.  
Adverse events leading to early treatment discontinuation and early study withdrawal will 
be summarized by arm and reason.  
Laboratory data with values outside of the normal ranges will be identified.  Additionally 
select laboratory data will be summarized by treatment arm and grade with use of 
NCI CTCAE.  Of note, abnormal laboratory data that are clinically significant will be 
reported as adverse events and summarized in the adverse event tables.  
Vital signs and other physical findings will be summarized by treatment arm.  
The incidence of HAHAs will be summarized in patients receiving obinutuzumab.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
133/P BO21223A7
The incidence of hepatitis B reactivation will be summarized in each arm of the substudy.  
4.10.5
PatientReport Outcomes
Unless otherwise specified, the PRO analyses will include all randomized patients who 
have a nonmissing baseline and at least one postbaseline PRO assessment.  Patients 
in this subset will be analyzed according to their randomized treatment assignment, 
regardless of treatment received.  The analyses will be performed separately in the 
overall population and in the follicular population.  
The percentage of participants randomized to each treatment group who complete the 
FACTLym questionnaire at each specified assessment point after baseline (i.e., PRO 
completion rates) will be calculated and compared.  If significant differences in PRO 
completion rates are observed, additional analyses may be performed to examine the 
potential for reporting biases.  
For each PRO endpoint, descriptive statistics for recorded values at each visit and 
changes from baseline will be presented using the PRO analysis set.  
The proportion of patients who meet the following criteria (minimum important difference) 
for response (Carter et al. 2008) will be summarized by visit with use of available data:  

6 point improvement in the FACTLym TOI

3 point improvement in the FACTLym subscale score

7 point improvement in the FACTLym total score
Analysis of certain time points will be selected as secondary in nature.  
The EQ5D is a questionnaire with five questions, each with three categories 
(no problem, moderate problem, severe problems) and a visual analogue scale 
from 0 (worst possible health state) to 100 (best possible health state).  The number 
and percentage of patients in each of the three categories for each question will be 
tabulated.  
4.10.6
Pharmacokinetic and Pharmacodynamic Analyses
a.
Pharmacokinetic Analysis
Individual and mean serum obinutuzumab concentration versus time data will be 
tabulated and plotted.  The serum pharmacokinetics of obinutuzumab will be analyzed 
as detailed below.  
Nonlinear mixed effects modeling (with software NONMEM; Beal et al. 2009) will be 
used to analyze the obinutuzumab pharmacokinetic data in a subset of patients 
receiving obinutuzumab.  The available pharmacokinetic profile data in patients with 
indolent NHL will be combined and used to develop a pharmacokinetic model including 
the effect of major covariates (e.g., sex, race/ethnicity, weight, biochemical and 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
134/P BO21223A7
hematologic parameters at baseline, degree of underlying disease) on the main 
pharmacokinetic parameters (e.g., total clearance of drug).  
Exploratory graphical analyses will be performed to assess whether the occurrence of 
serious adverse events and abnormalities in the safety laboratory parameters in patients 
treated with obinutuzumab could be attributed to exposure.  Exploratory graphical 
analysis will as well be performed to assess whether the variability in response could be 
attributed to the variability in obinutuzumab exposure.  Relevant observed relationships 
between exposure and safety or efficacy parameters may be further characterized using 
different approaches such as logistic regression analysis and indirect response modeling.  
b.
Pharmacodynamic Analysis
For each visit at which CD19+ Bcell measurements are taken, the following B-cell data 
will be listed for individual patients by treatment arm:  

Absolute counts

Percentage relative to baseline count for the individual

Extent of CD19+ Bcell depletion (nadir)

Duration of depletion

Time to recovery
CD19+ Bcell measurements will be summarized for each visit by the two treatment 
arms.  The parameters summarized will be CD19+ Bcell counts and percentage relative 
to baseline count, nadir, time to nadir, duration of depletion, and time to recovery.  
Exploratory analyses will be performed to assess the possible relationship between the 
pharmacokinetics of obinutuzumab and Bcell depletion.  
Further details of the analysis will be given in the Statistical Analysis Plan.  
4.10.7
Exploratory Analyses 
Histological transformation rate at first progression is defined as the appearance of 
diffuse areas of large lymphoma cells within a nodal or extranodal site.  For this purpose, 
a biopsy or a cytological examination should be obtained at progression, if possible.  
This material should be available for central pathological review.  This analysis will be 
restricted to patients with a biopsy at first progression.  The transformation rate at first 
progression in the treatment groups will be compared using stratified CMH tests.  Rates 
and 95% confidence limits will be estimated for each treatment group.  
Conversion rate is defined as the proportion of patients with a PR or SD at the end of 
induction therapy who convert to a CR or to a PR/CR, respectively, at any time during 
maintenance therapy or postinduction observation.  The conversion rate in 


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the treatment groups will be compared using stratified CMH tests.  Rates and 
95% confidence limits will be estimated for each treatment group.  
Selected exploratory analysis for the MZL cohort will be performed.  
The potential association between FcR genotype, response category, MRD qualitative 
status (negative or positive), and PFS will be assessed using Kaplan-Meier curves and 
stratified logrank tests.  Response rates by FcR genotype and MRD negativity status 
will be compared using 2 tests and logistic regression.  In addition, FcR genotype and 
MRD negative status will be included in multivariate analyses of PFS and response rates 
as described in Sections 4.10.3.a and 4.10.3.b.  Additional details of the exploratory 
analyses will be provided in the Statistical Analysis Plan.  
Biomarker data such as gene expression analysis will not be fully available at the time 
of the final analyses, and the analyses may not be included in the clinical study report.  
4.10.8
Handling of Missing Data
For PFS, patients who do not have documented disease progression or death will be 
treated as censored observations on the date of the last tumor assessment.  
For overall survival, patients who do not have documented deaths will be censored on 
the last date they were known to be alive.  
For response endpoints, patients with no response assessments (for whatever reason) 
will be considered non-responders.  
4.10.9
Determination of Sample Size
Estimates of the number of events required to demonstrate efficacy with regard to PFS 
are based on the following assumptions:  

Twosided logrank test at the 0.05 level of significance

Powered for follicular lymphoma patient subset

Eighty percent power to detect a hazard ratio for GChemo versus RChemo of 
0.74, corresponding to an improvement in 3year PFS from 70.7% to 77.4% or in 
median PFS from 6 years to 8.1 years (35%)
Note that estimates of median PFS are not likely to be reached in either 
study arm.  

Exponential distribution of PFS

An annual dropout rate of 2.5%


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
Performance of interim analyses on PFS:  one for futility when approximately 
30% of the total (investigatorassessed) PFS events have occurred and one for 
efficacy when approximately 67% of the total PFS events have occurred.  Efficacy 
and (nonbinding) futility boundaries will be computed using the LanDeMets 
approximation to the O’Brien-Fleming boundary shape.  
The futility boundary will be nonbinding.  
In addition, a futility analysis based on CR rates at the end of induction determined by 
CT (or MRI, but not PET) will be performed on the first 170 follicular lymphoma patients 
randomized.  With these assumptions, 370 PFS events are required to achieve 80% 
power for the primary analysis.  Recruitment will be staggered in order to recruit the 
first 170 patients in a smaller number of sites (approximately 125 sites), followed by the 
activation of all (approximately 200250) sites after the IDMC meeting for futility based 
on CR rates.  It is expected that during the first stage, after a 6month ramp up, 
18 patients per month will be recruited, and after the IDMC meeting and another 
4-month ramp up, an accrual rate of 37 patients per month is expected.  The 1200 
follicular patients enrolled over 49 months and followed for an additional 29 months will 
be required to provide 370 PFS events, with a total duration for PFS followup of 
approximately 78 months (6.5 years).  
Approximately 200 additional patients with nonfollicular lymphoma will be enrolled.  
This number   was based on a study of enrollment feasibility, which indicated that 
200 patients would likely be enrolled in 49 months, in addition to the planned follicular 
enrollment.  Although the study would not be powered to detect statistically significant 
differences in this 200patient cohort, there would be a reasonable chance of detecting 
a trend.  
The pharmacokinetic assessments will apply to a subpopulation of approximately 
460 patients receiving obinutuzumab.  This is the minimum number of patients needed 
to accurately construct a population pharmacokinetic model and will allow for the 
evaluation of the relationship between exposure and pharmacodynamic markers of 
response.  Approximately 120 follicular patients will undergo pharmacokinetic sampling 
from each of the three chemotherapy groups (GCHOP, GCVP, and G-bendamustine), 
and 100 additional patients with nonfollicular lymphoma will also undergo sampling.  
This sample size is believed to be sufficient to characterize with confidence the 
pharmacokinetics of obinutuzumab in the target population as well as the relationships 
between exposure to obinutuzumab and response.  The pharmacokinetic sampling 
schedule in this study was determined using an optimal sampling strategy with the 
software PFIM (Bazzoli et al. 2010) and should result in a precision of parameter 
estimates lower than 20% for the main pharmacokinetic parameters.  
In addition to the determination of T, B, and NK cells that are determined in all patients, 
absolute and relative B cell subsets determined by multicolor flow cytometry (FACS) 
based on a combination of several CD antigens and immunoglobulins over time will also 


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be analyzed in approximately 60 patients of each therapeutic group (RCHOP, 
GCHOP, R-CVP, GCVP, Rbendamustine, Gbendamustine) as well as in all patients 
with splenic MZL.  Because of the exploratory nature of this assessment and its 
complementary information to the determination of T, B, and NK cells, this sample size is 
arbitrary, but it is estimated to provide sufficient data for generation of a first hypothesis.  
BCL2/IgH (MRD) analysis is exploratory in nature and currently it is not known what 
difference in MRD negativity between Rand Gchemotherapy is to be expected.  
In order to generate a first comprehensive data set and since the difference between 
R- and Gchemotherapy may be small, MRD assessment will be done in all patients 
with follicular lymphoma.  
4.10.10
Interim and Final Analyses
Although the study is open label, Sponsor personnel will not have access to by-arm 
efficacy and safety summaries prior to the formal reporting of study results.  In order to 
monitor safety, Sponsor drug safety and medical monitoring staff will have access to the 
treatment assignments of particular patients.  
An IDMC will evaluate interim analysis results and determine whether the trial will be 
stopped early.  All summaries and analyses by treatment arm for the IDMC review will 
be prepared by an IDCC.  Members of the IDMC will be external to the Sponsor and the 
study team and will follow a charter that outlines their roles and responsibilities.  
The interim safety monitoring plan is described in Section 3.4.  Three interim analyses 
are planned:  two for futility and one for efficacy.  The first interim analysis will be based 
on differences in end of induction CR rates in the first 170 enrolled follicular lymphoma 
patients.  The analysis will be conducted once the 170 follicular lymphoma patients have 
reached their endofinduction response assessment or have withdrawn prematurely.  
The IDMC may recommend to stop the study for futility if the observed difference in CR 
rate based on CT (or MRI, but not PET) is 3% in favor of G-Chemo (i.e., CR rate needs 
to be 3% higher on GChemo vs. R-Chemo).  
The second interim analysis (futility on PFS) will be conducted when 30% of the required 
PFS events (i.e., approximately 111 events) will have occurred.  The IDMC may 
recommend to stop the study for futility if the observed hazard ratio of obinutuzumab 
over rituximab is 1 (futility boundary based on nonbinding O´BrienFleming 
betaspending function).  
At the time of the third interim analysis (efficacy on PFS) that will be conducted when 
67% of the events have occurred (i.e., approximately 248 events), all patients will have 
been enrolled and followed for an estimated minimum of 11 months.  PFS will be 
tested at the significance level determined using the O´BrienFleming alphaspending 
function so the overall Type I error rate will be maintained at the 0.05 level.  
With 67% information, the alpha spending is 0.012.  


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The IDMC will also review safety summaries at each of the interim analyses, in addition 
to the ongoing periodic safety monitoring.  
In the event that the follicular lymphoma population accrues but the nonfollicular 
lymphoma population fails to accrue the planned number of patients, the analyses will be 
triggered by the PFS events in the follicular subset regardless of when the nonfollicular 
lymphoma population has completed enrollment.  
Further details of the interim analyses will be described in the IDMC charter and 
Statistical Analysis Plan.  
4.11
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this trial, including quality 
checking of the data.  The data will be collected via EDC through use of eCRFs.  The 
site 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.  Data from 
the central laboratory or IRC will be sent directly to the Sponsor, with use of the 
Sponsor’s standard procedures to handle and process the electronic transfer of these 
data.  eCRFs and correction documentation will be maintained in the EDC system’s 
audit trail.  System backups for data stored with the Sponsor and records retention for 
the study data will be consistent with the Sponsor’s standard procedures.  
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording protocoldefined adverse 
events (AEs) and serious adverse events (SAEs); measurement of protocol-specified 
hematology and clinical chemistry variables; measurement of protocolspecified vital 
signs; and other protocolspecified tests that are deemed critical to the safety evaluation 
of the study drug(s).  
The Sponsor or its designee is responsible for reporting relevant SAEs to the Competent 
Authority, other applicable regulatory authorities, and participating investigators, in 
accordance with ICH guidelines, FDA regulations, European Clinical Trials Directive 
(Directive 2001/20/EC), and/or local regulatory requirements.  
The Sponsor or its designee is responsible for reporting unexpected fatal or 
life-threatening events associated with the use of the study drug to the regulatory 
agencies and competent authorities by telephone or fax within 7 calendar days after 
being notified of the event.  The Sponsor or its designee will report other relevant SAEs 
associated with the use of the study medication to the appropriate competent authorities 
(according to local guidelines), investigators, and central Institutional Review Boards 


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(IRBs) or Ethics Committees (ECs) (except in countries where investigators are 
responsible for reporting to their IRBs per local requirements) by a written safety report 
within 15 calendar days of notification.  
PRO data will be elicited from the patients in this study to more fully characterize the 
clinical profile of obinutuzumab.  The methods for collecting and analyzing PRO data are 
different from those for the ascertainment of observed or volunteered adverse 
events.   Because of these differences, PRO data will not be reported as adverse 
events and no attempt will be made to resolve any noticeable discrepancies between 
PRO data and observed or volunteered adverse events.  The PRO data will be 
presented in separate tables, figures, and data listings from the adverse event data and 
will be included in the appropriate section of the final study report, as indicated in the 
statistical analysis plan.  
5.1.1
Adverse Event
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an IMP or other protocol-imposed intervention, regardless of 
attribution.  
This includes the following:  

AEs not previously observed in the patient that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with NHL progression 
that were not present prior to the AE reporting period (see Section 5.2.1)

Complications that occur as a result of protocolmandated interventions 
(e.g., invasive procedures such as biopsies)

AEs that occur prior to assignment of study treatment that are related to a 
protocol-mandated intervention (e.g., invasive procedures such as biopsies, 
medication washout, or no treatment runin).  

Preexisting medical conditions (other than NHL), judged by the investigator to have 
worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period
5.1.2
Serious Adverse Event
An SAE is any AE that is any of the following:  

Fatal (i.e., the AE actually causes or leads to death)

Life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death)

Requires or prolongs inpatient hospitalization

Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions)


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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
A congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to the investigational product(s)

Considered a significant medical event by the investigator (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
All AEs that do not meet any of the criteria for serious should be regarded as 
non-serious AEs.  
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity 
of an AE (as in mild, moderate, or severe pain); the event itself may be of relatively 
minor medical significance (such as severe headache).  “Serious” is a regulatory 
definition and is based on patient or event outcome or action criteria usually associated 
with events that pose a threat to a patient’s life or vital functions.  Seriousness 
(not severity) serves as the guide for defining regulatory reporting obligations.  
Severity and seriousness should be independently assessed when recording AEs 
and SAEs on the eCRF.  
5.1.3
ProtocolDefined Events of Special Interest/Non-Serious 
Expedited Adverse Events
The following adverse events of special interest will need to be reported to the Sponsor 
expeditiously (see Section 5.4 for reporting instructions):  

Tumor lysis syndrome (irrespective of regulatory seriousness criteria)

Serious IRR

Serious neutropenia

Serious infections

Second malignancies
Hepatitis B reactivation will be followed as an AE of particular interest.  
5.2
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all AEs and SAEs (as defined in 
Section 5.1) are recorded on the eCRF and reported to the Sponsor in accordance 
with protocol instructions.  
5.2.1
Adverse Event Reporting Period
After informed consent but prior to initiation of study medications, only SAEs caused 
by a protocolmandated intervention will be recorded (e.g., SAEs related to invasive 
procedures such as biopsies, medication washout, or no treatment runin).  


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After the initiation of study medications (Sponsor product or other IMP/NonIMP), AEs 
and SAEs should be recorded as follows (unless patient begins NALT):  

All AEs (related and unrelated) will be recorded up to 28 days after the last dose 
of study drug.  

Grade 3 AEs (related and unrelated) will be recorded up to 6 months after the 
last dose of study drug.  

Grade 3 or 4 infections (related and unrelated) will be recorded up to 24 months 
after the last dose of study drug.  

Unrelated SAEs will be recorded up to 12 months after the last dose of study drug.  
After the initiation of study medications (Sponsor product or other IMP/NonIMP), AEs 
and SAEs should be recorded indefinitely: 

Study drug-related SAEs (even if the study has been closed).  

Second malignancies (even if study has been closed)
5.2.2
Eliciting Adverse Events
A consistent methodology of nondirective questioning for eliciting AEs at all patient
evaluation time points should be adopted.  Examples of nondirective questions include:  
“How have you felt since your last clinic visit?”  
“Have you had any new or changed health problems since you were last 
here?”  
5.2.3
Assessment of Severity and Causality of Adverse Events
Investigators will seek information on AEs and SAEs at each patient contact.  All AEs 
and SAEs, whether reported by the patient or noted by authorized study personnel, will 
be recorded in the patient’s medical record and on the Adverse Event eCRF.  
For each AE and SAE recorded on the applicable eCRF, the investigator will make an 
assessment of seriousness (see Section 5.1.2 for seriousness criteria), severity, and 
causality.  
Table 15 provides guidance for grading AE severity and Table 16 provides guidance 
for assessing the causal relationship to the investigational products.  
The AE grading (severity) scale found in the NCI CTCAE (Version 4.0) will be used for 
AE reporting. 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
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Table 15 Adverse Event Grading (Severity) Scale
Grade
Severity
Alternate Description a
1
Mild (apply eventspecific 
NCI CTCAE grading criteria)
Asymptomatic or mild 
symptoms; clinical or diagnostic 
observations only; intervention 
not indicated
2
Moderate (apply event-specific 
NCI CTCAE grading criteria)
Minimal, local, or noninvasive 
intervention indicated; limiting 
age-appropriate IADLs b
3
Severe (apply eventspecific 
NCI CTCAE grading criteria)
Severe or medically significant 
but not immediately life 
threatening; hospitalization or 
prolongation of hospitalization 
indicated; disabling; limiting 
self-care ADLs c
4
Life threatening
Lifethreatening consequences; 
urgent intervention indicated
5
Death related to AE
ADLsactivities of daily living; AEadverse event; CTCAECommon 
Terminology Criteria for Adverse Events; IADLsinstrumental activities of 
daily living; NCINational Cancer Institute.  
The NCI CTCAE (Version 4.0) is available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
Note:  Regardless of severity, some events may also meet regulatory serious 
criteria.  Refer to definitions of an SAE (see Section 5.1.2).  
a Use these alternative definitions for Grade 1, 2, 3, and 4 events when the 
observed or reported AE is not in the NCI CTCAE listing.  
b ADLs refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.  
c Selfcare ADLs refer to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden.  
To ensure consistency of causality assessments, investigators should apply the 
following general guidelines:  
Table 16 Causal Attribution Guidance
Is the AE/SAE suspected to be caused by the investigational product on the 
basis of facts, evidence, sciencebased rationales, and clinical judgment?
YES
The temporal relationship of the AE/SAE to investigational product 
administration makes a causal relationship possible, AND other 
drugs, therapeutic interventions, or underlying conditions do not 
provide sufficient explanation for the AE/SAE.  
NO
The temporal relationship of the AE/SAE to investigational product 
administration makes a causal relationship unlikely, OR other drugs, 
therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the AE/SAE.   


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Note:  The investigator’s assessment of causality for individual AE reports is part of the 
study documentation process.  Regardless of the “Yes” or “No” causality assessment for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities.  
5.3
PROCEDURES FOR RECORDING ADVERSE EVENTS
a.
Diagnosis/Causative Event versus Signs and Symptoms
All AEs and SAEs should be reported.  
If known, a diagnosis should be recorded on the eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, 
and elevated transaminases).  However, if a constellation of signs and/or symptoms 
cannot be medically characterized as a single syndrome at the time of reporting, each 
individual sign and/or symptom should be recorded as an AE or SAE on the eCRF.  
If a constellation of signs and/or symptoms can be medically characterized as a single 
syndrome (e.g., nausea and vomiting), the most medically significant sign and/or 
symptom should be reported as the adverse event and the additional signs and/or 
symptoms captured in the additional case details section of the eCRF.  If a diagnosis is 
subsequently established, the reported event term should be updated to reflect the 
medical diagnosis.  
In general, AEs occurring secondary to other events (e.g., cascade of events or clinical 
sequelae) should be identified by their primary cause (causative event) and the 
additional sequelae captured in the additional case details section of the eCRF.  
However, AEs occurring secondary to an initiating event that are separated in time 
or medically significant should be recorded as independent events on the eCRF.  
For example, if a severe gastrointestinal hemorrhage leads to a renal failure, both events 
should be recorded separately on the eCRF.  
Reporting of InfusionRelated Reactions:  
Within this protocol, the Sponsor is using the following definition to identify adverse 
events which qualify as potential IRR:  
A potential IRRall adverse events occurring during or within 24 hours from the end 
of antibody infusion that are judged as related to the antibody by the investigator.  
The only exception to the rule that the diagnosis is the preferred term for AE reporting is 
the reporting of IRRs.  For reporting purposes only (but not for clinical decision making), 
the adverse event containing the diagnosis IRR and all signs and symptoms that fall 
under the sponsor definition of a potential IRR (e.g., fever, hypotension)  have to be 
reported  as separate adverse events.  


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Each single infusion of antibody could lead to an IRR, therefore a separate IRR and 
signs and symptoms should be reported for each administration.
b.
Persistent or Recurrent Adverse Events
A persistent AE is one that extends continuously, without resolution between patient 
evaluation time points.  Such events should be recorded only once in the eCRF, and 
their initial grade and their most severe grade should be given on the Adverse Event 
eCRF.  
A recurrent AE is one that occurs and resolves between patient evaluation time points 
and subsequently recurs.  All recurrent AEs should be recorded as separate AEs on 
Adverse Event eCRF.  
c.
Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management 
will be recorded as AEs or SAEs on the eCRF.  Criteria for clinical significance are 
the following:  

Laboratory abnormality is accompanied by clinical symptoms.  

Laboratory abnormality requires study drug dose modification or interruption 
or permanent discontinuation of study treatment.  

Laboratory abnormality requires more frequent followup assessments, further 
diagnostic investigation, etc.  

Laboratory abnormality requires a change in concomitant medication, therapy, 
or treatment.  
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5the upper limit of normal associated 
with cholecystitis), only the diagnosis (e.g., cholecystitis) needs to be recorded on 
the Adverse Event eCRF.  
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded as an AE or SAE on the eCRF.  If the 
laboratory abnormality can be characterized by a precise clinical term, the clinical term 
should be recorded as the AE or SAE.  For example, an elevated serum potassium level 
of 7.0 mEq/L should be recorded as “hyperkalemia.”  
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded as AEs or SAEs on the eCRF, unless their severity, 
seriousness, or etiology changes.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
145/P BO21223A7
d.
Deaths
For this protocol, PFS is the primary efficacy endpoint.  Deaths that occur during the 
protocolspecified AE reporting period (see Section 5.2.1) that are attributed by the 
investigator solely to progression of NHL will be recorded only on the Study 
Discontinuation eCRF.  All other on-study deaths, regardless of attribution, will be 
recorded on an eCRF and expeditiously reported to the Sponsor.  An IDMC will monitor 
the frequency of death from all causes.  
When recording a death on an eCRF, the event or condition that caused or contributed 
to the fatal outcome should be recorded as the single medical concept on the eCRF.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
record “Unexplained Death” on the eCRF.  
During poststudy survival followup, deaths attributed to progression of NHL will be 
recorded only on the Survival eCRF (i.e., not on the Adverse Event eCRF).  
e.
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the start of the study.  
Such conditions should be recorded on the Medical and Surgical History eCRF.  
A preexisting medical condition should be recorded as an AE or SAE only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on an 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”).  
f.
Progression of NonHodgkin's Lymphoma
Progression of NHL should not be recorded as an AE or SAE if it is clearly consistent 
with the suspected progression of the underlying cancer as defined by the criteria as 
determined by protocol.  These data will be captured as efficacy assessment data only.  
Hospitalization due solely to the progression of underlying NHL should NOT be reported 
as an SAE.  Clinical symptoms of progression may be reported as AEs if the symptom 
cannot be determined as exclusively because of the progression of the underlying 
malignancy or does not fit the expected pattern of progression for the disease under 
study.  
Symptomatic deterioration may occur in some patients.  In this situation, progression 
is evident in the patient’s clinical symptoms but is not supported by the tumor 
measurements.  Or, the disease progression is so evident that the investigator may elect 
not to perform further disease assessments.  In such cases, the determination of clinical 
progression is based on symptomatic deterioration.  These determinations should be a 


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rare exception because every effort should be made to document the objective 
progression of underlying malignancy.  
If there is any uncertainty about an AE being due only to the disease under study, 
it should be reported as an AE or SAE.  
g.
Hospitalization, Prolonged Hospitalization, or Surgery
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol.  All 
hospitalizations (any overnight stay in an acute care hospital) should also be 
documented in the Medical Resource Use Form along with the admission and discharge 
dates.  
There are some hospitalization scenarios that do not require reporting as an SAE when 
there is no occurrence of an AE.  These scenarios include a planned hospitalization or 
prolonged hospitalization to:  

Perform an efficacy measurement for the study

Undergo a diagnostic or elective surgical procedure for a preexisting medical 
condition that has not changed

Receive scheduled therapy for the target disease of the study
h.
Pregnancy
If a female patient becomes pregnant while receiving investigational therapy or within 
1 year after the last dose of investigational product or if the partner of a male patient 
becomes pregnant while receiving investigational therapy or within 3 months after the 
last dose of investigational product and paternity can be assured, a Pregnancy Report 
eCRF should be completed within 24 hours of learning of the pregnancy.  The EDC 
system will generate an automatic PDF report that is delivered to the Sponsor.  If the 
EDC is not accessible, the paper forms will have to be filled out, printed and faxed to the 
Sponsor, with use of the fax numbers listed in Section 5.4.2.  When the EDC is available 
again, the investigator will have to enter the data again in the eCRF.  
Abortion, whether therapeutic or spontaneous, should always be classified as serious 
(because the Sponsor considers these medically significant), recorded on an eCRF, 
and expeditiously reported to the Sponsor.  
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to the investigational product should be recorded and reported 
as an SAE.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
147/P BO21223A7
5.4
EXPEDITED REPORTING REQUIREMENTS FOR SERIOUS 
ADVERSE EVENTS AND PROTOCOLDEFINED EVENTS 
OF SPECIAL INTEREST
5.4.1
Reporting Requirements for Fatal/LifeThreatening SAEs 
Related to Investigational Product
Any lifethreatening (i.e., imminent risk of death) or fatal AE that is attributed by the 
investigator to the investigational product will be telephoned to the Medical Monitor 
immediately, followed by submission of written case details on an eCRF within 24 hours 
as described herein.  
Medical Monitor contact information will be distributed to sites.  
An emergency medical call center help desk will access the Medical Emergency List, 
escalate emergency medical calls, provide medical translation service (if necessary), 
connect the investigator with the Roche/Genentech medical contact for this study, and 
track all calls.  The emergency medical call center help desk will be manned 24 hours a 
day, 7 days a week.  Tollfree numbers will be distributed to all investigators running 
Roche Product Development clinical trials.  The help desk will be used for medical 
emergencies that occur outside regular business hours or when the Medical Monitor 
cannot be reached.  
5.4.2
Reporting Requirements for All SAEs and ProtocolDefined 
Events of Special Interest
Investigators will submit reports of all SAEs, regardless of attribution, and all 
protocol-defined events of special interest and pregnancies to the Sponsor within 
24 hours after learning of the events.  For initial SAE and protocoldefined events of 
special interest reports, investigators should record all case details that can be gathered 
within 24 hours on an eCRF and submit the report via the EDC system.  A report will be 
generated and sent to the Sponsor's Drug Safety Department by the EDC system.  In 
the event the EDC system is unavailable, a completed SAE or Serious/NonSerious 
Expedited Adverse Event paper reporting form and fax coversheet should be faxed 
immediately upon completion to the Sponsor’s Drug Safety Department or its designee 
at the fax numbers indicated below.  Once the EDC system is available, all information 
will need to be entered and submitted via the EDC system.  
Sites in the United States:  
Fax No.:
(650) 225-4682
Alternate Fax No.:
(650) 225-5288
For exU.S. sites:  Countryspecific contact information will be supplied to sites.  
Relevant followup information should be submitted to the Sponsor’s Drug Safety 
Department or its designee as soon as it becomes available and/or upon request.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
148/P BO21223A7
Related SAEs must be collected and reported regardless of the time that has elapsed 
from the last study drug administration, even if the study has been closed.  Suspected 
unexpected serious adverse reactions (SUSARs) are reported to investigators at each 
site and associated IRB/EC when the following conditions occur:  

The event must be an SAE.  

There must be a certain degree of probability that the event is an adverse reaction 
from the administered drug.  

The adverse reaction must be unexpected, that is to say not foreseen in the 
Summary of Product Characteristics (for an authorized medicinal product) or the 
Investigator’s Brochure (for an unauthorized medicinal product).  
When all patients at a particular site are off treatment as defined by the protocol:  

Only individual SUSAR (suspected unexpected serious adverse reaction) reports 
originating in that particular trial will be forwarded to the site and associated IRB/EC 
on an expedited basis.  

Individual SUSARs considered to be a significant safety issue and/or which result 
in the Sponsor recommending a change to the Informed Consent Form will be 
reported in an expedited manner to all investigators and IRBs/ECs.  

SUSAR reports originating from other trials using the same IMP will be provided 
every 6 months to investigators and IRBs/ECs conducting long-term followup 
studies (with the exception of significant SUSARs, which will be reported in an 
expedited manner).  
5.5
TYPE AND DURATION OF FOLLOWUP OF PATIENTS 
AFTER ADVERSE EVENTS
The investigator should follow all unresolved AEs and SAEs until the events are resolved 
or stabilized, the patient is lost to follow up, or it has been determined that the study 
treatment or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs 
(with dates) should be documented on the Adverse Event eCRF and in the patient’s 
medical record to facilitate source data verification (SDV).  
For some SAEs, the Sponsor or its designee may follow up by telephone, fax, electronic 
mail, and/or a monitoring visit to obtain additional case details deemed necessary to 
appropriately evaluate the SAE report (e.g., hospital discharge summary, consultant 
report, or autopsy report).  
5.6
POSTSTUDY ADVERSE EVENTS
At the last scheduled visit, the investigator should instruct each patient to report to the 
investigator any subsequent SAEs that the patient’s personal physician believes could 
be related to prior study treatment.  
The investigator should notify the study Sponsor of any death or other SAE occurring at 
any time after a patient has discontinued or terminated study participation if believed to 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
149/P BO21223A7
be related to prior study treatment.  The Sponsor should also be notified if the 
investigator should become aware of the development of cancer or of a congenital 
anomaly in a subsequently conceived offspring of a patient that participated in this study.  
The investigator should report these events to the Sponsor's Drug Safety Department on 
the study eCRF.  If the study eCRF is no longer available, the investigator should report 
the event directly to the Sponsor's Drug Safety Department via phone at (888) 8352555.  
5.7
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 through use of the reference safety information 
in the documents listed below:  
Drug
Document
Obinutuzumab
Obinutuzumab Oncology Investigator's Brochure
Rituximab
Mabthera Summary of Product Characteristics
Bendamustine
Levact Summary of Product Characteristics
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 applicable 
reference document.  
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.
INVESTIGATOR REQUIREMENTS
6.1
STUDY INITIATION
Before the start of this study and any studyrelated procedures at a specific site, the 
following documents must be on file with the Sponsor:  

Statement of investigator signed by the Principal Investigator
The names of any subinvestigators must appear on this form.  Investigators 
must also complete all regulatory documentation as required by local and 
national regulations.  

Current curricula vitae and evidence of licensure of the Principal Investigator 
and all subinvestigators

Complete financial disclosure forms for the Principal Investigator and 
all subinvestigators


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
150/P BO21223A7

Assurance number or IRB statement of compliance

Written documentation of IRB/EC approval of the protocol (identified by protocol 
number or title and date of approval) and Informed Consent Form (identified by 
protocol number or title and date of approval)

A copy of the IRB/EC-approved Informed Consent Form
The Sponsor or its designee must review any proposed deviations from 
the sample Informed Consent Form.  

Current laboratory certification of the laboratory performing the analysis 
(if other than a Sponsor-approved central laboratory), as well as current reference 
ranges for all laboratory tests

A Clinical Research Agreement signed and dated by the study site

Investigator's Brochure Receipt signed and dated by the Principal Investigator

Certified translations of an approved Informed Consent Form, and any other written 
information to be given to the patient (when applicable), IRB/EC approval letters, 
and pertinent correspondence

PD01 Form signed and dated by the Principal Investigator

Canada only when applicable:  original Qualified Investigator Undertaking Form, 
signed by each Canadian investigator involved in the study

For global studies, a list of required documents will be provided to you by your local 
site monitor.  
6.2
STUDY COMPLETION
The following data and materials are required by the Sponsor before a study can be 
considered complete or terminated:  

Laboratory findings, clinical data, and all special test results from screening through 
the end of the study follow-up period

All laboratory certifications for laboratories performing the analysis (if other than 
Sponsorapproved central laboratory), as well as current normal laboratory ranges 
for all laboratory tests

eCRFs (including queries) properly completed by appropriate study personnel and 
electronically signed and dated by the investigator

Completed Drug Accountability Records (Retrieval Record, Drug Inventory Log, and 
Inventory of Returned Clinical Material forms)

Copies of protocol amendments and IRB/EC approval/notification, if appropriate

A summary of the study prepared by the Principal Investigator (IRB summary close 
letter is acceptable)

All essential documents (e.g., curriculum vitae for each Principal Investigator 
and subinvestigator, statement of compliance with local laws and regulations)

A signed and dated Protocol Amendment Acceptance Form(s) (PD01) [if applicable]


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
151/P BO21223A7

Updated financial disclosure forms for the Principal Investigator and all 
subinvestigators (applicable for 1 year after the last patient has completed the study)
6.3
INFORMED CONSENT FORMS
The Sponsor’s Sample Informed Consent Form will be provided to each site.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sample Informed Consent Form or any alternate consent forms proposed by the site 
(collectively, the “Consent Forms”) before IRB/EC submission.  Patients must be 
re-consented to the most current version of the Consent Forms during their participation 
in the study.  The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for regulatory purposes.  
The Consent Forms must be signed by the patient or the patient’s legally authorized 
representative before his or her participation in the study.  The case history for each 
patient shall document the informed consent process and that written informed consent 
was obtained prior to participation in the study.  A copy of each signed Consent Form 
must be provided to the patient or the patient’s legally authorized representative.  If 
applicable, it will be provided in a certified translation of the local language.  
All signed and dated Consent Forms must remain in each patient’s study file and must 
be available for verification by study monitors at any time.  
The Informed Consent Form should be revised whenever there are changes to 
procedures outlined in the informed consent or when new information becomes available 
that may affect the willingness of the patient to participate.  
For any updated or revised Consent Forms, the case history for each patient shall 
document the informed consent process and that written informed consent was obtained 
for the updated/revised Consent Form for continued participation in the study.  The final 
revised IRB/ECapproved Informed Consent Form must be provided to the Sponsor for 
regulatory purposes.  
If the site utilizes a separate Authorization Form for patient authorization to use and 
disclose personal health information under the U.S. Health Insurance Portability and 
Accountability Act regulations, the review, approval, and other processes outlined above 
apply except that IRB/EC review and approval may not be required per study site 
policies.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
152/P BO21223A7
6.3.1
Pregnant Partner Consent
Partner consent will be requested if applicable.  
6.3.2
Roche Clinical Repository Informed Consent
It is the responsibility of the investigator or a person designated by the investigator (if 
acceptable under local regulations) to obtain written informed consent from each 
individual who has consented to have his or her samples stored for future research 
in the RCR after adequate explanation of the aims, methods, objectives, and potential 
hazards.  Patients must receive an explanation that they are completely free to refuse 
collection of their samples for future research and may withdraw their samples at any 
time and for any reason during the 15year storage period of the specimens.  The 
informed consent for an optional specimen donation will be incorporated as a specific 
section into the main Informed Consent Form.  A second, separate, specific signature 
consenting to specimen donation will be required to document the study participant’s 
agreement to collection of his or her samples for future research; if the participant 
declines, he or she will check a “no” box in the appropriate section and not provide 
a second signature.  
The eCRF for the associated clinical study contains a page for documenting patient 
informed consent to the RCR, and this must be completed appropriately.  
6.4
DEATH OR LOSS OF COMPETENCE OF PARTICIPANT WHO 
HAS DONATED A SPECIMEN THAT IS STORED IN THE ROCHE 
CLINICAL REPOSITORY
In case the Informed Consent Form and/or the study protocol do not provide any specific 
provisions for death or loss of competence, specimen and data will continue to be used 
as part of RCR research.  
6.5
COMMUNICATION WITH THE INSTITUTIONAL REVIEW BOARD 
OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator (or by the Sponsor on behalf of the Principal Investigator, if specified by 
local legislation) for review and approval before the study is initiated.  In addition, any 
patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the regulatory 
requirements and policies and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol changes or 
amendments and of any unanticipated problems involving risk to human patients 
or others.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
153/P BO21223A7
In addition to the requirements to report protocoldefined AEs to the Sponsor, 
investigators are required to promptly report to their respective IRB/EC all unanticipated 
problems involving risk to human patients.  Some IRBs/ECs may want prompt 
notification of all SAEs, whereas others require notification only about events that are 
serious, assessed to be related to study treatment, and are unexpected.  Investigators 
may receive written Investigational New Drug (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 regulatory requirements and 
with the policies and procedures established by their IRB/EC and archived in the site’s 
study file.  
Sampling for the RCR is contingent on review and approval for the optional exploratory 
biomarker assessments and written informed consent by an appropriate regulatory body 
(depending on the country where the study is performed) and a site’s IRB/EC.  If a 
regulatory authority or site’s IRB/EC does not approve the sampling for the optional 
exploratory assessments, the section on optional biomarker sampling will not be 
applicable.  
6.6
STUDY MONITORING REQUIREMENTS
Site visits will be conducted by an authorized representative to inspect study data, 
patients’ medical records, and eCRFs.  The Principal Investigator will permit the 
Sponsor's monitors/representatives and collaborators, the U.S. FDA, other regulatory 
agencies, IRBs, and the respective national or local health authorities to inspect facilities 
and records relevant to this study.  
6.7
ELECTRONIC CASE REPORT FORMS
eCRFs are to be completed using the Medidata (RAVE) EDC system.  Sites will receive 
training and 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 examining personnel or the study 
coordinator as appropriate.  The eCRF should be reviewed and electronically signed and 
dated by the investigator.  
In addition, at the end of the study, the investigator will receive patient data for his or her 
site in a readable format on a compact disc that must be kept with the study records.  
6.8
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing SDV to confirm that critical protocol data 
(i.e., source data) entered into the eCRFs by authorized site personnel are accurate, 
complete, and verifiable from source documents.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
154/P BO21223A7
Source documents are where patient data are recorded and documented for the first 
time.  They include but are not limited to hospital records, clinical and office charts, 
laboratory notes, memoranda, patient diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, patientcompleted PRO 
questionnaires, 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.  
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must never be obliterated or destroyed. 
To facilitate SDV, the 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 investigational site must also allow inspection by 
applicable regulatory authorities.  
6.9
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), 
the electronic record can serve as the source document if the system has been validated 
in accordance with FDA requirements pertaining to computerized systems used in 
clinical research.  An acceptable computerized data collection system (for clinical 
research purposes) would be one that 1) allows data entry only by authorized individuals; 
2) prevents the deletion or alteration of previously entered data and provides an audit 
trail for such data changes (e.g., modification of file); 3) protects the database from 
tampering; and 4) ensures data preservation.  
In collaboration with the study monitor, the Sponsor’s Quality Assurance group may 
assist in assessing whether electronic records generated from computerized medical 
record systems used at investigational sites can serve as source documents for the 
purposes of this protocol.  
If a site’s computerized medical record system is not adequately validated for the 
purposes of clinical research (as opposed to general clinical practice), 
applicable hardcopy source documents must be maintained to ensure that critical 
protocol data entered into the eCRFs can be verified.  
6.10
STUDY MEDICATION ACCOUNTABILITY
All study drug required for completion of this study will be provided by the Sponsor.  
The recipient will acknowledge receipt of the drug by returning the appropriate 
documentation form indicating shipment content and condition.  Damaged supplies will 
be replaced.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
155/P BO21223A7
Accurate records of all study drug received at, dispensed from, returned to, and 
disposed of by the study site should be recorded by using the Drug Inventory Log.  
Study drug will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or be returned to the Sponsor with the 
appropriate documentation, as determined by the study site.  If the study site chooses 
to destroy study drug, the method of destruction must be documented.  
The Sponsor must evaluate and approve the study site’s drug destruction standard 
operating procedure prior to the initiation of drug destruction by the study site.  
6.11
DISCLOSURE OF DATA
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 regulatory agencies, national and local health 
authorities, the Sponsor's monitors/representatives and collaborators, and the IRB/EC 
for each study site, if appropriate.  
6.12
RETENTION OF RECORDS
U.S. FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP 
(see Section 4.9 of the guideline) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including eCRFs, 
consent forms, laboratory test results, and medication inventory records be retained by 
the Principal Investigator for 2 years after the last marketing application approval in an 
ICH region or after at least 2 years have elapsed since formal discontinuation of clinical 
development of the investigational product.  All state and local laws for retention of 
records also apply.  
No records should be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor for transfer of any records to another 
party or moving them to another location.  
For studies conducted outside the United States under a U.S. IND, the Principal 
Investigator must comply with the record retention requirements set forth in the 
U.S. FDA IND regulations and the relevant national and local health authorities, 
whichever is longer.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
156/P BO21223A7
6.13
FINANCIAL DISCLOSURE
The investigator will provide the Sponsor with sufficient accurate financial information 
(e.g., PD35 in the United States) to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities.  
The investigator is responsible to promptly update any information provided to the 
Sponsor if relevant changes occur in the course of the investigation and for 1 year 
following the completion of the study (last patient, last visit).  
7.
CLINICAL STUDY REPORT
A clinical study report will be written and distributed to health authorities as required by 
applicable regulatory requirements.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
157/P BO21223A7
8.
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Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
158/P BO21223A7
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Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
159/P BO21223A7
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32. Ghielmini M, Schmitz S, Cogliatti S, et al. Prolonged treatment with rituximab in 
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33. GLOBOCAN 2008 (IARC). Section of cancer information [resource on the Internet]. 
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35. Hainsworth J, Litchy S, Barton J, et al. Singleagent rituximab as firstline and 
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36. Hainsworth JD, Litchy S, Burris HA III, et al. Rituximab as firstline and maintenance 
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37. Herold M, Haas A, Srock S, et al. Rituximab added to firstline mitoxantrone, 
chlorambucil, and prednisolone chemotherapy followed by interferon maintenance 
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Study Group hematology and oncology study. J Clin Oncol 2007;25:198692.


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
160/P BO21223A7
38. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to 
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39. Hirt C, Schuler F, Kiefer T, et al. Rapid and sustained clearance of circulating 
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40. Hochster H, Weller E, Gascoyne R, et al. Maintenance rituximab after 
cyclophosphamide, vincristine, and prednisone prolongs progressionfree survival 
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45. Klepfish A, Gilles L, Ioannis K, et al. Enhancing the action of rituximab in chronic 
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48. Lyman GH, Dale D, Friedberg J, et al. Incidence and predictors of low chemotherapy 
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J Clin Oncol 2004;22:430211.


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
161/P BO21223A7
49. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with 
CVP as firstline treatment for advance follicular lymphoma. Blood 2005;105:141723.
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60. Persky D, Dornan D, Goldman B, et al. Fc gamma receptor 3a genotype predicts 
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61. Plosker GL, Figgitt DP. Rituximab: a review of its use in nonHodgkin's lymphoma 
and chronic lymphocytic leukaemia [review]. Drugs 2003;63:80343. 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
162/P BO21223A7
62. Rambaldi A, Carlotti E, Oldani E, et al. Quantitative PCR of bone marrow 
BCL2/IgH + cells at diagnosis predicts treatment response and longterm outcome 
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63. Reiser M, Wenger M, Nickenig C, et al. Serum levels and pharmacokinetics of 
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64. Robinson KS, Williams ME, van der Jagt RH, et al. Phase II multicenter study of 
bendamustine plus rituximab in patients with relapsed indolent Bcell and mantle cell 
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65. Rummel MJ, AlBatran S, Kim SZ, et al. Bendamustine plus rituximab is effective and 
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non-Hodgkin’s lymphoma. J Clin Oncol 2005;23:33839.
66. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is 
superior in respect of progression free survival and CR rate when compared to CHOP 
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mantle cell lymphomas: final results of a randomized Phase III study of the STIL 
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67. Rummel MJ, von Gruenhagen U, Niederle N, et al. Bendamustine plus rituximab 
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68. Salles G, Morschhauser F, Lamy T, et al. Phase I study of RO5072759 (GA101) in 
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Proc Am Soc Clin Oncol 2009;114:abstract 1704.
69. Salles G, Mounier N, de Guibert S, et al. Rituximab combined with chemotherapy and 
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70. Salles G, Seymour J, Offner F, et al. Rituximab maintenance for 2 years in patients 
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71. Sehn LH, Assouline SE, Stewart DA, et al. A Phase I study of GA101 (RO5072759) 
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1987;82:110918.


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
163/P BO21223A7
73. Smith MR. Rituximab (monoclonal antiCD20 antibody): mechanisms of action and 
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76. Treon S, Agus D, Link B, et al. CD20directed antibodymediated immunotherapy 
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81. Weng WK, Negrin RS, Lavori P, et al. Immunoglobulin G Fc receptor FcRIIIa 
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85. Zucca E, Conconi A, Martinelli G, et al. Chlorambucil plus rituximab produces better 
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Blood 2010;116:abstract 432.


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
164/P BO21223A7
86. Zucca E, Dreyling M; ESMO Guidelines Working Group. Gastric marginal zone 
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1995;89:839.


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
165/P BO21223A7
APPENDIX A1
Study Flowchart:  Induction Treatment with CHOP plus Rituximab/Obinutuzumab (21Day Cycles)
Screening
Treatment Period
Induction 
Completion
/ET Visit a
SD
35
SD
14
C1, D1
(SD1)
C1, D8
(SD8)
C1, D15
(SD15)
C2, D1
(SD22)
C3, D1
(SD43)
C4, D1
(SD64)
C5, D1
(SD85)
C6, D1
(SD106)
C7, D1
(SD127)
C8, D1
(SD148)
Informed consent
x
Optional RCR informed 
consent
x
Discussion of fertility issues 
and sperm banking (in patients 
of childbearing age)
x
Inclusion/exclusion criteria
x
Tumor tissue sample for 
quality assurance pathology 
review b
x
Demographics and medical 
history c
x
x
FLIPI prognostic risk:  follicular 
patients
x
FLIPI2 prognostic risk:  
follicular patients
x
IPI score:  nonfollicular 
patients
x
Complete physical 
examination d
x
Targeted physical 
examination d
x
x
x
x
x
x
x
x
x


APPENDIX A1  
Study Flowchart:  Induction Treatment with CHOP plus Rituximab/Obinutuzumab (21Day Cycles) 
(Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
166/P BO21223A7
Screening
Treatment Period
Induction 
Completion
/ET Visit a
SD
35
SD
14
C1, D1
(SD1)
C1, D8
(SD8)
C1, D15
(SD15)
C2, D1
(SD22)
C3, D1
(SD43)
C4, D1
(SD64)
C5, D1
(SD85)
C6, D1
(SD106)
C7, D1
(SD127)
C8, D1
(SD148)
Height, weight, BSA e
x
x
x
x
x
x
x
x
x
x
Vital signs f
x
x
x
x
x
x
x
x
x
x
x
x
IADLs/ADLs
x
ECOG Performance Status
x
x
x
x
x
x
x
x
x
B symptoms
x
x
x
12lead ECG
x
x
Left heart ejection fraction 
(2DECHO or MUGA scan)
x g
x
Hematology h
x
x
x
x
x
x
x
x
x
x
x
x
Serum chemistryh
x
x
x
x
x
x
x
x
x
x
Urine dipstick for protein i
x
x
Serum electrophoresis, M 
protein, and immunofixation 
(only in patients with MZL) j
x
x
x
Coagulation (PTT or aPTT, PT 
or INR)
x
Pregnancy test k
x
x
HBV, HCV, and HTLV1 
serology l
x
HBV DNA PCR m
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
CHOP chemotherapy n
x
x
x
x
x
x
Arm A:  rituximab infusion o
x
x
x
x
x
x
x
x


APPENDIX A1  
Study Flowchart:  Induction Treatment with CHOP plus Rituximab/Obinutuzumab (21Day Cycles) 
(Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
167/P BO21223A7
Screening
Treatment Period
Induction 
Completion
/ET Visit a
SD
35
SD
14
C1, D1
(SD1)
C1, D8
(SD8)
C1, D15
(SD15)
C2, D1
(SD22)
C3, D1
(SD43)
C4, D1
(SD64)
C5, D1
(SD85)
C6, D1
(SD106)
C7, D1
(SD127)
C8, D1
(SD148)
Arm B:  obinutuzumab 
infusion p
x
x q
x q
x
x
x
x
x
x
x
New antilymphoma
treatment ff
x
Imagingbased tumor 
assessment r
x
x
x
FDGPET s
x
(x)
x 
Bone marrow biopsy t
x
x
Bone marrow aspirate for 
BCL2/IgH analysis:  follicular 
patients u
x
x
FcR typing v
x
Blood for BCL2/IgH analysis:  
follicular patients w
x
x
x
HAHA samples:  
obinutuzumab arm only x,q
x
x
PK sampling:  subset in 
obinutuzumab arm q,y
x
x
x
x
x
x
x
Leukocyte 
immunophenotyping (FACS) z
x
x
x
x
Quantitative immunoglobulins 
(IgA, IgG, IgM)
x
x
Optional serum and plasma 
samples for RCR aa
(x)


APPENDIX A1  
Study Flowchart:  Induction Treatment with CHOP plus Rituximab/Obinutuzumab (21Day Cycles) 
(Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
168/P BO21223A7
Screening
Treatment Period
Induction 
Completion
/ET Visit a
SD
35
SD
14
C1, D1
(SD1)
C1, D8
(SD8)
C1, D15
(SD15)
C2, D1
(SD22)
C3, D1
(SD43)
C4, D1
(SD64)
C5, D1
(SD85)
C6, D1
(SD106)
C7, D1
(SD127)
C8, D1
(SD148)
Tumor tissue sample at time of 
relapse or transformation
(x) bb
Adverse events cc
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications dd
x
x
x
x
x
x
x
x
x
x
x
x
x
PRO questionnaires ee
x
x
x
ADLs Activities of Daily Living; AE adverse event; aPTT activated partial thromboplastin time; BSA body surface area; BUNblood urea 
nitrogen; C Cycle; CHOP cyclophosphamide, doxorubicin, vincristine, and prednisone (prednisolone or methylprednisolone [MP]); CR complete 
response; CT computed tomography; CVP cyclophosphamide, vincristine, and prednisone (prednisolone, MP);  D Day; 
2D-ECHO twodimensional echocardiogram; ECG electrocardiogram; ECOG Eastern Cooperative Oncology Group; eCRF electronic Case 
Report Form; EDTAethylenediaminetetraacetic acid; EOIend of infusion; EQ5DEuropean Quality of Life (EuroQol) Questionnaire; ET early 
termination; FACS fluorescenceactivated cell sorter; FACT-Lym Functional Assessment of Cancer Therapy for Lymphoma; 
FDG 18F-fluorodeoxyglucose; FLIPI Follicular Lymphoma International Prognostic Index; G GA101; HAHA human antihuman antibody; 
HBcAb hepatitis B core antibody; HBsAb hepatitis B surface antibody; HBsAg hepatitis B surface antigen; HBV hepatitis B virus; 
HCV hepatitis C virus; HTLV human T-lymphotropic virus; IADLs Instrumental Activities of Daily Living; INR international normalized ratio; 
IPI International Prognostic Index; IV intravenous; LDH lactate dehydrogenase; MRDminimum residual disease; MRI magnetic resonance 
imaging; MUGA multiple-gated acquisition; MZL marginal zone lymphoma; NK natural killer cells; PCR polymerase chain reaction; 
PET positron emission tomography; PK pharmacokinetic; PR partial response; PRO patient-reported outcome; PT prothrombin time; 
PTT partial thromboplastin time; R rituximab; RBC red blood cell; RCR Roche Clinical Repository; SAE serious adverse event; SD Study 
Day; WBCwhite blood cell.
Notes:  On treatment days, all assessments should be performed prior to dosing unless otherwise noted.  
The Cycle 1 Day 1 visit should be scheduled to allow subsequent visits to occur without delay.  Study visits during induction treatment should occur 
on the scheduled day ± 4 days), with the exception of delays resulting from toxicities.  Visits on Days 8 and 15 of C1 are optional for patients in the 
rituximab arm and are done if standard of care at the site.  Visits on D15 of C28 are optional for all patients and are done if standard of care at the 
site.  
(x) conditional/optional; refer to footnote for details.  


APPENDIX A1  
Study Flowchart:  Induction Treatment with CHOP plus Rituximab/Obinutuzumab (21Day Cycles) 
(Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
169/P BO21223A7
a Induction completion should occur within 68 weeks after C8D1 (i.e., SD190SD204).  An early termination visit should occur within 48 weeks 
after last dose (in case of early termination due to adverse event) or within 28 weeks after last dose (in case of early termination due to clinical 
disease progression).  In case of withdrawal from treatment due to toxicity, the first followup visit is scheduled 3 months (14 days) after last 
dose (“Month 27”; see Appendix A-5).  
b A tissue sample is required for retrospective central confirmation of diagnosis and CD20 positivity of lymphoma and should be dated from within 
12 months prior to study entry.  Tissue samples dated 12 months prior to study entry can be accepted only if tissue material is available for 
retrospective confirmation, if there is no clinical indication for transformation of disease, and if the request for additional biopsy would be 
unethical treatment of the patient.  Bone marrow alone is not suited to make the diagnosis of follicular lymphoma.   In patients with splenic MZL 
without splenic tissue available for histologic review, the bone marrow must be submitted for retrospective central confirmation.  All tissue 
samples should be sent for quality assurance pathology review within 4 months after randomization.  A formalinfixed paraffinembedded tissue 
sample is preferred over 1520 sections (35m thickness) on coated slides.  If the tissue sample is small, fewer sections (minimum within 
range of 612) can be accepted.  Remainders of the tissue blocks will be returned to local pathology in accordance with local regulations.  
c At screening, obtain demographic data and complete medical history.  On Cycle 1 Day 1, obtain medical history since the screening visit.  
d Complete physical examination includes all systems described in Section 4.5.1.a, including assessment of lymph nodes, hepatomegaly, 
and splenomegaly.  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).  
e Height is measured at screening only.  It is recommended that the DuBois BSA formula be used; however, BSA may be calculated using the 
investigator’s preferred formula.  
f
Includes blood pressure, pulse rate, and temperature.  On rituximab or obinutuzumab treatment days, vital signs should be measured prior to the 
infusion, then approximately every 15 minutes for 90 minutes, approximately every 30 minutes until the end of the infusion, and approximately 
every 60 minutes until the infusion line is removed.  
g Performed at screening if not performed within 6 months prior to screening.  


APPENDIX A1  
Study Flowchart:  Induction Treatment with CHOP plus Rituximab/Obinutuzumab (21Day Cycles) 
(Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
170/P BO21223A7
h Samples should be drawn within 72 hours prior to the study drug infusion on treatment days.  Hematology includes hemoglobin, hematocrit, 
platelet count, RBC count, WBC count, and absolute neutrophil count as routine components.  Percent or absolute differential count (segmented 
neutrophils, banded neutrophils, eosinophils, lymphocytes, monocytes, basophils, malignant lymphocytes) are done if clinically indicated (e.g., 
for differential diagnosis of any kind of clinically relevant cytopenia/cytophilia or, e.g., if other undefined cells are present in the peripheral blood).  
In case of splenic MZL, the percent or absolute number of malignant lymphocytes (“villous lymphocytes”) in peripheral blood should be assessed.   
Additional samples for hematology can be drawn according to the standard of care at the site.  Serum chemistry includes sodium, potassium, 
chloride, bicarbonate (if clinically indicated), BUN, uric acid, serum creatinine, calcium, total bilirubin, total protein, albumin, phosphorus, ALT and 
AST, alkaline phosphatase, creatinine clearance, LDH, and 2 microglobulin (creatinine clearance and 2 microglobulin required only at 
screening).  Visits on D8 and D15 of C1 are optional for hematology and serum chemistry for patients in the rituximab arm and for chemistry for 
patients in the obinutuzumab arm and are done if standard of care at the site.  Visits on D15 of C28 are optional for all patients and are done if 
standard of care at the site.  Values of serum chemistry/hematology from these optional visits may be obtained from local laboratories and 
should be entered into the eCRF if these visits took place.  
i
In a fresh sample of midstream urine, a dipstick testing for proteinuria is required.  
j
Serum electrophoresis is required in all patients with MZL and should report percentage of albumin, alpha 1, alpha 2, beta, and gamma fraction,
as well absence/presence of an M protein.  If an M protein is present, it should be quantified in g/L and the Ig subtype (IgG, IgA, IgM, IgD, 
lightchain kappa, or lightchain lambda) determined by immunofixation.  If no M protein is found at baseline, serum electrophoresis and 
immunofixation do not need to be repeated at later time points.  
k All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening.  Urine 
pregnancy tests will be performed at specified subsequent visits and may be performed more frequently if required by local legislation.  If a urine 
pregnancy test result is positive, dosing will be delayed until the patient’s status is determined by a serum pregnancy test.  
l
HBsAg, HBcAb, and HCV antibody serology required for all patients.  HCV RNA required for patients who are HCV antibody positive. HTLV 
required for patients from endemic countries (Japan, the Caribbean basin, South America, subSaharan Africa, and Melanesia). Additional 
serology for HBsAb required prior to Cycle 1 Day 1 for patients who are HBsAg negative and HBcAb positive at screening.  
m For patients who are HBsAg negative and HBcAb positive at screening only.  HBV DNA levels will be measured centrally by realtime PCR with 
use of an assay with a limit of quanitification of at least 29 IU/mL.  


APPENDIX A1  
Study Flowchart:  Induction Treatment with CHOP plus Rituximab/Obinutuzumab (21Day Cycles) 
(Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
171/P BO21223A7
n CHOP consists of cyclophosphamide 750 mg/m2 IV on Day 1 of each cycle, doxorubicin 50 mg/m2 IV on Day 1 of each cycle, vincristine 
1.4 mg/m2 IV (maximum 2 mg) on Day 1 of each cycle, and prednisone (prednisolone) 100 mg (or methylprednisolone [MP] 80 mg in 
countries/sites without availability of prednisone or prednisolone) orally on Days 1–5 of each cycle.  When rituximab or obinutuzumab is 
administered on the same day as prednisone (prednisolone, MP), it is recommended that prednisone (prednisolone, MP) be given prior to the 
rituximab or obinutuzumab infusion.  The order of administration of cyclophosphamide, doxorubicin, and vincristine will be determined by local
institutional practice, but these agents should be administered at least 30 minutes after rituximab or obinutuzumab.  Dosage calculations for 
chemotherapy should be based on the patient’s BSA.  Empiric dose adjustment in obese patients (defined as a body mass index 30, as 
measured in kg/m2) is not recommended, but may be implemented if required by institutional guidelines.  There will be no dose modification for
changes in patients’ weight unless the weight increases or decreases by 10% from weight at screening.  The weight that triggered a dose 
adjustment will be taken as the new reference weight for future dose adjustments.  
o Rituximab 375 mg/m2 will be administered by IV infusion.  Rituximab should be administered after premedication with oral 
acetaminophen/paracetamol and an antihistamine such as diphenhydramine hydrochloride (unless contraindicated) and allopurinol (for patients 
with high tumor burden, if pretreatment with allopurinol is deemed appropriate).  When given on the same day as CHOP chemotherapy, 
rituximab should be administered after prednisone (prednisolone, MP) but at least 30 minutes prior to cyclophosphamide, doxorubicin, and 
vincristine.  
p Obinutuzumab 1000 mg will be administered by IV infusion.  Obinutuzumab should be administered after premedication with oral 
acetaminophen/paracetamol and an antihistamine such as diphenhydramine hydrochloride (unless contraindicated), and allopurinol (for patients 
with high tumor burden, if pretreatment with allopurinol is deemed appropriate). When given on the same day as CHOP chemotherapy, 
obinutuzumab should be administered after prednisone (prednisolone, MP) but at least 30 minutes prior to cyclophosphamide, doxorubicin, and 
vincristine.  
q Patients receiving obinutuzumab only.  
r
Imagingbased tumor assessment:  At screening, CT scan (with contrast) of the chest, abdomen, pelvis (and neck, if clinically indicated) should 
be done within 35 days prior to randomization.  CT scans for response assessment should be done within 14 days prior to C5D1 and at the 
induction completion/early termination visit and may be limited to areas of prior involvement if required by local regulatory authorities. Any time 
the investigator suspects disease progression, a full tumor assessment must be performed, including a CT scan (limited to areas of prior 
involvement if required by local authorities).  MRIs with a non-contrast CT scan of the chest may be used for patients for whom CT scans with 
contrast are contraindicated.  If MRI is used at screening, then MRI should be used throughout the study (same method during the entire study).  
Combined FDGPET/CT scans may be used only if performed with contrast and if collected with resolution sufficient to allow accurate and 
consistent comparison of target lesion measurements with subsequent CT scans.  Measurement of lymphoma lesions by ultrasound is not the 
preferred option because of the inherent interexaminer variability.  However, in patients with splenic MZL, the spleen is considered a target 
lesion, and its size should be determined by ultrasound (length and thickness), CT/MRI, or by physical examination.  For ultrasound/CT/MRI or 
physical examination measurements, local guidelines for determining normal organ size are acceptable.  


APPENDIX A1  
Study Flowchart:  Induction Treatment with CHOP plus Rituximab/Obinutuzumab (21Day Cycles) 
(Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
172/P BO21223A7
s FDGPET is mandatory in the first 170 patients with follicular lymphoma at screening and at induction completion/ET (only if the result of the 
screening PET was positive) at all sites where a scanner is available.  This may require specific approval in some countries.  In such instances, 
PET becomes mandatory only after necessary approvals have been obtained.  In the overall population, PET remains optional and at the 
investigator’s discretion.  If done, screening PET should be performed within 35 days prior to randomization.  Within 14 days prior to C5D1, PET 
is optional and may be done at the investigator’s discretion.  At induction completion/ET, PET should be obtained within 68 weeks after C8D1 
(i.e., SD190SD204).  An ET visit PET should occur within 48 weeks after last dose (in case of ET due to adverse event) or within 28 weeks 
after last dose (in case of ET due to clinical disease progression).  The diagnosis of disease progression should not be based on PET alone but 
should always be confirmed by CT (MRI) imaging.  PET results should not be used to make treatment decisions.
  
t
A bone marrow biopsy (trephine) biopsy examination for local pathology must be performed at screening unless it was performed within 3 
months prior to Cycle 1 Day 1.  If positive at screening (i.e., showing infiltration by lymphoma), a subsequent bone marrow biopsy is required at 
the induction completion visit for patients who achieve a CR.  In patients with continued bone marrow involvement or in patients with PR due to 
other reasons at EOI, a subsequent bone marrow biopsy may be required to confirm a CR at a later time point (e.g., during
maintenance/observation).  Any additional (unscheduled) bone marrow biopsies performed during the study will be at the discretion of the 
investigator.  
u A bone marrow aspirate for central minimum residual disease assessment by PCR detection of BCL2/IgH rearrangement is performed in all 
patients with follicular lymphoma at screening.  If the patient already had a diagnostic bone marrow biopsy without an aspirate within 3 months 
prior to Cycle 1 Day 1 before  screening, it is still mandatory to perform the bone marrow aspirate for MRD assessment at screening, but the 
biopsy for pathology itself does not have to be repeated (see footnote t).  At the induction completion/ET visit, a bone marrow aspirate sample is 
mandatory in responders (CR PR) in whom bone marrow involvement was diagnosed by morphology at screening and is optional but strongly 
recommended in responders (CR PR) in whom no bone marrow involvement was diagnosed by morphology at screening.  
The recommendation is based on the observation that, at screening, bone marrow involvement is detectable on the level of minimal residual 
disease in the large majority of patients even if it appears to be negative by morphology.  For each bone marrow aspirate performed on a patient, 
4 mL of an EDTA-anticoagulated bone marrow aspirate is requested.  
v A 3 mL blood sample will be taken for determination of FcRIIIa, FcRIIa, and FcRIIb/IIc polymorphisms.  Only patients who have successfully 
passed screening and are fully eligible for the study should have this sample taken.  
w For follicular lymphoma patients only, a 9.5 mL EDTA blood sample will be taken for the analysis of clonal BCL2/IgH rearrangement (as a 
potential marker of tumor burden) at screening, before C5D1, and at induction completion/ET in all patients.  
x A 5 mL blood sample will be taken for HAHA analysis in all patients receiving obinutuzumab (Arm B) before first administration of GCHOP 
(baseline sample) and at induction completion/ET visit.  
y Peak and trough PK samples for obinutuzumab levels should be drawn in a subset of approximately 460 patients receiving obinutuzumab 
(Arm B), per the schedule in Appendix B.  All PK samples will be collected from the arm opposite to that receiving the infusion.  


APPENDIX A1  
Study Flowchart:  Induction Treatment with CHOP plus Rituximab/Obinutuzumab (21Day Cycles) 
(Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
173/P BO21223A7
z A 5 mL blood sample will be taken for the assessment of B cells, T cells, neutrophils, and NK cells in all patients (TBNK panel). This will include 
determination of relative and absolute numbers of CD3+, CD4+ CD8+, CD19+, and CD56+ subsets.  In addition, a more detailed analysis of B cell 
counts will be performed in approximately 60 patients of each therapeutic group (RCHOP, GCHOP, RCVP, GCVP, R-bendamustine, G-
bendamustine) and in all patients with splenic MZL based on the markers CD45/CD19/CD22/CD79b/CD5/CD10/lambda/kappa (B cell panel).  
aa If the patient consents to additional research, a 6 mL serum and a 6 mL plasma sample should be drawn prior to study drug administration for 
storage in the RCR.  With consent to optional research, the residual tumor tissue specimens from the baseline biopsy sample will also be stored 
in the RCR.  
bb If an additional biopsy is done as part of the standard of care at the time of relapse or transformation, a tissue sample will be collected at that 
time.  A formalin-fixed paraffin embedded tissue block is preferred over 1520 sections on coated slides.  
cc Prior to initiation of study medications, only SAEs caused by a protocolmandated intervention will be recorded.  After initiation of study 
medications, AEs will be recorded as follows:  all AEs will be recorded up to 28 days after the last dose of study drug, Grade 3 or 4 AEs will be 
recorded up to 6 months after the last dose of study drug, Grade 3 infections will be recorded up to 24 months after the last dose of study drug, 
unrelated SAEs will be recorded up to 12 months after the last dose of study drug, and study drug–related SAEs and secondary malignancies 
will be recorded indefinitely (even if the study has been closed).  
dd Observation and collection of concomitant medication information will be continued throughout the study.  
ee PRO questionnaires (FACTLym, EQ5D) should be administered prior to any treatment assessments.  PRO questionnaires should also be 
administered at first assessment after report of disease progression.  
ff Any response assessments performed after a patient progressed and received NALT should be reported.


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
174/P BO21223A7
APPENDIX A2 
Study Flowchart:  Induction Treatment with CVP plus Rituximab/Obinutuzumab (21Day Cycles)
Screening
Treatment Period
Induction 
Completion/
ET Visit a
SD
35
SD
14
C1, D1
(SD1)
C1, D8
(SD8)
C1, D15
(SD15)
C2, D1
(SD22)
C3, D1
(SD43)
C4, D1
(SD64)
C5, D1
(SD85)
C6, D1
(SD106)
C7, D1
(SD127)
C8, D1
(SD148)
Informed consent
x
Optional RCR informed 
consent
x
Discussion of fertility 
issues and sperm banking 
(in patients of childbearing 
age)
x
Inclusion/exclusion criteria
x
Tumor tissue sample for 
quality assurance 
pathology review b
x
Demographics and 
medical history c
x
x
FLIPI prognostic risk:  
follicular patients
x
FLIPI2 prognostic risk:  
follicular patients
x
IPI score:  nonfollicular 
patients
x
Complete physical 
examination d
x
Targeted physical 
examination d
x
x
x
x
x
x
x
x
x


APPENDIX A2 
Study Flowchart:  Induction Treatment with CVP plus Rituximab/Obinutuzumab (21Day Cycles) 
(Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
175/P BO21223A7
Height, weight, BSA e
x
x
x
x
x
x
x
x
x
x
Vital signs f
x
x
x
x
x
x
x
x
x
x
x
x
IADLs/ADLs
x
ECOG Performance Status
x
x
x
x
x
x
x
x
x
B symptoms
x
x
x
12lead ECG
x
x
Hematology g
x
x
x
x
x
x
x
x
x
x
x
x
Serum chemistry g
x
x
x
x
x
x
x
x
x
x
Urine dipstick for protein h
x
x
Serum electrophoresis, M 
protein, and 
immunofixation (only in 
patients with MZL) i
x
x
x
Coagulation (PTT or aPTT, 
PT or INR)
x
Pregnancy test j
x
x
HBV, HCV, and HTLV1 
serology k
x
HBV DNA PCR l
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
CVP chemotherapy m
x
x
x
x
x
x
x
x
Arm A:  rituximab infusion n
x
x
x
x
x
x
x
x
Arm B:  obinutuzumab 
infusion o, p
x
x
x
x
x
x
x
x
x
x
New antilymphoma 
treatment ee
x


APPENDIX A2 
Study Flowchart:  Induction Treatment with CVP plus Rituximab/Obinutuzumab (21Day Cycles) 
(Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
176/P BO21223A7
Imagingbased tumor 
assessment q
x
x
x
FDGPET r
x
(x)
x
Bone marrow biopsy s
x
x
Bone marrow aspirate for 
BCL2/IgH analysis:  
follicular patients t
x
x
FcR typing u
x
Blood for BCL2/IgH
analysis:  follicular patients 
v
x
x
x
HAHA samples:  
obinutuzumab arm only p, w
x
x
PK sampling:  subset in 
obinutuzumab arm p, x
x a
x
x
x
x
x
x
Leukocyte 
immunophenotyping 
(FACS) y
x
x
x
x
Quantitative 
immunoglobulins (IgA, IgG, 
IgM)
x
x
Optional serum and 
plasma samples for RCR z
(x)
Tumor tissue sample at 
time of relapse or 
transformation
(x) aa
Adverse events bb
x
x
x
x
x
x
x
x
x
x
x
x
x


APPENDIX A2 
Study Flowchart:  Induction Treatment with CVP plus Rituximab/Obinutuzumab (21Day Cycles) 
(Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
177/P BO21223A7
Concomitant medications
cc
x
x
x
x
x
x
x
x
x
x
x
x
x
PRO questionnaires dd
x
x
x
ADLs Activities of Daily Living; AEadverse event; aPTT activated partial thromboplastin time; BSAbody surface area; BUNblood urea 
nitrogen; CCycle; CHOPcyclophosphamide, doxorubicin, vincristine, and prednisone (prednisolone or methylprednisolone [MP]); CRcomplete 
response; CT computed tomography; CVPcyclophosphamide, vincristine, and prednisone (prednisolone, MP); DDay; ECGelectrocardiogram; 
ECOGEastern Cooperative Oncology Group; eCRF electronic Case Report Form; EDTAethylenediaminetetraacetic acid; EOIend of 
infusion; EQ5DEuropean Quality of Life (EuroQol) Questionnaire; ET early termination; FACSfluorescenceactivated cell sorter; 
FACT-Lym Functional Assessment of Cancer Therapy for Lymphoma; FDG 18F-fluorodeoxyglucose; 
FLIPIFollicular Lymphoma International Prognostic Index; GGA101; HAHAhuman antihuman antibody; HBcAbhepatitis B core antibody; 
HBsAbhepatitis B surface antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; HTLVhuman 
T-lymphotropic virus; IADLs Instrumental Activities of Daily Living; INR international normalized ratio; IPIInternational Prognostic Index;
IVintravenous; LDHlactate dehydrogenase; MRDminimum residual disease; MRImagnetic resonance imaging; MZLmarginal zone 
lymphoma; NKnatural killer cells; PCRpolymerase chain reaction; PET positron emission tomography; PKpharmacokinetic; 
PRpartial response; PRO patient-reported outcome; PT prothrombin time;  PTT partial thromboplastin time; Rrituximab; RBCred blood cell; 
RCRRoche Clinical Repository; SAEserious adverse event; SDStudy Day; WBCwhite blood cell.  
Notes:  On treatment days, all assessments should be performed prior to dosing unless otherwise noted.  
The Cycle 1 Day 1 visit should be scheduled to allow subsequent visits to occur without delay.  Study visits during induction treatment should occur 
on the scheduled day ( 4 days), with the exception of delays resulting from toxicities.  Visits on Days 8 and 15 of Cycle 1 are optional for patients 
in the rituximab arm and are done if standard of care at the site.  Visits on Day 15 of Cycles 28 are optional for all patients and are done if 
standard of care at the site.  
(x)conditional/optional; refer to footnote for details.  
a Induction completion should occur  within 68 weeks after C8D1 (i.e., SD190SD204).  An early termination visit should occur within 48 weeks 
after last dose (in case of early termination due to adverse event) or within 28 weeks after last dose in case of early termination due to clinical 
disease progression).  In case of withdrawal from treatment due to toxicity, the first followup visit is scheduled 3 months (14 days) after last 
dose (“Month 27”; see Appendix A-5). 


APPENDIX A2 
Study Flowchart:  Induction Treatment with CVP plus Rituximab/Obinutuzumab (21Day Cycles) 
(Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
178/P BO21223A7
b A tissue sample is required for retrospective central confirmation of diagnosis and CD20 positivity of lymphoma and should be dated from within 
12 months prior to study entryi.  Tissue samples dated 12 months prior to study entry can be accepted only if tissue material is available for 
retrospective confirmation, if there is no clinical indication for transformation of disease, and if the request for additional biopsy would be 
unethical treatment of the patient.  Bone marrow alone is not suited to make the diagnosis of follicular lymphoma.  In patients with splenic MZL 
without splenic tissue available for histologic review, the bone marrow must be submitted for retrospective central confirmation.  All tissue 
samples should be sent for quality assurance pathology review within 4 months after randomization.  A formalinfixed paraffinembedded tissue 
sample is preferred over 1520 sections (35µm thickness) on coated slides.  If the tissue sample is small, fewer sections (minimum within 
range of 612) can be accepted.  Remainders of the tissue blocks will be returned to local pathology in accordance with local regulations.  
c At screening, obtain demographic data and complete medical history.  On Cycle 1 Day 1 obtain medical history since the screening visit.  
d Complete physical examination includes all systems described in Section 4.5.1.a, including assessment of lymph nodes, hepatomegaly, 
and splenomegaly.  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).  
e Height is measured at screening only.  It is recommended that the DuBois BSA formula be used; however, BSA may be calculated using the 
investigator’s preferred formula.  
f
Includes blood pressure, pulse rate, and temperature.  On rituximab or obinutuzumab treatment days, vital signs should be measured prior to the 
infusion, then approximately every 15 minutes for 90 minutes, approximately every 30 minutes until the end of the infusion, and approximately 
every 60 minutes until the infusion line is removed.  
g Samples should be drawn within 72 hours prior to the study drug infusion on treatment days.  Hematology includes hemoglobin, hematocrit, 
platelet count, RBC count, WBC count, and absolute neutrophil count as routine components.  Percent or absolute differential count (segmented 
neutrophils, banded neutrophils, eosinophils, lymphocytes, monocytes, basophils, malignant lymphocytes) are done if clinically indicated (e.g., 
for differential diagnosis of any kind of clinically relevant cytopenia/cytophilia or, e.g., if other undefined cells are present in the peripheral blood).  
In case of splenic MZL, the percent or absolute number of malignant lymphocytes (“villous lymphocytes”) in peripheral blood should be assessed.  
Additional samples for hematology can be drawn according to the standard of care at the site.  Serum chemistry includes sodium, potassium, 
chloride, bicarbonate (if clinically indicated), BUN, uric acid, serum creatinine, calcium, total bilirubin, total protein, albumin, phosphorus, ALT and 
AST, alkaline phosphatase, creatinine clearance, LDH, and 2 microglobulin (creatinine clearance and 2 microglobulin required only at 
screening).  Visits on Days 8 and 15 of Cycle 1 are optional for hematology and chemistry for patients in the rituximab arm and for chemistry for 
patients in the obinutuzumab arm and are done if standard of care at the site.  Visits on Day 15 of Cycles 28 are optional for all patients and are 
done if standard of care at the site.  Values of serum chemistry/hematology from these optional visits may be obtained from local laboratories 
and should be entered into the eCRF if these visits took place.  
h In a fresh sample of midstream urine, a dipstick testing for proteinuria is required.  
i
Serum electrophoresis is required in all patients with MZL and should report percentage of albumin, alpha 1, alpha 2, beta, and gamma fraction, 
as well absence/presence of an M protein.  If an M protein is present, it should be quantified in g/L and the Ig subtype (IgG, IgA, IgM, IgD, 
lightchain kappa, or lightchain lambda) determined by immunofixation.  If no M protein is found at baseline, serum electrophoresis and 
immunofixation do not need to be repeated at later time points.  


APPENDIX A2 
Study Flowchart:  Induction Treatment with CVP plus Rituximab/Obinutuzumab (21Day Cycles) 
(Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
179/P BO21223A7
j
All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening.  Urine 
pregnancy tests will be performed at specified subsequent visits and may be performed more frequently if required by local legislation.  If a urine 
pregnancy test result is positive, dosing will be delayed until the patient’s status is determined by a serum pregnancy test.  
k HBsAg, HBcAb, and HCV antibody serology required for all patients.  HCV RNA required for patients who are HCV antibody positive.  HTLV 
required for patients from endemic countries (Japan, the Caribbean basin, South America, subSaharan Africa, and Melanesia).  Additional 
serology for HBsAb required prior to Cycle 1 Day 1 for patients who are HBsAg negative and HBcAb positive at screening.  
l
For patients who are HBsAg negative and HBcAb positive at screening only.  HBV DNA levels will be measured centrally by realtime PCR with 
use of an assay with a limit of quanitification of at least 29 IU/mL.  
m CVP consists of cyclophosphamide 750 mg/m2 IV on Day 1 of each cycle, vincristine 1.4 mg/m2 IV (maximum 2 mg) on Day 1 of each cycle, 
and prednisone (prednisolone) 100 mg (or MP 80 mg in countries/sites without availability of prednisone/prednisolone) orally on Days 1–5 of 
each cycle.  When rituximab or obinutuzumab is administered on the same day as prednisone (prednisolone, MP), it is recommended that 
prednisone (prednisolone, MP) be given prior to the rituximab or obinutuzumab infusion.  The order of administration of cyclophosphamide and 
vincristine will be determined by local institutional practice, but these agents should be administered at least 30 minutes after rituximab or 
obinutuzumab.  Dosage calculations for chemotherapy should be based on the patient’s BSA.  Empiric dose adjustment in obese patients 
(defined as a body mass index 30, as measured in kg/m2) is not recommended, but may be implemented if required by institutional guidelines.  
There will be no dose modification for changes in patients’ weight unless the weight increases or decreases by 10% from weight at screening.  
The weight that triggered a dose adjustment will be taken as the new reference weight for future dose adjustments.
n Rituximab 375 mg/m2 will be administered by IV infusion.  Rituximab should be administered after premedication with oral 
acetaminophen/paracetamol and an antihistamine such as diphenhydramine hydrochloride (unless contraindicated) and allopurinol (for patients 
with high tumor burden, if pretreatment with allopurinol is deemed appropriate).  When given on the same day as CVP chemotherapy, rituximab 
should be administered after prednisone (prednisolone, MP) but at least 30 minutes prior to cyclophosphamide and vincristine.
o Patients receiving obinutuzumab only.  
p Obinutuzumab 1000 mg will be administered by IV infusion.  Obinutuzumab should be administered after premedication with oral 
acetaminophen/paracetamol and an antihistamine such as diphenhydramine hydrochloride (unless contraindicated) and allopurinol (for patients 
with high tumor burden, if pretreatment with allopurinol is deemed appropriate).  When given on the same day as CVP chemotherapy, 
obinutuzumab should be administered after prednisone (prednisolone, MP) but at least 30 minutes prior to cyclophosphamide and vincristine.  


APPENDIX A2 
Study Flowchart:  Induction Treatment with CVP plus Rituximab/Obinutuzumab (21Day Cycles) 
(Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
180/P BO21223A7
q Imagingbased tumor assessment:  At screening, CT scan (with contrast) of the chest, abdomen, pelvis (and neck, if clinically indicated) should 
be done within 35 days prior to randomization.  CT scans for response assessment should be done within 14 days prior to C5D1 and at the 
induction completion/early termination visit, and may be limited to areas of prior involvement if required by local regulatory authorities. Any time 
the investigator suspects disease progression, a full tumor assessment must be performed, including a CT scan (limited to areas of prior 
involvement if required by local authorities).  MRIs with a noncontrast CT scan of the chest may be used for patients for whom CT scans with 
contrast are contraindicated.  If MRI is used at screening, then MRI should be used throughout the study (same method during the entire study).  
Combined FDGPET/CT scans may be used only if performed with contrast and if collected with resolution sufficient to allow accurate and 
consistent comparison of target lesion measurements with subsequent CT scans.  Measurement of lymphoma lesions by ultrasound is not the 
preferred option because of the inherent interexaminer variability.  However, in patients with splenic MZL, the spleen is considered a target 
lesion, and its size should be determined by ultrasound (length and thickness), CT/MRI, or by physical examination.  For ultrasound/CT/MRI or 
physical examination measurements, local guidelines for determining normal organ size are acceptable.  
r
FDGPET is mandatory in the first 170 patients with follicular lymphoma at screening and at induction completion/ET (only if screening PET was 
positive) at all sites where a scanner is available.  This may require specific approval in some countries.  In such instances, PET becomes 
mandatory only after necessary approvals have been obtained.  In the overall population, PET remains optional and at the investigator’s 
discretion.  If done, screening PET should be performed within 35 days prior to randomization.  Within 14 days prior to C5D1, PET is optional 
and may be done at the investigator’s discretion.  At induction completion/ET, PET should be obtained within 68 weeks after C8D1 (i.e., 
SD190SD204).  An ET visit PET should occur within 48 weeks after last dose (in case of ET due to adverse event) or within 28 weeks after 
last dose (in case of ET due to clinical disease progression).  The diagnosis of disease progression should not be based on PET alone but 
should always be confirmed by CT (MRI) imaging.  PET results should not be used to make treatment decisions.  
s A bone marrow biopsy (trephine) for local pathology must be performed at screening unless it was performed within 3 months prior to Cycle 1 
Day 1.  If positive at screening (i.e., showing infiltration by lymphoma), a subsequent bone marrow examination is required at the induction 
completion visit for patients who achieve a CR.  In patients with continued bone marrow involvement or in patients with PR due to other reasons 
at EOI, a subsequent bone marrow biopsy may be required to confirm a CR at a later time point (e.g., during maintenance/observation).  Any 
additional (unscheduled) bone marrow examinations performed during the study will be at the discretion of the investigator.  
t
A bone marrow aspirate for central MRD assessment by PCR detection of BCL2/IgH rearrangement is performed in all patients with follicular 
lymphoma at screening.  If the patient already had a diagnostic bone marrow biopsy without an aspirate within 3 months prior to Cycle 1 Day 1, it 
is still mandatory to perform the bone marrow aspirate for MRD assessment at screening, but then the biopsy for pathology does not have to be 
repeated.  At the induction completion/ET visit, a bone marrow aspirate sample is mandatory in responders (CRPR) in whom bone marrow 
involvement was diagnosed by morphology at screening and is optional but strongly recommended in responders (CR PR) in whom no bone 
marrow involvement was diagnosed by morphology at screening.  The recommendation is based on the observation that, at screening, bone 
marrow involvement is detectable on the level of minimal residual disease in the large majority of patients even if it appears to be negative by 
morphology.  For each bone marrow examination performed on a patient, 4 mL of an EDTA-anticoagulated bone marrow aspirate is requested.  
u A 3 mL blood sample will be taken for determination of FcRIIIa, FcRIIa, and FcRIIb/IIc polymorphisms.  Only patients who have successfully 
passed screening and are fully eligible for the study should have this sample taken.  


APPENDIX A2 
Study Flowchart:  Induction Treatment with CVP plus Rituximab/Obinutuzumab (21Day Cycles) 
(Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
181/P BO21223A7
v For follicular lymphoma patients only, a 9.5 mL EDTA blood sample will be taken for the analysis of clonal BCL2/IgH rearrangement (as a 
potential marker of tumor burden) at screening, before C5D1, and at the induction completion/ET in all patients.  
w A 5 mL blood sample will be taken for HAHA analysis in all patients receiving obinutuzumab (Arm B) before first administration of GCVP 
(baseline sample) and at induction completion/ET visit.  
x Peak and trough PK samples for obinutuzumab levels should be drawn in a subset of patients receiving obinutuzumab (Arm B), per the schedule 
in Appendix B.  All PK samples will be collected from the arm opposite to that receiving the infusion.
y A 5 mL blood sample will be taken for the assessment of Bcells, T cells, and NKcells in all patients (TBNK panel).  This will include 
determination of relative and absolute numbers of CD3+, CD4+ CD8+, CD19+, and CD56+ subsets.  In addition, a more detailed analysis of B cell 
counts will be performed in approximately 60 patients of each therapeutic group (RCHOP, GCHOP, RCVP, GCVP, R-bendamustine, 
Gbendamustine) and in all patients with splenic MZL based on the markers CD45/CD19/CD22/CD79b/CD5/CD10/lambda/kappa (B cell panel).
zz If the patient consents to additional research, 6 mL serum and 6 mL plasma samples should be drawn prior to study drug administration for 
storage in the RCR.  With consent to optional research, the residual tumor tissue specimens from the baseline biopsy sample will also be stored 
in the RCR.
aa If an additional biopsy is done as part of the standard of care at the time of relapse or transformation, a tissue sample will be collected at that 
time.  A formalinfixed paraffinembedded tissue block is preferred over 1520 sections on coated slides).  
bb Prior to initiation of study medications, only SAEs caused by a protocolmandated intervention will be recorded.  After initiation of study 
medications, AEs will be recorded as follows:  all AEs will be recorded up to 28 days after the last dose of study drug, Grade 3 or 4 AEs will be 
recorded up to 6 months after the last dose of study drug, Grade 3 infections will be recorded up to 24 months after the last dose of study drug, 
unrelated SAEs will be recorded up to 12 months after the last dose of study drug, and study drug–related SAEs and secondary malignancies
will be recorded indefinitely (even if the study has been closed).  
cc Observation and collection of concomitant medication information will be continued throughout the study.  
dd PRO questionnaires (FACTLym, EQ5D) should be administered prior to any treatment assessments.  PRO questionnaires should also be 
administered at first assessment after report of disease progression.  
ee Any response assessments performed after a patient progressed and received NALT should be reported.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
182/P BO21223A7
APPENDIX A3 
Study Flowchart:  Induction Treatment with Bendamustine plus Rituximab/Obinutuzumab (28Day 
Cycles)
Screening
Treatment Period
Induction 
Completion/
ET Visit a
SD
35
SD
14
C1, D1
(SD1)
C1, D2
(SD2)
C1, D8
(SD8)
C1, D15
(SD15)
C1, D22
(SD22)
C2, D1
(SD29)
C3, D1
(SD57)
C4, D1
(SD85)
C5, D1
(SD113)
C6, D1
(SD141)
Informed consent
x
Optional RCR informed 
consent
x
Discussion of fertility issues 
and sperm banking (in 
patients of childbearing 
age)
x
Inclusion/exclusion criteria
x
Tumor tissue sample for 
quality assurance 
pathology review b
x
Demographics and medical 
history c
x
x
FLIPI prognostic risk:  
follicular patients
x
FLIPI2 prognostic risk:  
follicular patients
x
IPI score:  nonfollicular 
patients
x
Complete physical 
examination d
x
Targeted physical 
x
x
x
x
x
x
x


APPENDIX A3 
Study Flowchart:  Induction Treatment with Bendamustine plus Rituximab/Obinutuzumab (28Day 
Cycles) (Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
183/P BO21223A7
Screening
Treatment Period
Induction 
Completion/
ET Visit a
SD
35
SD
14
C1, D1
(SD1)
C1, D2
(SD2)
C1, D8
(SD8)
C1, D15
(SD15)
C1, D22
(SD22)
C2, D1
(SD29)
C3, D1
(SD57)
C4, D1
(SD85)
C5, D1
(SD113)
C6, D1
(SD141)
examination d
Height, weight, BSA e
x
x
x
x
x
x
x
x
Vital signs f
x
x
x
x
x
x
x
x
x
x
IADLs/ADLs
x
ECOG Performance Status
x
x
x
x
x
x
x
B symptoms
x
x
x
12lead ECG
x
x
Hematology g
x
x
x
x
x
x
x
x
x
x
x
Serum chemistry g
x
x
x
x
x
x
x
x
Urine dipstick for protein h
x
x
Serum electrophoresis, 
M protein, and
immunofixation (only in 
patients with MZL) i
x
x
x
Coagulation (PTT or aPTT, 
PT or INR)
x
Pregnancy test  j
x
x
HBV, HCV, and HTLV1 
serology k
x
HBV DNA PCR l
(x)
(x)
(x)
(x)
(x)
(x)
(x)
Bendamustine m
x
x
x
x
x
x
x
Arm A:  rituximab infusion n
x
x
x
x
x
x


APPENDIX A3 
Study Flowchart:  Induction Treatment with Bendamustine plus Rituximab/Obinutuzumab (28Day 
Cycles) (Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
184/P BO21223A7
Screening
Treatment Period
Induction 
Completion/
ET Visit a
SD
35
SD
14
C1, D1
(SD1)
C1, D2
(SD2)
C1, D8
(SD8)
C1, D15
(SD15)
C1, D22
(SD22)
C2, D1
(SD29)
C3, D1
(SD57)
C4, D1
(SD85)
C5, D1
(SD113)
C6, D1
(SD141)
Arm B:  obinutuzumab
infusion o
x
x p
x p
x
x
x
x
x
New antilymphoma 
treatment ee
x
Imagingbased tumor 
assessment q
x
x
x
FDGPET r
x
(x)
x
Bone marrow biopsy s
x
x
Bone marrow aspirate for 
BCL2/IgH analysis:  
follicular patients t
x
x
FcR typing u
x
Blood for BCL2/IgH
analysis:  follicular 
patients v
x
x
x
HAHA samples:  
obinutuzumab arm only p, w
x
x
PK sampling:  subset in 
obinutuzumab arm p, x
x a
x a
x a
x a
x a
x a
x a
x a
Leukocyte 
immunophenotyping 
(FACS):  subset y
x
x
x
x
Quantitative 
immunoglobulins (IgA, 
IgG, IgM)
x
x


APPENDIX A3 
Study Flowchart:  Induction Treatment with Bendamustine plus Rituximab/Obinutuzumab (28Day 
Cycles) (Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
185/P BO21223A7
Screening
Treatment Period
Induction 
Completion/
ET Visit a
SD
35
SD
14
C1, D1
(SD1)
C1, D2
(SD2)
C1, D8
(SD8)
C1, D15
(SD15)
C1, D22
(SD22)
C2, D1
(SD29)
C3, D1
(SD57)
C4, D1
(SD85)
C5, D1
(SD113)
C6, D1
(SD141)
Optional serum and plasma 
samples for RCR z
(x)
Tumor tissue sample at 
time of relapse or 
transformation
(x) aa
Adverse events bb
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications cc
x
x
x
x
x
x
x
x
x
x
x
x
PRO questionnaires dd
x
x
x
ADLs Activities of Daily Living; AE adverse event; aPTT activated partial thromboplastin time; BSA body surface area; BUNblood urea 
nitrogen; C Cycle; CHOP cyclophosphamide, doxorubicin, vincristine, and prednisone (prednisolone or methylprednisolone [MP]); CR complete 
response; CT computed tomography; CVP cyclophosphamide, vincristine, and prednisone (prednisolone, MP);  D Day; 
ECG electrocardiogram; ECOG Eastern Cooperative Oncology Group; eCRF electronic Case Report Form; EDTAethylenediaminetetraacetic 
acid; EOIend of infusion; EQ5DEuropean Quality of Life (EuroQol) Questionnaire; ET early termination; FACS fluorescenceactivated cell 
sorter; FACT-Lym Functional Assessment of Cancer Therapy for Lymphoma; FDG 18Ffluorodeoxyglucose; FLIPI Follicular Lymphoma 
International Prognostic Index; G GA101; HAHA human antihuman antibody; HBcAb hepatitis B core antibody; HBsAb hepatitis B surface 
antibody; HBsAg hepatitis B surface antigen; HBV hepatitis B virus; HCV hepatitis C virus; HTLV human Tlymphotropic virus; 
IADLs Instrumental Activities of Daily Living; INR international normalized ratio; IPI International Prognostic Index; IV intravenous; 
LDH lactate dehydrogenase; MRDminimum residual disease; MRI magnetic resonance imaging; MZL marginal zone lymphoma; NK natural 
killer;  PCR polymerase chain reaction; PET positron emission tomography; PK pharmacokinetic; PR partial response; PRO patient-reported 
outcome; PT prothrombin time; PTT partial thromboplastin time; R rituximab; RBC red blood cell; RCR Roche Clinical Repository; 
SAE serious adverse event; SD Study Day; WBCwhite blood cell.  
Notes:  On treatment days, all assessments should be performed prior to dosing unless otherwise noted.
The Cycle 1 Day 1 visit should be scheduled to allow subsequent visits to occur without delay.  Study visits during induction treatment should occur 
on the scheduled day ( ± 4 days), with the exception of delays resulting from toxicities.  Visits on Days 8 and 15 of Cycle 1 are optional for patients 
in the rituximab arm and are done if standard of care at the site.  Visits on Day 15 of Cycles 26 are optional for all patients and are done if 
standard of care at the site.  Values of serum chemistry/hematology from these optional visits may be obtained from local laboratories and should 
be entered into the eCRF if these visits took place.  


APPENDIX A3 
Study Flowchart:  Induction Treatment with Bendamustine plus Rituximab/Obinutuzumab (28Day 
Cycles) (Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
186/P BO21223A7
(x)conditional/optional; refer to footnote for details.  
a Induction completion should occur within 68 weeks after C6, D1 (i.e., SD190SD204).  An early termination visit should occur within 48 weeks 
after last dose (in case of early termination due to adverse event) or within 28 weeks after last dose (in case of early termination due to clinical 
disease progression).  In case of withdrawal from treatment due to toxicity, the first followup visit is scheduled 3 months (14 days) after last 
dose (“Month 27”; see Appendix A-5).  
b A tissue sample is required for retrospective central confirmation of diagnosis and CD20 positivity of lymphoma and should be dated from within 
12 months prior to study entry.  Tissue samples dated 12 months prior to study entry can be accepted only if tissue material is available for 
retrospective confirmation, if there is no clinical indication for transformation of disease, and if the request for additional biopsy would be 
unethical treatment of the patient.  Bone marrow alone is not suited to make the diagnosis of follicular lymphoma.  In patients with splenic MZL 
without splenic tissue available for histologic review, the bone marrow must be submitted for retrospective central confirmation.  All tissue 
samples should be sent forquality assurance pathology review within 4 months after randomization.  A formalinfixed paraffin-embedded tissue 
sample is preferred over 1520 sections (35-µm thickness) on coated slides.  If the tissue sample is small, fewer sections (minimum within 
range of 612) can be accepted. Remainders of the tissue blocks will be returned to local pathology in accordance with local regulations.  
c At screening, obtain demographic data and complete medical history.  On Cycle 1 Day 1, obtain medical history since the screening visit.  
d Complete physical examination includes all systems described in Section 4.5.1.a, including assessment of lymph nodes, hepatomegaly, 
and splenomegaly.  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).  
e Height is measured at screening only.  It is recommended that the DuBois BSA formula be used; however, BSA may be calculated using the 
investigator’s preferred formula.  
f
Includes blood pressure, pulse rate, and temperature.  On rituximab or obinutuzumab treatment days, vital signs should be measured prior to the 
infusion, then approximately every 15 minutes for 90 minutes, approximately every 30 minutes until the end of the infusion, and approximately 
every 60 minutes until the infusion line is removed.  
g Samples should be drawn within 72 hours prior to the study drug infusion on treatment days.  Hematology includes hemoglobin, hematocrit, 
platelet count, RBC count, WBC count, and absolute neutrophil count as routine components.  Percent or absolute differential count (segmented 
neutrophils, banded neutrophils, eosinophils, lymphocytes, monocytes, basophils, malignant lymphocytes) are done if clinically indicated (e.g., 
for differential diagnosis of any kind of clinically relevant cytopenia/cytophilia or, e.g., if other undefined cells are present in the peripheral blood).  
In case of splenic MZL, the percent or absolute number of malignant lymphocytes (“villous lymphocytes”) in peripheral blood should be assessed.  
Additional samples for hematology can be drawn according to the standard of care at the site.  Serum chemistry includes sodium, potassium, 
chloride, bicarbonate (if clinically indicated), BUN, uric acid, serum creatinine, calcium, total bilirubin, total protein, albumin, phosphorus, ALT and 
AST, alkaline phosphatase, creatinine clearance, LDH, and 2 microglobulin (creatinine clearance and 2 microglobulin required only at 
screening).  Visits on Days 8 and 15 of Cycle 1 are optional for hematology and chemistry for patients in the rituximab arm and for chemistry in 
patients in the obinutuzumab arm and are done if standard of care at the site. Visits on Day 15 of Cycles 28 are optional for all patients and are 
done if standard of care at the site.  Values of serum chemistry/hematology from these optional visits may be obtained from local laboratories 
and should be entered into the eCRF if these visits took place.  


APPENDIX A3 
Study Flowchart:  Induction Treatment with Bendamustine plus Rituximab/Obinutuzumab (28Day 
Cycles) (Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
187/P BO21223A7
h In a fresh sample of midstream urine, a dipstick testing for proteinuria is required.  
i
Serum electrophoresis is required in all patients with MZL and should report percent of albumin, alpha 1, alpha 2, beta, and gamma fraction, as 
well absence/presence of an M protein.  If an M protein is present, it should be quantified in g/L and the Ig subtype (IgG, IgA, IgM, IgD, 
lightchain kappa, or light-chain lambda) determined by immunofixation.  If no M protein is found at baseline, serum electrophoresis and 
immunofixation do not need to be repeated at later time points.  
j
All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening.  Urine 
pregnancy tests will be performed at specified subsequent visits and may be performed more frequently if required by local legislation.  If a urine 
pregnancy test result is positive, dosing will be delayed until the patient’s status is determined by a serum pregnancy test.  
k HBsAg, HBcAb, and HCV antibody serology required for all patients.  HCV RNA required for patients who are HCV antibody positive.  HTLV 
required for patients from endemic countries (Japan, the Caribbean basin, South America, subSaharan Africa, and Melanesia).  Additional 
serology for HBsAb required prior to Cycle 1 Day 1 for patients who are HBsAg negative and HBcAb positive at screening.  
l
For patients who are HBsAg negative and HBcAb positive at screening only.  HBV DNA levels will be measured centrally by realtime PCR with 
use of an assay with a limit of quantification of at least 29 IU/mL.  
m Bendamustine will be administered at 90 mg/m2 IV on Days 1 and 2 of each cycle, with 100 mg oral prednisone/prednisolone or 80 mg 
methylprednisolone also administered prior to the first dose of rituximab or obinutuzumab on Day 1 of Cycle 1.  Bendamustine should be 
administered at least 30 minutes after rituximab or obinutuzumab when administered on the same day.  Dosage calculations should be based on 
the patient’s BSA.  Empiric dose adjustment in obese patients (defined as a body mass index 30, as measured in kg/m2) is not recommended 
but may be implemented if required by institutional guidelines.  There will be no dose modification for changes in patients’ weight unless the 
weight increases or decreases by 10% from weight at screening.  The weight that triggered a dose adjustment will be taken as the new 
reference weight for future dose adjustments.  
n Rituximab 375 mg/m2 will be administered by IV infusion.  Rituximab should be administered after premedication with oral 
acetaminophen/paracetamol and an antihistamine such as diphenhydramine hydrochloride (unless contraindicated).  When given on the same 
day, rituximab should be administered prior to bendamustine.  It is recommended to treat with allopurinol 23 days prior to start of the cycle in 
patients with high tumor burden, if pretreatment with allopurinol is deemed appropriate.  However, allopurinol must not be given on days of 
bendamustine administration.  
o Obinutuzumab 1000 mg will be administered by IV infusion.  Obinutuzumab should be administered after premedication with oral 
acetaminophen/paracetamol and an antihistamine such as diphenhydramine hydrochloride (unless contraindicated) and allopurinol (for patients 
with high tumor burden, if pretreatment with allopurinol is deemed appropriate).  When given on the same day, obinutuzumab should be 
administered prior to bendamustine.  Allopurinol must not be given on days of bendamustine administration.  
p Patients receiving obinutuzumab only.  


APPENDIX A3 
Study Flowchart:  Induction Treatment with Bendamustine plus Rituximab/Obinutuzumab (28Day 
Cycles) (Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
188/P BO21223A7
q Imagingbased tumor assessment:  At screening, CT scan (with contrast) of the chest, abdomen, pelvis (and neck, if clinically indicated) should 
be done within 35 days prior to randomization.  CT scans for response assessment should be done within 14 days prior to C4 D1 and at the 
induction completion/early termination visit, and may be limited to areas of prior involvement if required by local regulatory authorities. Any time 
the investigator suspects disease progression, a full tumor assessment must be performed, including a CT scan (limited to areas of prior 
involvement if required by local authorities).  MRIs with a noncontrast CT scan of the chest may be used for patients for whom CT scans with 
contrast are contraindicated.  If MRI is used at screening, then MRI should be used throughout the study (same method during the entire study).  
Combined FDGPET/CT scans may be used only if performed with contrast and if collected with resolution sufficient to allow accurate and 
consistent comparison of target lesion measurements with subsequent CT scans.  Measurement of lymphoma lesions by ultrasound is not the 
preferred option because of the inherent interexaminer variability.  However, in patients with splenic MZL, the spleen is considered a target 
lesion, and its size should be determined by ultrasound (length and thickness), CT/MRI, or by physical examination.  For ultrasound/CT/MRI or 
physical examination measurements, local guidelines for determining normal organ size are acceptable.  
r
FDGPET is mandatory in the first 170 patients with follicular lymphoma at screening and at induction completion/ET  (only if the result of the 
screening PET was positive) at all sites where a scanner is available.  This may require specific approval in some countries.  In such instances, 
PET becomes mandatory only after necessary approvals have been obtained.  In the overall population, PET remains optional and at the 
investigator’s discretion.  If done, screening PET should be performed within 35 days prior to randomization.  Within 14 days prior to C4, D1, 
PET is optional and may be done at the investigator’s discretion.  At induction completion/ET, PET should be obtained within 68 weeks after 
C6D1 (i.e., SD182SD197).  An ET visit PET should occur within 48 weeks after last dose (in case of ET due to adverse event) or within 28 
weeks after last dose (in case of ET due to clinical disease progression).  The diagnosis of disease progression should not be based on PET 
alone but should always be confirmed by CT (MRI) imaging.  PET results should not be used to make treatment decisions.  
s A bone marrow biopsy (trephine) for local pathology must be performed at screening unless it was performed within 3 months prior to Cycle 1 
Day 1.  If positive at screening (i.e., showing infiltration by lymphoma), a subsequent bone marrow examination is required at the induction 
completion visit for patients who achieve a CR.  In patients with continued bone marrow involvement or in patients with PR due to other reasons 
at EOI, a subsequent bone marrow biopsy may be required to confirm a CR at a later time point (e.g., during maintenance/observation)  Any 
additional (unscheduled) bone marrow examinations performed during the study will be at the discretion of the investigator.  
t
A bone marrow aspirate for central by PCR detection of BCL2/IgH rearrangement is performed in all patients with follicular lymphoma at 
screening.  If the patient already had a diagnostic bone marrow biopsy without an aspirate within 3 months prior to Cycle 1 Day 1 before 
screening, it is still mandatory to perform the bone marrow aspirate for MRD assessment at screening, but the biopsy for pathology itself does 
not have to be repeated.  At the induction completion/ET visit, a bone marrow aspirate sample is mandatory in responders (CR PR) in whom 
bone marrow involvement was diagnosed by morphology at screening and is optional but strongly recommended in responders (CR PR) in 
whom no bone marrow involvement was diagnosed by morphology at screening.  The recommendation is based on the observation that, at 
screening, bone marrow involvement is detectable on the level of minimal residual disease in the large majority of patients even if it appears to 
be negative by morphology.  For each bone marrow examination performed on a patient, 4 mL of an EDTA-anticoagulated bone marrow aspirate 
is requested.  
u A 3 mL blood sample will be taken for determination of FcRIIIa, FcRIIa, and FcRIIb/IIc polymorphisms.  Only patients who have successfully 
passed screening and are fully eligible for the study should have this sample taken.  


APPENDIX A3 
Study Flowchart:  Induction Treatment with Bendamustine plus Rituximab/Obinutuzumab (28Day 
Cycles) (Cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
189/P BO21223A7
v For follicular lymphoma patients only, a 9.5 mL EDTA blood sample will be taken for the analysis of clonal BCL2/IgH rearrangement (as a 
potential marker of tumor burden) at screening, before C4, D1, and at induction completion/ET in all patients.  
w A 5 mL blood sample will be taken for HAHA analysis in all patients receiving obinutuzumab (Arm B) before first administration of 
Gbendamustine (baseline sample) and at induction completion/ET visit.  
x Peak and trough PK samples for obinutuzumab levels should be drawn in a subset of patients receiving obinutuzumab (Arm B), per the schedule 
in Appendix B.  All PK samples will be collected from the arm opposite to that receiving the infusion.  
y A 5 mL blood sample will be taken for the assessment of B cells, T cells, and NK cells in all patients (TBNK panel).  This will include 
determination of relative and absolute numbers of CD3+, CD4+ CD8+, CD19+, and CD56+ subsets.  In addition, a more detailed analysis of B cells 
counts will be performed in approximately 60 patients of each therapeutic group (RCHOP, GCHOP, RCVP, GCVP, Rbendamustine, 
G-bendamustine) and in all patients with splenic MZL based on the markers CD45/CD19/CD22/CD79b/CD5/CD10/lambda/kappa (Bcell panel).
z If the patient consents to additional research, serum and plasma samples should be drawn prior to study drug administration for storage in the 
RCR.  With consent to optional research, the residual tumor tissue specimens from the baseline biopsy sample will also be stored in the RCR.
aa If an additional biopsy is done as part of the standard of care at the time of relapse or transformation, a tissue sample will be collected at that 
time.  A formalinfixed paraffin embedded tissue block is preferred over 1520 sections on coated slides.  
bb Prior to initiation of study medications, only SAEs caused by a protocolmandated intervention will be recorded.  After initiation of study 
medications, AEs will be recorded as follows:  all AEs will be recorded up to 28 days after the last dose of study drug, Grade 3 or 4 AEs will be 
recorded up to 6 months after the last dose of study drug, Grade 3 infections will be recorded up to 24 months after the last dose of study drug, 
unrelated SAEs will be recorded up to 12 months after the last dose of study drug, and study drug–related SAEs and secondary malignancies
will be recorded indefinitely (even if the study has been closed).  
cc Observation and collection of concomitant medication information will be continued throughout the study.  
dd PRO questionnaires (FACTLym, EQ5D) should be administered prior to any treatment assessments.  PRO questionnaires should also be 
administered at first assessment after report of disease progression.  
ee Any response assessments performed after a patient progressed and received NALT should be reported.


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
190/P BO21223A7
APPENDIX A4 
Study Flowchart:  Maintenance Treatment and Observation 
Months from Cycle 8, Day 1 (CHOP/CVP), Cycle 6, Day 1 
(bendamustine) (14 days)
Maintenance Treatment and Observation Period
Maintenance 
or 
Observation 
Completion/ 
ET Visit a
2
4
6
8
10
12
14
16
18
20
22
24
Targeted physical examination b
x
x
x
x
x
x
x
x
x
x
x
x
x
Weight and BSA
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs c
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG Performance Status
x
x
x
x
x
x
x
x
x
x
x
x
x
B symptoms
x
x
x
x
x
x
x
x
x
x
x
x
x
Hematology d
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum chemistry e
x
x
x
x
x
xe
x
x
x
x
x
x
x
Urine dipstick for protein f
x
x
x
x
Serum electrophoresis, M protein, and immunofixation (only 
in patients with MZL) g
x
x
x
x
x
Pregnancy test h
x
HBV DNA PCR i
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
Arm A:  rituximab infusion j
x
x
x
x
x
x
x
x
x
x
x
x
Arm B:  obinutuzumab infusion k
x
x
x
x
x
x
x
x
x
x
x
x
New antilymphoma treatment x
x
x
x
x
x
x
x
x
x
x
x
x
x
Imagingbased tumor assessment l
x
x
x
x
x
FDGPET m
(x)
(x)
(x)
(x)
(x)
Blood for BCL2/IgH analysis:  follicular patients n
x
x
x
x
x
HAHA samples:  obinutuzumab arm maintenance only o
x
x
x


APPENDIX A4 (cont'd)
Study Flowchart:  Maintenance Treatment and Observation
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
191/P BO21223A7
HAHA samples:  obinutuzumab arm observation only o
x
x
x
PK sampling:  subset in obinutuzumab arm, maintenance 
only p
x
x
x
x
x
PK sampling: subset in obinutuzumab arm, observation only q
x
x
x
x
x
Leukocyte immunophenotyping (FACS) r
x
x
Quantitative immunoglobulins (IgA, IgG, IgM)
x
Tumor tissue sample at time of relapse
(x) s
Bone marrow biopsy
(x) t
Adverse events u
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications v
x
x
x
x
x
x
x
x
x
x
x
x
x
PRO questionnaires w
x
x
x
AEadverse event; BSAbody surface area; CHOPcyclophosphamide, doxorubicin, vincristine, and prednisone 
(prednisolone/methylprednisolone); CT computed tomography; CVPcyclophosphamide, vincristine, and prednisone 
(prednisolone/methylprednisolone); ECOGEastern Cooperative Oncology Group; EDTAethylenediaminetetraacetic acid; EOIend of infusion; 
EQ5DEuropean Quality of Life (EuroQol) Questionnaire; ET early termination; FACSfluorescenceactivated cell sorter; 
FACT-Lym Functional Assessment of Cancer Therapy for Lymphoma; FDG 18Ffluorodeoxyglucose; GGA101; HAHAhuman antihuman 
antibody; HBcAbhepatitis B core antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; IVintravenous; LDHlactate 
dehydrogenase; MRImagnetic resonance imaging; MZLmarginal zone lymphoma; NKnatural killer;  PCRpolymerase chain reaction; 
PET positron emission tomography; PKpharmacokinetic; PRpartial response; PROpatient-reported outcome; Rrituximab; RBC red blood 
cell; SAEserious adverse event; SDstable disease; WBCwhite blood cell.  
Notes:  On treatment days, all assessments should be performed prior to dosing unless otherwise noted.  
Study visits should occur on the scheduled day (14 days), with the exception of delays resulting from toxicities.  In case of toxicity, the study visit 
should be shifted by 14 days if the window allows.  If toxicity is still present, next treatment can be delayed up to 42 days.  The delay should be 
caught up within the next few subsequent visits to keep the duration of maintenance to a maximum of 24 months.  If the end of induction visit was 
done 8 weeks after the last dose of immunochemotherapy, the first maintenance visit should be scheduled 714 days later in order to keep an 
interval between end of induction and maintenance month 2.  
(x)conditional/optional; refer to footnote for details.  


APPENDIX A4 (cont'd)
Study Flowchart:  Maintenance Treatment and Observation
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
192/P BO21223A7
a Patients who complete the maintenance treatment or observation period or who discontinue early will be asked to return to the clinic within 
2135 days after the last immunotherapy dose or date of the decision to discontinuation for a maintenance or observation completion/ET visit.  
The completion/ET visit will be approximately 25 months after Cycle 8, Day 1 (CHOP/CVP), or Cycle 6, Day 1 (bendamustine).  At any time that 
the investigator suspects disease progression, a full tumor assessment must be performed, including a CT scan (limited to areas of prior 
involvement if required by local authorities).  Patients who continue to demonstrate a response to treatment at the completion/ET and those who 
have stable disease will continue to be assessed every 3 months (14 days) (CT every 6 months 14 days) for an additional 3 years and then 
every 6 months 14 days (CT yearly 14 days) for 2 years or until disease progression, study withdrawal, or relapse (whichever occurs first).  In 
case of withdrawal from treatment due to toxicity, the first followup visit is scheduled 3 months (14 days) after last dose (“Month 27”; see 
Appendix A-5).  
b 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).  
c Includes blood pressure, pulse rate, and temperature.  On rituximab or obinutuzumab treatment days, vital signs should be measured prior to the 
infusion, then approximately every 30 minutes until the end of the infusion and approximately every 60 minutes until the infusion line is removed.  
d Samples should be drawn within 72 hours prior to the study drug infusion on treatment days.  Hematology includes hemoglobin, hematocrit, 
platelet count, RBC count, WBC count, and absolute neutrophil count as routine components.  Percent or absolute differential count (segmented 
neutrophils, banded neutrophils, eosinophils, lymphocytes, monocytes, basophils, malignant lymphocytes) are done if clinically indicated (e.g., 
for differential diagnosis of any kind of clinically relevant cytopenia/cytophilia or, e.g., if other undefined cells are present in the peripheral blood).  
In case of splenic MZL, the percent or absolute number of malignant lymphocytes (“villous lymphocytes”) in peripheral blood should be assessed. 
Additional samples for hematology can be drawn according to the standard of care at the site.  
e Samples should be drawn within 72 hours prior to the study drug infusion on treatment days.  Serum chemistry includes sodium, potassium, 
calcium, ALT, AST, total bilirubin, serum creatinine, alkaline phosphatase, phosphorus, total protein, albumin, and LDH.  Creatinine clearance 
according to CockcroftGault formula must be assessed 1 year after the last treatment in all patients in the observation arm.  
f
In a fresh sample of midstream urine, a dipstick testing for proteinuria is required.  
g Serum electrophoresis is required in all patients with MZL and should report percent of albumin, alpha 1, alpha 2, beta, and gamma fraction, as 
well absence/presence of an M protein.  If an M protein is present, it should be quantified in g/L and the Ig subtype (IgG, IgA, IgM, IgD, 
lightchain kappa, or lightchain lambda) determined by immunofixation.  If no M protein is found at baseline, serum electrophoresis and 
immunofixation do not need to be repeated at later time points.  
h A urine pregnancy test should be performed for all women of childbearing potential (including those who have had a tubal ligation) at the 
completion of maintenance therapy.  If a urine pregnancy test result is positive, the patient’s status is determined by a serum pregnancy test.  
i
Performed monthly, for patients who are HBsAg negative and HBcAb positive at screening only.  HBV DNA levels will be measured centrally by 
real-time PCR with use of an assay with a limit of quantification of at least 29 IU/mL.  
j
Patients in Arm A may continue to receive rituximab 375 mg/m2 IV every 2 months (14 days) for up to 2 additional years or until evidence of 
clinical progression (whichever occurs first).  
k Patients in Arm B may continue to receive obinutuzumab 1000 mg IV every 2 months (14 days) for up to 2 additional years until evidence of 
clinical progression (whichever occurs first).  


APPENDIX A4 (cont'd)
Study Flowchart:  Maintenance Treatment and Observation
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
193/P BO21223A7
l
Imagingbased tumor assessment:  CT scan (with contrast) of the chest, abdomen, pelvis (and neck, if clinically indicated).  CT scans for 
response assessment should be done within 14 days prior to the followup study visit and may be limited to areas of prior involvement if 
required by local regulatory authorities.  Any time the investigator suspects disease progression, a full tumor assessment must be performed, 
including a CT scan (limited to areas of prior involvement if required by local authorities).  MRIs with a noncontrast CT scan of the chest may be 
used for patients for whom CT scans with contrast are contraindicated.  If MRI is used at screening, then MRI should be used throughout the 
study (same method during the entire study).  Combined FDGPET/CT scans may be used only if performed with contrast and if collected with 
resolution sufficient to allow accurate and consistent comparison of target lesion measurements with subsequent CT scans.  Measurement of 
lymphoma lesions by ultrasound is not the preferred option because of the inherent interexaminer variability.  However, in patients with splenic 
MZL, the spleen is considered a target lesion, and its size should be determined by ultrasound (length and thickness), CT/MRI, or by physical 
examination.  For ultrasound/CT/MRI or physical examination measurements, local guidelines for determining normal organ size are acceptable.  
PET is optional and may be done at the investigator’s discretion.  
m FDGPET is optional and may be done at investigator’s discretion.  
n For follicular lymphoma patients only, a 9.5 mL EDTA blood sample will be taken for the analysis of clonal BCL2/IgH rearrangement (as a 
potential marker of tumor burden) in all patients.  
o A 5 mL blood sample will be taken for HAHA analysis in all patients receiving obinutuzumab (Arm B).  
p A blood sample for obinutuzumab levels should be drawn in a subset of patients from the obinutuzumab arm (Arm B) during maintenance at 
Months 6, 12, 18, and 24, and at the maintenance or observation completion visit/ET. For patients receiving obinutuzumab maintenance, a 
trough sample (04 hours before the start of infusion) and a peak sample (030 minutes after the end of infusion) should be drawn at each time 
point.  All PK samples will be collected from the arm opposite to that receiving the infusion.  
q A blood sample for obinutuzumab levels should be drawn in a subset of patients from the obinutuzumab arm (Arm B) during observation at 
Months 4 and 8, 18 and 24 and at the observation completion visit/ET.  For patients in observation, only one sample should be drawn at each 
time point.  All PK samples will be collected from the arm opposite to that receiving the infusion.  
r
A 5 mL blood sample will be taken for the assessment of B cells, T cells, and NK cells in all patients (TBNK panel).  This will include 
determination of relative and absolute numbers of CD3+, CD4+ CD8+, CD19+, and CD56+ subsets.  In addition, a more detailed analysis of B cells 
counts will be performed in approximately 60 patients of each therapeutic group (RCHOP, GCHOP, R-CVP, GCVP, R-bendamustine, G-
bendamustine) and in all patients with splenic MZL based on the markers CD45/CD19/CD22/CD79b/CD5/CD10/lambda/kappa (B cell panel).  
s If an additional biopsy is done as part of the standard of care at the time of relapse or transformation, a tissue sample will be collected at that 
time.  A formalinfixed paraffin embedded tissue block is preferred over 1520 sections (35m thickness) on coated slides.  
t
In patients with continued bone marrow involvement or in patients without additional bone marrow biopsy at end of induction or PR/SD due to 
other reasons at EOI, a subsequent bone marrow biopsy may be required to confirm a CR at a later time point (e.g., during 
maintenance/observation).  
u All AEs will be recorded up to 28 days after the last dose of study drug, Grade 3 or 4 AEs will be recorded up to 6 months after the last dose of 
study drug, Grade 3 infections will be recorded up to 24 months after the last dose of study drug, unrelated SAEs will be recorded up to 
12 months after the last dose of study drug, and study drug–related SAEs and secondary malignancies will be recorded indefinitely (even if the 
study has been closed).  


APPENDIX A4 (cont'd)
Study Flowchart:  Maintenance Treatment and Observation
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
194/P BO21223A7
v Observation and collection of concomitant medication information will be continued throughout the study.  
w PRO questionnaires (FACTLym, EQ5D) should be administered prior to any treatment assessments.  PRO questionnaires should also be 
administered at first assessment after report of disease progression.  
x Any response assessments performed after a patient progressed and received NALT should be reported.


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
195/P BO21223A7
APPENDIX A5 
Study Flowchart:  FollowUp
Months from Cycle 8, Day 1 (CHOP/CVP), Cycle 6, Day 1 
(Bendamustine), or Last Treatment Cycle (Early 
Termination) 
(14 days)
Year 1
Year 2
Year 3
Year 4
Year 5
27
30
33
36
39
42
45
48
51
54
57
60
66
72
78
84
Targeted physical examination a
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG Performance Status
x
x
x
x
x
x
x
x
B symptoms
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hematology b
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum electrophoresis, M protein, and immunofixation (only 
in patients with MZL) c
x
x
x
x
x
x
x
x
Lactate dehydrogenase
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
HBV DNA PCR and AST/ALT d
(x)
(x)
(x)
(x)
New antilymphoma treatment e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Survival followup e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Imagingbased tumor assessment f
x
x
x
x
x
x
x
x
FDGPET g
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
Blood for BCL2/IgH analysis:  follicular patients h
x
x
x
x
x
x
x
x
HAHA samples (GA 101 arm only) i
x
x
x
x
PK sampling (only in subset of obinutuzumab maintenance
patients) j
x
x
x
x
x
Leukocyte immunophenotyping (FACS) k
x
x
x
x
x
Quantitative immunoglobulins (IgA, IgG, IgM)
x
x
x
x
x
Tumor tissue sample at time of relapse
(x) l


APPENDIX A5 (cont'd)
Study Flowchart:  FollowUp
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
196/P BO21223A7
Months from Cycle 8, Day 1 (CHOP/CVP), Cycle 6, Day 1 
(Bendamustine), or Last Treatment Cycle (Early 
Termination) 
(14 days)
Year 1
Year 2
Year 3
Year 4
Year 5
27
30
33
36
39
42
45
48
51
54
57
60
66
72
78
84
Adverse events m
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications n
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PRO questionnaires (FACTLym, EQ5D) o
x
x
x
x
x
Urine dipstick for protein p
x
x
x
x
Creatinine clearanceq
x
AE adverse event; CHOP cyclophosphamide, doxorubicin, vincristine, and prednisone (prednisolone/methylprednisolone); CT computed 
tomography; CVP cyclophosphamide, vincristine, and prednisone (prednisolone/methylprednisolone); ECOG Eastern Cooperative Oncology 
Group; EDTAethylenediaminetetraacetic acid; EQ5DEuropean Quality of Life (EuroQol) Questionnaire; FACS fluorescenceactivated cell 
sorter; FACT-Lym Functional Assessment of Cancer Therapy for Lymphoma; FDG 18Ffluorodeoxyglucose; HAHA human antihuman 
antibody; G GA101; HBcAb hepatitis B core antibody; HBsAg hepatitis B surface antigen; HBV hepatitis B virus; MRI magnetic resonance 
imaging; MZL marginal zone lymphoma; NK natural killer; PCR polymerase chain reaction; PDprogressive disease; PET positron emission 
tomography; PK pharmacokinetic; PRO patient-reported outcome; R rituximab; RBC red blood cell; SAE serious adverse event; WBC white 
blood cell.  
(x) conditional/optional; refer to footnote for details.  
Study visits should occur on the scheduled days (14 days).  
a 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).  
b Hematology includes hemoglobin, hematocrit, platelet count, RBC count, WBC count, and absolute neutrophil count as routine components.  
Percent or absolute differential count (segmented neutrophils, banded neutrophils, eosinophils, lymphocytes, monocytes, basophils, malignant 
lymphocytes) are done if clinically indicated (e.g., for differential diagnosis of any kind of clinically relevant cytopenia/cytophilia or, e.g., if other 
undefined cells are present in the peripheral blood).  In case of splenic MZL, the percent or absolute number of malignant lymphocytes (“villous 
lymphocytes”) in peripheral blood should be assessed.  Additional samples for hematology can be drawn according to the standard of care at the 
site.  
c Serum electrophoresis is required in all patients with MZL and should report percent of albumin, alpha 1, alpha 2, beta, and gamma fraction, as 
well absence/presence of an M protein.  If an M protein is present, it should be quantified in g/L and the Ig subtype (IgG, IgA, IgM, IgD, 
lightchain kappa, or lightchain lambda) determined by immunofixation.  If no M protein is found at baseline, serum electrophoresis and 
immunofixation do not need to be repeated at later time points.  


APPENDIX A5 (cont'd)
Study Flowchart:  FollowUp
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
197/P BO21223A7
d Performed every 4 weeks, for patients who are HBsAg negative and HBcAb positive at screening only.  HBV DNA levels will be measured 
centrally by realtime PCR with use of an assay with a limit of quantification of at least 29 IU/mL.  
e Patients with disease progression will be followed for new antilymphoma treatment and survival twice per year until the end of the study    
(approximately 10.2 years).  For patients who progressed and received NALT, any response after NALT should be reported. Patients who 
complete the 5 years of followup without disease progression will be followed for PD, new antilymphoma treatment, and survival.  The first visit 
in survival followup should be performed 6 months after the last clinical visit.  
f
Imagingbased tumor assessment:  CT scan (with contrast) of the chest, abdomen, pelvis (and neck, if clinically indicated).  CT scans for 
response assessment should be done within 14 days prior to the followup study visit and may be limited to areas of prior involvement if required 
by local regulatory authorities. Any time the investigator suspects disease progression, a full tumor assessment must be performed, including a 
CT scan (limited to areas of prior involvement if required by local authorities).  MRIs with a non-contrast CT scan of the chest may be used for 
patients for whom CT scans with contrast are contraindicated.  If MRI is used at screening, then MRI should be used throughout the study (same 
method during the entire study).  Combined FDGPET/CT scans may be used only if performed with contrast and if collected with resolution 
sufficient to allow accurate and consistent comparison of target lesion measurements with subsequent CT scans.  Measurement of lymphoma 
lesions by ultrasound is not the preferred option because of the inherent interexaminer variability.    However, in patients with splenic MZL, the 
spleen is considered a target lesion, and its size should be determined by ultrasound (length and thickness), CT/MRI, or by physical examination.  
For ultrasound/CT/MRI or physical examination measurements, local guidelines for determining normal organ size are acceptable. 
g FDGPET is optional and may be done at the investigator’s discretion.  
h For follicular lymphoma patients only, a 9.5 mL EDTA blood sample will be taken for the analysis of clonal BCL2/IgH rearrangement 
(as a potential marker of tumor burden) in all patients.  
I
A blood sample will be taken for HAHA analysis in all patients receiving obinutuzumab (Arm B).  
j
A blood sample will be taken for PK analysis in a subset of patients who received obinutuzumab as maintenance.  All PK samples will be 
collected from the arm opposite to that receiving the infusion.  
k A 5 mL blood sample will be taken for the assessment of B cells, Tcells, neutrophils, and NK cells in all patients (TBNK panel).  This will include 
determination of relative and absolute numbers of CD3+, CD4+ CD8+,CD19+, and CD56+ subsets.  In addition, a more detailed analysis of B cell 
counts will be performed in approimately. 60 patients of each therapeutic group (RCHOP, GCHOP, RCVP, GCVP, R-bendamustine, 
Gbendamustine) and in all patients with splenic MZL based on the markers CD45/CD19/CD22/CD79b/CD5/CD10/lambda/kappa (B cell panel).  
l
If an additional biopsy is done as part of the standard of care at the time of relapse or transformation, a tissue sample will be collected at that 
time. A formalinfixed paraffin embedded tissue block is preferred over 1520 sections (35 µm thickness) on coated slides.  
m All AEs will be recorded up to 28 days after the last dose of study drug, Grade 3 or 4 AEs will be recorded up to 6 months after the last dose 
of study drug, Grade 3 infections will be recorded up to 24 months after the last dose of study drug, unrelated SAEs will be recorded up to 
12 months after the last dose of study drug, and study drugrelated SAEs and secondary malignancies will be recorded indefinitely (even if the 
study has been closed).  
n Observation and collection of concomitant medication information will be continued throughout the study.  


APPENDIX A5 (cont'd)
Study Flowchart:  FollowUp
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
198/P BO21223A7
o PRO questionnaires (FACTLym, EQ5D) should be administered prior to any treatment assessments.  PRO questionnaires should also be 
administered at first assessment after report of disease progression.  
p In a fresh sample of midstream urine, a dipstick testing for proteinuria is required.  
q Glomerular filtration rate should be measured according to Cockroft Gault 1 year after last treatment. 


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
199/P BO21223A7
APPENDIX B 
Pharmacokinetic Assessments
Ideally, all pharmacokinetic (PK) 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.  
Pharmacokinetic Sampling Schedule:  
The PK sampling schedule below is applicable to a subset of patients receiving 
obinutuzumab.  Approximately 23 samples per obinutuzumab-treated patient will be 
collected during the study.  
Study Visit
Time Point
Type of Sample
Cycle 1, Day 1
Preinfusion
Obinutuzumab Serum
Postinfusion
Obinutuzumab Serum
Cycle 1, Day 8
Preinfusion
Obinutuzumab Serum
Postinfusion
Obinutuzumab Serum
Cycle 1, Day 15
Preinfusion
Obinutuzumab Serum
Postinfusion
Obinutuzumab Serum
Cycle 1, Day 22 (Benda)
No dose given
Obinutuzumab Serum
Cycle 2, Day 1 
(CVP/CHOP/Benda) 
Preinfusion 
Obinutuzumab Serum
Postinfusion
Obinutuzumab Serum
Cycle 4, Day 1
Preinfusion 
Obinutuzumab Serum
Postinfusion
Obinutuzumab Serum
Cycle 6, Day 1
Preinfusion 
Obinutuzumab Serum
Postinfusion
Obinutuzumab Serum
Induction Completion/Early 
Termination Visit
No dose given 
Obinutuzumab Serum
Maintenance Months 6, 
12, 18, and 24
Preinfusion
Obinutuzumab Serum
Postinfusion
Obinutuzumab Serum
Maintenance or 
Observation 
completion/ET
No dose given
Obinutuzumab Serum
Observation Months 4, 8, 
18, 24, and observation 
completion/ET
No dose given
Obinutuzumab Serum
Followup (only in patients 
who received maintenance 
treatment with 
obinutuzumab)
Months 27, 30, 36, 42, and 
48
No dose given
Obinutuzumab Serum


APPENDIX B (cont’d)
Pharmacokinetic Assessments
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
200/P BO21223A7
Note:  Preinfusion samples should be drawn 04 hours before the start of infusion.  
Post-infusion samples should be drawn 030 minutes after the end of the infusion. All 
PK samples will be collected from the arm opposite to that receiving the infusion.  
Bendabendamustine.


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
201/P BO21223A7
APPENDIX C 
Modified Version of the 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:  

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
If the GTD measures between 1.11.5 cm, the short axis must measure 
1.0 cm.  

All extranodal lesions must measure 1.0 cm in the GTD.  

If possible, the lesions should be from disparate regions of the body

Should include mediastinal and retroperitoneal areas of disease whenever these 
sites are involved

Extranodal lesions within the liver or spleen must be at least 1.0 cm in 
two perpendicular dimensions.  
In splenic marginal zone lymphoma (MZL) only:  The spleen should be selected as 
target lesion if splenomegaly is present.  Spleen size should be determined for splenic 
MZL by ultrasound if possible or by CT/MRI or by physical examination.  
Selection of Nontarget Lesions
Nontarget 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 nontarget lesions, including any measurable lesions that were not chosen as target 
lesions.  Examples of nontarget lesions include:  

All bone lesions, irrespective of the modality used to assess them

Lymphangitis of the skin or lung

Cystic lesions

Splenomegaly (except splenic MZL) and hepatomegaly (all lymphomas)

Irradiated lesions

Measurable lesions beyond the maximum number of six

Groups of lesions that are small and numerous
Pleural/pericardial effusions and/or ascites


APPENDIX C (cont'd)
Modified Version of the Revised Response Criteria 
for Malignant Lymphoma
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
202/P BO21223A7

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.  
Existing effusions/ascites:  Effusions, ascites, or other fluid collections will be 
followed as nontarget 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 Assess (UA) Lesion Category
This category is reserved for target and nontarget lesions that are deemed UA because:  

One or more target/nontarget cannot be assessed (e.g., inadequate scan coverage, 
contrast, artifacts, or other factors).  

Assessment methods used were inconsistent with those used (e.g., modality 
change, change in contrast administration).  

One or more target/nontarget lesions were excised or irradiated and have not 
reappeared or increased.  
Examples of UA 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.  
Not Done (ND) Lesion Category
This category is reserved for target and nontarget lesions identified at baseline that were 
not imaged at a subsequent time point. Such incidents should be avoided with utmost 
diligence since they are likely to make response assessment impossible for the affected 
time point.  


APPENDIX C (cont'd)
Modified Version of the Revised Response Criteria 
for Malignant Lymphoma
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
203/P BO21223A7
For the following cases, the ND lesion category should not be used:  

Lesions which were imaged but which were not measured by the 
radiologist/reviewer.  In such cases, the radiologist has to provide a measurement 
unless the lesion is assessed as UA.  

Lesions which were imaged but resolved completely.  
Effects of UA and ND Lesions on Response Assessment
If a target lesion is classified as UA or ND after baseline, the sum of the product of the 
diameters (SPD)/area (whichever applies) of the target lesions cannot accurately be 
determined for that time point.  Therefore, a response of CR, PR, or SD cannot be 
assigned for that time point and the response assessment will be UA for this time point 
unless unequivocal progression is determined on the basis of nontarget or new lesions, 
or the evaluable target lesions.  
PD can be determined without evaluation of all sites of disease on the basis of the GTD, 
area or SPD for target lesions, evaluation of unequivocal progression in nontarget 
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 both dimensions, should be categorized as TSTM or 
BML. The lesion, node, or mass should be assigned measurements of 5 mm5 mm (for 
the GTD and the short axis) on the Source Document for the purpose of calculating the 
area.  If that lesion increases in size to 5 mm in any dimension afterward, its true size
(GTD and short axis) should be recorded.  If lesions have completely disappeared, a 
value of “0” should be assigned for the long and short axis dimensions.  The purpose of 
the assigned value for the measurement is the acknowledgment that small findings are 
not accurately measured.  


APPENDIX C (cont'd)
Modified Version of the Revised Response Criteria 
for Malignant Lymphoma
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
204/P BO21223A7
Time Point Response
Target Lesions
NonTarget 
Lesions
New Lesions1
Time Point 
Response
CR
CR
No
CR
CR
SD
No
PR
CR
UA/ND
No
UA
PR
UA/ND
No
UA
PR
CR
No
PR
PR
SD
No
PR
SD
UA/ND
No
UA
SD
CR
No
SD
SD
SD
No
SD
PD
ANY
Yes/No
PD
ANY
PD
Yes/No
PD
ANY
ANY
Yes
PD
UA/ND
NonPD
No
UA
UA/ND
UA/ND
No
UA
CR
NA3
No
CR
PR
NA3
No
PR
SD
NA3
No
SD
NA2
SD
No
SD
NA2
CR
No
CR
NA2
UA/ND
No
UA
NA2
NA3
No
UA
Modified from Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for 
malignant lymphoma. J Clin Oncol 2007;25:57986.  
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 UA, 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.  
Response should be determined on the basis of radiographic and clinical evidence of 
disease with use of the modified 2007 Cheson criteria below.  


APPENDIX C (cont'd)
Modified Version of the Revised Response Criteria 
for Malignant Lymphoma
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
205/P BO21223A7
FDGPET scans are mandatory in the first 170 patients with follicular lymphoma 
at sites where a PET scanner is available and where an approval has been 
obtained at screening and at completion of induction/end of treatment (only if the 
result of screening PET was positive) to assess response at the completion of 
induction (68 weeks after Day 1 of the last cycle).  An early termination visit 
PET should occur within 48 weeks after the last dose (in case of early 
termination due to adverse event) or within 28 weeks after last dose 
(in case of early termination due to clinical disease progression).  
An analysis of response rates including the assessment by FDGPET scans will be 
performed as exploratory analyses for scientific purposes.  
The use of FDGPET for assessment of response has been clarified following the 
recommendations as published by Cheson et al. (2007) and Juweid et al. (2007).  
However, FDGPET scans alone without confirmatory computed tomography (CT) 
progression should not be used for assessment of relapsed or progressive disease.  
For the determination of complete response or partial remission for patients with no 
pretreatment PET scan or when their PET scan is positive before treatment, a 
post-treatment residual mass of any size is permitted as long as it is PET negative.  
In addition, assessment of PET results should be made according to the criteria of 
Juweid et al. (2007).  
Complete Remission (CR)
1.
Complete disappearance of all detectable clinical evidence of disease 
and disease-related symptoms if present prior to therapy
2.
The spleen and/or liver, if considered enlarged prior to therapy on the basis of 
a physical examination or CT scan, should not be palpable on physical examination 
and should be considered normal size by imaging studies, and nodules related to 
lymphoma should disappear.  However, determination of splenic involvement is not 
always reliable because a spleen considered normal in size may still contain 
lymphoma, whereas an enlarged spleen may reflect variations in anatomy, blood 
volume, the use of hematopoietic growth factors, or causes other than lymphoma.  


APPENDIX C (cont'd)
Modified Version of the Revised Response Criteria 
for Malignant Lymphoma
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
206/P BO21223A7
3.
If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must 
have cleared on repeat bone marrow biopsy.  The biopsy sample on which this 
determination is made must be adequate (20 mm unilateral core).  If the sample 
is indeterminate by morphology, it should be negative by immunohistochemistry.  
A sample that is negative by immunohistochemistry but demonstrating a small 
population of clonal lymphocytes by flow cytometry will be considered a CR until 
data become available demonstrating a clear difference in patient outcome.  
4.
In patients with splenic MZL, normalization of the blood counts 
(hemoglobin 12 g/dL; platelets 100109/L; neutrophils 1.5109/L and no 
evidence of circulating clonal B cells) will be required.  For determination of splenic 
response by ultrasound/CT/MRI/physical examination, local guidelines for 
determining normal organ size are acceptable, but the spleen must be of normal 
size with no intrasplenic lesion present.  
5.
In patients with extranodal (MALT) MZL with gastrointestinal involvement at 
screening the response should be assessed with both endoscopy and histology.  
Definition of complete histologic regression is obtained when the posttreatment 
biopsies show no sign of remaining lymphoma but instead an empty tunica propria 
with small basal clusters of lymphocytes and scattered plasma cells.  
6.
In patients with MZL and paraprotein at screening, paraprotein must be absent by 
serum electrophoresis and immunofixation.  
In patients for whom PET imaging is available, a second response assessment should 
be made with incorporation of PET imaging results:  

The designation of CR requires the following:  all CR requirements as described 
above for a CTonly CR.  However, if there is a PET scan positive before therapy, a 
posttreatment residual mass of any size is permitted as long as it is PET negative.  
Partial Remission (PR)
1.
50% decrease in SPD of up to 6 of the largest dominant nodes or nodal masses.  
These nodes or masses should be selected according to the following:  a) they 
should be clearly measurable in at least 2 perpendicular dimensions; b) if possible, 
they should be from disparate regions of the body; c) they should include 
mediastinal and retroperitoneal areas of disease whenever these sites are involved.  
2.
No increase in the size of the other nodes, liver, or spleen
3.
Splenic and hepatic nodules must regress by 50% in their SPD or, for single 
nodules, in the greatest transverse diameter.  
4.
With the exception of splenic and hepatic nodules, involvement of other organs 
is usually assessable and no measurable disease should be present.  


APPENDIX C (cont'd)
Modified Version of the Revised Response Criteria 
for Malignant Lymphoma
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
207/P BO21223A7
5.
Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive prior to treatment.  However, if positive, the cell type should be specified 
(e.g., largecell lymphoma or small neoplastic B cells).  Patients who achieve a 
complete remission by the above criteria but who have persistent morphologic bone 
marrow involvement will be considered partial responders.  
6.
No new sites of disease should be observed (e.g., nodes 1.5 cm in any axis).  
In patients for whom PET imaging is available, a second response assessment should 
be made:  

For patients with no pretreatment PET scan or if the PET scan was positive before 
therapy, the posttreatment PET should be positive in at least one previously 
involved site.  Assessment of PET should follow the criteria described by Juweid et 
al. 2007.  
In splenic MZL, partial response in the spleen is defined as a reduction of splenomegaly 
from baseline by ≥50%, but the spleen is still of abnormal size.  
In extranodal (MALT) MZL, partial histologic regression is defined as posttreatment 
biopsy samples revealing either focal atypical lymphoid cells or lymphoepithelial 
destruction and an empty tunica propria as signs of lymphoma regression.  
Stable Disease (SD)
Failing to attain the criteria needed for a CR or PR but not fulfilling those for progressive 
disease (see below).  
In patients for whom PET imaging is available, a second response assessment should 
be made:  

PET should be positive at prior sites of disease with no new areas of involvement 
on the posttreatment CT or PET scan.  Assessment of PET should follow the 
criteria described by Juweid et al. (2007).  


APPENDIX C (cont'd)
Modified Version of the Revised Response Criteria 
for Malignant Lymphoma
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
208/P BO21223A7
Relapsed Disease (RD; after CR) or Progressive Disease (PD; for Patients 
with 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 be considered 
abnormal only if its short axis is 1.0 cm.  Lymph nodes 1.0 cm by 1.0 cm will not be 
considered as abnormal for relapse or progressive disease.  
1.
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size.  
2.
At least a 50% increase from nadir in the SPD of any previously involved nodes, or 
in a single involved node, or the size of other lesions (e.g., splenic or hepatic 
nodules).  To be considered progressive disease, a lymph node with a diameter of 
the short axis of less than 1.0 cm must increase by 50% and to a size 
of 1.5 1.5 cm or more than 1.5 cm in the long axis.  
3.
At least a 50% increase in the longest diameter of any single previously identified 
node more than 1 cm in its short axis.  
4.
In patents with gastric MALT, relapse of the underlying gastric MALT lymphoma will 
be diagnosed whenever lymphoepithelial lesions are again present after the patient 
had entered CR.  
5.
If FDGPET has been obtained, PD should be designated only if there are 
CT criteria for progression and the lesions are PET positive if the patient had 
PET-positive disease prior to therapy.  FDGPET is not mandatory for surveillance 
of progression.  
6.
In splenic MZL, in addition to criteria 15, PD should be designated if spleen size 
increases due to lymphoma by ≥50% from nadir or becomes of unequivocally 
abnormal size again after having reached normal size before.  
Measurable extranodal disease should be assessed in a manner similar to that 
for nodal disease.  For these recommendations, the spleen is considered nodal disease.  
Clarification 1:  The investigators should be aware that, in small lymph nodes, a 
difference of only a few millimeters can result in an increase of more than 50% in the 
calculation of the SPD.  Since the precision in comparing small differences in the 
diameters with former CT scans may be limited, in this situation, the investigator should 
check very carefully whether the observed differences can be a result of these limitations.  
This is especially important if a small increase is seen in only one site.  Progression 
should be assessed only if it is considered unequivocal progression.  A new evaluation 
after some weeks may be necessary to determine whether there was true progression in 
that lesion. 


APPENDIX C (cont'd)
Modified Version of the Revised Response Criteria 
for Malignant Lymphoma
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
209/P BO21223A7
Clarification 2:  In cases where only one target lesion was documented at baseline and it 
has subsequently been surgically removed after the baseline scan was obtained and 
after the first day of treatment, the response assignment will be considered UA unless 
there is progression elsewhere, qualifying the time point as PD.  
References:  
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.  
Matutes E, Oscier D, Montalban C, et al. Splenic marginal zone lymphoma 
proposals for a revision of diagnostic, staging and therapeutic criteria. Leukemia 
2008;22:487–95.  








Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
213/P BO21223A7
APPENDIX E 
EuroQol's EQ5D Questionnaire
By placing a checkmark in one box in each group below, please 
indicate which statements best describe your own health state today.  
Mobility
I have no problems in walking about

I have some problems in walking about

I am confined to bed

SelfCare
I have no problems with selfcare

I have some problems washing or dressing myself

I am unable to wash or dress myself

Usual Activities (e.g., work, study, housework, family, or
leisure activities)
I have no problems with performing my usual activities

I have some problems with performing my usual activities

I am unable to perform my usual activities

Pain/Discomfort
I have no pain or discomfort

I have moderate pain or discomfort

I have extreme pain or discomfort

Anxiety/Depression
I am not anxious or depressed

I am moderately anxious or depressed

I am extremely anxious or depressed



Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
214/P BO21223A7
APPENDIX F 
Commonly Used CYP1A2 Inhibitors and Inducers
Based on the product information for bendamustine, no formal clinical 
assessments of pharmacokinetic drug-drug interactions between bendamustine 
and other drugs have been conducted.   Bendamustine's active metabolites, 
gamma-hydroxy bendamustine (M3) and N-desmethylbendamustine (M4), 
are formed via cytochrome P450 CYP1A2.  Inhibitors of CYP1A2 
(e.g., fluvoxamine, ciprofloxacin) have potential to increase plasma 
concentrations of bendamustine and decrease plasma concentrations of active 
metabolites.  Inducers of CYP1A2 (e.g., omeprazole, smoking) have potential to 
decrease plasma concentrations of bendamustine and increase plasma 
concentrations of its active metabolites.   
The medications listed below are not contraindicated; however, caution should 
be used, or alternative treatments with medications that are not CYP1A2 
inhibitors or inducers should be considered if concomitant treatment with 
CYP1A2 inhibitors or inducers is needed for your patient's medical 
condition.   This list is not exhaustive.  
CYP1A2 Inhibitors
CYP1A2 Inhibitors (continued)
Amiodarone
Ketoconazole
Amitriptyline
Lidocaine
Amlodipine
Losartan
Anastrozole
Erythromycin
Caffeine
Estrogens
Cimetidine (Tagamet)
Mexiletine
Ciprofloxacin (Cipro)
Modafenil
Citalopram
Nifedipine
Clarithromycin
Olanzapine
Clotrimazole
Omeprazole
Clozapine
Ondansetron
Diclofenac
Paroxetinee
Diltiazem
Propafenone
Echinacea 
Propanolol
Ethinyl Estradiol
Ranitidine
Fluoroquinolones
Sertraline
Fluconazole
Fluvoxamine
Gemfibrozil
Ginseng
Imipramine
Isoniazid


APPENDIX F (cont'd)
Commonly Used CYP1A2 Inhibitors and Inducers
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
215/P BO21223A7
CYP1A2 Inducers
Barbiturates (e.g., Phenobarbital)
Cruciferous vegetables (broccoli, cauliflower, arugula, brussel sprouts, cabbage, kale, chard, 
turnips, radishes, wasabi, bok choy, watercress, collard greens)
Chargrilled meat
Carbamazepine (e.g., Tegretol)
Primidone
Rifampin (e.g., Rifadin)
Smoking
Triamterene (Dyrenium)
Zolmitriptan (Zomig)
Adapted from ctep.cancer.gov/protocolDevelopment/docs/cyp1a2.doc
Sample Card to be handed to patients on the BO21223 study. This card may be 
adapted to comply with local guidelines:  
During this clinical study, I am receiving a drug called bendamustine.  This drug 
is approved for the treatment of lymphoma in the United States of America and a 
number of the European Union member states.  The following medications and 
substances are examples of drugs and substances that may alter blood levels of 
bendamustine:  
Fluvoxamine
Ciprofloxacin
Omeprazole
Smoking
Caution must be used or alternative treatments be considered if treatment with 
one of these listed drugs or substances or another CYP1A2 inhibitor or inducer is 
needed. 
If you have further questions, please contact the study doctor whose name and 
contact number are indicated on the other side of this card.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
216/P BO21223A7
APPENDIX G 
Inclusion Criteria for Patients with Gastric 
Extranodal Marginal Zone Lymphoma
The following patients with gastric extranodal marginal zone lymphoma are eligible 
for enrollment:  

Patients with Helicobacter pylori–negative disease that is de novo or has relapsed 
following local therapy (i.e., surgery or radiotherapy)

Patients originally diagnosed with H. pylori–positive disease that remained stable, 
progressed, or relapsed following antibiotic therapy, including the following:  
Patients with clinical (endoscopic) and histological evidence of disease 
progression at any time after H. pylori eradication
Patients with stable disease with persistent lymphoma at least 1 year after 
H. pylori eradication
Patients with disease that relapsed (without H. pylori reinfection) after a 
remission
Patients who failed either firstline antibiotics or further local treatment (surgery 
or radiotherapy)


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
217/P BO21223A7
APPENDIX H 
ECOG Performance Status Scale and Ann Arbor Staging
ECOG Performance Status Scale
Grade
Description
0
Fully active, able to carry on all pre-disease performance 
without restriction
1
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature, 
e.g., light housework or office work
2
Ambulatory and capable of all self-care but unable to 
carry out any work activities.  Up and about 50% of 
waking hours
3
Capable of only limited self-care, confined to a bed or 
chair 50% of waking hours
4
Completely disabled.  Cannot carry on any self-care.  
Totally confined to a bed or chair
5
Dead
Ann Arbor Staging
Stage I
Involvement of a single lymph node region (I) or of a single extralymphatic organ 
or site (IE) a
Stage II
Involvement of two or more lymph node regions or lymphatic structures on the 
same side of the diaphragm alone (II) or with involvement of limited, contiguous 
extralymphatic organ or tissue (IIE)
Stage III
Involvement of lymph node regions on both sides of the diaphragm (III) which may 
include the spleen (IIIS) or limited, contiguous extralymphatic organ or siteb (IIIE), 
or both (IIIES)
Stage IVb
Diffuse or disseminated foci of involvement of one or more extralymphatic organs 
or tissues, with or without associated lymphatic involvement
a The designation “E” generally refers to extranodal contiguous extension (i.e., proximal or 
contiguous extranodal disease) that can be encompassed within an irradiation field 
appropriate for nodal disease of the same anatomic extent. A single extralymphatic site as 
the only site of disease should be classified as IE, rather than Stage IV.  
b Involvement of bone marrow at screening will always qualify for Ann Arbor Stage IV and 
should be recorded as extranodal involvement.  
All cases are subclassified to indicate the absence (A) or presence (B) of the systemic 
(“B”) symptoms of significant unexplained fever (38C), night sweats, or unexplained 
weight loss exceeding 10% of body weight during the 6 months prior to diagnosis.  


APPENDIX H (cont'd)
ECOG Performance Status Scale and Ann Arbor Staging
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
218/P BO21223A7
Adapted from:  
Carbone PP, Kaplan HS, Musshoff K, et al. Report of the committee on 
Hodgkin’s disease staging classification. Cancer Res 1971;31:1860-1.  
Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to 
discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds 
meeting. J Clin Oncol 1989;7:1630-6.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
219/P BO21223A7
APPENDIX I 
Calculation of Creatinine Clearance 
Using the Cockcroft-Gault Formula
Creatinine Clearance (men)(140Age)Lean Body Weight [kilograms]
                                                   Serum Creatinine (mg/dL)72
Creatinine Clearance (women)0.85 (140Age)Lean Body Weight 
[kilograms]
                                                          Serum Creatinine (mg/dL)72
Reference:  
Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from 
adjusted serum creatinine (editorial). Nephron 1992;62:249.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
220/P BO21223A7
APPENDIX J
Rituximab Preparation Instructions
All transfer procedures require strict adherence to aseptic techniques, preferably in 
a laminar flow hood.  Prepare rituximab solution as follows  

Refrigerate 2C8Call materials and solutions prior to use.  Do not freeze or 
store at room temperature.  

Use sterile, nonpyrogenic disposable containers, syringes, needles, stopcocks, 
and transfer tubing, etc.  

Transfer of rituximab from the glass vial should be made by using a suitable sterile 
graduated syringe and large gauge needle.  

Transfer the appropriate amount of rituximab from the graduated syringe into a 
partially filled IV pack containing sterile pyrogenfree 0.9sodium chloride solution 
saline solution.  Discard any unused portion left in the vial.  

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.  

Place an IV administration into the outflow port of the bag containing the infusion 
solution.  

NOTE  DO NOT USE 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.  
CAUTIONDO NOT ADMINISTER AS AN IV PUSH OR BOLUS.  

Do not infuse concomitantly with another IV solution or IV medications.  
It is recommended that rituximab be given at a dilution of 2 mg/mL for ease in calculating 
dose administration.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
221/P BO21223A7
APPENDIX K
Obinutuzumab Preparation Instructions
Reconstituted obinutuzumab drug product intended for IV infusion is prepared by dilution 
of the drug product into an infusion bag containing 0.9% sodium chloride, to the final 
drug concentration of 4 mg/mL.  Using a 250 mL infusion bag containing 0.9% sodium 
chloride, withdraw and discard 40 mL of the sodium chloride.  Withdraw 40 mL of 
obinutuzumab from a single glass vial and inject into an infusion bag (discard any 
unused portion of obinutuzumab left in the vial).  Gently invert the infusion bag to mix the 
solution; do not shake.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
222/P BO21223A7
APPENDIX L
Bendamustine Preparation Instructions
Bendamustine Preparation Instructions
For preparation of the readyforuse solution, the contents of one bendamustine vial are 
dissolved in water for injection as follows:  
First dissolve contents of the bendamustine vial containing 25 mg bendamustine 
hydrochloride in 10 mL water for injection or contents of bendamustine vial containing 
100 mg bendamustine hydrochloride in 40 mL water for injection, while shaking the vial.  
Once a clear solution has been obtained (generally after 510 minutes), the total 
bendamustine dose is diluted immediately with 0.9% NaCl solution to a final volume of 
500 mL.  Bendamustine must not be diluted with other basic infusion or injection 
solutions apart from isotonic saline solution.  
After reconstitution and dilution, chemical and physical stability has been demonstrated 
for 3.5 hours at 25 ºC/ 60% RH and 2 days at 2°C to 8°C in polyethylene bags.  
From a microbiological point of view, the readytouse preparation should be used 
immediately unless the dilution method precludes the risk of microbial contamination.  
If the readytouse preparation is not used immediately, the user is responsible for the 
duration and conditions of storage.  
Incompatibilities
Bendamustine must not be mixed with other substances in an infusion.  The powder 
must be dissolved only in water for injection and further diluted with isotonic saline.  


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
223/P BO21223A7
APPENDIX M 
Follicular Lymphoma International Prognostic Index 
and International Prognostic Index
Follicular Lymphoma International Prognostic Index (FLIPI)
Risk Factors
AnnArbor Stage III or IV
Age 60 years
Serum LDH 1ULN
Anemia (hemoglobin 120 g/L)
Involved nodal areas 4
FLIPI Risk Group
Number of FLIPI Risk Factors
Low
0 or 1
Intermediate
2
High
35
FLIPIFollicular Lymphoma International Prognostic Index; LDHlactate dehydrogenase; 
ULNupper limit of normal.  
The results of FDGPET should not be taken into account for calculation of FLIPI since this 
prognostic score was established without FDGPET.  
Adapted from:  
SolalCeligny P, Roy P, Colombat P, et al. Follicular lymphoma international 
prognostic index. Blood 2004;104:125864.  


APPENDIX M (cont'd)
Follicular Lymphoma International Prognostic Index 
and International Prognostic Index
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
224/P BO21223A7
Follicular Lymphoma International Prognostic Index (FLIPI) Nodal Areas
Reference modified from:  
SolalCeligny P, Roy P, Colombat P, et al. Follicular lymphoma international 
prognostic index. Blood 2004;104:1258–64.  


APPENDIX M (cont'd)
Follicular Lymphoma International Prognostic Index 
and International Prognostic Index
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
225/P BO21223A7
Follicular Lymphoma International Prognostic Index (FLIPI) 2
Risk Factors
Bone marrow involvement
Age 60 years
2 microglobulin 1ULN
Anemia (hemoglobin 120 g/L)
Longest diameter of largest involved node 6 cm
FLIPI2 Risk Group
Number of FLIPI2 Risk Factors
Low
0
Intermediate
1 or 2
High
35
FLIPI2Follicular Lymphoma International Prognostic Index 2; LDHlactate 
dehydrogenase; ULNupper limit of normal.  
The results of FDGPET should not be taken into account for calculation of FLIPI2 since 
this prognostic score was established without FDGPET.  
Adapted from:  
The results of FDGPET should not be taken into account for calculation of FLIPI2 since 
this prognostic score was established without FDGPET.:  
Federico M, Bellei M, Marcheselli L, et al. Follicular Lymphoma International 
Prognostic Index 2: a new prognostic index for follicular lymphoma developed by 
the International Follicular Lymphoma Prognostic Factor Project. J Clin Oncol 
2009;27:455562.  


APPENDIX M (cont'd)
Follicular Lymphoma International Prognostic Index 
and International Prognostic Index
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
226/P BO21223A7
International Prognostic Index (IPI) 
Risk Factors
AnnArbor Stage III or IV
Age 60 years
Serum LDH 1ULN
ECOG Performance Status 2
Extranodal involvement 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; 
LDHlactate dehydrogenase; ULNupper limit of normal.
The results of FDGPET should not be taken into account for calculation of IPI since this 
prognostic score was established without FDGPET.  
Adapted from:  
The International NonHodgkin’s Lymphoma Prognostic Factors Project. 
A predictive model for aggressive nonHodgkin's lymphoma. N Engl J Med 
1993;329:98799.


Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
227/P BO21223A7
APPENDIX N
Activities of Daily Living Scale and 
Instrumental Activities of Daily Living Scale
Katz Basic Activities of Daily Living (ADLs) Scale
Independence
Dependence
Activities
Points (1)
NO supervision, direction, or 
personal assistance
Points (0)
WITH supervision, direction, 
personal assistance, or total care
Points (1 or 0)
Bathing (sponge bath, tub bath, or 
shower):  Receives either no 
assistance or assistance in bathing 
only one part of body
Bathing:  Needs help with bathing 
more than one part of the body, 
getting in or out of the tub or 
shower; requires total bathing
Bathing
Points:_____
Dressing:  Gets clothes and 
dresses without any assistance 
except for tying shoes
Dressing:  Needs help with 
dressing self or needs to be 
completely dressed
Dressing
Points:______
Toileting:  Goes to toilet room, uses 
toilet, arranges clothes, and returns 
without any assistance (may use 
cane or walker for support and may 
use bedpan/urinal at night)
Toileting:  Needs help transferring 
to the toilet or cleaning self, or uses 
bedpan or commode
Toileting
Points:______
Transferring:  Moves in and out of 
bed and chair without assistance 
(may use cane or walker)
Transferring:  Needs help in 
moving from bed to chair or 
requires a complete transfer
Transferring
Points:______
Continence:  Controls bowel and 
bladder completely by self (without 
occasional "accidents")
Continence:  Is partially or totally 
incontinent of bowel or bladder
Continence
Points:______
Feeding:  Feeds self without 
assistance (except for help with
cutting meat or buttering bread)
Feeding:  Needs partial or total 
help with feeding or requires 
parenteral feeding
Feeding
Points:______
Total 
Points:________
Scoring:
6 pointshigh (patient independent)
0 pointslow (patient very dependent)
Reference:  
Katz S, Down TD, Cash HR, et al. Progress in the development of the index of ADL. 
Gerontologist 1970;10:20.  


APPENDIX N 
Activities of Daily Living Scale and 
Instrumental Activities of Daily Living Scale (cont.)
Protocol:  ObinutuzumabF. HoffmannLa Roche, Ltd
228/P BO21223A7
Lawton–Brody Instrumental Activities of Daily Living (IADLs) Scale
A. Ability to Use Telephone
1. Operates telephone on own initiative
looks up and dials numbers, etc.
2. Dials a few wellknown numbers
3. Answers telephone but does not dial
4. Does not use telephone at all
1 
1 
1 
0 
E. Laundry
1. Does personal laundry completely
2. Launders small itemsrinses
stockings, etc.
3. All laundry must be done by others
1 
1 
0 
B. Shopping
1. Takes care of all shopping needs
independently
2. Shops independently for small
purchases
3. Needs to be accompanied on any
shopping trip
4. Completely unable to shop
1 
0 
0 
0 
F. Mode of Transportation
1. Travels independently on public
transportation or drives own car
2. Arranges own travel via taxi, but does
not otherwise use public transportation
3. Travels on public transportation when
accompanied by another
4. Travel limited to taxi or automobile with
assistance of another
5. Does not travel at all
1 
1 
1 
0 
0 
C. Food Preparation
1. Plans, prepares, and serves adequate
meals independently
2. Prepares adequate meals if supplied
with ingredients
3. Heats, serves, and prepares meals or
prepares meals but does not maintain
adequate diet
4. Needs to have meals prepared
and served
1 
0 
0 
0 
G. Responsibility for Own Medications
1. Is responsible for taking medication in
correct dosages at correct time
2. Takes responsibility if medication is
prepared in advance in separate dosage
3. Is not capable of dispensing own
medication
1 
0 
0 
D. Housekeeping
1. Maintains house alone or with
occasional assistance (e.g., "heavy work
domestic help")
2. Performs light daily tasks such as dish
washing, bed making
3. Performs light daily tasks but cannot
maintain acceptable level of cleanliness
4. Needs help with all home maintenance
tasks
5. Does not participate in any
housekeeping tasks
1 
1 
1 
1 
0 
H. Ability to Handle Finances
1. Manages financial matters
independently (budgets, writes checks,
pays rent, bills, goes to bank),
collects and keeps track of income
2. Manages daytoday purchases,
but needs help with banking, major
purchases, etc.
3. Incapable of handling money
1 
1
0
Total Points: 

SAP_001.pdf: 
 
Official Title: 
A Multicenter, Phase III, Open-Label, Randomized Study in 
Previously Untreated Patients With Advanced, Indolent Non-
Hodgkin's Lymphoma Evaluating The Benefit of Obinutuzumab 
(RO5072759) Plus Chemotherapy Compared With Rituximab Plus 
Chemotherapy Followed By Obinutuzumab or Rituximab 
Maintenance Therapy in Responders 
NCT Number: 
NCT01332968 
Document Date: 
SAP Version 2: 12-April-2016 
 
 


Name
Reason for Signing
Date and Time
(UTC)
12-Apr-2016 11:08 06
Company Signatory
STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL 
 
CONFIDENTIAL 
 
This is a F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BO21223 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A MULTICENTER, PHASE III, OPEN-LABEL, RANDOMIZED STUDY 
IN PREVIOUSLY UNTREATED PATIENTS WITH ADVANCED, 
INDOLENT NON-HODGKIN'S LYMPHOMA EVALUATING THE 
BENEFIT OF OBINUTUZUMAB (RO5072759) PLUS 
CHEMOTHERAPY COMPARED WITH RITUXIMAB PLUS 
CHEMOTHERAPY FOLLOWED BY OBINUTUZUMAB OR 
RITUXIMAB MAINTENANCE THERAPY IN RESPONDERS 
PROTOCOL NUMBER: 
BO21223 
STUDY DRUG: 
RO5072759 (GAZYVA®, GAZYVARO™, GA101, 
obinutuzumab) 
VERSION NUMBER: 
2 
IND NUMBER: 
104405 
EUDRACT NUMBER: 
2010-024132-41 
SPONSOR: 
F. Hoffmann–La Roche Ltd 
PLAN PREPARED BY: 
 
DATE FINAL: 
17 September 2012 
DATE AMENDED: 
See electronic date stamp below. 
Protocol Number: 
 Report Number: 
Clinical Study Report: RO5072759 - F. Hoffmann-La Roche Ltd
BO21223
1110536
1


STATISTICAL ANALYSIS PLAN AMENDMENT 
RATIONALE 
The previous version of the statistical analysis plan (SAP) was submitted to the U.S. 
Food and Drug Administration (FDA) on 19 December 2012.  The following changes are 
included in the amended SAP (version 2): 
• 
The definition of “progression” was clarified and now contains symptomatic 
deterioration and disease transformation. 
• 
Specified that histological information (follicular lymphoma [FL] or marginal zone 
lymphoma [MZL]) from the IXRS will be used for the determination of analysis 
populations in accordance with the protocol. 
• 
The best overall response as an endpoint was removed in accordance with the 
protocol. 
• 
The description of the minimal residual disease (MRD) analysis was removed as it 
will be provided in a separate report. 
• 
The description of patient-reported outcomes (PRO) analysis was shortened.  The 
pre-specified analysis in the Clinical Study Report will follow what has been outlined 
in the protocol. 
• 
The section on medical resource utilization was shortened. 
• 
The section on pharmacokinetic outcome measures was re-worded. 
• 
Some of the sensitivity analyses were re-worded and two additional sensitivity 
analyses were added. 
• 
Minor editorial changes were made to improve clarity and consistency. 
• 
Appendix 1 (study protocol synopsis) and Appendix 2 (study flowchart) were 
updated to reflect the current version of the study protocol. 
• 
Appendix 3 was updated to reflect the current version of the independent Data 
Monitoring Committee (iDMC) charter. 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
2/ Statistical Analysis Plan BO21223 
Protocol Number: 
 Report Number: 
Clinical Study Report: RO5072759 - F. Hoffmann-La Roche Ltd
BO21223
1110536
2


TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE............................. 2 
1. 
BACKGROUND ............................................................................................ 5 
2. 
STUDY DESIGN ........................................................................................... 5 
2.1 
Protocol Synopsis.................................................................... 6 
2.2 
Outcome Measures ................................................................. 6 
2.2.1 
Primary Efficacy Outcome Measures ...................................... 6 
2.2.2 
Secondary Efficacy Outcome Measures.................................. 7 
2.2.3 
Clinical and Biomarker Exploratory Outcome 
Measures................................................................................. 8 
2.2.4 
Patient-Reported Outcome Measures ..................................... 8 
2.2.5 
Pharmacoeconomic Outcomes – Medical 
Resource Utilization................................................................. 8 
2.2.6 
Pharmacokinetic Outcome Measures...................................... 8 
2.2.7 
Safety Outcome Measures ...................................................... 9 
2.3 
Determination of Sample Size ................................................. 9 
2.4 
Analysis Timing ..................................................................... 11 
3. 
STUDY CONDUCT..................................................................................... 11 
3.1 
Randomization....................................................................... 11 
3.2 
Independent Review Facility.................................................. 12 
3.3 
Data Monitoring ..................................................................... 12 
4. 
STATISTICAL METHODS .......................................................................... 13 
4.1 
Analysis Populations ............................................................. 13 
4.1.1 
Intent-to-Treat Follicular Population....................................... 13 
4.1.2 
Intent-to-Treat Population...................................................... 13 
4.1.3 
Per-Protocol Population......................................................... 13 
4.1.4 
Pharmacokinetic Evaluable Population ................................. 13 
4.1.5 
Safety Population .................................................................. 14 
4.2 
Analysis of Study Conduct..................................................... 14 
4.3 
Analysis of Treatment Group Comparability .......................... 14 
4.4 
Efficacy Analysis.................................................................... 14 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
3/ Statistical Analysis Plan BO21223 
Protocol Number: 
 Report Number: 
Clinical Study Report: RO5072759 - F. Hoffmann-La Roche Ltd
BO21223
1110536
3


4.4.1 
Primary Efficacy Endpoint...................................................... 14 
4.4.2 
Secondary Efficacy Endpoints............................................... 15 
4.4.3 
Exploratory Efficacy Endpoints.............................................. 16 
4.4.4 
Sensitivity Analyses............................................................... 16 
4.4.5 
Subgroup Analyses ............................................................... 17 
4.4.6 
Patient-Reported Outcomes .................................................. 17 
4.4.7 
Pharmacoeconomic Analyses ............................................... 18 
4.4.8 
Pharmacokinetic Analyses..................................................... 18 
4.4.9 
Pharmacodynamic Analysis................................................... 18 
4.5 
Safety Analyses..................................................................... 18 
4.5.1 
Exposure to Study Medication............................................... 18 
4.5.2 
Adverse Events ..................................................................... 19 
4.5.3 
Laboratory Data..................................................................... 19 
4.5.4 
Vital Signs.............................................................................. 19 
4.6 
Missing Data.......................................................................... 20 
4.7 
Interim Analyses .................................................................... 20 
5. 
REFERENCES ........................................................................................... 22 
 
 
LIST OF TABLES 
Table 1 
Timing of Analyses: Primary Efficacy and Futility........................ 11 
 
 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 23 
Appendix 2 
Study Flowchart .......................................................................... 35 
Appendix 3 
iDMC Charter.............................................................................. 36 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
4/ Statistical Analysis Plan BO21223 
Protocol Number: 
 Report Number: 
Clinical Study Report: RO5072759 - F. Hoffmann-La Roche Ltd
BO21223
1110536
4


 
1. 
BACKGROUND 
This document expands upon the statistical section of Study Protocol BO21223 and 
provides additional detail of the planned statistical analyses.  The analyses outlined in 
this document will supersede those specified in the protocol. 
Study BO21223 was developed to examine the efficacy and safety of obinutuzumab 
(also known as RO5072759, GA101, GAZYVA®, or GAZYVARO™) compared with 
rituximab, in combination with chemotherapy (cyclophosphamide, doxorubicin, 
vincristine, and prednisone or prednisolone [CHOP]; cyclophosphamide, vincristine, and 
prednisone or prednisolone [CVP]; or bendamustine), and followed by obinutuzumab or 
rituximab maintenance therapy for responders in previously untreated patients with 
advanced, indolent non-Hodgkin’s lymphoma (NHL). 
2. 
STUDY DESIGN 
Study BO21223 is an open-label, international, multicenter, randomized, Phase III study 
of patients with previously untreated, advanced, indolent NHL to investigate the efficacy 
and safety of obinutuzumab plus chemotherapy, followed by obinutuzumab maintenance 
therapy for responders (patients who demonstrate a complete response [CR] or a partial 
response [PR]), compared with rituximab plus chemotherapy followed by rituximab 
maintenance therapy for up to 2 years for responders.  Patients who demonstrate stable 
disease (SD) at the end of induction therapy will be followed for progression for up to 
2 years according to the same follow-up schedule as responders (CR or PR) receiving 
maintenance therapy. 
Prior to the initiation of the study, each site will choose one of the three chemotherapy 
regimens (CHOP, CVP, or bendamustine), and all patients with follicular lymphoma (FL) 
at that site will receive the chosen chemotherapy regimen for the duration of the study; 
however, a site may switch to another regimen if new scientific data become available 
and following Sponsor approval.  For marginal zone lymphoma (MZL) patients, the 
investigator will have the option of choosing one of the three chemotherapy regimens 
(CHOP, CVP, or bendamustine) for each patient.  All patients will then be randomized to 
receive either rituximab plus chemotherapy, followed by rituximab maintenance therapy 
in responders, or obinutuzumab plus chemotherapy followed by obinutuzumab 
maintenance therapy in responders.  Treatment phase is then defined as induction plus 
up to two years of maintenance. 
Approximately 1200 patients with follicular lymphoma will be recruited and randomly 
assigned either to the arm receiving obinutuzumab plus chemotherapy followed by 
obinutuzumab maintenance in responders, or to the arm receiving rituximab plus 
chemotherapy followed by rituximab maintenance in responders in a 1:1 ratio.  In 
addition, approximately 200 patients with MZL will be recruited and randomly assigned 
to the same two treatment arms in a 1:1 ratio. 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
5/ Statistical Analysis Plan BO21223 
Protocol Number: 
 Report Number: 
Clinical Study Report: RO5072759 - F. Hoffmann-La Roche Ltd
BO21223
1110536
5


 
2.1 
PROTOCOL SYNOPSIS 
The protocol synopsis is in Appendix 1.  For additional details, see the Study Flowchart 
in Appendix 2. 
2.2 
OUTCOME MEASURES 
Response and progression will be assessed according to the modified Revised 
Response Criteria for Malignant Lymphoma ([modified RRCML], Cheson et al. 2007; see 
Appendix C of the protocol).  For patients with MZL with paraproteinemia, a criterion 
requiring the absence of paraprotein was added to the modified RRCML to meet the 
requirements of a CR.  For patients with only splenic MZL, additional hematological 
parameters (hemoglobin >12 g/dL; platelets >100 × 109/L; neutrophils >1.5 × 109/L; and 
no evidence of circulating clonal B cells) will be required for reaching CR status.  The 
assessment of response and progression by the investigator will be considered the 
primary analysis for all of the endpoints described in the study. 
Response and progression will also be assessed by an Independent Review Committee 
(IRC).  In the United States, IRC-assessed endpoints will be the basis of regulatory 
decisions.  Both investigator and IRC assessments will be analyzed as primary and 
secondary outcomes as specified below. 
2.2.1 
Primary Efficacy Outcome Measures 
The primary efficacy endpoint for this study is progression-free survival (PFS) in follicular 
lymphoma patients as assessed by the investigator. 
Although the primary efficacy endpoint is investigator-assessed PFS, PFS on the basis 
of IRC review will also be analyzed to support the primary analysis.  In the United States, 
IRC-assessed PFS will be the basis of regulatory decisions. 
An additional measure for confirming clinical response is taking positron emission 
tomography (PET) into consideration.  Exploratory analyses suggest that response 
assessment including PET may be superior over clinical response assessment alone 
(Trotman et al. 2011).  Therefore, assessment of response including PET will also be 
examined. 
The primary efficacy endpoint, PFS, is defined in patients with follicular lymphoma 
(referred to as the follicular lymphoma population that is regarded as the primary 
analysis population) as the time from randomization to the first occurrence of 
progression, relapse, or death from any cause, where symptomatic deterioration and 
disease transformation are counted as a progression throughout.  PFS for patients 
without disease progression, relapse, or death will be censored at the time of the last 
tumor assessment or, if no tumor assessments were performed after the baseline visit, 
on the date of randomization. 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
6/ Statistical Analysis Plan BO21223 
Protocol Number: 
 Report Number: 
Clinical Study Report: RO5072759 - F. Hoffmann-La Roche Ltd
BO21223
1110536
6


 
2.2.2 
Secondary Efficacy Outcome Measures 
A secondary outcome measure of PFS will be applied to all randomized patients 
(including follicular and marginal zone lymphoma patients, henceforth referred to as the 
overall population). 
The following secondary outcome measures apply to the overall population and the 
follicular lymphoma population (in a first step, definitions of these secondary outcome 
measures will not consider PET assessments; as appropriate, further secondary 
endpoints will be defined to include PET assessments; see Section 4.4.2 for details): 
• 
CR rate at the end of induction, defined as the percentage of patients with CR as 
the end-of-induction response.  All other cases are designated CR non-responders. 
• 
Overall survival (OS), defined as the time from the date of randomization to the date 
of death from any cause.  OS for patients who are not reported to have died at the 
time of the analysis will be censored at the date at which the patient was last known 
to be alive, as documented by the investigator. 
• 
Overall response rate (ORR) on the basis of the end-of-induction response.  The 
ORR is defined as the percentage of patients with CR or PR as the end-of-induction 
response.  All other cases are designated non-responders. 
• 
Event-free survival (EFS), defined as the time from randomization to disease 
progression or relapse, death from any cause, or initiation of any non-protocol-
specified anti-lymphoma treatment (NALT).  If the specified event (disease 
progression or relapse, death, or 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 on the date of 
randomization. 
• 
Time to next anti-lymphoma treatment (TTNALT) is defined as the time from the 
date of randomization to the start date of the next anti-lymphoma treatment or death 
from any cause.  Patients without a TTNALT event will be censored at the date at 
which the patient was last known to be alive. 
• 
Disease-free survival (DFS), defined as the time from the date of the first 
occurrence of a documented CR to the date of disease progression, relapse, or 
death from any cause (PFS event) for the subgroup of patients with a response of 
CR at any time prior to NALT.  DFS for patients who have had no documented 
disease progression, relapse, or have not died after CR, will be censored at the last 
disease assessment date. 
• 
Duration of response, 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 event) for the subgroup of patients with a response of CR or PR 
any time prior to NALT.  For patients achieving a response who have not 
experienced disease progression, relapse, or died prior to the time of the analysis, 
the duration of response will be censored on the date of last disease assessment. 
• 
Histologic transformation rate from an indolent to a more aggressive NHL at first 
progression, defined as the appearance of diffuse areas of large lymphoma cells 
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(e.g., FL grade 3b, diffuse large B-cell lymphoma [DLBCL], Burkitt-like lymphoma, 
acute lymphoblastic leukemia, prolymphocytic leukemia, and others) within a tumor 
site in patients with a repeated biopsy at the time of disease progression or relapse. 
• 
Conversion rate, defined as the proportion of patients with a PR at the end of 
induction therapy who convert to a CR, and patients with SD at the end of induction 
therapy who convert to a CR or to a PR, at any time during maintenance therapy or 
post-induction observation. 
As with PFS, the secondary endpoints of CR rate and ORR will also be evaluated on the 
basis of IRC assessment. 
 
2.2.3 
Clinical and Biomarker Exploratory Outcome Measures 
Among the follicular lymphoma patient population receiving obinutuzumab, the portion of 
patients with anti-obinutuzumab antibodies (HAHA) will be assessed after the last dose 
and during the washout phase until month 48 follow-up. 
Analysis of other biomarker and exploratory endpoints as defined in the protocol, but not 
mentioned here, will be provided in separate reports. 
2.2.4 
Patient-Reported Outcome Measures 
The high-level patient-reported outcome (PRO) measures are as follows: 
• 
Change from baseline to the end of study in PROs based on the Functional 
Assessment of Cancer Therapy for Lymphoma (FACT-Lym) instrument. 
• 
European Quality of Life EQ-5D summary scores at baseline, during treatment, after 
treatment, at the last assessment prior to progression, and at the first assessment 
after progression. 
 
2.2.5 
Pharmacoeconomic Outcomes – Medical Resource Utilization 
Medical resource utilization data will be described if requested. 
 
2.2.6 
Pharmacokinetic Outcome Measures 
The pharmacokinetic (PK) analysis from this study will be used as an external validation 
of the earlier developed population PK model, separately for FL and MZL. 
The PK outcomes are as follows: 
• 
Generate simulations from the final model to illustrate typical predictions and inter-
individual variability of concentrations for FL and MZL patients, overall and by 
covariates identified by the model. 
• 
Generate and summarize individual predictions of the total clearance of the drug 
(CL), the volume of distribution for the central compartment (VC), the volume of 
distribution under steady-state conditions (VSS), the maximum concentration 
observed (Cmax), the steady-state concentration at the end of a dosing interval 
(Ctrough), the terminal half-life (t1/2,term), the effective half-life (t1/2,eff), and the area 
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under the concentration–time curve from time zero to the end of the dosing period 
(AUC0-τ) by disease and by covariates. 
• 
Generate individual exposure estimates for graphical exposure-response analysis. 
2.2.7 
Safety Outcome Measures 
The safety outcome measures include: 
• 
Incidence, nature, and severity of adverse events (including serious adverse events) 
compared between the two treatment arms. 
• 
Deaths 
• 
Changes in vital signs, physical findings, and clinical laboratory results. 
• 
Incidence of hepatitis B reactivation.  Hepatitis B reactivation will be defined as an 
elevation in serum hepatitis B virus (HBV) DNA to >29 IU/L. 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
The primary endpoint of investigator-assessed PFS was used for sample size estimation.  
Estimates of the number of events required to demonstrate efficacy with respect to PFS 
were made on the basis of the following assumptions: 
• 
Two-sided log-rank test at the 0.05 level of significance. 
• 
Powered for the follicular lymphoma population. 
• 
Eighty percent power to detect a hazard ratio for obinutuzumab-combined 
chemotherapy versus rituximab-combined chemotherapy of 0.74, corresponding to 
an improvement in 3-year PFS from 70.7% to 77.4% or in median PFS from 6 to 
8.1 years (35%).  Estimates of median PFS are not likely to be reached in either 
study arm. 
• 
Exponential distribution of PFS. 
• 
An annual dropout rate of 2.5%. 
• 
Performance of interim analyses on PFS: one futility analysis when approximately 
30% of the total (investigator-assessed) PFS events have occurred (2nd Interim 
[futility]; see Table 1), and one efficacy analysis (3rd Interim [efficacy]; see Table 1) 
when approximately 67% of the total (investigator-assessed) PFS events have 
occurred.  Efficacy and (non-binding) futility boundaries will be calculated using the 
Lan-DeMets approximation to the O’Brien-Fleming boundary shape. 
In addition, a futility analysis on the basis of CR rates at the end of induction (1st Interim 
[futility]; see Table 1), as determined by CT (or magnetic resonance imaging [MRI], but 
not PET), will be performed on the first 170 randomized follicular lymphoma patients.  
For this CR futility analysis, we expect that approximately 15% of the total investigator-
assessed PFS events have occurred. 
With the above assumptions, 370 PFS events are required to achieve 80% power for the 
primary analysis (Final; according to Table 1).  Recruitment will be staggered to recruit 
the first 170 patients at a smaller number of sites (first stage, approximately 125 sites), 
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followed by the activation of all sites (approximately 250 sites) after the independent 
Data Monitoring Committee (iDMC) meeting for the 1st Interim (futility).  It is expected 
that during the first stage, after a 6-month ramp up, 18 patients per month will be 
recruited; after the iDMC meeting for the 1st Interim (futility) and another 4-month ramp 
up, an accrual rate of 37 patients per month is expected.  Twelve hundred follicular 
patients, enrolled over 49 months and followed for an additional 29 months after 
randomization of the last patient, will be required to provide 370 PFS events, with a total 
duration of PFS follow-up of approximately 78 months (6.5 years).  It is anticipated that 
in the worst case, the number of corresponding IRC events at clinical cut-off would be, at 
most, 10% lower than the number of investigator-assessed events.  Such a worst case 
loss in number of events would result in a reduction in the power of approximately 5% to 
detect the assumed treatment difference.  The primary analysis will incorporate all 
events up to the clinical cut-off date.  This analysis will capture 370 investigator-
assessed PFS events. 
Approximately 200 additional patients with non-follicular lymphoma (i.e., with MZL) will 
be enrolled.  This number was selected on the basis of estimation from the enrollment 
feasibility assessment prior to the start of the study.  This estimation indicated that at 
least 200 MZL patients would likely be enrolled in 49 months, in addition to the planned 
follicular lymphoma patient enrollment.  As such, data from the MZL patients can be 
interpreted in context of subgroup analyses.  However, this subgroup is not powered to 
detect statistically significant differences. 
Pharmacokinetic assessments will apply to a subpopulation of approximately 
460 patients receiving obinutuzumab.  This sample size will allow the accurate 
identification and quantification of the influence of covariates on PK parameters.  In 
addition, this sample size is reasonable to indicate whether the variability in 
pharmacodynamic markers of response (e.g., tumor size shrinkage) could be attributed 
to exposure.  Approximately 120 patients with follicular lymphoma will undergo 
pharmacokinetic sampling from each of the three chemotherapy groups (obinutuzumab-
CHOP, obinutuzumab-CVP, and obinutuzumab-bendamustine), and 100 additional 
patients with non-follicular lymphoma will also undergo sampling.  This sample size is 
believed to be sufficient to confidently characterize the pharmacokinetics of 
obinutuzumab in the target population, as well as the relationship between the exposure 
to obinutuzumab and response.  The pharmacokinetic sampling schedule in this study 
was determined using an optimal sampling strategy and should result in a coefficient of 
variation of <20% for the main pharmacokinetic parameter estimates.  In addition to the 
determination of T, B, and NK cells in all patients, absolute and relative B cell subsets 
will be determined by multicolor flow cytometry (FACS) on the basis of a combination of 
several CD antigens and surface immunoglobulins over time in approximately 
60 patients of each therapeutic group (rituximab-CHOP, obinutuzumab-CHOP, 
rituximab-CVP, obinutuzumab-CVP, rituximab-bendamustine, and obinutuzumab-
bendamustine), as well as in all patients with splenic MZL.  Because of the exploratory 
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nature of this assessment and its complementary information to the determination of T, 
B, and NK cells, this sample size is arbitrary, but it is estimated to provide sufficient data 
for the generation of an initial hypothesis. 
2.4 
ANALYSIS TIMING 
On the basis of the assumptions outlined in Section 2.3, the timing of the three interim 
and final analyses have been estimated as outlined below (Table 1). 
Table 1 
Timing of Analyses: Primary Efficacy and Futility 
Analysis 
Type 
Approximate Timing 
of Analysis on the 
Basis of Investigator-
Assessed PFS Events 
in fITT (Percentage of 
Information) 
Approximate 
Timing of 
Analysis under 
H1 (in Months 
after FPI in 
fITT) 
Endpoint 
Adjusted 
Two-Sided 
α-Level 
Cumulative 
Two-Sided 
α-Level 
1st interim 
(futility) 
170 follicular 
lymphoma patients 
EOI response 
 
EOI CR rate
NA 
NA 
2nd interim 
(futility) 
111 PFS events 
(30%) 
43 
INV PFS 
0.000085 
0.000085 
3rd interim 
(efficacy) 
248 PFS events 
(67%) 
60 
INV PFS 
0.012 
0.012 
Final 
370 PFS events 
(100%) 
79 
INV PFS 
0.046 
0.05 
CR = Complete Response; EOI = end-of-induction; FPI = first patient in; H1 = alternative 
hypothesis; INV = investigator-assessed; PFS = progression-free survival; fITT = intent-to-treat 
ollicular lymphoma population 
f 
Further details of the interim analyses can be found in Section 4.7. 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION 
After written informed consent has been obtained and eligibility has been established, 
the study site will obtain the patient’s unique identification number and treatment 
assignment from an interactive voice or web-based response system (IXRS®).  
Randomization will be performed separately for patients with follicular and non-follicular 
lymphoma through the IXRS with the use of a hierarchical dynamic randomization 
scheme. 
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The randomization scheme will ensure approximately equal sample sizes in the two 
treatment arms for the following stratification factors: 
• 
Chemotherapy regimen (CHOP, CVP, or bendamustine). 
• 
FL International Prognostic Index (FLIPI; version 1 [Solal-Celigny et al. 2004]) risk 
group (low, intermediate, or high) in patients with follicular lymphoma or 
International Prognostic Index (IPI) risk group (low or low-intermediate vs. high-
intermediate or high) in patients with non-follicular lymphoma. 
• 
Geographic region (Western Europe, Eastern Europe, South and Central America, 
North America, Asia, or other). 
The randomization scheme is designed with three levels.  The first level ensures 
approximately equal numbers of patients between the two treatment arms overall.  If the 
first level is balanced, the second level ensures treatment balance within the strata 
defined by 1) chemotherapy regimen (CHOP, CVP, bendamustine), and 2) either the 
FLIPI risk group (low, intermediate, high) in follicular lymphoma patients or the IPI risk 
group (low or low-intermediate risk vs. intermediate-high or high risk) in non-follicular 
lymphoma patients.  If the first two levels are balanced, the third level ensures treatment 
balance within each geographic region (Western Europe, Eastern Europe, South and 
Central America, North America, Asia, or other). 
Because of the two different study arms with different administration schedules, it is very 
difficult to maintain blinding for the investigators.  Therefore, this study will be conducted 
in an open-label manner.  However, the IRC will remain blinded to treatment assignment. 
Discordances between the IXRS and the electronic Case Report Form (eCRF) data will 
be summarized. 
3.2 
INDEPENDENT REVIEW FACILITY 
An independent assessment of response and progression, on the basis of CT (or MRI) 
scans plus pertinent clinical data (with or without PET), will be provided by an IRC with 
appropriate expertise in interpreting radiology and oncology examinations.  The IRC 
assessment will be blinded with respect to treatment arm and investigator assessment.  
Instructions to sites for processing and submitting imaging scans will be provided by the 
IRC.  IRC membership and the procedures to be followed for the study can be found in 
the IRC charter (see Appendix 3). 
For all investigator-assessed response analyses (interim end-of-treatment response, and 
PFS [futility and efficacy], and final PFS), there will be a corresponding analysis of the 
IRC-determined data. 
3.3 
DATA MONITORING 
An iDMC will conduct periodic interim reviews of safety summaries, beginning 
approximately 1 month after the enrollment of the first patient, and then approximately 
every 2 months until at least 100 patients have completed two cycles of study treatment.  
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The iDMC will then conduct reviews of safety summaries approximately every 6 months.  
All summaries and analyses reviewed by the iDMC will be prepared by an independent 
Data Coordinating Center (iDCC).  Safety will be evaluated by monitoring dose delays 
and dose intensity, adverse events, serious adverse events, and deaths. 
Further details of the definition, the role, and the responsibility of the iDMC are provided 
in a separate document, the iDMC charter (see Appendix 3). 
4. 
STATISTICAL METHODS 
Except where specified, all continuous variables will be summarized with descriptive 
statistics (the number of non-missing values, mean, standard deviation, median, 
minimum, and maximum).  All categorical variables will be summarized by treatment 
group with frequency counts and percentages. 
All statistical tests will be two-sided. 
4.1 
ANALYSIS POPULATIONS 
For the determination of analysis populations, histological information (FL or MZL) from 
the IXRS will be used. 
4.1.1 
Intent-to-Treat Follicular Population 
The primary efficacy analysis population is the intent-to-treat follicular lymphoma 
population (fITT), defined as all randomized patients with follicular histology.  Patients 
will be analyzed according to the treatment arm to which they were randomized. 
4.1.2 
Intent-to-Treat Population 
The primary and key secondary efficacy parameters will be determined in the intent-to-
treat population, defined as all randomized patients (overall population, ITT). 
4.1.3 
Per-Protocol Population 
A per-protocol analysis population is not defined for this study.  The protocol violations 
will be documented. 
4.1.4 
Pharmacokinetic Evaluable Population 
Pharmacokinetic analyses and the evaluable population will be defined in a separate 
analysis plan. 
Patient data will be included in the PK analysis if they contain sufficient dosing 
information and at least one adequately documented and quantifiable concentration per 
patient. 
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4.1.5 
Safety Population 
The safety analysis population will include all patients who receive any amount of study 
drug (obinutuzumab, rituximab, or chemotherapy [CHOP, CVP, or bendamustine]), and 
patients will be analyzed according to the treatment received (i.e., a patient who 
received obinutuzumab at least once for any reason will be analyzed under the 
obinutuzumab-chemotherapy treatment arm; if only chemotherapy and/or rituximab was 
received, the patient will be analyzed under the rituximab-chemotherapy treatment arm). 
4.2 
ANALYSIS OF STUDY CONDUCT 
Enrollment, eligibility violations, study drug administration, and patient disposition will be 
summarized according to treatment arm in all randomized patients, as well as by 
histology (follicular and non-follicular).  A summary of patient disposition will include 
whether treatment was completed or discontinued early, and the reason for early 
treatment discontinuation. 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
All analyses will be performed for the follicular lymphoma population, as well as for the 
overall population, unless otherwise specified. 
Demographic and baseline characteristics, including ⎯ but not limited to ⎯ sex, age, race, 
ethnicity, baseline weight, height, baseline body surface area (BSA), and Eastern 
Cooperative Oncology Group (ECOG) performance status (at baseline), as well as Ann 
Arbor stage (at baseline), will be summarized according to treatment arm in all 
randomized patients and by histology (follicular vs. non-follicular).  A table will 
summarize the three stratification factors (chemotherapy, FLIPI/IPI score, and 
geographic region).  Medical history, including diagnosis (e.g., follicular lymphoma, MZL) 
and time since diagnosis (categorical), will be summarized according to treatment group. 
Should country policy prohibit the collection of race or age information, then patients will 
appear in the missing category of summary tables. 
4.4 
EFFICACY ANALYSIS 
4.4.1 
Primary Efficacy Endpoint 
The primary analysis of the study will test the equality of PFS distributions in the 
obinutuzumab plus chemotherapy (G-Chemo) and rituximab plus chemotherapy 
(R-Chemo) arms, as follows: 
H0: PFSG-Chemo = PFSR-Chemo 
vs.  
H1: PFSG-Chemo ≠ PFSR-Chemo 
 
The treatment comparison will be made in the fITT population using a two-sided, 
stratified log-rank test (overall level of significance of 0.05) that was stratified by 
chemotherapy regimen (CHOP, CVP, or bendamustine) and FLIPI risk group (low, 
intermediate, or high).  For cases in which a patient is misrandomized with respect to a 
stratification factor (i.e., there is a discrepancy between the IXRS-recorded stratification 
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factor level and the eCRF-recorded stratification factor level for chemotherapy regimen 
or FLIPI), the eCRF data will be used in the primary analysis.  Discordances between 
the IXRS and the eCRF data will be summarized.  Because geographic region is not 
expected to be strongly prognostic, region will not be included as a factor in the stratified 
analyses, to avoid loss of efficiency. 
Kaplan-Meier methodology will be used to estimate PFS distribution for each treatment 
arm.  These curves will also provide a visual description of the differences among 
treatment arms.  Estimates of treatment effect will be expressed as hazard ratios 
through the use of a stratified Cox proportional hazards analysis, including 95% 
confidence intervals. 
The median PFS is not expected to be reached in this study; hence, the estimated 
2-year and 3-year probabilities, including 95% confidence intervals, will be used to 
describe PFS in addition to the hazard ratio. 
4.4.2 
Secondary Efficacy Endpoints 
All analyses of secondary efficacy endpoints will be performed for the follicular 
lymphoma population and the overall population, with the exception of PFS, which will 
be analyzed only in the overall population as a secondary efficacy endpoint (PFS for fITT 
is the primary efficacy endpoint). 
To adjust for multiple testing of key secondary efficacy endpoints, thereby controlling the 
overall type I error at a two-sided level of significance of 0.05, a fixed sequence testing 
procedure will be used (Westfall and Krishen 2001).  The following endpoints will be 
tested in the order given (see also Section 2.2.2 for secondary endpoints not included in 
the fixed sequence testing procedure): 
• 
PFS in all randomized patients. 
• 
CR rate without PET at the end of induction therapy in the follicular lymphoma 
population. 
• 
CR rate without PET at the end of induction therapy in the overall population. 
• 
OS in the follicular lymphoma population. 
• 
OS in the overall population. 
• 
ORR without PET at the end of induction therapy in the follicular lymphoma 
population. 
• 
ORR without PET at the end of induction therapy in the overall population. 
The remaining secondary endpoints (EFS; TTNALT; DFS; duration of response; CR rate 
and ORR taking into account PET [where applicable]) will not be adjusted for multiple 
testing. 
A given hypothesis in the list above will only be rejected once all previous hypotheses 
have been rejected at a two-sided level of significance of 0.05.  All analyses will be 
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performed on the basis of the investigator’s assessment.  For U.S. regulatory decision 
making, the key secondary analyses of PFS, CR rate, and ORR will be performed on the 
basis of IRC assessments.  The same fixed testing sequence as for the investigator-
assessed endpoints will be applied. 
Time-to-event endpoints, such as OS, EFS, DFS, duration of response, and TTNALT, 
will be analyzed using the same statistical methods as described for the primary analysis 
of PFS (see Section 4.4.1).  Indolent histology (follicular or non-follicular) will also be 
included as a stratification factor in the stratified analyses for the ITT population. 
Response rates in the treatment groups will be compared using stratified Cochran-
Mantel-Haenszel (CMH) tests.  The stratification factors are the same as those specified 
for the PFS analysis.  In addition, rates and 95% confidence intervals will be reported for 
each treatment group. 
The histological transformation rate at first progression and the conversion rate will be 
compared using stratified CMH tests.  Rates, including 95% confidence intervals, will be 
estimated for each treatment group. 
4.4.3 
Exploratory Efficacy Endpoints 
The fITT population is the primary population for all efficacy measures and will be the 
only population examined for all exploratory analyses (or a subgroup of this population, 
as defined below). 
The potential association between FcγR genotype, response category, minimal residual 
disease (MRD) qualitative status (negative or positive), and PFS will be assessed using 
Kaplan-Meier curves and log-rank tests.  Response rates by FcγR genotype and MRD 
negativity status at the end of induction treatment will be compared using χ2 tests and 
logistic regression.  In addition, FcγR genotype and MRD-negative status will be included 
in multivariate analyses of PFS and response rates, as described in Sections 4.4.2 and 
4.4.4. 
4.4.4 
Sensitivity Analyses 
The fITT population is the primary population for all efficacy measures and will be the 
only population examined in all sensitivity analyses.  The following sensitivity analyses 
for both IRC and investigator-assessed PFS will be performed: 
• 
Unstratified log-rank test. 
• 
Re-randomization test of the primary endpoint to assess the sensitivity of the 
stratified log-rank test to the dynamic randomization procedure.  See Kaiser 2012 
for details. 
• 
The impact of loss to follow-up will be assessed by a worst-case analysis that 
assigns event outcomes to patients who withdrew prior to disease progression in the 
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obinutuzumab arm at the next scheduled disease assessment date and censored 
outcomes to patients in the rituximab arm at the last disease assessment date. 
• 
A missed assessment potential impact analysis will be performed to assess the 
robustness of the result of the analysis of PFS.  In this analysis, if patients have 
missed an assessment prior to the date of the clinical data cut-off or prior to PD, 
they will be counted as having progressed of the day after their last complete 
response assessment. 
• 
PFS analyses will be repeated with censoring at the initiation of NALT prior to 
disease progression, to assess potential confounding of the treatment effect 
estimates by subsequent therapy. 
• 
Patients who discontinue the study treatment for other reasons than disease 
progression or death will be counted as having progressed at the time of 
discontinuation (event will be date of last dose for early treatment discontinuations). 
• 
Patients who died more than 6 months after their last response assessment and 
showed no sign of progression will be censored at the last available response 
assessment. 
For IRC and investigator-assessed CR rate and ORR, the effect of prognostic factors on 
the probability of a CR and an overall response will be assessed in an exploratory 
analysis with the use of logistic regression. 
4.4.5 
Subgroup Analyses 
Subgroup analyses of investigator-assessed PFS, IRC-assessed PFS, CR rate and 
ORR (all without PET) will be performed for the fITT and ITT populations according to 
prognostic factors to assess internal consistency.  The estimated probabilities in yearly 
intervals, as well as the hazard ratio and their 95% confidence intervals (for time-to-
event endpoints) or response rates, as well as the odds ratio and their 95% confidence 
intervals (for binary endpoints), will be reported separately for each level of the following 
subgroups: 
• 
Baseline characteristics (age at randomization, sex, race). 
• 
Stratification factors (chemotherapy regimen, FLIPI or IPI risk group, geographic 
region). 
• 
Potential prognostic factors (including, but not limited to, ECOG performance status, 
Ann Arbor stage, histology [follicular vs. non-follicular], Fcγ receptor status, activities 
of daily living [ADL], instrumental activities of daily living [IADL]). 
All patient characteristics and prognostic factors are measured at or before 
randomization. 
4.4.6 
Patient-Reported Outcomes 
Unless otherwise specified, PRO analyses will include all randomized patients who have 
a baseline and at least one post-baseline PRO assessment.  Patients in this subset will 
be analyzed according to their randomized treatment assignment, irrespective of the 
treatment received.  The analyses will be performed separately for fITT and ITT, and the 
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PRO sections in the clinical study report will be reported according to what was specified 
in the protocol. 
4.4.7 
Pharmacoeconomic Analyses 
Analysis of pharmacoeconomic data and production of a final pharmacoeconomic report 
will be handled separately from the final clinical report of this study.  Information 
obtained from the collection of medical care utilization data in this study may be 
combined with other data, such as cost data or other clinical parameters, in the 
production of a final pharmacoeconomic report. 
4.4.8 
Pharmacokinetic Analyses 
Pharmacokinetic analyses will be defined in a separate final pharmacokinetic report. 
4.4.9 
Pharmacodynamic Analysis 
For each visit at which CD19+ B-cell measurements are made, the following B-cell data 
will be listed for individual patients by treatment arm: 
• 
Absolute counts 
• 
Percentage relative to baseline count for the individual 
• 
Extent of CD19+ B-cell depletion (nadir) 
• 
Duration of depletion 
• 
B-cell depletion is defined as a CD19 measurement of <0.07 × 109/L and can only 
occur after at least one dose of study drug has been administered.  Time to 
depletion is defined as the number of days between the first intake of study drug 
and the date of first depletion. 
• 
B-cell recovery is defined as a CD19 measurement of ≥0.07 × 109/L, for which the 
patient’s previous CD19 measurement revealed B-cell depletion.  B-cell recovery 
will only be considered possible after the patient has had his last dose of study 
treatment.  Time to B-cell recovery will be defined as the time from B-cell depletion 
until B-cell recovery. 
4.5 
SAFETY ANALYSES 
The population for analyzing safety will be the safety analysis population.  Key treatment 
exposure and adverse event tables will also be generated by tumor histology. 
4.5.1 
Exposure to Study Medication 
Treatment exposure will be summarized, including the number of cycles received by 
each patient, and the cumulative dose will be summarized by treatment arm. 
Withdrawals of patients from study treatment will be reported as listings and summary 
tables. 
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4.5.2 
Adverse Events 
Verbatim descriptions of adverse events will be mapped to the most recent version of 
the Medical Dictionary for Regulatory Activities (MedDRA) thesaurus terms and graded 
according to National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE), Version 4.0.  For adverse events, the most extreme severity will be used 
for reporting.  All adverse events occurring during or after the first treatment will be 
summarized by treatment arm and divided by body system, NCI CTCAE grade, and 
relationship to trial treatment.  In tables of the overall incidence of adverse events, 
patients who experienced the same event on more than one occasion are counted only 
once in the calculation of event frequency, and the adverse event with the most extreme 
severity will be included. 
For selected events of particular interest (e.g., infusion-related reaction [IRR], infections, 
tumor lysis syndrome [TLS], or neutropenia), more detailed analyses will be conducted.  
The analysis will depend on the specific question of interest for that particular adverse 
event. 
Adverse events leading to early treatment discontinuation and early study withdrawal will 
be summarized by treatment arm and reason. 
In addition, all serious adverse events will be summarized. 
Deaths reported during the study treatment period and those reported after treatment 
completion or discontinuation will be summarized by treatment arm. 
4.5.3 
Laboratory Data 
Laboratory data with values outside of the normal ranges will be identified.  Additionally, 
selected laboratory data will be summarized according to treatment arm and graded 
according to NCI CTCAE, Version 4.0.  Of note, abnormal laboratory data that are 
clinically significant will be reported as adverse events and summarized in the adverse 
event tables.  Shift from baseline tables will be assessed on the basis of the NCI CTCAE, 
Version 4.0 grading system. 
The incidence of hepatitis B reactivation will be summarized in each arm. 
The incidence of HAHAs will be summarized in patients receiving obinutuzumab. 
4.5.4 
Vital Signs 
Vital signs (absolute values and changes from baseline) will be summarized according to 
treatment arm over time, without any replacement for missing data.  Descriptive statistics 
will be tabulated for ECOG performance status.  ECG, left ventricular ejection fraction 
(LVEF), and physical examination abnormalities will be listed. 
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4.6 
MISSING DATA 
For PFS, patients who do not have documented disease progression or death will have 
observations censored on the date of the last tumor assessment or, if no tumor 
assessments were performed after the baseline visit, at the time of randomization. 
For OS, patients for whom death has not been documented will have observations 
censored on the last date at which they were known to be alive. 
For response endpoints, patients with no response assessments (for any reason) will be 
considered non-responders. 
4.7 
INTERIM ANALYSES 
Although the study is open-label, Sponsor personnel will not have access to by-arm 
efficacy and safety summaries prior to the formal reporting of study results.  To monitor 
safety, Sponsor drug safety and medical monitoring staff will have access to the 
treatment assignments of particular patients. 
An iDMC will evaluate interim analysis results and provide a recommendation as to 
whether to stop the trial early.  However, all interim analyses are non-binding and the 
Sponsor will make the final decision regarding early termination of the trial for reasons of 
either futility or efficacy. 
All summaries and analyses according to treatment arm will be prepared by an iDCC for 
the iDMC review.  Members of the iDMC will be external to the Sponsor and the study 
team, and will follow a charter that outlines their roles and responsibilities. 
The interim safety monitoring plan is described in Section 3.3.  Three interim analyses 
are planned: two for futility (one on CR and one on PFS) and one for efficacy (on PFS). 
The first interim futility analysis will be based on differences in end-of-induction CR rates 
in the first 170 enrolled follicular lymphoma patients.  The analysis will be conducted 
once the 170 follicular lymphoma patients have reached their end-of-induction response 
assessment or have withdrawn prematurely.  The iDMC may recommend halting the 
study for futility if the observed difference in CR rates on the basis of CT (or MRI, but not 
PET) is <3% in favor of obinutuzumab-chemotherapy (i.e., CR rate needs to be ≥3% 
higher for obinutuzumab-chemotherapy relative to rituximab-chemotherapy).  The iDMC 
will consider further supporting data (e.g., PET, MRD), as described in the futility 
analysis specifications, for their recommendation. 
The second interim analysis (futility on PFS) will be conducted when 30% of the required 
investigator-assessed PFS events (i.e., approximately 111 events) will have occurred.  
The iDMC may recommend stopping the study for futility if the observed hazard ratio of 
obinutuzumab over rituximab is >1 (futility boundary assessed on the basis of the non-
binding O’Brien-Fleming β-spending function). 
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At the time of the third interim analysis (efficacy on PFS) that will be conducted when 
67% of the events have occurred (i.e., approximately 248 events), all patients will have 
been enrolled and followed for an estimated minimum of 11 months.  PFS will be tested 
at the significance level determined using the O’Brien-Fleming α-spending function such 
that the overall type I error rate will be maintained at the 0.05 level.  With 67% 
information, the α spending is 0.012. 
The (final) primary efficacy analysis will take place when 370 investigator-assessed PFS 
events have been observed among the follicular population. 
A corresponding analysis will be performed on the basis of IRC-assessed PFS events 
observed in the same timeframe as the 370 investigator-assessed PFS events.  It is 
anticipated that the number of IRC events will be slightly lower (by approximately 10%) 
than the investigator-determined events. 
In the event that the trial is terminated early (at an interim analysis), an analysis would 
examine all IRC data up to ⎯ and no further than ⎯ the time of study termination. 
The iDMC will also review safety summaries at each of the interim analyses, in addition 
to ongoing, periodic safety monitoring. 
In the event that the follicular lymphoma population accrues the planned number of 
patients, but the non-follicular lymphoma population fails to accrue the planned number 
of patients, the analyses will be triggered by the PFS events in the follicular lymphoma 
subset irrespective of when the non-follicular lymphoma population has completed 
enrollment. 
Further details of the interim analyses will be described in the iDMC charter. 
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5. 
REFERENCES 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. J Clin Oncol 2007;25:579–86. 
Kaiser, LD. Dynamic randomization and a randomization model for clinical trials data. 
Stat Med 2012;31:3858–73. 
Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic 
index. Blood 2004;104:1258–64. 
Trotman J, Fournier M, Lamy T, et al. Positron Emission Tomography-Computed 
Tomography (PET-CT) After Induction Therapy Is Highly Predictive of Patient 
Outcome in Follicular Lymphoma: Analysis of PET-CT in a Subset of PRIMA Trial 
Participants. J Clin Onc 2011;29:3194–200. 
Westfall PH, Krishen A. Optimally weighted, fixed sequence and gatekeeper multiple 
testing procedures. J Stat Plan Inference 2001;99:25–40. 
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Appendix 1  
Protocol Synopsis
PROTOCOL SYNOPSIS 
TITLE: 
A MULTICENTER, PHASE III, OPEN-LABEL, RANDOMIZED 
STUDY IN PREVIOUSLY UNTREATED PATIENTS WITH 
ADVANCED INDOLENT NON-HODGKIN'S LYMPHOMA 
EVALUATING THE BENEFIT OF GA101 (RO5072759) 
PLUS CHEMOTHERAPY COMPARED WITH RITUXIMAB 
PLUS CHEMOTHERAPY FOLLOWED BY GA101 OR 
RITUXIMAB MAINTENANCE THERAPY IN RESPONDERS 
PROTOCOL NUMBER: 
BO21223
Eudract Number: 
2010-024132-41
STUDY DRUG: 
RO5072759 (GA101, obinutuzumab)
PHASE: 
III
INDICATION: 
Indolent non-Hodgkin's lymphoma
IND:
104405 
SPONSOR:
F. Hoffmann–La Roche, Ltd (ex-U.S.) 
Grenzacherstrasse 124 
4070 Basel, Switzerland  
 
Objectives 
Primary Objective 
The primary objective for this study is as follows: 
• To evaluate the efficacy of obinutuzumab (GA101, RO5072759) plus chemotherapy 
followed by obinutuzumab maintenance therapy compared with rituximab plus 
chemotherapy followed by rituximab maintenance therapy in patients with previously 
untreated advanced follicular lymphoma, as measured by investigator-assessed 
progression-free survival (PFS) 
Secondary Objectives 
The following secondary objective applies to patients with previously untreated advanced 
indolent non-Hodgkin’s lymphoma (NHL) (i.e., overall population): 
• To evaluate and compare investigator-assessed PFS between the two arms 
The following secondary objectives apply to patients with previously untreated advanced 
indolent NHL (i.e., overall population) and to the subset of patients with previously untreated 
advanced follicular lymphoma (i.e., follicular population): 
• To evaluate and compare Independent Review Committee (IRC)–assessed PFS between 
the two arms 
• To evaluate and compare overall response and CR after the end of induction treatment, 
as assessed by the investigator, between the two arms, with and without FDG-PET 
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Appendix 1  
Protocol Synopsis (cont.)  
• To evaluate and compare overall response and CR after the end of induction treatment, 
as assessed by the investigator, between the two arms, with and without 
18F-fluorodeoxyglucose positron emission tomography (FDG-PET) 
• To evaluate and compare overall survival, EFS, disease-free survival (DFS), duration 
of response, and time to next anti-lymphoma treatment between the two arms. 
EFS, DFS, and duration of response will be based on investigator assessment. 
• To evaluate and compare the safety profiles between the two arms during induction and 
maintenance 
• To assess patient-reported outcomes (PROs) in both arms 
Study Design 
This is an open-label, international, multicenter, randomized, Phase III study to investigate the 
efficacy and safety of obinutuzumab plus chemotherapy followed by obinutuzumab 
maintenance therapy for responders (CR or PR) compared with rituximab plus chemotherapy 
followed by rituximab maintenance therapy for responders in patients with previously untreated 
advanced indolent NHL.  Prior to the initiation of the study, each site will choose one of three 
chemotherapy regimens (CHOP, CVP, or bendamustine) that is considered to be the standard 
of care for follicular lymphoma; all patients with follicular lymphoma at that site will receive the 
chosen chemotherapy regimen for the duration of the study (a site may switch to another 
regimen if new scientific data become available and after Sponsor approval).  For non-follicular 
NHL, the investigator will have the option of choosing one of the three chemotherapy regimens 
(CHOP, CVP, or bendamustine) for each patient.  All patients will then be randomized to either 
rituximab plus chemotherapy or obinutuzumab plus chemotherapy.   
Approximately 1200 patients with follicular lymphoma will be recruited and randomly assigned in 
a 1:1 ratio to either obinutuzumab plus chemotherapy followed by obinutuzumab maintenance 
in responders or rituximab plus chemotherapy followed by rituximab maintenance in responders.  
In addition, approximately 200 patients with marginal zone lymphoma (MZL) will be recruited 
and randomly assigned in a 1:1 ratio to the two treatment arms. 
The schedule for administration of rituximab or obinutuzumab will be dependent upon the 
accompanying chemotherapy regimen.  In the control arm of the study (Arm A), six to eight 
doses of rituximab at 375 mg/m2 will be administered by IV infusion with the accompanying 
chemotherapy regimen.  In the experimental arm of the study (Arm B), eight to ten doses of 
obinutuzumab (including two additional doses of obinutuzumab on Days 8 and 15 of Cycle 1) 
at an absolute (flat) dose of 1000 mg will be administered by IV infusion with the accompanying 
chemotherapy regimen.  Patients who demonstrate a CR or PR at the end of induction therapy 
will continue to receive rituximab at 375 mg/m2 (Arm A) or obinutuzumab at a flat dose of 1000 
mg (Arm B) every 2 months until disease progression for up to 2 years.  Patients who 
demonstrate SD at the end of induction therapy will be followed for progression for up to 2 years 
according to the same follow-up schedule as responding patients (CR or PR) receiving 
maintenance (observation).  If induction therapy was stopped for toxicity or any reason other 
than toxicity, then patients are discontinued from study treatment and go into follow-up directly. 
All patients will be assessed for disease response by the investigator through use of regular 
clinical and laboratory examinations and computed tomography (CT) scans according to a 
modified version of the Revised Response Criteria for Malignant Lymphoma (see Appendix C). 
Additional response criteria based on paraprotein assessment are in effect for the MZL 
population and based on hematological parameters and spleen size for the subset of splenic 
MZL patients.  During induction treatment, tumor assessment is performed after three cycles for 
patients receiving bendamustine, after four cycles for patients receiving CVP or CHOP, and at 
the completion of induction therapy. 
Following the completion of induction therapy, patients receiving maintenance therapy 
(CR or PR) or undergoing observation (SD) will be followed clinically every 2 months for 2 years 
(with CT scans every 4 months for the first year and then every 6 months for the second year).  
For patients who have not progressed at the maintenance or observation completion visit  
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Appendix 1  
Protocol Synopsis (cont.)  
(25 months from Day 1 of Cycle 8 [CHOP/CVP arms] or Cycle 6 [bendamustine arm]), disease 
assessments will continue every 3 months for 3 years (with CT scans every 6 months) and then 
every 6 months for 2 years (with CT scans every year) (follow-up for disease progression).  
After 5 years of follow-up or disease progression (whichever comes first), patients will still be 
followed every 6 months for overall survival and new anti-lymphoma treatment (NALT), or for 
disease progression if applicable,  until the end of the study, which will be approximately 
10.2 years after inclusion of the first patient.  Patients who terminate induction early without PD 
will be followed for PD, as per Appendix A-5, and in the extended follow-up for PD, NALT and 
overall survival.  Patients who terminate induction early because of PD will go directly into the 
extended follow-up for NALT and overall survival.  Patients who discontinue the protocol-
defined treatment path and need to start anNALT in the absence of disease progression 
(e.g., if wrong diagnosis at screening and new diagnosis requires a change of treatment) will be 
followed for disease progression and overall survival. 
An independent radiologic and oncologic review of the responses of all patients by an IRC will 
also be conducted for the futility and efficacy analyses with and without PET. 
Patients who discontinue all components of study therapy prior to disease progression 
(e.g., for toxicity) will enter the follow-up phase of the study and will continue to be followed for 
PD and overall survival (regardless of whether they subsequently receive NALT). 
A retrospective quality assurance pathology review will be conducted on pathology samples to 
evaluate histology and CD20 status in addition to other prognostic features. 
An IDMC will conduct periodic interim reviews of safety summaries, starting approximately 
1 month after enrollment of the first patient and then approximately every 2 months until 
100 patients have completed two cycles of study treatment.  Afterward, the IDMC will conduct 
reviews of safety summaries approximately every 6 months.  All summaries and analyses 
reviewed by the IDMC will be prepared by an Independent Data Coordinating Center (IDCC).  
Safety will be evaluated by monitoring dose delays and dose intensity, adverse events, 
serious adverse events, and deaths.  These will be graded using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0.  Laboratory 
safety assessments will include regular monitoring of hematology, blood chemistry, and tests of 
immunologic parameters.  In addition, tests for the presence of human anti-human antibodies 
(HAHAs) will be performed only in all patients receiving obinutuzumab. 
Outcome Measures 
Primary Efficacy Outcome Measure 
The primary efficacy endpoint, PFS in patients with follicular lymphoma, is defined as the time 
from randomization to the first occurrence of progression or relapse as assessed by the 
investigator according to the Revised Response Criteria for Malignant Lymphoma, or death from 
any cause. 
Secondary Efficacy Outcome Measures 
For the endpoints below that specify disease response, response will be assessed by the 
investigator according to the Revised Response Criteria for Malignant Lymphoma and additional 
response criteria for MZL. 
The following secondary outcome measure applies to patients with previously untreated 
advanced indolent NHL (i.e., overall population): 
• Investigator-assessed PFS 
 
The following secondary outcome measures apply to patients with previously untreated 
advanced indolent NHL (i.e., overall population) and to the subset of patients with previously 
untreated advanced follicular lymphoma (i.e., follicular population): 
• IRC-assessed PFS 
• CR and overall response (CR or PR) at the end of induction, as assessed by the investigator 
with and without FDG-PET 
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Appendix 1  
Protocol Synopsis (cont.)  
• CR and overall response (CR or PR) at the end of induction, as assessed by the IRC 
with and without FDG-PET 
• Overall survival, defined as the time from randomization to death from any cause 
• EFS, defined as the time from randomization to disease progression/relapse as assessed by 
the investigator, death from any cause, or start of an NALT 
• DFS, defined for patients with a best overall response (BOR) of CR as the time from first 
occurrence of a documented CR to PD as assessed by the investigator or death from any 
cause.  Patients who have had no documented disease progression or have not died after CR 
will be censored at the last disease assessment date. 
• Duration of response, defined for patients with a BOR of CR or PR as the time from first 
occurrence of a documented CR or PR to disease progression/relapse as assessed by the 
investigator or death from any cause.  For patients achieving a response who have not 
progressed, relapsed, or died at the time of the analysis, duration of response will be censored 
on the date of last disease assessment. 
• Time to next anti-lymphoma treatment, defined as the time from randomization to start of 
new non-protocol anti-lymphoma therapy or death from any cause 
• Change from baseline to the end of study in PROs based on the FACT-Lym instrument, 
as outlined below. 
Change from baseline in all domains of the FACT-G 
Change from baseline in the total outcome index (TOI) (range, 0−116):  sum of physical 
well-being (7 items), functional well-being (7 items), and Lym subscale (15 items) scores 
Change from baseline in the FACT-Lym subscale score (range, 0−60):  
15 lymphoma-specific items 
Change from baseline in the FACT-Lym total score (range, 0−168):  sum of physical 
well-being (7 items), social/family well-being (7 items), emotional well-being (6 items), 
functional well-being (7 items), and Lym subscale (15 items) scores 
• EQ-5D summary scores at baseline, during treatment, after treatment, at the last 
assessment prior to progression, and at the first assessment after progression 
Analysis of medical resource utilization data will be provided if required. 
Safety Plan 
This trial is designed to allow for early termination or a modification of the protocol (in particular, 
the dosing regimens) for safety concerns, based on the advice of an IDMC.  The IDMC will be 
incorporated into the study to review safety data on a regular basis, including adverse events of 
special interest.  The IDMC will meet 1 month after enrollment of the first patient and then 
approximately every 2 months until 100 patients have completed two cycles of study treatment.  
Afterward, the IDMC will meet approximately every 6 months.  Both the Sponsor and the IDMC 
can request ad hoc IDMC meetings if potential safety concerns arise.  Following each meeting, 
the IDMC will recommend to the Sponsor whether the study should continue according to the 
protocol or may suggest changes to the protocol based on the outcome of the data review.  
In exceptional cases, the IDMC may recommend stopping the study or closing a treatment arm 
as a result of safety reasons.  The IDMC will also perform a safety review at the preplanned 
interim analyses for futility and efficacy.   
Risks Associated with Obinutuzumab Therapy 
The commonly experienced IRRs have been characterized by fever, chills, flushing, nausea, 
vomiting, hypotension, hypertension, and fatigue, as well as 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, Version 3.0, 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 slowing or interruption of the  
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Appendix 1  
Protocol Synopsis (cont.)  
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. 
Cases of tumor lysis syndrome have been reported with obinutuzumab administration.  To date, 
no patient has required hemodialysis for renal failure.  Patients with a high tumor burden, 
including patients with a lymphocyte count of ≥ 25 × 109/L (particularly, patients with B-cell CLL 
and MCL), are at increased risk for tumor lysis syndrome and severe IRRs. 
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 granulocyte colony stimulating factors 
(G-CSF) has been found to result in a rapid normalization of neutrophils, similar to what has 
been observed in patients treated with rituximab.  The use of G-CSF is allowed for treatment of 
neutropenia in this study.  Primary prophylaxis with G-CSF is recommended according to the 
American Society of Clinical Oncology (ASCO), European Organisation for Research and 
Treatment of Cancer (EORTC), and European Society for Medical Oncology (ESMO) 
guidelines, namely for patients who are ≥60 years old and/or with comorbidities.  The use of 
G-CSF is strongly recommended in Cycle 1 for all patients treated with obinutuzumab plus 
CHOP (G-CHOP). 
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.  
Based on the available evidence to date the greatest risk of hemorrhage in 
obinutuzumab-treated patients is observed in the first cycle.  A clear relationship between 
thrombocytopenia and hemorrhagic events has not been established.  Patients treated with 
concomitant medication, which could possibly worsen thrombocytopenia-related events, such 
as 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.  
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. 
Serious infections, including fatal, bacterial, fungal, and new or reactivated viral infections 
(e.g., cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile 
virus, and hepatitis B and C) 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 stem-cell transplant.  The risk of such infections with obinutuzumab is unknown.  
Physicians should be aware of symptoms suggestive of progressive multifocal 
leukoencephalopathy (PML) and consider the diagnosis of PML in any patient presenting with 
new-onset neurologic manifestations.  Evaluation of PML includes but is not limited to 
consultation with a neurologist, brain magnetic resonance imaging (MRI), and lumbar puncture.  
To date, there have been no reports of patients experiencing PML while or after receiving 
obinutuzumab. 
Cases (including fatal) of John Cunningham virus (JCV) infection resulting in PML 
(destructive infection of oligodendrocytes of the central nervous system white matter) have been 
reported in patients treated with anti-CD20 therapies, including rituximab and obinutuzumab. 
 
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Appendix 1  
Protocol Synopsis (cont.)  
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 to quantify DNA of JCV in the cerebrospinal fluid. 
Therapy with obinutuzumab and rituximab should be withheld during the investigation of 
potential PML and permanently discontinued in the 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 treatment of PML. 
Risks Associated with Rituximab Therapy 
Patients treated with rituximab in combination with chemotherapy are at risk for IRRs.  Fatal 
infusion reactions within 24 hours after 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, adult respiratory distress syndrome, myocardial infarction, ventricular 
fibrillation, cardiogenic shock, anaphylactoid events, or death. 
Patients may be at risk for tumor lysis syndrome.  A high number of circulating malignant cells 
(≥ 25,000/mm3) or high tumor burden confers a greater risk of tumor lysis syndrome.  For 
patients with evidence of tumor lysis syndrome, rituximab should be discontinued and the 
patient treated as clinically indicated. 
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 diagnosis 
of hepatitis was approximately 4 months after the initiation of rituximab and approximately 
1 month after the last dose. 
Patients with chronic hepatitis B viral infection (i.e., hepatitis B surface antigen [HBsAg] positive) 
are at risk for reactivation and will be excluded from the study.  Patients with evidence of prior 
hepatitis B exposure or who are carriers (defined as HBsAg negative and hepatitis B core 
antibody [HBcAb] positive) are at a lower risk for reactivation.  In a study of 51 HBV carriers with 
diffuse large B-cell lymphoma who received rituximab, 12% of patients developed evidence of 
reactivation (Niitsu et al. 2010).  Patients who demonstrate evidence of reactivation while 
receiving an appropriate anti-viral therapy will discontinue study treatment. 
Rare cases of PML have been reported in patients treated with rituximab alone or in 
combination with other immunosuppressive medications.  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 after the patient's last infusion 
of rituximab. 
Angina and cardiac arrhythmias have occurred with rituximab treatment and can be life 
threatening.  Patients in the CHOP arm who have been treated with doxorubicin, an 
anthracycline-based chemotherapy, are at risk for cardiotoxicity and will be required to have 
assessments of left ventricular ejection fraction (LVEF) at baseline and at the end of induction 
treatment. 
Serious infections, including fatal, bacterial, fungal, and new or reactivated viral infections 
(e.g., cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile 
virus, and hepatitis B and C), can occur during and up to 1 year following the completion of 
rituximab-based therapy. 
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Appendix 1  
Protocol Synopsis (cont.)  
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 (TEN).  The 
onset of these reactions in patients treated with rituximab has varied from 1 to 13 weeks 
following rituximab exposure. 
Abdominal pain, bowel obstruction, and perforation, in some cases leading to death, can occur 
in patients receiving rituximab in combination with chemotherapy.  In postmarketing reports of 
rituximab, the mean time to documented gastrointestinal perforation was 6 days 
(range, 1−77 days) in patients with NHL. 
Risks Associated with CHOP or CVP Chemotherapy 
Please refer to prescribing information for doxorubicin, cyclophosphamide, vincristine, and 
prednisone/prednisolone/methylprednisolone for risks related to CHOP or CVP chemotherapy. 
Risks Associated with Bendamustine Chemotherapy 
Patients treated with bendamustine are likely to experience myelosuppression.  Blood counts 
will be monitored weekly during the first cycle and then frequently throughout subsequent cycles 
of treatment.  Patients who experience Grade 3 or 4 neutropenia or thrombocytopenia should 
be monitored until neutrophil and platelet values return to at least Grade 2.  The use of myeloid 
growth factors for the primary and secondary prevention of febrile neutropenia is permitted. 
Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in 
postmarketing reports.  Infection has been associated with hospitalization, septic shock, and 
death.  Patients with myelosuppression following treatment with bendamustine are more 
susceptible to infections. 
Infusion reactions to bendamustine have occurred commonly in clinical trials.  Symptoms 
include fever, chills, pruritis, and rash.  In rare instances, severe anaphylaxis and anaphylactoid 
reactions have occurred, particularly in the second and subsequent cycles of therapy.  Patients 
should be monitored clinically and discontinue drug for every reaction. 
Tumor lysis syndrome has been reported in association with bendamustine treatment in clinical 
trials and in postmarketing reports.  The onset tends to be within the first treatment cycle of 
bendamustine and without intervention may lead to acute renal failure and death.  Preventive 
measures include maintaining adequate volume status and close monitoring of blood chemistry, 
particularly potassium and uric acid levels.  Allopurinol has also been used during the beginning 
of bendamustine therapy.  However, there may be an increased risk of severe skin toxicity when 
bendamustine and allopurinol are administered concomitantly. 
A number of skin reactions have been reported in clinical trials and postmarketing safety reports.  
These events have included rash, toxic skin reactions, and bullous exanthema.  Some events 
occurred when bendamustine was given in combination with other anti-cancer agents, so the 
precise relationship to bendamustine is uncertain. 
In a study of bendamustine in combination with rituximab, one case of TEN occurred.  TEN has 
been reported for rituximab.  Cases of Stevens-Johnson syndrome and TEN, some fatal, have 
been reported when bendamustine was administered concomitantly with allopurinol and other 
medications known to cause these syndromes.  Allopurinol must not be given on days of 
bendamustine administration.  Patients with skin reactions should be monitored closely.  
If skin reactions are severe or progressive, bendamustine should be withheld. 
Premalignant and malignant diseases, including myelodysplastic syndrome, myeloproliferative 
disorders, acute myeloid leukemia, and bronchial carcinoma, have developed in patients treated 
with bendamustine.  The association with bendamustine has not been determined. 
There are postmarketing reports of bendamustine extravasation resulting in hospitalization from 
erythema, marked swelling, and pain.  Precautions should be taken to avoid extravasation, 
including monitoring of the IV infusion site for redness, swelling, pain, infections, and necrosis 
during and after administration of bendamustine. 
Rare cases of transfusion-associated graft versus host disease have been reported following 
treatment of low-grade B cell malignancies with the purine analogues fludarabine.  The situation  
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Protocol Synopsis (cont.)  
with newer purine antagonists such as bendamustine is unclear.  Transfusions, if required, 
should be performed according to national guidelines. 
Certain medications may interact with bendamustine.  Caution should be used or alternative 
treatments considered if concomitant treatment with CYP1A2 inhibitors or inducers is needed.  
CYP1A2 inhibitors and inducers are not contraindicated.  During treatment with bendamustine, 
patients will be provided with a card to keep with them that provides notification to other health 
care providers that the patient is taking bendamustine as a participant in a clinical study 
(see Appendix F). 
Study Treatment 
In the control arm (Arm A), six to eight doses of rituximab at 375 mg/m2 will be administered by 
IV infusion with the accompanying chemotherapy regimen during induction, as outlined below: 
• 
R-CHOP:  Rituximab will be administered on Day 1 of Cycles 1−8 (21-day cycles).  CHOP 
will be administered on Day 1, with prednisone/prednisolone/methylprednisolone also 
administered on Days 2–5, of Cycles 1−6. 
• 
R-CVP:  Rituximab will be administered on Day 1 of Cycles 1–8 (21-day cycles).  CVP will 
be administered on Day 1, with prednisone/prednisolone/methylprednisolone also 
administered on Days 2–5, of Cycles 1–8. 
• 
R-bendamustine:  Rituximab will be administered on Day 1 of Cycles 1−6 (28-day cycles).  
Bendamustine will be administered on Days 1 and 2 of Cycles 1−6, with 
prednisone/prednisolone/methylprednisolone also administered on Day 1 of Cycle 1. 
If it is the strong preference of the investigator or of the site (e.g., for logistical or safety reasons), 
the administration of rituximab on the day prior to CHOP or CVP or bendamustine with 
premedication is allowed.  It is also allowed to split the antibody infusion over 2 days if the 
patient is at increased risk for an IRR (high tumor burden, high peripheral lymphocyte count).  
However, both optional changes to the administration schedule have to be done equally in both 
study arms (R-Chemo and G-Chemo) in order to avoid any bias.  Premedication before 
antibody administration in Cycle 1 is recommended and may include 100 mg 
prednisone/prednisolone or 80 mg methylprednisolone orally (within 12 hours but at least 60 
minutes prior to start of antibody infusion) or IV (if less than 60 minutes prior to start of antibody 
infusion) in order to minimize cytokine release syndrome or allergic reactions.  Premedication 
with prednisone/prednisolone/methylprednisolone is mandatory in patients who had an IRR until 
no IRRs occur anymore during antibody infusion.  Withhold antihypertensive medication 
12 hours prior to start of antibody infusion and during the infusion.   
Patients randomized to receive rituximab plus chemotherapy who achieve a CR or PR at the 
end of induction therapy will continue to receive rituximab at 375 mg/m2 every 2 months until 
disease progression for up to 2 years.   
In the experimental arm (Arm B), eight to ten doses of obinutuzumab at 1000 mg will be 
administered by IV infusion with the accompanying chemotherapy regimen during induction, as 
outlined below. 
• 
G-CHOP:  Obinutuzumab will be administered on Days 1, 8, and 15 of Cycle 1 and on Day 
1 of Cycles 2–8 (21-day cycles).  CHOP will be administered on Day 1, with 
prednisone/prednisolone/methylprednisolone also administered on Days 2–5, of Cycles 1–6. 
• 
G-CVP:  Obinutuzumab will be administered on Days 1, 8, and 15 of Cycle 1 and on Day 1 
of Cycles 2−8 (21-day cycles).  CVP will be administered on Day 1, with 
prednisone/prednisolone/methylprednisolone also administered on Days 2–5, of Cycles 1–8. 
• 
G-bendamustine:  Obinutuzumab will be administered on Days 1, 8, and 15 of Cycle 1 and 
on Day 1 of Cycles 2−6 (28-day cycles).  Bendamustine will be administered on Days 1 and 
2 of Cycles 1−6, with prednisone/prednisolone/methylprednisolone administered on Day 1 
of Cycle 1. 
If it is the strong preference of the investigator or of the site (e.g., for logistical or safety reasons), 
the administration of obinutuzumab is allowed on the day prior to CHOP or CVP or  
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Protocol Synopsis (cont.)  
bendamustine.  It is also allowed to split the antibody infusion over 2 days if the patient is at 
increased risk for an IRR (high tumor burden, high peripheral lymphocyte count).  However, 
both optional changes to the administration schedule have to be done equally in both study 
arms (R-Chemo and G-Chemo) in order to avoid any bias.  Premedication before antibody 
administration in Cycle 1 is recommended and may include 100 mg prednisone/prednisolone or 
80 mg methylprednisolone orally (within 12 hours but at least 60 minutes prior to start of 
antibody infusion) or IV (if less than 60 minutes prior to start of antibody infusion) in order to 
minimize cytokine release syndrome or allergic reactions.  Premedication with 
prednisone/prednisolone/methylprednisolone is mandatory in patients who had an IRR until no 
IRRs occur anymore during antibody infusion.  Withhold antihypertensive medication 12 hours 
prior to start of antibody infusion and during the infusion. 
Patients randomized to receive obinutuzumab plus chemotherapy who achieve a CR or PR at 
the end of induction therapy will continue to receive obinutuzumab at 1000 mg every 2 months 
until disease progression for up to 2 years.   
Concomitant Therapy and Clinical Practice  
Patients who use oral contraceptives, hormone-replacement therapy, or other maintenance 
therapy should continue their use. 
Patients may receive prophylactic anti-viral medication to prevent hepatitis B reactivation in 
countries where they are administered as part of the standard of care or national guidelines. 
The use of rasburicase for the treatment of tumor lysis syndrome and the prevention of 
hyperuricemia is allowed according to institutional guidelines. 
The use of antibiotic and/or anti-viral prophylaxis according to institutional guidelines is also 
allowed. 
Primary prophylaxis with granulocyte colony stimulating factors (G-CSF) is recommended as 
per the American Society of Clinical Oncology (ASCO), European Organisation for Research 
and Treatment of Cancer (EORTC), and European Society for Medical Oncology (ESMO) 
guidelines⎯namely, in patients who are ≥ 60 years of age and/or with comorbidities.  The use 
of G-CSF prophylaxis is strongly recommended in Cycle 1 for all patients treated with 
GA101 + CHOP. 
Harvesting of stem cells by G-CSF alone (no additional chemotherapeutic agent) is allowed only 
if it is done between Cycle 5 Day 1 and Cycle 8 Day 1 (R/G-CHOP or R/G-CVP) or Cycle 4 
Day 1 and Cycle 6 Day 1 (R/G-Bendamustine).   
Patients who experience obinutuzumab infusion-related temperature elevations of > 38.5°C 
or other minor infusion-related symptoms may be treated symptomatically with 
acetaminophen/paracetamol (≥ 500 mg) and/or H1- and H2-receptor antagonists 
(e.g., diphenhydramine, ranitidine).  Serious infusion-related events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory 
distress should be managed with additional supportive therapies (e.g., supplemental oxygen, β2 
agonists/epinephrine, and/or corticosteroids) as clinically indicated according to standard clinical 
practice. 
It is mandatory to follow the ASCO/EORTC/ESMO guidelines about the use of myeloid growth 
factors for the primary prevention of febrile neutropenia throughout the trial. 
Mesna (2-mercaptoethane sulfonate sodium) may be administered as prophylaxis per 
institutional guidelines for patients treated with CHOP or CVP. 
Use of the following therapies is prohibited during the study: 
• Cytotoxic chemotherapy (other than bendamustine, cyclophosphamide, doxorubicin, 
or vincristine) 
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Protocol Synopsis (cont.)  
Although MTX is a chemotherapeutic agent, due to the low doses used in treating 
rheumatoid arthritis (typically 7.5 to a maximum of 20 mg/week) it is not considered 
chemotherapy for lymphoma.  Therefore, patients treated before or during study conduct 
with MTX for rheumatoid arthritis are still eligible to participate in the study.  It is 
recommended to stop MTX 2-3 weeks prior to starting immunochemotherapy since the 
combination of MTX and immunochemotherapy increases the risk of 
immunosuppression and the risk of infection, but MTX may be resumed during 
maintenance/observation/follow-up, if clinically indicated 
• Radiotherapy 
• Immunotherapy (other than rituximab and obinutuzumab) 
• Hormone therapy (other than contraceptives, hormone-replacement therapy, or megestrol 
acetate) 
Hormonal therapy (e.g., GmRH-agonists) for egg cell harvest/fertility preservation prior 
to randomization is allowed in women of childbearing age 
• Any therapies intended for the treatment of NHL whether U.S. Food and Drug Administration 
approved or experimental (outside of this study) 
Statistical Methods 
Primary Efficacy Analysis 
The primary analysis population for efficacy is the intent-to-treat follicular population, defined as 
all randomized patients with follicular histology, according to local diagnosis provided in 
interactive voice or Web-based response system (IxRS).  Patients will be analyzed according to 
the treatment arm to which they were randomized.    
The primary efficacy endpoint, PFS in patients with follicular lymphoma, is defined as the time 
from randomization to the first occurrence of progression or relapse as assessed by the 
investigator according to the Revised Response Criteria for Malignant Lymphoma or death from 
any cause.  PFS for patients without disease progression, relapse, or death will be censored at 
the time of the last tumor assessment or, if no tumor assessments were performed after the 
baseline visit, at the time of randomization. 
Although the primary efficacy endpoint is the investigator-assessed PFS, PFS based on IRC 
assessments will also be analyzed to support the primary analysis.  In the United States, 
IRC-assessed PFS will be the basis for regulatory decisions. 
The primary analysis of the study will test the equality of PFS distributions in the obinutuzumab 
plus chemotherapy (G-Chemo) and rituximab plus chemotherapy (R-Chemo) arms, as follows: 
H0: PFSG-Chemo = PFSR-Chemo versus 
 
H1: PFSG-Chemo ≠ PFSR-Chemo
Treatment comparison will be made using a two-sided stratified log-rank test (0.05 significance 
level) stratified by chemotherapy regimen (CHOP, CVP, or bendamustine) and FLIPI risk group 
(low, intermediate, or high).  Kaplan−Meier methodology will be used to estimate PFS 
distribution for each treatment arm.  The Kaplan–Meier curve will provide a visual description of 
the differences across treatment arms.  Estimates of the treatment effect will be expressed as 
hazard ratios through use of a stratified Cox proportional-hazards analysis, including 
95% confidence limits.   
Median PFS is not expected to be reached in this study; hence, the 3-year and 4-year rates will 
be used to describe PFS in addition to the hazard ratio.   
Missing Data   
For PFS, patients who do not have documented disease progression or death will be treated as 
censored observations on the date of the last tumor assessment. 
For overall survival, patients who do not have documented deaths will be censored on the last 
date they were known to be alive. 
 
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Appendix 1  
Protocol Synopsis (cont.)  
For response endpoints, patients with no response assessments (for whatever reason) will be 
considered non-responders. 
Determination of Sample Size   
Estimates of the number of events required to demonstrate efficacy with regard to PFS are 
based on the following assumptions: 
• Two-sided log-rank test at the 0.05 level of significance  
• Powered for follicular lymphoma patient subset 
• Eighty percent power to detect a hazard ratio for G-Chemo versus R-Chemo of 0.74, 
corresponding to an improvement in 3-year PFS from 70.7% to 77.4% or in median PFS 
from 6 years to 8.1 years (35%) 
Note that estimates of median PFS are not likely to be reached in either study arm. 
• Exponential distribution of PFS 
• An annual dropout rate of 2.5% 
• Performance of interim analyses on PFS: one for futility when approximately 30% of the 
total (investigator-assessed) PFS events have occurred and one for efficacy when 
approximately 67% of the total PFS events have occurred.  Efficacy and (nonbinding) futility 
boundaries will be computed using the Lan-DeMets approximation to the O’Brien-Fleming 
boundary shape. 
The futility boundary will be nonbinding. 
In addition, a futility analysis based on CR rates at the end of induction determined by CT (or 
MRI, but not PET) will be performed on the first 170 follicular lymphoma patients randomized. 
With these assumptions, 370 PFS events are required to achieve 80% power for the primary 
analysis.  Recruitment will be staggered in order to recruit the first 170 patients in a smaller 
number of sites (approximately 125 sites), followed by the activation of all 
(approximately 200−250) sites after the IDMC meeting for futility based on CR rates.  
It is expected that during the first stage, after a 6-month ramp up, 18 patients per month will be 
recruited, and after the IDMC meeting and another 4-month ramp up, an accrual rate of 37 
patients per month is expected.  The 1200 follicular patients enrolled over 49 months 
and followed for an additional 29 months will be required to provide 370 PFS events, with a total 
duration for PFS follow-up of approximately 78 months (6.5 years). 
Approximately 200 additional patients with non-follicular lymphoma will be enrolled.  This number 
was based on a study of enrollment feasibility, which indicated that 200 patients would likely be 
enrolled in 49 months, in addition to the planned follicular enrollment.  Although the study would 
not be powered to detect statistically significant differences in this 200-patient cohort, there would 
be a reasonable chance of detecting a trend.   
The pharmacokinetic assessments will apply to a subpopulation of approximately 460 patients 
receiving obinutuzumab.  This is the minimum number of patients needed to accurately construct 
a population pharmacokinetic model and will allow for the evaluation of the relationship between 
exposure and pharmacodynamic markers of response.  Approximately 120 follicular patients will 
undergo pharmacokinetic sampling from each of the three chemotherapy groups (G-CHOP, 
G-CVP, and G-bendamustine), and 100 additional patients with non-follicular lymphoma will also 
undergo sampling.  This sample size is believed to be sufficient to characterize with confidence 
the pharmacokinetics of obinutuzumab in the target population as well as the relationships 
between exposure to obinutuzumab and response.  The pharmacokinetic sampling schedule in 
this study was determined using an optimal sampling strategy with the software PFIM and should 
result in a precision of parameter estimates lower than 20% for the main pharmacokinetic 
parameters. 
Interim and Final Analyses   
Although the study is open label, Sponsor personnel will not have access to by-arm efficacy and 
safety summaries prior to the formal reporting of study results.  In order to monitor safety, 
Sponsor drug safety and medical monitoring staff will have access to the treatment assignments  
 
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Appendix 1  
Protocol Synopsis (cont.)  
of particular patients.  An IDMC will evaluate interim analysis results and determine whether the 
trial will be stopped early.   
Three interim analyses are planned:  two for futility and one for efficacy.  The first interim 
analysis will be based on differences in end of induction CR rates in the first 170 enrolled 
follicular lymphoma patients.  The analysis will be conducted once the 170 follicular lymphoma 
patients have reached their end-of-induction response assessment or have withdrawn 
prematurely.  The IDMC may recommend to stop the study for futility if the observed difference 
in CR rate based on CT (or MRI, but not PET) is < 3% in favor of G-Chemo (i.e., CR rate needs 
to be ≥ 3% higher on G-Chemo vs. R-Chemo). 
The second interim analysis (futility on PFS) will be conducted when 30% of the required PFS 
events (i.e., approximately 111 events) will have occurred.  The IDMC may recommend to stop 
the study for futility if the observed hazard ratio of obinutuzumab over rituximab is > 1 
(futility boundary based on nonbinding O´Brien-Fleming beta-spending function). 
At the time of the third interim analysis (efficacy on PFS) that will be conducted when 67% of 
the events have occurred (i.e., approximately 248 events), all patients will have been enrolled 
and followed for an estimated minimum of 11 months.  PFS will be tested at the significance 
level determined using the O´Brien-Fleming alpha-spending function so the overall Type I error 
rate will be maintained at the 0.05 level.  With 67% information, the alpha spending is 0.012. 
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Appendix 3  
iDMC Charter 
 
 
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CHARTER FOR THE INDEPENDENT DATA MONITORING 
COMMITTEE 
TITLE: 
A MULTICENTER, PHASE III, OPEN-LABEL, 
RANDOMIZED STUDY IN PREVIOUSLY 
UNTREATED PATIENTS WITH ADVANCED 
INDOLENT NON-HODGKIN'S LYMPHOMA 
EVALUATING THE BENEFIT OF GA101 
(RO5072759) PLUS CHEMOTHERAPY COMPARED 
WITH RITUXIMAB PLUS CHEMOTHERAPY 
FOLLOWED BY GA101 OR RITUXIMAB 
MAINTENANCE THERAPY IN RESPONDERS 
PROTOCOL: 
BO21223  
AUTHORS: 
, Study Statistician 
, Clinical Science 
EUDRACT NUMBER: 
2010-024132-41 
SPONSOR: 
F. Hoffmann–La Roche, Ltd.  
APPROVED BY: 
, 
 
DATE FINAL: 
9 July 2013 (version 3) 
26 October 2011 (version 2) 
4 July 2011 (version 1) 
 
Confidential 
This is a F. Hoffmann-La Roche, Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche, Ltd. 
 
iDMC Charter:  obinutuzumab⎯F. Hoffmann−La Roche, Ltd 
BO21223 
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TABLE OF CONTENTS 
1. 
INTRODUCTION .......................................................................................... 7 
2. 
ROLE OF THE COMMITTEE...................................................................... 10 
2.1 
Safety……….......................................................................... 10 
2.2 
Efficacy………. ...................................................................... 10 
2.3 
Study Conduct....................................................................... 11 
3. 
ORGANIZATIONAL FLOW......................................................................... 11 
4. 
COMMITTEE MEMBERSHIP ..................................................................... 13 
4.1 
Members………..................................................................... 13 
4.2 
Financial Disclosure and Conflict of Interest.......................... 14 
4.3 
Duration of iDMC Membership .............................................. 14 
5. 
COMMITTEE MEETINGS........................................................................... 14 
5.1 
Organizational Meeting.......................................................... 14 
5.2 
Scheduled Interim Analysis Meetings.................................... 15 
5.2.1 
Open Session........................................................................ 15 
5.2.2 
Closed Session...................................................................... 15 
5.3 
Unscheduled Meetings .......................................................... 16 
6. 
COMMUNICATION..................................................................................... 16 
6.1 
Open Reports ........................................................................ 16 
6.2 
Closed Reports...................................................................... 16 
6.3 
iDMC Minutes........................................................................ 16 
6.4 
iDMC Recommendations....................................................... 16 
6.4.1 
Safety Recommendations...................................................... 17 
6.4.1.1 Consequences Following Hold due to an Event................... 17 
6.4.1.2 Consequences Following Discontinuation of the 
Entire Study........................................................................................ 17 
6.4.2 
Efficacy Recommendations ................................................... 17 
6.4.2.1 CR Futility Analysis .............................................................. 18 
6.4.2.2 PFS Futility Analysis (at 30% PFS information) ................... 18 
6.4.2.3 PFS Efficacy Analysis (at 67% PFS information)................. 19 
6.5 
Sponsor Decisions................................................................. 19 
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7. 
REFERENCES ........................................................................................... 20 
 
 
LIST OF TABLES 
Table 1 Terms and Abbreviations......................................................................... 8 
 
 
LIST OF FIGURES 
Figure 1 Organizational Flow.............................................................................. 12 
 
 
LIST OF APPENDICES 
Appendix 1 Closed Reports................................................................................ 21 
Appendix 2 Open Reports .................................................................................. 23 
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1. 
INTRODUCTION 
Study BO21223 is an open-label, international, multicenter, randomized, Phase III study 
to investigate the efficacy and safety of obinutuzumab (GA101) plus chemotherapy 
followed by obinutuzumab maintenance therapy for responders (complete response [CR] 
or partial response [PR]) compared with rituximab plus chemotherapy followed by 
rituximab maintenance therapy for responders in patients with previously untreated 
advanced indolent non-Hodgkin’s lymphoma (NHL).   
For follicular lymphoma, prior to the initiation of the study, each site will choose one of 
three chemotherapy regimens considered to be the standard of care for follicular 
lymphoma:  
• 
CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone [or 
prednisolone]) 
• 
CVP (cyclophosphamide, vincristine, and prednisone [or prednisolone]) 
• 
Bendamustine  
 
All patients with follicular lymphoma at that site will receive the chosen chemotherapy 
regimen for the duration of the study (a site may switch to another regimen if new 
scientific data become available and after Sponsor approval).   
For non-follicular NHL, the investigator will have the option of choosing one of the three 
chemotherapy regimens (CHOP, CVP, or bendamustine) for each patient. 
Approximately 1200 patients with follicular lymphoma will be recruited and randomly 
assigned in a 1:1 ratio to either obinutuzumab plus chemotherapy followed by 
obinutuzumab maintenance in responders or rituximab plus chemotherapy followed by 
rituximab maintenance in responders.  In addition, approximately 200 patients with 
marginal zone lymphomas will be recruited and randomly assigned in a 1:1 ratio to the 
two treatment arms.  
The primary objective of this study is to demonstrate superiority in progression-free 
survival (PFS) with obinutuzumab plus chemotherapy compared with rituximab plus 
chemotherapy in patients with follicular lymphoma, based on investigator-assessed PFS. 
Secondary objectives include comparison of PFS, event−free survival (EFS), 
disease−free survival (DFS), duration of response, time to next anti−lymphoma 
treatment on overall population, comparison of overall and complete response (OR and 
CR) rates and overall survival (OS), in follicular lymphoma and overall population, and 
safety between treatment arms. 
PFS, overall response rate (ORR) and CR will also be assessed by an independent 
review committee (IRC) and will form secondary objectives. In the United States, IRC 
assessments will be the basis for regulatory decisions. 
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Terms and abbreviations used in this charter are defined in Table 1. 
Table 1 
Terms and Abbreviations 
Abbreviation 
Definition 
audited data 
data compared with their original source (physician’s records, 
laboratory results, etc.) to ensure integrity and reliability 
blinded data 
data for which treatment assignment is not identified at the group 
level (treatment groups pooled) 
Study Management 
Team (SMT) 
team composed of Sponsor representatives directly involved with the 
trial; includes Medical Monitor, biostatistician, and Global Study 
Manager  
CHOP 
cyclophosphamide, doxorubicin, vincristine, and prednisone [or 
prednisolone]) 
CRF 
case report form 
CR 
complete response 
CRO 
contract research organization 
CVP 
cyclophosphamide, vincristine, and prednisone [or prednisolone]) 
DFS 
disease−free survival 
DRB 
Data Review Board, consisting of employees of the Sponsor 
empowered to make critical decisions, such as whether to accept a 
recommendation from the iDMC to stop the clinical trial(s). For this 
study, the DRB is composed of the Chief Medical Officer 
(decision-maker), the Oncology Therapeutic Area Head, the Drug 
Safety Head, the Global Regulatory Head, and the Global Biometrics 
Head (Data Review Board Chair).  The DRB Chair is Roche’s point 
of contact for the iDMC members after the iDMC has reviewed 
unblinded data. 
EFS 
event−free survival 
FDG 
fluorodeoxyglucose 
frozen database 
Database that has been checked for consistency, completeness, 
and accuracy and to which no changes have been made after a 
specified date 
HR 
hazard ratio 
iDCC 
independent Data Coordinating Center wherein external data 
analysts provide current, accurate, and unblinded interim data 
summaries to the iDMC 
For this study: IST GmbH Soldnerstrasse 1, 68219 Mannheim, 
Germany  
iDMC 
independent Data Monitoring Committee 
IRC 
Independent review committee 
SAP 
statistical analysis plan 
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Abbreviation 
Definition 
IxRS 
Interactive voice/web response system 
Medical Monitor 
Sponsor employee who is responsible for the overall conduct of a 
trial; also known as the clinical scientist 
NHL 
non-Hodgkin’s lymphoma (NHL).   
ORR 
overall response rate 
OS 
overall survival 
PET 
positron emission tomography 
PFS 
progression-free survival 
pooled data 
data for which treatment arms are combined 
Roche Group 
The Roche Group includes, among others, the following entities: 
F. Hoffmann–La Roche (Basel, Switzerland), Hoffmann–La Roche, 
Inc. (Nutley, USA), Roche Products, Ltd. (Welwyn, United Kingdom), 
Genentech, Inc. (South San Francisco, USA), Shanghai Roche 
Pharmaceuticals, Ltd. (Shanghai, China), Roche Palo Alto, LLC 
(Palo Alto, USA) 
F. Hoffmann–La Roche, Ltd. 
Sponsor 
unblinded data 
Data for which treatment assignment is identified as G-chemo or R-
chemo at the group level  
 
 
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2. 
ROLE OF THE COMMITTEE 
2.1 
SAFETY
 
The independent Data Monitoring Committee (iDMC) shares with the Sponsor the 
responsibility for regularly monitoring the overall safety of the patients in the trial.  
By carefully reviewing overall rates of deaths, serious adverse events, and other 
specified safety events, the iDMC will help the Sponsor minimize patient exposure 
to unnecessary risk.  The iDMC will also evaluate benefit and risk by reviewing efficacy 
and safety data during the scheduled interim analyses. 
At the beginning of the study, intensive monitoring and analysis of all significant safety 
events will be performed. The first safety analysis by the iDMC will take place 1 month 
after randomization of the first patient and then approximately every 2 months until 100 
patients (50 per arm) have completed two cycles of study treatment.  Afterwards, the 
iDMC will meet approximately every 6 months.  Both the Sponsor and the iDMC can 
request ad hoc iDMC meetings if potential safety concerns arise.  
For details of what will be presented to iDMC at each safety review, please see 
Appendix 1. 
2.2 
EFFICACY
 
The iDMC will be used to evaluate efficacy at three formal interim analyses, as well as 
periodic safety reviews as described in Section 2.1, and to recommend if the trial should 
be stopped early.  Interim analyses of efficacy data will be conducted according to the 
methods specified in the study protocol and Statistical Analysis Plan (SAP).  
Recommendations to stop the trial because of substantial evidence of efficacy or lack of 
efficacy (futility) of the study drug must be based on the specified interim analysis 
methodology. 
Three interim analyses are planned; two for futility and one for efficacy.  The first interim 
analysis will be based on differences between the two treatment groups in end of 
induction CR rates in the first 170 enrolled follicular lymphoma patients.  The analysis 
will be conducted once the 170 follicular lymphoma patients have reached their 
end−of−induction response assessment or have withdrawn prematurely.  The iDMC may 
recommend to stop the study for futility if the observed difference in CR rates is <3% 
in favor of obinutuzumab plus chemotherapy (i.e., CR rate should be ≥3% higher on 
obinutuzumab plus chemotherapy vs. rituximab plus chemotherapy to continue the 
study).  
The second interim analysis (futility on PFS) will be conducted when 30% of the required 
PFS events (i.e., approximately 111 events) have occurred among follicular lymphoma 
patients only.  The iDMC may recommend to stop the study for futility if the observed 
hazard ratio (HR) of obinutuzumab over rituximab is >1 (futility boundary based on 
non−binding O’Brien−Fleming beta-spending function).  
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At the time of the third interim analysis (efficacy on PFS) that will be conducted when 
67% of the events have occurred (i.e., approximately 248 events) among follicular 
lymphoma patients only, it is expected that all patients will have been enrolled and 
followed for an estimated minimum of 11 months.  PFS will be tested at the significance 
level determined using the O’Brien − Fleming alpha-spending function so the overall 
type I error rate will be maintained at the 0.05 level. With 67% information, the alpha 
spent is 0.012. 
Details of the efficacy analyses, and boundaries for interim analyses for the expected 
number of events, are specified in the interim SAP.  An overview of the outputs is 
provided in Appendix 1 . 
2.3 
STUDY CONDUCT 
The iDMC may alert the Sponsor to possible concerns related to the conduct of the trial.  
These include, but are not limited to, concerns about the appropriateness of the study 
population on the basis of characteristics of enrolled patients, adequacy of the 
randomization process, protocol violations, problems with protocol compliance, and 
problems with data completeness and cleanliness. 
3. 
ORGANIZATIONAL FLOW 
Figure 1 illustrates the relationships between the Study team, the iDMC, the independent 
Data Coordinating Center (iDCC), the interactive voice/web response system (IxRS) 
vendor, the Data Review Board (DRB), and regulatory agencies. 
 
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4. 
COMMITTEE MEMBERSHIP 
4.1 
MEMBERS
 
Chair: 
, Ph.D. 
Professor of 
 
 
  
Germany 
Members: 
, M.D.  
Professor 
 
UK  
 
, M.D., Ph.D. 
Professor of 
 
 
 
, US 
 
Address details of administrative 
 of Prof. 
:  
 
 
 
 
Telephone 
 
e-mail: 
 
, M.D., Ph.D. 
 
 
Professor of 
 
 Professor of
  
 
 US 
 
, M.D., Ph.D. 
 
 
, Spain 
 
Each member's curriculum vitae is available in the Sponsor's files and will be provided to 
any regulatory agency upon request. 
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4.2 
FINANCIAL DISCLOSURE AND CONFLICT OF INTEREST 
No iDMC member may participate in the study as an investigator, co-investigator, 
subinvestigator, or patient, or in any other capacity that might compromise his or her 
privileged activities on the iDMC. 
iDMC members are strongly discouraged from owning any stock in Roche (such as 
bearer shares, non-voting equity security [NES or Genussscheine], or American 
Depository Receipts [ADR]) or owning any stock in any other Sponsor of the study.  In 
no event may iDMC members own stock in Roche or any other Sponsor of the study in 
excess of U.S. $50,000.  iDMC members must disclose any payments they or their 
immediate family members may have received from the Roche Group in excess of 
U.S.$10,000 or its equivalent in the 12 months prior to the ratification of the charter.  
Such payments may include any combination of consulting fees, honoraria, donations of 
equipment, grants to fund ongoing research, or other payments exclusive of 
reimbursements to support the costs of conducting clinical trials. 
iDMC members must disclose whether they serve on other iDMCs and whether any of 
these committees is involved with study drugs within the same therapeutic class as 
obinutuzumab.  Members will attest that membership in other committees will not 
interfere with their objective judgment while serving on the trial, and the final decision will 
be made by the Chair of the iDMC. 
The iDMC will be responsible for deciding whether consultancies or financial interests of 
the members may materially affect objectivity.  This decision will be based on whether 
there is a reasonable belief that a member’s objectivity is in doubt.  Members of the 
iDMC will be responsible for advising the Sponsor of any changes in their financial 
interests in pharmaceutical companies, biotechnology companies, or contract research 
organizations (CROs) and any changes in consultancies that might lead to potential 
conflicts of interest.  Members of the iDMC who develop potential or significant 
perceived conflicts of interest that may materially affect objectivity will be asked to resign 
from the iDMC and will be replaced. 
4.3 
DURATION OF IDMC MEMBERSHIP 
iDMC membership will extend for the duration of the trial, up to the time the database is 
locked and the study is unblinded.  If a member leaves the iDMC, the Sponsor will select 
a replacement.  
5. 
COMMITTEE MEETINGS 
5.1 
ORGANIZATIONAL MEETING 
The first meeting of the iDMC will be an organizational meeting.  This meeting will 
formally establish the iDMC and thoroughly acquaint the iDMC with the protocol and 
interim analysis plan.  It also affords the iDMC an opportunity to recommend final 
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revisions to the charter and to the communication plan between the iDMC and the 
Sponsor. 
In addition to the iDMC members, the organizational meeting will be attended by 
members of the Study Management Team (SMT), one or more representatives of the 
DRB and the iDCC Statistician. 
The following documents will be provided: 
• 
Final protocol 
• 
eCRF 
• 
Draft iDMC charter 
• 
Investigator brochure 
• 
Interim analysis plan if available (to be sent to iDMC latest prior to the first interim 
efficacy analysis as outlined in Section 2.2). 
  
5.2 
SCHEDULED INTERIM ANALYSIS MEETINGS 
According to the study protocol, three interim analyses and regular safety review are 
scheduled for the review of the accrued efficacy and safety data.  Additional interim 
analyses may be conducted at the request of the iDMC or the SMT. 
The iDMC meetings will be separated into two sessions. There will be an open session 
followed by a closed session, for which open and closed reports will be presented and 
discussed respectively. 
5.2.1 
Open Session 
The open session will serve as a general study update and will provide a forum for iDMC 
members to question the Sponsor about the trial and to seek additional information 
deemed relevant to the interim analysis.  Attendees will be the iDMC members, the 
iDCC Statistician, the Sponsor’s Medical Monitor and biostatistician, others as appointed 
by the Sponsor and representatives from the German Low Grade Lymphoma Study, the 
Ostdeutsche Studiengruppe für Hämatologie und Onkologie, and the National Cancer 
Research Institute.  This will be the only portion of the meeting during which the Sponsor 
representatives discuss the trial with the iDMC. 
5.2.2 
Closed Session 
At the closed session, the iDMC will discuss the unblinded data and make 
recommendations regarding the study.  Only iDMC members and the iDCC Statistician 
will attend the closed session.  The Sponsor will not have access to the closed reports 
until study completion. However, if the iDMC recommends the study to be stopped then 
the DRB may request unblinded data as outlined in Section 6.5. 
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5.3 
UNSCHEDULED MEETINGS 
In addition to the regularly scheduled safety reviews, an unscheduled review of the data 
may be performed at the request of the iDMC or SMT, on the basis of a perceived 
concern for patient safety.  The iDCC will prepare the necessary reports to which the 
Sponsor will remain blinded. 
6. 
COMMUNICATION 
The DRB Chair is the Sponsor’s single point of contact for the iDMC members after the 
iDMC members have reviewed the unblinded data. iDMC members are to treat all 
communications regarding this clinical study, including reports, data, review meeting 
discussions, teleconferences, and meeting minutes, as confidential material. 
6.1 
OPEN REPORTS 
The open reports will be prepared by the iDCC and distributed to the open-session 
attendees and the DRB Chair within 5 business days prior to each bimonthly safety 
review meeting and within 10 business days prior to the 6-monthly safety review 
meetings and interim analysis meetings.  The open reports, which will be based on 
pooled blinded data, will not include safety or efficacy data, as described in Appendix 2. 
6.2 
CLOSED REPORTS 
The closed reports will be prepared by the iDCC and provided to the iDMC within 
5 business days prior to each bimonthly safety review meeting and within 10 business 
days prior to the latter safety review meetings and interim analysis meetings.  Closed 
reports will be reviewed at closed sessions and will include unblinded efficacy and safety 
data, as well as unblinded baseline characteristics and protocol deviation data, 
as described in Appendix 1. 
6.3 
IDMC MINUTES 
The iDMC Chair or a designated member of the iDMC, with the assistance of the iDCC 
Statistician, will prepare minutes of the open and closed sessions within 1 week 
following each iDMC meeting.  Minutes of the open session will be distributed to the 
iDMC, the iDCC Statistician, the Sponsor’s Medical Monitor and Biostatistician and the 
DRB Chair.  Minutes of the closed session will be distributed to the iDMC and the iDCC 
Statistician only.   
At the conclusion of the study, a complete set of the minutes of the closed sessions and 
the closed reports will be sent to the Sponsor study biostatistician.   
6.4 
IDMC RECOMMENDATIONS 
At each interim analysis and safety review, the iDMC will recommend that the trial either 
continues or stops.  The iDMC may also recommend a protocol amendment.  
The recommendations will be based on the guidelines outlined in Section 2 with further 
details given below for Safety (Section 6.4.1) and Efficacy (Section 6.4.2).   
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Recommendations will be made by a majority vote of the iDMC members in attendance. 
The Chair, the iDCC Statistician, and two additional medical members of the iDMC must 
be present for the meeting to be quorate.  The iDCC Statistician does not have a vote 
but needs to be present at the meeting to help the iDMC interpret the data.  If the vote is 
a tie, the Chair has the casting vote. 
The iDMC Chair will notify the DRB Chair of the iDMC’s recommendations, in a meeting 
or by telephone (e-mail may also be used if time zones make either a meeting or a 
telephone call unfeasible), immediately after the closed session and will follow up with a 
written communication within 24 hours. 
6.4.1 
Safety Recommendations 
Following each review of the safety data, the iDMC should make one of the following 
recommendations to the DRB: 
1. 
Continuation of the study without modification 
2. 
Continuation of the study with modification 
3. 
Suspension of recruitment pending further evaluation of a safety issue 
4. 
Discontinuation of the entire study (unacceptable safety profile in all arms) 
Should the iDMC recommendation be (3) or (4) and the Sponsor accepts the 
recommendation then one of the following actions will be taken. 
6.4.1.1 
Consequences Following Hold due to an Event 
If the accepted recommendation after safety review is that recruitment be placed on hold, 
then all further randomization will stop.  The event causing concern will be thoroughly 
investigated by the Sponsor. The Sponsor will report the outcome of this investigation to 
the iDMC. Depending on these findings the iDMC will recommend continuing recruitment 
or discontinuing the study.  
6.4.1.2 
Consequences Following Discontinuation of the Entire Study 
If the accepted recommendation is that the entire study be discontinued during the 
recruitment period then further randomization will stop immediately.  
In case of a safety concern, patients already randomized who have not completed the 
treatment schedule will be withdrawn from treatment. The timing of this action will 
depend on the nature and severity of the events causing discontinuation and will be 
determined by the Sponsor in consultation with the iDMC.  However, if efficacy without 
toxicity was observed for any patient, this patient may continue treatment as scheduled 
at the investigator’s discretion and if the patient wishes to continue. 
6.4.2 
Efficacy Recommendations 
The following guidelines may be used by the iDMC for making stopping 
recommendations based on the interim efficacy analyses. 
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Although these guidelines are in place, the iDMC has authority to deviate from these 
guidelines if safety or additional efficacy analyses (e.g. robustness assessments) 
indicate that a different recommendation is more appropriate. 
6.4.2.1 
CR Futility Analysis 
The iDMC may recommend stopping the study for futility if the observed difference in 
IRC-assessed end of induction CR rates is < 3% in favor of G-chemo (see Section 2.2).  
In addition the following should be considered before recommending stopping the study: 
• 
Difference in investigator-assessed CR rates 
• 
Consistency of the observed difference in IRC−assessed CR rates with that of 
investigator-assessed CR rate difference  
• 
Differences in CR rate when positron emission tomography (PET) results are 
incorporated into the response assessments (for both investigator and IRC 
assessments) at end of induction  
• 
Differences in minimal residual disease (MRD) results 
• 
Differences in overall response (OR) rates at end of induction 
 
IRC−assessed CR rates are chosen for the primary decision making for this futility 
analysis because response rate assessed by IRC is considered to provide more uniform 
data (Osby et al. 2001). 
An additional measure for confirming clinical response is taking fluorodeoxyglucose 
(FDG)−PET into consideration, but this remains experimental due to ongoing technical 
validation and standardization issues.  However, CR assessment including PET has 
been suggested as being superior to clinical CR alone in predicting time-based 
outcomes (PFS).  Therefore assessment of response including FDG-PET should also be 
examined.   
For a detailed outline of the recommendation to the iDMC how to reach a futility 
recommendation we refer to the CR futility interim analysis specification document. 
6.4.2.2 
PFS Futility Analysis (at 30% PFS information) 
The iDMC may recommend stopping the study for futility if the investigator-assessed 
PFS crosses the pre-defined boundary (HR >1, see Section 2.2). In addition the 
following should be considered before recommending stopping the study: 
• 
Consistency of the HR estimate with that of IRC-assessed PFS  
• 
Consistency when using an unstratified analysis instead of the primary stratified 
analysis  
• 
Differences in response rates (CR and OR) 
 
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6.4.2.3 
PFS Efficacy Analysis (at 67% PFS information) 
1. 
The iDMC may recommend stopping the study at 67% PFS information (i.e., the 
primary analysis of the study will be conducted) when the primary endpoint, based 
on investigator-assessed PFS, crosses the pre-defined boundary (see above 
Section 2.2). In addition the following should be considered before recommending 
stopping the study: 
To evaluate the robustness of the treatment effect as measured by investigator-
assessed PFS, the iDMC should consider the consistency of the HR estimate 
with that of IRC-assessed PFS.  
Consistency in results should be fulfilled when using an unstratified analysis 
instead of the primary stratified analysis for PFS. 
2. 
The iDMC is guided to recommend study continuation as planned if the result of the 
primary analysis does not cross the pre-specified boundary and/or is not persuasive 
and/or is not consistent with the secondary analyses described above under 1. 
Although these guidelines are in place, the iDMC has authority to deviate from these 
guidelines if safety or additional efficacy analyses (e.g., robustness assessments) 
indicate that a different recommendation is more appropriate. 
6.5 
SPONSOR DECISIONS 
Upon receipt of the iDMC’s recommendations, the DRB will review the recommendations, 
obtain input or additional data as deemed necessary from the iDMC, SMT, regulatory 
agencies, or other bodies such as the Ethics Committee/Internal Review Board, and, on 
behalf of the Sponsor, accept or reject the recommendations. 
If the iDMC and the DRB agree to amend the protocol or to stop the trial, the Sponsor 
will inform regulatory agencies of the decision prior to notifying the investigational 
centers and Ethics Committees.  In case of urgent safety restrictions the investigators 
may be notified prior to informing regulatory agencies.  Public disclosure of the decision, 
as appropriate, will be made by the Sponsor.   
If the iDMC recommends that the trial be stopped prematurely for efficacy reasons, the 
DRB may request unblinded data from the iDCC upon which to base its decision (proper 
Health Authority feedback will be sought prior to making this request). If the DRB 
decides to continue the trial, the DRB Chair will first discuss with the iDMC Chair the 
rationale for the decision and, thereafter, will provide a written explanation of the 
decision to the iDMC within 3 business days.  At no point in the trial will the clinical team 
have access to the unblinded interim data. 
The DRB Chair will communicate all decisions to the iDMC Chair and the Sponsor’s 
Statistician.  The Sponsor’s DRB regulatory representative or designee will communicate 
the Sponsor’s decisions to regulatory agencies as appropriate.  The iDMC Chair will 
communicate the Sponsor’s decision to the rest of the iDMC. 
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7. 
REFERENCES 
1. Osby E, Taube A, Cavallin-Ståhl E, et al. Reproducibility of tumor response 
evaluation in patients with high-grade malignant non-Hodgkin's lymphoma. 
Med Oncol. 2001;18(2):137−40. 
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Appendix 1 
Closed Reports 
Closed reports will contain listings and summaries by treatment arm. 
Safety monitoring every 2 months 
• 
Demographics and disease characteristics 
• 
All AEs 
• 
Grade 3 and 4 AEs 
• 
SAEs 
• 
AEs of special interest: 
– 
Tumor lysis syndrome 
– 
Serious infections 
– 
Serious neutropenia 
– 
Serious infusion-related reactions (IRRs) 
• 
Event of particular interest 
– 
Hepatitis B reactivation 
• 
Laboratory data (hematology and biochemistry) 
• 
Treatment discontinuations 
• 
Treatment exposure 
• 
Deaths 
Safety monitoring every 6 months 
The same outputs as given above for bimonthly safety will be provided. In addition the 
following will be provided: 
• 
Detailed information regarding study treatment and chemotherapy (e.g., dosing, 
cycle length) for evaluation of dose density and dose intensity 
• 
Concomitant medications 
• 
Narratives on tumor lysis syndrome (TLS) 
Efficacy Interim Analysis for CR futility 
The following list outlines the outputs that will be provided at the interim futility analysis 
based on CR rate. Details will be given in the interim SAP. 
• 
Summary of IRC-assessed CR rates at end of induction 
• 
Summary of Investigator-assessed CR rates at end of induction 
• 
Summary of IRC-assessed CR rates at end of induction including PET 
• 
Summary of Investigator-assessed CR rates at end of induction including PET 
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APPENDIX 1 (cont’d) 
Closed Reports 
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• 
Summary of MRD results 
• 
Summary of OR rates at end of induction  
– 
By IRC including and excluding PET  
– 
By investigator including and excluding PET  
Efficacy Interim Analyses for PFS 
The following list outlines the outputs that will be provided at interim efficacy analyses. 
Details will be given in the interim SAP. 
• 
Investigator-assessed PFS summary 
– 
Stratified and non-stratified 
• 
Investigator-assessed Kaplan-Meier plot  
• 
IRC-assessed PFS summary 
– 
Stratified and non-stratified 
• 
IRC-assessed Kaplan-Meier plot  
• 
OS summary and Kaplan-Meier plot (only at second efficacy IA) 
– 
Stratified and non-stratified 
• 
Complete and overall response rates at end of induction 
 
 
 
 
 
 
 
 
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Appendix 2 
Open Reports 
The following data will be included in open reports (treatment arms combined): 
• 
Recruitment rates 
• 
Patient disposition – stratification factors 
• 
Protocol violations/data problems 
 
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