Clinical trial NCT02729896
Conditions: Lymphoma
Sponsor: Hoffmann-La Roche
Start date: 2016-11-09; Completion date: 2019-10-07
Enrollment: 36 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety, efficacy, pharmacokinetics, and immunogenicity of obinutuzumab + Atezo + Pola in participants with relapsed or refractory (RR) FL and rituximab + Atezo + Pola in participants with RR DLBCL. The study will include an initial dose-escalation phase designed to determine the recommended Phase 2 dose (RP2D) for Pola in this treatment combination, followed by an expansion phase in which Pola will be given at the RP2D. All participants will receive induction treatment with obinutuzumab + Atezo + Pola for 6 cycles. RR FL participants achieving a complete response (CR), partial response (PR), or stable disease (SD) at the end of induction (EOI) will receive maintenance treatment with obinutuzumab.

Detailed description:

Arms: arm 1: During the induction treatment Cycle 1 (21-day cycles): participants will receive obinutuzumab on Days 1, 8, and 15 and Pola on Day 1; Cycles 2-6: participants will receive obinutuzumab on Day 1, Atezo on Day 1, and Pola on Day 1. This is followed by obinutuzumab on Day 1 of every other month starting with Month 1 for 24 months, during maintenance treatment for FL participants. arm 2: For FL during the induction treatment Cycle 1 (21-day cycles): participants will receive obinutuzumab on Days 1, 8, and 15 and Pola at identified RP2D (decided from dose-escalation phase) on Day 1; Cycles 2-6: participants will receive obinutuzumab on Day 1 and Pola at RP2D on Day 1. This is followed by obinutuzumab on Day 1 of every other month starting with Month 1 for 24 months (during maintenance treatment for FL participants). arm 3: For DLBCL, during the induction treatment Cycles 1-6 (21-day cycles): participants will receive rituximab on Day 1 and Pola on Day 1.
Interventions: intervention 1: Atezolizumab [TECENTRIQ] intervention 2: Obinutuzumab intervention 3: Polatuzumab Vedotin intervention 4: Rituximab
Intervention descriptions: intervention 1: Atezolizumab will be administered by intravenous (IV) infusion at a flat dose of 1200 milligram (mg) every 3 weeks (Q3W) on Day 1 of Cycles 2-6, given in 21-day cycles during induction treatment.

NOTE: Atezolizumab treatment has been discontinued in all participants currently on study treatment. intervention 2: Obinutuzumab will be administered by IV infusion at a flat dose of 1000 mg on Days 1, 8, and 15 of Cycle 1, and on Day 1 of Cycles 2-6, given in 21-day cycles during induction treatment, and on Day 1 of every other month during maintenance treatment (1 cycle=21 days; infusion rate starts at 50 mg/hour (hr) and increases every 30 min to a maximum of 400 mg/hr). intervention 3: Polatuzumab vedotin will be administered by IV infusion. For relapsed or refractory FL either 1.4 mg/kilogram (kg) or 1.8 mg/kg (dose-escalation phase) and at RP2D (dose-expansion phase) on Day 1 of Cycles 1-6 will be given in 21-day cycles during induction treatment. For relapsed or refactory DLBCL, 1.8 mg/kg will be given during run-in phase and either 1.8 mg/kg or 1.4 mg/kg during the expansion phase (1 cycle=21 days; infusion rate starts with 90 min and decreases to 30 min). intervention 4: Rituximab will be administered by IV infusion at 375 mg/m˄2 on Day 1 of Cycles 1-6 during induction treatment (1 cycle-21 days; infusion rate starts with 50 mg/hr and increases every 30 min to a maximum of 400 mg/hr).

Protocol documents:
Prot_SAP_001.pdf: 
 
Official Title: 
 
A Phase Ib/II Study Evaluating the Safety and Efficacy of 
Obinutuzumab in Combination With Atezolizumab Plus Polatuzumab 
Vedotin in Patients With Relapsed or Refractory Follicular Lymphoma 
and Rituximab in Combination With Atezolizumab Plus Polatuzumab 
Vedotin in Patients With Relapsed or Refractory Diffuse Large B-Cell 
Lymphoma 
NCT Number: 
NCT02729896    
Document Date: 
Protocol Version 8: 07-November-2018 
 
 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  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.
Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
Protocol BO29561, Version 8
PROTOCOL
TITLE:
A PHASE Ib/II STUDY EVALUATING THE SAFETY AND EFFICACY OF 
OBINUTUZUMAB IN COMBINATION WITH ATEZOLIZUMAB PLUS 
POLATUZUMAB VEDOTIN IN PATIENTS WITH RELAPSED OR 
REFRACTORY FOLLICULAR LYMPHOMA AND RITUXIMAB IN 
COMBINATION WITH ATEZOLIZUMAB PLUS POLATUZUMAB 
VEDOTIN IN PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE 
LARGE B-CELL LYMPHOMA
PROTOCOL NUMBER:
BO29561
VERSION NUMBER:
8
EUDRACT NUMBER:
2015-004845-25
IND NUMBER:
128036
TEST PRODUCT:
Obinutuzumab (RO5072759)
Rituximab (RO0452294)
Atezolizumab (RO5541267)
Polatuzumab vedotin (RO5541077)
MEDICAL MONITOR:
, Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  12 November 2015 
DATES AMENDED:
Version 2:  14 January 2016
Version 3:  28 June 2016
Version 4:  17 November 2016
Version 5:  4 May 2017
Version 6:  21 December 2017
Version 7:  1 May 2018
Version 8:  See electronic date stamp below.
 
07-Nov-2018 02:00:10
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
2/Protocol BO29561, Version 8
PROTOCOL AMENDMENT, VERSION 8
RATIONALE
Protocol BO29561 has been amended to include new safety information.  Changes to 
the protocol, along with a rationale for each change, are summarized below:

Lists of risks for atezolizumab and guidelines for managing patients who experience 
atezolizumab-associated adverse events have been revised to include nephritis 
(Sections 5.1.3 and 5.1.7.2 [Table 14]).

Considering no new safety signals have been identified since protocol amendment 
Version 7, regular Internal Monitoring Committee assessments will no longer take 
place and ad hoc meetings maybe called at the discretion of the Medical Monitor in 
case of newly identified safety signals (Section 3.1.4).

Post-trial access language was changed allowing patients still under study treatment 
to enter an extension study in case of earlier closure of Study BO29561 
(Section 4.3.4).

The Medical Monitor information has been updated (Section 5.4.1).

The survival follow-up period has been added back to Appendices 1 and 2 for the 
assessment of new anti-lymphoma treatment and survival follow-up.  Survival 
follow-up was removed in error during the previous amendment.

Appendix 3 has been updated to remove pharmacokinetic sampling one year after 
the last dose of polatuzumab vedotin.  As most of the patients have discontinued 
study treatment and have not provided this sample, collecting these data from the 
remaining patients (n3) will be of limited value.
Substantive new information appears in italics.  Additional minor changes have been 
made to improve clarity and consistency.  This amendment represents cumulative 
changes to the original protocol.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13
PROTOCOL SYNOPSIS .................................................................................... 14
1.
BACKGROUND .......................................................................................... 25
1.1
Background on Non-Hodgkin's Lymphoma ........................... 25
1.1.1
Follicular Lymphoma ............................................................. 25
1.1.2
Diffuse Large B-Cell Lymphoma............................................ 25
1.2
Background on Obinutuzumab .............................................. 26
1.2.1
Nonclinical Studies with Obinutuzumab................................. 27
1.2.2
Clinical Studies with Obinutuzumab ...................................... 27
1.2.2.1
Clinical Safety of Obinutuzumab............................................ 27
1.2.2.2
Clinical Pharmacokinetics of Obinutuzumab.......................... 28
1.2.2.3
Clinical Efficacy of Obinutuzumab in Patients with 
Non-Hodgkin’s Lymphoma .................................................... 28
1.3
Background on Atezolizumab................................................ 29
1.3.1
Nonclinical Studies with Atezolizumab .................................. 30
1.3.2
Clinical Studies with Atezolizumab ........................................ 30
1.3.2.1
Summary of Clinical Safety of Atezolizumab ......................... 30
1.3.2.2
Clinical Pharmacokinetics of Atezolizumab ........................... 32
1.3.2.3
Summary of Clinical Activity of Atezolizumab........................ 32
1.4
Background on Polatuzumab vedotin .................................... 33
1.4.1
Nonclinical Studies with Polatuzumab Vedotin...................... 33
1.4.2
Clinical Studies with Polatuzumab Vedotin............................ 34
1.4.2.1
Clinical Safety of Polatuzumab Vedotin................................. 34
1.4.2.2
Clinical Pharmacokinetics of Polatuzumab 
Vedotin .................................................................................. 35
1.4.2.3
Clinical Activity of Polatuzumab Vedotin................................ 36
1.5
Study Rationale and Benefit-Risk Assessment...................... 37
1.5.1
Rationale for Protocol BO29561, Version 7........................... 37
1.5.2
PD-L1/PD-1 Pathway in Lymphoma ...................................... 38
1.5.3
Clinical Experience with PD-L1/PD-1 Pathway 
Inhibitors in Lymphoma.......................................................... 38
1.5.4
Rationale for Treatment Combination.................................... 39


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1.5.4.1
Mechanistic Rationale............................................................ 39
1.5.4.2
Nonclinical Data..................................................................... 40
1.5.4.3
Clinical Data .......................................................................... 41
1.5.5
Benefit-Risk Assessment....................................................... 44
2.
OBJECTIVES AND ENDPOINTS ............................................................... 44
2.1
Safety Objective .................................................................... 45
2.2
Efficacy Objectives ................................................................ 45
2.2.1
Primary Efficacy Objective..................................................... 45
2.2.2
Secondary Efficacy Objectives .............................................. 45
2.2.3
Exploratory Efficacy Objectives ............................................. 46
2.3
Pharmacokinetic Objective .................................................... 46
2.4
Immunogenicity Objectives.................................................... 46
2.5
Biomarker Objective .............................................................. 46
3.
STUDY DESIGN......................................................................................... 47
3.1
Description of the Study......................................................... 47
3.1.1
Overview of Study ................................................................. 47
3.1.2
G Atezo Pola Treatment Group (Patients with 
Follicular Lymphoma) ............................................................ 48
3.1.2.1
Dose-Escalation Phase ......................................................... 48
3.1.2.2
Expansion Phase................................................................... 51
3.1.3
R Atezo Pola Treatment Group (Patients with 
Diffuse Large B-Cell Lymphoma)........................................... 51
3.1.3.1
Treatment Regimens and Safety Run-In Rules ..................... 51
3.1.4
Internal Monitoring Committee............................................... 52
3.1.5
Safety Follow-Up ................................................................... 53
3.2
End of Study and Length of Study......................................... 53
3.3
Rationale for Study Design.................................................... 53
3.3.1
Rationale for Patient Population ............................................ 53
3.3.2
Rationale for Dose and Schedule.......................................... 54
3.3.2.1
Rationale for Obinutuzumab and Rituximab Dose 
and Schedule......................................................................... 54
3.3.2.2
Rationale for Atezolizumab Dose and Schedule.................... 54
3.3.2.3
Rationale for Polatuzumab Vedotin Dose and 
Schedule................................................................................ 56


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3.3.2.4
Rationale for Treatment Duration .......................................... 57
3.3.3
Rationale for PET-CT-Based Complete 
Response as the Primary Efficacy Endpoint.......................... 58
3.3.4
Rationale for Biomarker Assessments................................... 59
3.3.4.1
Rationale for Analysis of DLBCL Subtype, BCL2, 
and MYC................................................................................ 59
3.3.4.2
Rationale for Assessment of Immune-Related
Biomarkers ............................................................................ 59
3.3.4.3
Rationale for Analysis of CD79b:  Assessment of 
Therapeutic Target Expression.............................................. 60
4.
MATERIALS AND METHODS .................................................................... 60
4.1
Patients.................................................................................. 60
4.1.1
Inclusion Criteria.................................................................... 61
4.1.2
Exclusion Criteria................................................................... 62
4.2
Method of Treatment Assignment.......................................... 65
4.3
Study Treatment.................................................................... 66
4.3.1
Formulation, Packaging, and Handling.................................. 66
4.3.1.1
Obinutuzumab ....................................................................... 66
4.3.1.2
Atezolizumab......................................................................... 66
4.3.1.3
Polatuzumab Vedotin ............................................................ 66
4.3.1.4
Rituximab............................................................................... 66
4.3.2
Dosage, Administration, and Compliance.............................. 67
4.3.2.1
Obinutuzumab ....................................................................... 67
4.3.2.2
Atezolizumab......................................................................... 70
4.3.2.3
Polatuzumab Vedotin ............................................................ 70
4.3.2.4
Rituximab............................................................................... 70
4.3.2.5
Induction Treatment with Obinutuzumab or 
Rituximab, and Polatuzumab Vedotin (G Pola 
or R Pola) ........................................................................... 72
4.3.2.6
Post-Induction Treatment ...................................................... 73
4.3.2.7
Premedication and Other Prophylaxis Treatment.................. 73
4.3.3
Investigational Medicinal Product Accountability ................... 75
4.3.4
Post-Trial Access to, Obinutuzumab, Rituximab, 
and Polatuzumab Vedotin...................................................... 75
4.4
Concomitant Therapy ............................................................ 75


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4.4.1
Permitted Therapy................................................................. 75
4.4.2
Prohibited Therapy ................................................................ 76
4.5
Study Assessments ............................................................... 76
4.5.1
Informed Consent Forms, Screening Log, and 
Patient Screening .................................................................. 77
4.5.2
Medical History and Demographic Data ................................ 77
4.5.3
Physical Examinations........................................................... 78
4.5.4
Vital Signs.............................................................................. 78
4.5.5
Tumor and Response Evaluations......................................... 79
4.5.6
Radiographic Assessments ................................................... 79
4.5.6.1
Bone Marrow Assessments................................................... 79
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 80
4.5.8
Electrocardiograms................................................................ 83
4.5.9
Samples for Roche Clinical Repository.................................. 83
4.5.9.1
Overview of the Roche Clinical Repository............................ 83
4.5.9.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 83
4.5.9.3
Sample Collection.................................................................. 84
4.5.9.4
Confidentiality........................................................................ 84
4.5.9.5
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 85
4.5.9.6
Withdrawal from the Roche Clinical Repository..................... 85
4.5.9.7
Monitoring and Oversight....................................................... 85
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 86
4.6.1
Patient Discontinuation.......................................................... 86
4.6.2
Study Treatment Discontinuation........................................... 86
4.6.3
Study and Site Discontinuation.............................................. 87
5.
ASSESSMENT OF SAFETY....................................................................... 88
5.1
Safety Plan ............................................................................ 88
5.1.1
Risks Associated with Obinutuzumab.................................... 88
5.1.1.1
Infusion-Related Reactions.................................................... 88
5.1.1.2
Hypersensitivity Reactions..................................................... 89


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5.1.1.3
Tumor Lysis Syndrome.......................................................... 89
5.1.1.4
Neutropenia........................................................................... 89
5.1.1.5
Thrombocytopenia................................................................. 89
5.1.1.6
Infections ............................................................................... 90
5.1.1.7
Immunizations ....................................................................... 91
5.1.1.8
Worsening of Pre-existing Cardiac Conditions ...................... 91
5.1.1.9
Gastrointestinal Perforation ................................................... 91
5.1.2
Risks Associated with Rituximab........................................... 91
5.1.2.1
Infusion-Related Reactions.................................................... 91
5.1.2.2
Infections (Including Serious Infections) ................................ 91
5.1.2.3
Hepatitis B Reactivation......................................................... 92
5.1.2.4
Progressive Multifocal Leukoencephalopathy........................ 92
5.1.2.5
Neutropenia........................................................................... 92
5.1.2.6
Tumor Lysis Syndrome.......................................................... 92
5.1.2.7
Impaired Immunization Response ......................................... 93
5.1.2.8
Severe Skin Reactions .......................................................... 93
5.1.2.9
Gastrointestinal Perforation ................................................... 93
5.1.3
Risks Associated with Atezolizumab ..................................... 93
5.1.4
Risks Associated with Polatuzumab Vedotin......................... 93
5.1.4.1
Identified Risks for Polatuzumab Vedotin .............................. 94
5.1.4.2
Potential Risks for Polatuzumab Vedotin............................... 94
5.1.5
Risk of Overlapping Toxicities and Drug-Drug 
Interactions............................................................................ 96
5.1.6
Concomitant Skin, Oral Mucosa, and Ocular 
Toxicity Observed in Patients with RR FL Treated 
with G Atezo Pola ............................................................ 98
5.1.7
Management of Specific Adverse Events .............................. 98
5.1.7.1
Systemic Immune Activation.................................................. 99
5.1.7.2
Toxicities during Induction Treatment.................................. 101
5.1.7.3
Toxicities during Maintenance Treatment............................ 113
5.2
Safety Parameters and Definitions ...................................... 113
5.2.1
Adverse Events ................................................................... 113
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 114


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5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 115
5.2.4
Dose-Limiting Toxicities (Immediately Reportable 
to the Sponsor).................................................................... 116
5.2.5
Selected Adverse Events..................................................... 116
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 116
5.3.1
Adverse Event Reporting Period ......................................... 117
5.3.2
Eliciting Adverse Event Information..................................... 117
5.3.3
Assessment of Severity of Adverse Events ......................... 117
5.3.4
Assessment of Causality of Adverse Events ....................... 118
5.3.5
Procedures for Recording Adverse Events.......................... 119
5.3.5.1
Infusion-Related Reactions.................................................. 119
5.3.5.2
Diagnosis versus Signs and Symptoms............................... 119
5.3.5.3
Adverse Events That are Secondary to Other 
Events.................................................................................. 119
5.3.5.4
Persistent or Recurrent Adverse Events.............................. 120
5.3.5.5
Abnormal Laboratory Values ............................................... 120
5.3.5.6
Abnormal Vital Sign Values ................................................. 121
5.3.5.7
Abnormal Liver Function Tests............................................ 122
5.3.5.8
Deaths ................................................................................. 122
5.3.5.9
Preexisting Medical Conditions............................................ 122
5.3.5.10
Lack of Efficacy or Worsening of Lymphoma....................... 123
5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 123
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Treatment Administration........................................ 123
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 124
5.4.1
Emergency Medical Contacts.............................................. 125
5.4.2
Reporting Requirements for Serious Adverse 
Events, Adverse Events of Special Interest, and 
Dose-Limiting Toxicities....................................................... 125
5.4.2.1
Events That Occur prior to Study Treatment 
Initiation ............................................................................... 125
5.4.2.2
Events That Occur after Study Treatment 
Initiation ............................................................................... 125


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5.4.3
Reporting Requirements for Pregnancies............................ 125
5.4.3.1
Pregnancies in Female Patients.......................................... 125
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 126
5.4.3.3
Abortions ............................................................................. 126
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 126
5.5
Follow-Up of Patients after Adverse Events ........................ 127
5.5.1
Investigator Follow-Up......................................................... 127
5.5.2
Sponsor Follow-Up .............................................................. 127
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 127
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 128
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 128
6.1
Determination of Sample Size ............................................. 129
6.2
Definition of Analysis Populations........................................ 129
6.3
Summaries of Conduct of Study.......................................... 129
6.4
Summaries of Demographic and Baseline 
Characteristics..................................................................... 129
6.5
Safety Analyses................................................................... 130
6.6
Efficacy Analyses ................................................................ 130
6.6.1
Primary Efficacy Endpoint.................................................... 130
6.6.2
Secondary Efficacy Endpoints............................................. 131
6.6.3
Exploratory Efficacy Endpoints............................................ 131
6.7
Pharmacokinetic Analyses................................................... 131
6.8
Immunogenicity Analyses.................................................... 132
6.9
Biomarker Analyses............................................................. 132
6.10
Interim Analyses .................................................................. 132
7.
DATA COLLECTION AND MANAGEMENT ............................................. 132
7.1
Data Quality Assurance....................................................... 132
7.2
Electronic Case Report Forms............................................. 133
7.3
Source Data Documentation................................................ 133
7.4
Use of Computerized Systems ............................................ 133
7.5
Retention of Records........................................................... 134


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8.
ETHICAL CONSIDERATIONS.................................................................. 134
8.1
Compliance with Laws and Regulations .............................. 134
8.2
Informed Consent................................................................ 134
8.3
Institutional Review Board or Ethics Committee.................. 135
8.4
Confidentiality...................................................................... 136
8.5
Financial Disclosure ............................................................ 136
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 137
9.1
Study Documentation .......................................................... 137
9.2
Protocol Deviations.............................................................. 137
9.3
Site Inspections ................................................................... 137
9.4
Administrative Structure....................................................... 137
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 137
9.6
Protocol Amendments ......................................................... 138
10. REFERENCES ......................................................................................... 139


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LIST OF TABLES
Table 1
Induction Treatment for Dose-Escalation Phase......................... 49
Table 2
Maintenance Treatment for the GAtezoPola Treatment 
Group.......................................................................................... 50
Table 3
Induction Treatment for Expansion Phase .................................. 51
Table 4
Induction Treatment for Patients with Diffuse Large B-Cell 
Lymphoma .................................................................................. 52
Table 5
Administration of First and Subsequent Infusions of 
Rituximab.................................................................................... 72
Table 6
Induction Treatment in Patients with Follicular Lymphoma......... 73
Table 7
Induction Treatment in Patients with Diffuse Large B-Cell 
Lymphoma .................................................................................. 73
Table 8
Maintenance Treatment for Patients with Follicular 
Lymphoma .................................................................................. 73
Table 9
Premedication............................................................................. 74
Table 10
Proposed Non-Inherited Biomarkers for Exploratory 
Research..................................................................................... 82
Table 11
Diagnostic Criteria and Recommended Management for 
Systemic Immune Activation..................................................... 100
Table 12
Guidelines for Management of Hematologic Toxicities that 
Occur during Induction Treatment (Except Days 8 and 15 of 
Cycle 1)..................................................................................... 101
Table 13
Guidelines for Management of Hematologic Toxicities That 
Occur on Days 8 and 15 of Cycle 1 .......................................... 102
Table 14
Guidelines for Management of Non-Hematologic Toxicities...... 103
Table 15
Guidelines for Management of Toxicities that Occur during 
Maintenance Treatment ............................................................ 113
Table 16
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 118
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 52
Figure 2
Guidelines for Obinutuzumab Infusions:  First Infusion............... 68
Figure 3
Guidelines for Obinutuzumab Infusions:  Second and 
Subsequent Infusions ................................................................. 69


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LIST OF APPENDICES
Appendix 1
Schedule of Assessments for Patients with Follicular 
Lymphoma ................................................................................ 146
Appendix 2
Schedule of Assessments for Patients with Diffuse Large 
B-Cell Lymphoma ..................................................................... 152
Appendix 3
Pharmacokinetic and Immunogenicity Sampling Schedule for 
Obinutuzumab, Atezolizumab, and Polatuzumab Vedotin ........ 157
Appendix 4
Pharmacokinetic and Immunogenicity Sampling Schedule for 
Rituximab, Atezolizumab, and Polatuzumab Vedotin................ 159
Appendix 5
Lugano Response Criteria for Malignant Lymphoma 
Appendix 6
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 165
Appendix 7
Ann Arbor Staging..................................................................... 166
Appendix 8
Follicular Lymphoma International Prognostic Index................. 167
Appendix 9
Anaphylaxis Precautions........................................................... 168
Appendix 10
Preexisting Autoimmune Diseases ........................................... 169
Appendix 11
Calculation of Creatinine Clearance Using the 
Cockcroft-Gault Formula........................................................... 170


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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE Ib/II STUDY EVALUATING THE SAFETY 
AND EFFICACY OF OBINUTUZUMAB IN 
COMBINATION WITH ATEZOLIZUMAB PLUS 
POLATUZUMAB VEDOTIN IN PATIENTS WITH 
RELAPSED OR REFRACTORY FOLLICULAR 
LYMPHOMA AND RITUXIMAB IN COMBINATION 
WITH ATEZOLIZUMAB PLUS POLATUZUMAB 
VEDOTIN IN PATIENTS WITH RELAPSED OR 
REFRACTORY DIFFUSE LARGE B-CELL 
LYMPHOMA
PROTOCOL NUMBER:
BO29561
VERSION NUMBER:
8
EUDRACT NUMBER:
2015-004845-25
IND NUMBER:
128036
TEST PRODUCT:
Obinutuzumab (RO5072759)
Rituximab (RO0452294)
Atezolizumab (RO5541267)
Polatuzumab vedotin (RO5541077)
MEDICAL MONITOR:
, Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by your local study monitor. 


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
14/Protocol BO29561, Version 8
PROTOCOL SYNOPSIS
TITLE:
A PHASE IB/II STUDY EVALUATING THE SAFETY AND 
EFFICACY OF OBINUTUZUMAB IN COMBINATION WITH 
ATEZOLIZUMAB PLUS POLATUZUMAB VEDOTIN IN PATIENTS 
WITH RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA 
AND RITUXIMAB IN COMBINATION WITH ATEZOLIZUMAB PLUS 
POLATUZUMAB VEDOTIN IN PATIENTS WITH RELAPSED OR 
REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA
PROTOCOL NUMBER:
BO29561
VERSION NUMBER:
8
EUDRACT NUMBER:
2015-004845-25
IND NUMBER:
128036
TEST PRODUCT:
Obinutuzumab (RO5072759)
Rituximab (RO0452294)
Atezolizumab (RO5541267)
Polatuzumab vedotin (RO5541077)
PHASE:
Phase Ib/II
INDICATION:
Follicular lymphoma or diffuse large B-cell lymphoma
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the safety, efficacy, pharmacokinetics, and immunogenicity of induction 
treatment consisting of obinutuzumab in combination with atezolizumab plus polatuzumab 
vedotin (G Atezo Pola) in patients with relapsed or refractory FL and rituximab in 
combination with atezolizumab polatuzumab vedotin (R Atezo Pola) in patients with 
relapsed or refractory DLBCL, followed by post-induction treatment with G Atezo (referred to 
as maintenance) in patients with FL who achieve a CR, a PR, or stable disease at EOI and 
post-induction treatment with R Atezo (referred to as consolidation) in patients with DLBCL 
who achieve a CR or PR at EOI.  Specific objectives and corresponding endpoints for the study 
are outlined below.
In this study, "study treatment" refers to the combination of all study treatment components.
Safety Objective
The safety objectives for this study are as follows:

To determine the recommended Phase II dose (RP2D) for polatuzumab vedotin when given 
in combination with fixed doses of obinutuzumab and atezolizumab on the basis of the 
following endpoint:

Incidence of DLTs during Cycle 1 and 2 of study treatment 

To evaluate the safety and tolerability of the G Atezo Pola treatment group and the 
R Atezo Pola treatment group on the basis of the following endpoints:
Nature, frequency, severity, and timing of adverse events
Changes in clinical laboratory results during and following study treatment 
administration


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Efficacy Objective
Response will be determined through use of the positron emission tomography and computed 
tomography (PET-CT) scans or CT scans alone, using Revised Lugano Response Criteria for 
Malignant Lymphoma, hereinafter referred to as modified Lugano 2014 criteria.  Response will 
be determined by the investigator.
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of induction treatment 
with G Atezo Pola in relapsed or refractory FL and R Atezo Pola in relapsed or refractory 
DLBCL on the basis of the following endpoint:

CR at EOI, as determined by the investigator on the basis of PET-CT scans 
Secondary Efficacy Objectives
The secondary efficacy objective for this study is to evaluate the efficacy of induction treatment 
with G Atezo Pola and maintenance treatment with G Atezo in relapsed or refractory FL 
and of induction treatment with R Atezo Pola and consolidation treatment with R Atezo in 
relapsed or refractory DLBCL on the basis of the following endpoints:

CR at EOI, as determined by the investigator on the basis of CT scans alone

Objective response (defined as a CR or PR) at EOI, as determined by the investigator on 
the basis of PET-CT scans

Objective response (defined as a CR or PR) at EOI, as determined by the investigator on 
the basis of CT scans alone

Best response of CR or PR during the study, as determined by the investigator on the basis 
of CT scans alone
Exploratory Efficacy Objectives
The exploratory efficacy objective for this study is to evaluate the long-term efficacy of 
G Atezo Pola on the basis of the following endpoints:

For patients who have positive PET scans at EOI:
CR at 12 months, as determined by the investigator on the basis of PET-CT scans in 
FL patients

Overall survival (OS), defined as the time from initiation of study treatment to death from 
any cause
Pharmacokinetic Objective
The PK objective for this study is to characterize the pharmacokinetics of obinutuzumab, 
rituximab, atezolizumab, and polatuzumab vedotin when given in combination, on the basis of 
the following endpoints:

Observed serum obinutuzumab concentration at specified timepoints

Observed serum atezolizumab concentration at specified timepoints

Observed serum and plasma concentrations of polatuzumab vedotin and relevant analytes 
(total antibody, acMMAE, and unconjugated MMAE) at specified timepoints
Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to 
obinutuzumab, rituximab, atezolizumab, and polatuzumab vedotin on the basis of the following 
endpoints:

Incidence of human anti-human antibodies (HAHAs) to obinutuzumab during the study 
relative to the prevalence of HAHAs at baseline

Incidence of human anti-chimeric antibodies (HACAs) to rituximab during the study relative 
to the prevalence of HACAs at baseline


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
Incidence of ATAs to atezolizumab during the study relative to the prevalence of ATAs at 
baseline

Incidence of ATAs to polatuzumab vedotin during the study relative to the prevalence of 
ATAs at baseline
The exploratory immunogenicity objective for this study is to evaluate potential effects of HAHAs 
or ATAs on the basis of the following endpoint:

Correlation between HAHA or ATA status and efficacy, safety, or PK endpoints
Biomarker Objective
The exploratory biomarker objective for this study is to identify non-inherited biomarkers that are 
predictive of response to study treatment (i.e., predictive biomarkers), are associated with 
progression to a more severe disease state (i.e., prognostic biomarkers), are associated with 
acquired resistance to study treatment, are associated with susceptibility to developing adverse 
events, can provide evidence of study treatment activity, can increase the knowledge and 
understanding of lymphoma biology or study treatment mechanism of action, or can contribute 
to improvement of diagnostic assays, on the basis of the following endpoint:

Association between non-inherited biomarkers and efficacy, safety, pharmacokinetic, or 
immunogenicity endpoints
Study Design
Description of Study
This Phase Ib/II, open-label, multicenter, non-randomized, dose-escalation study will evaluate 
the safety, efficacy, pharmacokinetics, and immunogenicity of G Atezo Pola in patients with 
relapsed or refractory FL and R Atezo Pola in patients with relapsed or refractory DLBCL.
Following the Dear Investigator Letter issued on 1 March 2018, enrollment has been stopped 
and atezolizumab treatment has been discontinued in all patients still receiving study treatment.  
Number of Patients
Overall, it was planned to have 8392 patients enrolled in this study, at approximately 
20 investigative sites around the world. As of 1 March 2018, 13 patients with RR FL and 
23 patients with RR DLBCL were enrolled in the study.
Target Population
This study will enroll patients with FL and DLBCL who meet the eligibility criteria presented 
below.
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2

For G Atezo Pola treatment group: relapsed or refractory FL after treatment with at least
one prior chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody 
and for which no other more appropriate treatment option exists as determined by the 
investigator

For R Atezo Pola treatment group:  relapsed or refractory DLBCL after treatment with at 
least one prior chemoimmunotherapy regimen that included an anti-CD20 monoclonal 
antibody, in patients who are not eligible for second line combination 
(immuno-)chemotherapy and autologous stem-cell transplantation, or who have failed 
second line combination (immuno-)chemotherapy, or experienced disease progression 
following autologous stem-cell transplantation

Histologically documented CD20-positive lymphoma as determined by the local laboratory

FDG-avid lymphoma (i.e., PET-positive lymphoma)


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
At least one bi-dimensionally measurable lesion (1.5 cm in its largest dimension by CT 
scan or magnetic resonance imaging [MRI])

Availability of a representative tumor specimen and the corresponding pathology report for 
retrospective central confirmation of the diagnosis of FL or DLBCL
If archival tissue is unavailable or unacceptable, a pretreatment core-needle, excisional 
or incisional tumor biopsy is required.  Cytological or fine-needle aspiration samples 
are not acceptable.
If the patient received anti-lymphoma treatment between the time of the most recent 
available biopsy and initiation of study treatment, or if the available biopsy was 
performed more than 6 months prior to Day 1 of Cycle 1 (initiation of study treatment) 
for patients with DLBCL or more than 12 months prior to Day 1 of Cycle 1 for patients 
with FL, a core-needle biopsy is strongly recommended.

For women who are not postmenopausal ( 12 months of non-therapy-induced amenorrhea 
and age 45 years) or surgically sterile (absence of ovaries and/or uterus): agreement to 
remain abstinent or to use single highly effective or combined contraceptive methods that 
result in a failure rate of 1% per year during the treatment period for 5 months after the 
last dose of atezolizumab, 12 months after the last dose of rituximab, 12 months after 
the last dose of polatuzumab vedotin, and 18 months after the last dose of obinutuzumab.
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not acceptable methods of contraception.
Examples of highly effective contraceptive methods with a failure rate of 1% per year 
include tubal ligation, male sterilization, hormonal implants, established, proper use of 
combined oral or injected hormonal contraceptives, and certain intrauterine devices. 
Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical 
cap) may be combined to achieve a failure rate of1% per year. Barrier methods must 
always be supplemented with the use of a spermicide.

For women of childbearing potential, a negative serum pregnancy test result within 7 days
prior to commencement of dosing. Women who are considered not to be of childbearing 
potential are not required to have a pregnancy test.

For men, agreement to remain abstinent or to use a condom plus an additional 
contraceptive method that together result in a failure rate of 1% per year during the 
treatment period and for at least three months after the last dose of obinutuzumab, 
rituximab, and atezolizumab, and five months after the last dose of polatuzumab vedotin 
and agreement to refrain from donating sperm during this same period.
Men with a pregnant partner must agree to remain abstinent or to use a condom for 
the duration of the pregnancy.
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not acceptable methods of contraception.
Male patients considering preservation of fertility should bank sperm before treatment 
with polatuzumab vedotin.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Grade 3b follicular lymphoma

History of transformation of indolent disease to DLBCL

Known CD20-negative status at relapse or progression

Central nervous system (CNS) lymphoma or leptomeningeal infiltration

Prior allogeneic SCT

Completion of autologous SCT within 100 days prior to Day 1 of Cycle 1 


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
Prior standard or investigational anti-cancer therapy as specified below:
Fludarabine or alemtuzumab within 12 months prior to Day 1 of Cycle 1
Radioimmunoconjugate within 12 weeks prior to Day 1 of Cycle 1
Monoclonal antibody or ADC within 4 weeks prior to Day 1 of Cycle 1
Radiotherapy, chemotherapy, hormonal therapy, or targeted small-molecule therapy 
within 2 weeks prior to Day 1 of Cycle 1
AntiPD-1, antiPD-L1, anti-CTLA4, antiCD137/41-BB agonist, or anti-CD40 agonist 
antibodies

Clinically significant toxicity (other than alopecia) from prior treatment that has not resolved 
to Grade 2 (per NCI CTCAE v4.0) prior to Day 1 of Cycle 1

Treatment with systemic immunosuppressive medications, including, but not limited to, 
prednisone, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor agents 
within 2 weeks prior to Day 1 of Cycle 1
Treatment with inhaled corticosteroids and mineralocorticoids is permitted.
If corticosteroid treatment is urgently required for lymphoma symptom control prior to 
the start of study treatment, up to 100 mg of prednisone or equivalent can be given for 
a maximum of 5 days, but all tumor assessments must be completed prior to initiation 
of corticosteroid treatment.

History of solid organ transplantation

History of severe allergic or anaphylactic reaction to humanized, chimeric, or murine 
monoclonal antibodies

Known hypersensitivity or allergy to murine products

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or 
any component of the atezolizumab, obinutuzumab, rituximab, or polatuzumab vedotin 
formulations

Known history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis or evidence of active pneumonitis on screening chest 
CT scan.
History of radiation pneumonitis in the radiation field (fibrosis) is allowed.

Active bacterial, viral, fungal, or other infection or any major episode of infection requiring 
treatment with IV antibiotics within 4 weeks of Day 1 of Cycle 1
Caution should be exercised when considering the use of obinutuzumab and rituximab 
in patients with a history of recurring or chronic infections.

Receipt of oral or intravenous antibiotics for treatment of serious infections within 4 weeks 
prior to Day 1 of Cycle 1

Positive for hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (HBcAb), or 
hepatitis C virus (HCV) antibody at screening

Known history of HIV positive status
For patients with unknown HIV status, HIV testing will be performed at screening if 
required by local regulations.

History of PML

Vaccination with a live virus vaccine or live attenuated vaccine within 28 days prior to Day 1 
of Cycle 1, or anticipation that such a live, attenuated vaccine will be required during the 
study

History of other malignancy that could affect compliance with the protocol or interpretation 
of results, with the exception of the following:
Curatively treated carcinoma in situ of the cervix, good-prognosis ductal carcinoma in 
situ of the breast, basal- or squamous-cell skin cancer, Stage I melanoma, or low-
grade, early-stage localized prostate cancer


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Any previously treated malignancy that has been in remission without treatment 
for 2 years prior to enrollment

History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis
Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid-replacement hormone may be eligible for this study.
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be 
eligible for this study.

Grade 1 peripheral neuropathy present at screening

Evidence of any significant, uncontrolled concomitant disease that could affect compliance 
with the protocol or interpretation of results, including significant cardiovascular disease 
(such as New York Heart Association Class III or IV cardiac disease, myocardial infarction 
within the previous 6 months, unstable arrhythmia, or unstable angina) or significant 
pulmonary disease (such as obstructive pulmonary disease or history of bronchospasm)

Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of Cycle 1, 
or anticipation of a major surgical procedure during the course of the study

Inadequate hematologic function (unless due to underlying lymphoma), defined as follows:
Hemoglobin 9 g/dL
ANC 1.5109/L
Platelet count 75 109/L

Inadequate liver function defined as follows (unless due to underlying lymphoma): 
For patients enrolled in the dose escalation:
AST ULN or serum total bilirubin ULN
For patients enrolled in the expansion phase:
AST or ALT 2.5 ULN
Serum total bilirubin 1.5 ULN (or 3 ULN for patients with Gilbert syndrome)

Any of the following abnormal laboratory values (unless due to underlying lymphoma):
Creatinine 1.5 times the upper limit of normal (ULN) (unless creatinine clearance is 
normal) or calculated creatinine clearance 40 mL/min (using the Cockcroft-Gault 
formula)
INR or PT 1.5 ULN in the absence of therapeutic anticoagulation
PTT or aPTT 1.5 ULN in the absence of a lupus anticoagulant

Pregnant or lactating, or intending to become pregnant during the study
Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to Day 1 of Cycle 1.

Life expectancy 3 months

Unable to comply with the study protocol, in the investigator’s judgment
End of Study
The end of this study is defined as the time when all enrolled patients with FL and all enrolled 
patients with DLBCL have completed the 90-day safety follow-up visit, following completion or 
premature discontinuation of study treatment. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4 years.


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Investigational Medicinal Products
Test Product (Investigational Drug)
Dosing with atezolizumab has been discontinued in all patients.
Obinutuzumab
Obinutuzumab will be supplied by the Sponsor as an investigational medicinal product (IMP).  
Obinutuzumab will be provided as a single-dose, sterile liquid formulation in a 50-mL glass vial 
containing 1000 mg/40 mL of obinutuzumab.  In addition to the drug substance, the liquid is also 
composed of histidine, trehalose, and poloxamer 188.  For information on the formulation and 
handling of obinutuzumab, see the obinutuzumab Investigator’s Brochure and the Pharmacy 
Manual.
Atezolizumab
Atezolizumab was supplied by the Sponsor as an IMP.  Atezolizumab Drug Product is provided 
in a single-use, 20-mL USP/Ph. Eur. Type 1 glass vial as a colorless to slightly yellow, sterile, 
preservative-free clear liquid solution intended for IV administration.  The vial is designed to 
deliver 20 mL (1200 mg) of atezolizumab solution but may contain more than the stated volume 
to enable delivery of the entire 20-mL volume.  Extraction of 14 mL of atezolizumab solution will 
contain an 840-mg dose.  For information on the formulation and handling of atezolizumab, see 
the atezolizumab Investigator’s Brochure and the Pharmacy Manual.
Polatuzumab Vedotin
Polatuzumab vedotin will be supplied by the Sponsor as an IMP.  Polatuzumab vedotin will be 
provided as a sterile, white to off-white, preservative-free lyophilisate in single-use vials. For 
information on the formulation and handling of polatuzumab vedotin, see the polatuzumab 
vedotin Investigator's Brochure and the Pharmacy Manual.
Rituximab
Rituximab will be supplied by the Sponsor as an IMP. 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.  For information on 
the formulation and handling of rituximab, see the Rituximab Investigator's Brochure and the 
Rituximab Pharmacy Manual.
Statistical Methods
Efficacy Analyses
The primary and secondary efficacy analyses will include all patients enrolled in the expansion 
phase, and will be performed by treatment group.  In addition, patients with FL who received 
polatuzumab vedotin at the RP2D during the dose-escalation phase will be pooled for analysis 
with patients with FL treated in the expansion phase. Patients with DLBCL from the safety run-in 
phase will be pooled for analysis with patients with DLBCL treated in the expansion phase at 
the same polatuzumab vedotin dose.
Determination of Sample Size
Limited dose-finding will be conducted during the dose-escalation phase of polatuzumab 
vedotin in combination with obinutuzumab and atezolizumab.  The estimated sample size 
follows from the dose-escalation rules for a standard 3 3 algorithm.  A total of 9 patients with 
RR FL were enrolled in the dose-escalation phase (3 patients in the Pola 1.4-mg dose cohort 
and 6 patients in the Pola 1.8-mg dose cohort), and a total of 7 patients with RR DLBCL were 
enrolled into the safety run-in phase and treated with 1.8 mg polatuzumab vedotin.  During the 
expansion phase, 3440 patients with DLBCL and 3437 patients with FL (for a total of 
40 patients with FL at RP2D in the dose-escalation and expansion phases) were planned to be 
enrolled.  Overall, approximately 8392 patients were planned to be enrolled in the study.  As of 
1 March 2018, 13 patients with RR FL and 23 patients with RR DLBCL were enrolled in the 
study.
The primary efficacy analysis will be the estimation of the true proportion of patients expected to 
obtain a PET-CTdefined CR at EOI. 


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Interim Analyses
No interim analyses are planned and review of safety and/or efficacy data by the Internal 
Monitoring Committee may be requested by and carried out at the discretion of the Medical 
Monitor.  Further details regarding the rules and guidelines of data review will be provided in an 
IMC charter.  


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ABC
activated B cell-like (subgroup)
acMMAE
antibody-conjugated MMAE
ADC 
antibody-drug conjugate
ALP
alkaline phosphatase
ATA
anti-therapeutic antibody
Atezo
atezolizumab
BSA
body surface area
CHOP
cyclophosphamide, doxorubicin, vincristine, and 
prednisone
CI
confidence interval
CLL
chronic lymphocytic leukemia
CR
complete response
CRO
contract research organization
CT
computed tomography
Ctrough
trough concentration
CVP
cyclophosphamide, vincristine, and prednisone
DHAP
dexamethasone, cytosine arabinoside, and cisplatin
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EFS
event-free survival
EOI
end of induction
EORTC
European Organization for Research and Treatment of 
Cancer
ESMO
European Society for Medical Oncology
FDA
U.S. Food and Drug Administration
FDG
fluorodeoxyglucose
FL
follicular lymphoma
FLIPI, FLIPI2
Follicular Lymphoma International Prognostic Index
Follicular Lymphoma International Prognostic Index 2
G
obinutuzumab (GA101)
GCB
germinal-center B cell–like (subgroup)
GCP
Good Clinical Practice


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Abbreviation
Definition
G-CSF
granulocyte colony-stimulating factor
GEP
gene expression profile
GFP
green fluorescent protein
GI
gastrointestinal
HAHA
human anti-human antibody
HACA
human anti-chimeric antibody
HbA1c
glycosylated hemoglobin 
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HD
Hodgkin’s disease
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HR
hazard ratio
HSCT
hematopoietic stem cell transplantation
ICE
ifosfamide, carboplatin, and etoposide
ICH
International Conference on Harmonisation
IFN-
interferon alpha
IFN-
interferon gamma
IL
interleukin
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug
IPI
International Prognostic Index
irAE
immune-related adverse event
IRB
Institutional Review Board
IRR
infusion-related reaction
IV
intravenous
IxRS
interactive voice or web-based response system
LMWH
low-molecular-weight heparin
Lugano 2014 criteria
Lugano Response Criteria for Malignant Lymphoma 
MCL
Mantle cell lymphoma
MRD
minimal residual disease
MRI
magnetic resonance imaging
MZL
marginal zone lymphoma


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Abbreviation
Definition
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
NE
not estimable
NHL
non-Hodgkin’s lymphoma
NK cells
natural killer cells
NSCLC
nonsmall cell lung cancer
ORR
objective response rate
OS
overall survival
PD
pharmacodynamic
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic
PML
progressive multifocal leukoencephalopathy
Pola
polatuzumab vedotin
PR
partial response
q2w
every 2 weeks
Q3W
every 3 weeks
q4w
every 4 weeks
R
rituximab
RR
relapsed/refractory
RANKL
Receptor activator of nuclear factor kappa-B ligand
RCR
Roche Clinical Repository
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended Phase II dose
SCID
severe compromised immunodeficient
SCT
stem-cell transplantation
SJS
Stevens-Johnson syndrome
TAb
Total antibody
TEN
toxic epidermal necrolysis
TFH
Follicular helper T cells
TIL
tumor-infiltrating lymphocyte
TLS
tumor lysis syndrome
ULN
upper limit of normal


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
25/Protocol BO29561, Version 8
1.
BACKGROUND
1.1
BACKGROUND ON NON-HODGKIN'S LYMPHOMA
Non-Hodgkin’s lymphoma (NHL) is the most common hematologic malignancy in adults.  
In 2013, there were an estimated 69,740 new cases and 19,020 deaths due to the 
disease in the United States (Siegel et al. 2013).  In Europe, there were an estimated 
93,400 new cases and 37,900 deaths in 2012 (Ferlay et al. 2013).  Non-Hodgkin’s 
lymphoma is most often of B-cell origin, including a wide range of different subtypes of 
B-cell lymphoma, broadly divided into indolent and aggressive lymphomas, each with 
unique characteristics.
1.1.1
Follicular Lymphoma
Indolent B-cell lymphomas are a heterogeneous group of malignant lymphomas and 
account for approximately one-third of all NHLs.  Follicular lymphoma (FL) is the most 
common subtype of indolent B-cell lymphoma, accounting for about 22% of all newly 
diagnosed cases of NHL (Armitage and Weisenburger 1998).  Approximately 90% of the 
cases have at (14;18) translocation, which juxtaposes BCL2 with the IgH locus and 
results in overexpression of the anti-apoptotic protein, BCL2.
Despite therapies currently available, FL remains an incurable disease.  The addition of 
rituximab, an anti-CD20 monoclonal antibody, to commonly used induction 
chemotherapy, including cyclophosphamide, doxorubicin, vincristine, and prednisone 
CHOP (CHOP cyclophosphamide, doxorubicin, vincristine, and prednisone), 
cyclophosphamide, vincristine, and prednisone CVP (CVP cyclophosphamide, 
vincristine, and prednisone); fludarabine, or bendamustine (Dreyling et al. 2014; 
Zelenetz et al. 2013), followed by rituximab maintenance therapy led to prolonged 
remission and improved patient outcomes.  Updated results from Study MO18264 
confirmed the benefit of 2-year rituximab maintenance in patients responding to first-line 
immunotherapy, with a 6-year progression-free survival (PFS) of 59.2% compared with 
42.7% in the observation arm (p0.0001) (Salles et al. 2013).
Despite significant therapeutic progress with the use of chemoimmunotherapy as 
first-line treatment, most patients will eventually experience disease relapse.  Relapses 
are characterized by increasing refractoriness and decreasing duration of response to 
subsequent lines of therapy.  Thus, new treatments are needed to improve the outcome 
for these patients.
1.1.2
Diffuse Large B-Cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive NHL, 
accounting for approximately 30% of all NHLs diagnosed annually (Armitage and 
Weisenburger 1998).  The use of immunochemotherapy, most commonly
rituximabCHOP (R-CHOP) for newly diagnosed DLBCL, led to a significant 
improvement in survival in patients in all age groups.  In older patients (60 years of 
age), R-CHOP was associated with a 2-year event-free survival (EFS) rate of 57% and a 


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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10-year survival rate of 43.5% (Coiffier et al. 2010).  In younger patients (1860 years of 
age) with favorable prognostic features, R-CHOP demonstrated a 3-year EFS rate of 79% 
and a survival rate at 3 and 6 years of 93% and 74.3%, respectively 
(Pfreundschuh et al. 2011).  However, nearly 40% of patients with DLBCL will eventually 
die of relapsed disease or disease that is refractory to first-line treatment.  Patients with 
a high-risk International Prognostic Index (IPI) have a 5-year PFS rate of only 40% 
following treatment with R-CHOP (Zhou et al. 2014).
Second-line treatments consist of high-dose chemotherapy regimens such as 
rituximabifosfamide, carboplatin, and etoposide (R-ICE) or rituximabdexamethasone,
cytosine arabinoside, and cisplatin (R-DHAP) followed by autologous stem-cell 
transplantation (SCT).  Approximately half of the patients do not achieve a complete 
remission after salvage treatment (Gisselbrecht et al. 2010).  Moreover, elderly patients 
or patients with comorbidities are often deemed ineligible for this aggressive therapy.
Specific molecular subsets of DLBCL are associated with an inferior outcome following 
R-CHOP therapy.  Germinal center B celllike (GCB) DLBCL had a better prognosis 
than activated (non-germinal) B celllike (ABC) DLBCL, with a 3-year survival rate of 
84% versus 56%, respectively (p0.001) (Lenz et al. 2008).  Several genetic 
abnormalities predictive of poor outcome have been identified in DLBCL, including MYC
rearrangement, BCL2 and BCL6 overexpression, and TP53 mutations.  Rearrangement 
in MYC (MYC-positive DLBCL) has been reported in 9%17% of DLBCL cases and 
often correlates with the GCB DLBCL phenotype (Savage et al. 2009; 
Barrans et al. 2010).  The DLBCL treated with R-CHOP has a markedly worse 5-year 
survival rate in patients with MYC-positive DLBCL compared with MYC-negative DLBCL 
(33% vs. 72%) (Savage et al. 2009).  Concurrent MYC and IGH-BCL2 rearrangement 
("double-hit" DLBCL), observed in 2%11% of patients with DLBCL, represents a 
DLBCL subset with an inferior outcome (5-year PFS of 18%; 5-year survival of 27%) 
(Savage et al. 2009; Dunleavy et al. 2014).  Mutations in TP53 have been described in 
approximately 20% of patients with DLBCL and are strong predictors of poor overall 
survival (Young et al. 2008; Xu-Monette et al. 2012).
The DLBCL remains a disease with high unmet medical need.  Novel targeted therapies 
are needed to move treatment options beyond R-CHOP.
1.2
BACKGROUND ON OBINUTUZUMAB
Obinutuzumab is a novel glycoengineered type II anti-CD20 antibody.  Compared with 
rituximab, obinutuzumab is characterized by more potent direct B-cell death induction 
and increased affinity for FcRIII receptors expressed on natural killer (NK) cells, 
macrophages, and monocytes, resulting in enhanced antibody-dependent cellular 
cytotoxicity and antibody-dependent cellular phagocytosis (Beers et al. 2010; 
Mössner et al. 2010; Herter et al. 2014).  Together, these characteristics confer 
obinutuzumab with enhanced immune effector functions and B-cell-depleting activity 
compared with rituximab.


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
27/Protocol BO29561, Version 8
Obinutuzumab is approved for use in combination with chlorambucil for the treatment of 
patients with previously untreated chronic lymphocytic leukemia (CLL).  Obinutuzumab is 
also approved for use in combination with bendamustine followed by obinutuzumab 
maintenance for the treatment of patients with FL who did not respond to or who 
progressed during or after treatment with rituximab or a rituximab-containing regimen
and in combination with chemotherapy, followed by obinutuzumab maintenance for the 
treatment of patients with previously untreated follicular lymphoma, in the United States, 
Europe, and many other countries.  Obinutuzumab continues to be investigated in a 
large clinical program.
1.2.1
Nonclinical Studies with Obinutuzumab
In nonclinical studies, obinutuzumab demonstrated superior depletion of normal B cells 
(measured as CD19+ depletion) from the blood of healthy volunteers 
(Mössner et al. 2010) and of malignant B cells from the blood of patients with CLL 
(Patz et al. 2011).  Nonclinical xenograft experiments performed with obinutuzumab as 
monotherapy and in combination with chemotherapy have consistently showed that 
obinutuzumab has promising anti-tumor activity (Mössner et al. 2010; Dalle et al. 2011) 
and have demonstrated the superiority of obinutuzumab over rituximab 
(Herting et al. 2014).
For more detailed nonclinical information on obinutuzumab, refer to the Obinutuzumab 
Investigator’s Brochure.
1.2.2
Clinical Studies with Obinutuzumab
Obinutuzumab is being studied in patients with CLL, indolent and aggressive NHL, and 
solid tumors.  Available efficacy results from the NHL cohorts in these studies and 
available safety results from all patients are summarized below.
For more detailed clinical information on obinutuzumab, including results in the CLL 
cohorts of the clinical studies and clinical pharmacology data, please refer to the 
Obinutuzumab Investigator’s Brochure.
1.2.2.1
Clinical Safety of Obinutuzumab
As of 31 October 2017, 4981 patients have received obinutuzumab via clinical trial 
participation.  Patients with NHL (including DLBCL, indolent B-cell lymphoma, and CLL) 
have been treated with obinutuzumab given as monotherapy or in combination with 
CHOP, bendamustine, FC, or chlorambucil, at doses ranging from 502000 mg.  Overall, 
the safety of obinutuzumab monotherapy and obinutuzumab combination therapy was 
manageable.
The most frequent causes of death were disease progression and adverse events 
associated with infectious diseases.  This is consistent with the study population and the 
disease under treatment.  The incidence of fatal adverse events was similar across all 
ongoing trials.  In Study GAO4768g (obinutuzumab 1000 mg vs. 2000 mg), the 


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
28/Protocol BO29561, Version 8
incidence of deaths did not increase with increased obinutuzumab dose (7.5% and 2.6%, 
respectively).
Of particular interest, a high incidence of infusion-related reactions (IRRs) was observed 
consistently in all obinutuzumab trials.  The reported incidence of IRRs varied across 
studies.  The incidence of IRRs in relapsed or refractory patients receiving 
obinutuzumab monotherapy was 100% in CLL (n38) and 82.4% in NHL (n205) in 
Studies BO21003 and BO20999 (pooled data).  Anaphylaxis has also been reported in 
patients treated with obinutuzumab.
Other important risks associated or potentially associated with obinutuzumab are tumor 
lysis syndrome (TLS), neutropenia (including prolonged and late-onset neutropenia), 
thrombocytopenia (including acute thrombocytopenia), infections (including progressive 
multifocal leukoencephalopathy [PML] and hepatitis B virus [HBV] reactivation), 
prolonged B-cell depletion, impaired immunization response, worsening of preexisting 
cardiac conditions, gastrointestinal (GI) perforation, immunogenicity, and second 
malignancies.  The important identified risks associated with obinutuzumab are 
presented in detail in Section 5.1.1 and in the obinutuzumab Investigator’s Brochure.
1.2.2.2
Clinical Pharmacokinetics of Obinutuzumab
On the basis of available pharmaockinetic (PK) data, a two-compartment PK model 
comprising both a linear clearance pathway and a non-linear time-varying clearance 
pathway adequately describes serum obinutuzumab concentration data.  The initial 
clearance of obinutuzumab is 2higher than the steady-state clearance, consistent 
with a decrease in the time-varying clearance component, which is high at the start of 
treatment and declines with repeated cycles of obinutuzumab treatment.  The 
time-varying clearance pathway is consistent with target-mediated drug disposition, such 
that at the start of treatment, there is a large quantity of CD20-positive cells that rapidly 
bind to obinutuzumab.  Repeated dosing with obinutuzumab saturates the pool of 
CD20-positive cells, hence reducing this component in clearance.  The linear clearance 
pathway is consistent with catabolism of IgG antibodies and is therefore independent of 
CD20-positive cells.  Refer to the Obinutuzumab Investigator’s Brochure for additional 
details.
1.2.2.3
Clinical Efficacy of Obinutuzumab in Patients with 
Non-Hodgkin’s Lymphoma
In studies of obinutuzumab monotherapy in patients with relapsed or refractory NHL 
(studies BO20999, BO21003, YP25623, and JO21900), the proportion of patients who 
had a response (complete response [CR] or partial response [PR]) at the end of 
treatment (as determined on the basis of computed tomography [CT] scans alone) 
ranged from 28% to 58%.  The CR rate ranged from 0% to 19%.
In early studies of obinutuzumab in combination with chemotherapy (e.g., CHOP, FC, 
or bendamustine) in patients with previously untreated or relapsed or refractory NHL 


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
29/Protocol BO29561, Version 8
(studies BO21000, GAO4915g, and GAO4753g), the proportion of patients with a CR or 
PR at the end of induction (EOI) treatment ranged from 69% to 96%.  The CR rate with 
combination therapy was 35%39% in patients with previously untreated FL, 11%50% 
in patients with relapsed or refractory indolent NHL, and 55% in patients with previously 
untreated DLBCL.
A Phase III study, GAO4753g, investigated obinutuzumabbendamustine (G-benda) 
compared with bendamustine alone in patients with rituximab-refractory indolent NHL 
(n396).  Patients in the G-benda arm who had not experienced disease progression at 
the end of induction received obinutuzumab monotherapy every 2 months for up to 
2 years.  On the basis of positive results from this study, demonstrating significant 
improvement in PFS in the G-benda arm, with a median investigator-assessed PFS of 
29 versus 14 months (hazard ratio [HR]: 0.52; 95% CI: 0.39, 0.70; p 0.0001) 
(Sehn et al. 2015), obinutuzumab was granted approval for use in patients with FL who 
did not respond to or who progressed during or after treatment with rituximab or a 
rituximab-containing regimen (see Section 1.2).
A Phase III study, BO21223, investigated obinutuzumabchemotherapy (G-benda, 
G-CVP, G-CHOP) compared with rituximabchemotherapy followed by obinutuzumab 
or rituximab maintenance in patients with previously untreated indolent NHL (FL cohort, 
n1202).  On the basis of positive results that demonstrated significant improvement in 
PFS in the obinutuzumab chemotherapy arm (stratified HR INV PFS 0.66 [95% CI: 0.51 
to 0.85; p0.0012]), the Independent Data Monitoring Committee recommended that the 
study be unblinded to the Sponsor at a pre-planned interim analysis (Marcus et al. 2017).
A Phase III study, BO21005, investigated obinutuzumabCHOP (G-CHOP) compared 
with rituximabCHOP (R-CHOP) in patients with previously untreated DLBCL.  The 
study did not meet its primary endpoint of PFS at final analysis. Based upon the 
BO21005 efficacy results, this study protocol is amended (version 4) to cease evaluating 
obinutuzumab in patients with relapsed or refractory DLBCL; these patients will receive 
instead atezolizumab in combination with rituximab and polatuzumab vedotin.
1.3
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
its interaction with its receptors, PD-1 and B7-1 (also known as CD80).  Both of these 
interactions are reported to provide inhibitory signals to T cells.  Therapeutic blockage of 
PD-L1 binding by atezolizumab is expected to enhance the magnitude and quality of the 
tumor-specific T-cell responses, resulting in improved anti-tumor activity.  Atezolizumab
was engineered to impair its binding to Fc receptors, thus eliminating detectable 
FC-effector function and associated antibody-mediated clearance of activated effector 
T cells (Teffs).


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
30/Protocol BO29561, Version 8
Atezolizumab is approved for the treatment of patients with locally advanced or 
metastatic urothelial cancer who (1) have disease progression during or following 
platinum-containing chemotherapy or (2) have disease progression within 12 months of 
neoadjudvant or adjuvant treatment with platinum-containing chemotherapy.  
Atezolizumab is also approved for patients with metastatic non-small cell lung cancer 
who have disease progression during or following platinum-containing chemotherapy. 
Atezolizumab is being investigated as a potential treatment in multiple solid tumors and 
hematologic malignancies in humans.
1.3.1
Nonclinical Studies with Atezolizumab
The safety, pharmacokinetics, and toxicokinetics of atezolizumab were investigated in 
mice and cynomolgus monkeys to support intravenous (IV) administration and to aid in 
projecting the appropriate starting dose in humans.  Given the similar binding of 
atezolizumab for cynomolgus monkey and human PD-L1, the cynomolgus monkey was 
selected as the primary and relevant nonclinical model for understanding the safety, 
pharmacokinetics, and toxicokinetics of atezolizumab.  Overall, the nonclinical 
pharmacokinetics and toxicokinetics observed for atezolizumab supported entry into 
clinical studies and provided adequate safety factors for the proposed Phase I starting 
doses.  The results of the toxicology program were consistent with the anticipated 
pharmacologic activity of downmodulating the PD-L1/PD-1 pathway.  Improved immune 
responses and the potential to increase immune-associated inflammatory lesions were 
identified as possible safety risks in patients.
Refer to the atezolizumab Investigator's Brochure for details on the nonclinical studies.
1.3.2
Clinical Studies with Atezolizumab
Atezolizumab is currently being tested in multiple Phase I, II, and III studies, both as 
monotherapy and in combination with several anti-cancer therapies.  The majority of the 
safety and efficacy data summarized below are from Phase Ia Study PCD4989g, a 
multicenter, first-in-human, open-label, dose-escalation trial evaluating the safety, 
tolerability, immunogenicity, pharmacokinetics, exploratory pharmacodynamics (PD), 
and preliminary evidence of biologic activity of atezolizumab administered as a single 
agent by IV infusion every 3 weeks (Q3W) to patients with locally advanced or 
metastatic solid tumors or hematologic malignancy.
1.3.2.1
Summary of Clinical Safety of Atezolizumab
The safety data for atezolizumab have been derived from Study PCD4989g, in which 
atezolizumab is being used as single-agent therapy in patients with locally advanced or 
metastatic solid tumors or hematologic malignancies.  As of the data cutoff date of 
15 December 2015, the clinical database contained preliminary safety data from 
629 patients who received atezolizumab at doses ranging from 0.0120 mg/kg across 
multiple tumor types.  No dose-limiting toxicities have been observed at any dose level, 
no maximum tolerated dose and no clear dose related trends in the incidence of adverse 
events have been determined.


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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The safety profile of atezolizumab as a single agent is observed to be consistent across 
different indications.
Summary of Adverse Events
Adverse events were reported in 619 of the 629 safety-evaluable patients (98.4%).  
Adverse events occurring in 10% of treated patients included fatigue, decreased 
appetite, nausea, pyrexia, constipation, cough, dyspnea, diarrhea, anemia, vomiting, 
asthenia, back pain, headache, arthralgia, pruritus, rash, abdominal pain, insomnia, 
peripheral edema, urinary tract infection, dizziness, and chills.  Grade 3 adverse events 
were reported in approximately 43% of patients.
Treatment-related adverse events (per investigator’s assessment of causality) were 
reported in 444 of 629 (70.6%) patients.  Grade 34 treatment-related events occurring 
in 5 patients (0.8%) were reported in 13.7% of patients, with fatigue and asthenia 
(1.3% each), AST increased and dyspnea (1.1% each), and hyponatremia (0.8%).
Serious adverse events (SAEs) have been reported in 261 of 629 patients (41.5%) in 
Study PCD4989g.  Reported SAEs were consistent with the underlying disease.  
Treatment-related SAEs were reported in 9.1% of patients.  Atezolizumab-related SAEs
occurring in 2 patients (0.3%) were pyrexia (2.1%); dyspnea (0.8%); pneumonitis
(0.6%); fatigue, malaise, hypoxia, and colitis (0.5% each); and bone pain (0.3%).
Ten patients (1.6%) had Grade 5 events.  The three events assessed by the investigator 
as related to atezolizumab were death (not otherwise specified), hepatic failure, and 
pulmonary hypertension.
Additional details for each case are provided in the Atezolizumab Investigator’s Brochure.
Immune-Related Adverse Events
Given the mechanism of action of atezolizumab, events associated with inflammation or 
immune related adverse events have been closely monitored during the atezolizumab 
clinical program.  To date, immune-related adverse events associated with atezolizumab 
include pneumonitis, hepatitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, 
myasthenic syndrome/myasthenia gravis, meningoencephalitis, and myocarditis.
Guidelines for the management of potential immune related adverse events are 
described in Section 5.1.6.


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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Refer to the Atezolizumab Investigator’s Brochure for details on immune related adverse 
events observed in patients treated with atezolizumab.  Guidelines for the management 
of immune related adverse events are described in the Atezolizumab Investigator’s 
Brochure.
1.3.2.2
Clinical Pharmacokinetics of Atezolizumab
On the basis of available preliminary PK data (for doses ranging from 0.0320 mg/kg), 
atezolizumab appeared to show linear pharmacokinetics at doses 1 mg/kg.  Serum 
atezolizumab concentrations exhibited a biphasic disposition with an initial rapid 
distribution phase followed by a slow elimination phase.  For the 1 mg/kg and 20 mg/kg 
dose groups, the mean apparent clearance (CL) ranged from 3.503.55 mL/day/kg and 
the mean volume of distribution at steady state (Vss) ranged from 4865.7 mL/kg, which 
are consistent with the expected profile of an IgG1 antibody in humans.  Atezolizumab 
exhibited non-linear pharmacokinetics at doses of 1 mg/kg (i.e., 0.030.3 mg/kg), 
which is likely due to target-mediated clearance at lower concentrations.
The development of anti-therapeutic antibodies (ATAs) has been observed in all dose 
cohorts and was associated with changes in pharmacokinetics for some patients in the 
lower dose cohorts (0.3, 1, and 3 mg/kg).  The development of detectable ATAs has not 
had a significant impact on pharmacokinetics for doses ranging from 1020 mg/kg.  
Patients treated with atezolizumab at 10, 15, and 20 mg/kg have maintained the 
expected target trough levels of drug despite the detection of ATAs.  To date, no clear 
relationship between the detection of ATAs and adverse events or infusion reactions has 
been observed.
Please refer to the atezolizumab Investigator’s Brochure for details on clinical 
pharmacokinetics and immunogenicity.
1.3.2.3
Summary of Clinical Activity of Atezolizumab
Patients with multiple tumor types were included in Study PCD4989g, with the largest 
cohorts consisting of patients with nonsmall cell lung cancer (NSCLC), renal cell 
carcinoma (RCC), and urothelial bladder cancer (UBC).  Clinical activity of atezolizumab 
monotherapy was observed in a broad range of malignancies, including NSCLC, RCC, 
melanoma, bladder cancer, colorectal cancer, head and neck cancer, gastric cancer, 
breast cancer and sarcoma.  Analyses of response by PD-L1 expression status in 
tumor-infiltrating immune cells (ICs) and tumor cells (TCs) in baseline tumor tissue were 
also conducted.
Efficacy results, based on a data cutoff date of 15 December 2015, are summarized 
below for patients with hematologic malignancies.  Please see the Atezolizumab
Investigator’s Brochure for clinical activity of single-agent atezolizumab and in 
combination studies in solid tumors. 


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Eleven patients with refractory or relapsed hematologic malignancies have been treated 
with atezolizumab in Study PCD4989g.  This includes patients with multiple myeloma 
(n4), FL (n3), cutaneous T-cell lymphoma (n2), DLBCL (n1), and Hodgkin’s 
lymphoma (n1).  Among the 10 patients who were evaluable for response, the best 
response was PR for the 2 patients with cutaneous T-cell lymphoma; stable disease for 
the 3 patients with FL, the 1 patient with Hodgkin’s lymphoma, and 2 patients with 
multiple myeloma; and progressive disease for the remaining 2 patients with multiple 
myeloma.
1.4
BACKGROUND ON POLATUZUMAB VEDOTIN
Polatuzumab vedotin (DCDS4501A) is an antibodydrug conjugate (ADC) consisting of 
a humanized IgG1 antihuman CD79b monoclonal antibody (MCDS4409A) and a potent 
anti-mitotic agent, mono-methyl auristatin E (MMAE), linked through a protease-labile 
linker, maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl.
The CD79b is a cell-surface antigen with restricted expression on mature B cells, with 
the exception of plasma cells.  It is expressed in a majority of B-cell-derived 
malignancies, including nearly all B-cell lymphoma and CLL samples tested (Dornan 
et al. 2009).  Antibodies bound to CD79b are rapidly internalized, which makes CD79b 
ideally suited for targeted delivery of cytotoxic agents (Polson et al. 2007; Polson et al. 
2009).
The MMAE has a mode of action that is similar to that of vincristine, which is a 
component of standard chemotherapy (e.g., R-CHOP used for treatment of lymphoma).  
Following binding at the cell-surface epitope and internalization of the ADC by the 
targeted cell, MMAE is released following cleavage of the linker by lysosomal enzymes.  
The MMAE then binds to tubulin and inhibits microtubule polymerization, resulting in 
inhibition of cell division and cell growth (Doronina et al. 2003).  This therapeutic 
approach takes advantage of the specific targeting capability of the antibody, the 
cytotoxic activity of MMAE, and the increased potency of MMAE compared with 
vincristine.
Polatuzumab vedotin is being investigated as a potential treatment against hematologic 
malignancies in humans.
1.4.1
Nonclinical Studies with Polatuzumab Vedotin
Comprehensive pharmacologic, pharmacokinetic, pharmacodynamic, and toxicology 
studies were conducted to support the entry of polatuzumab vedotin into clinical trials.  
Because polatuzumab vedotin specifically recognizes CD79b on B cells of humansbut 
not on those of cynomolgus monkeys, rats, or micea surrogate ADC (DCDS5017A) 
that binds to cynomolgus monkey CD79b was generated to assess the antigen-
dependent activities in cynomolgus monkeys.  The structure, binding epitope, and 
binding affinity of the surrogate ADC are similar to that of polatuzumab vedotin.  
Polatuzumab vedotin displayed potent and selective inhibition of tumor cell proliferation 


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in vitro.  Polatuzumab vedotin demonstrated activity in nonclinical murine xenograft 
models of human CD79b-positive B-cell lymphoma.  Additionally, when combined with 
rituximabchemotherapy (i.e., cyclophosphamide, doxorubicin, and prednisone [CHP] or 
bendamustine), polatuzumab vedotin demonstrated superior anti-tumor activity in 
xenograft models of B-cell lymphoma when compared with polatuzumab vedotin as a 
single agent or in combination with standard immunochemotherapy (Dornan et al. 2009).  
The pharmacokinetics and safety of polatuzumab vedotin and the surrogate ADC were 
characterized in repeat-dose toxicity studies in rats and cynomolgus monkeys.  
Polatuzumab vedotin and the surrogate ADC were well tolerated in both species at the 
tested doses.  In both monkeys and rats, the predominant antigen-independent findings 
associated with exposure to polatuzumab vedotin or the surrogate ADC were reversible 
bone marrow toxicity and associated peripheral blood cell effects, likely related to the 
pharmacologic activity of MMAE.  The PK profiles of polatuzumab vedotin and the 
surrogate ADC suggested that the pharmacokinetics of the ADC were driven mainly by 
the antibody component (similar serum concentrationtime profile between the ADC and 
total monoclonal antibody).
Refer to the Polatuzumab Vedotin Investigator’s Brochure for complete details of the 
biochemical composition and nonclinical studies.
1.4.2
Clinical Studies with Polatuzumab Vedotin
Clinical data on polatuzumab vedotin are available from one completed Phase I/Ib study 
(DCS4968g), and the ongoing Phase Ib/II studies GO27834, GO29044 and GO29365 in 
patients with B-cell lymphoma.
Available safety and efficacy data from these studies are summarized in Sections 1.4.2.1
and 1.4.2.3, respectively.  Preliminary safety data from 39 patients receiving 
polatuzumab vedotin in combination with obinutuzumab in Study GO27834; from 
21 patients receiving polatuzumab vedotin in combination with rituximabbendamustine 
and 28 patients receiving polatuzumab vedotin in combination with 
obinutuzumabbendamustine in an ongoing Phase Ib/II study (GO29365); and from
39 patients receiving polatuzumab vedotin in combination with rituximabCHP and 
14 patients receiving polatuzumab vedotin in combination with obinutuzumabCHP in 
the ongoing Phase Ib/II study (GO29044) are summarized in Section 1.5.4.3.  Limited 
safety data from 7 patients receiving single-agent polatuzumab vedotin in an ongoing 
Phase I study (JO29138) are provided in the polatuzumab vedotin Investigator's 
Brochure.
Refer to the Polatuzumab Vedotin Investigator’s Brochure for more details on clinical 
information, including clinical pharmacology data.
1.4.2.1
Clinical Safety of Polatuzumab Vedotin
Clinical safety data are provided for 280 patients with B-cell lymphoma or CLL who 
received polatuzumab vedotin as a single agent (Study DCS4968g), in combination with 


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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rituximab (Studies DCS4968g and GO27834), in combination with rituximabCHP 
(Study GO29044), or in combination with rituximabbendamustine (Study GO29365).
In Study DCS4968g, Grade 3 adverse events were reported in 50 of 68 patients (74%) 
with B-cell lymphoma (indolent B-cell lymphoma, DLBCL, and mantle cell lymphoma 
[MCL]) who received single-agent polatuzumab vedotin; the most common events 
(10% of patients) were neutropenia (38%) and anemia (9%).  Grade 3 adverse 
events were reported in 13 of 18 patients (72%) with CLL who received single-agent 
polatuzumab vedotin; the most common events (10% of patients) were neutropenia 
(17%) and diarrhea, anemia, hyponatremia, febrile neutropenia, and fatigue (11%).  
The SAEs were reported in 35 of 86 patients.  The most frequently reported SAEs
among the 95 patients treated with polatuzumab vedotin alone (n86) or in combination 
with rituximab (n9) were febrile neutropenia, pyrexia, and lung infection (4% each), 
followed by diarrhea and peripheral sensory neuropathy (3% each).
The overall safety profile of polatuzumab vedotin in combination with rituximab was 
similar to that of single-agent polatuzumab vedotin.  In Study DCS4968g, Grade 3 
adverse events were reported in 7 of 9 patients (78%) with B-cell lymphoma; the most 
common events (2 or more patients) were neutropenia (5 patients) and anemia and 
febrile neutropenia (2 patients each).  The SAE were reported in 5 of 9 patients (56%).  
In Study GO27834, Grade 3 adverse events were reported in 51 of 79 patients (65%) 
with B-cell lymphoma; the most common events (5% of patients) were neutropenia 
(24%), diarrhea (8%), febrile neutropenia (5%), and dyspnea (5%).  The SAEs were 
reported in 28 of 79 patients (35%), with febrile neutropenia being the most frequently 
reported (6%).
In Study GO29365, Grade 3 adverse events were reported in 11 of 21 patients (52%) 
with B-cell lymphoma who received polatuzumab vedotin in combination with rituximab 
plus bendamustine. The most frequent events (10% of patients) were nausea (43%), 
diarrhea (38%) and fatigue (43%).
In Study GO29044, Grade 3 adverse events were reported in 18 of 39 patients (46%) 
with B-cell lymphoma who received polatuzumab vedotin in combination with 
rituximabplus CHP. The most frequent events (10% of patients) were fatigue 39, 
nausea (36%), and diarrhea (33%).
A total of 38 deaths have been reported:  11 deaths in patients treated with single-agent 
polatuzumab vedotin and 27 in patients treated with polatuzumab vedotin combined with 
rituximab.  The majority of deaths were judged as related to disease progression, and 
none of the deaths were judged as related to polatuzumab vedotin.
1.4.2.2
Clinical Pharmacokinetics of Polatuzumab Vedotin
The pharmacokinetics of antibody-conjugated MMAE (acMMAE), total antibody (TAb), 
and unconjugated MMAE appear to be dose-proportional across the dose range of 


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0.12.4 mg/kg of polatuzumab vedotin.  At the 2.4 mg/kg dose, mean half-life values 
ranged from 5.26.3 days for acMMAE and from 6.28.1 days for TAb.  Mean CL values 
ranged from 16.223.8 mL/day/kg for acMMAE and from 11.4 to 28.0 mL/day/kg for TAb, 
which suggests that the disposition of acMMAE, as characterized by a small 
steady-state volume of distribution and slow clearance, is largely dominated by its 
antibody component.  Across doses tested (0.12.4 mg/kg), the exposure of acMMAE 
was higher than that of unconjugated MMAE, with acMMAE having 100- to 150-fold 
higher Cmax values and 50-fold higher AUCinf values.  MMAE peak concentrations were 
reached 23 days after dosing.  The mean half-life for unconjugated MMAE was 
2.96.4 days, which is similar to the corresponding value for acMMAE and suggestive of 
formation ratelimited kinetics of unconjugated MMAE due to the ADC catabolism.  
Combination with the anti-CD20 antibody rituximab does not appear to affect the 
pharmaockinetics of acMMAE, TAb, or unconjugated MMAE in the relapsed or refractory 
B-cell lymphoma patient population.
1.4.2.3
Clinical Activity of Polatuzumab Vedotin
Clinical activity data are provided below for patients receiving polatuzumab vedotin as a 
single agent in Study DCS4968g and in combination with rituximab in studies DCS4968g 
and GO27834.  In both studies, patients received treatment Q3W until progression or 
unacceptable toxicity, for up to 1 year.
Polatuzumab vedotin demonstrated clinical activity when given as a single agent to 
patients with relapsed or refractory disease in Study DCS4968g.  At the highest dose of 
2.4 mg/kg, objective responses (CR or PR) were observed in 7 of 16 (44%) patients with 
indolent B-cell lymphoma and 14 of 27 (52%) patients with DLBCL.  At a dose of 
1.8 mg/kg, a PR was observed in 2 of 4 patients with DLBCL and in 2 of 2 patients with 
MCL, and no objective responses were observed in the 5 patients with CLL.  At the data 
cutoff date, the median duration of response was 6.2 months (95% CI: 3.3, 19.3 months) 
for the 2.4 mg/kg dose and 6.6 months (95% CI: 2.3, 11.4 months) for the 1.8 mg/kg 
dose.  At the 2.4 mg/kg dose, median PFS was 7.9 months (95% CI: 3.0, 11.6 months) 
for patients with indolent B-cell lymphoma and 5.0 months (95% CI: 2.3, 6.8 months) for 
patients with DLBCL.  Median PFS was 4.6 months (95% CI: 1.4, 13.9 months) for 
patients with DLBCL treated at the 1.8 mg/kg dose.
Polatuzumab vedotin also demonstrated clinical activity when administered in 
combination with rituximab in patients with relapsed or refractory indolent or aggressive 
B-cell lymphoma (Study DCS4968g); in combination with rituximab and bendamustine in 
patients with relapsed or refractory FL or DLBCL (Study GO29365); and in combination 
with and CHP in patients with relapsed or refractory B-cell lymphoma or previously 
untreated DLBCL (Study GO29044). Preliminary results from these studies are 
presented in Section 1.5.4.3.


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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1.5
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Despite significant therapeutic progress with the addition of rituximab to chemotherapy 
for first-line treatment of patients with B-cell NHL, FL and DLBCL remain an area of high 
medical need in which novel targeted therapies are required to improve patient outcome 
(see Section 1.1).  Patients ultimately relapse, and subsequent active and well-tolerated 
therapies are needed.  Emerging evidence of the activity of new drugs that target 
tumor-associated cell-surface antigens (e.g., monoclonal antibodies), tumor 
microenvironment, and checkpoint inhibitors that target the PD-1/PD-L1 axis opens the 
way to more targeted treatment approaches as a new treatment paradigm.  This study 
will evaluate the activity of a novel triplet combination of obinutuzumab or rituximab plus 
atezolizumab, and polatuzumab vedotin.
1.5.1
Rationale for Protocol BO29561, Version 7
On 1 March 2018, the Sponsor communicated in a Dear Investigator Letter the decision 
to stop enrollment and to discontinue atezolizumab treatment in all patients still receiving 
study treatment, due to a safety signal observed in Study BO29561.
The safety signal observed was the concomitant occurrence of severe and
difficult-to-treat dermatitis, oral mucositis, and ocular events, refractory to standard 
treatment with corticosteroids, in 2 patients with relapsed/refractory (RR) FL treated with 
obinutuzumab (G), atezolizumab (Atezo), and polatuzumab vedotin (Pola).
This constellation of concurrent severe events is not consistent with the safety profile of 
the individual study drugs, neither with safety observations from ongoing studies with
atezolizumabobinutuzumab nor from studies with 
obinutuzumab/rituximabpolatuzumab vedotin. Hence, this unique T-cell,
immune-mediated toxicity was assessed as specifically related to the triplet combination 
of atezolizumabpolatuzumab vedotinobinutuzumab. Atezolizumab was discontinued 
in all patients still receiving study treatment due to the perceived contribution to the 
clinical findings, through its mode of action.
A review of the overall safety data in patients with RR DLBCL treated with 
atezolizumabrituximabpolatuzumab vedotin did not reveal any new safety signals, 
and no immune-mediated adverse events were reported.  However, based on the 
available preliminary safety and efficacy data both in the RR FL and RR DLBCL cohorts, 
the Sponsor assesses the benefit-risk of atezolizumabobinutuzumabpolatuzumab 
vedotin in patients with RR FL and of atezolizumabrituximabpolatuzumab vedotin in 
patients with RR DLBCL to be uncompelling. 
The benefit-risk of obinutuzumabpolatuzumab vedotin and rituximabpolatuzumab 
vedotin combinations, without atezolizumab,remains unchanged, with no new safety 
signals derived from ongoing studies (see Section 1.5.4.3 and the Polatuzumab 
Investigator’s Brochure).


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1.5.2
PD-L1/PD-1 Pathway in Lymphoma
The PD-L1/PD-1 pathway serves as an immune checkpoint to temporarily dampen 
immune responses in states of chronic antigen stimulation such as chronic infection or 
cancer.  A PD-L1 is an extracellular protein that downregulates immune responses 
through binding to its two receptors, PD-1 and B7-1.  PD-1 is an inhibitory receptor 
expressed on T cells following T-cell activation, and expression is sustained in states of 
chronic stimulation (Blank et al. 2005; Keir et al. 2008).  B7-1 is a molecule expressed 
on antigen-presenting cells and activated T cells.  Binding of PD-L1 to PD-1 and B7-1 
inhibits T-cell proliferation and activation, cytokine production, and cytolytic activity, 
leading to the functional inactivation or exhaustion of T cells (Butte et al. 2007).  
Overexpression of PD-L1 on tumor cells has been reported to impede anti-tumor 
immunity, resulting in immune evasion (Blank and Mackensen 2007).  Therefore, 
interruption of the PD-L1/PD-1 pathway represents an attractive strategy for restoring 
tumor-specific T-cell immunity.
Antibody-mediated PD-1 blockage has already been successfully exploited as a 
therapeutic strategy in solid tumors (Brahmer et al. 2012; Topalian et al. 2012;
Herbst et al. 2013) and is currently being evaluated in hematologic malignancies 
(see Section 1.5.3).  Increased PD-L1 expression has been reported on tumor cells and 
on immune or microenvironment cells in various lymphoid malignancies.  PD-L1 is highly 
expressed in Hodgkin’s lymphomas, anaplastic large-cell lymphoma, and DLBCL, 
particularly the ABC or non-GCB subtypes (Andorsky et al. 2011).  Sponsor internal 
data (unpublished) from patients with previously untreated DLBCL enrolled in 
Study AVF4065g showed 67.5% of patients with lymphoma that is positive for PD-L1 
as assessed by immunohistochemistry (staining 5% of cells), including 23% of patients 
with strong PD-L1 expression (staining in 25% of cells).  In FL, PD-L1 is expressed on 
tumor-infiltrating lymphocytes (TILs), macrophages, peripheral blood T cells, and 
monocytes, but not on tumor cells (Myklebust et al. 2013).
1.5.3
Clinical Experience with PD-L1/PD-1 Pathway Inhibitors in 
Lymphoma
Several PD-1 and PD-L1 inhibitors are currently being investigated in various lymphoma 
malignancies.
Pidilizumab (CT-011), a humanized IgG-1monoclonal antibody that targets PD-1, has 
been tested in Phase I and II clinical studies in hematologic malignancies.  Pidilizumab 
administered as a single agent after autologous SCT in patients with DLBCL 
(Armand et al. 2013) or in combination with rituximab in patients with relapsed FL 
(Westin et al. 2014) was well tolerated and showed potential clinical benefit.  No 
autoimmune- or treatment-related Grade 3 or 4 adverse events have been reported in 
these studies.  Among patients with relapsed FL who received pidilizumab in 
combination with rituximab (n32), responders have been shown to express higher 
levels of PD-L1 on peripheral blood T cells and monocytes at baseline relative to 


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non-responders.  Additionally, in this study, gene expression profile (GEP) analysis 
performed on baseline tumor biopsy specimens from 18 patients showed a correlation 
between PFS and gene expression signature of activated T-cells.  The GEP studies 
identified 41 genes more highly expressed in Teffs compared with follicular helper T cells 
(TFHs).  Low expression of this signature suggests a lower number of Teffs and higher 
number of TFHs within the tumor.  Consistent with the expectation that Teffs are likely to 
have anti-tumor effects, whereas TFHs are likely to have pro-tumor effects, a low 
expression of this signature is predictive of less tumor shrinkage and resulted in a 
shorter PFS in this study, as median PFS was 12.7 months (95% CI: 6.5, 21.6 months) 
for patients with low signature expression and not reached for patients with high 
signature expression (Westin et al. 2014). 
Nivolumab (BMS-936558), a fully human IgG4 monoclonal antibody that targets PD-1, 
was recently evaluated in a Phase I dose-escalation study that tested doses of 1 and 
3 mg/kg in patients with relapsed or refractory lymphoid malignancies.  Preliminary data 
indicate that 1 patient experienced dose-limiting toxicities (DLTs) of Grade 3 pneumonia 
and pneumonitis at the 1 mg/kg dose and 1 patient experienced DLTs of Grade 3 
eosinophilia and diplopia at the 3 mg/kg dose (expansion in progress at this dose; 
Lesokhin et al. 2014).  The objective response rate (ORR) and CR rate in patients with 
B-cell NHL were 28% and 7%, respectively, including an ORR of 36% in patients with 
DLBCL and 40% in patients with FL (Armand et al. 2014; Lesokhin et al. 2014).
Atezolizumab, which is included in the treatment regimen investigated in this study, is a 
first-in-class PD-L1 inhibitor being tested in multiple tumor types (Section 1.3.2).  
Atezolizumab was safely administered to 11 patients with various hematologic 
malignancies (including 7 patients with lymphoma) enrolled in Study PCD4989g.  
Atezolizumab 1200 mg Q3W is currently being evaluated in combination with 
obinutuzumab in an ongoing Phase Ib study (GO29383) in patients with relapsed or 
refractory DLBCL or FL (Section 1.5.4.3).
1.5.4
Rationale for Treatment Combination
Previously, this study included treatment with atezolizumab, obinutuzumab or rituximab, 
and polatuzumab vedotin.  However, following the Dear Investigator Letter issued on 
1 March 2018 due to a safety signal observed in the atezolizumabobinutuzumab
polatuzumab vedotin (GAtezoPola) treatment group (see Section 1.5.1 and 
Section 5.1.6), the study treatment regimen has been changed.  Atezolizumab has been 
discontinued in all patients still receiving study treatment, and thus, previously enrolled 
patients with RR FL will continue to receive obinutuzumab and polatuzumab vedotin, 
and previously enrolled patients with RR DLBCL will continue to receive rituximab and 
polatuzumab vedotin, as applicable.
1.5.4.1
Mechanistic Rationale
Obinutuzumab and atezolizumab, as well as rituximab and atezolizumab, have 
complementary mechanisms of action, acting at different steps of the anti-tumor immune 


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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response.  Both rituximab and obinutuzumab induce tumor-cell killing with subsequent 
release of tumor antigens for immune presentation (immunogenic cell death) and both 
trigger antibody-dependent cellular cytotoxicity (ADCC).  Additionally, obinutuzumab was 
engineered to augment ADCC, resulting in enhanced binding to FcRIIIA/B (CD16a/b).  
Thus, obinutuzumab has a stronger ability to enhance T-cell priming and immune-cell 
activation through interactions with NK cells, T cells, dendritic cells, 
monocytes/macrophages, and neutrophils carrying FcRIIIA or FcRIIIB.  Atezolizumab 
affects primarily the effector phase of the immune response by restoring cytotoxic T-cell 
function.  Polatuzumab vedotin has a targeted cytotoxic effect on B cells, minimizing 
cytotoxic effects on hematologic cells that do not express CD79b therefore preserving 
T-cell function (Dornan et al. 2009; Polson et al. 2009).  The combination of 
obinutuzumab or rituximab plus atezolizumab, and polatuzumab vedotin may provide 
increased clinical benefit through enhanced immunomodulatory effects combined with 
the cytotoxic potential of a targeted immunochemotherapy.
1.5.4.2
Nonclinical Data
Obinutuzumab or Rituximab and Atezolizumab
As presented in Section 1.2.1, nonclinical xenograft experiments consistently 
demonstrated superiority of obinutuzumab over rituximab.
Studies of obinutuzumabatezolizumab and rituximab atezolizumab have not been 
performed in nonclinical murine models because there are no suitable models for testing 
the combination.  However, synergism was exhibited when the combination of a 
surrogate anti-mouse PD-L1 antibody, and an anti-mouse CD20-depleting antibody was 
tested using a syngeneic A20 lymphoma model in immune-competent mice.  Results 
from this study demonstrated superior tumor-growth inhibition and extended time to 
progression when compared with either agent alone.  Combination and single-agent 
treatments were well tolerated, with no significant loss of body weight in any group over 
the study duration.  Enhanced combination efficacy was also observed in a study using 
A20 cells transfected with human CD20 and green fluorescent protein (data available 
upon request).
Although the anti-CD20 agent used in this study is not completely identical to 
obinutuzumab, the results provide compelling proof of concept for exploring this 
combination in clinical trials.
Obinutuzumab or Rituximab and Polatuzumab Vedotin
The anti-tumor activity of either rituximab or obinutuzumab in combination with 
polatuzumab vedotin was evaluated in a disseminated human MCL Z138 xenograft 
model in severe compromised immunodeficient (SCID) beige mice.  Results from this 
study showed significantly increased survival with the combinations compared with each 
respective monotherapy (Roche Research Report 1048504).


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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Superiority of the combinations over rituximab or obinutuzumab alone was also 
demonstrated in a nonclinical study performed in an MCL Z138 xenograft model in SCID 
CD16 transgenic mice.  This study used SCID FcgR3a transgenic mice, which express 
the human FcgR3a receptor on murine NK cells, allowing higher impact of NK-mediated 
ADCC on the efficacy measure.  Both combinations showed significantly increased 
survival compared with each respective monotherapy (Roche Research Report 
1061010).
Atezolizumab and Polatuzumab vedotin
Studies of atezolizumabpolatuzumab vedotin have not been performed in nonclinical 
models because there are no suitable murine models for testing the atezolizumab-based 
combinations.  However, the complementary mechanism of action of the two drugs
(Section 1.5.4.1) supports further investigation in the clinical setting.
1.5.4.3
Clinical Data
Obinutuzumab or Rituximab and Atezolizumab
No studies have been performed evaluating rituximab and atezolizumab to date.
A Phase Ib study of atezolizumab in combination with obinutuzumab in patients with 
relapsed or refractory FL and DLBCL (Study GO29383) is currently in progress.  
Preliminary results indicated that atezolizumab combined with obinutuzumab was well 
tolerated, with evidence of clinical activity in this patient population.  A total of 49 patients 
were enrolled and dosed:  26 patients with FL and 23 patients with DLBCL.  The doublet 
combination appears to be safe and tolerable, and the safety profile is consistent with 
what has been observed with the respective single agents and the diseases under study.  
As of the 14 June 2017 data cutoff, a review of safety data from Study GO29383 in 
patients with FL (n=26) and DLBCL (n=23) did not reveal any new safety signals.  The 
most commonly reported (>20%) treatment-emergent adverse events included the 
following preferred terms:  fatigue, pyrexia, nausea, diarrhea, abdominal pain, cough, 
and decreased appetite.  The most common Grade 34 treatment-related adverse 
events were neutropenia (8%), diarrhea (8%), and pain (8%).  There were no adverse 
events with fatal outcomes reported in patients with FL.  Atezolizumabobinutuzumab 
demonstrated encouraging signs of response in patients heavily pretreated and 
refractory with relapsed/refractory FL.  The ORR at the end of induction assessment 
(Lugano 2014 Response Criteria by positron emission tomography and computed 
tomography [PET-CT]) was 56.5% in the RR FL cohort and 16% in the RR DLBCL 
cohort.  The median duration of response and median PFS at the time of clinical cutoff in 
the RR FL cohort were 15.0 and 15.1 months, respectively (Palomba et al. 2017).


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Rituximab and Polatuzumab Vedotin
Phase Ib/II data suggest that polatuzumab vedotin in combination with rituximab has 
activity in relapsed or refractory FL and DLBCL, with a generally acceptable safety and 
tolerability profile. As presented in Section 1.4.2.1 , the overall safety profile of 
polatuzumab vedotin in combination with rituximab was similar to that of single-agent 
polatuzumab vedotin.
In Study DCS4968g evaluating rituximab in combination with polatuzumab vedotin at a 
dose of 2.4 mg/kg, objective responses were observed in 7 of 9 patients with indolent 
B-cell lymphoma, DLBCL, or MCL (78%); 2 of the 7 patients had CRs.  Median duration 
of response among these patients was 12.3 months (95% CI: 4.3, not estimable [NE]).  
Median PFS was 12.5 months (95% CI: 6.9, 17.4 months).  In Study GO27834, at a 
dose of 2.4 mg/kg, objective responses were observed in 14 of 20 patients with FL 
(70%) and 21 of 39 patients with DLBCL (54%); at a dose of 1.8 mg/kg, objective 
responses were observed in 15 of 20 patients with FL (75%).  Median duration of 
response was 12.9 months (95% CI: 6.7, NE) and 13.2 months (95% CI: 7.2, 21.2) for 
patients who received polatuzumab vedotin 1.8 mg/kg (FL) or 2.4 mg/kg (FL or DLBCL), 
respectively. At the 2.4 mg/kg dose, median PFS was 15.1 months (95% CI: 11.8, NE) 
among the 20 patients with FL and 5.6 months (95% CI: 4.2, 12.7 months) among the 
39 patients with DLBCL.  Among the 20 patients with relapsed or refractory FL treated 
with 1.8 mg/kg polatuzumab vedotin in combination with rituximab median PFS was 
18.1 months (95% CI: 9.9, NE).
Preliminary data are available for two other ongoing Phase Ib/II studies:  one study 
(GO29365) of rituximabpolatuzumab vedotin (1.8 mg/kg)bendamustine in patients 
with relapsed or refractory FL or DLBCL and one study (GO29044) of 
rituximabpolatuzumab vedotin (1.4 or 1.8 mg/kg)CHP in patients with relapsed or 
refractory B-cell lymphoma or previously untreated DLBCL.
In Study GO29365, as of 28 January 2016, safety data were available from 21 patients 
enrolled in the Phase Ib safety run-in or Phase II portions of the study, who received 
polatuzumab vedotin (1.8 mg/kg) in combination with bendamustinerituximab.  In the 
1.8 mg/kg PoVBR group, 11 of 21 patients (52%) experienced Grade 34 events, most 
common being neutropenia.  The SAEs have been reported in 7 of 21 patients (33%).  
No Grade 5 adverse events have been reported.  One patient discontinued treatment 
due to an adverse event. Peripheral neuropathy has been reported in 4 of 21 patients 
(19%).  In patients with DLBCL, the only Grade 34 adverse event reported in 2 or more 
patients was lymphocyte count decreased (2 patients) while in patients with FL, 
Grade 34 adverse events reported in 2 or more patients were neutropenia (2 patients) 
and diarrhea (2 patients).  In the efficacy evaluable population, objective responses were 
observed in 7 of 7 patients with FL (100%) and 3 of 7 patients with DLBCL (43%).
In Study GO29044, as of 5 February 2016, data are available from 13 patients with 
relapsed or refractory NHL enrolled in dose-escalation cohorts 1.0 mg/kg (n3), 


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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1.4 mg/kg (n3), and 1.8 mg/kg (n7) and from 26 patients enrolled in the 
dose-expansion phase of the study who received polatuzumab vedotin (1.8 mg/kg) in 
combination with R-CHP who received polatuzumab vedotin in combination with R-CHP.  
In the 1.8 mg/kg PoVR-CHP group, 15 of 32 of patients (47%) experienced Grade 34 
events, most common being neutropenia.  The SAEs have been reported in 11 of 
32 patients (34%).  No Grade 5 adverse events have been reported.  Two patients 
discontinued treatment because of adverse events. Peripheral neuropathy has been 
reported in 9 of 32 patients (28%).  Across all the three dose cohorts, the most 
frequently reported Grade 34 adverse events were neutropenia (23%), febrile 
neutropenia (13%), thrombocytopenia (5%), pneumonia (5%), and hypertension (5%).  
In the efficacy evaluable population, objective responses were observed in 29 of 
31 patients (94%).
Obinutuzumab and Polatuzumab Vedotin
Several ongoing Phase Ib/II studies are assessing the safety and clinical activity of 
obinutuzumabpolatuzumab vedotin with or without chemotherapy.
Preliminary safety data are available from an ongoing Phase II study (GO27834) of 
obinutuzumab in combination with polatuzumab vedotin (1.8 mg/kg) in patients with 
relapsed or refractory FL or DLBCL.  As of 15 April 2016, 65 patients with either 
relapsed or refractory follicular lymphoma (N30) or relapsed or refractory diffuse-large 
B-cell lymphoma (N35) have been enrolled, 64 of whom have received at least one 
dose of polatuzumab vedotin (1.8 mg/kg) in combination with obinutuzumab.  Of the 
65 patients, 82% patients experienced at least one adverse event; 26% of patients have 
experienced SAEs, most common being infections; 39% of patients experienced 
Grade 34 events, most common being neutropenia.  There was one Grade 5 adverse 
event of disease progression. Four patients discontinued treatment because of adverse 
events, 3 of which were unrelated adverse events. Peripheral neuropathy has been 
reported in 11 of 64 patients (27.5%).  Adverse events occurring in 10% of patients 
were fatigue, diarrhea, nausea, chills, constipation, dyspnea, headache, decreased 
appetite, dizziness, pyrexia, asthenia, and vomiting.  In the efficacy evaluable 
population, at a dose of 1.8 mg/kg, objective responses were observed in 8 of 
12 patients with FL (67%) and 3 of 15 patients with DLBCL (20%).  As of the data cutoff 
date, median duration of response had not been reached, and PFS data were immature, 
with median PFS point estimates of 8.3 and 1.9 months in patients with relapsed or 
refractory FL and DLBCL, respectively.
Preliminary data are also available for two of the ongoing Phase Ib/II studies:  one study 
(GO29365) of obinutuzumabpolatuzumab vedotin (1.8 mg/kg)bendamustine in 
patients with relapsed or refractory FL or DLBCL and one study (GO29044) of 
obinutuzumabpolatuzumab vedotin (1.4 or 1.8 mg/kg)CHP in patients with relapsed 
or refractory B-cell lymphoma or previously untreated DLBCL.  Refer to Polatuzumab 
Vedotin Investigator Brochure for preliminary safety and clinical activity from these 
studies.


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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1.5.5
Benefit-Risk Assessment 
In summary, this study combines treatments with different mechanisms of action that 
have demonstrated clinical activity against B-cell lymphoma.  Currently available data for 
obinutuzumab or rituximab in combination with either atezolizumab or polatuzumab 
vedotin support and provide the rationale for a potentially improved benefit-risk ratio in 
patients with FL or DLBCL and further support the clinical development of the triple 
combination.  Overlapping toxicities are anticipated and will be closely monitored and 
managed in the clinical trial setting with adverse event management guidance and 
periodic safety data review.  Additionally, drug-drug interactions (DDIs) are unlikely to 
occur (see Section 5.1.5).
Following the Dear Investigator Letter issued on 1 March 2018 due to a safety signal 
observed in the GAtezoPola treatment group (see Section 1.5.1 and Section 5.1.6)
and evaluation of preliminary safety and efficacy data from the two study treatment 
groups, the Sponsor assesses the benefit-risk of atezolizumabobinutuzumab
polatuzumab vedotin in patients with RR FL and of atezolizumabrituximab
polatuzumab vedotin in patients with RR DLBCL to be uncompelling (see Section 1.5.1).  
Due to the perceived role of atezolizumab in the T-cell mediated events, the Sponsor 
decided to discontinue atezolizumab in all patients still receiving study treatment, but 
allow patients deriving benefit to continue study treatment without atezolizumab.  The
benefit-risk of obinutuzumabpolatuzumab vedotin and rituximabpolatuzumab vedotin 
combinations, without atezolizumab, remains unchanged, with no new safety signals 
derived from ongoing studies (see Section 1.5.4.3 and the Polatuzumab Investigator’s 
Brochure).
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the safety, efficacy, pharmacokinetics, and immunogenicity of 
induction treatment consisting of obinutuzumab in combination with atezolizumab plus 
polatuzumab vedotin (GAtezoPola) in patients with relapsed or refractory FL and 
rituximab in combination with atezolizumabpolatuzumab vedotin (RAtezoPola) in 
patients with relapsed or refractory DLBCL, followed by post-induction treatment with 
GAtezo (referred to as maintenance) in patients with FL who achieve a CR, a PR, or 
stable disease at EOI and post-induction treatment with RAtezo (referred to as 
consolidation) in patients with DLBCL who achieve a CR or PR at EOI (see Section 3.1
for details).  Specific objectives and corresponding endpoints for the study are outlined 
below, in accordance to study changes from Protocol BO29561, Version 7.
In this study, "study treatment" refers to the combination of all study treatment 
components.


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2.1
SAFETY OBJECTIVE
The safety objectives for this study are as follows:

To determine the recommended Phase II dose (RP2D) for polatuzumab vedotin 
when given in combination with fixed doses of obinutuzumab and atezolizumab on 
the basis of the following endpoint:
Incidence of DLTs during Cycles 1 and 2 of study treatment:

To evaluate the safety and tolerability of the GAtezoPola treatment group and 
the RAtezoPola treatment group on the basis of the following endpoints:
Nature, frequency, severity, and timing of adverse events
Changes in clinical laboratory results during and following study treatment 
administration
2.2
EFFICACY OBJECTIVES
Response will be determined through use of the PET-CT scans or CT scans alone, 
using Revised Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014; 
see Appendix 5), hereinafter referred to as modified Lugano 2014 criteria.  Response will 
be determined by the investigator.
2.2.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of induction 
treatment with GAtezoPola in relapsed or refractory FL and RAtezoPola in 
relapsed or refractory DLBCL on the basis of the following endpoint:

CR at EOI, as determined by the investigator on the basis of PET-CT scans
2.2.2
Secondary Efficacy Objectives
The secondary efficacy objective for this study is to evaluate the efficacy of induction 
treatment with GAtezoPola and maintenance treatment with GAtezo in relapsed or 
refractory FL and of induction treatment with RAtezoPola and consolidation 
treatment with RAtezo in relapsed or refractory DLBCL on the basis of the following 
endpoints:

CR at EOI, as determined by the investigator on the basis of CT scans alone

Objective response (defined as a CR or PR) at EOI, as determined by the 
investigator on the basis of PET-CT scans

Objective response (defined as a CR or PR) at EOI, as determined by the 
investigator on the basis of CT scans alone

Best response of CR or PR during the study, as determined by the investigator on 
the basis of CT scans alone


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2.2.3
Exploratory Efficacy Objectives
The exploratory efficacy objective for this study is to evaluate the long-term efficacy of 
GAtezoPola on the basis of the following endpoints:

For patients who have positive PET scans at EOI:
CR at 12 months, as determined by the investigator on the basis of PET-CT 
scans in FL patients

Overall survival (OS), defined as the time from initiation of study treatment to death 
from any cause
2.3
PHARMACOKINETIC OBJECTIVE
The PK objective for this study is to characterize the pharmacokinetics of obinutuzumab, 
rituximab, atezolizumab, and polatuzumab vedotin when given in combination, on the 
basis of the following endpoints:

Observed serum obinutuzumab concentration at specified timepoints

Observed serum rituximab concentration at specified timepoints

Observed serum atezolizumab concentration at specified timepoints

Observed serum and plasma concentrations of polatuzumab vedotin and relevant 
analytes (total antibody, acMMAE, and unconjugated MMAE) at specified timepoints
2.4
IMMUNOGENICITY OBJECTIVES
The immunogenicity objective for this study is to evaluate the immune response to 
obinutuzumab, rituximab, atezolizumab, and polatuzumab vedotin on the basis of the 
following endpoints:

Incidence of human anti-human antibodies (HAHAs) to obinutuzumab during the 
study relative to the prevalence of HAHAs at baseline

Incidence of human anti-chimeric antibodies (HACAs) to rituximab during the study 
relative to the prevalence of HACAs at baseline

Incidence of ATAs to atezolizumab during the study relative to the prevalence of 
ATAs at baseline

Incidence of ATAs to polatuzumab vedotin during the study relative to the 
prevalence of ATAs at baseline
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
HAHAs, HACAs or ATAs on the basis of the following endpoint:

Correlation between HAHA, HACA or ATA status and efficacy, safety, or PK 
endpoints
2.5
BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to identify non-inherited biomarkers 
that are predictive of response to study treatment (i.e., predictive biomarkers), are 
associated with progression to a more severe disease state (i.e., prognostic biomarkers), 


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are associated with acquired resistance to study treatment, are associated with 
susceptibility to developing adverse events, can provide evidence of study treatment 
activity, can increase the knowledge and understanding of lymphoma biology or study 
treatment mechanism of action, or can contribute to improvement of diagnostic assays, 
on the basis of the following endpoint:

Association between non-inherited biomarkers (listed in Section 4.5.7) and efficacy, 
safety, pharmacokinetic, or immunogenicity endpoints
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study
This Phase Ib/II, open-label, multicenter, non-randomized, dose-escalation study will 
evaluate the safety, efficacy, pharmacokinetics, and immunogenicity of GAtezoPola 
in patients with RR FL and RAtezoPola in patients with RR DLBCL.
Following the Dear Investigator Letter issued on 1 March 2018, enrollment has been 
stopped and atezolizumab treatment has been discontinued in all patients still receiving 
study treatment. Protocol BO29561, Version 7 formalizes these changes to the study.
A study schema is provided in Figure 1.
Overall, it was planned to have 8392 patients enrolled in this study, at approximately 
20 investigative sites around the world.  As of 1 March 2018, 13 patients with RR FL and 
23 patients with RR DLBCL were enrolled in the study.
To characterize the PK properties of obinutuzumab, rituximab, atezolizumab, and 
polatuzumab vedotin as well as the immunogenicity of obinutuzumab, rituximab, 
atezolizumab, and polatuzumab vedotin when given in combination, blood samples will 
be taken at various timepoints before and during dosing (Appendix 2).
During induction treatment, all patients will have a CT scan performed at the end of 
Cycle 2, to confirm absence of early disease progression.  Because of the potential for 
tumor flares with immunotherapies, which result in early apparent radiographic 
progression (pseudoprogression/tumor immune infiltration), including the appearance of 
new lesions followed by delayed response (Wolchok et al. 2009), patients whose 
CT scans meet criteria for disease progression at the end of Cycle 2 may continue to 
receive study treatment, at the discretion of the investigator and following discussion 
with the Medical Monitor, if at least two of the following criteria are met:

Absence of symptoms and signs that indicate unequivocal disease progression

No decline in Eastern Cooperative Oncology Group (ECOG) Performance Status

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions


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
Patients with radiographic evidence of progression at the end of Cycle 2 who 
continue to receive study treatment per the above criteria should have a CT scan 
repeated 48 weeks later.
3.1.2
GAtezoPola Treatment Group (Patients with Follicular 
Lymphoma)
3.1.2.1
Dose-Escalation Phase
The purpose of the dose-escalation phase was to identify the RP2D for polatuzumab 
vedotin when combined with fixed doses of obinutuzumab and atezolizumab as 
induction treatment.  A total of 9 patients with RR FL were enrolled in the 
dose-escalation phase (3 patients in the Pola 1.4-mg dose cohort and 6 patients in the 
Pola 1.8-mg dose cohort) and treated in accordance with the treatment regimens and 
the dose-escalation rules described in Section 3.1.2.1.2. 
No DLTs were observed at either the Pola 1.4-mg or 1.8-mg Pola dose levels. 
Therefore, Pola 1.8 mg was selected as the RP2D, and enrollment in the expansion 
phase of the study proceeded.
3.1.2.1.1
Definition of Dose-Limiting Toxicity
In this study, a DLT is defined as any one of the following events occurring during 
Cycles 1 and 2 of treatment and assessed by the investigator as related to study 
treatment:

Adverse event of any grade that leads to a delay of more than 14 days the start of 
the next treatment cycle 

Hematologic adverse event that meets any of the following criteria:
Grade 3 or 4 neutropenia in the presence of sustained fever of 38C (lasting 
5 days) or a documented infection
Grade 4 neutropenia lasting 7 days
Grade 3 or 4 thrombocytopenia that results in significant bleeding per 
investigator judgment
Grade 4 thrombocytopenia lasting 7 days

Grade 3 or 4 non-hematologic adverse event, with the following exceptions:
Grade 3 or 4 IRRs
Note that IRRs may occur even after a small amount of drug has been 
administered (i.e., IRRs are not dose dependent).
Grade 3 diarrhea that responds to therapy within 72 hours
Grade 3 nausea or vomiting that occurs in the absence of premedication and 
responds to adequate therapy within 72 hours
Grade 3 fatigue that resolves to Grade 2 within 7 days
Grade 3 laboratory abnormality that is asymptomatic and deemed by the 
investigator not to be clinically significant


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Other toxicities occurring during Cycles 1 and 2 that are considered to be clinically 
relevant and related to study treatment, as determined by the investigator and the 
Medical Monitor may also be considered DLTs.
3.1.2.1.2
Treatment Regimens and Dose-Escalation Rules
A 33 dose-escalation schema was used.  Induction treatment was administered in 
21-day cycles, as outlined in Table 1.  Obinutuzumab and atezolizumab will remain at 
fixed doses during the dose-escalation phase.  For polatuzumab vedotin, there are two 
possible dose levels:  1.4 or 1.8 mg/kg.  If the starting dose of 1.4 mg/kg is safe and 
tolerable, the polatuzumab vedotin dose will be escalated to 1.8 mg/kg.  Intrapatient 
dose escalation is not allowed.
Table 1
Induction Treatment for Dose-Escalation Phase
Cycle
G Atezo Pola (21-Day Cycles)
1
Obinutuzumab 1000 mg IV on Days 1, 8, and 15
Polatuzumab vedotin 1.4 mg/kg or 1.8 mg/kg IV on Day 1
26
Obinutuzumab 1000 mg IV on Day 1
Atezolizumab 1200 mg IV on Day 1 
Polatuzumab vedotin 1.4 mg/kg or 1.8 mg/kg IV on Day 1
IVintravenous.
Dose escalation occurred in accordance with the rules listed below:
First Dosing Group (Polatuzumab Vedotin 1.4 mg/kg)

A minimum of 3 patients will initially be sequentially enrolled in the first dosing group 
(polatuzumab vedotin 1.4 mg/kg).  The 3 patients will be enrolled at least 24 hours 
apart.

If none of the first 3 DLT-evaluable patients experiences a DLT, enrollment of the 
second dosing group (i.e., polatuzumab vedotin 1.8 mg/kg) may proceed.

If 1 of the first 3 DLT-evaluable patients experiences a DLT, the dosing group will be 
expanded to at least 6 patients.  If there are no further DLTs in the first 
6 DLT-evaluable patients, enrollment of the second dosing group may proceed.

If 2 or more of the first 36 DLT-evaluable patients experience a DLT, the RP2D will 
have been exceeded, and dose escalation will stop and study will be discontinued.
Second Dosing Group (Polatuzumab Vedotin 1.8 mg/kg)

A minimum of 3 patients will initially be enrolled sequentially in the second dosing 
group (polatuzumab vedotin 1.8 mg/kg).  The 3 patients will be enrolled at least 
24 hours apart.

If none or 1 of the first 3 DLT-evaluable patients experiences a DLT, the dosing 
group will be expanded to at least 6 patients.  If there are no further DLTs, 
1.8 mg/kg will be declared the RP2D for polatuzumab vedotin.


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
If 2 or more of the first 36 DLT-evaluable patients experience a DLT, the RP2D will 
have been exceeded, and 1.4 mg/kg will be declared the RP2D for polatuzumab 
vedotin.
The highest dose at which fewer than 2 of 6 patients DLT-evaluable patients (i.e., 33%) 
experience a DLT was declared the RP2D for polatuzumab vedotin that will be used in 
the expansion phase.
On the basis of a review of real-time safety data and available preliminary PK data, dose 
escalation may be halted or modified by the Sponsor as deemed appropriate.
Relevant demographic, adverse event, laboratory, and PK (if available) data will be 
reviewed prior to dose-escalation decisions, by the Medical Monitor in consultation with 
the Principal Investigator and participating investigators.
Although the DLT assessment window is defined as Cycles 1 and 2, cumulative toxicities 
occurring beyond Cycle 2 may be considered when determining the RP2D.
Patients enrolled in the dose-escalation phase that achieved a CR, a PR, or stable 
disease at EOI received maintenance treatment with GAtezo.
As of 1 March 2018, patients with RR FL eligible to or already receiving maintenance 
treatment will continue to receive obinutuzumab maintenance treatment, as outlined 
in Table 2.  Maintenance treatment should start 8 weeks (1 week) after Day 1 of 
Cycle 6 and will continue until disease progression or unacceptable toxicity for up to 
24 months.
Table 2
Maintenance Treatment for the GAtezoPola Treatment Group
Patients
Treatment
Patients with FL
Maintenance treatment consisting of the following, administered for 
24 months a (from Month 1Month 24):
Obinutuzumab 1000 mg IV on Day 1 of every other month 
(i.e., every 2 months), starting with Month 1
FLfollicular lymphoma; IVintravenous.
a 1 month28 days.


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3.1.2.2
Expansion Phase
The expansion phase was designed to further assess the safety and efficacy of the 
combination of atezolizumab with obinutuzumab plus polatuzumab vedotin, when given 
as induction treatment and atezolizumab with obinutuzumab as maintenance treatment 
in patients with FL.
During the expansion phase, 3437 patients with FL (for a total of 40 patients with FL 
treated at the RP2D in the dose-escalation and expansion phases) were planned to be 
enrolled.  As of 1 March 2018, patients with RR FL will continue to be treated as outlined 
in Table 3.
Table 3
Induction Treatment for Expansion Phase
Cycle
GAtezoPola (21-Day Cycles) Treatment Group
16
Obinutuzumab 1000 mg IV on Days 1, 8, and 15
Polatuzumab vedotin at 1.8 mg/kg IV on Day 1
IVintravenous.
Patients with FL who achieve a CR, a PR, or stable disease at EOI will receive 
maintenance treatment with obinutuzumab, as outlined in Table 2.  Maintenance 
treatment should start 8 weeks (1 week) after Day 1 of Cycle 6 and will continue until 
disease progression or unacceptable toxicity for up to 24 months.  Polatuzumab vedotin 
will not be given as a post-induction treatment.
3.1.3
RAtezoPola Treatment Group (Patients with Diffuse Large 
B-Cell Lymphoma)
Study enrollment took place in two phases:  an initial safety run-in phase followed by an 
expansion phase.
A total of 7 patients with RR DLBCL were enrolled into the safety run-in phase at the 
Pola 1.8-mg dose level, and treated in accordance with the treatment regimens and the 
dose-escalation rules described in Section 3.1.3.1.  No DLTs were observed, and Pola 
1.8 mg was selected as the RP2D, and enrollment in the expansion phase of the study 
proceeded.
3.1.3.1
Treatment Regimens and Safety Run-In Rules
Patients with DLBCL enrolled in the safety run-in phase and the expansion phase were 
planned to receive induction treatment with RAtezoPola for a total of 6 cycles.  
Patients achieving a CR or PR at EOI were eligible to receive consolidation treatment 
with RAtezo. 
As of 1 March 2018, patients with RR DLBCL will continue to be treated as outlined in 
Table 4.  As of Protocol BO29561, Version 7, patients who have completed or 
prematurely discontinued induction treatment will proceed to the safety follow-up without 
consolidation treatment.


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Table 4
Induction Treatment for Patients with Diffuse Large B-cell 
Lymphoma
Cycle
RAtezo Pola (21-Day Cycles) Treatment Group
16
Rituximab 375 mg/m2 IV on Day 1
Polatuzumab vedotin 1.8 mg/kg IV on Day 1
IVintravenous.
Figure 1
Study Schema
Ccycle; CRcomplete response; D day; D1C6Day 1 of Cycle 6; EOIend of induction; 
FLfollicular lymphoma; G obinutuzumab; Mmonth; Polapolatuzumab vedotin; PRpartial 
response; Rrituximab; q2m every 2 months; SDstable disease.
3.1.4
Internal Monitoring Committee
An IMC will monitor patient safety throughout the study.  The IMC will include Sponsor 
representatives from Clinical Science, Drug Safety, Biostatistics, and Statistical
Programming and Analysis.  In addition to the ongoing assessment of the incidence and 
nature of adverse events (particularly Grade 3 events), SAEs, deaths, and laboratory 
abnormalities performed by the investigator and the Medical Monitor, the IMC will review 
data supporting the determination of the RP2D and then, at regular intervals during the 
expansion phase.  At the time of each review, the IMC will make appropriate 


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recommendations (e.g., the study should continue as planned, additional analyses 
should be performed, enrollment should be held pending further safety evaluations).  
Decisions will be made in consideration of the totality of the available data. Ad hoc 
meetings may be called in addition to scheduled meetings, as necessary, to provide 
recommendations on management of any potential new safety signals.  Following 
protocol amendment Version 7, patients are no longer receiving atezolizumab or
polatuzumab.  Therefore, regular IMC assessments will no longer take place.  Ad hoc 
meetings to review safety data maybe called at the discretion of the Medical Monitor in 
case of newly identified safety signals.  Specific operational details such as the 
committee’s composition, frequency and timing of meetings, members' roles and 
responsibilities, and data to be reviewed will be detailed in an IMC charter.
3.1.5
Safety Follow-Up
Patients who complete treatment or prematurely discontinue treatment will be required to 
perform the end-of-treatment assessments and complete the 90-day safety follow-up 
visit.  Details are provided in the schedule of assessments (see Appendix 1 and 
Appendix 2).
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the time when all enrolled patients with FL and all 
enrolled patients with DLBCL have completed the 90-day safety follow-up visit, following 
completion or premature discontinuation of study treatment. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4 years.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Patient Population
As discussed in Section 1.1, despite significant therapeutic progress with the use of 
chemoimmunotherapy as first-line treatment, FL remains essentially an incurable 
disease.  Patients invariably relapse, and subsequent active and well-tolerated agents 
are needed.  Although approximately 60% of patients with DLBCL have long-term 
responses with R-CHOP as first-line treatment, patients with advanced DLBCL have a 
lower chance of being cured.  Success rates with salvage therapy and autologous
transplantation are poor, highlighting the urgent need for novel therapeutic approaches 
for these patients.
On the basis of a compelling biologic and clinical rationale, as presented in Section 1.5, 
the combination of obinutuzumab, or rituximab with atezolizumab and polatuzumab 
vedotin is a promising approach to expand the number of patients with relapsed or 
refractory FL and DLBCL who achieve remission and to prolong response duration in 
these patients.


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3.3.2
Rationale for Dose and Schedule
3.3.2.1
Rationale for Obinutuzumab and Rituximab Dose and Schedule
For patients with FL, the dose and schedule of obinutuzumab in the induction regimen 
will be 1000 mg IV on Days 1, 8, and 15 of Cycle 1 and Day 1 of each subsequent 
21-day cycle (Cycles 26).  This is based on the recommended dose and schedule of 
obinutuzumab in the ongoing Phase III program in patients with NHL.  For this protocol, 
patients will be treated for 6 cycles during the induction phase.  The dose and schedule 
of obinutuzumab in the maintenance regimen (FL) will be 1000 mg IV administered 
every 2 months for up to 2 years.  This dosing administration is based on the 
obinutuzumab maintenance regimen that was administered in the Phase III GAO4753g 
study (Sehn et al. 2015).
For patients with DLBCL, the dose and schedule of rituximab in the induction regimen 
will be 375 mg/m2 on Day 1 of each 21-day cycle (Cycles 16).  This is based on the 
recommended dose and schedule for rituximab in this setting (see Rituximab 
Investigator’s Brochure and NCCN Guidelines2016).  For this protocol, patients will be 
treated for 6 cycles during the induction phase.  The dose and schedule of rituximab in 
the consolidation regimen (DLBCL) was 375 mg/m2 IV administered every 2 months for 
up to 8 months.  The consolidation regimen was modeled after the FL maintenance 
therapy.  The rationale for treatment duration is presented in Section 3.3.2.4.
3.3.2.2
Rationale for Atezolizumab Dose and Schedule
Previously, atezolizumab was administered at a flat dose consisting of one of the 
following:  1) 1200 mg Q3W (on Day 1 of Cycles 26, given in 21-day cycles with 
GPola or RPola as induction treatment) or 2) 1680 mg every 4 weeks (Q4W) 
(840 mg on Days 1 and 2 of each month, given with obinutuzumab/rituximab as 
post-induction treatment).  Both dosages are equivalent to an average body 
weightbased dose of 15 mg/kg Q3W.
The dosage of 15 mg/kg Q3W was selected as the RP2D for atezolizumab on the basis 
of both nonclinical studies and available clinical data from Study PCD4989g, as
described below.
The target exposure for atezolizumab was projected on the basis of clinical and 
nonclinical parameters, including nonclinical tissue distribution data in tumor-bearing 
mice, target-receptor occupancy in the tumor, and observed atezolizumab interim 
pharmacokinetics in humans.  The target trough concentration (Ctrough) was projected to 
be 6 g/mL on the basis of several assumptions, including the following:  
a) 95% tumor-receptor saturation is needed for efficacy and b) the tumor interstitial 
concentration-to-plasma ratio is 0.30 on the basis of tissue distribution data in 
tumor-bearing mice.
In Study PCD4989g, the first in-human study in patients with advanced solid tumors and 
hematologic malignancies, 30 patients were treated with atezolizumab at doses ranging 


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from 0.0120 mg/kg Q3W during the dose-escalation stage and 247 patients were 
treated with atezolizumab at doses of 10, 15, or 20 mg/kg Q3W during the 
dose-expansion stage.  Anti-tumor activity has been observed across all dose cohorts.  
There was no evidence of dose-dependent toxicity in this study.  The maximum tolerated 
dose of atezolizumab was not reached, and no DLTs were observed at any dose.  ATAs 
to atezolizumab were associated with changes in pharmacokinetics for some patients in 
the lower dose cohorts (0.3, 1, and 3 mg/kg), but patients treated at 10, 15, and 
20 mg/kg maintained the expected target trough levels of drug despite the detection of 
ATAs.  To date, no relationship has been observed between the development of 
measurable ATAs and safety or efficacy.  After review of available PK and ATA data for 
a range of doses, 15 mg/kg Q3W was identified as the an atezolizumab dosing regimen 
that would maintain Ctrough at6 g/mL, while further safeguarding against interpatient 
variability and the potential effect of ATAs that could lead to subtherapeutic levels of 
atezolizumab.
Simulations (Bai et al. 2012) do not suggest any clinically meaningful differences in 
exposure following a fixed dose compared with a body weightadjusted dose.
On the basis of this analysis, a fixed dose of 1200 mg Q3W (equivalent to a 
weight-based dose of 15 mg/kg Q3W) was defined as the RP2D.
For the Q4W dosing interval, the fixed dose of 1680 mg Q4W is the equivalent of a 
weight-based dose of 15 mg/kg Q3W.  Population PK modeling suggests that the AUC 
would be comparable to that of 1200 mg Q3W (data available on request).  The total 
dose of 1680 mg will be administered as 840 mg on Day 1 and Day 2 of each month.  
With the current atezolizumab manufacturing process, there is a theoretical risk of 
exceeding safe limits for manufacturing process-derived impurities, such as host cell 
DNA and endotoxins, at daily doses of 1200 mg.  Thus, the total dose of 1680 mg will 
be split into two daily doses of 840 mg each.  The manufacturing processes for 
atezolizumab are capable of clearing such impurities to safe levels, and tests for 
impurities are performed as a part of the manufacturing processes.  However, splitting of 
the atezolizumab dose is being implemented at this stage of clinical development to 
further minimize the potential risk.
In Study PCD4989g, atezolizumab was safely administered to 11 patients with various 
hematologic malignancies (including 7 patients with lymphoma) at doses of 15 mg/kg 
Q3W (n1) or 20 mg/kg Q3W (n10).  Atezolizumab 1200 mg Q3W is currently being 
evaluated in combination with obinutuzumab in an ongoing Phase Ib study 
(Study GO29383) in patients with relapsed or refractory DLBCL or FL 
(see Section 1.3.2).  Atezolizumab was added to obinutuzumab/rituximab starting with 
Cycle 2 to avoid overlapping IRRs during the first infusion of obinutuzumab, which is 
known to be associated with the highest incidence and risk of severe IRRs.  Consistent 
with the dosing schedule used in Study GO29383, in this study, atezolizumab was 
added to G/RPola starting with Cycle 2.


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As of Protocol BO29561, Version 7, dosing with atezolizumab is discontinued in all 
patients still receiving study treatment.
3.3.2.3
Rationale for Polatuzumab Vedotin Dose and Schedule
For this study, the starting dose of polatuzumab vedotin will be 1.4 mg/kg, every 21 days 
and the dose will be escalated to a final dose of 1.8 mg/kg in relapsed or refractory FL, if 
tolerated.  The starting dose of polatuzumab vedotin will be 1.8 mg/kg, every 21 days in 
relapsed or refractory DLBCL patients.
Polatuzumab vedotin dosing for this study is based on the experience from the Phase I
study (DCS4968g) with single−agent polatuzumab vedotin and the Phase II study 
(GO27834) with polatuzumab vedotin in combination with rituximab in patients with 
relapsed or refractory NHL, the majority of whom had relapsed or refractory FL or
DLBCL.  In these studies, most evidence of anti-tumor activity was observed at 
doses 1.8 mg/kg.
Evidence from Study DCS4968g indicates that duration of study treatment might be 
limited by tolerability to polatuzumab vedotin at the 2.4 mg/kg dose due to high rates of 
treatment discontinuation due to peripheral neuropathy (sensory and/or motor) which 
has been identified as a known risk (see Section 5.1.4.1).  Polatuzumab vedotin was 
shown to demonstrate single-agent activity at the 1.8 mg/kg dose level 
(Palanca-Wessels et al. 2015).  Consequently, Study GO27834 was amended to add a 
cohort with the purpose of determining whether polatuzumab vedotin 1.8 mg/kg in 
combination with the standard dose of rituximab would result in improved tolerability 
while maintaining efficacy in patients with FL.  Results from an ad hoc analysis 
comparing the 2.4 mg/kg and 1.8 mg/kg polatuzumab vedotin doses in combination with 
rituximab were reported (Advani et al. 2015).  A high ORR was observed at both doses 
(76% at 2.4 mg/kg and 75% at 1.8 mg/kg), with a higher rate of CRs at 2.4 mg/kg 
(44% at 2.4 mg/kg and 10% at 1.8 mg/kg), although there was no observed differences 
in duration of response or progression free survival.  At both doses, adverse event and 
discontinuation rates were reduced through 8 cycles of treatment (corresponding to 
approximately 6 months' duration) when compared with treatment through disease 
progression.  On the basis of these findings and to minimize the risk for development of 
peripheral neuropathy (sensory and/or motor), polatuzumab vedotin will be given for a 
maximum of 6 months, and the maximum dose of polatuzumab vedotin will be 1.8 mg/kg.
Several ongoing Phase Ib/II studies are assessing the safety and clinical activity of 
obinutuzumab plus polatuzumab vedotin alone or in combination with chemotherapy.  
In study GO27834, evaluating polatuzumab vedotin in combination with 
rituximab/obinutuzumab, the dose of polatuzumab vedotin is 1.8 mg/kg every 
21 days (see Section 1.5.4.3).
In Study GO29044 evaluating polatuzumab vedotin in combination with rituximab/ 
obinutuzumab-CHP, the starting dose of polatuzumab vedotin of 1.4 mg/kg and the 


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1.8 mg/kg dose were shown to be safe (see Section 1.5.4.3).  In Study GO29365 
evaluating polatuzumab vedotin in combination with obinutuzumab/rituximab
bendamustine, the dose of polatuzumab vedotin is 1.8 mg/kg.  Based on the available 
experience with polatuzumab vedotin in combination with obinutuzumab with or without 
chemotherapy described above, the dose of 1.4 mg/kg is anticipated to be tolerated 
when polatuzumab vedotin is combined with obinutuzumab and atezolizumab.  
Therefore 1.4 mg/kg of polatuzumab will be the starting dose in relapsed or refractory FL 
patients, if tolerated, will be escalated to a final dose of 1.8 mg/kg.
Based on the available data for polatuzumab vedotin 1.8 mg/kg in combination with 
rituximab and chemotherapy, it is not deemed necessary to run a specific 
dose-escalation for polatuzumab vedotin in this treatment combination.  A safety run-in 
is included to assess the preliminary safety of RPola when added to atezolizumab, 
before the expansion phase.
Given the maximum 6-month duration for polatuzumab vedotin owing to the risk of 
peripheral neuropathy with cumulative dosing, polatuzumab vedotin will not be 
administered as post-induction treatment.
3.3.2.4
Rationale for Treatment Duration
Previously in this study, patients with RR FL received 6 cycles of GAtezoPola
induction treatment followed by extended maintenance treatment with GAtezo and 
patients with RR DLBCL received 6 cycles of RAtezoPola induction treatment 
followed by extended consolidation treatment with RAtezo.
The objective of post-induction treatment is to improve the response to induction 
therapy, either by improving the quality of the clinical response (e.g., converting a PR to 
a CR) or by eradicating minimal residual disease (MRD) to achieve a molecular 
response, thus reducing the risk of relapse.
Despite recent improvements in therapy for FL, including demonstrated benefit from 
2-year rituximab maintenance in patients responding to first-line immunochemotherapy 
(Study MO18264), FL is still not considered curable, with a 6-year PFS of 59.2% 
(Salles et al. 2013).  A Phase III study, Study GAO4753g, investigated obinutuzumab
plus bendamustine (GB) compared with bendamustine alone in patients with 
rituximab-refractory indolent NHL (n396; including 321 patients with FL).  Patients in 
the GB group who had not experienced disease progression at EOI received 
obinutuzumab monotherapy every 2 months for up to 2 years.  On the basis of positive 
results from this study, demonstrating significant improvement in PFS in the GB arm, 
with a median investigator-assessed PFS of 29 versus 14 months (HR0.52; 95% CI: 
0.39, 0.70; p0.0001) (Sehn et al. 2015), the Independent Data Monitoring Committee 
recommended that the study be unblinded to the Sponsor.  These data support further 
investigation of obinutuzumab in combination with new targeted drugs in the setting of 
induction and maintenance treatment for patients with FL.  On the basis of the 


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nonclinical rationale (presented in Section 1.5.4.2), it is hypothesized that the addition of 
atezolizumab to obinutuzumab may enhance and prolong the anti-tumor immune 
response and provide significant clinical benefit to patients.  Nonclinical data 
demonstrating synergism between obinutuzumab and atezolizumab, associated with a 
low risk of overlapping toxicities, provide the rationale for administering atezolizumab as 
maintenance treatment on a monthly basis for the same period of 2 years.  As of 
Protocol BO29561, Version 7, atezolizumab treatment is discontinued, and maintenance 
treatment will consist of obinutuzumab monotherapy (see Section 3).
Patients with relapsed or refractory DLBCL who are not suitable for or do not benefit 
from consolidative autologous transplantation exhibit a poor prognosis.  Responses 
obtained with different rituximab treatment regimens tested in clinical trials 
(e.g., rituximab in combination with bendamustine, with gemcitabine plus oxaliplatin, or 
with lenalidomide) are of short duration, with the longest reported median PFS of 
approximately 7 months observed in one study of rituximab plus bendamustine 
(Ohmachi et al. 2013).  Thus, 8 months of consolidation treatment with RAtezo, for 
total treatment duration of approximately 12 months, aimed at prolonging the anti-tumor 
immune response, and was considered to be a reasonable exploratory therapeutic 
approach with an anticipated positive benefit-risk ratio.  On the basis of the 
complementary mechanism of action between rituximab and atezolizumab, and 
considering the aggressiveness of refractory or relapsed DLBCL, the study was 
designed to investigate the safety and efficacy of this doublet in the consolidation 
setting.  As of Protocol BO29561, Version 7, atezolizumab treatment is discontinued,
and hence, consolidation treatment is removed.  Patients with RR DLBCL will be treated 
only through the induction phase with rituximab and polatuzumab vedotin.
3.3.3
Rationale for PET-CT-Based Complete Response as the 
Primary Efficacy Endpoint
In DLBCL, the prognostic value of the post-treatment fluorodeoxyglucose (FDG) PET-CT 
scan has been well documented (Thomas et al. 2010; Vitolo et al. 2010).  PET-CT scans 
have been implemented in the Lugano 2014 criteria (Cheson et al. 2014) and are 
commonly used to assess efficacy in medical practice and clinical trials in lymphoma.  
More recently, the value of post-induction PET-CT status has been investigated as a 
prognostic marker for long-term outcome in patients with FL.  In the first-line setting, 
results from a pooled analysis of 246 patients enrolled in three studies and having 
PET-CT scans available at the end of chemoimmunotherapy showed, with a median 
follow-up of 55 months, a 4-year PFS in PET-CTpositive and PET-CTnegative 
patients of 23.2% (95% CI: 11.1%, 37.9%) versus 63.4% (95% CI: 55.9%, 70.0%; 
p0.001), respectively, and a 4-year survival of 87.2% (95% CI: 71.9%, 94.5%) versus 
97.1% (95% CI: 93.2%, 98.8%; (p0.0001), respectively (Trotman et al. 2014).  In the 
relapsed FL setting, results from a preliminary analysis of Phase II study (BO21003) 
comparing obinutuzumab versus rituximab monotherapy demonstrated that the 
post-induction PET-CT status is strongly prognostic of PFS.  With a median follow-up of 


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32.1 months, the risk of disease progression was significantly reduced in 
PET-CTnegative compared with PET-CTpositive patients, regardless of the 
assessment criteria, either International Harmonization Project criteria (HR: 0.25; 
95% CI: 0.191, 0.807; p0.0083) or European Organization for Research and Treatment 
of Cancer (EORTC) criteria (HR, 0.39; 95% CI: 0.191, 0.807; p0.0083)
(Kostakoglu et al. 2014).
In response to developments involving PET-CT status, the 11th International Conference 
of Malignant Lymphoma imaging group provided an updated guidance for the use of 
PET-CT scan results for lymphoma staging and response assessment 
(Lugano 2014 criteria [Appendix 5]; Cheson et al. 2014).
3.3.4
Rationale for Biomarker Assessments
3.3.4.1
Rationale for Analysis of DLBCL Subtype, BCL2, and MYC
The DLBCL cell-of-origin prognostic subgroups (ABC and GCB), defined using gene 
expression profiling, have been associated with different clinical outcomes in patients 
receiving R-CHOP for DLBCL, with GCB subgroups demonstrating a better prognosis 
than ABC groups (3-year survival rate of 84% vs. 56%, respectively; p0.001) 
(Lenz et al. 2008).
A Bcl-2 overexpression has been shown to have prognostic value in DLBCL 
(Iqbal et al. 2006).  Next-generation sequencing studies have also shown that BCL2 is 
the most mutated gene in patients with GCB DLBCL, observed in up to 35% of cases 
(Schuetz et al. 2012).  Approximately 9%17% of patients with newly diagnosed DLBCL 
harbor an underlying MYC rearrangement, and these patients are at high risk of 
treatment failure with R-CHOP (Savage et al. 2009).  A subset of patients with 
MYC-positive DLBCL also harbors an additional BCL2 rearrangement.  These 
"double-hit" lymphomas are associated with a very poor outcome (Savage et al. 2009; 
Dunleavy et al. 2014).  Overexpression of Bcl-2 and Myc in DLBCL has also been 
observed in the absence of translocation.  This "double-positive" DLBCL status is also 
associated with worse prognosis (Green et al. 2012; Johnson et al. 2012; Hu et al. 2013).
Correlative investigations are essential to understand mechanisms of both sensitivity 
and resistance to therapy in patients with mutational profiles that predict poor response 
to standard treatment.
3.3.4.2
Rationale for Assessment of Immune-Related Biomarkers
Over the last decade, tumor microenvironment and host immunity have emerged as 
critical determinants of cancer development and response to therapy.  There is an 
increasing body of evidence regarding the prognostic value of TILs in B-cell lymphoma.  
CD8-positive cytotoxic T-cell infiltrate has been identified as a biomarker of poor 
prognosis in DLBCL (Galand et al. 2012).  More recently, analysis of peripheral T-cell 
receptor repertoire demonstrated impaired T-cell diversity in B-cell lymphoma, with 
expansion of oligoclonal clusters of CD8-positive T cells and expansion of T-regulatory 


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cells associated with an increased degree of skewing observed within the CDR3 region 
(Fozza et al. 2014).  A recent study of 12 melanoma patients treated with ipilimumab, a 
blocker of the immunologic checkpoint CTLA-4, showed a correlation between T-cell 
receptor diversity in the peripheral blood at baseline and patient outcomes 
(Postow et al. 2014).
This study will investigate the potential correlation of TIL signature and the status of 
peripheral T-cell receptor repertoire (diversity and quantity of receptors) with response to 
study treatment.
A fresh biopsy prior to commencing Cycle 2 is requested if an adequate accessible 
tumor site is available. The rationale is to better understand changes in 
immune-infiltrate and immune status, including PD-L1 expression after treatment with 
obinutuzumab and polatuzumab vedotin. Published results suggest that expression of 
PD-L1 in tumors correlates with response to anti−PD-1 therapy (Herbst et al. 2014; 
Powles et al. 2014).  Other exploratory markers, such as potential predictive and 
prognostic markers that are related to response or clinical benefit of atezolizumab, tumor 
immunobiology, and tumor type markers, may also be analyzed.
Increase in T-cell activation biomarkers has been observed in peripheral blood following 
atezolizumab administration in cancer patients (Herbst et al. 2014).  Cytokines that are 
characteristic of activated T-cells (e.g., IL-18, interferon gamma [IFN-]) and potential 
correlation with response to treatment will be assessed in this study.
A recent publication (Rossille et al. 2014) described the prognostic effect of soluble 
PD-L1 in DLBCL.  The value of soluble PD-L1 as a biomarker in FL is unknown.  Soluble 
PD-L1 levels at baseline will be assessed in this study to support an exploratory 
biomarker analysis.
3.3.4.3
Rationale for Analysis of CD79b:  Assessment of Therapeutic 
Target Expression
CD79b is a signal-transducing subunit of the B-cell receptor that is rapidly internalized 
upon binding to polatuzumab (Jang et al. 2010).  Nonclinical experiments have 
demonstrated that the activity of ADCs like polatuzumab vedotin depend on the 
presence of the target, internalization, and sensitivity to the payload drug (Zheng et al. 
2009; Pfeifer et al. 2015).  To ascertain the expression of CD79b in this study, CD79b 
will be assessed by IHC.
4.
MATERIALS AND METHODS
4.1
PATIENTS
This study will enroll patients with FL and DLBCL who meet the eligibility criteria 
presented below.


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4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years

ECOG Performance Status of 0, 1, or 2 (see Appendix 6)

For GAtezoPola treatment group: relapsed or refractory FL after treatment with 
at least one prior chemoimmunotherapy regimen that included an anti-CD20 
monoclonal antibody and for which no other more appropriate treatment option 
exists as determined by the investigator

For RAtezoPola treatment group:  relapsed or refractory DLBCL after treatment 
with at least one prior chemoimmunotherapy regimen that included an anti-CD20 
monoclonal antibody, in patients who are not eligible for second line combination 
(immuno-) chemotherapy and autologous stem-cell transplantation or who have 
failed second line combination (immuno-) chemotherapy or experienced disease 
progression following autologous stem-cell transplantation

Histologically documented CD20-positive lymphoma as determined by the local 
laboratory

FDG-avid lymphoma (i.e., PET-positive lymphoma)

At least one bi-dimensionally measurable lesion (1.5 cm in its largest dimension by 
CT scan or magnetic resonance imaging [MRI])

Availability of a representative tumor specimen and the corresponding pathology 
report for retrospective central confirmation of the diagnosis of FL or DLBCL
If archival tissue is unavailable or unacceptable, a pretreatment core-needle, 
excisional or incisional tumor biopsy is required.  Cytological or fine-needle 
aspiration samples are not acceptable.
Further details are provided in Section 4.5.6.
If the patient received anti-lymphoma treatment between the time of the most 
recent available biopsy and initiation of study treatment, or if the available 
biopsy was performed more than 6 months prior to Day 1 of Cycle 1 (initiation 
of study treatment) for patients with DLBCL or more than 12 months prior to 
Day 1 of Cycle 1 for patients with FL, a core-needle biopsy is strongly 
recommended.

For women who are not postmenopausal (12 months of non−therapy−induced 
amenorrhea and age 45 years) or surgically sterile (absence of ovaries and/or 
uterus):  agreement to remain abstinent or to use single highly effective or combined 
contraceptive methods that result in a failure rate of 1% per year during the 
treatment period for 5 months after the last dose of atezolizumab,12 months 
after the last dose of rituximab, 12 months after the last dose of polatuzumab 
vedotin, and 18 months after the last dose of obinutuzumab.


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Abstinence is only acceptable if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.
Examples of highly effective contraceptive methods with a failure rate of 1% 
per year include tubal ligation, male sterilization, hormonal implants, 
established, proper use of combined oral or injected hormonal contraceptives, 
and certain intrauterine devices.  Alternatively, two methods (e.g., two barrier 
methods such as a condom and a cervical cap) may be combined to achieve a 
failure rate of 1% per year.  Barrier methods must always be supplemented 
with the use of a spermicide.

For women of childbearing potential, a negative serum pregnancy test result within 
7 days prior to commencement of dosing.  Women who are considered not to be of 
childbearing potential are not required to have a pregnancy test.

For men, agreement to remain abstinent or to use a condom plus an additional 
contraceptive method that together result in a failure rate of 1% per year during the 
treatment period and for at least three months after the last dose of obinutuzumab, 
rituximab, and atezolizumab, and five months after the last dose of polatuzumab 
vedotin and agreement to refrain from donating sperm during this same period.
Men with a pregnant partner must agree to remain abstinent or to use a 
condom for the duration of the pregnancy.
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.
Male patients considering preservation of fertility should bank sperm before 
treatment with polatuzumab vedotin.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Grade 3b follicular lymphoma

History of transformation of indolent disease to DLBCL

Known CD20-negative status at relapse or progression

Central nervous system (CNS) lymphoma or leptomeningeal infiltration

Prior allogeneic SCT

Completion of autologous SCT within 100 days prior to Day 1 of Cycle 1 

Prior standard or investigational anti-cancer therapy as specified below:
Fludarabine or alemtuzumab within 12 months prior to Day 1 of Cycle 1
Radioimmunoconjugate within 12 weeks prior to Day 1 of Cycle 1
Monoclonal antibody or ADC within 4 weeks prior to Day 1 of Cycle 1


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Radiotherapy, chemotherapy, hormonal therapy, or targeted small-molecule 
therapy within 2 weeks prior to Day 1 of Cycle 1
AntiPD-1, antiPD-L1, anti-CTLA4, antiCD137/41-BB agonist, or anti-CD40 
agonist antibodies

Clinically significant toxicity (other than alopecia) from prior treatment that has not 
resolved to Grade 2 (per National Cancer Institute Common Terminology Criteria 
for Adverse Events [NCI CTCAE] v4.0) prior to Day 1 of Cycle 1

Treatment with systemic immunosuppressive medications, including, but not limited 
to, prednisone, azathioprine, methotrexate, thalidomide, and antitumor necrosis 
factor agents within 2 weeks prior to Day 1 of Cycle 1
Treatment with inhaled corticosteroids and mineralocorticoids is permitted.
If corticosteroid treatment is urgently required for lymphoma symptom control 
prior to the start of study treatment, up to 100 mg of prednisone or equivalent 
can be given for a maximum of 5 days, but all tumor assessments must be 
completed prior to initiation of corticosteroid treatment.

History of solid organ transplantation

History of severe allergic or anaphylactic reaction to humanized, chimeric, or murine 
monoclonal antibodies

Known hypersensitivity or allergy to murine products

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab, obinutuzumab, rituximab, or 
polatuzumab vedotin formulations

Known history of idiopathic pulmonary fibrosis, organizing pneumonia 
(e.g., bronchiolitis obliterans), drug-induced pneumonitis or evidence of active 
pneumonitis on screening chest CT scan.
History of radiation pneumonitis in the radiation field (fibrosis) is allowed.

Active bacterial, viral, fungal, or other infection or any major episode of infection 
requiring treatment with IV antibiotics within 4 weeks of Day 1 of Cycle 1
Caution should be exercised when considering the use of obinutuzumab and 
rituximab in patients with a history of recurring or chronic infections.

Receipt of oral or intravenous antibiotics for treatment of serious infections within 
4 weeks prior to Day 1 of Cycle 1

Positive for hepatitis B surface antigen (HBsAg), total hepatitis B core antibody 
(HBcAb), or hepatitis C virus (HCV) antibody at screening

Known history of HIV positive status
For patients with unknown HIV status, HIV testing will be performed at 
screening if required by local regulations.

History of PML


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
Vaccination with a live virus vaccine or live attenuated vaccine within 28 days prior 
to Day 1 of Cycle 1, or anticipation that such a live, attenuated vaccine will be 
required during the study

History of other malignancy that could affect compliance with the protocol or 
interpretation of results, with the exception of the following:
Curatively treated carcinoma in situ of the cervix, good-prognosis ductal 
carcinoma in situ of the breast, basal- or squamous-cell skin cancer, Stage I 
melanoma, or low-grade, early-stage localized prostate cancer
Any previously treated malignancy that has been in remission without treatment 
for 2 years prior to enrollment

History of autoimmune disease, including, but not limited to, myasthenia gravis, 
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid 
syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré 
syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (Appendix 10) for a 
comprehensive list of autoimmune diseases)
Patients with a history of autoimmune-related hypothyroidism on a stable dose 
of thyroid-replacement hormone may be eligible for this study.
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen 
may be eligible for this study.

Grade 1 peripheral neuropathy present at screening

Evidence of any significant, uncontrolled concomitant disease that could affect 
compliance with the protocol or interpretation of results, including significant 
cardiovascular disease (such as New York Heart Association Class III or IV cardiac 
disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or 
unstable angina) or significant pulmonary disease (such as obstructive pulmonary 
disease or history of bronchospasm)

Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of 
Cycle 1, or anticipation of a major surgical procedure during the course of the study

Inadequate hematologic function (unless due to underlying lymphoma), defined as 
follows:
Hemoglobin 9 g/dL
ANC 1.5109/L
Platelet count 75109/L

Inadequate liver function defined as follows (unless due to underlying lymphoma): 
For patients enrolled in the dose escalation:
AST Upper limit of normal (ULN) or serum total bilirubin ULN


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For patients enrolled in the expansion:
AST or ALT 2.5ULN
Serum total bilirubin 1.5ULN (or 3ULN for patients with Gilbert 
syndrome)

Any of the following abnormal laboratory values (unless due to underlying 
lymphoma):
Creatinine 1.5 times the ULN (unless creatinine clearance is normal) or 
calculated creatinine CL 40 mL/min (using the Cockcroft-Gault formula; 
Appendix 11)
INR or PT 1.5ULN in the absence of therapeutic anticoagulation
PTT or aPTT 1.5ULN in the absence of a lupus anticoagulant

Pregnant or lactating, or intending to become pregnant during the study
Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days prior to Day 1 of Cycle 1.

Life expectancy 3 months

Unable to comply with the study protocol, in the investigator’s judgment
4.2
METHOD OF TREATMENT ASSIGNMENT
This is a Phase Ib/II, open-label, multicenter, non-randomized, dose-escalation study of 
GAtezoPola in patients with relapsed or refractory FL and RAtezoPola in patients 
with relapsed or refractory DLBCL.  During the dose-escalation phase, an interactive 
voice or web-based response system (IxRS) was used to assign patients with relapsed 
or refractory FL to dosing groups that vary according to the dose of polatuzumab vedotin 
given during induction treatment.  During the expansion phase, patients with relapsed or 
refractory FL and DLBCL will receive polatuzumab vedotin at the RP2D during induction 
treatment.  Atezolizumab and obinutuzumab or rituximab was to be given at stable 
doses to all patients, during both induction and post-induction treatment.  Post-induction 
treatment (for eligible patients only) will depend on lymphoma histology (see Section 3.1
for details).  As of 1 March 2018, patients with RR FL in the expansion phase will 
continue to be treated with GPola during induction (see Table 3) and patients on 
maintenance treatment will continue treatment with obinutuzumab (see Table 2).  
Patients with RR DLBCL will continue to be treated with RPola during induction 
(see Table 4), and patients with RR DLBCL who have completed or prematurely 
discontinued induction treatment will proceed to the safety follow-up without 
consolidation treatment.
Enrollment tracking will be performed through use of the IxRS.  Prior to initiation of 
screening, the study site should confirm via the IxRS that slots are available for 
enrollment.  After written informed consent has been obtained and preliminary eligibility 
has been established, the study site will submit documentation supporting eligibility to 
the Sponsor and obtain the Sponsor’s approval to enroll the patient.  Once the Sponsor 


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reviews and approves the patient for enrollment, the patient number will be assigned and 
the patient will be enrolled via the IxRS.  The Sponsor will communicate to the sites 
impending closure of screening for the dose-escalation and expansion phases.
4.3
STUDY TREATMENT 
The investigational medicinal products (IMPs) for this study are obinutuzumab, rituximab, 
atezolizumab, and polatuzumab vedotin.
As of Protocol BO29561, Version 7, dosing with atezolizumab is discontinued in all 
patients.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Obinutuzumab
Obinutuzumab will be supplied by the Sponsor as an IMP.  Obinutuzumab will be 
provided as a single-dose, sterile liquid formulation in a 50-mL glass vial containing 
1000 mg/40 mL of obinutuzumab.  In addition to the drug substance, the liquid is also 
composed of histidine, trehalose, and poloxamer 188.  For information on the 
formulation and handling of obinutuzumab, see the Obinutuzumab Investigator’s 
Brochure and the Pharmacy Manual.
4.3.1.2
Atezolizumab
Atezolizumab was supplied by the Sponsor as an IMP.  Atezolizumab Drug Product is 
provided in a single-use, 20-mL USP/Ph. Eur. Type 1 glass vial as a colorless to slightly 
yellow, sterile, preservative-free clear liquid solution intended for IV administration.  The 
vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution but may contain 
more than the stated volume to enable delivery of the entire 20-mL volume.  Extraction 
of 14 mL of atezolizumab solution will contain an 840-mg dose.  For information on the 
formulation and handling of atezolizumab, see the Atezolizumab Investigator’s Brochure 
and the Pharmacy Manual.
4.3.1.3
Polatuzumab Vedotin
Polatuzumab vedotin will be supplied by the Sponsor as an IMP.  Polatuzumab vedotin 
will be provided as a sterile, white to off-white, preservative-free lyophilisate in single-use 
vials. For information on the formulation and handling of polatuzumab vedotin, see the 
polatuzumab vedotin Investigator's Brochure and the Pharmacy Manual.
4.3.1.4
Rituximab
Rituximab will be supplied by the Sponsor as an IMP.  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.  For information on the formulation and handling of rituximab, see the 
Rituximab Investigator's Brochure and the Rituximab Pharmacy Manual.


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4.3.2
Dosage, Administration, and Compliance
The treatment regimens are summarized in Table 6, Table 7, and Table 8
(see Sections 4.3.2.4 and 4.3.2.5).  Premedication should be administered as described 
in Section 4.3.2.7.
Any overdose or incorrect administration of any of the study treatments should be noted 
on the Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of any of the study treatments 
should be recorded on the Adverse Event eCRF.
4.3.2.1
Obinutuzumab
Obinutuzumab will be administered by IV infusion at an absolute (flat) dose of 1000 mg 
on Days 1, 8, and 15 of the first cycle and on Day 1 of each subsequent cycle during 
induction treatment, and on Day 1 of every other month (i.e., every 2 months) during 
maintenance treatment.
Obinutuzumab should be administered as an IV infusion through a dedicated line in an 
environment in which full resuscitation facilities are immediately available and under the 
close supervision of an experienced physician.  Obinutuzumab infusions will be 
administered per the instructions outlined in Figure 2 and Figure 3.  For patients with 
bulky lymphadenopathy, the infusion may be given slowly over a longer period of time, 
or the dose may be split and given over more than 1 day.
No dose modification for obinutuzumab is allowed.  Additional guidelines for treatment 
delays or discontinuation are provided in Section 5.1.6.
Premedication with a corticosteroid, antihistamine, and analgesic/antipyretic, as outlined 
in Section 4.3.2.7 and Table 9, is required to reduce the incidence and severity of IRRs.  
For anaphylaxis precautions, see Appendix 9.


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Figure 2
Guidelines for Obinutuzumab Infusions:  First Infusion
IRRinfusion-related reaction.
a All patients should receive full premedication with oral corticosteroid, oral analgesic/anti-pyretic, and antihistamine prior to the first obinutuzumab 
infusion.  Refer to Section 4.3.2.7 for details.
b Supportive treatment should include acetaminophen/paracetamol and an antihistamine such as diphenhydramine, if not administered within the 
previous 4 hours.  Intravenous saline may be indicated.  For bronchospasm, urticaria, or dyspnea, patients may require antihistamines, oxygen, 
corticosteroids (e.g., 100 mg oral prednisone or equivalent), and/or bronchodilators.  For anaphylaxis precautions, see Appendix 9.


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Figure 3
Guidelines for Obinutuzumab Infusions:  Second and Subsequent Infusions
IRR infusion-related reaction.
a Patients should receive full premedication with oral corticosteroid, antihistamine, and oral analgesic/anti-pyretic prior to the obinutuzumab 
infusion.  Refer to Section 4.3.2.7 for details.  In the case of a recurrent Grade 3 IRR, obinutuzumab may be discontinued at the discretion of the 
investigator, following an individual benefit-risk assessment.
b Patients who experience wheezing, urticaria, or other symptoms of anaphylaxis must receive full premedication prior to all subsequent doses.


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4.3.2.2
Atezolizumab
Atezolizumab was administered by IV infusion at a flat dose consisting of one of the 
following:  a) 1200 mg Q3W (on Day 1 of Cycles 2-6, given in 21-day cycles as induction 
treatment) or b) 1680 mg Q4W (840 mg on Days 1 and 2 of each month, given as 
maintenance or consolidation treatment).  Detailed atezolizumab dosing regimens are 
provided in Table 6 for induction treatment and in Table 8 for post-induction treatment 
(Sections 4.3.2.4 and 4.3.2.5).
No dose modification for atezolizumab is allowed.  Guidelines for treatment delays or 
discontinuation are provided in Section 5.1.6.
4.3.2.3
Polatuzumab Vedotin
Polatuzumab vedotin will be administered by IV infusion on Day 1 of Cycles 16 during 
induction treatment; polatuzumab vedotin will not be administered during consolidation 
or maintenance treatment. For relapsed or refractory FL, during the dose-escalation 
phase, the dose of polatuzumab vedotin for each patient will depend on dose 
assignment (1.4 or 1.8 mg/kg).  During the expansion phase, the dose of polatuzumab 
vedotin for each patient will depend on the RP2D established during the dose-escalation 
phase. For relapsed or refractory DLBCL, during the safety run-in phase the starting 
dose of polatuzumab vedotin will be 1.8 mg/kg. During expansion phase, the dose of 
polatuzumab vedotin will be 1.8 or 1.4 mg/Kg depending on the tolerability of the 
combination observed during Safety run-in.
The patient’s weight obtained during screening (Days 28 to 1) should be used for 
dose determination for all treatment cycles.  If the patient’s weight within 96 hours prior 
to Day 1 of a given treatment cycle is 10% higher or lower than the weight obtained 
during screening, the new weight should be used to calculate the dose.  The weight that 
triggered a dose adjustment will be taken as the new reference weight for future dose 
adjustments.  All subsequent doses should be modified accordingly.
Polatuzumab vedotin infusions will be administered as follows:

The initial dose will be administered to patients who are well hydrated over 
90 (10) minutes.

The polatuzumab vedotin infusion may be slowed or interrupted for patients 
experiencing infusion-associated symptoms.  Following the Cycle 1 Day 1 and 
Cycle 2 Day 1 dose, patients will be observed for 90 minutes for IRRs.  If prior 
infusions have been well tolerated, subsequent doses of polatuzumab vedotin may 
be administered over 30 (10) minutes, followed by a 30-minute observation period 
after the infusion.
4.3.2.4
Rituximab
Rituximab will be administered by IV infusion at the dose of 375 mg/m2 on Day 1 of 
Cycles 1−6 during induction treatment and on Day 1 of every other month (i.e., every 
2 months) during consolidation treatment.


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Body surface area (BSA) will be determined at screening and should be used to 
calculate the dose of rituximab throughout the study unless the patient’s weight 
increases or decreases by 10% from screening, in which case BSA should be 
recalculated and used for subsequent dosing.  In obese patients (defined as body mass 
index 30 kg/m2), there is no BSA cap and actual body weight, not adjusted weight, is 
recommended.  Empiric dose adjustment for obese patients may be implemented per 
institutional guidelines.
The infusion of rituximab may be split over two days if the patient is at increased risk for 
an IRR (high tumor burden or high peripheral lymphocyte count).  Administration of 
rituximab may be continued on the following day, if needed, for patients who experience 
an adverse event during the rituximab infusion. 
If a dose of rituximab is split over two days, both infusions must occur with appropriate 
premedication (see Section 4.3.2.7) and at the first infusion rate (see Table 5).
Rituximab infusions will be administered according to the instructions in Table 5.  If a 
patient tolerates the first three cycles of study treatment without significant infusion 
reactions, rituximab may be administered as a rapid infusion in accordance with local 
institutional guidelines.
During the treatment period, rituximab must be administered to patients in a setting 
where full emergency resuscitation facilities are immediately available.  Patients should 
be under close supervision of the investigator at all times. 
Rituximab should be administered as a slow IV infusion through a dedicated line.  After 
the end of the first infusion, the IV line or central venous catheter should remain in place 
for 2 hours in order to administer IV drugs, if necessary.  If no adverse events occur 
after 2 hours, the IV line may be removed or the central venous catheter may be 
de-accessed.  For subsequent infusions, the IV line or central venous catheter should 
remain in place for at least 1 hour after the end of the infusion.  If no adverse events 
occur after 1 hour, the IV line may be removed or the central venous catheter may be 
de-accessed.


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Table 5
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/hr.

If no infusion-related or 
hypersensitivity reaction occurs, 
increase the infusion rate in 50-mg/hr 
increments every 30 minutes to a 
maximum of 400 mg/hr.

If a reaction develops, stop or slow 
the infusion.  Administer medications 
and supportive care in accordance 
with institutional guidelines.  If the 
reaction has resolved, resume the 
infusion at a 50% reduction in rate 
(i.e., 50% of rate being used at the 
time when the reaction occurred).

If the patient experienced an infusion-related or 
hypersensitivity reaction during the prior 
infusion, use full premedication, including 
100 mg of prednisone/prednisolone or 80 mg of 
methylprednisolone or equivalent (until no 
further IRR occurs); begin infusion at an initial 
rate of 50 mg/hr; and follow instructions for first
infusion.

If the patient tolerated the prior infusion well 
(defined by an absence of Grade 2 reactions 
during a final infusion rate of 100 mg/hr), 
begin infusion at a rate of 100 mg/hr.

If no reaction occurs, increase the infusion rate 
in 100-mg/hr increments every 30 minutes to a 
maximum of 400 mg/hr.

If a reaction develops, stop or slow the infusion.  
Administer medications and supportive care in 
accordance with institutional guidelines.  If the 
reaction has resolved, resume the infusion at a 
50% reduction in rate (i.e., 50% of rate being 
used at the time when the reaction occurred).
No dose modification for rituximab is allowed.  Guidelines for treatment delays or 
discontinuation are provided in Section 5.1.6.
Premedication with a corticosteroid, analgesic/antipyretic, and antihistamine, as outlined 
in Section 4.3.2.7, is required to reduce the incidence and severity of IRRs.  For 
anaphylaxis precautions, see Appendix 9.
4.3.2.5
Induction Treatment with Obinutuzumab or Rituximab, and 
Polatuzumab Vedotin (GPola or RPola)
Patients will receive induction treatment, administered in 21-day cycles, as follows:

Patients with FL will receive 6 cycles of induction treatment consisting of 
obinutuzumab and polatuzumab vedotin for Cycles 16 as outlined in Table 6.

Patients with DLBCL will receive 6 cycles of induction treatment consisting of 
rituximab and polatuzumab vedotin for Cycles 16 as outlined in Table 7.
Obinutuzumab or rituximab will be administered first, followed by a line flush (unless 
there is a central line with more than one line/port) and then polatuzumab vedotin.
For patients at increased risk for IRRs (high tumor burden), the first obinutuzumab and 
rituximab infusion may be split and administered over 2 days. If split, obinutuzumab 
should be given as 100 mg on Day 1 and 900 mg on Day 2.


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For patients who experience an IRR during obinutuzumab or rituximab infusion, 
administration of polatuzumab vedotin may be delayed by 1 day if clinically required.
Table 6
Induction Treatment in Patients with Follicular Lymphoma
Treatment
Dose
Route
Regimen (21-day Cycles)
Cycle 1
Cycle 26
Obinutuzumab
1000 mg
IV
Days 1, 8, and 15
Day 1
Polatuzumab vedotin 
1.4 mg/kg or 1.8 mg/kg
IV
Day 1
Day 1
FLfollicular lymphoma; IVintravenous.
Table 7
Induction Treatment in Patients with Diffuse Large B-cell 
Lymphoma
Treatment
Dose
Route
Regimen (21-Day Cycles)
Cycle 1
Cycles 26
Rituximab
375 mg/m2
IV
Day 1
Day 1
Polatuzumab vedotin
1.8 mg/kg a
IV
Day 1
Day 1
DLBCLdiffuse large B-cell lymphoma; IVintravenous.
a Dose may be de-escalated to 1.4 mg/kg.
4.3.2.6
Post-Induction Treatment
Patients with FL who achieve a CR, a PR, or stable disease at EOI will receive 
maintenance treatment with obinutuzumab for 24 months, as outlined in Table 8.
Maintenance treatment should start 8 weeks (1 week) after Day 1 of Cycle 6 and will 
continue until disease progression or unacceptable toxicity for up to 24 months.
Table 8
Maintenance Treatment for Patients with Follicular Lymphoma
Treatment
Dose
Route
Regimen (Months 124)
Obinutuzumab
1000 mg
IV
Day 1 of every other month (i.e., every 
2 months), starting with Month 1
FLfollicular lymphoma; IVintravenous.
4.3.2.7
Premedication and Other Prophylaxis Treatment
Patients should receive premedication as outlined in Table 9 below.


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Table 9
Premedication
Timepoint
Patients Requiring Premedication
Premedication
Administration
Cycle 1, 
Day 1

All patients

Oral corticosteroid a
Administer at least 1 hour prior to 
obinutuzumab or rituximab infusion

All patients

Antihistamine drug b

Oral analgesic/anti-pyretic c
Administer at least 30 minutes prior to 
obinutuzumab or rituximab infusion

Patients at risk for TLS (e.g., because of
bulky disease or renal impairment 
(creatinine clearance 70 mL/min)

Allopurinol or suitable alternative 
such as rasburicase, along with 
adequate hydration
Administer prior to obinutuzumab or 
rituximab infusion
Cycle 1, 
Days 8 and 
15
Cycles 2 
and 
beyond,
Day 1

Patients with no IRR during the previous 
infusion

Oral analgesic/anti-pyretic c
Administer at least 30 minutes prior to 
obinutuzumab infusion. For patients 
receiving rituximab premedication may be 
omitted at the investigator’s discretion.

Patients with Grade 1 or 2 IRR during the 
previous infusion

Antihistamine drug b

Oral analgesic/anti-pyretic c
Administer at least 30 minutes prior to 
obinutuzumab infusion

Patients with Grade 3 IRR, wheezing, 
urticaria, or other symptoms of 
anaphylaxis during the previous infusion

Patients with bulky disease

Oral corticosteroid a
Administer at least 1 hour prior to 
obinutuzumab or rituximab infusion

Antihistamine drug b

Oral analgesic/anti-pyretic c
Administer at least 30 minutes prior to 
obinutuzumab infusion

Patients still at risk for TLS

Allopurinol or suitable alternative 
such as rasburicase, along with 
adequate hydration
Administer prior to obinutuzumab or 
rituximab infusion
IRRinfusion-related reaction; TLStumor lysis syndrome.
a Treat with 100 mg of prednisone or prednisolone, 20 mg of dexamethasone, or 80 mg of methylprednisolone.  Hydrocortisone should not be 
used because it has not been effective in reducing rates of IRR.
b For example, 50 mg of diphenhydramine.
c For example, 1000 mg of acetaminophen/paracetamol.


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4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (obinutuzumab, rituximab, and 
polatuzumab vedotin) will be provided by the Sponsor.  The study site will acknowledge 
receipt of IMPs using the IxRS to confirm the shipment condition and content.  Any 
damaged shipments will be replaced.
An IMP will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or returned to the Sponsor with the 
appropriate documentation.  The site’s method of IMP destruction must be agreed to by 
the Sponsor.  The site must obtain written authorization from the Sponsor before any 
IMP is destroyed, and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Trial Access to, Obinutuzumab, Rituximab, and 
Polatuzumab Vedotin
Patients may continue to receive study treatment and undergo scheduled assessments 
as part of an extension study.  Currently, the Sponsor does not have any plans to 
provide post-trial access to any IMP or interventions to patients who do not qualify for 
the extension study. The Roche Global Policy on Continued Access to Investigational 
Medicinal Product is available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to the screening period to the visit at EOI or at the end of post-induction 
treatment, whichever occurs later.  All such medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
Premedication should be administered as described in Section 4.3.2.7.
Patients who use oral contraceptives, hormone replacement therapy, or other 
maintenance therapy should continue their use. 
Patients using concomitant medication that could possibly worsen 
thrombocytopenia-related events (e.g., platelet inhibitors and anticoagulants) may be at 
a greater risk of bleeding.  When possible, replace prior vitamin K antagonist therapy 
with low-molecular-weight heparin (LMWH) prior to Day 1 of Cycle 1.


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Hematopoietic growth factors are allowed if clinically indicated and used in accordance 
with the prescribing information.  Granulocyte colony-stimulating factor (G-CSF) may be 
administered in each cycle of therapy as primary prophylaxis for neutropenia, per 
American Society of Clinical Oncology, EORTC, and European Society for Medical 
Oncology guidelines or per each site’s institutional standards.
Prophylactic treatment with antibiotics should be administered as per standard practice.
The patients who receive strong CYP3A4 inhibitors or P-glycoprotein (P-gp) inhibitors in 
combination with polatuzumab vedotin will be closely monitored for any adverse 
reactions.
Necessary supportive measures for optimal medical care will be given throughout the 
study according to institutional standards.
4.4.2
Prohibited Therapy
Use of the following therapies (excluding protocol-specified treatments) is prohibited 
during the study:

Any anti-cancer therapy, approved or investigational, other than intrathecal CNS
prophylaxis

Hormonal therapy other than contraceptives, stable hormone replacement therapy, 
or megestrol acetate

Biologic agents other than hematopoietic growth factors (as described in 
Section 4.3.2.7)

Immunostimulatory agents, including, but not limited to, IFN-, IFN-, or IL-2
Immunostimulatory agents, in combination with atezolizumab, could potentially
increase the risk for autoimmune conditions.  Patients should not receive other 
immunostimulatory agents for 10 weeks after the last dose of atezolizumab.

Vaccines, as outlined below:
Any live, attenuated vaccine (e.g., FluMist) is prohibited while the patient is 
receiving atezolizumab and for a period of five months after discontinuation of 
atezolizumab.  Inactivated influenza vaccines are allowed only during flu 
season.
Vaccination with live vaccines is not recommended during treatment with 
obinutuzumab and until B-cell recovery.
4.5
STUDY ASSESSMENTS 
See Appendix 1 and Appendix 2 for the schedules of assessments performed during the 
study.


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4.5.1
Informed Consent Forms, Screening Log, and Patient 
Screening
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Results of standard-of-care tests or examinations performed prior to obtaining informed 
consent, and within the defined window, may be used as screening and baseline 
assessments (see Appendix 1 and Appendix 2); such tests do not need to be repeated 
for screening purposes (e.g., screening tumor assessment).
Study treatment should be initiated within 28 days after the Informed Consent Form has 
been signed.
Patients who fail screening based on longer waiting time for certain results or due to 
study administrative reasons (e.g., a dose cohort on enrollment hold) can be rescreened 
at a later date, and only once, if they were deemed eligible before the screen failure. 
The decision to rescreen individual patients will be made jointly by the Roche Medical 
Monitor and the investigator and any other person the investigator or Medical Monitor 
considers necessary to assist with this decision.  Any such decision and the reasons for 
it will be clearly documented.  Any out of window assessments need to be repeated and 
undergo a complete review by the Roche Medical Monitor.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, reproductive status, 
smoking history, and alcohol and drug abuse.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) used by the patient within seven days prior to the screening 
period will be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
The following clinical parameters relative to disease history, diagnosis, and prognostic 
indices will be recorded at screening:

Date of initial diagnosis

ECOG Performance Status (see Appendix 6)

B symptoms (unexplained fever 38C, night sweats, and unexplained weight loss 
10% of body weight over 6 months)


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
Ann Arbor staging (see Appendix 7)

For patients with FL:  Follicular Lymphoma International Prognostic Index (FLIPI) 
and Follicular Lymphoma International Prognostic Index 2 (FLIPI2) (see Appendix 8)

For patients with DLBCL:  The IPI (see Appendix 8)

Prior anti-lymphoma treatment, as well as response to prior treatment, date of 
disease progression in relation to start date of prior treatment, and date of last dose 
of prior treatment
4.5.3
Physical Examinations
A complete physical examination should be performed at screening and should include 
an evaluation of the head, eyes, ears, nose, and throat and the cardiovascular, 
dermatological, musculoskeletal, respiratory, GI, genitourinary, and neurological systems.  
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
As part of tumor assessment, the physical examination should include evaluation for the 
presence of enlarged nodes, palpable hepatomegaly, and splenomegaly.  This 
information will be recorded on the appropriate tumor assessment eCRF.
At subsequent visits (or as clinically indicated), targeted (limited, symptom-directed) 
physical examinations should be performed.  Targeted physical examinations should be 
limited to systems of primary relevance (e.g., cardiovascular and respiratory systems), 
systems associated with symptoms (newly emergent or monitored from baseline), and 
areas associated with tumor assessment (lymph nodes, liver, spleen, and any other 
areas identified at baseline) (see Section 4.5.5).
Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, body temperature, 
and systolic and diastolic blood pressures while the patient is in a seated position.  Vital 
sign measurements will be performed as outlined in the schedules of assessments 
(see Appendix 1 and Appendix 2), but the associated data, other than the data collected 
at screening, do not need to be recorded on the eCRF (except in the case of an adverse 
event as presented in Section 5.3.5.6).


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4.5.5
Tumor and Response Evaluations
All evaluable or measurable disease must be documented at screening and re-assessed 
at each subsequent tumor evaluation.  Response will be assessed by the investigator on 
the basis of PET and CT scans using the Lugano 2014 criteria (see Appendix 5).  In this 
study, the Lugano 2014 criteria for a PET-CT-based CR and PR have been modified, as 
outlined below:

A designation of PET-CT-based CR requires normal bone marrow by morphology 
for patients with bone marrow involvement at baseline.  If indeterminate by 
morphology, immunohistochemistry should be negative.

A designation of PET-CTbased PR requires that CT-based response criteria for a 
CR or PR be met in addition to the PET-CTbased response criteria for a PR.
4.5.6
Radiographic Assessments
The PET scans should include skull-base to mid-thigh.  Full body PET scans should be 
performed when clinically appropriate.
The CT scans with oral and IV contrast should include chest, abdomen, and pelvic scans.  
The CT scans of the neck should be included if clinically indicated (i.e., if evidence of 
disease upon physical examination) and must be repeated throughout the study if there 
is disease involvement at baseline.
The PET-CT scans and diagnostic CT scans should be acquired according to a 
standardized imaging manual, which will be provided to all sites.
If contrast is medically contraindicated (e.g., patients with contrast allergy or impaired 
renal clearance), MRI scans of the chest, abdomen, and pelvis (and neck, if clinically 
indicated) and a non-contrast CT scan of the chest may be performed.  If MRI scans 
cannot be obtained, CT scans without contrast are permitted as long as these allow 
consistent and precise measurement of the targeted lesions during the study treatment 
period.
The same radiographic assessment modality must be used for all response evaluations 
to ensure consistency across different timepoints (including unscheduled assessments).
A full tumor assessment, including radiographic assessment, must be performed any 
time disease progression or relapse is suspected.  Additional details regarding imaging 
procedures will be provided in the Imaging Manual.
4.5.6.1
Bone Marrow Assessments
Bone marrow examinations are required at screening for staging purposes in all patients 
and should be performed within approximately 3 months prior to Day 1 of Cycle 1.


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If bone marrow infiltration is present at screening, a bone marrow biopsy is required at 
the EOI response assessment for all patients who may have achieved a CR.  In patients 
with a PR at EOI, a subsequent bone marrow examination may be required to confirm a 
CR at a later timepoint.
Any additional (unscheduled) bone marrow examinations performed during the study will 
be at the discretion of the investigator.
4.5.7
Laboratory, Biomarker, and Other Biological Samples
Local Laboratory Assessments
Samples for the following laboratory tests will be analyzed at the study site's local 
laboratory for analysis:

Hematology:  hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
percent or absolute WBC differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, and other cells) 

Chemistry panel (serum or plasma):  sodium, potassium, glucose, BUN or urea, 
creatinine, calculated creatinine clearance, calcium, total bilirubin, direct bilirubin, 
total protein, albumin, ALT, AST, alkaline phosphatase (ALP), LDH, uric acid, 
glycosylated hemoglobin (HbA1c), amylase, and lipase.
HbA1c will be measured only at screening and can be obtained in a non-fasting 
state.

Thyroid-stimulating hormone, triiodothyronine, thyroxine (T4)

2 microglobulin

Coagulation: INR, aPTT (or PTT), and PT

Pregnancy test
All women of childbearing potential will have a serum pregnancy test at 
screening (within 7 days of Day 1 of Cycle 1).  In addition, urine pregnancy 
testing is required monthly during induction.  If a urine pregnancy test is positive, 
it must be confirmed by a serum pregnancy test.

Viral serology 
Hepatitis B testing includes HBsAg and total HBcAb.  
Hepatitis C testing includes HCV antibody.

Quantitative immunogloblulins:  IgA, IgG, and IgM
Central Laboratory Assessments
The following samples will be sent to one or several Sponsor-designated central 
laboratories or to the Sponsor for analysis:

Serum samples for obinutuzumab PK analysis using a validated assay

Serum samples for rituximab PK analysis using a validated assay

Serum samples for atezolizumab PK analysis using a validated assay


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
Serum and plasma samples for polatuzumab vedotin PK analysis using a validated 
assay

Serum samples for assessment of HAHAs to obinutuzumab using a validated assay

Serum samples for assessment of HACAs to rituximab using a validated assay

Serum samples for assessment of ATAs to atezolizumab using a validated assay

Serum samples for assessment of ATAs to polatuzumab vedotin using a validated 
assay

Tumor tissue samples and the corresponding pathology report for retrospective 
central confirmation of the diagnosis of FL or DLBCL, and for exploratory research 
on candidate biomarkers (see Table 10).
The specimen must contain adequate evaluable tumor cells (20% for 
excisional biopsy and 50% for core biopsy).
Formalin-fixed paraffin-embedded tissue blocks are preferred over slides.  
Tissue blocks that are not formalin fixed will be accepted in countries that use a 
fixative other than paraformaldehyde, but information on the type of fixative 
should be included.  If a tissue block is not available, 1520 serial, freshly cut, 
unstained slides accompanied by a punch biopsy may be sent.  A tumor block 
or punch biopsy is required for construction of a tissue microarray.  If less than 
1520 unstained serial slides are available, the study site should consult the 
Sponsor (or delegate) regarding the acceptability of a fewer number of slides.
If archival tissue is unavailable or unacceptable according to the above criteria, 
a pretreatment core-needle, excisional, or incisional tumor biopsy is required.  
Cytological or fine-needle aspiration samples are not acceptable.
If the patient received anti-lymphoma treatment between the time of the most 
recent available biopsy and initiation of study treatment, or if the available 
biopsy was performed more than 6 months prior to Day 1 of Cycle 1 (initiation 
of study treatment) for patients with DLBCL or more than 12 months prior to 
Day 1 of Cycle 1 for patients with FL, a core-needle biopsy is strongly 
recommended.
The sample should be shipped according to instructions provided in the 
laboratory manual.  The remainder of the tissue blocks will be returned to the 
local pathology laboratory, according to country-specific procedures.
Analysis methods will be detailed in the Biomarker Analysis Plan.

Tumor biopsy samples obtained prior to the start of Cycle 2 and at the time of 
progression (unless no adequate tumor site is accessible) for exploratory research 
on candidate biomarkers (Table 10)

Serum samples for exploratory research on candidate biomarkers (see Table 10)

Whole blood samples for exploratory research on candidate biomarkers 
(see Table 10)

Whole blood samples for isolation of peripheral blood mononuclear cells for 
exploratory research on candidate biomarkers (see Table 10)


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Exploratory biomarker research may include, but will not be limited to, the biomarkers 
listed in Table 10.
Table 10 Proposed Non-Inherited Biomarkers for Exploratory Research
Sample Type
Timing
Proposed 
Non-Inherited Biomarkers
Archival or fresh tumor 
tissue
Prior to study (archival) or 
baseline (fresh)

For patients with DLBCL only:  
DLBCL cell-of-origin subtype 
(ABC vs. GCB), MYC, BCL2, 
Epstein-Barr virus status

CD79b 

Lymphoma-related genetic 
changes (DNA) and gene 
expression (mRNA)

PD-L1, HLA-1

CD8 and other biomarkers of 
T-cell subpopulations

Biomarkers of other immune 
cells (such as macrophages)
Tumor tissue biopsy
Prior to the start of Cycle 2 
and at the time of 
progression (unless no 
adequate tumor site is 
accessible)

PD-L1 

CD8 and other biomarkers of 
T-cell subpopulations and other 
immune cells
Plasma
Baseline

Soluble PD-L1
Plasma
Baseline and subsequent 
timepoints during treatment

Cytokines characteristic of T-cell 
activation (e.g., IL-18, IFN-)
PBMCs isolated from 
whole blood
Baseline and subsequent 
timepoints during treatment

T-cell receptor repertoire
Whole blood
Baseline and subsequent 
timepoints during and after 
treatment

Lymphocyte 
immunophenotyping, including 
B-cell counts (CD19), T-cell 
counts (CD3, CD4, and CD8), 
and NK cell counts (CD16 and 
CD56) 
ABCactivated B cell–like; DBLCLdiffuse large B-cell lymphoma; GCBgerminal-center 
B cell-like; HLAhuman lymphocyte antigen; IFN-interferon gamma; ILinterleukin; 
NKnatural killer; PBMCperipheral blood mononuclear cell.
Note:  Exploratory biomarker research may include, but will not be limited to, the biomarkers 
listed in this table.
Samples collected for PK and immunogenicity analyses may be used for assay 
development purposes and additional safety and immunogenicity assessments, as 
appropriate.


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Biological samples will be destroyed when the final Clinical Study Report has been 
completed, unless the patient gives specific consent for the leftover samples to be stored 
for optional exploratory research (see Section 4.5.9).
4.5.8
Electrocardiograms
Single, resting, 12-lead ECG recordings will be obtained at specified timepoints, as 
outlined in the schedules of assessments (see Appendix 1 and Appendix 2), and may be 
obtained at unscheduled timepoints as clinically indicated.  ECGs for each patient should 
be obtained using the same machine wherever possible.  Interpretation of the ECG 
should be performed by the investigator.
4.5.9
Samples for Roche Clinical Repository 
4.5.9.1
Overview of the Roche Clinical Repository
The Roche Clinical Repository (RCR) is a centrally administered group of facilities used 
for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized 
therapy for patients in the future.
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  The RCR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.9.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RCR are contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site’s Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RCR sampling, this section of the protocol (Section 4.5.9) will not be 
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4.5.9.3
Sample Collection
The following samples will be collected for research purposes, including, but not limited 
to, research on dynamic (non-inherited) biomarkers related to obinutuzumab, 
atezolizumab, polatuzumab vedotin, NHL, or other types of cancer:

Peripheral blood (i.e., whole blood, plasma, and serum)

Leftover tumor tissue from lymph node biopsy (archival and/or fresh biopsy)

Leftover peripheral blood
For all samples, dates of consent should be recorded on the associated RCR page of 
the eCRF.  For sampling procedures, storage conditions, and shipment instructions, see 
the laboratory manual.
The RCR specimens will be destroyed no later than 15 years after the date of final 
closure of the associated clinical database.  The RCR storage period will be in 
accordance with the IRB/EC-approved Informed Consent Form and applicable laws 
(e.g., health authority requirements).
4.5.9.4
Confidentiality
Confidentiality for All Roche Clinical Repository Specimens
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise.
Additional Confidentiality for Specimens Used for Genetic Research
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens collected for genetic research.  
Upon receipt by the RCR, specimens for genetic research are "double-coded" by 


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replacing the patient identification number with a new independent number.  Data 
generated from the use of these specimens and all clinical data transferred from the 
clinical database and considered relevant are also labeled with this same independent 
number.  A "linking key" between the patient identification number and this new 
independent number is stored in a secure database system.  Access to the linking key is 
restricted to authorized individuals and is monitored by audit trail.  Legitimate operational 
reasons for accessing the linking key are documented in a standard operating procedure.  
Access to the linking key for any other reason requires written approval from the Pharma 
Repository Governance Committee and Roche’s Legal Department, as applicable.
4.5.9.5
Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient’s agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
4.5.9.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient’s wishes through use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient’s withdrawal 
from Study BO29561 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient’s withdrawal from the RCR does not constitute withdrawal 
from Study BO29561.
4.5.9.7
Monitoring and Oversight
The RCR specimens will be tracked in a manner consistent with Good Clinical Practice 
(GCP) by a quality-controlled, auditable, and appropriately validated laboratory 
information management system, to ensure compliance with data confidentiality as well 
as adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche’s monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 


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of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples.
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance (e.g., consistent failure to show up for scheduled visits)
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.
If a patient withdraws consent, this request must be documented in the source 
documents and signed by the investigator.  Study personnel may use a public 
information source (e.g., county records) to obtain information about survival status.
4.6.2
Study Treatment Discontinuation
Study treatment should be permanently discontinued in patients who experience any of 
the following:

Anaphylaxis, acute respiratory distress, or Grade 4 IRR
If a Grade 3 IRR is recurrent during the second and subsequent cycles, study 
treatment may be discontinued at the discretion of the investigator, following an 
individual benefit-risk assessment.

Life-threatening adverse event

Grade 3 nonimmune-related adverse event that is considered to be related to 
study treatment and does not resolve to Grade 2 within 21 days

Nonimmune-related adverse event that is considered to be treatment related and 
requires study treatment to be withheld for 21 days

Grade 3 immune-related adverse event that is considered to be related to 
atezolizumab or requires atezolizumab to be withheld for 42 days, unless 
approved by the Medical Monitor

Any adverse event that meets criteria for permanent discontinuation per guidelines 
provided in Section 5.1


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
Disease progression
Because of the potential for tumor flares with immunotherapies, resulting in 
early apparent radiographic progression (pseudoprogression/tumor immune 
infiltration), including the appearance of new lesions followed by delayed 
response (Wolchok et al. 2009), patients whose CT scans meet the criteria for 
disease progression may continue to receive study treatment at the discretion 
of the investigator and following discussion with the Medical Monitor, if certain 
criteria are met (see Section 4.1 for details).  Cases of delayed 
pseudoprogression have also been described in patients with solid tumors 
treated with immunotherapies.  In case of CT- findings suggestive for 
pseudoprogression in patients with persistent clinical benefit, the investigator 
should contact the Medical Monitor to discuss further patient management.  
Patients who continue to receive study treatment should have a CT scan 
repeated 48 weeks later.

Pregnancy
In case of toxicity solely attributable to one drug of the combination requiring 
discontinuation, the other study drugs may be continued for patients experiencing clinical 
benefit as determined by the investigator after discussion with the Medical Monitor.
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.
Patients who discontinue study treatment will not be replaced, except as outlined below:

During the dose-escalation phase, patients who discontinue study treatment prior to 
completing the DLT assessment window for reasons other than a DLT will be 
replaced by an additional patient at that same dose level.

During the expansion phase, patients who discontinue study treatment prior to 
receiving at least one dose of each component of the combination will be replaced.
4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence


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
Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for GCP

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients in this study is based on clinical experience with study 
treatment components in completed and ongoing studies.  The anticipated important 
safety risks of IMPs in this study (i.e., obinutuzumab, rituximab, atezolizumab, and 
polatuzumab vedotin) are outlined below.  Refer to the Obinutuzumab, Rituximab, 
Atezolizumab, and Polatuzumab Vedotin Investigator’s Brochures for a complete 
summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this trial.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities 
(see Section 4.1).  In addition, patients will undergo adequate safety monitoring during 
the study, as described in this section and in Section 4.5.  Finally, guidelines for 
managing adverse events, including criteria for dosage modification and treatment 
delays or discontinuation, have been provided (see Section 5.1.6).
5.1.1
Risks Associated with Obinutuzumab
The following adverse events are considered to be important risks associated or 
potentially associated with obinutuzumab:  IRRs, hypersensitivity reactions, TLS, 
neutropenia (including prolonged and late onset neutropenia), thrombocytopenia 
(including acute thrombocytopenia), infections (including PML and HBV reactivation), 
prolonged B-cell depletion, impaired immunization response, worsening of preexisting 
cardiac conditions, GI perforation, immunogenicity, and second malignancies.  These 
events, with the exception of prolonged B-cell depletion, immunogenicity, and second 
malignancies, are described below.
5.1.1.1
Infusion-Related Reactions
IRRs have been reported predominantly during the first infusion of obinutuzumab.  The 
incidence and severity of IRRs decreased substantially with the second and subsequent 
infusions.  In the majority of patients, IRRs were mild or moderate and resolved with the 
slowing or interruption of the infusion and supportive care.  The commonly experienced 
IRRs have been characterized by nausea, fatigue, chills, hypotension, fever, vomiting, 
dyspnea, flushing, hypertension, headache, tachycardia, dizziness, diarrhea, and other 
symptoms.
IRRs may be clinically indistinguishable from IgE-mediated allergic or anaphylactic 
reactions; anaphylaxis has been reported in patients treated with obinutuzumab.


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Hypotension may occur during obinutuzumab IV infusions.  Therefore, withholding of 
anti-hypertensive treatments should be considered for 12 hours prior to and throughout 
each obinutuzumab infusion and for the first hour after administration.  Patients at acute 
risk of hypertensive crisis should be evaluated for the benefits and risks of withholding 
their anti-hypertensive medication.
Patients who have preexisting cardiac or pulmonary conditions should be monitored 
carefully throughout the infusion and the postinfusion period.
Guidelines for medical management of IRRs and anaphylaxis are provided in 
Section 4.3.2.1 and Appendix 9.
5.1.1.2
Hypersensitivity Reactions
Hypersensitivity reactions with immediate (e.g., anaphylaxis) and delayed onset 
(e.g., serum sickness) have been reported in patients treated with obinutuzumab.  
Hypersensitivity reactions typically occur after previous exposure and very rarely with the 
first infusion.  If a hypersensitivity reaction is suspected during or after an infusion, the 
infusion should be stopped and treatment permanently discontinued.
5.1.1.3
Tumor Lysis Syndrome
The TLS, including fatal events, has been reported with obinutuzumab administration.  
Patients at risk for TLS (e.g., because of bulky disease or renal insufficiency) should 
receive adequate hydration and premedication with allopurinol or an alternative 
uricostatic agent as indicated in Section 4.3.2.7 (see Table 9).  Additional guidelines for 
management of TLS in this study are provided in Section 5.1.6.
5.1.1.4
Neutropenia
Grade 3 or 4 neutropenia, including febrile neutropenia, has been reported with 
obinutuzumab administration.  Neutropenia resolved spontaneously or with use of 
hematopoietic growth factors.  Patients who experience Grade 3 or 4 neutropenia 
should be closely monitored until neutrophil values return to at least Grade 2.  Cases of 
late-onset neutropenia (ANC 1000 cells/L occurring 28 days after obinutuzumab 
treatment has been completed or stopped) or prolonged neutropenia (ANC 
1000 cells/L that does not resolve after 28 days without obinutuzumab treatment) 
have also been reported.  Prophylactic treatment with antibiotics should be administered 
as per standard practice.  The use of G-CSF is allowed for treatment of neutropenia in 
this study.  Guidelines for primary prophylaxis with G-CSF are provided in 
Section 4.3.2.7.
5.1.1.5
Thrombocytopenia
Severe and life-threatening thrombocytopenia, including acute thrombocytopenia 
(occurring within 24 hours after the infusion), has been observed during treatment with 
obinutuzumab.  In patients with CLL exposed to obinutuzumab, fatal hemorrhagic events 
have also been reported in Cycle 1.  A clear relationship between thrombocytopenia and 


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hemorrhagic events has not been established.  Patients receiving concomitant 
medication that could possibly worsen thrombocytopenia related events (e.g., platelet 
inhibitors and anticoagulants) may be at greater risk of bleeding.  When possible, 
replace prior vitamin K antagonist therapy with LMWH prior to Day 1 of Cycle 1.  
Patients should be closely monitored for thrombocytopenia, especially during the first 
cycle.  For patients who experience thrombocytopenia, 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) may be performed at the discretion of the treating physician, according to 
institutional practice.
5.1.1.6
Infections
On the basis of its mechanism of action, resulting in profound B-cell depletion, 
obinutuzumab may be associated with an increased risk of infections.  Obinutuzumab 
should not be administered to patients with active infection, and caution should be 
exercised when including patients with a history of recurrent or chronic infections.
Serious bacterial, fungal, and new or reactivated viral infections can occur during and 
following the completion of obinutuzumab therapy.  Fatal infections have been reported.
In the Gallium study (BO21223), a high incidence of infections was observed in all 
phases of the study (81%), including follow-up (19%), with the highest incidence 
observed during maintenance (70%) in recipients of obinutuzumab and chemotherapy.  
During the follow-up phase, Grade 35 infections (12%) were observed more in patients 
who received obinutuzumab plus bendamustine in the induction phase.
Reactivation of hepatitis B in patients with chronic hepatitis (HBsAg positive) with 
evidence of prior hepatitis B exposure or in patients who are carriers (HBsAg negative 
and HBcAb positive) has been reported with other anti-CD20 antibodies.  The risk is 
increased particularly when anti-CD20 antibodies are administered with 
immunosuppressive therapies, such as steroids or chemotherapy.  Patients who are 
positive for HBsAg and HBcAb are not eligible for this study.
JC viral infection resulting in PML has been reported in patients treated with 
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 symptoms with 
corticospinal tract findings (e.g., muscular weakness, paralysis, and sensory 
disturbances), sensory abnormalities, cerebellar symptoms, and visual field defects are 
common.  Some signs or symptoms regarded as "cortical" (e.g., aphasia or visual-spatial 
disorientation) may occur.  Evaluation of PML includes, but is not limited to, consultation 
with a neurologist, brain MRI, and lumbar puncture (cerebrospinal fluid testing for 
JC viral DNA).  Additional guidelines for medical management of PML in this study are 
provided in Section 5.1.6.


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5.1.1.7
Immunizations
The safety of immunization with live vaccines following obinutuzumab therapy has not 
been studied.  Thus, vaccination with live virus vaccines is not recommended during 
treatment and until B-cell recovery.
5.1.1.8
Worsening of Pre-existing Cardiac Conditions
In patients with underlying cardiac disease and treated with obinutuzumab, adverse 
events such as angina pectoris, acute coronary syndrome, myocardial infarction, heart 
failure, and arrhythmias, including atrial fibrillation and tachyarrhythmia, have been 
observed.  These events may occur as part of an IRR and can be fatal.  Therefore, 
patients with a history of cardiac disease should be monitored closely.  In addition, these 
patients should be hydrated with caution to prevent a potential fluid overload.
5.1.1.9
Gastrointestinal Perforation
The GI perforation has been reported in patients treated with obinutuzumab, mainly in 
NHL, including fatal events.  Patients with GI involvement should be monitored for signs 
of GI perforation.
5.1.2
Risks Associated with Rituximab
The following adverse events are considered to be important risks associated or 
potentially associated with rituximab:  An IRRs, infections (including PML and HBV 
reactivation), neutropenia (including prolonged neutropenia), TLS, impaired 
immunization response, severe skin reactions, and GI perforation.  Details for these risks 
are provided below; refer to Rituximab Investigator’s Brochure for full information.
5.1.2.1
Infusion-Related Reactions
Acute IRRs are very common in patients receiving rituximab (occurring in 10% of 
patients) based on clinical trial experience.  However, serious IRRs are uncommonly 
reported (occurring in 1 of 1,000 and 1 of 100 patients) and are rarely fatal (occurring 
in 1 of 10,000 and 1 of 1,000 patients).  Most IRRs occur with the first administration 
of rituximab.  Rituximab-induced IRRs consist of a cluster of symptoms and signs 
occurring during or within 24 hours of a rituximab infusion which may be related to 
cytokine release and/or other chemical mediators, and these acute IRRs overlap with 
“cytokine release syndrome.”  Anaphylactic and other hypersensitivity reactions have 
been reported following rituximab administration, and clinical manifestations of these 
reactions are similar to cytokine release syndrome.  In contrast to cytokine release 
syndrome, true hypersensitivity reactions typically occur within minutes of starting the 
rituximab infusion.
5.1.2.2
Infections (Including Serious Infections)
Serious infections, including fatal bacterial, fungal, and new or reactivated viral infections, 
can occur during and up to 1 year following completion of rituximab-based therapy. 


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5.1.2.3
Hepatitis B Reactivation
Reactivation of hepatitis B ranges from asymptomatic reactivations (detected by 
changes in laboratory parameters only) to fulminant liver failure and death.  Patients with 
chronic hepatitis B (HBsAg positive) viral infection 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 anti-HBcAb positive) are at a lower risk for 
reactivation.  Patients who demonstrate evidence of reactivation while receiving an 
appropriate anti-viral therapy will be discontinued from study treatment.
5.1.2.4
Progressive Multifocal Leukoencephalopathy
Rare cases of PML have also been reported in patients treated with rituximab alone or in 
combination with other immunosuppressive medications (Goldberg et al. 2002; 
Calabrese et al. 2007; Carson and Bennett 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 rare, but it 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 SCT.  Most cases of PML were diagnosed within 12 months of the 
patients’ last infusion of rituximab.
5.1.2.5
Neutropenia
Neutropenia is very common in patients receiving rituximab (occurring in 10% of 
patients) based on clinical trial experience.  However, delayed onset neutropenia is very 
rare (occurring in 1 of 10,000 patients), and the incidence of prolonged neutropenia is 
unknown.  Neutropenia may lead to serious or overwhelming infection, especially if 
profound (Grade 34), prolonged, associated with breaches in natural mucosal barriers 
(e.g., diarrhea and/or mucositis), and/or other immunological defects (e.g., lymphopenia, 
hypogammaglobulinemia, and acquired immunodeficiency syndrome).  Despite an 
increase in incidence of neutropenia and Grade 34 neutropenia associated with 
rituximab, most studies have not reported a significant increase in serious neutropenic 
infections.
5.1.2.6
Tumor Lysis Syndrome
Patients treated with rituximab may be at risk for TLS.  Severe tumor TLS is very rare in 
patients receiving rituximab (occurring in 1 of 10,000 patients), based on postmarketing 
experience.  Signs and symptoms (e.g., hyperuricemia, hyperkalemia, hypocalcemia, 
hyperphosphatemia, acute renal failure, and elevated LDH) that are consistent with TLS 
have been reported to occur after the first MabThera/Rituxan IV infusion in patients with 
high numbers of circulating malignant lymphocytes.  A high number of circulating 
malignant cells (25,000/mm3) or high tumor burden confers a greater risk of TLS.  For 
patients with evidence of TLS, rituximab should be discontinued, and the patient should 
be treated as clinically indicated.


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5.1.2.7
Impaired Immunization Response
B-cell depletion is expected (and desired) during rituximab therapy and is directly related 
to its mechanism of action. In theory, peripheral B-cell depletion may reduce the 
effectiveness of immunization, since patients may not be able to mount an effective 
humoral immune response to foreign antigens.
5.1.2.8
Severe Skin Reactions
Severe reactions, including fatal mucocutaneous reactions, can occur in patients 
receiving rituximab.  The onset of these reactions in patients treated with rituximab has 
varied from 113 weeks following rituximab exposure. The majority of the TEN/SJS 
cases reported with rituximab were associated with additional risk factors. Fatal outcome 
also appeared to increase in patients who were exposed to multiple risk factors for 
TEN/SJS.
5.1.2.9
Gastrointestinal 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 GI perforation 
was 6 days (range: 177 days) in patients with NHL.
5.1.3
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-related hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, 
hypophysitis, myocarditis, and nephritis.  In addition, systemic immune activation is a 
potential risk when atezolizumab is given in combination with other immunomodulating 
agents.  Refer to Section 6 of the Atezolizumab Investigator's Brochure for a detailed 
description of anticipated safety risks for atezolizumab.
Guidelines for management of atezolizumab-associated non-hematologic toxicity are 
provided in Table 14 and Table 15.
5.1.4
Risks Associated with Polatuzumab Vedotin 
The clinical safety profile of polatuzumab vedotin based on clinical data obtained in the 
ongoing Phase I and II studies is summarized in Section 1.4.  On the basis of clinical 
data to date, the following identified and potential risks are described below.  Guidelines 
around the management of these risks through dose and schedule modifications are 
described in Section 5.1.6.  Refer also to the current Polatuzumab Vedotin Investigator’s 
Brochure for complete and updated details.


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5.1.4.1
Identified Risks for Polatuzumab Vedotin
On the basis of clinical experience with polatuzumab vedotin in patients treated in the 
current Phase I and II studies, neutropenia and peripheral neuropathy are identified risks 
of polatuzumab vedotin.
Neutropenia
Neutropenia and neutropenia-associated events resulted in protocol-mandated dose 
reductions and/or delays.  Serious neutropenia including febrile neutropenia has been 
reported during treatment with polatuzumab vedotin.  Patients with inadequate 
hematologic function will be excluded from this study (see Section 4.1.2).  Patients 
receiving study treatment will be regularly monitored for evidence of marrow toxicity with 
complete blood counts.  Treatment may be delayed for hematologic toxicities as 
described in Section 5.1.6.  The G-CSF may be administered for neutropenia as 
described in Section 4.3.2.7.
Peripheral Neuropathy
Patients receiving polatuzumab vedotin may develop or experience worsening of 
peripheral neuropathy.  Patients in clinical trials with polatuzumab vedotin should be 
monitored for symptoms of neuropathy (sensory and/or motor), including hypoesthesia, 
hyperesthesia, paresthesia, dysesthesia, discomfort, a burning sensation, weakness, 
gait disturbance, or neuropathic pain.  Patients experiencing new or worsening 
peripheral neuropathy may require a dose delay, change in dose, or discontinuation of 
treatment and should be managed according to the protocol.  Study treatment dose and 
schedule modifications for peripheral neuropathy are described in Section 5.1.6.
5.1.4.2 Potential Risks for Polatuzumab Vedotin
Infections
Reports in the literature state that granulocytopenia is a major predisposing factor to 
infections in patients with B-cell lymphoma.  Patients receiving chemotherapy for B-cell 
lymphoma with a granulocyte count of 500 cells/L experienced a higher incidence of 
infections than those with a count of 500 cells/L.
Progressive Multifocal Leukoencephalopathy
 
 
 
 
 
 
 
 
 
 


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Infusion-Related Events
Because of the potential for infusion reactions, administration of polatuzumab vedotin 
will be performed in a setting with access to emergency equipment and staff who are 
trained to monitor and respond to medical emergencies.  All patients will be monitored 
for infusion reactions during the infusion and immediately afterward (for additional 
instructions on the monitoring and management of infusion reactions, see 
Section 4.3.2.3).  Precautions for suspected anaphylactic reaction during study drug 
infusions are provided in Section 4.3.2.3.  The initial dose of polatuzumab vedotin may 
be administered with premedication with acetaminophen, antihistamines, or 
corticosteroids per institutional standard practice at the discretion of the Investigator.  
Premedication should be instituted for subsequent doses if IRRs are observed in 
patients who receive their first dose of polatuzumab vedotin without premedications 
(see Section 4.3.2.3).  Significant issues with polatuzumab vedotin IRRs have not been 
observed.
Tumor Lysis Syndrome
There is the potential risk of TLS if treatment with polatuzumab vedotin results in the 
rapid destruction of a large number of tumor cells.  If any evidence of this occurs during 
the study, tumor lysis prophylaxis measures will be instituted.  Patients who are 
considered to have a high tumor burden (e.g., bulky lymphadenopathy) and who are 
considered to be at risk for tumor lysis by the investigator will receive tumor lysis 
prophylaxis (e.g., allopurinol 300 mg/day orally or a suitable alternative treatment 
[according to institutional practice] starting 1224 hours before study treatment) and 
must be well hydrated before the initiation of study treatment on Day 1 of Cycle 1.  
Patients should continue to receive repeated prophylaxis with allopurinol and adequate 
hydration before each subsequent infusion, as deemed appropriate by the investigator.
Bone Marrow Toxicity
Patients with inadequate hematologic function will be excluded from this study (see 
Section 4.1.2).  Patients receiving study treatment will be regularly monitored for 
evidence of marrow toxicity with complete blood counts.  Treatment may be delayed for 
hematologic toxicities as described in Section 5.1.6. 
Transfusion support for anemia and thrombocytopenia is also permitted at the discretion 
of the treating physician.


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Immunogenicity
As with any recombinant antibody, polatuzumab vedotin may elicit an immune response, 
and patients may develop antibodies against polatuzumab vedotin.  Patients will be 
closely monitored for any potential immune response to polatuzumab vedotin.  
Appropriate screening, confirmatory, and characterization assays will be employed to 
assess ATAs before, during, and after the treatment with polatuzumab vedotin.  
Reproductive Toxicity
Adverse effects on human reproduction and fertility are anticipated with the 
administration of polatuzumab vedotin given the mechanism of action of MMAE.  
Standard exclusion criteria are used to ensure that patients of childbearing potential 
(male or female) are using adequate contraceptive methods. 
Specific Gastrointestinal Toxicity 
Diarrhea, constipation, anorexia, nausea, and vomiting have been reported frequently as 
treatment-emergent adverse events in studies DCS4968g and GO27834 with 
polatuzumab vedotin.  Diarrhea has been responsible for study drug modification and 
discontinuations.
Hyperglycemia
Hyperglycemia has been observed in patients treated with polatuzumab vedotin as well 
as with other ADCs that use the same vc-MMAE platform.  Hyperglycemia has been 
reversible upon holding or discontinuing treatment of the ADCs and/or initiation or 
adjustment of anti-hyperglycemic medications.
Hepatotoxicity
Hepatotoxicity has been observed in patients treated with polatuzumab vedotin in both 
the Phase I and II trials.  Although the relationship between hepatotoxicity and 
polatuzumab vedotin has not been definitively determined, transient, dose-related 
increases in hepatic enzymes were noted in nonclinical rat studies.  No hepatotoxicity 
was noted following administration of the surrogate ADC in cynomolgus monkeys.  
Elevations of transaminases have been reported in patients receiving polatuzumab 
vedotin and have ranged in intensity from Grades 13.  These have been reversible with 
and without dose modification.
5.1.5
Risk of Overlapping Toxicities and Drug-Drug Interactions
As with any experimental regimen, there is a risk of unexpected/unknown toxicities that 
may occur during the study. Two patients with RR FL treated with obinutuzumab, 
atezolizumab, and polatuzumab vedotin experienced the concomitant occurrence of 
severe and difficult-to-treat dermatitis, oral mucositis, and ocular events refractory to 
standard treatment with corticosteroids.  The severity and the concomitant observation 
of this constellation of events is not consistent with the safety profile of the individual 
drugs (see Section 5.1.6), and hence constitutes an unexpected safety signal. 


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Hematologic toxicity (mainly neutropenia) is the most common toxicity associated with 
obinutuzumab, rituximab, and polatuzumab vedotin.  The risk of overlapping hematologic 
toxicity with the addition of atezolizumab to obinutuzumab/rituximab and polatuzumab 
vedotin is expected to be low.  There is no expectation for the combination to enhance 
the risk of peripheral sensory neuropathy associated with polatuzumab vedotin.  
Considering the risk associated with each individual component of the combination 
(Section 5.1.1, Section 5.1.3, and Section 5.1.4), the expected overlapping 
non-hematologic toxicities are IRRs, infections, skin rash, GI toxicity, and 
hepatotoxicity/elevated liver transaminases.  Additionally, there is an identified risk of 
TLS with obinutuzumab and rituximab and a potential risk with polatuzumab vedotin 
because these agents can result in the rapid destruction of a large number of tumor 
cells.  Therefore, overlapping toxicity in regard to TLS cannot be excluded.  Guidelines 
for management of patients who develop TLS are provided in Table 14.
The risk of clinically relevant PK DDIs is low between obinutuzumab/rituximab, 
atezolizumab, and polatuzumab vedotin.  Obinutuzumab/rituximab and polatuzumab 
vedotin are known to deplete or decrease circulating B cells and tumor burden, which 
may potentially affect the target-mediated clearance of obinutuzumab and polatuzumab 
vedotin.  However, in relapsed or refractory FL and DLBCL, the baseline B-cell count is 
low; therefore, the likelihood of B-cellmediated pharmacokinetic DDI is relatively low.  
This hypothesis is supported by preliminary results from the ongoing Study GO27834 in 
relapsed or refractory FL and DLBCL, where no interaction was observed between 
polatuzumab vedotin and rituximab.
In addition, the risk of CYP- and P-gpmediated DDI between obinutuzumab/rituximab
atezolizumab, and polatuzumab vedotin is considered low, as addressed below.
Obinutuzumab, rituximab, atezolizumab, and the antibody component of polatuzumab 
vedotin are therapeutic proteins, and are therefore not anticipated to interact directly with 
CYP isoforms or other drug-metabolizing enzymes or drug transporters.  Cytokine 
modulation may be considered as an indirect mechanism through which a monoclonal 
antibody could alter CYP expression.  For this treatment combination however, the 
unconjugated MMAE component of polatuzumab vedotin is considered the only moiety 
that could potentially be affected by a DDI involving this indirect mechanism.  
Administration of obinutuzumab results in merely transient increases in cytokine levels 
after the first infusion, and no increases are observed after subsequent infusions.  
Preclinical studies with anti-CD79 antibodies showed a low risk for release of systemic 
pro-inflammatory cytokines (Schmidt and Wittrup 2009).  In vitro data indicate that 
atezolizumab is unlikely to induce cytokine release.  Taken together, these results 
suggest that obinutuzumab/rituximab, atezolizumab, and polatuzumab vedotin are
unlikely to precipitate DDIs via indirect effects on cytokines. 
Simulation results based on a physiologically-based PK model (Chen et al. 2015) 
suggest that unconjugated MMAE exposure is unlikely to be altered by 50% when 


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polatuzumab vedotin is co-administered with strong CYP3A inhibitors or inducers and 
MMAE is unlikely to cause a DDI effect on other CYP substrates, supporting a low 
probability for a clinically significant DDI with unconjugated MMAE.  However, patients 
who receive concomitant medications that are strong CYP3A or P-gp inhibitors should 
be closely monitored for adverse reactions.
The potential for ATA-mediated DDIs among study treatment agents is considered low 
because the treatment combination is anticipated to deplete B-cells, and thus reduce the 
body’s ability to produce ATAs.
5.1.6
Concomitant Skin, Oral Mucosa, and Ocular Toxicity Observed 
in Patients with RR FL Treated with GAtezoPola 
Two patients with RR FL treated with obinutuzumab, atezolizumab, and polatuzumab 
vedotin experienced a concomitant severe dermatitis, oral mucositis, and ocular 
toxicities in the form of scleritis and conjunctivitis, respectively, partially responding to 
standard treatment with high dose corticosteroids.  T-cell infiltration was observed in the
skin biopsy of these 2 patients. Whereas the exact mechanism underlying the 
concomitant occurrence of severe dermatitis, oral mucositis, and ocular toxicities is 
unknown; there may be an increased risk for patients to develop immune adverse events
derived from the combination of these drugs by activation of the immune effectors.
Atezolizumab was discontinued in all patients still receiving study treatment due to the 
perceived contribution to the clinical findings, through its mode of action.
The concomitant occurrence of severe and difficult-to-treat dermatitis, oral mucositis, 
and ocular toxicities in these 2 patients is not consistent with the safety profile of the 
individual drugs (refer to the Investigator’s Brochures of the individual drugs). In addition, 
no similar combination of toxicities has been observed in ongoing studies evaluating 
atezolizumabobinutuzumab and obinutuzumab/rituximabpolatuzumab vedotin.  
Hence, this unique T-cell, immune-mediated toxicity was assessed as specifically related 
to the combination of obinutuzumab, atezolizumab, and polatuzumab vedotin.
Patients should be monitored carefully for any signs or symptoms of immune-related 
events including dermatitis, mucositis, and ocular toxicities. 
5.1.7
Management of Specific Adverse Events
Study treatment may be delayed for toxicity for a maximum amount of time, as specified 
in the tables below. If study treatment is delayed for longer than the specified maximum, 
study treatment will be permanently discontinued.
Treatment delays apply to all toxicities described below; dose modifications apply only to 
polatuzumab vedotin in the event of neurotoxicity (see Table 14 and Table 16).  There 
will be no dose reductions of obinutuzumab or atezolizumab.


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Guidelines for management of systemic immune activation are provided in 
Section 5.1.7.1.  Guidelines for management of toxicities during induction are provided in 
Section 5.1.7.2.  Guidelines for management of toxicities during post-induction are 
provided in Section 5.1.7.3.
5.1.7.1
Systemic Immune Activation
Systemic immune activation is a rare condition characterized by an excessive immune 
response.  Given the mechanism of action of atezolizumab, this condition is considered 
a potential risk when given in combination with other immunomodulating agents.  
Systemic immune activation should be included in the differential diagnosis for patients 
who, in the absence of an alternative etiology, develop a sepsis-like syndrome after 
administration of atezolizumab, and the initial evaluation should include the following:

CBC with peripheral smear

PT, PTT, fibrinogen, and D-dimer

Ferritin

Triglycerides

AST, ALT, and total bilirubin

LDH

Complete neurologic and abdominal examination (assess for hepatosplenomegaly)
If systemic immune activation is still suspected after the initial evaluation, contact the 
Medical Monitor for additional recommendations.


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Table 11 Diagnostic Criteria and Recommended Management for Systemic 
Immune Activation
Systemic Immune Activation Diagnostic Criteria 
(applicable only when alternative etiologies have been excluded)
Major Criteria
Minor Criteria

Fever 38.5C on more than one occasion

Ferritin 3000 ng/mL

Cytopenias (Grade 2 in two or more 
lineages)

Age-adjusted soluble IL-2 receptor 
elevated by 2 standard deviations

Severe dysfunction in two or more organs

Decreased fibrinogen

Splenomegaly 

Hemophagocytosis in bone marrow, spleen, 
or lymph nodes

Elevated GGT or LFTs (AST, ALT, or total 
bilirubin)

Elevated triglycerides

Elevated LDH

Decreased natural killer cell activity
Diagnosis and Management of Systemic Immune Activation
Number of Criteria
Diagnosis
Action to Be Taken
4 major criteria
Consistent 
with systemic 
immune 
activation

Permanently discontinue atezolizumab.

Consider treatment with tocilizumab (4 mg/kg IV) and IV 
corticosteroids (i.e., methylprednisolone 1 g once daily 
or equivalent).

Contact the Medical Monitor for additional 
recommendations.

Consider HLH-94 protocol if there is no clinical 
improvement.
3 major criteria
OR
2 major plus 
3 minor criteria
Probable 
systemic 
immune 
activation

Depending on clinical severity, follow guidelines for 
“Consistent with systemic immune activation” or 
“Possible systemic immune activation” diagnosis.

The Medical Monitor may be contacted for 
recommendations.
2 major plus 
2 minor criteria
OR
1 major plus 
4 minor criteria
Possible 
systemic 
immune 
activation

Withhold atezolizumab.

Consider treatment with IV corticosteroids.

The Medical Monitor may be contacted for additional 
recommendations.

Follow guidelines for “Consistent with systemic immune 
activation” diagnosis if there is no clinical improvement 
or if clinical worsening occurs.

If clinical improvement occurs, atezolizumab may be 
resumed following a benefit-risk assessment by the 
Medical Monitor.
GGT-glutamyl transpeptidase; IL-2interleukin-2; IV intravenous; LFT liver function test.
Notes:  Criteria are adapted from a Delphi Survey of 26 experts who provided helpful criteria in 
the positive diagnosis of hemophagocytic syndrome in adult patients (Hejblum et al. 2014).  
Case reports and recommendations have been published for cytokine-release syndrome 
(Teachey et al. 2013; Maude et al. 2014), and, on the basis of etiologic similarities, these 
practices have been incorporated into the above treatment recommendations. These 
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An adverse event of systemic immune activation should be reported on the Adverse 
Event eCRF if it meets the criteria for "consistent with systemic immune activation" or 
"probable systemic immune activation" as outlined above in Table 11.
5.1.7.2
Toxicities during Induction Treatment
Hematologic Toxicities during Induction Treatment
Table 12 provides guidelines for management of hematologic toxicities that occur during 
induction treatment, with the exception of Days 8 and 15 of Cycle 1.
Table 13  provides guidelines for management of hematologic toxicities that occur at 
Days 8 and 15 of Cycle 1, when patients are to receive treatment with obinutuzumab 
only.
Hematologic toxicity is defined as neutropenia, anemia, or thrombocytopenia.  
Lymphopenia is not considered a hematologic toxicity but rather an expected outcome of 
therapy.
Table 12 Guidelines for Management of Hematologic Toxicities that Occur 
during Induction Treatment (Except Days 8 and 15 of Cycle 1)
Event
Action To Be Taken
Grade 3 or 4 
hematologic 
toxicity

Withhold study treatment. a

Administer RBCs or platelets as required.

If patient has not already initiated G-CSF, initiate prophylactic G-CSF for 
current and subsequent cycles.

For patients receiving primary thromboprophylaxis who develop platelet count 
of 20,000/L, reduce the dose of LMWH or consider temporarily withholding 
platelet inhibitors, as applicable.  If the patient’s condition doesn’t allow for 
reduction of the LMWH dose or interruption of platelet inhibitor treatment, 
adequate platelet transfusion support and close monitoring of hematologic 
and coagulation functions are required.

If there is improvement to Grade 2 or baseline by Day 1 of the next cycle or 
21 days after the scheduled start date of the next cycle, resume 
obinutuzumab/rituximab, and polatuzumab vedotin at full dose.

If study treatment is withheld for 21 days, permanently discontinue study 
treatment.

Permanently discontinue study treatment if any of the following events occur:
–
Grade 3 or 4 thrombocytopenia that results in significant bleeding per 
investigator judgment
–
Recurrent Grade 3 or 4 neutropenia associated with fever 38°C lasting 
5 days or documented infection despite use of G-CSF
–
Recurrent Grade 4 neutropenia or thrombocytopenia lasting 7 days 
despite use of G-CSF (for neutropenia)
G-CSFgranulocyte colony-stimulating factor; LMWHlow-molecular-weight heparin.
a For neutropenia, treatment should be withheld only for sustained (7 days) Grade 3 
neutropenia or Grade 3 neutropenia associated with fever (temperature 38.5C).


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Table 13 Guidelines for Management of Hematologic Toxicities That Occur 
on Days 8 and 15 of Cycle 1
Event
Action to Be Taken
Febrile neutropenia or 
neutropenia with infection

Withhold obinutuzumab until resolution of fever and infection 
(as applicable).

If the event is ongoing at Day 1 Cycle 2, follow instructions in 
Table 12.
Note:  Obinutuzumab should not be withheld for asymptomatic 
neutropenia.
Severe 
thrombocytopenia a or 
bleeding

Withhold obinutuzumab until platelet count50,000/L and 
resolution of bleeding.

If receiving LMWH, reduce the dose.

If receiving platelet inhibitors, consider temporarily withholding 
platelet inhibitors.

If the event is ongoing at Day 1 Cycle 2, follow instructions in 
Table 12.
LMWHlow-molecular-weight heparin.
a Severe thrombocytopenia is defined as a platelet count 10,000/L for patients who are not 
receiving concomitant anticoagulants or platelet inhibitors and 20,000/L for patients who 
are receiving concomitant anticoagulants or platelet inhibitors.
Non-Hematologic Toxicities during Induction Treatment
Table 14 provides guidelines for management of non-hematologic toxicities that occur 
during induction treatment.
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.  
For detailed information regarding management of adverse events associated with 
atezolizumab, refer to the Atezolizumab Investigator’s Brochure.


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Table 14 Guidelines for Management of Non-Hematologic Toxicities
Event
Action To Be Taken
General guidance for treatment 
delays and discontinuation

For patients receiving obinutuzumab, if toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15, these doses 
of obinutuzumab will not be skipped but given after resolution of toxicity. 

When a treatment cycle is delayed because of a toxicity resulting from any component of the regimen, all 
study treatment should generally be held and resumed together to remain synchronized.

If one drug is discontinued, treatment with the other two drugs may be continued for patients experiencing 
clinical benefit as determined by the investigator after discussion with the Medical Monitor.

Permanently discontinue study treatment if any of the following events occur:
–
Grade 3 nonimmune-related adverse event that is considered to be treatment related and does not 
resolve to Grade 2 within 21 days
–
Nonimmune-related adverse event that is considered to be treatment related and requires study 
treatment to be withheld for 21 days
IRRs and anaphylaxis

Guidelines for the management of IRRs are provided in Section 4.3.2.1 for obinutuzumab, Section 4.3.2.2 for 
atezolizumab, Section 4.3.2.3 for polatuzumab vedotin, and Section 4.3.2.4 for rituximab. 

Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of its potential for 
causing agranulocytosis.

In case of anaphylaxis, study treatment should be permanently discontinued. 
Systemic immune activation

Follow guidance in Section 5.1.7.1 .
TLS

Withhold study treatment until symptoms completely resolve.  Perform chemistry panel on a regular bases 
during the first week.

Correct electrolyte abnormalities, monitor renal function, cardiac function and fluid balance, and administer 
supportive care, including dialysis as indicated.  Rasburicase therapy (if approved by the local health 
authority) may be administered as needed to reduce hyperuricemia.

If symptoms resolve completely, obinutuzumab/rituximab, and polatuzumab vedotin may be resumed at full 
dose.


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Table 14 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action To Be Taken
Dermatologic
toxicity
Grade 4

Permanently discontinue study treatment.
Grade 3
First occurrence

Withhold study treatment.  

Consult with a dermatologist.  A biopsy should be considered unless contraindicated.

If immune etiology is suspected, consider oral prednisone 10 mg or equivalent.  If event is unresolved after 
4872 hours, administer oral prednisone 60 mg or equivalent.

If there is improvement to Grade 1, resume obinutuzumab/rituximab and polatuzumab vedotin at full dose.  

Permanently discontinue obinutuzumab/rituximab and polatuzumab in the event of Stevens-Johnson 
syndrome or toxic epidermal necrolysis.
Second occurrence

Permanently discontinue study treatment.
Grade 1 or 2

Continue study treatment

Administer symptomatic therapy with antihistamines as needed

If immune related toxicity related to atezolizumab is suspected, consider topical steroids and, for Grade 2, 
higher potency topical steroids if rash unresolved.
AST, ALT, or 
bilirubin 
increase
Grade 3 
(or 10ULN for 
patients with liver 
involvement)

Withhold study treatment

Monitor liver function tests at least every 7 days while holding treatment.

Investigate etiology.  Consult with a hepatologist if immune etiology is suspected (refer to Atezolizumab 
Investigator’s Brochure for guidance on investigations).

For immune related hepatopathy:
–
Treat with corticosteroids following guidance provided in the Atezolizumab Investigator’s Brochure
–
Obinutuzumab and polatuzumab vedotin may be resumed at full dose at investigator’s discretion. 

If immune etiology is unlikely and there is improvement to Grade1, resume obinutuzumab/rituximab and 
polatuzumab vedotin at full dose.
Permanently discontinue study treatment for life-threatening liver toxicity.


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Table 14 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action To Be Taken
AST, ALT, or 
bilirubin 
increase (cont.)
Grade 2 lasting
57 days

If immune etiology is suspected, treat with corticosteroids according to guidance provided in the 
Atezolizumab Investigator’s Brochure.
Amylase or 
lipase increase
+/-abdominal 
pain
Grade 3

Withhold study treatment.

Investigate etiology.  Consult with a gastroenterologist if immune etiology is suspected.

Treat with corticosteroids according to guidance provided in the Atezolizumab Investigator’s Brochure.
–
If there is improvement to Grade 1 and patient is asymptomatic, or improvement to Grade ≤ 2 if lipase 
or amylase increase is an isolated and asymptomatic laboratory abnormality, resume 
obinutuzumab/rituximab and polatuzumab vedotin at full dose.  

Permanently discontinue study treatment for life-threatening pancreatitis or recurrent Grade 4 amylase or 
lipase elevations.
Grade 2 long 
lasting (3wks)

Continue study treatment.

If immune etiology is suspected, consider oral prednisone 10 mg/day or equivalent.
Hyperglycemia
Grade 34

Initiate treatment with insulin.

Monitor for glucose control.
Symptomatic 
adrenal 
insufficiency
Grade 24

Refer patient to endocrinologist.

Perform appropriate imaging.

Initiate treatment with 12 mg/kg/day intravenous methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.


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Table 14 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action To Be Taken
Diarrhea/Colitis
Grade 4

Permanently discontinue study treatment.

Investigate etiology.  Consult with a gastroenterologist (refer to Atezolizumab Investigator’s Brochure for 
guidance on investigations in case of suspected immune-related colitis).

Treat with corticosteroids according to guidance provided in the Atezolizumab Investigator’s Brochure.
Grade 2 or 3

Withhold study treatment.

Investigate etiology.  Consult with a gastroenterologist if immune etiology is suspected (refer to 
Atezolizumab Investigator’s Brochure for guidance on investigations).

Treat immune diarrhea/colitis with corticosteroids according to guidance provided in the Atezolizumab 
Investigator’s Brochure.

If diarrhea/colitis improves to Grade 1, resume obinutuzumab and polatuzumab vedotin at full dose.  
Ocular toxicity 
Grade 3 or 4

Withhold obinutuzumab/rituximab and polatuzumab vedotin.

Investigate etiology.  Consult with an ophthalmologist.

Treat immune-related toxicity attributable to atezolizumab with systemic corticosteroids according to 
guidance provided in the Atezolizumab Investigator’s Brochure. 

If there is improvement to Grade 1, resume obinutuzumab/rituximab and polatuzumab vedotin at full dose.
Grade 1 or 2

Investigate etiology.  Consult with an ophthalmologist.

Treat with topical corticosteroid eye drops.  If symptoms persist, topical immunosuppressive therapy may 
also be considered.
Hypothyroidism

Investigate etiology.  Consult with an endocrinologist (refer to Atezolizumab Investigator’s Brochure for 
guidance on investigations).

Start thyroid replacement hormone.

Monitor TSH weekly.
For asymptomatic and symptomatic patients with elevation of TSH:

Continue study treatment.


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Table 14 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action To Be Taken
Hyperthyroidism
For asymptomatic patients with TSH 0.5 mU/L:

Perform TSH, free T4, and T3 tests every 4 weeks.
For asymptomatic patients with TSH 0.1 mU/L or symptomatic patients:

Consider consultation with an endocrinologist.

Administer methimazol as needed.
Hypophysitis 
(panhypopituitarism)
Grade 4

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.

Initiate hormone replacement if clinically indicated.
Grade 2 or 3

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.

Initiate hormone replacement if clinically indicated.

For recurrent hypophysitis, treat as a Grade 4 event.
New-onset neurologic manifestations 
suggestive of PML

Withhold study treatment.

Consult with a neurologist if PML is suspected (refer to Section 5.1.1.6  for guidance on 
investigations).

If PML is ruled out, resume obinutuzumab/rituximab and polatuzumab vedotin at full dose.

If PML is confirmed, permanently discontinue study treatment. 


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Table 14 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Neurotoxicity other 
than neurologic 
manifestations 
suggestive of PML
Grade 4 or Myasthenia 
gravis (any grade) or 
Guillain-Barre (any 
grade)

Permanently discontinue study treatment.
Grade 2 or 3 

Withhold study treatment.  Investigate etiology.

If neurotoxicity is considered likely related to polatuzumab vedotin and there is improvement to 
Grade 1 within 21 days, resume study treatments for subsequent cycles as follows:
–
Resume obinutuzumab/rituximab at full dose. 
–
For patients who started at 1.8 mg/kg, resume polatuzumab vedotin at a reduced dose of 
1.4 mg/kg.  For patients who started at 1.4 mg/kg, permanently discontinue polatuzumab 
vedotin.
Immune-related meningoencephalitis

Withhold study treatment.

Refer patient to neurologist (see Atezolizumab Investigator’s Brochure for guidance on 
investigations).

Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.  If event does not improve 
within 48 hours after initiating corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1:
–
Resume obinutuzumab/rituximab at full dose and polatuzumab vedotin at current dose.
–
Taper corticosteroids over 1 month.  


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Table 14 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action To Be Taken
Immune-related 
myocarditis
Grade 34

Permanently discontinue study treatment and contact Medical Monitor.

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider antiarrhythmic drugs, temporary 
pacemaker, ECMO, or VAD as appropriate.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over1 month.

Investigator might consider continuation of obinutuzumab/rituximab and polatuzumab vedotin, 
based on an individual benefit-risk assessment, and in consultation with the Medical Monitor.
Grade 2

Withhold study treatment.

Initiate treatment as per institutional guidelines and consider antiarrhythmic drugs, temporary 
pacemaker, ECMO, or VAD as appropriate.

Consider treatment with 12 mg/kg/day IV methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.

If event resolves to Grade 1 or better, resume study treatment.
Grade 1

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines.


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Table 14 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Immune-related 
nephritis
Grade 3 or 4

Permanently discontinue study treatment and contact Medical Monitor.

Refer patient to renal specialist.

Consider renal biopsy and supportive measures as indicated.

Corticosteroids and/or additional immunosuppressive agents should be administered as 
clinically indicated.

If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset.b  Contact Medical Monitor.

Refer patient to renal specialist.

Consider renal biopsy and supportive measures as indicated.

Corticosteroids and/or additional immunosuppressive agents should be administered as 
clinically indicated.

If event resolves to Grade 1 or better, resume atezolizumab. c

If event does not resolve to Grade 1 or better while withholding atezolizumab, permanently 
discontinue atezolizumab and contact Medical Monitor. d
Grade 1

Continue study treatment.

Monitor kidney function, including creatinine, closely until values resolve to within normal 
limits or to baseline values.


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Table 14 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action To Be Taken
Pneumopathy, 
non-infectious 
(i.e., dyspnea, hypoxia, 
pulmonary infiltrates)
Grade 3 
or 4

Withhold obinutuzumab/rituximab and polatuzumab vedotin.

Investigate etiology.  Consult with a pulmonologist if immune etiology is suspected (refer to Atezolizumab 
Investigator’s Brochure for guidance on investigations).

Treat immune related pneumopathy with corticosteroids according to guidance provided in the 
Atezolizumab Investigator’s Brochure. 

If symptoms have resolved and CT lung findings are clear, obinutuzumab and polatuzumab vedotin may 
be resumed at full dose. 
Grade 2

Treat with corticosteroids according to guidance provided in the Atezolizumab Investigator’s Brochure.
Other non-hematologic 
and non-immune-
related toxicities 
(i.e., not described 
above), excluding 
alopecia, nausea, and 
vomiting 
Grade 4

Permanently discontinue study treatment.
Grade 2 
or 3

Withhold study treatment.

If there is improvement to Grade 1 or baseline, resume obinutuzumab/rituximab and polatuzumab 
vedotin at current dose. 

In case of laboratory abnormalities that are isolated, asymptomatic, and considered not clinically 
significant: 
–
For Grade 3 laboratory abnormalities, study treatment may be resumed at the current dose upon 
improvement to at least Grade 2.
–
For Grade 2 laboratory abnormalities, study treatment may be continued at the current dose at the 
investigator’s discretion.


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Table 14 Guidelines for Management of Non-Hematologic Toxicities (cont.)
CTcomputed tomography; ECMOextracorporeal membrane oxygenation; IRR infusion-related reaction; PMLprogressive multifocal 
leukoencephalopathy; MRImagnetic resonance imaging; NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse 
Events; NSAIDnonsteroidal anti-inflammatory drug; TLStumor lysis syndrome; TSHthyroid-stimulating hormone; ULNupper limit normal; 
VADventricular assist device.
a Graded according to NCI CTCAE Version 3.0.
b Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to the equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
c
If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 10 mg/day oral prednisone before 
atezolizumab can be resumed.
d Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-related 
event.  Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


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5.1.7.3
Toxicities during Maintenance Treatment
Table 15 provides guidelines for management of toxicities that occur during maintenance 
treatment.
Table 15 Guidelines for Management of Toxicities that Occur during 
Maintenance Treatment
Event
Action To Be Taken
Hematologic 
toxicity:
Grade 3 or 4

Withhold obinutuzumab/rituximab.

Administer G-CSF for neutropenia per institutional guidelines.

Administer RBCs or platelets as required.

If there is improvement to Grade 2, resume obinutuzumab at full 
dose.

If obinutuzumab is withheld for 42 days due to adverse event, 
permanently discontinue obinutuzumab/rituximab.
Non-hematologic 
toxicity:
Grade 2
For atezolizumab-related toxicities with possible immune etiology1:

Follow guidelines presented in Table 14 for the management of 
atezolizumab-related toxicities with possible immune etiology 
(i.e., autoimmune colitis, hepatitis, pancreatitis, hypothyroidism, 
hyperthyroidism, pneumopathy, skin toxicity, or ocular toxicity).
For non-immune mediated toxicities:

Withhold study treatment.

If there is improvement to Grade 1 or baseline, resume 
obinutuzumab/rituximab at full dose.

If study treatment is withheld for 42 days due to adverse event, 
permanently discontinue study treatment.
G-CSFgranulocyte colony-stimulating factor.
1 Please refer to atezolizumab Investigators Brochure for additional information.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
SAEs and adverse events of special interest, performing protocol-specified safety 
laboratory assessments, measuring protocol-specified vital signs, and conducting other 
protocol-specified tests that are deemed critical to the safety evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product


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
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study treatment

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A SAE is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs in-patient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study treatment

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
The SAEs are required to be reported by the investigator to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for reporting 
instructions).


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5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the adverse events of special interest listed below.
Adverse events of special interest to any study drug are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study treatment, as defined 
below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of any of the study treatment components is suspected.
Adverse events of special interest to obinutuzumab are as follows:

TLS of any grade of severity, and irrespective of causality

Second malignancies 
Adverse events of special interest to atezolizumab are as follows:

Pneumonitis

Colitis

Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency,
hyperthyroidism, and hypophysitis

Hepatitis, including AST or ALT > 10 x ULN

Systemic lupus erythematosus

Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or
myasthenia gravis, and meningoencephalitis

Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release
syndrome, influenza-like illness, systemic inflammatory response syndrome, and
systemic immune activation

Nephritis

Ocular toxicities (e.g., uveitis, retinitis)

Myositis


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
Myopathies, including rhabdomyolysis

Grade 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

Vasculitis
5.2.4
Dose-Limiting Toxicities (Immediately Reportable to the 
Sponsor)
During the DLT assessment window (Cycles 1 and 2), adverse events identified as DLTs, 
as defined in Section 3.1.2.1.1, are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).
5.2.5
Selected Adverse Events
Adverse events of special interest are listed in Section 5.2.3.  Selected adverse events 
in this study are defined as adverse events for which additional data collection or 
analyses will be performed.  Selected adverse events do not require immediate reporting 
if they are not serious (except for TLS and second malignancies).
The following adverse events are considered selected adverse events:

Thrombocytopenia, including acute thrombocytopenia (events occurring during and 
within 24 hours following obinutuzumab infusion)

Hepatitis B reactivation

Cardiac events

IRRs

All infections, including PML

Neutropenia, including prolonged neutropenia (neutropenia 1000 cells/L that 
does not resolve after 28 days without obinutuzumab treatment) and late-onset 
neutropenia (neutropenia 1000 cells/L occurring 28 days after obinutuzumab 
treatment has been completed or stopped) 

GI perforation

Peripheral neuropathy (motor and/or sensory)
Events for which additional data collection will be required are PML, Hepatitis B and 
Hepatitis B reactivation.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.


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For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study treatment, 
only SAEs caused by a protocol-mandated intervention (e.g., invasive procedures such 
as biopsies, discontinuation of medications) should be reported (see Section 5.4.2 for 
instructions for reporting SAEs).
After initiation of study treatment, all adverse events will be reported until 90 days 
after the last dose of study treatment.  After this period, the investigator should report 
any SAEs that are believed to be related to prior study treatment (see Section 5.6).
An exception is made for Grade 3 or 4 infections (related and unrelated to study 
treatment), which should be reported until up to 2 years after the last dose of 
obinutuzumab (GAtezoPola treatment group).
Similarly, second malignancies (related and unrelated to study treatment) will be 
reported indefinitely (even if the study has been closed) for patients who received 
obinutuzumab (see Section 5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE v4.0 will be used for 
assessing adverse event severity, with the exception of tumor flare reactions, which will 
be graded using NCI CTCAE v3.0.  Table 16 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 16 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to any of the study treatment components, 
indicating "yes" or "no" accordingly.  The following guidance should be taken into 
consideration:

Temporal relationship of event onset to the initiation of study treatment

Course of the event, considering especially the effects of study treatment 
modifications or discontinuation, or reintroduction of study treatment (as applicable)

Known association of the event with the study treatment or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment related factors that are known to be associated with the 
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For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after the end of study treatment 
infusion and are judged to be related to infusion of any of the study treatment 
components should be captured as a diagnosis (e.g., "infusion-related reaction") on the 
Adverse Event eCRF.  If possible, avoid ambiguous terms such as "systemic reaction."  
Associated signs and symptoms should be recorded on the dedicated Infusion-Related 
Reaction eCRF.  If a patient experiences both a local and systemic reaction to the same 
dose of study treatment, each reaction should be recorded separately on the Adverse 
Event eCRF, with signs and symptoms also recorded separately on the dedicated 
Infusion-Related Reaction eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.


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
If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious" 
to "serious," providing the date that the event became serious, and completing all data 
fields related to SAEs.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.


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If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia".
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).


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5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event) either as a SAEs or an adverse event of special interest (see Section 5.4.2).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of lymphoma should be recorded only on the 
Study Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study treatment, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.4.2).  An IMC will monitor the 
frequency of deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 


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recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Lymphoma
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on the Lugano 2014 criteria (see Appendix 5).  In rare cases, 
the determination of clinical progression will be based on symptomatic deterioration.  
However, every effort should be made to document progression through use of objective 
criteria.  If there is any uncertainty as to whether an event is due to disease progression, 
it should be reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a SAEs (per the 
definition of SAEs in Section 5.2.2), except as outlined below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study treatment 
administration or insertion of access device for study treatment administration) 

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Adverse Events Associated with an Overdose or Error in 
Treatment Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 


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associated with an overdose or incorrect administration of study treatment should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).
No experience with overdosage is available from human clinical trials.  In clinical trials 
with obinutuzumab doses ranging from 50 mg up to and including 2000 mg per infusion 
have been administered.  The incidence and intensity of adverse reactions reported in 
these studies did not appear to be dose-dependent.
Patients who experience overdose should have immediate interruption or reduction of 
their infusion and should be closely supervised.  Consideration should be given to the 
need for regular monitoring of blood cell count and for increased risk of infections while 
patients are B cell-depleted.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to any of the study treatments:

The SAEs (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

DLTs (see Section 5.2.4 for further details)

Pregnancies (see Section 5.4.3 for further details)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting SAEs to the local 
health authority and IRB/EC.


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5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Medical Monitor:
, Ph.D.
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events, Adverse 
Events of Special Interest, and Dose-Limiting Toxicities
5.4.2.1
Events That Occur prior to Study Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, only 
SAEs caused by a protocol-mandated intervention should be reported.  The 
SAE/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.
5.4.2.2
Events That Occur after Study Treatment Initiation
After initiation of study treatment, all adverse events will be reported until 90 days after 
the last dose of study treatment.  The DLTs will be reported during the DLT assessment 
window.  Investigators should record all case details that can be gathered immediately 
(i.e., within 24 hours after learning of the event) on the Adverse Event eCRF and submit 
the report via the electronic data capture (EDC) system.  A report will be generated and 
sent to Roche Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the SAE/Adverse Event of Special 
Interest Reporting Form provided to investigators should be completed and submitted to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system.
Instructions for reporting post-study adverse events are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 18 months after the last 


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dose of study treatment for patients in the GAtezoPola (FL) treatment group and 
within 12 months after the last dose of study treatment for patients in the RAtezoPola 
(DBCL) treatment group.  A Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study treatment and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any SAEs associated with the pregnancy 
(e.g., an event in the fetus, an event in the mother during or after the pregnancy, or a 
congenital anomaly/birth defect in the child) should be reported on the Adverse Event 
eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy Reporting Form 
when updated information on the course and outcome of the pregnancy becomes 
available.
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
5 months after the last dose of study treatment.  A Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study treatment.  
The pregnant partner will need to sign an Authorization for Use and Disclosure of 
Pregnancy Health Information to allow for follow-up on her pregnancy.  After the 
authorization has been signed, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  An investigator who is contacted by the male patient or his pregnant 
partner may provide information on the risks of the pregnancy and the possible effects 
on the fetus, to support an informed decision in cooperation with the treating physician 
and/or obstetrician.
5.4.3.3
Abortions
Any abortion should be classified as a SAE (as the Sponsor considers abortions to be 
medically significant), recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 


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classified as a SAE, recorded on the Adverse Event eCRF, and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all SAEs 
considered to be related to study treatment or trial-related procedures until a final outcome 
can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For SAEs, adverse events of special interest, and pregnancies, the Sponsor or a 
designee may follow up by telephone, fax, electronic mail, and/or a monitoring visit to 
obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 90 days after the last 
dose of study treatment), all deaths, regardless of cause, should be reported through 
use of the Long-Term Survival Follow-Up eCRF.
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study drug, the event should be reported through use 
of the Adverse Event eCRF.
An exception is made for Grade 3 and 4 infections (related and unrelated to prior study 
treatment), which should be reported until up to 2 years after the last dose of study 
treatment.
The Sponsor should also be notified of events of second malignancies indefinitely 
(related and unrelated to study treatment, even if the G+Atezo+pola treatment group or 
the overall study has been closed) for patients who received obinutuzumab.
If the EDC system is not available, the investigator should report these events directly to 
the Sponsor or its designee, either by faxing or by scanning and emailing the paper 


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Clinical Trial Serious Adverse Event/Adverse Event of Special Interest Reporting Form 
using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all SAEs and adverse events of special interest 
against cumulative product experience to identify and expeditiously communicate 
possible new safety findings to investigators, IRBs, ECs, and applicable health 
authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

Obinutuzumab Investigator's Brochure 

Atezolizumab Investigator’s Brochure

Polatuzumab Vedotin Investigator’s Brochure

Rituximab Investigator’s Brochure
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.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The study will include an initial dose-escalation phase followed by an expansion phase 
in relapsed or refractory FL patients; and a safety run-in phase followed by an expansion 
phase in relapsed or refractory DLBCL patients.  The dose-escalation phase is designed 
to determine the RP2D for polatuzumab vedotin when combined with fixed doses of 
obinutuzumab and atezolizumab in patients with relapsed or refractory FL.  During the 
expansion phase, patients with relapsed or refractory FL will undergo treatment with 
polatuzumab vedotin at the RP2D, obinutuzumab, and atezolizumab; and patients with 
relapsed or refractory DLBCL will undergo treatment with polatuzumab vedotin 1.8 or 
1.4 mg/kg, rituximab, and atezolizumab.
Study data will be summarized separately for each phase.  Data from the 
dose-escalation phase will be summarized by each polatuzumab vedotin dose cohort.  
Data from the expansion phase will be summarized by histologic subtype (i.e., FL or 
DLBCL).


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6.1
DETERMINATION OF SAMPLE SIZE
Limited dose-finding will be conducted during the dose-escalation phase of polatuzumab 
vedotin in combination with obinutuzumab and atezolizumab.  The estimated sample 
size follows from the dose-escalation rules for a standard 33 algorithm, as outlined in 
Section 3.1.  
A total of 9 patients with RR FL were enrolled in the dose-escalation phase (3 patients in 
the Pola 1.4-mg dose cohort and 6 patients in the Pola 1.8-mg dose cohort), and a total 
of 7 patients with RR DLBCL were enrolled into the safety run-in phase and treated with 
1.8 mg polatuzumab vedotin.  During the expansion phase, 3440 patients with DLBCL 
and 3437 patients with FL (for a total of 40 patients with FL at RP2D in the dose-
escalation and expansion phases) were planned to be enrolled.  Overall, approximately 
8392 patients were planned to be enrolled in the study.  As of 1 March 2018, 
13 patients with RR FL and 23 patients with RR DLBCL were enrolled in the study.
The primary efficacy analysis will be the estimation of the true proportion of patients 
expected to obtain a PET-CTdefined CR at EOI. 
6.2
DEFINITION OF ANALYSIS POPULATIONS
For both the safety and efficacy analyses, the following populations are defined:

The primary population will include patients who received at least 1 dose of each 
component of the combination.

The intent-to-treat population will include all patients enrolled in the study.
Patients with FL who receive polatuzumab vedotin at the RP2D during the 
dose-escalation phase will be pooled with patients who receive polatuzumab vedotin at 
the RP2D during the expansion phase.
6.3
SUMMARIES OF CONDUCT OF STUDY
Enrollment, major protocol violations, and discontinuations from the study will be listed.  
The incidence of treatment discontinuation for reasons other than disease progression 
will be tabulated.
Data related to the administration of study treatment components will be listed, and any 
dose modifications will be flagged.  The number of doses, treatment cycles, average 
dose received, and relative dose intensity for each treatment component will be 
summarized using descriptive statistics (mean, standard deviation, median, and range).
6.4
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics by treatment group, such as age, sex, race, 
and duration of malignancy, will be summarized using descriptive statistics (mean, 


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standard deviation, median, and range) for continuous variables and frequencies and 
percentages for categorical variables.
6.5
SAFETY ANALYSES
The safety analyses will be performed by treatment group, separately for each study 
phase (i.e., dose-escalation and expansion).  The main analysis for safety will include 
data until end of study.  Additionally, a censoring will be applied as of 1 March 2018 to 
the safety analyses, to evaluate the effect of the triplet drug combination in each 
treatment group.  The sensitivity analysis will be based on the censored safety dataset 
and will include data from patients as of 1 March 2018 plus the 90-day safety reporting 
window (see Section 5.3.1).  Patients enrolled and who have not received any treatment
with atezolizumab will be analyzed separately by treatment group, GPola and RPola.
Safety will be assessed through summaries of adverse events, changes from baseline in 
laboratory test results, and laboratory data with values outside of the normal ranges.
All adverse events occurring on or after the first dose of study treatment will be 
summarized by mapped term, appropriate thesaurus levels, and NCI CTCAE v4.0 grade.  
All SAEs, adverse events of special interest, and selected adverse events will be 
summarized and listed.
Deaths reported during the treatment period and during post-treatment follow-up will be 
listed.
Relevant laboratory results will be displayed by time, with Grade 3 and 4 values 
identified as appropriate.
6.6
EFFICACY ANALYSES
The primary and secondary efficacy analyses will include all patients enrolled in the 
expansion phase, and will be performed by treatment group.  In addition, patients with 
FL who received polatuzumab vedotin at the RP2D during the dose-escalation phase will 
be pooled for analysis with patients with FL treated in the expansion phase. Patients with 
DLBCL from the safety run-in phase will be pooled for analysis with patients with DLBCL 
treated in the expansion phase at the same polatuzumab vedotin dose.  A censoring will 
be applied as of 1 March 2018 to the efficacy analyses, to evaluate the effect of the 
triplet drug combination in each treatment group.  The efficacy analysis will be performed 
on the censored efficacy dataset, and will include data from patients as of 1 March 2018 
plus the corresponding assessment time window (see Appendix 1 and Appendix 2).
6.6.1
Primary Efficacy Endpoint
The primary efficacy analysis will be estimation of the proportion of patients achieving a 
CR at EOI, as determined by the investigator through use of the PET-CT-based Lugano 
2014 criteria (see Appendix 5).  Point estimates will be presented, along with the 


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corresponding two-sided 90% Clopper-Pearson exact CIs.  Patients without a 
post-baseline tumor assessment will be considered non-responders.
6.6.2
Secondary Efficacy Endpoints
The secondary efficacy analyses will be estimation of the proportion of patients 
achieving each of the following endpoints:

CR at EOI, as determined by the investigator on the basis of CT scans alone

Objective response (defined as a CR or PR) at EOI, as determined by the 
investigator on the basis of PET-CT scans

Objective response (defined as a CR or PR) at EOI, as determined by the 
investigator on the basis of CT scans alone

Best response of CR or PR during the study, as determined by the investigator on 
the basis of CT scans alone
Point estimates will be presented, along with the corresponding two-sided 90% 
Clopper-Pearson exact CIs.  Patients without a post-baseline tumor assessment will be 
considered non-responders.
6.6.3
Exploratory Efficacy Endpoints
Exploratory efficacy analyses will include estimation of the proportion of patients 
achieving each of the following endpoints:

For FL patients who have positive PET scans at EOI:  CR at 12 months, as 
determined by the investigator on the basis of PET-CT scans
Point estimates will be presented, along with the corresponding two-sided 90% 
Clopper-Pearson exact CIs.  Patients without a post-baseline tumor assessment will be 
considered non-responders.
OS will be summarized descriptively using the Kaplan-Meier method (Kaplan and Meier 
1958).  For the OS analysis, data for patients who have not died will be censored at the 
date the patient was last known to be alive.  Where medians are reached, the 
corresponding estimated median will be provided, along with the 95% CI using the 
method of Brookmeyer and Crowley (1982).
6.7
PHARMACOKINETIC ANALYSES
Plasma or serum concentrations of obinutuzumab, rituximab, atezolizumab, and 
polatuzumab vedotin will be tabulated, summarized, and plotted after appropriate 
grouping.  As appropriate, PK parameters (e.g., AUC, time to maximum concentration, 
maximum concentration, and half-life) may also be calculated, tabulated, and 
summarized after appropriate grouping.  Additional PK and PK/PD analyses 
(e.g., population modeling, including pooled analyses across studies) may also be 
performed as appropriate.  If done, these additional analyses may be reported 
separately from the Clinical Study Report.


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6.8
IMMUNOGENICITY ANALYSES
The immunogenicity analyses will include patients with at least one predose and one 
postdose HAHA, HACA or ATA assessment.
The numbers and proportions of post-treatment HAHA-, HACA- or ATA-positive patients 
and HAHA-, HACA- or ATA-negative patients at baseline and during both the treatment 
and follow-up periods will be summarized.  The relationship between HAHA, HACA or 
ATA status and safety, efficacy, and PK endpoints will be explored as appropriate.
6.9
BIOMARKER ANALYSES
Exploratory analyses of biomarkers related to tumor biology and study treatment 
mechanisms of action will be conducted.  Analyses will assess the prognostic and/or 
predictive value of candidate biomarkers with respect to investigator-assessed outcomes.  
Specifically, the association between candidate biomarkers and PET-CTdefined CR 
rate and OR rate, and potentially other measures of efficacy and safety, will be explored 
to assess potential prognostic or predictive value.  These analyses may not be included 
in the final study report because of their exploratory nature.  In addition to analysis in the 
context of this study, data will also be explored in aggregate with data from other studies.
6.10
INTERIM ANALYSES
No interim analyses are planned and review of safety and/or efficacy data by the IMC
may be requested by and carried out at the discretion of the Medical Monitor.  Further 
details regarding the rules and guidelines of data review will be provided in an IMC 
charter.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and any other 
externally-generated electronic study data will be sent directly to the Sponsor, using the 
Sponsor’s standard procedures to handle and process the electronic transfer of these 
data.
The eCRFs and correction documentation will be maintained in the EDC system’s audit 
trail.  System backups for data stored by the Sponsor and records retention for the study 
data will be consistent with the Sponsor’s standard procedures.


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7.2
ELECTRONIC CASE REPORT FORMS
The eCRFs are to be completed through use of a Sponsor-designated EDC system.  
Sites will receive training and have access to a manual for appropriate eCRF completion.  
The eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  The eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 


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as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic patient-reported outcome data (if applicable), Informed 
Consent Forms, laboratory test results, and medication inventory records, must be 
retained by the Principal Investigator for at least 15 years after completion or 
discontinuation of the study, or for the length of time required by relevant national or 
local health authorities, whichever is longer.  After that period of time, the documents 
may be destroyed, subject to local regulations.
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S.  
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union (E.U.) 
or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Home Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.


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If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.


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The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting SAEs to the local health 
authority and IRB/EC.  Investigators may receive written IND safety reports or other 
safety-related communications from the Sponsor.  Investigators are responsible for 
ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
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 national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (defined as the time 
when all enrolled patients with FL have completed or discontinued study treatment and 
all enrolled patients with DLBCL have been followed for at least 1 year after they have 
completed or discontinued study treatment.


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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.
The EDC will be used for this study.  An IxRS will be used to assign patient numbers.  
A central laboratory will be used for a subset of laboratory assessments as specified in 
Section 4.5.7; otherwise, local laboratories will be used.  A central independent review 
facility will be used to collect PET-CT and CT scans.  Data from this study will be shared 
with an Expert Scientific Committee that will provide scientific input for the benefit-risk 
assessment.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 


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requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
146/Protocol BO29561, Version 8
Appendix 1
Schedule of Assessments for Patients with Follicular Lymphoma
Screening a
Induction (6 months; 21-day cycles)
EOI
Maint. (24 months)
EOM b
90-Day 
Safety FU 
Visit (at 
3 Months) d
Survival 
FU 
Period 
(Q3M)kk
D 28 
to 
D 1
D 14 
to 
D 1
Cycle 1 
(1 days)
Cycles 26
(2 days)
After Last 
Induction 
Dose c
Monthly
(1 wk)
Every 
2 months
(1 wk)
35 days 
after 
Last 
Dose
D1
D8
D15
D1
D1
D1
Informed consent e
Demographic data
x
Medical history 
x
ECOG Performance Status
x
Vital signs f
x
x
x
x
x
x
x
x
x
Height
x
Weight
x
x
x
12-lead ECG
x
x g
x
Complete physical 
examination h, i
x
Targeted physical 
examination i, j
D1, Cycles 2 
and 4
x
x
x
x
Ann Arbor, FLIPI, and FLIPI2
x
B symptoms k
x
2 microglobulin
x
Hematology l
x
x m,n
x n
x n
x n (C2: D1, 
D8, D15
x g
x n
x
x
Chemistry panel (serum or 
plasma) o
x
x m,n
x n
x n
x n
x g
x n
x
x
Coagulation (INR, aPTT [or 
PTT], and PT)
x
Pregnancy test
x p
x p
x g
x
Hepatitis B and C testing q
x
TSH, T3, T4
x
Every 3 months
Quantitative IgA, IgG, IgM
x
x
x r
x
x
x


Appendix 1
Schedule of Assessments for Patients with Follicular Lymphoma (cont.)
Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
147/Protocol BO29561, Version 8
Screening a
Induction (6 months; 21-day cycles)
EOI
Maint. (24 months)
EOM b
90-Day 
Safety FU 
Visit (at 
3 Months) d
Survival 
FU 
Period 
(Q3M)kk
D 28 
to 
D 1
D 14 
to 
D 1
Cycle 1 
(1 days)
Cycles 26
(2 days)
After Last 
Induction 
Dose c
Monthly
(1 wk)
Every 
2 months
(1 wk)
35 days 
after 
Last 
Dose
D1
D8
D15
D1
D1
D1
HAHA sample for 
obinutuzumab
x s
ATA sample for atezolizumab 
and polatuzumab vedotin
x s
PK sample for obinutuzumab, 
atezolizumab and 
polatuzumab vedotin
x s
Plasma for soluble PD-L1
x n
Whole blood for lymphocyte 
immunophenotyping t
x n
x n
x
x r
x
x
Whole blood for T-cell receptor 
repertoire in PBMCs
x n
x n, u
x
x v
Plasma for cytokine analysis
x n
x n, u
Optional peripheral blood 
sample for RCR w
x n
Tumor tissue specimen 
(leftover tissue may be used 
for optional RCR specimen v)
x x
x y
x y
Concomitant medications z
x z
To be recorded continually until end of treatment z
Adverse events aa
x aa
To be assessed continually aa
PET-CT scan
x bb
x cc
x dd
CT scan ee
x ee
x ff
x cc
x ff
x gg
Bone marrow biopsy and 
aspirate 
x hh
x cc, ii
x ii
x hh, ii


Appendix 1
Schedule of Assessments for Patients with Follicular Lymphoma (cont.)
Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
148/Protocol BO29561, Version 8
Screening a
Induction (6 months; 21-day cycles)
EOI
Maint. (24 months)
EOM b
90-Day 
Safety FU 
Visit (at 
3 Months) d
Survival 
FU 
Period 
(Q3M)kk
D 28 
to 
D 1
D 14 
to 
D 1
Cycle 1 
(1 days)
Cycles 26
(2 days)
After Last 
Induction 
Dose c
Monthly
(1 wk)
Every 
2 months
(1 wk)
35 days 
after 
Last 
Dose
D1
D8
D15
D1
D1
D1
Study 
treatment 
administration
Obinutuzumab
jj
x
x
x
x
x
Polatuzumab 
vedotin jj
x
x
New anti-lymphoma 
treatment
x
x
Survival follow-up
x
ATAanti-therapeutic antibody; CCycle; CT computed tomography; Dday; ECOGEastern Cooperative Oncology Group; eCRF electronic 
Case Report Form; EOIend of induction; EOMend of maintenance; FLIPIFollicular Lymphoma International Prognostic Index; FUfollow-up; 
HAHAhuman anti-human antibody; Maint.maintenance; MRDminimal residual disease; MRImagnetic resonance imaging; NK natural 
killer; PBMCperipheral blood mononuclear cell; PET positron emission tomography; PKpharmacokinetic; Q3Mevery 3 months; RCRRoche 
Clinical Repository; T3triiodothyronine; T4thyroxine; TSHthyroid-stimulating hormone; wk week. Notes:  On treatment days, all assessments 
should be performed prior to dosing, unless otherwise specified.
Assessments shaded in gray should be performed as scheduled, but the associated data do not need to be recorded on the eCRF (except in the 
case of an adverse event).
a The screening period starts with the signing of the Informed Consent Form.  Results of standard-of-care tests or examinations performed prior to 
obtaining informed consent and within the defined window may be used as screening and baseline assessments; such tests do not need to be 
repeated for screening purposes.
b Patients who complete maintenance treatment or discontinue maintenance treatment prematurely will undergo assessments at EOM.
c EOI assessments should be performed 68 weeks after Day 1 of the last induction cycle.  As an exception, patients who discontinue induction 
treatment prematurely because of an adverse event may undergo EOI assessments 48 weeks after their last dose of study treatment. 
d Patients who complete treatment or prematurely discontinue treatment for reasons other than disease progression will undergo assessments at 
the 90-day safety follow-up visit.
e Informed consent must be documented before any study-specific screening procedure is performed. 


Appendix 1
Schedule of Assessments for Patients with Follicular Lymphoma (cont.)
Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
149/Protocol BO29561, Version 8
f
Vital signs include respiratory rate, pulse rate, body temperature, and systolic and diastolic blood pressures while the patient is in a seated 
position.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, 
record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  For obinutuzumab infusions:  For the first cycle, second 
cycle, and for patients who experience an infusion-related reaction, vital signs will be measured prior to the infusion, every 15 (5) minutes for 
the first 90 minutes of the infusion, and then every 30 (10) minutes until 1 hour after completion of the infusion.  For subsequent cycles, vital 
signs will be measured every 30 minutes during the infusion, except in patients who had experienced an infusion-related reaction during a prior 
infusion.  For polatuzumab vedotin infusions:  During the administration of polatuzumab vedotin, vital signs should be assessed before the start 
of the infusion, every 15 (5) minutes during the infusion, at the end of the infusion, and every 30 (10) minutes for 90 minutes following 
completion of dosing at Cycle 1 and at Cycle 2, and 30 (10) minutes following completion of dosing in subsequent cycles.
g Perform only in patients who will not be receiving maintenance treatment.
h Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and 
Baseline Conditions eCRF.
i
As part of tumor assessment, the physical examination should include evaluation for the presence of enlarged nodes, palpable hepatomegaly, 
and splenomegaly.  This information will be recorded on the appropriate tumor assessment eCRF. 
j
Includes systems of primary relevance (e.g., cardiovascular and respiratory systems), systems associated with symptoms (newly emergent or 
monitored from baseline), and areas associated with tumor assessment (lymph nodes, liver, spleen, and any other areas identified at baseline).  
Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
k Unexplained fever 38C, night sweats, and unexplained weight loss10% of body weight over 6 months. 
l
Includes hemoglobin, hematocrit, platelet count, RBC count, WBC count, and percent or absolute WBC differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells). 
m Screening laboratory assessments may be used for Day 1 of Cycle 1 if performed within 72 hours prior to Day 1 of Cycle 1. 
n Perform hematology and chemistry tests within 72 hours prior to Day 1 of each cycle during induction or every 2 months during maintenance, 
and within 24 hours prior to other timepoints during induction treatment.  Samples for exploratory biomarker research should be collected at the 
same time as hematology and chemistry samples. 
o Includes sodium, potassium, glucose, BUN or urea, creatinine, calculated creatinine clearance, calcium, total bilirubin, direct bilirubin, 
total protein, albumin, ALT, AST, alkaline phosphatase, glycosylated hemoglobin (HbA1c), amylase, lipase, LDH, and uric acid. HbA1c will be 
measured only at screening and can be obtained in a non-fasting state.
p All women of childbearing potential will have a serum pregnancy test at screening, within 7 days prior to Day 1 of Cycle 1.  Urine pregnancy tests 
will be performed at specified subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.


Appendix 1
Schedule of Assessments for Patients with Follicular Lymphoma (cont.)
Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
150/Protocol BO29561, Version 8
q Includes hepatitis B surface antigen, total hepatitis B core antibody, and hepatitis C virus antibody. 
r
Perform at the same time as tumor assessments at 12, 18, and 24 months after initiation of induction treatment. 
s See Appendix 3 for detailed schedule. 
t
Includes B-cell counts (CD19), T-cell counts (CD3, CD4, and CD8), and NK cell counts (CD16 and CD56). 
u Cycles 2 and 3 only. 
v Perform at the same time as tumor assessments at 12 and 18 months after initiation of induction treatment. 
w Requires separate patient consent for RCR participation.  Not applicable for a site that has not been granted approval for RCR sampling. 
x Availability of adequate archival or freshly biopsied tumor tissue samples should be confirmed at screening (see Section 4.5.7 for details). 
y A tumor biopsy sample will be collected prior to the start of Cycle 2 and at the time of progression unless no adequate tumor site is accessible. 
z Includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days prior to the screening period until the EOI or EOM visit, whichever occurs later. 
aa After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 90 days after the last dose of study 
treatment.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be 
related to prior study treatment (see Section 5.6).  An exception is made for Grade 3 or 4 infections (related and unrelated), which should be 
reported until up to 2 years after the last dose of obinutuzumab.  The investigator should follow each adverse event until the event has resolved 
to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  
Every effort should be made to follow all serious adverse events considered to be related to any of the study treatment components or trial-
related procedures until a final outcome can be reported. 
bb The screening PET-CT scan must be performed within 35 days prior to Day 1 of Cycle 1. 
cc Perform only for patients who have received at least two cycles of induction treatment. 
dd If PET-CT scan is positive at EOI, perform at 12 months after initiation of induction treatment, within 14 days prior to treatment administration. 
ee Includes CT scan of the neck (if clinically indicated), chest, abdomen, and pelvis.  If contrast is medically contraindicated (e.g., patients with 
contrast allergy or impaired renal clearance), MRI scans of the chest, abdomen, and pelvis (and neck, if clinically indicated) and a non-contrast 
CT scan of the chest may be performed.  Combined PET/CT scanners may be used to collect diagnostic CT scans, but only according to the 
technical guidelines in the imaging manual.  The screening CT scan must be performed within 35 days prior to Day 1 of Cycle 1. 


Appendix 1
Schedule of Assessments for Patients with Follicular Lymphoma (cont.)
Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
151/Protocol BO29561, Version 8
ff Perform within 7 days prior to Day 1 of Cycle 3, and at 12, 18, and 24 months after initiation of induction treatment, within 14 days prior to 
treatment administration.  Patients with radiographic evidence of progression at the end of Cycle 2 who continue to receive study treatment per 
criteria defined in Section 3.1.1 should have a CT scan repeated 48 weeks later.
gg Perform only if not done within the previous 3 months.
hh Bone marrow biopsy and aspirate must be performed within approximately 3 months prior to Day 1 of Cycle 1.
ii For patients with bone marrow involvement at screening, a repeat assessment will be performed at EOI if there is radiologic evidence of a 
complete response, and during maintenance or at EOM if there is radiologic evidence of a complete response or if clinically indicated 
(e.g., if there is clinical suspicion of progressive disease in the bone marrow with no radiologic evidence of progression).
jj Refer to Sections 4.3.2.5 and Section 4.3.2 for details on dosing and schedule.
kk Patients who experience disease progression or discontinued study treatment will be evaluated for survival status and new anti-lymphoma 
treatment every 3 months until the end of the study.  The end of the study is defined as the time when all enrolled patients with FL have 
completed or discontinued study treatment and all enrolled patients with DLBCL have been followed for at least 1 year after they have 
completed or discontinued study treatment.
  


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
152/Protocol BO29561, Version 8
Appendix 2
Schedule of Assessments for Patients with Diffuse Large B-Cell Lymphoma
Screening a
Induction 
(6 months; 21-day cycles)
EOI
90-Day Safety 
FU Visit 
(at 3 Months) c
Survival
FU Period 
(Q3M)ee
D 28 to 
D 1
D 14 to 
D 1
Cycle 1 
(1 day)
Cycles 26
(2 days)
After Last 
Induction Dose b
D1
D1
Informed consent d
x
Demographic data
x
Medical history
x
ECOG Performance Status
x
Vital signs e
x
x
x
x
Height
x
Weight
x
x
x
12-lead ECG
x
x
Complete physical examination f, g
x
Targeted physical examination g, h
D1, C2 and C4
x
x
Ann Arbor and IPI
x
B symptoms i
x
2 microglobulin
x
Hematology j
x
x k, l
x l
(C2: D1, D8, D15)
x
Chemistry panel (serum or 
plasma) m
x
x k, l
x l
x
Coagulation (INR, aPTT [or PTT], 
and PT)
x
Pregnancy test
x n
x n
x
Hepatitis B and C testing o
x
TSH, T3, T4
x
Every 3 months
Quantitative IgA, IgG, IgM
x
x
x
HACA sample for rituximab
x p


Appendix 2
Schedule of Assessments for Patients with Diffuse Large B-Cell Lymphoma (cont.)
Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
153/Protocol BO29561, Version 8
Screening a
Induction 
(6 months; 21-day cycles)
EOI
90-Day Safety 
FU Visit 
(at 3 Months) c
Survival
FU Period 
(Q3M)ee
D 28 to 
D 1
D 14 to 
D 1
Cycle 1 
(1 day)
Cycles 26
(2 days)
After Last 
Induction Dose b
D1
D1
ATA sample for atezolizumab and 
polatuzumab vedotin
x p
PK sample for rituximab, 
atezolizumab and polatuzumab 
vedotin
x p
Plasma for soluble PD-L1
x l
Whole blood for lymphocyte 
immunophenotyping q
x l
x l
x
x
Whole blood for T-cell receptor 
repertoire in PBMCs
x l
x l, r
x
Plasma for cytokine analysis
x l
x l, r
Optional peripheral blood sample 
for RCR s
x l
Tumor tissue specimen (leftover 
tissue may be used for optional 
RCR specimen s) 
x t
x u
x u
Concomitant medications
x v
To be recorded continually until end of treatment v
Adverse events w
x w
To be assessed continually w
PET-CT scan
x x
x y
CT scan z
x z
x aa
x y
Bone marrow biopsy and aspirate 
x bb
x y, cc
Study treatment 
administration
Rituximab dd
x
x
Polatuzumab 
vedotin dd
x
x
New anti-lymphoma treatment
x
Survival follow-up


Appendix 2
Schedule of Assessments for Patients with Diffuse Large B-Cell Lymphoma (cont.)
Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
154/Protocol BO29561, Version 8
ATAanti-therapeutic antibody; CCycle; CT computed tomography; Dday; ECOGEastern Cooperative Oncology Group; eCRF electronic 
Case Report Form; EOIend of induction; FUfollow-up; HAHAhuman anti-human antibody; IPIInternational Prognostic Index; MRImagnetic 
resonance imaging; NKnatural killer; PBMCperipheral blood mononuclear cell; PET positron emission tomography; PKpharmacokinetic; 
Q3Mevery 3 months; RCRRoche Clinical Repository; T3triiodothyronine; T4thyroxine; TSHthyroid-stimulating hormone; wk week.
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.  Assessments shaded in gray should 
be performed as scheduled, but the associated data do not need to be recorded on the eCRF (except in the case of an adverse event).  
a The screening period starts with the signing of the Informed Consent Form.  Results of standard-of-care tests or examinations performed prior to 
obtaining informed consent and within the defined window may be used as screening and baseline assessments; such tests do not need to be 
repeated for screening purposes.
b EOI assessments should be performed 68 weeks after Day 1 of the last induction cycle.  As an exception, patients who discontinue induction 
treatment prematurely because of an adverse event may undergo EOI assessments 48 weeks after their last dose of study treatment.
c Patients who complete treatment or prematurely discontinue treatment for reasons other than disease progression will undergo assessments at 
the 90-day safety follow-up visit.
d Informed consent must be documented before any study-specific screening procedure is performed.  
e Vital signs include respiratory rate, pulse rate, body temperature, and systolic and diastolic blood pressures while the patient is in a seated 
position.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, 
record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  For rituximab infusions:  Vital signs monitoring during 
infusion should be determined as per local label.  For polatuzumab vedotin infusions:  During the administration of polatuzumab vedotin, vital 
signs should be assessed before the start of the infusion, every 15 (5) minutes during the infusion, at the end of the infusion, and every 
30 (10) minutes for 90 minutes following completion of dosing at Cycle 1 and at Cycle 2, and 30 (10) minutes following completion of dosing in 
subsequent cycles. 
f
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and 
Baseline Conditions eCRF. 
g As part of tumor assessment, the physical examination should include evaluation for the presence of enlarged nodes, palpable hepatomegaly, 
and splenomegaly.  This information will be recorded on the appropriate tumor assessment eCRF. 
h Includes systems of primary relevance (e.g., cardiovascular and respiratory systems), systems associated with symptoms (newly emergent or 
monitored from baseline), and areas associated with tumor assessment (lymph nodes, liver, spleen, and any other areas identified at baseline).  
Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
i
Unexplained fever 38C, night sweats, and unexplained weight loss 10% of body weight over 6 months. 


Appendix 2
Schedule of Assessments for Patients with Diffuse Large B-Cell Lymphoma (cont.)
Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
155/Protocol BO29561, Version 8
j
Includes hemoglobin, hematocrit, platelet count, RBC count, WBC count, and percent or absolute WBC differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells). 
k Screening laboratory assessments may be used for Day 1 of Cycle 1 if performed within 72 hours prior to Day 1 of Cycle 1. 
l
Perform hematology and chemistry tests within 72 hours prior to Day 1 of each cycle during induction and within 24 hours prior to other 
timepoints during induction treatment.  Samples for exploratory biomarker research should be collected at the same time as hematology and 
chemistry samples. 
m Includes sodium, potassium, glucose, BUN or urea, creatinine, calculated creatinine clearance, calcium, total bilirubin, direct bilirubin, 
total protein, albumin, ALT, AST, alkaline phosphatase, glycosylated hemoglobin (HbA1c), amylase, lipase, LDH, and uric acid. HbA1c will be 
measured only at screening and can be obtained in a non-fasting state. 
n All women of childbearing potential will have a serum pregnancy test at screening, within 7 days prior to Day 1 of Cycle 1.  Urine pregnancy tests 
will be performed at specified subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
o Includes hepatitis B surface antigen, total hepatitis B core antibody, and hepatitis C virus antibody.  
p See Appendix 4 for detailed schedule. 
q Includes B-cell counts (CD19), T-cell counts (CD3, CD4, and CD8), and NK-cell counts (CD16 and CD56). 
r
Cycles 2 and 3 only. 
s Requires separate patient consent for RCR participation.  Not applicable for a site that has not been granted approval for RCR sampling.
t
Availability of adequate archival (obtained within 6 months prior to the initiation of study treatment) or freshly biopsied tumor tissue samples 
should be confirmed at screening (see Section 4.5.7 for details). 
u A tumor biopsy sample will be collected prior to the start of Cycle 2 and at the time of progression unless no adequate tumor site is accessible. 
v Includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days prior to the screening period until the EOI visit. 
w After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 90 days after the last dose of study 
treatment.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be 
related to prior study treatment (see Section 5.6).  The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort 
should be made to follow all serious adverse events considered to be related to any of the study treatment components or trial-related 
procedures until a final outcome can be reported.
x The screening PET-CT scan must be performed within 35 days prior to Day 1 of Cycle 1. 
y Perform only for patients who have received at least two cycles of induction treatment. 


Appendix 2
Schedule of Assessments for Patients with Diffuse Large B-Cell Lymphoma (cont.)
Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
156/Protocol BO29561, Version 8
z Includes CT scan of the neck (if clinically indicated), chest, abdomen, and pelvis.  If contrast is medically contraindicated (e.g., patients with 
contrast allergy or impaired renal clearance), MRI scans of the chest, abdomen, and pelvis (and neck, if clinically indicated) and a non-contrast 
CT scan of the chest may be performed.  Combined PET/CT scanners may be used to collect diagnostic CT scans, but only according to the 
technical guidelines in the imaging manual.  The screening CT scan must be performed within 35 days prior to Day 1 of Cycle 1. 
aa Perform within 7 days prior to Day 1 of Cycle 3.  Patients with radiographic evidence of progression at the end of Cycle 2 who continue to receive 
study treatment per criteria defined in Section 3.1.1 should have a CT scan repeated 48 weeks later.
bb Bone marrow biopsy and aspirate must be performed within approximately 3 months prior to Day 1 of Cycle 1. 
cc For patients with bone marrow involvement at screening, a repeat assessment will be performed at EOI if there is radiologic evidence of a 
complete response or if clinically indicated (e.g., if there is clinical suspicion of progressive disease in the bone marrow with no radiologic 
evidence of progression). 
dd Refer to Sections 4.3.2.5 and Section 4.3.2 for details on dosing and schedule.
ee Patients who experience disease progression or discontinued study treatment will be evaluated for survival status and new anti-lymphoma 
treatment every 3 months until the end of the study.  The end of the study is defined as the time when all enrolled patients with FL have 
completed or discontinued study treatment and all enrolled patients with DLBCL have been followed for at least 1 year after they have 
completed or discontinued study treatment.


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
157/Protocol BO29561, Version 8
Appendix 3
Pharmacokinetic and Immunogenicity Sampling Schedule for Obinutuzumab, 
Atezolizumab, and Polatuzumab Vedotin
Study Visit
Serum 
Obinutuzumab PK 
Sample a,b
Serum 
Atezolizumab 
PK Sample a
Serum Polatuzumab 
Vedotin PK Sample 
for Total Antibody a
Plasma Polatuzumab 
Vedotin PK Sample 
for Antibody-
Conjugated MMAE 
and Unconjugated 
MMAE a
Serum 
Obinutuzumab 
HAHA Sample a
Serum 
Atezolizumab 
ATA Sample a
Serum 
Polatuzumab 
Vedotin ATA 
Sample a
Induction (Cycles 16; 21-day cycles)
Cycle 1 
Day 1
Prior to infusion (any 
time prior to dose); 
30 10 minutes after 
end of infusion d

Prior to infusion (any 
time prior to dose)
Prior to infusion (any 
time prior to dose)
30 10 minutes after 
end of infusion 
Prior to infusion
(any time prior to 
dose)

Prior to 
infusion (any 
time prior to 
dose)
Day 8



Anytime during visit



Day 15



Anytime during visit



Cycle 2 
Day 1
Prior to infusion (within 
5 hr prior to dose)
30 10 minutes after 
end of infusion

Prior to infusion
(within 5 hr prior to 
dose)
Prior to infusion (within 
5 hr prior to dose);
30 10 minutes after 
end of infusion 


Prior to 
infusion (any 
time prior to 
dose)
Cycle 3
Day 1






Cycle 4
Day 1
Prior to infusion (within 
5 hr prior to dose);
30 10 minutes after 
end of infusion

Prior to infusion
(within 5 hr prior to 
dose)
Prior to infusion (within 
5 hr prior to dose); 
30 10 minutes after 
end of infusion 


Prior to 
infusion (any 
time prior to 
dose)
Cycle 6
Day 1
Prior to infusion (within 
5 hr prior to dose);
30 10 minutes after 
end of infusion


Prior to infusion (within 
5 hr prior to dose)
Prior to infusion
(any time prior to 
dose)




Appendix 3
Pharmacokinetic and Immunogenicity Sampling Schedule for Obinutuzumab, Atezolizumab, and 
Polatuzumab Vedotin (cont.)
Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
158/Protocol BO29561, Version 8
Study Visit
Serum 
Obinutuzumab PK 
Sample a,b
Serum 
Atezolizumab 
PK Sample a
Serum Polatuzumab 
Vedotin PK Sample 
for Total Antibody a
Plasma Polatuzumab 
Vedotin PK Sample 
for Antibody-
Conjugated MMAE 
and Unconjugated 
MMAE a
Serum 
Obinutuzumab 
HAHA Sample a
Serum 
Atezolizumab 
ATA Sample a
Serum 
Polatuzumab 
Vedotin ATA 
Sample a
Maintenance (Months 124)
Month 1
Day 1
Prior to infusion
(within 5 hr prior to 
dose)

Prior to infusion
(within 5 hr prior to 
dose)




Day 2






Month 4
Day 1







Months 7, 
13, and 19
Day 1
Prior to infusion
(within 5 hr prior to 
dose)






Discontinuation and Follow-Up b, c
Treatment 
discontinuation
Anytime during visit
Anytime during 
visit
Anytime during visit

Anytime during 
visit
Anytime 
during visit
Anytime 
during visit
12030 days after last 
dose of obinutuzumab, 
polatuzumab and 
atezolizumab 
(as appropriate for 
sample)
Anytime during visit
Anytime during 
visit
Anytime during visit

Anytime during 
visit
Anytime 
during visit
Anytime 
during visit
ATAanti-therapeutic antibody; HAHAhuman anti-human antibody; PKpharmacokinetic. 
a Sample collection timing is relative to specified drug.
b Samples collected for PK, HAHA, and ATA analysis may be used for additional PK, HAHA, and/or ATA assay development and validation and 
additional immunogenicity characterization, at the discretion of the clinical pharmacologist and/or the clinical scientist.
c The sampling applies once study treatment is discontinued for a given molecule (obinutuzumab, atezolizumab, or polatuzumab vedotin), 
irrespective of the study phase when discontinuation occurs (ie, induction or maintenance). 
d If the Cycle 1 Day 1 dose of obinutuzumab is split over two days, take the 30 and 10 minutes post end of infusion obinutuzumab PK sample 
after the end of the 900mg infusion on Day 2, and ensure that the date and time of the PK collection are accurately recorded.  


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
159/Protocol BO29561, Version 8
Appendix 4
Pharmacokinetic and Immunogenicity Sampling Schedule for Rituximab, 
Atezolizumab, and Polatuzumab Vedotin
Study Visit
Serum Rituximab PK 
Sample a,b
Serum 
Atezolizumab 
PK Sample a
Serum 
Polatuzumab 
Vedotin PK 
Sample for 
Total Antibody a
Plasma Polatuzumab 
Vedotin PK Sample for 
Antibody-Conjugated 
MMAE and 
Unconjugated MMAE a
Serum 
Rituximab
HACA Sample a
Serum 
Atezolizumab 
ATA Sample a
Serum 
Polatuzumab 
Vedotin ATA 
Sample a
Induction (Cycles 16; 21-day cycles)
Cycle 1 
Day 1
Prior to infusion (any 
time prior to dose); 
3010 minutes after 
end of infusion d

Prior to infusion 
(any time prior to 
dose)
Prior to infusion (any time 
prior to dose)
3010 minutes after end 
of infusion
Prior to infusion 
(any time prior to 
dose)

Prior to infusion 
(any time prior 
to dose)
Cycle 2 
Day 1
Prior to infusion 
(within 5 hr prior to 
dose)

Prior to infusion 
(within 5 hr prior 
to dose)
Prior to infusion (within 
5 hr prior to dose);
3010 minutes after end 
of infusion
Prior to infusion 
(any time prior to 
dose)

Prior to infusion 
(any time prior 
to dose)
Cycle 3
Day 1







Cycle 4
Day 1
Prior to infusion 
(within 5 hr prior to 
dose)

Prior to infusion 
(within 5 hr prior 
to dose)
Prior to infusion (within 
5 hr prior to dose)
3010 minutes after end 
of infusion
Prior to infusion 
(any time prior to 
dose)

Prior to infusion 
(any time prior
to dose)
Cycle 6
Day 1
Prior to infusion 
(within 5 hr prior to 
dose);
3010 minutes after 
end of infusion


Prior to infusion (within 
5 hr prior to dose)
Prior to infusion 
(any time prior to 
dose)




Appendix 4
Pharmacokinetic and Immunogenicity Sampling Schedule for Rituximab, Atezolizumab, and 
Polatuzumab Vedotin (cont.)
Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
160/Protocol BO29561, Version 8
Study Visit
Serum Rituximab PK 
Sample a,b
Serum 
Atezolizumab 
PK Sample a
Serum 
Polatuzumab 
Vedotin PK 
Sample for 
Total Antibody a
Plasma Polatuzumab 
Vedotin PK Sample for 
Antibody-Conjugated 
MMAE and 
Unconjugated MMAE a
Serum 
Rituximab
HACA Sample a
Serum 
Atezolizumab 
ATA Sample a
Serum 
Polatuzumab 
Vedotin ATA 
Sample a
Discontinuation and Follow-Upb, c
Treatment 
discontinuation
Anytime during visit
Anytime during 
visit
Anytime during 
visit

Anytime during 
visit
Anytime 
during visit
Anytime during 
visit
120 (30 days) after 
last dose of rituximab, 
polatuzumab and 
atezolizumab 
(as appropriate for 
sample)
Anytime during visit
Anytime during 
visit
Anytime during 
visit

Anytime during 
visit
Anytime 
during visit
Anytime during 
visit
1 year after last dose of 
polatuzumab vedotin


Anytime during 
visit



Anytime during 
visit
ATAanti-therapeutic antibody; HACAhuman anti-chimeric antibody; PKpharmacokinetic. 
a Sample collection timing is relative to specified drug.
b Samples collected for PK, HACA, and ATA analysis may be used for additional PK, HACA, and ATA assay development and validation and 
additional immunogenicity characterization, at the discretion of the clinical pharmacologist and/or the clinical scientist.
c The sampling applies once study treatment is discontinued for a given molecule (rituximab, atezolizumab, or polatuzumab vedotin), irrespective 
of the study phase when discontinuation occurs (i.e., induction). 
d If the Cycle 1 Day 1 dose of rituximab is split over two days, take the 30 and 10 minutes post end of infusion rituximab PK sample after the end 
of the rituximab infusion on Day 2, and ensure that the date and time of the PK collection are accurately recorded.  


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
161/Protocol BO29561, Version 8
Appendix 5
Lugano Response Criteria for Malignant Lymphoma
(Cheson et al. 2014)
In this study, the Lugano 2014 criteria for a PET-CTbased complete response (CR) and 
partial response (PR) have been modified, as outlined below:

A designation of PET-CTbased CR requires normal bone marrow by morphology 
for patients with bone marrow involvement at baseline.  If indeterminate by 
morphology, immunohistochemistry should be negative.

A designation of PET-CTbased PR requires that CT-based response criteria for a 
CR or PR be met in addition to the PET-CTbased response criteria for a PR.
Revised Criteria for Response Assessment
Response and Site
PET-CTBased Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic response (all of 
the following)
Lymph nodes 
and 
extralymphatic 
sites
Score 1, 2, or 3 a with or without a 
residual mass on 5PS b
It is recognized that in Waldeyer’s 
ring or extranodal sites with high 
physiologic uptake or with 
activation within spleen or marrow 
(e.g., with chemotherapy or 
myeloid colony-stimulating 
factors), uptake may be greater 
than normal mediastinum and/or 
liver.  In this circumstance, 
complete metabolic response may 
be inferred if uptake at sites of 
initial involvement is no greater 
than surrounding normal tissue 
even if the tissue has high 
physiologic uptake.
Target nodes/nodal masses must 
regress to1.5 cm in LDi
No extralymphatic sites of disease
Non-measured 
lesion
Not applicable
Absent
Organ 
enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in 
marrow
Normal by morphology; if 
indeterminate, IHC negative


Appendix 5
Lugano Response Criteria for Malignant Lymphoma
(Cheson et al. 2014) (cont.)
Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
162/Protocol BO29561, Version 8
Revised Criteria for Response Assessment
Response and Site
PET-CTBased Response
CT-Based Response
Partial
Partial metabolic response
Partial remission (all of the 
following)
Lymph nodes 
and 
extralymphatic 
sites
Score 4 or 5 b with reduced uptake 
compared with baseline and 
residual mass(es) of any size
50% decrease in SPD of up to 
six target measurable nodes and 
extranodal sites
At interim, these findings suggest 
responding disease
When a lesion is too small to 
measure on CT, assign 
5 mm 5 mm as the default value
At end of treatment, these findings 
indicate residual disease
When no longer visible, 00 mm
For a node 5 mm 5 mm, but 
smaller than normal, use actual 
measurement for calculation
Non-measured 
lesion
Not applicable
Absent/normal, regressed, but no 
increase
Organ 
enlargement
Not applicable
Spleen must have regressed by 
50% in length beyond normal
New lesions
None
None
Bone marrow
Residual uptake higher than uptake 
in normal marrow but reduced 
compared with baseline (diffuse 
uptake compatible with reactive 
changes from chemotherapy 
allowed).  If there are persistent 
focal changes in the marrow in 
the context of a nodal response, 
consideration should be given to 
further evaluation with MRI or 
biopsy or an interval scan.
Not applicable
No response or 
stable disease 
No metabolic response
Stable disease
Target 
nodes/nodal 
masses, 
extranodal 
lesions
Score 4 or 5 b with no significant 
change in FDG uptake from 
baseline at interim or end of 
treatment
50% decrease from baseline in 
SPD of up to six dominant, 
measurable nodes and 
extranodal sites; no criteria for 
progressive disease are met
Non-measured 
lesion
Not applicable
No increase consistent with 
progression
Organ 
enlargement
Not applicable
No increase consistent with 
progression
New lesions
None
None


Appendix 5
Lugano Response Criteria for Malignant Lymphoma
(Cheson et al. 2014) (cont.)
Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
163/Protocol BO29561, Version 8
Revised Criteria for Response Assessment
Response and Site
PET-CTBased Response
CT-Based Response
Bone marrow
No change from baseline
Not applicable
Progressive 
disease
Progressive metabolic disease
Progressive disease requires at 
least one of the following 
Individual target 
nodes/nodal 
masses
Score 4 or 5 b with an increase in 
intensity of uptake from baseline 
and/or
PPD progression:
Extranodal 
lesions
New FDG-avid foci consistent with 
lymphoma at interim or end-of-
treatment assessment
An individual node/lesion must be 
abnormal with:
LDi 1.5 cm and
Increase by 50% from PPD nadir 
and
An increase in LDi or SDi from nadir
0.5 cm for lesions 2 cm
1.0 cm for lesions 2 cm
In the setting of splenomegaly, the 
splenic length must increase 
by50% of the extent of its prior 
increase beyond baseline 
(e.g., a 15-cm spleen must 
increase to 16 cm).  If no prior 
splenomegaly, must increase by 
at least 2 cm from baseline.
New or recurrent splenomegaly 
New or clear progression of 
preexisting non-measured lesions


Appendix 5
Lugano Response Criteria for Malignant Lymphoma
(Cheson et al. 2014) (cont.)
Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
164/Protocol BO29561, Version 8
Revised Criteria for Response Assessment
Response and Site
PET-CTBased Response
CT-Based Response
New lesions
New FDG-avid foci consistent with 
lymphoma rather than another 
etiology (e.g., infection, 
inflammation); if uncertain 
regarding etiology of new lesions, 
biopsy or interval scan may be 
considered
Regrowth of previously resolved 
lesions
A new node1.5 cm in any axis
A new extranodal site1.0 cm in 
any axis; if 1.0 cm in any axis, 
its presence must be unequivocal 
and must be attributable to 
lymphoma
Assessable disease of any size 
unequivocally attributable to 
lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
5PS5-point scale; CT computed tomography; FDG fluorodeoxyglucose; 
GIgastrointestinal; IHCimmunohistochemistry; LDilongest transverse diameter of a 
lesion; MRImagnetic resonance imaging; PET positron emission tomography; PPDcross 
product of the LDi and perpendicular diameter; SDishortest axis perpendicular to the LDi; 
SPDsum of the product of the perpendicular diameters for multiple lesions.
a A score of 3 in many patients indicates a good prognosis with standard treatment, especially 
if at the time of an interim scan.  However, in trials involving PET where de-escalation is 
investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid 
undertreatment).  Measured dominant lesions:  Up to six of the largest dominant nodes, 
nodal masses, and extranodal lesions selected to be clearly measurable in two diameters.  
Nodes should preferably be from disparate regions of the body and should include, where 
applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid 
organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those 
noted on palpation.  Non-measured lesions:  Any disease not selected as measured; 
dominant disease and truly assessable disease should be considered not measured.  These 
sites include any nodes, nodal masses, and extranodal sites not selected as dominant or 
measurable or that do not meet the requirements for measurability but are still considered 
abnormal, as well as truly assessable disease, which is any site of suspected disease that 
would be difficult to follow quantitatively with measurement, including pleural effusions, 
ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that 
cannot be confirmed and followed by imaging.  In Waldeyer’s ring or in extranodal sites 
(e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with 
complete metabolic response, but should be no higher than surrounding normal physiologic 
uptake (e.g., with marrow activation as a result of chemotherapy or myeloid growth factors).
b PET 5PS:  1no uptake above background; 2uptake mediastinum; 3uptake 
mediastinum but liver; 4uptake moderately liver; 5uptake markedly higher than liver 
and/or new lesions; X new areas of uptake unlikely to be related to lymphoma.
REFERENCE
Cheson B, Fisher R, Barrington S, et al. Recommendations for initial evaluation, staging 
and response assessment of Hodgkin and nonHodgkin lymphoma: The Lugano 
Classification. J Clin Oncol 2014;32:305969.  


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
165/Protocol BO29561, Version 8
Appendix 6
Eastern Cooperative Oncology Group 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 bed or chair
5
Dead


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
166/Protocol BO29561, Version 8
Appendix 7
Ann Arbor Staging
Grade
Description
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 site (IIIE), or both (IIIES)
Stage IV b
Diffuse or disseminated foci of involvement of one or more 
extralymphatic organs or tissues, with or without associated 
lymphatic involvement
Note:  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.
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.
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.


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
167/Protocol BO29561, Version 8
Appendix 8
Follicular Lymphoma International Prognostic Index
Table 1
Follicular Lymphoma International Prognostic Index
FLIPI Risk Factor
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 to 5
FDGfluorodeoxyglucose; FLIPIFollicular Lymphoma International Prognostic Index; 
PET positron emission tomography; ULNupper limit of normal.
Note:  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.
Table 2
Follicular Lymphoma International Prognostic Index 2
FLIPI2 Risk Factor
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 to 5
FDGfluorodeoxyglucose; FLIPI2Follicular Lymphoma International Prognostic Index 2; 
PET positron emission tomography; ULNupper limit of normal.
Note:  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:  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.


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
168/Protocol BO29561, Version 8
Appendix 9
Anaphylaxis Precautions
EQUIPMENT NEEDED

Tourniquet

Oxygen

Epinephrine for subcutaneous, intravenous (IV), and/or endotracheal use in 
accordance with standard practice 

Antihistamines

Corticosteroids

IV infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, the 
following procedures should be performed:

Stop the study treatment infusion.

Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
treatment.  Do not obstruct arterial flow in the limb.

Maintain an adequate airway.

Administer glucocorticoids, antihistamines, epinephrine, or other medications as 
required by patient status and directed by the physician in charge.

Continue to observe the patient and document observations.


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
169/Protocol BO29561, Version 8
Appendix 10
Preexisting Autoimmune Diseases
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below will be excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with a 
medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study.  In addition, patients with transient autoimmune 
manifestations of an acute infectious disease that resolved upon treatment of the 
infectious agent are not excluded (e.g., acute Lyme arthritis).  Please contact the 
Medical Monitor regarding any uncertainty over autoimmune exclusions.
Acute disseminated
encephalomyelitis
Addison’s disease
Ankylosing spondylitis
Antiphospholipid antibody
syndrome
Aplastic anemia
Autoimmune hemolytic 
anemia
Autoimmune hepatitis
Autoimmune
hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune 
thrombocytopenic
purpura
Behcet’s disease
Bullous pemphigold
Chronic inflammatory
demyelinating
polyneuropathy
Chung-Strauss syndrome
Crohn’s disease
Dermatomyositis
Diabetes mellitus type 1
Dysautonomia
Epidermolysis bullosa 
acquista
Gestational pemphigoid
Giant cell arteritis
Goodpasture’s syndrome
Graves’ disease
Guillain-Barré syndrome
Hashimoto’s disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki’s disease
Lambert-Eaton myasthenia
syndrome
Lupus erythematosus
Lyme disease - chronic
Meniere’s syndrome
Mooren’s ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus
syndrome
Optic neuritis
Ord’s thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis nodusa
Polyarthritis
Polyglandular autoimmune
syndrome
Primary biliary cirrhosis
Psoriasis
Reiter’s syndrome
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren’s syndrome
Stiff-Person syndrome
Takayasu’s arteritis
Ulcerative colitis
Vitiligo
Vogt-Kovanagi-Harada 
disease
Wegener’s granulomatosis


Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
170/Protocol BO29561, Version 8
Appendix 11
Calculation of Creatinine Clearance Using the 
Cockcroft-Gault Formula
Creatinine clearance (men) (140Age)Lean body weight (kg)
Serum Creatinine (mg/dL) 72
Creatinine clearance (women)0.85 (140Age)Lean body weight (kg)
Serum Creatinine (mg/dL) 72
Adapted from:  Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from 
adjusted serum creatinine [editorial]. Nephron 1992;62:24956.