Conditions: Lymphoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 331
Healthy volunteers: no

Brief summary:
This study is a multicenter, open-label study of polatuzumab vedotin administered by intravenous (IV) infusion in combination with standard doses of bendamustine (B) and rituximab (R) or obinutuzumab (G) in participants with relapsed or refractory follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL). The study comprises two stages: a Phase Ib safety run-in stage and a Phase II stage. The anticipated time on treatment is 18 weeks for participants with DLBCL and 24 weeks for participants with FL.

Detailed description:

Arms:
arm 1: Polatuzumab vedotin will be administered with bendamustine and rituximab in participants with FL. arm 2: Bendamustine and rituximab will be administered alone (that is, without polatuzumab vedotin) as a control arm in participants with FL. arm 3: Polatuzumab vedotin will be administered with bendamustine and rituximab in participants with DLBCL. arm 4: Bendamustine and rituximab will be administered alone (that is, without polatuzumab vedotin) as a control arm in participants with DLBCL. arm 5: Polatuzumab vedotin will be administered with bendamustine and obinutuzumab in participants with FL. arm 6: Polatuzumab vedotin will be administered with bendamustine and obinutuzumab in participants with DLBCL. arm 7: Polatuzumab vedotin will be administered with bendamustine and rituximab in participants with DLBCL. arm 8: Polatuzumab vedotin will be administered with bendamustine and rituximab in participants with FL. arm 9: Polatuzumab vedotin will be administered with bendamustine and obinutuzumab in participants with DLBCL. arm 10: Polatuzumab vedotin will be administered with bendamustine and obinutuzumab in participants with FL. arm 11: In this New Formulation (NF) cohort, Polatuzumab vedotin (lyophilized) will be administered with bendamustine and rituximab in participants with DLBCL. arm 12: In this NF cohort, Polatuzumab vedotin (lyophilized) will be administered with bendamustine and rituximab in participants with DLBCL.

Interventions: intervention 1: Bendamustine intervention 2: Obinutuzumab intervention 3: Polatuzumab vedotin (Liquid) intervention 4: Rituximab intervention 5: Polatuzumab vedotin (Lyophilized)
Intervention descriptions: intervention 1: Bendamustine 90 milligrams per meter-squared (mg/m\^2) per day administered IV on Days 2 and 3 of Cycle 1, then on Days 1 and 2 of each subsequent cycle for up to 6 cycles (each cycle is 21 days in DLBCL and 28 days in FL). intervention 2: Obinutuzumab 1000 milligrams (mg) IV on Days 1, 8, and 15 of Cycle 1 and on Day 1 of each subsequent cycle for up to 6 cycles (each cycle is 21 days in DLBCL and 28 days in FL). intervention 3: Polatuzumab vedotin 1.8 milligrams per kilogram (mg/kg) administered IV on Day 2 of Cycle 1, then on Day 1 of each subsequent cycle for up to 6 cycles (each cycle is 21 days in DLBCL and 28 days in FL). intervention 4: Rituximab standard dose, 375 mg/m\^2 IV on Day 1 of each cycle for up to 6 cycles (each cycle is 21 days in DLBCL and 28 days in FL). intervention 5: Participants in the New Formulation (NF) Cohort (Arms G and H) will follow the same schedule and dosing requirements as participants in the other Phase II cohorts (Arms A-F).

Protocol document:
Prot_SAP_000.pdf: 
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.
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
Protocol GO29365, Version 8
PROTOCOL
TITLE:
A PHASE IB/II STUDY EVALUATING THE SAFETY, 
TOLERABILITY AND ANTI-TUMOR ACTIVITY OF 
POLATUZUMAB VEDOTIN IN COMBINATION WITH 
RITUXIMAB (R) OR OBINUTUZUMAB (G) PLUS 
BENDAMUSTINE (B) IN RELAPSED OR 
REFRACTORY FOLLICULAR OR DIFFUSE LARGE 
B-CELL LYMPHOMA
PROTOCOL NUMBER:
GO29365
VERSION NUMBER:
8
EUDRACT NUMBER:
2014-001361-28
IND NUMBER:
109409
NCT NUMBER:
NCT02257567
TEST PRODUCTS:
Polatuzumab vedotin, liquid (DCDS4501A)
Polatuzumab vedotin, lyophilized (DCDS4501S)
MEDICAL MONITOR:
, Pharm.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  23 May 2014
 
23-Mar-2020 16:56:09
Title
Approver's Name
Company Signatory
Date and Time (UTC)


DATES AMENDED:
Version 2:  27 April 2015
Version 3:  14 September 2015
Version 4:  11 July 2017
Version 5:  16 November 2017
Version 6:  31 May 2018
Version 7:  2 October 2018
Version 8:  See electronic date stamp.
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
2/Protocol GO29365, Version 8


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
3/Protocol GO29365, Version 8
PROTOCOL AMENDMENT, VERSION 8:
RATIONALE
Protocol GO29365 has been amended to implement the following changes:

Safety language for polatuzumab vedotin relating to the recategorization of identified
risks has been updated to align with the informed consent form and the 
Investigator’s Brochure (Section 5.1.1).

Safety language for bendamustine relating to hepatitis B reactivation and skin 
reactions has been updated to align with the informed consent form and the 
United Kingdom Summary of Product Characteristics (Section 5.1.3).

Medical Monitor and Emergency Medical Contact information has been updated 
(Section 5.4.1).

Updated reporting requirements for cases of second malignancies to be reported 
indefinitely for all enrolled subjects (Sections 5.3.1, 5.4.2.2, and 5.6).

Updated reporting requirements for cases of accidental overdose or medication 
error, which are no longer required to be reported within 24 hours after learning of 
the event (Section 5.3.5.12).
Additional minor changes have been made to improve clarity and consistency. 
Substantive new information appears in italics. This amendment represents cumulative 
changes to the original protocol.


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
4/Protocol GO29365, Version 8
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14
PROTOCOL SYNOPSIS .................................................................................... 15
1.
BACKGROUND .......................................................................................... 34
1.1
Background on Non-Hodgkin’s Lymphoma ........................... 34
1.1.1
Follicular Lymphoma ............................................................. 34
1.1.2
Diffuse Large B-Cell Lymphoma............................................ 35
1.2
Background on the Molecules ............................................... 36
1.2.1
Polatuzumab Vedotin ............................................................ 36
1.2.1.1
Polatuzumab Vedotin Background and 
Nonclinical Data..................................................................... 36
1.2.1.2
Polatuzumab Vedotin Clinical Data ....................................... 38
1.2.1.3
Pharmacokinetic and Pharmacodynamic 
Properties of Polatuzumab Vedotin ....................................... 42
1.3
Study Rationale and Benefit-Risk Assessment...................... 43
2.
OBJECTIVES.............................................................................................. 46
2.1
Primary Objectives (Main Study) ........................................... 46
2.2
Secondary Objectives (Main Study) ...................................... 47
2.2.1
Safety Objectives................................................................... 47
2.2.2
Pharmacokinetic Objectives .................................................. 47
2.2.3
Secondary Efficacy Objectives (Main Study) ......................... 48
2.2.4
Patient-Reported Outcome Objective .................................... 48
2.2.5
Exploratory Objectives........................................................... 49
2.3
Objectives for the New Formulation (Lyophilized) 
Cohort.................................................................................... 49
2.3.1
Arm G .................................................................................... 49
2.3.1.1
Primary Objective .................................................................. 49
2.3.1.2
Secondary Objectives............................................................ 50
2.3.2
Arm H .................................................................................... 50
2.3.2.1
Primary Objective .................................................................. 50
2.3.2.2
Secondary Objectives............................................................ 50
2.3.2.3
Exploratory Objectives........................................................... 51


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
5/Protocol GO29365, Version 8
3.
STUDY DESIGN......................................................................................... 51
3.1
Description of the Study......................................................... 51
3.1.1
Phase Ib:  Safety Run-In Stage ............................................. 55
3.1.1.1
Cohort Dosing Regimen ........................................................ 55
3.1.1.2
Definition of Safety Criteria during Safety Run-In .................. 57
3.1.1.3
Decision Rules for Safety Run-In Stage ................................ 58
3.1.2
Phase II:  Randomized and Expansion Stage and 
New Formulation Cohort........................................................ 59
3.1.2.1
Randomized Bendamustine plus Rituximab-
Containing Regimen .............................................................. 59
3.1.2.2
Non-Randomized Bendamustine Plus 
Obinutuzumab Containing Regimen...................................... 60
3.1.2.3
Phase II New Formulation Cohort:  Polatuzumab 
Vedotin (Lyophilized) plus BR................................................ 61
3.1.3
Internal Monitoring Committee............................................... 61
3.1.4
Independent Review Committee............................................ 62
3.2
End of Study.......................................................................... 62
3.3
Rationale for Study Design.................................................... 62
3.3.1
Rationale for Polatuzumab Vedotin Dose and 
Schedule................................................................................ 62
3.3.2
Rationale for Rituximab and Bendamustine 
Dosing and Schedule ............................................................ 63
3.3.3
Rationale for Obinutuzumab and Bendamustine 
Dosing and Schedule ............................................................ 64
3.3.4
Rationale for Stratification Factors......................................... 64
3.3.5
Rationale for PET-Defined Complete Response ................... 65
3.3.6
Rationale for Patient-Reported Outcomes............................. 65
3.3.7
Rationale for Collecting Lymph Node Biopsy 
Samples and Peripheral Blood for Biomarker 
Studies................................................................................... 65
3.4
Outcome Measures ............................................................... 66
3.4.1
Safety Outcome Measures .................................................... 66
3.4.2
Efficacy Outcome Measures.................................................. 66
3.4.3
Pharmacokinetic Outcome Measures.................................... 67
3.4.4
Patient-Reported Outcome Measure ..................................... 67
3.4.5
Exploratory Outcome Measures ............................................ 67


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
6/Protocol GO29365, Version 8
4.
MATERIALS AND METHODS .................................................................... 68
4.1
Patients.................................................................................. 68
4.1.1
Inclusion Criteria.................................................................... 68
4.1.2
Exclusion Criteria................................................................... 71
4.1.3
Criteria for Lymph Node Biopsy Tissue ................................. 73
4.2
Method of Treatment Assignment and Blinding..................... 74
4.3
Study Treatment.................................................................... 74
4.3.1
Formulation, Packaging, and Handling.................................. 74
4.3.1.1
Polatuzumab Vedotin ............................................................ 74
4.3.1.2
Rituximab............................................................................... 75
4.3.1.3
Bendamustine........................................................................ 75
4.3.1.4
Obinutuzumab ....................................................................... 75
4.3.2
Dosage, Administration, and Compliance.............................. 75
4.3.2.1
Bendamustine plus Rituximab Regimen................................ 75
4.3.2.2
Polatuzumab Vedotin plus BR Regimen................................ 76
4.3.2.3
Polatuzumab Vedotin plus BG Regimen................................ 77
4.3.2.4
Polatuzumab Vedotin ............................................................ 79
4.3.2.5
Rituximab............................................................................... 80
4.3.2.6
Obinutuzumab ....................................................................... 82
4.3.2.7
Bendamustine........................................................................ 84
4.3.3
Investigational Medicinal Product Accountability ................... 85
4.3.4
Post-Trial Access to Polatuzumab Vedotin............................ 85
4.4
Concomitant Therapy ............................................................ 86
4.4.1
Permitted Therapy................................................................. 86
4.4.1.1
Treatment and Prophylaxis of Neutropenia ........................... 86
4.4.1.2
Premedication before Rituximab and 
Obinutuzumab ....................................................................... 86
4.4.1.3
Premedication for Patients at High Risk for 
Tumor Lysis Syndrome.......................................................... 87
4.4.1.4
Prophylaxis for Infections....................................................... 87
4.4.1.5
Monitoring and Treatment for Hepatitis B 
Reactivation........................................................................... 87
4.4.1.6
Other Concomitant Medications ............................................ 88
4.4.2
Prohibited Therapy ................................................................ 88


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4.4.2.1
Immunizations ....................................................................... 89
4.5
Study Assessments ............................................................... 89
4.5.1
Informed Consent Forms and Screening Log........................ 89
4.5.2
Medical History and Demographic Data ................................ 89
4.5.3
Prognostic Indices ................................................................. 90
4.5.4
Physical Examinations........................................................... 90
4.5.5
Total Neuropathy Score Clinical Assessment........................ 90
4.5.6
Vital Signs.............................................................................. 91
4.5.7
Tumor and Response Evaluations......................................... 91
4.5.8
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 92
4.5.9
Electrocardiograms................................................................ 95
4.5.10
Patient-Reported Outcomes .................................................. 95
4.5.11
Samples for Roche Clinical Repository.................................. 96
4.5.11.1
Overview of the Roche Clinical Repository............................ 96
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 96
4.5.11.3
Sample Collection.................................................................. 96
4.5.11.4
Confidentiality........................................................................ 97
4.5.11.5
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 98
4.5.11.6
Withdrawal from the Roche Clinical Repository..................... 98
4.5.11.7
Monitoring and Oversight....................................................... 99
4.5.12
Timing of Study Assessments ............................................... 99
4.5.12.1
Screening and Pretreatment Assessments............................ 99
4.5.12.2
Assessments during Treatment............................................. 99
4.5.12.3
Follow-Up Assessments ...................................................... 100
4.5.12.4
Assessments at Unplanned Visits ....................................... 101
4.6
Patient, Treatment, Study, and Site 
Discontinuation.................................................................... 101
4.6.1
Patient Discontinuation........................................................ 101
4.6.2
Study Treatment Discontinuation......................................... 101
4.6.3
Study and Site Discontinuation............................................ 102
5.
ASSESSMENT OF SAFETY..................................................................... 103


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
8/Protocol GO29365, Version 8
5.1
Safety Plan .......................................................................... 103
5.1.1
Risks Associated with Polatuzumab Vedotin....................... 103
5.1.1.1
Known Risks........................................................................ 103
5.1.1.2
Potential Risks..................................................................... 105
5.1.2
Risks Associated with Rituximab Therapy........................... 107
5.1.2.1
Infusion-Related Reactions.................................................. 107
5.1.2.2
Tumor Lysis Syndrome........................................................ 107
5.1.2.3
Hepatitis B Reactivation....................................................... 107
5.1.2.4
Progressive Multifocal Leukoencephalopathy...................... 107
5.1.2.5
Cardiac Toxicity ................................................................... 108
5.1.2.6
Infection............................................................................... 108
5.1.2.7
Severe Mucocutaneous Reactions...................................... 108
5.1.2.8
Bowel Obstruction and Perforation...................................... 108
5.1.3
Risks Associated with Bendamustine .................................. 108
5.1.3.1
Myelosuppression................................................................ 108
5.1.3.2
Infection............................................................................... 109
5.1.3.3
Hepatitis B Reactivation...................................................... 109
5.1.3.4
Infusion-Related Reactions and Anaphylaxis ...................... 109
5.1.3.5
Tumor Lysis Syndrome........................................................ 109
5.1.3.6
Skin Reactions..................................................................... 109
5.1.3.7
Long-Term Stem-Cell Toxicity ............................................. 110
5.1.3.8
Extravasation of Bendamustine........................................... 110
5.1.3.9
Transfusion-Associated Graft versus Host 
Disease................................................................................ 110
5.1.3.10
Drug Interactions ................................................................. 110
5.1.4
Risks Associated with Obinutuzumab.................................. 110
5.1.4.1
Infusion-Related Reactions and Hypersensitivity 
Reactions (Including Anaphylaxis)....................................... 110
5.1.4.2
Tumor Lysis Syndrome........................................................ 111
5.1.4.3
Neutropenia......................................................................... 111
5.1.4.4
Thrombocytopenia............................................................... 111
5.1.4.5
Infection............................................................................... 112
5.1.4.6
Impaired Immunization Response......................................... 113
5.1.4.7
Worsening of Preexisting Cardiac Condition ....................... 113


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
9/Protocol GO29365, Version 8
5.1.4.8
Gastrointestinal Perforation ................................................. 113
5.1.5
Management of Specific Adverse Events ............................ 113
5.1.5.1
Dose Delays and Dose Modifications .................................. 113
5.1.5.2
Dose Modifications .............................................................. 113
5.1.5.3
Dose Delay.......................................................................... 114
5.1.5.4
Schedule Modifications........................................................ 114
5.1.5.5
Non-Hematologic Toxicities................................................. 114
5.1.5.6
Treatment Discontinuation Criteria ...................................... 121
5.2
Safety Parameters and Definitions ...................................... 122
5.2.1
Adverse Events ................................................................... 122
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 122
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 123
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 124
5.3.1
Adverse Event Reporting Period ......................................... 124
5.3.2
Eliciting Adverse Event Information..................................... 124
5.3.3
Assessment of Severity of Adverse Events ......................... 125
5.3.4
Assessment of Causality of Adverse Events ....................... 125
5.3.5
Procedures for Recording Adverse Events.......................... 126
5.3.5.1
Infusion-Related Reactions.................................................. 126
5.3.5.2
Diagnosis versus Signs and Symptoms............................... 126
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................. 127
5.3.5.4
Persistent or Recurrent Adverse Events.............................. 127
5.3.5.5
Abnormal Laboratory Values ............................................... 127
5.3.5.6
Abnormal Vital Sign Values ................................................. 128
5.3.5.7
Abnormal Liver Function Tests............................................ 129
5.3.5.8
Deaths ................................................................................. 129
5.3.5.9
Preexisting Medical Conditions............................................ 130
5.3.5.10
Lack of Efficacy or Worsening of Lymphoma....................... 130
5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 130


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
10/Protocol GO29365, Version 8
5.3.5.12
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error ............................................. 131
5.3.5.13
Patient-Reported Outcome Data ......................................... 132
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 132
5.4.1
Medical Monitors and Emergency Medical 
Contacts .............................................................................. 133
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 133
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 133
5.4.2.2
Events That Occur after Study Drug Initiation...................... 133
5.4.3
Reporting Requirements for Pregnancies............................ 134
5.4.3.1
Pregnancies in Female Patients.......................................... 134
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 134
5.4.3.3
Abortions ............................................................................. 135
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 135
5.5
Follow-Up of Patients after Adverse Events ........................ 135
5.5.1
Investigator Follow-Up......................................................... 135
5.5.2
Sponsor Follow-Up .............................................................. 135
5.6
Post-Study Adverse Events................................................. 136
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 136
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 136
6.1
Determination of Sample Size ............................................. 137
6.1.1
Phase Ib:  Safety Run-In Stage ........................................... 137
6.1.2
Phase II:  Randomized and Expansion Stage ..................... 137
6.1.3
Phase II:  New Formulation Cohort...................................... 139
6.1.3.1
Arm G .................................................................................. 139
6.1.3.2
Arm H .................................................................................. 140
6.2
Summaries of Conduct of Study.......................................... 141
6.3
Summaries of Treatment Group Comparability ................... 141
6.4
Efficacy Analyses ................................................................ 141
6.4.1
Primary Efficacy Endpoint.................................................... 142


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
11/Protocol GO29365, Version 8
6.4.2
Secondary Efficacy Endpoints............................................. 143
6.4.3
Exploratory Efficacy Endpoints............................................ 143
6.5
Safety Analyses................................................................... 144
6.6
Pharmacokinetic Analyses................................................... 144
6.7
Patient-Reported Outcome Analyses .................................. 145
6.8
Exploratory Analyses........................................................... 145
7.
DATA COLLECTION AND MANAGEMENT ............................................. 145
7.1
Data Quality Assurance....................................................... 145
7.2
Electronic Case Report Forms............................................. 146
7.3
Electronic Patient-Reported Outcome Data......................... 146
7.4
Source Data Documentation................................................ 147
7.5
Use of Computerized Systems ............................................ 147
7.6
Retention of Records........................................................... 147
8.
ETHICAL CONSIDERATIONS.................................................................. 148
8.1
Compliance with Laws and Regulations .............................. 148
8.2
Informed Consent................................................................ 148
8.3
Institutional Review Board or Ethics Committee.................. 149
8.4
Confidentiality...................................................................... 150
8.5
Financial Disclosure ............................................................ 150
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 151
9.1
Study Documentation .......................................................... 151
9.2
Protocol Deviations.............................................................. 151
9.3
Site Inspections ................................................................... 151
9.4
Administrative Structure....................................................... 151
9.5
Dissemination of Data and Protection of 
Trade Secrets...................................................................... 152
9.6
Protocol Amendments ......................................................... 153
10. REFERENCES ......................................................................................... 154


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
12/Protocol GO29365, Version 8
LIST OF TABLES
Table 1
Treatment Regimens for Relapsed/Refractory DLBCL ............... 44
Table 2
Safety Run-In Cohorts of Polatuzumab Vedotin with Starting 
Doses of Bendamustine and Rituximab or Obinutuzumab.......... 56
Table 3
Administration of First and Subsequent Infusions of 
Rituximab.................................................................................... 82
Table 4
Administration of First and Subsequent Infusions of 
Obinutuzumab............................................................................. 83
Table 5
Sample Collection....................................................................... 97
Table 6
Management of Infusion-Related Symptoms ............................ 115
Table 7
Guidelines for Dose Delay or Modification of Polatuzumab 
Vedotin, Rituximab, Obinutuzumab, or Bendamustine.............. 116
Table 8
Guidelines for Dose Delay for Obinutuzumab on Cycle 1, 
Day 8 and Cycle 1, Day 15 ....................................................... 120
Table 9
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 125
Table 10
Causal Attribution Guidance ..................................................... 126
Table 11
Clopper-Pearson Exact 95% Confidence Intervals for 
Assumed Observed CR Rates based on Sample Size of 40 
Patients..................................................................................... 138
Table 12
Clopper-Pearson Exact 95% Confidence Intervals for 
Assumed Observed CR Rates based on Sample Size of 20 
Patients..................................................................................... 139
Table 13
Estimated Polatuzumab Vedotin plus BR Complete 
Response Rate in R/R DLBCL.................................................. 141
LIST OF FIGURES
Figure 1
Preclinical Data in WSU-DLCL2.................................................. 45
Figure 2
Overview of Study Design........................................................... 54
Figure 3
Phase II Randomized:  Polatuzumab Vedotin Plus BR vs BR .... 60
Figure 4
Phase II Expansion:  Bendamustine Plus Obinutuzumab 
Regimen...................................................................................... 60
Figure 5
Phase II:  Non-Randomized NF Cohort ...................................... 61
Figure 6
Bendamustine plus Rituximab Regimen ..................................... 76
Figure 7
Polatuzumab Vedotin plus BR Regimen ..................................... 77
Figure 8
Polatuzumab Vedotin plus BG Regimen..................................... 79


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
13/Protocol GO29365, Version 8
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................ 160
Appendix 2
Pharmacokinetic and Anti-Drug Antibody Sampling Schedule.. 169
Appendix 3
Response Criteria for Malignant Lymphoma............................. 182
Appendix 4
Revised Criteria for Response Assessment:  Modified 
Lugano Classification................................................................ 186
Appendix 5
Recommendations for the Use of White Blood Cell Growth 
Factors...................................................................................... 192
Appendix 6
Recommended Anaphylaxis Management ............................... 193
Appendix 7
Total Neuropathy Score Clinical Assessment ........................... 194
Appendix 8
Therapy-Induced Neuropathy Assessment Scale (TINAS)....... 195
Appendix 9
Commonly Used CYP1A2 Inhibitors and Inducers (Drugs, 
Foods, Over the Counter Medications, and Supplements) ....... 196
Appendix 10
Follicular Lymphoma International Prognostic Index and 
International Prognostic Index................................................... 199


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
14/Protocol GO29365, Version 8
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE IB/II STUDY EVALUATING THE SAFETY, 
TOLERABILITY AND ANTI-TUMOR ACTIVITY OF 
POLATUZUMAB VEDOTIN IN COMBINATION WITH
RITUXIMAB (R) OR OBINUTUZUMAB (G) PLUS 
BENDAMUSTINE (B) IN RELAPSED OR 
REFRACTORY FOLLICULAR OR DIFFUSE LARGE 
B-CELL LYMPHOMA
PROTOCOL NUMBER:
GO29365
VERSION NUMBER:
8
EUDRACT NUMBER:
2014-001361-28
IND NUMBER:
109409
NCT NUMBER:
NCT02257567
TEST PRODUCTS:
Polatuzumab vedotin, liquid (DCDS4501A)
Polatuzumab vedotin, lyophilized (DCDS4501S)
MEDICAL MONITOR:
, Pharm.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 of 
the signed form to your local study monitor.


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
15/Protocol GO29365, Version 8
PROTOCOL SYNOPSIS
TITLE:
A PHASE IB/II STUDY EVALUATING THE SAFETY, 
TOLERABILITY AND ANTI-TUMOR ACTIVITY OF POLATUZUMAB 
VEDOTIN IN COMBINATION WITH RITUXIMAB (R) OR 
OBINUTUZUMAB (G) PLUS BENDAMUSTINE (B) IN RELAPSED 
OR REFRACTORY FOLLICULAR OR DIFFUSE LARGE B-CELL 
LYMPHOMA
PROTOCOL NUMBER:
GO29365
VERSION NUMBER:
8
EUDRACT NUMBER:
2014-001361-28
IND NUMBER:
109409
NCT NUMBER:
NCT02257567
TEST PRODUCTS:
Polatuzumab vedotin, liquid (DCDS4501A)
Polatuzumab vedotin, lyophilized (DCDS4501S)
PHASE:
Ib/II
INDICATION:
Follicular Lymphoma and Diffuse Large B-Cell Lymphoma
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Primary Objectives (Main Study)
This section outlines the primary objectives for the main study cohorts (i.e., Phase Ib, Phase II 
expansion, and Phase II randomized cohorts in patients with relapsed or refractory [R/R] diffuse 
large B-cell lymphoma (DLBCL) and R/R follicular lymphoma [FL]), which use the initial liquid 
formulation of polatuzumab vedotin.
The primary objectives of the Phase Ib portion of the study are as follows:

To assess the safety and tolerability of the combination of polatuzumab vedotin with 
bendamustine and rituximab (BR) or bendamustine and obinutuzumab (BG) when 
administered to patients with R/R FL or DLBCL

To identify the Recommended Phase II Dose (RP2D) for polatuzumab vedotin given in 
combination with BR or with BG in patients with R/R FL or DLBCL
The primary objective of the Phase II portion of the study is as follows:

To evaluate the efficacy of the combination of polatuzumab vedotin plus BR compared with 
BR alone in patients with R/R FL or DLBCL as measured by positron emission tomography 
(PET)-defined complete response (CR) rate using Modified Lugano Response Criteria 
(PETcomputed tomography [CT] criteria) at the time of primary response assessment 
(68 weeks after Cycle 6, Day 1 or last dose of study drug) and as defined by the 
Independent Review Committee (IRC)
Secondary Objectives (Main Study)
This section outlines the secondary and exploratory objectives for the main study cohorts 
(i.e., Phase Ib, Phase II expansion, and Phase II randomized cohorts in R/R DLBCL and 
R/R FL), which use the initial liquid formulation of polatuzumab vedotin.


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16/Protocol GO29365, Version 8
Safety Objectives
The safety objectives for this study are as follows:

To assess the safety and tolerability of the combination of polatuzumab vedotin with BR or 
BG when administered to patients with R/R FL or DLBCL during the Phase II portion of the 
study

To assess the immunogenicity of polatuzumab vedotin and obinutuzumab, as measured by 
the formation of anti-drug antibodies (ADAs)

To assess the potential relationships of such ADAs (anti-polatuzumab vedotin and 
anti-obinutuzumab) formation with other outcome measures (e.g., pharmacokinetics, 
efficacy, safety)
Pharmacokinetic Objectives
The pharmacokinetic (PK) objectives for this study are as follows:

To characterize the pharmacokinetics of polatuzumab vedotin in combination with BR or BG 
in patients with R/R FL or DLBCL

To assess potential PK interactions between polatuzumab vedotin and BR or BG

To evaluate the PK exposure response (e.g., efficacy, safety) relationship
Secondary Efficacy Objectives (Main Study)
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of the combination of polatuzumab vedotin and BR compared with 
BR alone according to Modified Lugano 2014 response criteria as measured by:

CR at the time of Primary Response Assessment based on PETCT, as determined by 
the investigator

Objective response (OR; CR or partial response [PR]) at the time of Primary Response 
Assessment, based on PET-CT, as determined by the investigator and IRC

CR at the time of Primary Response Assessment based on CT only, as determined by 
the investigator and IRC

OR at the time of Primary Response Assessment based on CT only, as determined by 
the investigator and IRC

Best objective response (BOR; CR or PR) while on study either by PET-CT or CT only,
as determined by the investigator

DLBCL cohorts only:  BOR, DOR and PFS based on PET-CT or CT, as determined by 
IRC

To evaluate the efficacy of the combination of polatuzumab vedotin plus BG according to 
Modified Lugano 2014 response criteria as measured by:

CR at the time of Primary Response Assessment based on PET-CT, as determined by 
the investigator and IRC

OR (CR or PR) at the time of Primary Response Assessment, based on PET-CT, as 
determined by the investigator and IRC

CR at the time of Primary Response Assessment based on CT only, as determined by 
the investigator and IRC

OR at the time of Primary Response Assessment based on CT only, as determined by 
the investigator and IRC

BOR (BOR, CR, or PR) while on study either by PET-CT or CT only as determined by 
the investigator

DLBCL cohorts only: BOR, DOR, and PFS while on study by either PET-CT or CT only,
as determined by IRC


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Patient-Reported Outcome Objective
The patient-reported outcome (PRO) objective for this study is to evaluate peripheral 
neuropathy symptom severity and interference on daily functioning and to better understand 
treatment impact, tolerability, and reversibility, as measured by the Therapy-Induced 
Neuropathy Assessment Scale (TINAS).
Exploratory Objectives
The exploratory objectives for this study are as follows:

To make a preliminary assessment of biomarkers related to the drug targets and 
mechanism of action of polatuzumab vedotin and/or rituximab or obinutuzumab, and/or of 
biomarkers related to disease biology and/or assessments that inform the improvement of 
diagnostic tools, and that might predict disease response or resistance to treatment with 
polatuzumab vedotin in combination with BR or BG in R/R FL or DLBCL, including but not 
limited to, the following:

CD79b expression

DLBCL prognostic subtype (activated B-cell type [ABC]/ germinal center B-cell type 
[GCB])

Lymphoma-associated mutations and markers of tumor immunobiology

Regulators of apoptosis such as BCL-2

Minimal residual disease (MRD) as quantified by measurements of lymphoma-specific 
markers DNA extracted from peripheral blood.  Lymphoma-specific markers from 
blood will be compared to those measured in DNA extracted from baseline tissue to 
identify the originating clone.

To evaluate the prognostic significance of interim PET-CT assessment
The exploratory efficacy objectives for this study are to evaluate longer-term outcomes for 
patients using the Modified Lugano 2014 response criteria, as measured by the following:

Duration of response (DOR) based on PET-CT or CT only, as determined by the 
investigator

Progression-free survival (PFS) based on PET-CT or CT only, as determined by the 
investigator

Event-free survival (EFS) based on PET-CT or CT only, as determined by the investigator

Overall survival (OS)
Objectives for the New Formulation (NF; Lyophilized) Cohort
Arm G
Primary Objective
The primary objective for Arm G is to evaluate the pharmacokinetics and safety of polatuzumab 
vedotin (lyophilized) plus BR in patients with R/R DLBCL, as follows:

Pharmacokinetics:  To characterize the pharmacokinetics of polatuzumab vedotin 
(lyophilized) in combination with BR in patients with R/R DLBCL

Safety: To assess the safety and tolerability of polatuzumab vedotin (lyophilized) in 
combination with BR
Secondary Objectives
Efficacy
The secondary objective for Arm G is to evaluate the efficacy of the combination of 
polatuzumab vedotin (lyophilized) plus BR as measured by and using Modified Lugano 
Response Criteria, as follows:

CR at the time of Primary Response Assessment (68 weeks after Cycle 6, Day 1 or last 
dose of study medication) based on PET-CT, as determined by investigator and IRC

OR (CR or PR) at the time of Primary Response Assessment, based on PET-CT, as 
determined by the investigator and IRC


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
18/Protocol GO29365, Version 8

CR at the time of Primary Response Assessment based on CT only, as determined by the 
investigator and IRC

OR at the time of Primary Response Assessment based on CT only, as determined by the 
investigator and IRC

BOR (CR or PR) while on study either by PET-CT or CT only, as determined by the 
investigator and IRC

DOR based on PET-CT or CT only, as determined by the investigator and IRC

PFS based on PET-CT or CT only, as determined by the investigator and IRC

EFS based on PET-CT or CT only, as determined by the investigator

OS
Safety
The safety objective for Arm G is to assess the immunogenicity of polatuzumab vedotin 
(lyophilized) as measured by the formation of ADAs.
Arm H
Primary Objective
The primary objective for Arm H of the study is to evaluate the efficacy of the combination of 
polatuzumab vedotin (lyophilized) plus BR in patients with R/R DLBCL, as measured by 
PET-CTdefined CR rate (using the Modified Lugano Response Criteria) at the time of Primary 
Response Assessment (68 weeks after Cycle 6, Day 1 or last dose of study drug) and as 
defined by the IRC.
Secondary Efficacy Objectives
The secondary efficacy objective for Arm H is to evaluate the efficacy of the combination of 
polatuzumab vedotin (lyophilized) plus BR, as measured by and using the Modified Lugano 
Response Criteria, as follows:

CR at the time of Primary Response Assessment based on PET-CT, as determined by 
investigator

OR (CR or PR) at the time of Primary Response Assessment, based on PET-CT, as 
determined by the investigator and IRC

BOR (CR or PR) while on study either by PET-CT or CT only, as determined by the 
investigator and IRC

DOR based on PET-CT or CT only, as determined by the investigator and IRC

PFS based on PET-CT or CT only, as determined by the investigator and IRC

EFS based on PET-CT or CT only, as determined by the investigator

OS
Safety Objectives
The safety objectives for Arm H are as follows:

To assess the safety and tolerability of polatuzumab vedotin (lyophilized) in combination 
with BR

To assess the immunogenicity of polatuzumab vedotin (lyophilized), as measured by the 
formation of ADAs
Pharmacokinetic Objectives
The PK objective is to characterize the pharmacokinetics of polatuzumab vedotin (lyophilized) in 
combination with BR in patients with R/R DLBCL.
Exploratory Objectives
The exploratory objective for this arm of the study is to assess biomarkers related to the drug 
target and mechanism of action of polatuzumab vedotin and/or rituximab, and/or of biomarkers 
related to disease biology and/or assessments that inform the improvement of diagnostic tools, 


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and that might predict disease response with polatuzumab vedotin in combination with BR in 
R/R DLBCL, including, but not limited to, the following:

CD79b expression

DLBCL prognostic subtype (ABC/GCB)

Regulators of apoptosis such as BCL-2 or c-MYC
Study Design
Description of Study
This design is a Phase Ib/II, multicenter, open-label study of polatuzumab vedotin administered 
by intravenous (IV) infusion in combination with standard doses of bendamustine (B) and 
rituximab (R) or obinutuzumab (G) in patients with relapsed or refractory FL or DLBCL.  The 
study will consist of two stages:  a Phase Ib safety run-in stage and a Phase II stage.  The dose 
of polatuzumab vedotin in combination with BR or BG will be determined during the safety 
runin stage of the study, separately for each lymphoma subtype (FL and DLBCL), and will be 
used in combination with BR or BG in the Phase II stage.  The Phase II stage will be 
randomized for patients treated with R-containing regimens and be non-randomized for patients 
treated with the G-containing regimen.  Throughout the study, there will be concurrent 
enrollment of patients having either FL or DLBCL.
The study will begin with a safety run-in stage followed by a randomization and expansion 
phase.  During the safety run-in phase, 6 patients will be treated with polatuzumab vedotin in 
combination with the BR regimen.  Once this cohort is safely cleared, 6 patients will be treated 
at the same dose level of polatuzumab vedotin in combination with the BG regimen.  If the first 
6 patients in the polatuzumab vedotin plus BR cohort safely clears after the first cycle, then the 
randomized Phase II stage comparing BR-containing regimens will commence and patients will 
be randomized to either polatuzumab vedotin plus BR or to BR alone (control arm).  
Randomization will occur separately for each of the two disease-specific cohorts of patients with 
either FL or DLBCL.  If the first 6 patients in the polatuzumab vedotin plus BG cohort safely 
clear the first cycle, then the expansion stage for obinutuzumab-containing regimen will 
commence.  Patients receiving polatuzumab vedotin plus BG will be enrolled into two expansion 
cohorts on the basis of histology of FL or DLBCL in order to expand the safety database and 
collect preliminary anti-lymphoma activity data.
The Phase II randomization portion of the study can commence once the safety run-in of the 
polatuzumab vedotin plus BR cohort has completed, which can occur before the BG safety 
runin cohort is completed.  The Phase II expansion portion of the study can commence once 
the safety run-in of the polatuzumab vedotin plus BG cohort has been completed.
Sites cannot enroll patients in rituximab-containing and obinutuzumab-containing phases 
simultaneously within the same histology.
The NF Cohort (Arm G and Arm H) is separate from the expansion and randomized phases of 
the main study. 
In Arm G of the NF Cohort, patients with R/R DLBCL will be treated with polatuzumab vedotin 
(lyophilized) in combination with BR to gain clinical PK and safety experience with the new 
lyophilized formulation of polatuzumab vedotin.  The NF Cohort is separate from the expansion 
and randomized phases.  Initially, up to 30 patients were to be enrolled in order to ensure 
adequate number of PK-evaluable patients.  Enrollment has been expanded to approximately 
40 patients, which will include approximately 10 second-line (2L) patients (patients with one 
prior line of therapy) in order to evaluate the efficacy of polatuzumab vedotin (lyophilized) in 
combination with BR in the 2L setting.  A PK-evaluable patient is defined as a patient from 
whom, at minimum, the PK samplings of all three analytes (i.e., total antibody, antibody 
conjugated mono-methyl auristatin E [acMMAE], and unconjugated mono-methyl auristatin E
[MMAE]) at Cycle 1 through Cycle 2, Day 1 are obtained.
In Arm H of the NF Cohort, patients with R/R DLBCL will be treated with polatuzumab vedotin 
(lyophilized) in combination with BR to further evaluate the clinical efficacy, to gain additional 
safety experience, and to expand evaluation in exploratory biomarker subsets.  Approximately 
60 patients in total will be enrolled in this arm.  A minimum of approximately 30% of patients 
who have previously received only one prior line of therapy (i.e., 2L therapy) will be enrolled in 


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
20/Protocol GO29365, Version 8
Arm H, and prioritization may be given to ensure such enrollment is achieved upon completion 
of enrollment in this arm.
Study treatment will be given in 28-day cycles for patients with FL and in 21-day cycles for 
patients with DLBCL.  The first day of treatment will constitute Study Day 1.  Patients will be 
treated up to a total of six cycles.
All patients will be evaluated for safety and efficacy according to the schedules of assessments.
All patients will be assessed for response to treatment by the investigator with the use of 
standard criteria according to the Modified Lugano Response Criteria at screening and at the 
following timepoints:

Interim response assessment (between Cycle 3, Day 15 and Cycle 4, Day 1)

Primary response assessment:  68 weeks after completion of study treatment (i.e., Day 1 
of Cycle 6 or after last dose of study drug)
Imaging at these timepoints must include FDG-PET (18F-fluorodeoxyglucose-positron emission 
tomography) and a diagnostic-quality CT scan with both oral and IV contrast.  A combined 
PETCT scan is encouraged if feasible.  An independent review of the responses of all patients 
will also be conducted to confirm the primary CR endpoint.  Patients will also be evaluated 
every 3 months thereafter until disease progression, death, withdrawal of consent, or initiation of 
another anti-cancer therapy.  Tumor assessments should also be performed to confirm clinical 
suspicion of relapse or disease progression for documentation.
Number of Patients
The study will enroll approximately 24 patients with either FL or DLBCL for the Phase Ib safety 
run-in stage at approximately 25 sites in the United States and Canada (up to 12 patients with 
the BR regimen and up to 12 patients with the BG regimen).
Approximately 80 sites globally will participate in the Phase II stage of the study, in which
approximately 160 patients with either R/R FL or R/R DLBCL will receive a BR-containing 
regimen in the randomization portion and approximately 40 patients with either R/R FL or R/R 
DLBCL will receive a BG-containing regimen in the safety expansion portion.
Arm G of the Phase II NF Cohort will enroll approximately 40 patients with R/R DLBCL who will 
receive polatuzumab vedotin (lyophilized) with BR.  Approximately 3035 sites of the total sites 
in the study will participate in this portion of the study.
Arm H of the Phase II NF Cohort will enroll approximately 60 patients with R/R DLBCL who will 
receive polatuzumab vedotin (lyophilized) with BR.  Approximately 4550 sites will participate in 
this arm.
Target Population
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for study entry:

Signed Informed Consent Form

Age 18 years

Able to comply with the study protocol, in the investigator’s judgment

Histologically confirmed FL (Grade 1, 2, or 3a) or DLBCL

Must have received at least one prior therapy for FL or DLBCL.  Patients must have either 
relapsed or have become refractory to a prior regimen as defined below. 
R/R FL
Relapsed to prior regimen(s) after having a documented history of response (CR, 
CR unconfirmed [CRu], or PR) of 6 months in duration from completion of regimen(s)
Refractory to any prior regimen, defined as no response to the prior therapy, or 
progression within 6 months of completion of the last dose of therapy
R/R DLBCL
Patients who are ineligible for second-line stem cell transplant (SCT), with progressive 
disease or no response (stable disease [SD]) 6 months from start of initial therapy 
(2L refractory)


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Patients who are ineligible for second-line SCT, with disease relapse after initial 
response 6 months from start of initial therapy (2L relapsed)
Patients who are ineligible for third-line (or beyond) SCT, with progressive disease 
(PD) or no response (SD) 6 months from start of prior therapy (3Lrefractory)
Patients who are ineligible for third-line (or beyond) SCT with disease relapse after 
initial response 6 months from start of prior therapy (3Lrelapsed)
In addition to the above defined responses to prior regimens, the Phase II NF Cohort 
(Arm G and Arm H) includes the following diagnoses by 2016 World Health 
Organization (WHO) classification of lymphoid neoplasms:
–
DLBCL, not otherwise specified (NOS) (including both GCB type and ABC type)
–
T-cell/histiocyte-rich large B-cell lymphoma
–
High-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangements
–
High grade B-cell lymphoma, NOS
–
Primary mediastinal (thymic) large B-cell lymphoma
–
Epstein-Barr virus positive DLBCL, NOS

If the patient has received prior bendamustine, response duration must have been 1 year 
(for patients who have relapse disease after a prior regimen)

At least one bi-dimensionally measurable lesion on imaging scan defined as 1.5 cm in its 
longest dimension 

Confirmed availability of archival or freshly collected tumor tissue prior to study enrollment
The Phase II NF Cohort (Arm G and Arm H) will be required to submit tissue and 
pathology report for central pathology review.

Life expectancy of at least 24 weeks

Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2

Adequate hematologic function unless inadequate function is due to underlying disease, 
such as extensive bone marrow involvement or hypersplenism secondary to the 
involvement of the spleen by lymphoma per the investigator.  Adequate hematologic 
function is defined as follows:
–
Hemoglobin 9 g/dL
–
Absolute neutrophil count 1.5109/L
–
Platelet count 75109/L

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 (refrain from heterosexual intercourse) or to use single highly effective or 
combined contraceptive methods that result in a failure rate of 1% per year during the 
treatment period and for 12 months after the last dose of rituximab or for 18 months after 
the last dose of obinutuzumab, and agreement to refrain from donating eggs.
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.


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
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 6 months after the last dose of study drug and agreement 
to refrain from donating sperm during this same period.
Men with a pregnant partner must agree to remain abstinent or to use a condom 
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:

History of severe allergic or anaphylactic reactions to humanized or murine monoclonal 
antibody (MAbs; or recombinant antibody-related fusion proteins) or known sensitivity or 
allergy to murine products

Contraindication to bendamustine, rituximab, or obinutuzumab

History of sensitivity to mannitol (mannitol is an excipient in bendamustine)

Prior use of any MAb, radioimmunoconjugate, or antibody drug conjugate (ADC) within 
5 half-lives or 4 weeks, whichever is longer, before Cycle 1, Day 1

Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, 
or any investigational agent for the purposes of treating cancer within 2 weeks prior to 
Cycle 1, Day 1
All acute, clinically significant treatment-related toxicity from prior therapy, except 
for alopecia, must have resolved to Grade 2 prior to Cycle 1, Day 1.
Recent treatment with rituximab is allowed given the timing of the last dose was 
greater than 2 weeks prior to Cycle 1, Day 1.
Should prior treatment fall under more than one exclusionary criterion (e.g., MAb
and immunotherapy), the more conservative criterion must be met.

Ongoing corticosteroid use 30 mg/day prednisone or equivalent, for purposes other than 
lymphoma symptom control
Patients receiving corticosteroid treatment 30 mg/day prednisone or equivalent 
must be documented to be on a stable dose prior to study enrollment and initiation 
of therapy (Cycle 1, Day 1).
Ongoing corticosteroid usage is permitted for the purpose of lymphoma symptom 
control.

Treatment with chimeric antigen receptor T-cell therapy within 100 days prior to 
Cycle 1, Day 1

Completion of autologous stem cell transplant within 100 days prior to Cycle 1, Day 1

Prior allogeneic SCT

Eligibility for autologous SCT 

Grade 3b follicular lymphoma

History of transformation of indolent disease to DLBCL

Primary or secondary CNS lymphoma

Current Grade 1 peripheral neuropathy


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
History of other malignancy that could affect compliance with the protocol or interpretation 
of results.  Exceptions include, but are not limited to:
Patients with a history of curatively treated basal or squamous cell carcinoma of 
the skin or in situ carcinoma of the cervix or ductal carcinoma in situ of the breast 
at any time prior to the study are eligible.
A patient with any other malignancy that has been treated with surgery alone with 
curative intent and the malignancy has been in remission without treatment for 
3 years prior to enrollment is eligible.
Patients with low-grade, early-stage prostate cancer with no requirement for 
therapy at any time prior to study are eligible.

Evidence of significant, uncontrolled concomitant diseases that could affect compliance with 
the protocol or interpretation of results, including significant cardiovascular disease (such as 
New York Heart Association Class III or IV cardiac disease, myocardial infarction within the 
last 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary disease 
(including obstructive pulmonary disease and history of bronchospasm)

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding 
fungal infections of nail beds) at study enrollment or any major episode of infection requiring 
treatment with IV antibiotics or hospitalization (relating to the completion of the course of 
antibiotics) within 4 weeks prior to Cycle 1, Day 1

Patients with suspected or latent tuberculosis
Latent tuberculosis should be confirmed according to local testing requirements.

Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive 
hepatitis B surface antigen [HBsAg] serology) 
Patients with occult or prior HBV infection (defined as negative HBsAg and 
positive hepatitis B core antibody [HBcAb]) may be included if HBV DNA is 
undetectable, provided that they are willing to undergo DNA testing on day 1 of 
every cycle and monthly for at least 12 months after the last cycle of study 
treatment.  Patients who have protective titers of hepatitis B surface antibody 
(HBsAb) after vaccination or prior but cured hepatitis B are eligible.

Positive test results for hepatitis C virus (HCV) antibody 
Patients who are positive for HCV antibody are eligible only if PCR is negative for 
HCV RNA.

Known history of HIV seropositive status
For patients with unknown HIV status, HIV testing will be performed at Screening 
if required by local regulations

Known infection human T-cell leukemia virus 1 (HTLV-1) virus 

Vaccination with a live vaccine within 28 days prior to treatment

Recent major surgery (within 6 weeks before the start of Cycle 1, Day 1) other than for
diagnosis

Women who are pregnant or lactating or who intend to become pregnant within a year of 
the last dose of study treatment in the rituximab cohorts or within 18 months of the last dose 
of study treatment in the obinutuzumab cohort

Any of the following abnormal laboratory values, unless abnormal laboratory values are due 
to underlying lymphoma per the investigator:
Creatinine 1.5upper limit of normal (ULN) or a measured creatinine clearance 
40 mL/min
AST or ALT 2.5ULN
Total bilirubin 1.5ULN.  Patients with documented Gilbert disease may be 
enrolled if total bilirubin is 3ULN
International normalized ratio (INR) or prothrombin time (PT) 1.5ULN in the 
absence of therapeutic anticoagulation


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Partial thromboplastin time (PTT) or activated partial thrombopastin time 
(aPTT) 1.5ULN in the absence of a lupus anticoagulant

Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
renders the patient at high risk from treatment complications
End of Study
The end of the study is defined as the timepoint at which all patients enrolled in the study have 
either had at least 2 years of follow-up from the time of the treatment-completion visit or have 
discontinued the study.
Length of Study
The length of study will be the time from screening of the first enrolled patient through 2 years 
after the treatment completion visit for the last enrolled patient.  The length of study is expected 
to be 50 months.
Outcome Measures
Safety Outcome Measures
The determination of the polatuzumab vedotin RP2D in combination with BR or BG will be 
assessed using the following primary safety outcome measures for the Phase Ib portion of the 
study:

Incidence, nature, and severity of adverse events and serious adverse events

Changes in vital signs, physical findings, ECGs, and clinical laboratory results during and 
following study treatment administration

Formation of ADAs
These safety outcome measures will also be assessed in the Phase II NF Cohort (Arm G and 
Arm H), in which patients with R/R DLBCL will be administered polatuzumab vedotin 
(lyophilized) plus BR.
Efficacy Outcome Measures
Response assessment will be determined according to Modified Lugano Response Criteria for 
Malignant Lymphoma. 

CR at primary response assessment (68 weeks after Cycle 6, Day 1, or last dose of study 
drug) based on PETCT, as determined by the investigator and IRC

OR (CR or PR) at primary response assessment based on PETCT, as determined by the 
investigator and IRC

CR at primary response assessment based on CT only, as determined by the investigator 
and IRC

OR (CR or PR) at primary response assessment based on CT only, as determined by the 
investigator and IRC

BOR (CR or PR) while on study based on PETCT or CT only, as determined by the 
investigator

NF cohort only:  OS and EFS based on PETCT or CT only, as determined by the 
investigator
In addition, for the DLBCL cohorts, IRC and investigator-assessed BOR, DOR and PFS will be 
performed.
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:

Serum and plasma concentrations of polatuzumab vedotin, bendamustine, rituximab, and 
obinutuzumab versus time


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
PK parameters based on concentrationtime data for polatuzumab vedotin, bendamustine, 
rituximab, and obinutuzumab when these drugs are given in combination
Serum and plasma concentrations of bendamustine and rituximab will not be assessed in the 
Phase II NF Cohort (Arm G and Arm H).
Patient-Reported Outcome Measure
The PRO measure for this study is as follows:

PROs of peripheral neuropathy symptom severity and symptom interference, as measured
by the TINAS
PRO measures will not be collected for the Phase II NF Cohort (Arm G and Arm H).
Exploratory Outcome Measures
The exploratory biomarker outcome measures for this study are as follows:

Biomarkers related to tumor biology and the mechanisms of action of polatuzumab vedotin 
and rituximab or obinutuzumab.  These include, but are not limited to, the assessment of 
potentially prognostic subsets (i.e., cell of origin), CD79b expression levels, apoptotic 
regulators (e.g., BCL-2), markers of immune infiltration and/or regulation (e.g., CD8, PD-L1), 
and identification of other potential prognostic factors.

Biomarkers will be assessed retrospectively using a tissue block (preferred) or 15 serial 
freshly cut, unstained slides plus punch biopsy of the tissue block from the time of initial 
diagnosis and, if possible, at the time of disease progression.

For quantitative assessment of MRD levels of the lymphoma clone in circulation, blood will 
be collected at baseline, between Cycle 3, Day 15 and Cycle 4, Day 1, and at end of 
treatment corresponding to tumor assessments.
Biomarkers will not be collected or assessed in Arm G of the Phase II NF Cohort.
Analysis methods will include immunohistochemistry, RNA-based assessment of gene 
expression, next-generation sequencing of lymphoma DNA in tissue and in peripheral blood to 
determine the levels of the lymphoma clone.  This analysis will enable a better understanding of 
the underlying biology of these tumors and how polatuzumab vedotin and rituximab or 
obinutuzumab alter their clinical course.  Other exploratory analyses may be conducted should 
additional slides remain following the planned biomarker analyses. 
The exploratory efficacy outcome measures for this study are as follows:  

DOR, defined as the time from the date of the first occurrence of a documented CR or PR 
to the date of disease progression, relapse, or death from any cause, for the subgroup of 
patients with a BOR of CR or PR, based on PETCT or CT only, as determined by the 
investigator assessment

PFS, defined as the time from date of randomization or first treatment (for G-containing 
arms) to the first occurrence of progression or relapse, or death from any cause, based on 
PETCT or CT only, as determined by the investigator assessment

EFS, defined as the time from date of randomization or first treatment (for G-containing 
arms) to any treatment failure including disease progression, relapse, initiation of new 
anti-lymphoma therapy, or death from any cause, whichever occurs first, based on PETCT 
or CT only, as determined by the investigator assessment.

OS, defined as the time from the date of randomization or first treatment (for G-containing 
arms) to the date of death from any cause
Investigational Medicinal Products
Test Product:  Polatuzumab Vedotin
Test Products:  Rituximab, Bendamustine, Obinutuzumab

Polatuzumab vedotin plus BR regimen
Patients will receive rituximab 375 mg/m2 intravenously on Day 1 of Cycle 1 and on 
Day 1 of each subsequent cycle for up to six cycles.  Following rituximab infusion, 


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polatuzumab vedotin will be administered on Day 2 of Cycle 1, then on Day 1 of each 
subsequent cycle.  Bendamustine 90 mg/m2 will be administered intravenously on 
Days 2 and 3 of Cycle 1, then on Days 1 and 2 of each subsequent cycle.

Polatuzumab vedotin plus BG regimen
Patients will receive obinutuzumab 1000 mg intravenously on Days 1, 8, and 15 of 
Cycle 1 and on Day 1 of each subsequent cycle for up to six cycles.  Following 
obinutuzumab infusion, polatuzumab vedotin will be administered on Day 2 of Cycle 1, 
then on Day 1 of each subsequent cycle.  Bendamustine 90 mg/m2 will be 
administered intravenously on Days 2 and 3 of Cycle 1, then on Days 1 and 2 of each 
subsequent cycle.
Comparator (Phase II Randomized Portion of Study)

BR regimen
Patients will receive rituximab 375 mg/m2 intravenously on Day 1 of Cycle 1 and on 
Day 1 of each subsequent cycle for up to six cycles.  Following rituximab infusion, 
bendamustine 90 mg/m2 will be administered intravenously on Days 2 and 3 of Cycle 1, 
then on Days 1 and 2 of each subsequent cycle.
Non-Investigational Medicinal Products
Not applicable.
Statistical Methods
Determination of Sample Size
The purpose of this study is to evaluate the safety, tolerability, and efficacy of polatuzumab 
vedotin in combination with BR or BG.
Phase Ib:  Safety Run-In Stage
In this study, approximately 24 patients will be enrolled during the safety run-in portion of the 
study.  This corresponds to treating a minimum 6 FL and 6 DLBCL patients with polatuzumab 
vedotin in combination with BR and 6 FL and 6 DLBCL patients with polatuzumab vedotin in 
combination with BG.  A combination will be deemed safe for the purpose of moving to the 
Phase II part of the study as long as 2 safety events are observed in a given 6-patient cohort 
as this is consistent with requirements for identification of a candidate RP2D based upon a 
standard 33 design.  
Phase II:  Randomized and Expansion Stage
A total of 200 patients will be enrolled in Phase II (40 patients for each treatment arm and 
histology in the rituximab-containing regimens and 20 patients for each histology group in the 
obinutuzumab-containing regimen).  In total, enrollment of approximately 224 patients is 
planned in order to evaluate the safety and efficacy of polatuzumab vedotin when combined 
with BR or BG.  The expected enrollment duration is approximately 25 months and the total 
study duration is anticipated to be approximately 50 months. 
The primary efficacy endpoint is CR rate as determined by PET-CT scan at the primary 
response assessment (68 weeks after Cycle 6, Day 1 or last dose of study drug) as assessed 
by IRC.  The primary analysis will be estimation of treatment-specific PET-CT CR rates as well 
as the difference in PET-CT CR rates between patients randomized to treatment with 
polatuzumab vedotin in combination with BR and those randomized to treatment with BR alone 
for each histological subtype.  
With 40 patients per arm, 95% exact Clopper-Pearson CIs for estimation of the true CR rate for 
would have a margin of error not exceeding 17%.  The following tables show Clopper-Pearson 
exact 95% CIs corresponding to observed CR rates ranging from 60% to 80% based on sample 
sizes of 40 and 20, respectively.  With 40 patients and an observed CR rate of at least 60%, a 
true CR rate below 43% can be ruled out with 95% confidence.  With 20 patients and an 
observed CR rate of at least 60%, a true CR rate below 36% can be ruled out with 95% 
confidence.  In addition, with 40 patients in each arm, assuming a 40% CR rate in the BR arm, 
and a 25% increase in CR rate when polatuzumab vedotin is added to BR, the 95% CI for the 
difference in CR rates is (3.8%, 46.2%).


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Clopper-Pearson Exact 95% Confidence Intervals for Assumed Observed CR Rates based 
on Sample Size of 40 Patients
Polatuzumab vedotinBR
CR rate
No. of Patients with CR 
(95% CI for rate)
80%
32 (64%, 91%)
75%
30 (59%, 87%)
70%
28 (53%, 83%)
65%
26 (48%, 79%)
60%
24 (43%, 75%)
BRbendamustinerituximab; CRcomplete response.
Clopper-Pearson Exact 95% Confidence Intervals for Assumed Observed CR Rates based 
on Sample Size of 20 Patients
Polatuzumab vedotinBG
CR rate
No. of Patients with CR
(95% CI for rate)
80%
16 (56%, 94%)
75%
15 (51%, 91%)
70%
14 (46%, 88%)
65%
13 (41%, 85%)
60%
12 (36%, 81%)
BGbendamustineobinutuzumab; CRcomplete response.
With respect to assessment of safety based on a sample size of 20 in each of the BG arms, the 
chance of observing at least one adverse event with true incidence of 10% is at least 88%.  
With 40 patients in each of the BR arms, there is at least an 87% chance of observing at least 
one adverse event with true incidence of 5%.
Phase II:  New Formulation Cohort
Arm G
For the NF Cohort (Arm G), the original sample size was approximately 2030 patients.  The 
objective of this cohort is to gain clinical PK experience with polatuzumab vedotin (lyophilized) 
in combination with BR in R/R DLBCL patients.  The currently proposed PK sampling scheme is 
considered sufficient to characterize the pharmacokinetics of polatuzumab vedotin related 
analytes by using the population PK analysis approach.  PK and safety outcomes will be 
descriptive.  Safety will be analyzed as described for the other cohorts.
The sample size for Arm G was initally planned to be approximately 2030 patients with the 
goal of obtaining 20 PK-evaluable patients.  PK evaluable is defined as the patient having at 
minimum PK data of all three analytes collected from Cycle 1 until Cycle 2, Day 1 after dosing of 
polatuzumab vedotin.  Since this evaluation is not a comparison of two randomized arms, it is 
not appropriate to prespecify the criteria of PK comparability.  However, when compared to the 
available data for patients that received Phase I/II material, 20 patients would achieve >80% 
power to obtain a 90% confidence interval for the geometric mean ratio (GMR) that falls within 
the 80%125% range, assuming that the true GMR equals 1.05 and the inter-individual 
variability of acMMAE area under the concentration timecurve (AUC) equals 20%.  


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In order to provide confirmatory support of the efficacy observed in the polatuzumab 
vedotinBR arm in the randomized cohort, an additional 10 patients with one prior line of 
therapy will be enrolled into this NF cohort to achieve similar representation of patients by lines 
of therapy.
The total sample size of 40 (3010) patients from Arm G would provide at least 87% power to 
detect PET CR of 40% under the hypotheses below, with one-sided 2.5% for exact binomial 
one-sample test:
H0: PET CR rate 17.5%, H1: PET CR rate >17.5%
Arm H
In order to further evaluate the clinical efficacy among patients with R/R DLBCL who are 
ineligible for transplant who received the new lyophilized formulation of polutuzumab vedotin in 
combination with BR, an additional arm (Arm H) has been added to the NF Cohort, which 
includes approximately an additional 60 patients with R/R DLBCL. Under the assumption of 40% 
PET-assessed CR rate at Primary Response Assessment, combining the 40 patients in Arm G 
of the NF Cohort with the 60 patients in Arm H (100 patients [4060]) will provide a more 
precise 95% CI (Clopper-Pearson exact CI) of (30%, 50%) (see the table below). Furthermore, 
this 95% CI completely excludes the 95% CI [17.5% (11%, 26%)] of the CR rate observed in the 
randomized BR arm with an assumed number of 100 patients.
Estimated Polatuzumab Vedotin plus BR Complete Response Rate in R/R DLBCL
CR 
Rate
n40
n60
n100
No. of 
Patients 
with CRs
95% CI of 
Rate
No. of 
Patients 
with CRs
95% CI of 
Rate
No. of 
Patients 
with CRs
95% CI of 
Rate
60%
24
(43%, 75%)
36
(47%, 72%)
60
(50%, 70%)
55%
22
(38%, 71%)
33
(42%, 68%)
55
(45%, 65%)
50%
20
(34%, 66%)
30
(37%, 63%)
50
(40%, 60%)
45%
18
(29%, 62%)
27
(32%, 58%)
45
(35%, 55%)
40%
16
(25%, 57%)
24
(28%, 53%)
40
(30%, 50%)
35%
14
(21%, 52%)
21
(23%, 48%)
35
(26%, 45%)
30%
12
(17%, 47%)
18
(19%, 43%)
30
(21%, 40%)
BRbendamustine and rituximab; CIconfidence interval; CRcomplete response; 
DLBCLdiffuse large B-cell lymphoma; R/Rrelapsed or refractory.
Primary Efficacy Endpoint
CR at Primary Response Assessment (68 weeks after Cycle 6, Day 1 or last dose of study 
drug) as measured by PET-CT scan and as determined by an IRC will be used as the primary 
efficacy endpoint.  This primary efficacy endpoint applies to the Phase II randomized cohorts 
treated with polatuzumab vedotin plus BR versus BR, as well as Arm H of the NF Cohort 
(individually and together with Arm G).  The CR rate, defined as the percentage of patients with 
CR, will be estimated and the corresponding Clopper-Pearson exact 95% CI will be constructed 
for each treatment arm.  The difference in CR rates between the combination of polatuzumab 
vedotinBR and BR randomized arms will be estimated along with the corresponding 95% CI on 
the basis of normal approximation to the binomial distribution.  An exploratory comparison of CR 
rates for the BR-containing regimens will be conducted using the Cochran Mantel Haenszel 2
test adjusted for randomization stratification factors.
Response assessment is determined using Modified Lugano Response Criteria.


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Secondary Efficacy Endpoints
Analyses of these endpoints will be identical to those described above for the primary efficacy 
endpoint of CR rate measured by PET-CT scan.

CR at Primary Response Assessment based on PET-CT, as determined by the investigator

CR at Primary Response Assessment based on PET-CT, as determined by IRC (for 
Phase II expansion (polatuzumab vedotin plus BG cohorts) and NF Cohort (Arm G) only)

OR (CR or PR) at Primary Response Assessment based on PET-CT, as determined by the 
investigator and IRC

CR at Primary Response Assessment based on CT only, as determined by the investigator 
and IRC

OR (CR or PR) at Primary Response Assessment based on CT only, as determined by the 
investigator and IRC

BOR (CR or PR) while on study based on PET-CT or CT only, as determined by the 
investigator

DLBCL cohorts only:  BOR, DOR and PFS based on PET-CT or CT only, as determined by 
IRC and investigator

NF cohort only:  OS and EFS based on PET-CT or CT only, as determined by the 
investigator
Exploratory Efficacy Endpoints
Among patients with a best overall response of CR or PR, DOR will be defined as the time from 
the initial CR or PR to the time of disease progression, relapsed or death from any cause, 
whichever occurs first.  If a patient does not experience death or disease progression before the 
end of the study, DOR will be censored on the date of the last tumor assessment.  DOR will be 
summarized descriptively with use of the Kaplan-Meier method.  If analytically possible, median 
DOR will be estimated, along with the corresponding 95% CI using the method of Brookmeyer 
and Crowley (1982).  No formal comparisons of DOR across treatment arms will be conducted.
PFS is defined as the period from the date of randomization or first treatment for 
non-randomized arms until the date of disease progression, relapse, or death from any cause, 
whichever occurs first.  For patients who have not progressed, relapsed, or died at the time of 
analysis, PFS will be censored on the date of last tumor assessment.  If no tumor assessments 
were performed after the Screening Visit, PFS will be censored at the date of randomization/first 
treatment.  The distribution of times for PFS will be summarized descriptively using the Kaplan-
Meier method to estimate median (if analytically possible), 1-year, and 2-year PFS and 95% CIs 
using Greenwood’s formula. 
EFS is defined as the time from date of randomization or first treatment for non-randomized 
arms to any treatment failure including disease progression, relapse, initiation of new 
antilymphoma treatment (NALT), or death, whichever occurs first.  If the specified event 
(disease progression/relapse, death, start of an NALT) does not occur, patients will be censored 
at the date of last tumor assessment.  For patients who do not have post-baseline tumor 
assessments or documentation of NALT, EFS will be censored at the time of randomization/first 
treatment.
OS is defined as the time from date of randomization or first treatment for non-randomized arms 
until the date of death from any cause.  Patients who have not died will be censored at the last 
date known to be alive.  
Analyses of EFS and OS will be identical to those outlined previously for PFS. 
Duration of follow-up will be estimated by reverse Kaplan-Meier method.
Safety Analyses
Safety will be assessed through summaries of adverse events, summaries of changes from 
screening assessments in laboratory test results, ECGs, and changes in vital signs.
All collected adverse event data will be summarized by phase of the study, treatment arm, and 
histological subtype.  All adverse events occurring on or after first study treatment will be 
summarized by mapped term, appropriate thesaurus levels, and National Cancer Institute 


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Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 toxicity grade.  
All serious adverse events will be listed separately and summarized.
Deaths reported during the study treatment period and those reported during follow-up after 
treatment discontinuation will be listed.
Relevant laboratory and vital sign (temperature, heart rate, respiratory rate, pulse oximetry, and 
blood pressure) data will be displayed by time, with NCI CTCAE v4.03 Grade 3 and 4 values 
identified where appropriate.
Pharmacokinetic Analyses
Individual and mean serum and plasma concentrations of polatuzumab vedotin, bendamustine, 
rituximab, and obinutuzumab versus time data will be tabulated and plotted.  Summary statistics 
of concentration data will be computed for each scheduled sampling time for each analyte.  PK 
parameters, such as area under the concentrationtime curve, maximum concentrations, 
systemic clearance, and steady-state volume of distribution may be estimated (as appropriate 
for the data collected).  Estimates for these parameters will be tabulated and summarized 
(mean and standard deviation).  PK parameters will be determined using the appropriate 
technique based on available data.  Non-compartmental analysis and/or population PK analysis 
method may be applied for PK parameter estimation.  Potential drug interactions may be 
assessed by comparison of PK in the current study with historical data.  Potential correlations 
between PK variability and demographic and pathophysiological covariates may be explored by 
population PK analysis.  Potential correlations between PK variability and pharmacodynamic, 
efficacy, and safety outcome may be explored by exploratory graphical analysis and PK-
pharmacodynamic modeling.  The assessment of PK parameters and related analysis will be 
performed per Sponsor’s discretion, based on the appropriateness of the PK data collected, the 
trial outcome, and the future development path for polatuzumab vedotin.
Patient-Reported Outcome Analyses
The TINAS will be scored using a corresponding user manual.  Summary statistics of the TINAS 
total and individual items with their changes from baseline will be calculated at each 
assessment timepoint.
Patients enrolled in the NF Cohort (Arm G and Arm H), receiving polatuzumab vedotin 
(lyophilized) plus BR, will be exempt from completing the TINAS.
Exploratory Analyses
Exploratory analyses of biomarkers related to tumor biology and the mechanisms of action of 
polatuzumab vedotin and rituximab or obinutuzumab will be conducted.  Analyses will assess 
prognostic and/or predictive value of candidate biomarkers separately for each histological 
subtype and both investigator and IRC assessed outcomes.  Specifically, the association 
between candidate biomarkers and PET-CT CR rate and OR rate and potentially other 
measures of efficacy and safety, independent of treatment, will be explored to assess potential 
prognostic value.  In addition, the potential effect modification of treatment effect on PET-CT CR 
rate and OR rate and potentially other measures of efficacy and safety, by biomarker status, will 
be explored to assess potential predictive value.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
ADC
antibody drug conjugate
ADCC
antibody-dependent cell-mediated cytotoxicity
AML
acute myeloid leukemia
ASCO
American Society of Clinical Oncology
B
bendamustine
BG
bendamustine and obinutuzumab
BOR
best objective response
BR
bendamustine and rituximab
BSA
body surface area
CHOP
cyclophosphamide, doxorubicin, vincristine, and prednisone
CL
clearance
CLL
chronic lymphocytic leukemia
CR
complete response
Cru
complete response unconfirmed
CT
computed tomography
CVP
cyclophosphamide, vincristine, and prednisone
DILI
drug-induced liver injury
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DOR
duration of response
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
EFS
event-free survival
EORTC
European Organization for Research on the Treatment of Cancer
ESMO
European Society for Medical Oncology
eCRF
electronic Case Report Form
EDC
electronic data capture
ePRO
electronic patient-reported outcome
FDA
(U.S.) Food and Drug Administration
FDG
18F-flurodeoxyglucose
FL
follicular lymphoma
FLIPI
Follicular Lymphoma International Prognostic Index
G
GA101 or obinutuzumab
G-CSF
granulocyte colony-stimulating factor
GELF
Groupe d’Etude des Lymphomes Folliculaires


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Abbreviation
Definition
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HIPAA
Health Insurance Portability and Accountability Act
HTLV-1
human T-cell leukemia virus 1
ICH
International Council for Harmonisation
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug Application
iNHL
indolent non-Hodgkin’s lymphoma
IPI
International Prognostic Index
IRB
Institutional Review Board
IRC
Independent Review Committee
IRR
infusion-related reaction
IV
intravenous
IxRS
interactive voice or Web-based response system
LMWH
low molecular-weight heparin
LPLV
last patient, last visit
Mab
monoclonal antibody
MC-VC-PABC
maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl
MMAE
mono-methyl auristatin E
MRD
minimal residual disease
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NALT
new anti-lymphoma treatment
NF
New Formulation
NHL
non-Hodgkin lymphoma
OR
objective response
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease
PET
positron emission topography
PFS
progression-free survival
PK
pharmacokinetic


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Abbreviation
Definition
PML
progressive multifocal leukoencephalopathy
PR
partial response
PRO
patient-reported outcome
R
rituximab
RCR
Roche Clinical Repository
RP2D
Recommended Phase II Dose
R/R
relapsed or refractory
SCT
stem cell transplant
SD
stable disease
TEN
toxic epidermal necrolysis
TINAS
Therapy-induced neuropathy assessment score
TLS
tumor lysis syndrome
TMA
tissue microarray
TNS
Total Neuropathy Score
ULN
upper limit of normal


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1.
BACKGROUND
1.1
BACKGROUND ON NON-HODGKIN’S LYMPHOMA
Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in adults.  
It is estimated that in 2010 there were 93,172 new cases of NHL in Europe and 
65,540 new cases in the United States (American Cancer Society 2010; 
GLOBOCAN 2010).  NHL is most often of B-cell origin and characterized by the 
expression of a membrane antigen, CD20, which is important in cell cycle initiation and 
differentiation (Anderson et al. 1984).  NHL can be divided into indolent and aggressive 
lymphomas.
1.1.1
Follicular Lymphoma
Indolent NHLs 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 NHL in the Western hemisphere and is associated with follicle-center 
B cells that typically contain the translocation t(14:18) which leads to overexpression of 
the intracellular anti-apoptotic protein BCL-2.  The clinical course of FL is characterized 
by remission and relapse (Gallagher et al. 1986).  The disease initially responds to 
radiation and to immunochemotherapy with conventional agents, but patients eventually 
experience multiple relapses distinguished by increasing refractoriness and decreasing 
duration of response in subsequent lines of therapy.  Patients with advanced-stage 
disease are usually not cured with conventional treatment and often ultimately die from 
recurrent disease or treatment-related toxicity.
Currently, two prognostic tools are used for patients with FL:  Follicular Lymphoma 
International Prognostic Index (FLIPI) and FLIPI2.  The FLIPI is a risk score developed 
in order to better categorize expected outcomes of patients with FL on the basis of 
baseline clinical characteristics, including number of involved nodal sites, serum LDH 
level, age, stage, and hemoglobin level (Solal-Celigny et al. 2004).  Although patients 
with low FLIPI risk tend to show long treatment-free intervals and survival times, 
higher-risk patients tend to progress quickly, with overall survival (OS) as short as 
5 years.  The FLIPI2 evaluates five parameters:  age, bone marrow involvement, 
hemoglobin level, greatest diameter of the largest involved lymph node 6 cm, and 
serum beta-2 microglobulin levels (Federico et al. 2009).
No standard treatment exists for the management of advanced FL, and data from the 
National LymphoCare registry demonstrate that practice varies widely among physicians 
(Friedberg et al. 2009).  For patients with FL requiring treatment, immunochemotherapy 
with rituximab (MabThera®, Rituxan®), a monoclonal antibody (MAb) directed against 
CD20, plus chemotherapy has demonstrated improvements in response rates, 
progression-free survival (PFS), and OS compared with chemotherapy alone in four 
studies (Hiddemann et al. 2005; Herold et al. 2007; Marcus et al. 2008; 
Salles et al. 2008).  Rituximab in combination with chemotherapy (e.g., CHOP 
[cyclophosphamide, doxorubicin, vincristine, and prednisone], CVP [cyclophosphamide, 


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vincristine, and prednisone], or purine analogue-based schemes such as those with 
fludarabine or bendamustine) for newly diagnosed patients with advanced Stage III and 
IV disease requiring treatment is strongly supported by both the 2009 European Society 
for Medical Oncology Guidelines Working Group recommendations (level of evidence [I], 
and grade of recommendation [B]) and the 2010 National Comprehensive Cancer
Network (NCCN) guidelines (Category 1 recommendation based on high-level evidence, 
with a uniform NCCN consensus) (Dreyling 2009; Zelenetz et al. 2010).
Despite these improvements, therapy for FL is not curative.  It is important to introduce 
new agents that may improve the degree and duration of treatment response 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 NHL cases (Armitage and Weisenburger 1998).  
DLBCL arises from mature B cells, the majority of which express a CD20 cell surface 
protein.  Several genetic abnormalities have been identified in subsets of patients with 
DLBCL.  The most frequently dysregulated genes include BCL6 (35%40%), BCL2 
(translocation 15%, amplification 24%), and cMYC (15%).
Standard-of-care therapies for NHL involve multi-agent chemotherapy with 
non-crossresistant mechanisms of action combined with immunotherapy.  In DLBCL, 
the addition of the CD20-directed MAb rituximab to CHOP-based chemotherapy results 
in significantly improved survival, as demonstrated by three randomized prospective 
studies, comprising a total of approximately 2000 patients with newly diagnosed 
advanced DLBCL (Coiffier et al. 2002, 2007, 2010; Feugier et al. 2005, 
Habermann et al. 2006, Pfreundschuh et al. 2008).  On the basis of the above studies, 
up to eight cycles of rituximab combined with six or eight cycles of CHOP or CHOP-like 
chemotherapy (R-CHOP) is considered to be the standard of care for patients with 
previously untreated DLBCL (Tilly et al. 2012; NCCN 2014), with approximately 60% of 
patients being cured of their disease.
Although there is currently no way to prospectively identify individual patients who will be 
cured, clinical factors are used to define prognostic risk groups associated with different 
outcomes.  The International Prognostic Index (IPI) is a prognostic tool that identifies five 
significant clinical factors that are prognostic of overall survival (Shipp et al. 1993):

Age (60 vs. 60 years)

Serum lactate dehydrogenase (LDH, normal vs. elevated) level

Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs. 24)

Stage (I or II vs. III or IV)

Extranodal site involvement (0 or 1 vs. 24)


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The IPI defines four distinct prognostic subgroups depending on the number of negative 
prognostic factors at diagnosis.  Although patients with low IPI (i.e., with no or only one 
negative prognostic finding) have overall excellent outcomes with 3-year PFS of 80%90% 
(Sehn et al. 2007; Advani et al. 2010), patients with higher risk have poorer outcomes 
with a 3-year PFS range of 33%70%.
Because age is an important consideration when determining the choice of treatment for 
DLBCL, the age-adjusted IPI (aa-IPI) was also developed and validated 
(Shipp et al. 1993).  The aa-IPI is based on stage, serum LDH, and ECOG performance 
status and was prognostic of response to therapy and overall survival.  Patients with a 
higher number of risk factors have lower rates of complete response (CR) to therapy, as 
well as lower rates of 5-year survival (Ziepert et al. 2010).
For patients who are not cured by first-line therapy, high-dose chemotherapy followed by 
autologous stem cell transplantation offers a second chance for cure in some of those 
patients.  However, approximately half of patients will not respond to subsequent therapy 
because of refractory disease (Gisselbrecht et al. 2010), and a significant number are 
ineligible for this aggressive therapy because of age or comorbidities.
Patients who either relapse after or are ineligible for stem cell transplantation because of 
refractory disease or frailty have poor outcomes.  Responses to subsequent therapies 
range from 10%35% in most cases (Robertson et al. 2007; Coleman et al. 2008; 
Wiernik et al. 2008) with only occasional durable responses.  The fact that most patients 
who are not cured by the standard frontline R-CHOP or comparable 
immunochemotherapy will die of lymphoma underscores the need for novel approaches 
in subsequent lines of therapy for this aggressive disease.
Despite improvements in clinical outcomes of patients with NHL due to advances in 
treatments such as rituximab, indolent B-cell malignancies remain incurable, as do 
approximately half of aggressive NHLs, especially those with intermediate or high IPI.  
A need exists for treatments that can significantly extend disease-free survival and OS in 
these patients, with at least acceptable, if not superior, safety and tolerability profiles.
1.2
BACKGROUND ON THE MOLECULES
1.2.1
Polatuzumab Vedotin
1.2.1.1
Polatuzumab Vedotin Background and Nonclinical Data
CD79b is a cell surface antigen whose expression is restricted to all mature B cells 
except plasma cells.  It is expressed in a majority of B-cellderived malignancies,
including nearly all NHL and chronic lymphocytic leukemia (CLL) samples tested 
(Dornan et al. 2009).  Antibodies bound to CD79b are rapidly internalized, which makes 
CD79b ideally suited for targeted delivery of cytotoxic agents (Polson et al. 2007;
Polson et al. 2009).  


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Polatuzumab vedotin (DCDS4501A [liquid formulation] and DCDS4501S [lyophilized 
formulation]) is an antibody drug conjugate (ADC) that contains a humanized
immunoglobulin G1 (IgG1) anti-human CD79b MAb (MCDS4409A) and a potent 
anti-mitotic agent, mono-methyl auristatin E (MMAE), linked through a protease labile 
linker, maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (MC-VC-PABC).  
MMAE has a mode of action similar to that of vincristine, which is a component of 
standard chemotherapy (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.  MMAE then 
binds to tubulin and disrupts the microtubule network, resulting in inhibition of cell 
division and cell growth (Doronina et al. 2003).  This therapeutic approach takes 
advantage of the specific targeting capability of the antibody and the cytotoxic activity of 
MMAE and the increased potency of MMAE compared with vincristine.  It is 
hypothesized that the addition of polatuzumab vedotin to a standard anti-CD20 antibody 
plus chemotherapy regimen will provide enhanced efficacy and safety to patients with 
NHL.
Comprehensive pharmacologic, pharmacokinetic (PK), pharmacodynamic, and 
toxicological 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 the cynomolgus monkey, rat, or mousea surrogate ADC 
(DCDS5017A) that binds to cynomolgus monkey CD79b was generated to assess the 
antigen-dependent activities in cynomolgus monkeys.  The structure, binding epitope, 
and binding affinity of the surrogate ADC are similar to that of polatuzumab vedotin.  
Polatuzumab vedotin has demonstrated efficacy in nonclinical mouse xenograft models 
of human CD79b-positive NHL.  Additionally, polatuzumab vedotin when combined with 
rituximab plus chemotherapy (rituximab in combination with cyclophosphamide, 
doxorubicin, and prednisone [CHP] or bendamustine) demonstrated better anti-tumor 
activity compared with polatuzumab vedotin as single agent or compared with a current 
standard of care regimen (R-CHOP or rituximab plus bendamustine [BR]) in xenograft 
models of NHL.  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.  The predominant antigen-independent findings 
associated with polatuzumab vedotin or surrogate ADC exposure were reversible bone 
marrow toxicity and associated peripheral blood cell effects in both monkeys and rats.  
The PK profiles of polatuzumab vedotin and the surrogate ADC suggested that the 
pharmacokinetics of the ADC was driven mainly by the antibody component (similar 
serum concentration-time profile between ADC and total MAb).
Refer to the Investigator’s Brochure for complete details of the biochemical composition 
and nonclinical studies of polatuzumab vedotin.


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1.2.1.2
Polatuzumab Vedotin Clinical Data
On the basis of nonclinical data, polatuzumab vedotin is currently being evaluated in 
Phase I and Phase II studies in relapsed/refractory (R/R) NHL.
The original formulation of polatuzumab vedotin is a liquid formulation and was used in 
the main study (i.e., Phase Ib, Phase II expansion, and Phase II randomized cohorts) in 
patients with either R/R FL or R/R DLBCL.  The liquid formulation is not stable after 
dilution into saline-containing IV bags, thus requiring a syringe pump for delivery.  
Therefore, a lyophilized formulation of polatuzumab vedotin has been developed to 
improve product stability upon dilution into saline-containing IV bags.  An initial 
170 mg/vial lyophilized configuration was developed and manufactured for a potentially 
higher dose configuration, which is no longer planned, and is currently in use in other 
clinical trials only for dosing up to 1.8 mg/kg.  A 140 mg/vial drug product was 
subsequently developed to support a target dose of 1.8 mg/kg.  The 170 mg/vial and the 
140 mg/vial drug product differ in only the fill volume and yield the same product 
concentration and composition when reconstituted as prescribed.  The lyophilized 
formulation of polatuzumab vedotin, referred to as “polatuzumab vedotin (lyophilized)” in 
this protocol, will be used in combination with BR in the Phase II New Formulation (NF)
Cohort enrolling patients with R/R DLBCL.  This additional cohort will hereafter be 
referred to as the NF Cohort. 
Complete and updated details of these data are provided in the Polatuzumab Vedotin
Investigator’s Brochure.
As of February 2013, clinical experience with polatuzumab vedotin has been available 
from two studies:

Study DCS4968g:  A Phase I study to evaluate the safety and tolerability and 
anti-tumor activity of polatuzumab vedotin and to determine the maximum tolerated 
dose (MTD)/RP2D as a single agent and in combination with rituximab in R/R NHL

Study GO27834:  A randomized Phase II study to evaluate the safety and 
anti-tumor activity of polatuzumab vedotin in combination with rituximab in patients 
with R/R DLBCL and FL.  A second vc-MMAE ADC targeting CD22 (pinatuzumab 
vedotin) combined with rituximab is also being evaluated in this study.  Patients are 
randomized to receive either polatuzumab vedotin or pinatuzumab vedotin in 
combination with rituximab
The clinical data cutoff dates for information about the ongoing Phase I study DCS4968g 
was 28 February 2013 and for the ongoing Phase II study GO27834, 22 February 2013. 
Study DCS4968g (Phase I):  Polatuzumab Vedotin Monotherapy and 
Polatuzumab Vedotin in Combination with Rituximab
A total of 95 patients have been enrolled into the Phase I study (Study DCS4968g), of 
whom 32 patients with NHL (indolent NHL [iNHL] or DLBCL) were enrolled in 
single-agent dose escalation, 11 patients were enrolled in an iNHL single-agent 


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expansion cohort, 23 patients were enrolled in the DLBCL single-agent expansion cohort, 
and 9 patients were enrolled in the Phase Ib polatuzumab vedotin plus rituximab 
combination treatment cohort.  Enrollment of patients with NHL into the study has been 
completed.  
The remaining 20 patientsall with CLLwere enrolled into single-agent dose 
escalation cohorts.  For details regarding the clinical data in patients with CLL, refer to 
the Polatuzumab Vedotin Investigator’s Brochure.
Safety
As of 28 February 2013, preliminary safety data were available for all 95 patients 
enrolled in the dose-escalation and expansion cohorts.
Dose-Limiting Toxicities in NHL
A dose-limiting toxicity (DLT) of Grade 4 neutropenia occurred in 1 of 10 DLT-evaluable 
patients in the 2.4-mg/kg single-agent cohort and in 1 of 9 DLT-evaluable patients in the 
2.4-mg/kgrituximab cohort.  Doses of polatuzumab vedotin 2.4 mg/kg as 
monotherapy or in combination with rituximab were not assessed.  Consequently, 
polatuzumab vedotin at 2.4 mg/kg was determined to be the RP2D as both monotherapy 
and in combination with rituximab.  Due to additional information about the risk/benefit 
profile of polatuzumab vedotin at the 2.4-mg/kg dose, the Sponsor is no longer pursuing 
the 2.4-mg/kg dose of polatuzumab vedotin.
Treatment Discontinuations due to Adverse Events
As of the clinical data cutoff date, study treatment discontinuation because of adverse 
events not due to the disease under study was reported in 19 of 95 patients (20.0%) and 
study treatment related adverse event leading to treatment discontinuation in 17 of 
95 patients (17.9%).  
The treatment-related events included Grade 2 peripheral neuropathy (9 patients), 
Grade 3 peripheral neuropathy (3 patients), Grade 4 peripheral neuropathy (1 patient), 
Grade 3 diarrhea (1 patient), and Grade 2 hyperesthesia, Grade 2 asthenia, Grade 3 
anemia, and Grade 4 thrombocytopenia (each occurring in 1 patient).  Two adverse 
events resulting in treatment discontinuation were reported as not related to study 
treatment and not due to the disease under study:  Grade 3 worsening hyponatremia 
(1 patient) and Grade 4 invasive fungal infection (1 patient).
Adverse events resulting in study treatment discontinuation that were considered not 
related to the disease under study were reported in 6 patients with DLBCL:  Grade 2 
peripheral neuropathy (4 patients), Grade 3 peripheral neuropathy (1 patient), and 
Grade 3 diarrhea (1 patient).  The only adverse event resulting in treatment 
discontinuation that was considered not related to the disease under study among the 
patients with CLL was Grade 4 invasive fungal infection (1 patient).  All other events 
were reported in patients with iNHL, including five events of Grade 2 peripheral 


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neuropathy (4 patients), two events of Grade 3 peripheral neuropathy (2 patients), one 
event of Grade 3 neutropenia (1 patient), and one Grade 2 mucosal inflammation 
(1 patient).  One patient with iNHL experienced five events that led to study treatment 
discontinuation (Grade 2 hyperesthesia, Grade 2 asthenia, Grade 3 anemia, Grade 3 
thrombocytopenia, and Grade 4 thrombocytopenia).
Adverse Events with Single-Agent Polatuzumab Vedotin
Adverse events, regardless of relationship to study drug, were reported in all 66 patients 
(100%) with NHL (iNHLDLBCL) who were treated with single-agent polatuzumab 
vedotin.  Treatment-emergent adverse events reported in 20% of patients included 
neutropenia (44%), diarrhea (38%), pyrexia (32%), nausea (32%), peripheral neuropathy 
(30%), fatigue (23%), and cough (21%).
Grade 3 adverse events, regardless of relationship to study drug, were reported in 
48 of 66 patients (72.7%) with NHL (iNHL or DLBCL).  Neutropenia was the most 
common adverse event experienced by more than 35% of the 66 patients with NHL.  
Thirty-one of 45 patients (68.8%) treated at the RP2D of 2.4 mg/kg experienced a 
Grade 35 adverse event.  Grade 34 adverse events of neutropenia were experienced 
by 10% of the patients.  Three Grade 5 events were reported:  1 patient died of sepsis, 
1 patient died of pulmonary vascular disorder, and 1 patient died from an unknown 
cause.  None of the deaths was assessed by the investigator as related to study 
treatment.
Adverse Events with Polatuzumab Vedotin Combined with Rituximab
In the Phase Ib cohort of Study DCS4968g, adverse eventsregardless of relationship 
to study drugwere reported in 9 of 9 patients (100%) who received polatuzumab 
vedotin (2.4 mg/kg) plus rituximab (375 mg/m²).  The most common adverse events 
reported in 2 patients were neutropenia, pyrexia, nausea, diarrhea, hyperuricemia, 
bone pain, fatigue, peripheral neuropathy, decreased appetite, chills, pain in extremity, 
pruritus, arthralgia, night sweats, hypokalemia, dysgeusia, increased blood creatinine, 
infusion-related reactions (IRRs), cough, constipation, thrombocytopenia, anemia, 
hyperglycemia, rash, alopecia, hypomagnesemia, upper abdominal pain, hyperhidrosis, 
myalgia, peripheral motor neuropathy, febrile neutropenia, hyperbilirubinemia, and tooth 
fracture.
Grade 3 adverse events, regardless of relationship to study drug, were reported in 7 of 
9 patients (77.8%) receiving polatuzumab vedotin in combination with rituximab in the 
Phase Ib cohort of Study DCS4968g.  Grade 34 neutropenia was reported in 5 patients, 
Grade 34 anemia in 2 patients, Grade 34 febrile neutropenia in 2 patients, and 
Grade 34 hyperglycemia in 2 patients.  No Grade 5 adverse events were reported.
Serious Adverse Events
From ongoing Phase I Study DCS4968g, a total of 44 serious adverse events were 
reported among 22 patients in the single-agent NHL (iNHL plus DLBCL) cohorts, 


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19 serious adverse events were reported in 11 patients in the CLL cohort, and 
15 serious adverse events were reported in 4 patients treated with polatuzumab vedotin 
plus rituximab.  Among all patients, the most common serious adverse events (occurring 
in 2% of patients) were:  Grade 1 or 2 pyrexia (6 patients), Grade 3 or 4 febrile 
neutropenia (4 patients), Grade 4 or 5 lung infection (3 patients), Grade 3 or 4 diarrhea 
(3 patients), Grade 3 or 4 hyperglycemia (2 patients), Grade 3 or 4 hyponatremia 
(2 patients), Grade 2 or 3 mental status changes (2 patients), Grade 3 or 4 peripheral 
neuropathy (2 patients), Grade 3 or 4 neutropenia (2 patients), Grade 4 or 5 pneumonia 
(2 patients), and acute renal failure (Grade 1 in 1 patient and Grade 4 in 1 patient).
Anti-Tumor Activity
Preliminary anti-tumor activity data for best overall response were available for 
88 of 95 patients (92.6%) as of the clinical data cutoff date.  Eighty-six of 88 patients 
(97.7%) had R/R iNHL, DLBCL, or CLL.  Most evidence of anti-tumor activity was 
observed at ADC doses 1.8 mg/kg.  Among patients with R/R iNHL, 13 of 22 patients 
(59%) treated with single-agent polatuzumab vedotin and 6 of 8 patients (75%) treated 
with polatuzumab vedotin plus rituximab had an investigator-assessed objective 
response (OR).  Among patients with R/R DLBCL, 14 of 26 patients (54%) treated with 
single-agent polatuzumab vedotin and 1 of 1 patient treated with polatuzumab vedotin 
plus rituximab had investigator-assessed OR.  Data regarding duration of response 
(DOR), PFS, and OS were insufficiently mature for reporting.
Study GO27834 (Phase II):  Polatuzumab Vedotin in Combination with 
Rituximab
Safety
As of the clinical data cutoff (22 February 2013), preliminary clinical safety data were 
available for all 15 patients enrolled and randomized to the polatuzumab vedotin plus 
rituximab treatment arm.  Treatment discontinuation due to adverse events had not been 
reported for any patient.
Adverse events, regardless of relationship to study drug, were reported in 
15 of 15 patients (100%) who received polatuzumab vedotin (2.4 mg/kg) plus rituximab 
(375 mg/m²).  The most common adverse events (all grades) reported in 2 patients 
were fatigue, nausea, diarrhea, neutropenia, vomiting, dry mouth, asthenia, arthralgia, 
back pain, and headache.
Grade 3 adverse events, regardless of relationship to study drug, were reported in 
4 of 15 patients (26.7%) receiving polatuzumab vedotin in combination with rituximab.  
Grade 3 or 4 neutropenia was reported in 2 patients, Grade 3 diarrhea was reported in 
1 patient, Grade 3 chest pain was reported in 1 patient, Grade 3 decreased neutrophil 
count was reported in 1 patient, and Grade 3 hypophosphatemia was reported in 
1 patient.


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A total of two serious adverse events were reported in 2 patients treated with 
polatuzumab vedotin plus rituximab:  Grade 2 pyrexia and Grade 2 chest tightness.  
Both serious adverse events were reported as not related to study drug treatment.
Anti-Tumor Activity
In this ongoing study, anti-tumor activity data were not sufficiently mature to report as of 
the clinical data cutoff date, because most patients had not yet undergone on-treatment 
tumor assessments to evaluate response.
1.2.1.3
Pharmacokinetic and Pharmacodynamic Properties of 
Polatuzumab Vedotin
The PK properties of polatuzumab vedotin conjugate (evaluated as antibody-conjugated 
MMAE [acMMAE]), total antibody, and unconjugated MMAE after the first dose of 
polatuzumab vedotin in patients with NHL, either as a single agent or in combination with 
rituximab, are summarized below.  The PK properties after repeated doses of 
polatuzumab vedotin are under investigation, but data are not yet available.
In patients with NHL, polatuzumab vedotin demonstrated a trend of linear 
pharmacokinetics for each measurement across the dose range from 0.1 to 2.4 mg/kg.  
On the basis of the results from DCS4968g, 2.4 mg/kg in patients with NHL, serum 
concentrations of total antibody and acMMAE reached peak values at the end of infusion.  
The distribution of total antibody and acMMAE appears to be restricted to the serum 
compartment, with mean steady-state volume of distribution (Vss) values of 
approximately 7087 mL/kg and approximately 93109 mL/kg for acMMAE and total 
antibody, respectively.  Mean clearance (CL) of acMMAE (approximately 
1521 mL/day/kg) was similar to CL of total antibody (approximately 1119 mL/day/kg), 
suggesting that acMMAE CL was largely dominated by its antibody component.  Mean 
terminal half-life for acMMAE was approximately 5.16.4 days and total antibody, 
approximately 8.1 days.  
Unconjugated MMAE reached maximal concentrations at 2.013.42 days after the first 
dose, suggesting a delayed formation due to catabolism of the conjugate.  There was a 
trend of increased Cmax and area under the concentrationtime curve (AUC)inf values 
with conjugate dose increase.  At each dose level, Cmax and AUCinf values for 
unconjugated MMAE were substantially lower compared with its parent analyte acMMAE, 
suggesting that the total MMAE level in the systemic circulation after conjugate 
administration was mainly composed of conjugated MMAE.  The t½ values ranged from 
2.935.81 days, which are relatively long for a small molecule and similar to the t½ value 
for conjugate, suggesting that the kinetics of unconjugated MMAE could be dominated 
by its formation from the conjugate.  On the basis of the t½ values, a small amount of 
accumulation was expected upon every 3-week dosing.
The PK profiles and parameters were similar in the absence and presence of rituximab, 
suggesting that rituximab has little impact on polatuzumab vedotin PK in the R/R NHL 


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patient population.  Given the various CYPs involved for metabolism of MMAE and 
bendamustine, the risks of PK interactions between them is low.
See the Polatuzumab Vedotin Investigator’s Brochure for additional details on nonclinical 
and clinical studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
B-cell NHL, including FL and DLBCL, express the CD20 antigen, and anti-CD20 therapy 
(rituximab) has been demonstrated to provide enhanced anti-tumor activity in 
combination with other agents targeting the disease leading to increased response rates, 
PFS and OS, which led to acceptance of rituximab as a standard component in initial 
therapy (Hiddemann et al. 2005; Herold et al. 2007; Marcus et al. 2008; 
Salles et al. 2008, Coiffier et al. 2002, 2007, 2010; Feugier et al. 2005, 
Habermann et al. 2006, Pfreundschuh et al. 2008). 
Progress has been made in the treatment of FL and DLBCL; however, a significant 
number of patients will not be cured of the disease.  Instead, they will experience relapse 
or die of progression or treatment-related toxicity.  There is a need for the continued 
development of safe and effective therapies for patients with disease that relapses or for 
those who develop refractory disease during or after first-line therapy.
Bendamustine with and without rituximab has demonstrated efficacy in patients with R/R 
iNHL (Rummel et al. 2005; Friedberg et al. 2008; Robinson et al. 2008; Kahl et al. 2010).  
Other available established therapies in this setting are either associated with high 
toxicity (e.g., fludarabine-based therapies, hematopoietic stem cell transplant) or have 
more limited effectiveness (e.g., R-CVP, rituximab monotherapy).  In a Phase II trial 
examining the efficacy of BR in patients with R/R FL, the OR rate was 92% and median 
PFS was 23 months (Robinson et al. 2008).  In addition, BR is recommended as a 
second-line therapy for patients with FL who either received alternative therapy in first 
line or who previously received bendamustine-based therapy and had a DOR of 1 year.
Commonly used regimens used to treat transplant eligible patients with R/R DLBCL are 
also used to treat transplant-ineligible patients (see Table 1).  Of note, not all of patients 
in these studies were pretreated with rituximab.  It is known from an analysis of the 
CORAL study (Gisselbrecht 2010) that patients who were pretreated with rituximab and 
relapse have a much worse outcome than those who were rituximab naive.  More 
commonly used chemotherapy regimens with or without rituximab for R/R DLBCL have 
overlapping toxicities (neurotoxicity and hematologic toxicity) with polatuzumab vedotin, 
making combination together unlikely.  BR is active in R/R DLBCL but is associated with 
manageable hematologic toxicity.  For these patients with DLBCL who are not 
candidates for high-dose therapy, BR is also a recommended second-line therapy 
(NCCN Guidelines 2014).


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Table 1
Treatment Regimens for Relapsed/Refractory DLBCL
R-ICE
x 3 cycles
(Gisselbrecht 2010)
R-DHAP
x 3 cycles
(Gisselbrecht 2010)
GDP
x 2 cycles
(Crump 2004)
R-GDP
x 2 cycles
(Crump 2013)
R-ESHAP
X 1-6 cycles
(Martin 2008)
R-GemOx
x 4-8 cycles
(Mounier 2013)
BR
x 6 cycles
(Ohmachi 2013)
BR
x 6 cycles
(Vacirca 2014)
N
202
194
52
619
(71% DLBCL)
163
49
59
59
ORR
CR/CRu
PFS
OS
64%
24%
31% at 3 y
47% at 3 y
63%
28%
42% at 3 y
51% at 3 y
49%
16%


45%


39% at 4 y
73%
35%
38% at 5 y
50% at 5 y
61%
44%
13% at 5 y
14% at 5 y
63%
37%
mPFS 6.7 m

46%
15%
mPFS 3.6 m

Transfusion
35% (PLT)
57% (PLT)
18% (PLT)
24% (PRBC)
18% (PLT)
30% (PLT)
47% (PRBC)
23% (PLT)
12% (PLT or 
PRBC)
NR
Heme toxicity 
and Infection
(G3, G4)
Infection with 
neutropenia 17%
Infection w/o 
neutropenia 6%
Infection with 
neutropenia 16%
Infection w/o 
neutropenia 8%
Neutropenia (33%, 
39%)
FN 14%
TCP (24%, 4%)
FN 9%
FN 34%
Neutropenia 
(73% G3)
FN (4% cycles)
TCP (44% G3)
Neutropenia (31%, 
46%)
FN (7% G3)
TCP (15%, 7%)
Infection (12% G3)
Neutropenia 
(29%, 7%)
Fever (29%)
FN (7% G4)
TCP (17%, 5%)
Neuro-
toxicity
NR
NR
G 2 sensory:  10%
G 2 motor: 4%
NR
G 2: 2 pts
G2:  37%
G3:  8%
NR
NR
BRbendamustine and rituximab; CRcomplete response; CRuCR unconfirmed; DLBCLdiffuse large B-cell lymphoma; FNfebrile neutropenia; 
GGrade; GDPgemcitabine, dexamethasone, cisplatin; m months; R-DHAPrituximab, dexamethasone, high dose cytarabine, cisplatin;
R-ESHAPrituximab, etoposide, methlyprednisolone, cytarabine, cisplatin; R-GDPrituximab and GDP; R-GemOxrituximab, gemcitabine, 
oxaliplatin; R-ICErituximab, ifosphamide, carboplatin, etoposide; Nnumber; NRnot reported; ORRoverall response rate; OSoverall survival; 
PFSprogression free survival; PLT platelet; PRBCpacked red blood cell; pts patients; TCPthrombocytopenia; w/owithout; yyears.


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Two studies have evaluated the combination of bendamustine and rituximab in R/R 
DLBCL (Ohmachi et al. 2013; Vacirca et al. 2014).  In one of the Phase II trials, the OR 
rate was 63% (37% CR/CRu) and median PFS was 6.7 months (Ohmachi et al. 2013); 
for the second Phase II trial, the OR rate was 46% and median PFS was 3.6 months 
(Vacirca et al. 2014).
Polatuzumab vedotin is an ADC designed for the targeted delivery of MMAE, a potent 
microtubule inhibitor to lymphoma cells expressing CD79b.  MMAE has a mechanism of 
action that is similar to that of vincristine.  To date, Phase I data suggest that 
polatuzumab vedotin in combination with rituximab has activity in R/R FL and DLBCL 
with a generally acceptable safety and tolerability profile.  Nonclinical data from murine 
xenograft models support the combination of bendamustine, rituximab, and polatuzumab 
vedotin and demonstrate significantly improved anti-lymphoma activity of the 
combination over BR alone (see Figure 1; Genentech data on file).
Figure 1
Preclinical Data in WSU-DLCL2
IVintravenous; MMAEmono-methyl auristatin; R-CHOPrituximab plus cyclophosphamide, 
doxorubicin, vincristine, and prednisone; R-CHP rituximab plus cyclophosphamide, doxorubicin, 
and prednisone.


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Obinutuzumab (G; also known as RO5072759, GA101, and GazyvaTM), a novel Type II 
and glycoengineered anti-CD20 antibody, has shown superiority over rituximab in a 
Phase III trial in first-line CLL (Goede et al. 2014).  Obinutuzumab is being compared 
with rituximab in two large Phase III studies in patients with previously untreated DLBCL 
(Study BO21005) and with previously untreated iNHL, including FL (Study BO21223).  
Under the assumption that these studies will demonstrate greater clinical benefit with 
obinutuzumab compared with rituximab-containing regimens, potentially altering the 
standard of care in NHL, it will be important to also assess the safety and efficacy of 
combining polatuzumab vedotin with obinutuzumab-containing regimens.
The combination of obinutuzumab with bendamustine is being evaluated in several 
ongoing studies, including two Phase Ib trials in patients with previously untreated 
follicular lymphoma (BO21000) and previously untreated CLL (GAO4779g), and two 
Phase III trials in patients with previously untreated iNHL (BO21223) and 
rituximab-refractory iNHL (GAO4753g).  Of the 41 patients with previously untreated 
follicular lymphoma in BO21000, 29% experienced Grade 3 or 4 neutropenia and 
10% had Grade 3 or 4 infection (Dyer et al. 2012).  In the GAO4779g study, 
11 of 20 (55%) patients with CLL experienced a Grade 3 or 4 neutropenia (including 
2 patients with Grade 3 or 4 febrile neutropenia) and 1 patient had a Grade 3 skin 
infection (Brown et al. 2013). 
Clinical trials with BR and BG have demonstrated efficacy but have been associated with 
neutropenia.  The goals of this Phase Ib/II study are to assess the safety, tolerability, 
and potential biologic and clinical activity of escalating doses of polatuzumab vedotin in 
combination with a standard regimen of an anti-CD20 antibody plus chemotherapy 
(rituximab plus bendamustine [BR] or obinutuzumab plus bendamustine [BG]) in patients 
with R/R FL or DLBCL.  The RP2D of polatuzumab vedotin in combination with BR or 
BG will be determined in the safety run-in portion of the study.  Following identification of 
the RP2D, the expansion portion of the study will further evaluate the safety and 
tolerability and clinical activity of polatuzumab vedotin plus BR compared with BR and 
polatuzumab vedotin plus BG in patients with R/R FL or DLBCL.
2.
OBJECTIVES
2.1
PRIMARY OBJECTIVES (MAIN STUDY)
This section outlines the primary objectives for the main study cohorts (i.e., Phase Ib, 
Phase II expansion, and Phase II randomized cohorts in patients with R/R DLBCL and 
R/R FL), which use the initial liquid formulation of polatuzumab vedotin.
Refer to Section 2.3 for the primary objectives of Arm G and Arm H of the NF Cohort 
(i.e., the Phase II NF Cohort in patients with R/R DLBCL), which uses the new 
lyophilized formulation of polatuzumab vedotin plus BR.


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The primary objectives of the Phase Ib portion of the study are as follows:

To assess the safety and tolerability of the combination of polatuzumab vedotin with 
BR or BG when administered to patients with R/R FL or DLBCL

To identify the RP2D for polatuzumab vedotin given in combination with BR or with 
BG in patients with R/R FL or DLBCL
The primary objective of the Phase II portion of the study is as follows:

To evaluate the efficacy of the combination of polatuzumab vedotin plus BR 
compared with BR alone in patients with R/R FL or DLBCL as measured by 
PET-defined CR rate using Modified Lugano Response Criteria (PET-CT criteria) 
(see Appendix 4) at the time of primary response assessment (68 weeks after 
Cycle 6, Day 1 or last dose of study drug) and as defined by the Independent 
Review Committee (IRC)
2.2
SECONDARY OBJECTIVES (MAIN STUDY)
This section outlines the secondary and exploratory objectives for the main study 
cohorts (i.e., Phase Ib, Phase II expansion, and Phase II randomized cohorts in R/R 
DLBCL and R/R FL), which use the initial liquid formulation of polatuzumab vedotin.
Refer to Section 2.3 for secondary objectives of Arm G and Arm H of the NF Cohort
(i.e., the Phase II NF R/R DLBCL Cohort), which use the new lyophilized formulation of 
polatuzumab vedotin plus BR.
2.2.1
Safety Objectives
The safety objectives for this study are as follows:

To assess the safety and tolerability of the combination of polatuzumab vedotin with 
BR or BG when administered to patients with R/R FL or DLBCL during the Phase II 
portion of the study

To assess the immunogenicity of polatuzumab vedotin and obinutuzumab, as 
measured by the formation of anti-drug antibodies (ADAs)

To assess the potential relationships of such ADAs (anti-polatuzumab vedotin and 
anti-obinutuzumab) formation with other outcome measures (e.g., PK, efficacy, 
safety)
2.2.2
Pharmacokinetic Objectives
The PK objectives for this study are as follows:

To characterize the pharmacokinetics of polatuzumab vedotin in combination with 
BR or BG in patients with R/R FL or DLBCL

To assess potential PK interactions between polatuzumab vedotin and BR or BG

To evaluate the PK exposure response (e.g., efficacy, safety) relationship


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2.2.3
Secondary Efficacy Objectives (Main Study)
The secondary efficacy objectives for this study are: 
To evaluate the efficacy of the combination of polatuzumab vedotin and BR compared 
with BR alone according to Modified Lugano 2014 response criteria as measured by:

CR at the time of Primary Response Assessment based on PET-CT, as determined 
by the investigator

Objective response (OR; CR or PR) at the time of Primary Response Assessment, 
based on PET-CT, as determined by the investigator and IRC

CR at the time of Primary Response Assessment based on CT only, as determined 
by the investigator and IRC

OR at the time of Primary Response Assessment based on CT only, as determined 
by the investigator and IRC

Best objective response (BOR; CR or PR) while on study either by PET-CT or CT
only, as determined by the investigator

DLBCL cohorts only:  BOR, DOR and PFS based on PET-CT or CT, as determined 
by IRC
To evaluate the efficacy of the combination of polatuzumab vedotin plus BG according to 
Modified Lugano 2014 response criteria as measured by: 

CR at the time of Primary Response Assessment based on PET-CT, as determined 
by the investigator and IRC

OR (CR or PR) at the time of Primary Response Assessment, based on PET-CT, as 
determined by the investigator and IRC

CR at the time of Primary Response Assessment based on CT only, as determined 
by the investigator and IRC

OR at the time of Primary Response Assessment based on CT only, as determined 
by the investigator and IRC

Best objective response (BOR, CR, or PR) while on study either by PET-CT or CT 
only, as determined by the investigator

DLBCL cohorts only: BOR, DOR, and PFS while on study by either PET-CT or CT 
only, as determined by IRC
2.2.4
Patient-Reported Outcome Objective
The patient-reported outcome (PRO) objective for this study is to evaluate peripheral 
neuropathy symptom severity and interference on daily functioning and to better 
understand treatment impact, tolerability, and reversibility, as measured by the 
Therapy-Induced Neuropathy Assessment Scale (TINAS).


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2.2.5
Exploratory Objectives
The exploratory objectives for this study are as follows:

To make a preliminary assessment of biomarkers related to the drug targets and 
mechanism of action of polatuzumab vedotin and/or rituximab or obinutuzumab, 
and/or of biomarkers related to disease biology and/or assessments that inform the 
improvement of diagnostic tools, and that might predict disease response or 
resistance to treatment with polatuzumab vedotin in combination with BR or BG in 
R/R FL or DLBCL including but not limited, to the following:
–
CD79b expression
–
DLBCL prognostic subtype (ABC/GCB)
–
Lymphoma-associated mutations and markers of tumor immunobiology
–
Regulators of apoptosis such as BCL-2
–
Minimal residual disease (MRD) as quantified by measurements of 
lymphoma-specific markers DNA extracted from peripheral blood.  
Lymphoma-specific markers from blood will be compared to those measured in 
DNA extracted from baseline tissue to identify the originating clone.

To evaluate the prognostic significance of interim PET-CT assessment
The exploratory efficacy objectives for this study are to evaluate longer-term outcomes 
for patients using the Modified Lugano 2014 response criteria, as measured by the 
following:

Duration of response (DOR) based on PET-CT or CT only, as determined by the 
investigator

Progression-free survival (PFS) based on PET-CT or CT only, as determined by the 
investigator

Event-free survival (EFS) based on PET-CT or CT only, as determined by the 
investigator

Overall survival (OS)
2.3
OBJECTIVES FOR THE NEW FORMULATION (LYOPHILIZED) 
COHORT
2.3.1
Arm G
2.3.1.1
Primary Objective
The primary objective for Arm G is to evaluate the pharmacokinetics and safety of 
polatuzumab vedotin (lyophilized) plus BR in patients with R/R DLBCL, as follows:

Pharmacokinetics:  To characterize the pharmacokinetics of polatuzumab vedotin 
(lyophilized) in combination with BR in patients with R/R DLBCL

Safety: To assess the safety and tolerability of polatuzumab vedotin (lyophilized) in 
combination with BR


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2.3.1.2
Secondary Objectives
2.3.1.2.1
Efficacy
The secondary objective for Arm G is to evaluate the efficacy of the combination of 
polatuzumab vedotin (lyophilized) plus BR as measured by and using Modified Lugano 
Response Criteria, as follows:

CR at the time of Primary Response Assessment (68 weeks after Cycle 6, Day 1 
or last dose of study medication) based on PET-CT, as determined by investigator 
and IRC

OR (CR or PR) at the time of Primary Response Assessment, based on PET-CT, as 
determined by the investigator and IRC

CR at the time of Primary Response Assessment based on CT only, as determined 
by the investigator and IRC

OR at the time of Primary Response Assessment based on CT only, as determined 
by the investigator and IRC

BOR (CR or PR) while on study either by PET-CT or CT only, as determined by the 
investigator and IRC

DOR based on PET-CT or CT only, as determined by the investigator and IRC

PFS based on PET-CT or CT only, as determined by the investigator and IRC

EFS based on PET-CT or CT only, as determined by the investigator

OS
2.3.1.2.2
Safety
The safety objective for Arm G is to assess the immunogenicity of polatuzumab vedotin 
(lyophilized), as measured by the formation of ADAs.
2.3.2
Arm H
2.3.2.1
Primary Objective
The primary objective for Arm H of the study is to evaluate the efficacy of the 
combination of polatuzumab vedotin (lyophilized) plus BR in patients with R/R DLBCL,
as measured by PET-CTdefined CR rate (using the Modified Lugano Response Criteria) 
(see Appendix 4) at the time of Primary Response Assessment (68 weeks after Cycle 6,
Day 1 or last dose of study drug) and as defined by the Independent Review Committee 
(IRC).
2.3.2.2
Secondary Objectives
2.3.2.2.1
Efficacy Objectives
The secondary efficacy objective for Arm H is to evaluate the efficacy of the combination 
of polatuzumab vedotin (lyophilized) plus BR, as measured by and using the Modified 
Lugano Response Criteria, as follows:

CR at the time of Primary Response Assessment based on PET-CT, as determined 
by investigator


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
OR (CR or PR) at the time of Primary Response Assessment, based on PET-CT, as 
determined by the investigator and IRC

BOR (CR or PR) while on study either by PET-CT or CT only, as determined by the 
investigator and IRC

DOR based on PET-CT or CT only, as determined by the investigator and IRC

PFS based on PET-CT or CT only, as determined by the investigator and IRC

EFS based on PET-CT or CT only, as determined by the investigator

OS
2.3.2.2.2
Safety Objectives
The safety objectives for Arm H are as follows:

To assess the safety and tolerability of polatuzumab vedotin (lyophilized) in 
combination with BR

To assess the immunogenicity of polatuzumab vedotin (lyophilized), as measured 
by the formation of ADAs
2.3.2.2.3
Pharmacokinetic Objectives
The PK objective is to characterize the pharmacokinetics of polatuzumab vedotin 
(lyophilized) in combination with BR in patients with R/R DLBCL.
2.3.2.3
Exploratory Objectives
The exploratory objective for this arm of the study is to assess biomarkers related to the 
drug target and mechanism of action of polatuzumab vedotin and/or rituximab, and/or of 
biomarkers related to disease biology and/or assessments that inform the improvement 
of diagnostic tools, and that might predict disease response with polatuzumab vedotin in 
combination with BR in R/R DLBCL, including, but not limited to, the following:

CD79b expression

DLBCL prognostic subtype (ABC/GCB)

Regulators of apoptosis such as BCL-2 or c-MYC
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This design is a Phase Ib/II, multicenter, open-label study of polatuzumab vedotin 
administered by IV infusion in combination with standard doses of bendamustine (B) and 
rituximab (R) or obinutuzumab (G) in patients with relapsed or refractory FL or DLBCL.  
The study will consist of two stages:  a Phase Ib safety run-in stage and a Phase II stage.  
The dose of polatuzumab vedotin in combination with BR or BG will be determined 
during the safety run-in stage of the study, separately for each lymphoma subtype (FL 
and DLBCL), and will be used in combination with BR or BG in the Phase II stage.  The 
Phase II stage will be randomized for patients treated with R-containing regimens and be 


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non-randomized for patients treated with the G-containing regimen.  Throughout the 
study, there will be concurrent enrollment of patients having either FL or DLBCL.
The study will begin with a safety run-in stage followed by a randomization and 
expansion phase.  During the safety run-in phase, 6 patients will be treated with 
polatuzumab vedotin in combination with the BR regimen.  Once this cohort is safely 
cleared, 6 patients will be treated at the same dose level of polatuzumab vedotin in 
combination with the BG regimen.  If the first 6 patients in the polatuzumab vedotin plus 
BR cohort safely clears after the first cycle, then the randomized Phase II stage 
comparing BR-containing regimens will commence and patients will be randomized to 
either polatuzumab vedotin plus BR or to BR alone (control arm).  Randomization will 
occur separately for each of the two disease-specific cohorts of patients with either FL or 
DLBCL.  If the first 6 patients in the polatuzumab vedotin plus BG cohort safely clear the 
first cycle, then the expansion stage for obinutuzumab-containing regimen will 
commence.  Patients receiving polatuzumab vedotin plus BG will be enrolled into two 
expansion cohorts on the basis of histology of FL or DLBCL in order to expand the 
safety database and collect preliminary anti-lymphoma activity data.
The Phase II randomization portion of the study can commence once the safety run-in of 
the polatuzumab vedotin plus BR cohort has completed, which can occur before the BG 
safety run-in cohort is completed.  The Phase II expansion portion of the study can 
commence once the safety run-in of the polatuzumab vedotin plus BG cohort has been
completed.
Sites cannot enroll patients in rituximab-containing and obinutuzumabcontaining 
phases simultaneously within the same histology.
The NF Cohort (Arm G and Arm H) is separate from the expansion and randomized 
phases of the main study. 
In Arm G of the NF Cohort, patients with R/R DLBCL will be treated with polatuzumab 
vedotin (lyophilized) in combination with BR to gain clinical PK and safety experience 
with the new lyophilized formulation of polatuzumab vedotin.  Initially, up to 30 patients 
were to be enrolled in order to ensure adequate number of PK-evaluable patients. 
Enrollment has been expanded to approximately 40 patients, which will include 
approximately 10 second-line (2L) patients (patients with one prior line of therapy) 
in order to evaluate the efficacy of polatuzumab vedotin (lyophilized) in combination with 
BR in the 2L setting. A PKevaluable patient is defined as a patient from whom, at 
minimum, the PK samplings of all three analytes (i.e., total antibody, acMMAE, and 
unconjugated MMAE) at Cycle 1 through Cycle 2, Day 1 are obtained.
In Arm H of the NF Cohort, patients with R/R DLBCL will be treated with polatuzumab 
vedotin (lyophilized) in combination with BR to further evaluate the clinical efficacy, to 
gain additional safety experience, and to expand evaluation in exploratory biomarker 


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subsets. Approximately 60 patients in total will be enrolled in this arm. A minimum of 
approximately 30% of patients who have previously received only one prior line of 
therapy (i.e., 2L therapy) will be enrolled in Arm H, and prioritization may be given to 
ensure such enrollment is achieved upon completion of enrollment in this arm.
Study treatment will be given in 28-day cycles for patients with FL and in 21-day cycles 
for patients with DLBCL.  The first day of treatment will constitute Study Day 1.  Patients 
will be treated up to a total of six cycles.
All patients will be evaluated for safety and efficacy according to the schedules of 
assessments (Appendix 1).
All patients will be assessed for response to treatment by the investigator with the use of 
standard criteria according to the Modified Lugano Response Criteria (Cheson et al. 
2014; see Appendix 4) at screening and at the following timepoints:

Interim response assessment (between Cycle 3, Day 15 and Cycle 4, Day 1)

Primary response assessment:  68 weeks after completion of study treatment 
(i.e., Day 1 of Cycle 6 or after last dose of study drug)
Imaging at these timepoints must include FDG-PET (18F fluorodeoxyglucose-positron 
emission tomography) and a diagnostic-quality CT scan with both oral and IV contrast.  
A combined PET-CT scan is encouraged if feasible.  An independent review of the 
responses of all patients will also be conducted to confirm the primary CR endpoint 
(see Section 3.1.4).  Patients will also be evaluated every 3 months thereafter until 
disease progression, death, withdrawal of consent, or initiation of another anti-cancer 
therapy.  Tumor assessments should also be performed to confirm clinical suspicion of 
relapse or disease progression for documentation.
The study will enroll approximately 24 patients with either FL or DLBCL for the Phase Ib 
safety run-in stage at approximately 25 sites in the United States and Canada (up to 
12 patients with the BR regimen and up to 12 patients with the BG regimen).
The Phase II stage of the study will enroll approximately 160 patients with either R/R FL 
or R/R DLBCL who will receive a BR-containing regimen (randomization portion) and 
approximately 40 patients with either R/R FL or R/R DLBCL who will receive a 
BG-containing regimen (safety expansion portion). Approximately 80 sites globally will 
participate in this portion of the study.  
Arm G of the Phase II NF Cohort will enroll approximately 40 patients with R/R DLBCL
who will receive polatuzumab vedotin (lyophilized) with BR.  Approximately 3035 sites 
of the total sites in the study will participate in this portion of the study.




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Figure 2
Overview of Study Design (cont.)
2Lsecond line; BRbendamustine and rituximab; BG bendamustine and obinutuzumab; 
DDay; DLBCLdiffuse large B-cell lymphoma; FLfollicular lymphoma; RP2Drecommended 
Phase II dose; R/Rrelapsed or refractory.
Notes:  Rituximab (375 mg/m2) D1 of each cycle, or obinutuzumab (1000 mg) D1, D8, and D15 in 
Cycle 1, then D1 of each subsequent cycle plus bendamustine (90 mg/m2) D2 and D3 in Cycle 1, 
then D1 and D2 in each subsequent cycle.
FL:  Treatment administered every 28 days x 6 cycles.
DLBCL:  Treatment administered every 21 days x 6 cycles.
a Polatuzumab vedotin (lyophilized) dose 1.8 mg/kg.
b Initially, approximately 20-30 patients were planned to be enrolled to ensure adequate number 
of PK-evaluable patients.  A PK-evaluable patient is defined as a patient from whom at 
minimum the PK samplings of all three analytes (i.e., total antibody, acMMAE, and 
unconjugated MMAE) at Cycle 1 through Cycle 2, Day 1 are obtained. Approximately 10 
additional patients with one prior line of therapy (i.e., 2L) will also be enrolled in this arm in 
order to evaluate the efficacy of polatuzumab vedotin (lyophilized) in combination with BR in 
this particular patient subpopulation, bringing the total arm size to approximately 40 patients.
c A minimum of approximately 30% of patients who previously received one prior line of therapy
(i.e., 2L) will be enrolled in this arm to ensure a sufficient number of efficacy-evaluable patients 
for this particular subpopulation. Prioritization may be given to ensure such enrollment is 
achieved upon completion of enrollment in this arm.
3.1.1
Phase Ib:  Safety Run-In Stage
The safety run-in stage of the study will assess the safety, tolerability, and 
pharmacokinetics of polatuzumab vedotin administered in combination with BR or BG.  
Prior vinca alkaloid therapy is allowed if any resulting neuropathy does not exceed 
Grade 1 at enrollment.
3.1.1.1
Cohort Dosing Regimen
Patients will be enrolled in separate FL and DLBCL cohorts in Phase Ib safety run-in as 
shown in Table 2.  The dose level for polatuzumab vedotin will be 1.8 mg/kg.  Cohort 1a 
refers to the cohort receiving rituximab.  Cohort 1b refers to the cohort receiving 
obinutuzumab.  The selection of the dose level was made on the basis of the absence of 
DLTs observed at this dose level when administered as a single agent in the Phase I 
study DCS4968g.  Polatuzumab vedotin will be administered in combination with either 
BR or BG.  Sites cannot enroll patients in rituximab-containing and 
obinutuzumab-containing phases simultaneously within the same histology.


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Table 2
Safety Run-In Cohorts of Polatuzumab Vedotin with Starting 
Doses of Bendamustine and Rituximab or Obinutuzumab
Histology
Dose 
Cohort
Starting Doses
Polatuzumab vedotin
Bendamustine
Anti-CD20 Antibody
FL
(every 28 day dosing)
1a
(n6)
1.8 mg/kg
90 mg/m2
Rituximab
375 mg/m2
1b
(n6)
1.8 mg/kg
90 mg/m2
Obinutuzumab 
1000 mg
DLBCL
(every 21 day dosing)
1a
(n6)
1.8 mg/kg
90 mg/m2
Rituximab
375 mg/m2
1b
(n6)
1.8 mg/kg
90 mg/m2
Obinutuzumab 
1000 mg
DLBCLdiffuse large B-cell lymphoma; FLfollicular lymphoma.
Patients will be monitored for adverse events during the safety observation period from 
Cycle 1, Day 1 to Cycle 2, Day 1 for a minimum of 28 days for FL patients and 21 days 
for DLBCL patients.  Any patient who does not complete the full safety-observation 
period for any reason other than adverse events will be considered non-evaluable for 
safety run-in analysis decisions and/or RP2D assessment and will be replaced by an 
additional patient in the same cohort.
For each cohort during the safety run-in, the first patient treated will receive the first 
infusion of polatuzumab vedotin at least 24 hours before any subsequent patient in that 
cohort is treated in order to allow sufficient time to assess the occurrence of any severe 
and unexpected acute drug or infusion-related toxicities.
During the safety run-in, a safety analysis will be performed after the first 3 patients 
receiving polatuzumab vedotin plus BR have completed the safety observation period.  
After the first 3 patients have safely cleared as determined by an internal safety review, 
an additional 3 patients will be added to the same cohort.  The IMC will perform a safety 
analysis after 6 patients in each histology group have completed the safety observation 
period.  Once the IMC provides a recommendation for the RP2D for the polatuzumab 
plus BR regimen, enrollment into the polatuzumab vedotin plus BG and the Phase II 
randomization portion will commence.  After the first 3 patients have safely cleared as 
determined by an internal safety review, an additional 3 patients will be added to the 
same cohort.  Decisions will be made by the Sponsor’s Medical Monitor in consultation 
with the Safety Science Leader, Biostatistician, and participating investigators.  The 
decision to continue enrollment in the current cohort or to open the next cohort will be 
based upon review of all relevant safety data including but not limited to adverse event 
and laboratory data.


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3.1.1.2
Definition of Safety Criteria during Safety Run-In
During the safety run-in stage of the study, toxicity that will prevent further enrollment 
into Phase Ib and opening of Phase II will be defined as any of the following study 
treatment related adverse events occurring during the safety observation period as 
described below.
All adverse events are to be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03, unless otherwise 
indicated.  If a patient experiences an adverse event as defined below, he or she will be 
treated according to clinical practice and will be monitored for resolution of the toxicity.  
Decreases in B cells, lymphopenia, and leukopenia due to lymphopenia will not be 
considered an adverse event because they are expected pharmacodynamic outcomes 
of rituximab, obinutuzumab, or polatuzumab vedotin treatments.
The following criteria will be used in the safety analysis during the safety run-in stage:

Any adverse event regardless of grade that leads to a delay of at least 7 days to the 
start of the next cycle 

Grade 3 non-hematologic toxicity that is not attributed to disease progression or 
another clearly identified cause, excluding the following:
–
Grade 3 diarrhea that responds to standard-of-care therapy within 72 hours
–
Grade 3 nausea or vomiting, in the absence of premedication, that responds to 
standard-of-care therapy within 72 hours
–
Grade 3 laboratory abnormality that is asymptomatic and deemed by the 
investigator not to be clinically significant
–
Reversible Grade 3 non-allergic infusion toxicities (including symptoms such as 
fever, chills/rigors, nausea, vomiting, pruritus, headache, rhinitis, rash, asthenia, 
and/or hypoxia in the absence of signs/symptoms of respiratory distress) 
occurring during or within 24 hours after completing an infusion and resolving 
within 24 hours
–
Grade 3 allergic toxicities such as wheezing, bronchospasm, shortness of 
breath, and/or stridor in the presence or absence of hypoxia, and/or urticaria 
are not excluded and should be considered an AE meeting safety run-in criteria.  
(Patients with infusion-related Grade 3 wheezing, hypoxia, or generalized 
urticaria must be permanently discontinued from study drug on the first 
occurrence.)
–
Grade 3 elevation in ALT or AST, provided the following criteria are met:
ALT or AST level is no greater than 8the upper limit of normal (ULN)
ALT or AST elevation resolves to Grade 2 (5ULN) within 7 days
Total and direct bilirubin and other laboratory parameters of liver synthetic 
function (e.g., prothrombin time) are normal
No clinical signs or symptoms of hepatic injury


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Any case involving an increase in hepatic transaminase 3baseline AND 
an increase in direct bilirubin 2ULN, WITHOUT any findings of 
cholestasis or jaundice or signs of hepatic dysfunction AND in the absence 
of other contributory factors (e.g., worsening of metastatic disease or 
concomitant exposure to known hepatotoxic agent or of a documented 
infectious etiology) is suggestive of potential drug-induced liver injury (DILI) 
(according to Hy’s Law) and will be considered an adverse event meeting 
safety run-in criteria.

All Grade 3 or 4 hematological toxicities considered by the investigator to be related 
to polatuzumab vedotin and not attributable to another clearly identifiable cause with 
the exception of the following:
–
Lymphopenia, which is an expected outcome of therapy
–
Grade 4 neutropenia in the absence of granulocyte colony-stimulating factor 
(G-CSF) that is not accompanied by temperature elevation (oral or tympanic 
temperature of 100.4F [38C]) and improves to Grade 3 within 1 week and 
further improves to Grade 2 (or to 80% of the baseline value, whichever is 
lower) within another week 
–
Grade 3 neutropenia in the absence of G-CSF that is not accompanied by 
temperature elevation (oral or tympanic temperature of 100.4F [38C]) and 
improves to Grade 2 (or to 80% of the baseline value, whichever is lower) 
within 1 week 
–
Grade 3 or 4 leukopenia
–
Grade 4 thrombocytopenia that does not result in bleeding and improves to 
Grade 3 within 1 week and further improves to Grade 2 (or to 80% of the 
baseline value, whichever is lower) within another week without platelet 
transfusion
–
Grade 3 thrombocytopenia that does not result in bleeding and improves to 
Grade 2 (or to 80% of the baseline value, whichever is lower) within 1 week 
without platelet transfusion
–
Grade 3 or 4 anemia that does not require an emergent transfusion
If a patient experiences an adverse event as described above, the patient will be 
observed for resolution of the toxicity.  If the adverse event resolves to Grade 2 (or to 
80% of the baseline value) and if it is determined to be in the patient’s best interest to 
continue study treatment (after discussion between the treating investigator and the 
Medical Monitor), the patient may continue to receive polatuzumab vedotin.
3.1.1.3
Decision Rules for Safety Run-In Stage
Safety data from the patients enrolled during the Safety Run-In Stage will be used to 
determine the dose of polatuzumab vedotin used during the Phase II randomization and 
expansion stage of the study.


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The following rule will apply during the safety run-in:

If any adverse events, as defined per Section 3.1.1.2 are observed in 33% of the 
patients enrolled in a given cohort, further enrollment of the cohort will be halted.
Additional patients may be enrolled into a given cohort in the absence of excess toxicity 
to acquire additional safety data.  Additional patients may be enrolled at dose levels 
below 1.8 mg/kg of polatuzumab vedotin (i.e., 1.4 mg/kg) based upon review of all safety 
data by the Sponsor (including the IMC).
3.1.2
Phase II:  Randomized and Expansion Stage and 
New Formulation Cohort
The study will include approximately 160 patients who will receive a BR-containing 
regimen in the randomized Phase II portion (see Figure 3) and 40 patients who will 
receive a BG-containing regimen in the safety expansion portion (non-randomized; see 
Figure 4).  In addition, in the Phase II NF Cohort, approximately 100 patients will receive 
polatuzumab vedotin (lyophilized) with BR (~40 patients in Arm G and ~60 patients in 
Arm H).
Patients in the Phase II portion will receive polatuzumab vedotin at the RP2D
determined during the Phase Ib portion of the study.  Sites cannot enroll patients in 
rituximab-containing and obinutuzumab-containing phases simultaneously within the 
same histology.
3.1.2.1
Randomized Bendamustine plus Rituximab-Containing 
Regimen
Approximately 80 patients with R/R FL will be randomized to receive polatuzumab 
vedotin plus BR (Arm A) or BR alone (Arm B).  Approximately 80 patients with R/R 
DLBCL will be randomized to receive polatuzumab vedotin plus BR (Arm C) or BR alone 
(Arm D) (see Figure 3).
Patients will be randomized 1:1 within each histology group with the use of stratified 
permuted blocks such that all treatment arms will enroll the same number of patients 
(n40 in each of the treatment arms).  Randomization will be stratified according to the
following factors:

DOR to prior therapy:  12 months versus 12 months (DLBCL, FL)

Disease burden:  high versus low (FL only)
High-disease burden by modified GELF criteria (named for the cooperative group 
Groupe d’Etude des Lymphomes Folliculaires) (Brice et al. 1997), defined as presence 
of any one of the following:  largest nodal or extranodal mass 7 cm, three or more nodal 
sites with diameter 3 cm, ascites or pleural effusion, risk of organ compression or 
compromise, symptomatic splenic enlargement, LDH, beta-2 microglobulin greater than 
ULN, or presence of systemic symptoms.


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Figure 3
Phase II Randomized:  Polatuzumab Vedotin Plus BR vs BR
BRbendamustine and rituximab; DLBCLdiffuse large B-cell lymphoma; FLfollicular 
lymphoma; R/Rrelapsed or refractory.
3.1.2.2
Non-Randomized Bendamustine Plus Obinutuzumab 
Containing Regimen
Approximately 20 patients with R/R FL (Arm E) and 20 patients with R/R DLBCL (Arm F) 
will receive polatuzumab vedotin plus BG in the safety-expansion stage (see Figure 4).
Figure 4
Phase II Expansion:  Bendamustine Plus Obinutuzumab Regimen
BG bendamustine plus obinutuzumab; DLBCLdiffuse large B-cell lymphoma; 
FLfollicular lymphoma; R/Rrelapsed or refractory.
A schedule of assessments is provided in Appendix 1.


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3.1.2.3
Phase II New Formulation Cohort: Polatuzumab Vedotin 
(Lyophilized) plus BR
Approximately 100 patients with R/R DLBCL will receive polatuzumab vedotin 
(lyophilized) plus BR in the NF Cohort with approximately 40 patients in Arm G and 
approximately 60 patients in Arm H (see Figure 5). 
Figure 5
Phase II:  Non-Randomized NF Cohort
2L=second line; BRbendamustine plus rituximab; DLBCLdiffuse large B-cell lymphoma; 
NFnew formulation; PKpharmacokinetic; R/Rrelapsed or refractory.
a Intially, up to 30 patients were to be enrolled to ensure adequate number of PK-evaluable
patients. Approximately 10 additional patients with one prior line of therapy (i.e. 2L) will also 
be enrolled in this arm in order to evaluate the efficacy of polatuzumab vedotin (lyophilized) in 
combination with BR in this particular patient subpopulation, bringing the total arm size to 
approximately 40 patients.
b A minimum of approximately 30% of patients with one prior line of therapy (i.e., 2L) will be 
enrolled in this arm to ensure a sufficient number of efficacy-evaluable patients for this 
particular subpopulation. Prioritization may be given to ensure such enrollment is achieved 
upon completion of enrollment in this arm.
3.1.3
Internal Monitoring Committee
An IMC will be established to monitor patient safety throughout the study and provide a 
recommendation on whether to continue into Phase II of the study after completion of 
the Phase Ib safety run-in stage.  The IMC will include the Roche/Genentech Medical 
Monitor, at least one other medical doctor or Clinical Science representative who is not 
directly involved in the study, and representatives from Clinical Drug Safety, Biostatistics, 
and Statistical Programming and Analysis.  In addition to the ongoing assessment of the 
incidence and nature of toxicity as defined in Section 3.1.1.3, adverse events 
(particularly Grades 3), serious adverse events, deaths, and laboratory abnormalities
by the investigator and the Medical Monitor, the IMC will review all necessary cumulative 
data at regular intervals during the study, including the NF cohort. At the time of each 
review, the IMC will make one of the following recommendations:  the trial continues as 
planned, a study arm stops, the protocol is amended, additional analyses need to be 
performed, or enrollment will be held pending further safety evaluations.  Decisions will 
be made in consideration of the totality of the available data.  Ad hoc meetings may be 
called in addition to scheduled meetings, as necessary, to provide recommendations on 
management of any new safety issues.  Specific operational details, such as the 
R/R DLBCL
Polatuzumab vedotin (lyophilized)BR 
(n40) a
ARM G
R/R DLBCL
Polatuzumab vedotin (lyophilized) BR 
(n60) b
ARM H


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committee's composition, frequency and timing of meetings, and members' roles and 
responsibilities, will be detailed in an IMC Charter.
3.1.4
Independent Review Committee
An Independent Review Committee (IRC) composed of board-certified radiologists and 
an oncologist with experience in malignant lymphoma will assess all patients for 
response (see Appendix 4) on the basis of imaging results and bone marrow biopsy 
results for all patients during the Phase II portion of the study.  Decisions will be guided 
by a Charter specific to the independent review.
3.2
END OF STUDY
The end of the study is defined as the timepoint at which all patients enrolled in the study 
have either had at least 2 years of follow-up from the time of the treatmentcompletion
visit or have discontinued the study.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Polatuzumab Vedotin Dose and Schedule
Polatuzumab vedotin dosing for this study was based on the experience from the 
ongoing Phase I Study DCS4968g with single-agent polatuzumab vedotin in relapsed 
and refractory patients with iNHL and DLBCL.  Most evidence of anti-tumor activity was 
observed at doses 1.8 mg/kg.
Bendamustine in combination with anti-CD20 monoclonal antibodies has its own degree 
of myelosuppression; therefore, the dose of polatuzumab vedotin that is given with 
standard doses of bendamustine and rituximab or bendamustine and obinutuzumab may 
not reach the same MAD (maximum assessed dose) as that achieved with polatuzumab 
vedotin monotherapy.  The number of cycles (six 21-day or 28-day cycles) of this 
regimen (polatuzumab vedotin plus BR or BG) that will be evaluated in this study is 
consistent with other anti-CD20 plus bendamustine regimens used to treat NHL and has 
been shown to be sufficient to provide durable responses.
The NF Cohort involving patients with R/R DLBCL will be treated with the 140 mg/vial 
lyophilized formulation of polatuzumab vedotin (Arm G and Arm H) in combination with 
BR.  The initial formulation of polatuzumab vedotin is a liquid formulation and was used 
in the initial cohorts of this study (i.e., Phase Ib, Phase II expansion, and Phase II 
randomized) in patients with either R/R FL or R/R DLBCL.  A 170 mg/vial lyophilized 
formulation of polatuzumab vedotin was developed to support an initial expected clinical 
dose of 2.4 mg/kg and is currently in use in other clinical trials.  A 140 mg/vial lyophilized 
drug product was subsequently developed to support a target dose of 1.8 mg/kg.  Both 
the 170 mg/vial and 140 mg/vial lyophilized drug products differ in only the fill volume.  
The 140 mg/vial lyophilized polatuzumab vedotin is planned for later clinical trials and 
proposed for commercialization and will be used in combination with BR in the Phase II
NF Cohort (Arm G and Arm H) enrolling patients with R/R DLBCL.


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3.3.2
Rationale for Rituximab and Bendamustine Dosing 
and Schedule
Bendamustine with and without rituximab has demonstrated efficacy in patients with R/R 
iNHL (Rummel et al. 2005; Friedberg et al. 2008; Robinson et al. 2008; Kahl et al. 2010).  
Other available established therapies in this setting are either associated with high
toxicity (e.g., fludarabine-based therapies, hematopoietic stem cell transplant) or have 
more limited effectiveness (e.g., R-CVP, rituximab monotherapy).
Indolent NHL, Including Follicular Lymphoma
Two studies have investigated bendamustine in combination with rituximab in R/R 
indolent lymphomas (Robinson et al. 2008; Rummel et al. 2010).  In both studies, 
rituximab was administered at a standard dose of 375 mg/m2 on Day 1, followed by 
bendamustine 90 mg/m2 on Days 1 and 2 of a 28-day cycle.  The major Grade 3 or 
Grade 4 toxicity with this regimen was reversible neutropenia, observed in 36% of 
patients.
DLBCL
Two studies have evaluated the combination of bendamustine and rituximab in R/R 
DLBCL (Ohmachi et al. 2013; Vacirca et al. 2014).  In both studies, rituximab was 
administered at standard dose of 375 mg/m2 on Day 1, followed by bendamustine 
120 mg/m2 over 2 consecutive days for up to six cycles.  Cycles were administered on a 
21-day (Ohmachi et al. 2013) or a 28-day cycle (Vacirca et al. 2014).
The most frequent Grade 3 or 4 adverse events observed in both studies were 
hematologic including neutropenia (Ohmachi:  31% Grade 3, 46% Grade 4; 
Vacirca: 29% Grade 3, 7% Grade 4) and febrile neutropenia (Ohmachi:  7% Grade 3, 
Vacirca: 7% Grade 4).
In the Ohmachi study, 29% of patients (15 of 51) who received Cycle 2 and 32% 
(14 of 44) who received Cycle 3 required a dose reduction.  Per study protocol, dose 
reductions of bendamustine from 120 mg/m2 to 90 mg/m2 were made for patients who 
developed Grade 4 hematologic toxicities, Grade 3 neutropenia lasting for 14 days or 
more, Grade 2 thrombocytopenia, or other Grade 3 or 4 non-hematologic toxicities.  If
toxicities recurred, then doses were further reduced to 60 mg/m2.  Because 
approximately one third of patients required a dose reduction in Cycle 1, this study will 
use a starting bendamustine dose of 90 mg/m2 administered over 2 consecutive days on 
a 21-day cycle.  Additionally, the International Consensus Panel recommended a 
bendamustine dose and schedule of 90 mg/m2 every 3 weeks when combined with 
rituximab for aggressive NHL (Cheson et al. 2010).
Rituximab plus Bendamustine as Control Group
BR is considered a relevant comparator arm because other available established 
therapies in both the R/R FL and DLBCL settings are either associated with high toxicity 
(e.g., fludarabine-based therapies, hematopoietic stem cell transplant) or have more 


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limited effectiveness (e.g., R-CVP, rituximab monotherapy).  Furthermore, BR is 
recommended as a second-line therapy for patients with FL who either received 
alternative therapy in first line or who previously received bendamustine-based therapy 
and had a DOR of 1 year.  In a Phase II trial examining the efficacy of BR in patients
with R/R FL, the OR rate was 92% and median PFS was 23 months 
(Robinson et al. 2008).  For patients with DLBCL who are not candidates for high-dose 
therapy, BR is also a recommended second-line therapy (NCCN Guidelines 2014).
3.3.3
Rationale for Obinutuzumab and Bendamustine Dosing 
and Schedule
The combination of obinutuzumab with bendamustine is being evaluated in several 
ongoing studies, including two Phase Ib trials in patients with previously untreated 
follicular lymphoma (BO21000) and previously untreated CLL (GAO4779g), and 
two Phase III trials in patients with previously untreated iNHL (BO21223) and 
rituximab-refractory iNHL (GAO4753g).  Of the 41 patients with previously untreated 
follicular lymphoma in BO21000, 29% experienced Grade 3 or 4 neutropenia and 10% 
had Grade 3 or 4 infection (Dyer et al. 2012).  In the GAO4779g study, 11 of 20 (55%) 
patients with CLL experienced a Grade 34 neutropenia (including 2 patients with 
Grade 3 or 4 febrile neutropenia) and 1 patient had a Grade 3 skin infection 
(Brown et al. 2013).
In all of these studies, bendamustine is administered at the standard dose (90 mg/m2) 
and on the schedule used in combination with other anti-CD20 MAbs in the front-line and 
R/R NHL setting.  The recommended dose and schedule for obinutuzumab in this 
regimen is 1000 mg on Days 1, 8, and 15 of Cycle 1 and Day 1 of each subsequent 
cycle (Cycles 26).
To maintain consistency with these ongoing trials, the same bendamustine and 
obinutuzumab dosing schedule will be administered.  However, the study regimen will be 
administered using a 28-day cycle for patients with FL and using a 21-day cycle for 
patients with DLBCL as reported in the bendamustine and rituximab combination trials 
(Robinson et al. 2008; Rummel et al. 2010; Ohmachi et al. 2013; Vacirca et al. 2014).
3.3.4
Rationale for Stratification Factors
The clinical course of FL is extremely variable.  Although a major determinant of 
prognosis in newly diagnosed FL is the FLIPI, in relapsed disease the most powerful 
predictor of outcome is the depth and duration of response to previous therapy.  Patients 
with response duration of 1 year to prior therapy had markedly better duration of 
response to rituximab-based subsequent therapy at relapse (Coiffier et al. 2011).
In addition to previous response duration, the prognosis of patients with relapsed FL is 
affected by tumor burden.  Although the method for measurement of disease burden 
varies, the two major approaches are the FLIPI and the GELF criteria.  In relapsed FL, 
the GELF criteria appeared to be superior in predicting PFS (Coiffier et al. 2011).


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For relapsed DLBCL, predictive factors have included initial remission duration of
1 year and the absence of bulky disease at the time of stem cell transplantation 
(Sweetenham 2005).
Given the marked heterogeneity in outcome based on these risk factors, patients will be 
stratified at randomization to take these factors into account.
3.3.5
Rationale for PET-Defined Complete Response
PET scanning has been shown in multiple settings to be a more accurate tool for 
assessing activity of lymphoma than CT imaging.  In aggressive lymphomas, such as 
DLBCL, PET-defined CR is a better predictor of PFS than response as defined by CT.  
The correlation of PET-defined response and PFS has not been as extensively studied 
in indolent lymphomas.  However, a recent evaluation of PET-defined response in 
patients with FL treated with standard induction therapy using rituximab plus 
chemotherapy demonstrated that although PFS was not different between patients 
achieving PR versus CR, as defined by CT scan, when response criteria incorporating 
PET were used, patients who achieved PET-negative CR had a significantly longer PFS 
than did patients achieved only a PR as defined by PET (Trotman et al. 2011).  These 
findings indicate that response, as defined by PET, correlates with longer-term outcomes 
in patients with FL, similar to aggressive lymphomas.
3.3.6
Rationale for Patient-Reported Outcomes
Peripheral sensory neuropathy is an adverse drug reaction (ADR) of polatuzumab 
vedotin.  Peripheral neuropathy in several forms, including sensory and/or motor 
neuropathy, is experienced by a majority of patients treated with polatuzumab vedotin.  It 
is known that a discrepancy exists between healthcare provider interpretation and 
reporting of these events and a patient’s self-assessment of their experience with 
peripheral neuropathy.  This discrepancy is due, in part, to the lack of an adequate 
patient-reported measure of symptomatic burden of peripheral neuropathy on daily 
functioning.  The primary objective of the PRO assessment in the Phase Ib/II study is to 
comprehensively assess and quantify the symptomatic burden and personal tolerability 
of this adverse event.  The objective is to provide a better understanding of the clinical 
profile of polatuzumab vedotin from a patient perspective using a novel validated 
measure known as the TINAS (Thomas et al. 2012).
3.3.7
Rationale for Collecting Lymph Node Biopsy Samples and 
Peripheral Blood for Biomarker Studies
Biomarkers in the tumor that are associated with drug target, mechanism of action, and 
NHL biologyincluding immune infiltratemay correlate with outcome and carry 
predictive or prognostic value.  The activity of ADCs is dependent on a number of factors 
including the presence of the antibody target, internalization of the ADC, and sensitivity 
of the tumor cell to the payload drug; therefore, analysis of these factors may identify 
markers predictive of response.  In addition, new therapeutic approaches in DLBCL 


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appear to result in differential activity in DLBCL prognostic activated B cell (ABC) versus 
germinal center B cell (GCB); it is, therefore, of interest to understand the activity of a 
novel treatment in these DLBCL subtypes.  Finally, resistance to cytotoxic treatment may 
be a result of high expression of anti-apoptotic regulators such as BCL-2.  Novel immune 
therapy approaches for treatment of tumors aim to re-enable a host immune response 
against the tumor cells.  Assessments of apoptotic regulators and immune-infiltrate and 
their correlation with response are warranted for potential future treatments in 
combination with BCL-2 inhibitors and immune therapy.
To understand resistance mechanisms to rituximab, bendamustine, or polatuzumab 
vedotin, collection of a lymph node tissue sample for biopsy is requested from patients 
who have progressive disease (PD) after a response.  This biopsy will allow for the 
assessment of changes that may be involved in resistance to treatment and for 
developing novel treatment approaches.
Tumor-associated biomarkers may also be detected in blood.  Because tumor tissue is 
often limited and difficult to acquire, the evaluation of diagnostic assays for blood-borne 
markers that are representative of the current disease state is of high interest.
3.4
OUTCOME MEASURES
3.4.1
Safety Outcome Measures
The determination of the polatuzumab vedotin RP2D in combination with BR or BG will 
be assessed using the following primary safety outcome measures for the Phase Ib 
portion of the study:

Incidence, nature, and severity of adverse events and serious adverse events

Changes in vital signs, physical findings, ECGs, and clinical laboratory results 
during and following study treatment administration

Formation of ADAs
These safety outcome measures will also be assessed in the Phase II NF Cohort (Arm G
and Arm H) in which patients with R/R DLBCL will be administered polatuzumab vedotin 
(lyophilized) plus BR.
3.4.2
Efficacy Outcome Measures
Response assessment will be determined according to Modified Lugano Response 
Criteria for Malignant Lymphoma (Lugano Classification; Cheson et al. 2014; see 
Appendix 4). 

CR at primary response assessment (68 weeks after Cycle 6, Day 1 or last dose of 
study drug) based on PET-CT, as determined by the investigator and IRC 

OR (CR or PR) at primary response assessment based on PET-CT, as determined 
by the investigator and IRC


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
CR at primary response assessment based on CT only, as determined by the 
investigator and IRC

OR (CR or PR) at primary response assessment based on CT only, as determined 
by the investigator and IRC

BOR (CR or PR) while on study based on PET-CT or CT only, as determined by the 
investigator

NF cohort only:  OS and EFS based on PET-CT or CT only, as determined by the 
investigator
In addition, for the DLBCL cohorts, IRC and investigator-assessed BOR, DOR, and PFS 
will be performed.
3.4.3
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:

Serum and plasma concentrations of polatuzumab vedotin, bendamustine, rituximab, 
and obinutuzumab versus time

PK parameters based on concentrationtime data for polatuzumab vedotin, 
bendamustine, rituximab, and obinutuzumab when these drugs are given in 
combination
Serum and plasma concentrations of bendamustine and rituximab will not be assessed 
in the Phase II NF Cohort (Arm G and Arm H).
Refer to Appendix 2 for the schedule of PK assessments.
3.4.4
Patient-Reported Outcome Measure
The PRO outcome measure for this study is as follows:

PROs of peripheral neuropathy symptom severity and symptom interference, as 
measured by the TINAS (Thomas et al. 2012; see Appendix 8)
PRO measures will not be collected for the Phase II NF Cohort (Arm G and Arm H).
3.4.5
Exploratory Outcome Measures
The exploratory biomarker outcome measures for this study are as follows:

Biomarkers related to tumor biology and the mechanisms of action of polatuzumab 
vedotin and rituximab or obinutuzumab.  These include, but are not limited to, the 
assessment of potentially prognostic subsets (i.e., cell of origin), CD79b expression 
levels, apoptotic regulators (e.g., BCL-2), markers of immune infiltration and/or
regulation (e.g., CD8, PD-L1), and identification of other potential prognostic factors.

Biomarkers will be assessed retrospectively using a tissue block (preferred) or 
15 serial freshly cut, unstained slides plus punch biopsy of the tissue block from the 
time of initial diagnosis and, if possible, at the time of disease progression.


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
For quantitative assessment of MRD levels of the lymphoma clone in circulation, 
blood will be collected at baseline, Cycle 3, Day 15 and Cycle 4, Day 1, and at end 
of treatment corresponding to tumor assessments.
Biomarkers will not be collected or assessed in Arm G of the Phase II NF Cohort.
Analysis methods will include immunohistochemistry, RNA-based assessment of gene 
expression, next-generation sequencing of lymphoma DNA in tissue and in peripheral 
blood to determine the levels of the lymphoma clone.  This analysis will enable a better 
understanding of the underlying biology of these tumors and how polatuzumab vedotin 
and rituximab or obinutuzumab alter their clinical course. Other exploratory analyses 
may be conducted should additional slides remain following the planned biomarker 
analyses. 
The exploratory efficacy outcome measures for the main study are as follows:  

DOR, defined as the time from the date of the first occurrence of a documented CR 
or PR to the date of disease progression, relapse, or death from any cause, for the 
subgroup of patients with a best overall response of CR or PR, based on PET-CT or 
CT only, as determined by the investigator assessment

PFS, defined as the time from date of randomization or first treatment (for 
G-containing arms) to the first occurrence of progression or relapse, or death from 
any cause, based on PET-CT or CT only, as determined by the investigator 
assessment

EFS, defined as the time from date of randomization or first treatment (for 
G-containing arms) to any treatment failure including disease progression, relapse, 
initiation of new anti-lymphoma therapy, or death from any cause, whichever occurs 
first, based on PET-CT or CT only, as determined by the investigator assessment

OS, defined as the time from the date of randomization or first treatment (for 
G-containing arms) to the date of death from any cause
4.
MATERIALS AND METHODS
4.1
PATIENTS
Eligible patients must have R/R FL or DLBCL and meet the following inclusion and 
exclusion criteria.
4.1.1
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for study entry:

Signed Informed Consent Form (ICF)

Age 18 years

Able to comply with the study protocol, in the investigator’s judgment

Histologically confirmed FL (Grade 1, 2, or 3a) or DLBCL


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
Must have received at least one prior therapy for FL or DLBCL.  Patients must have 
either relapsed or have become refractory to a prior regimen as defined below. 
R/R FL
Relapsed to prior regimen(s) after having a documented history of response 
(CR, CR unconfirmed [CRu], or PR) of 6 months in duration from completion 
of regimen(s)
Refractory to any prior regimen, defined as no response to the prior therapy, or 
progression within 6 months of completion of the last dose of therapy
R/R DLBCL
Patients who are ineligible for second-line stem cell transplant (SCT), with 
progressive disease or no response (stable disease [SD]) 6 months from start 
of initial therapy (2L refractory)
Patients who are ineligible for second-line SCT, with disease relapse after 
initial response 6 months from start of initial therapy (2L relapsed)
Patients who are ineligible for third-line (or beyond) SCT, with progressive 
disease or no response (SD) 6 months from start of prior therapy 
(3Lrefractory)
Patients who are ineligible for third-line (or beyond) SCT with disease relapse 
after initial response 6 months from start of prior therapy (3Lrelapsed)
In addition to the above defined responses to prior regimens, the Phase II NF 
Cohort (Arm G and Arm H) will include the following diagnoses by 2016 WHO 
classification of lymphoid neoplasms:
–
DLBCL, not otherwise specified (NOS) (including both germinal center 
B-cell type and activated B-cell type)
–
T-cell/histiocyte-rich large B-cell lymphoma
–
High-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 
rearrangements
–
High grade B-cell lymphoma, NOS
–
Primary mediastinal (thymic) large B-cell lymphoma
–
Epstein-Barr virus positive DLBCL, NOS

If the patient has received prior bendamustine, response duration must have been 
1 year (for patients who have relapsed disease after a prior regimen)

At least one bi-dimensionally measurable lesion on imaging scan defined as 
1.5 cm in its longest dimension 

Confirmed availability of archival or freshly collected tumor tissue prior to study 
enrollment
The Phase II NF Cohort (Arm G and Arm H) will be required to submit tissue
and pathology report for central pathology review.

Life expectancy of at least 24 weeks


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
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2

Adequate hematologic function unless inadequate function is due to underlying 
disease, such as extensive bone marrow involvement or hypersplenism secondary 
to the involvement of the spleen by lymphoma per the investigator.  Adequate 
hematologic function is defined as follows:
–
Hemoglobin 9 g/dL
–
ANC 1.5109/L
–
Platelet count 75109/L

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 (refrain from heterosexual intercourse) or 
to use single highly effective or combined contraceptive methods that result in a
failure rate of 1% per year during the treatment period and for 12 months after the 
last dose of rituximab or for 18 months after the last dose of obinutuzumab, and 
agreement to refrain from donating eggs.
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 6 months after the last dose of study drug and 
agreement to refrain from donating sperm during this same period.
Men with a pregnant partner must agree to remain abstinent or to use a 
condom 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.


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4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of severe allergic or anaphylactic reactions to humanized or murine MAbs 
(or recombinant antibody-related fusion proteins) or known sensitivity or allergy to 
murine products

Contraindication to bendamustine, rituximab, or obinutuzumab 

History of sensitivity to mannitol (mannitol is an excipient in bendamustine)

Prior use of any MAb, radioimmunoconjugate, or ADC within 5 half-lives or 4 weeks, 
whichever is longer, before Cycle 1, Day 1

Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive 
therapy, or any investigational agent for the purposes of treating cancer within 
2 weeks prior to Cycle 1, Day 1
All acute, clinically significant treatment-related toxicity from prior therapy, except 
for alopecia, must have resolved to Grade 2 prior to Cycle 1, Day 1.
Recent treatment with rituximab is allowed given the timing of the last dose was 
greater than 2 weeks prior to Cycle 1, Day 1.
Should prior treatment fall under more than one exclusionary criterion (e.g., MAb 
and immunotherapy), the more conservative criterion must be met.

Ongoing corticosteroid use 30 mg/day prednisone or equivalent, for purposes other 
than lymphoma symptom control
Patients receiving corticosteroid treatment 30 mg/day prednisone or equivalent 
must be documented to be on a stable dose prior to study enrollment and 
initiation of therapy (Cycle 1, Day 1).
Ongoing corticosteroid usage is permitted for the purpose of lymphoma symptom 
control. For further details refer to Section 4.4.1.6.

Treatment with chimeric antigen receptor T-cell therapy within 100 days prior to 
Cycle 1, Day 1

Completion of autologous stem cell transplant within 100 days prior to Cycle 1,
Day 1

Prior allogeneic SCT

Eligibility for autologous SCT

Grade 3b follicular lymphoma

History of transformation of indolent disease to DLBCL

Primary or secondary CNS lymphoma

Current Grade 1 peripheral neuropathy


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
History of other malignancy that could affect compliance with the protocol or 
interpretation of results.  Exceptions include, but are not limited to:
Patients with a history of curatively treated basal or squamous cell carcinoma of 
the skin, in situ carcinoma of the cervix or ductal carcinoma in situ of the breast
at any time prior to the study are eligible.
A patient with any other malignancy that has been treated with surgery alone with 
curative intent and the malignancy has been in remission without treatment for 
3 years prior to enrollment is eligible.
Patients with low-grade, early-stage prostate cancer with no requirement for 
therapy at any time prior to study are eligible.

Evidence of significant, uncontrolled concomitant diseases that could affect 
compliance with the protocol or interpretation of results, including significant 
cardiovascular disease (such as New York Heart Association Class III or IV cardiac 
disease, myocardial infarction within the last 6 months, unstable arrhythmias, or 
unstable angina) or significant pulmonary disease (including obstructive pulmonary 
disease and history of bronchospasm)

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection 
(excluding fungal infections of nail beds) at study enrollment or any major episode of 
infection requiring treatment with intravenous (IV) antibiotics or hospitalization 
(relating to the completion of the course of antibiotics) within 4 weeks prior to 
Cycle 1, Day 1

Patients with suspected or latent tuberculosis
Latent tuberculosis should be confirmed according to local testing requirements.

Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive 
hepatitis B surface antigen [HBsAg] serology) 
Patients with occult or prior HBV infection (defined as negative HBsAg and 
positive hepatitis B core antibody [HBcAb]) may be included if HBV DNA is 
undetectable, provided that they are willing to undergo DNA testing on Day 1 of 
every cycle and monthly for at least 12 months after the last cycle of study 
treatment.  Patients who have protective titers of hepatitis B surface antibody 
(HBsAb) after vaccination or prior but cured hepatitis B are eligible.

Positive test results for hepatitis C virus (HCV) antibody 
Patients who are positive for HCV antibody are eligible only if PCR is negative for 
HCV RNA.

Known history of HIV seropositive status
For patients with unknown HIV status, HIV testing will be performed at Screening 
if required by local regulations

Known infection human T-cell leukemia virus 1 (HTLV-1) virus 

Vaccination with a live vaccine within 28 days prior to treatment


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
Recent major surgery (within 6 weeks before the start of Cycle 1, Day 1) other than 
for diagnosis

Women who are pregnant or lactating or who intend to become pregnant within a 
year of the last dose of study treatment in the rituximab cohorts or within 18 months 
of the last dose of study treatment in the obinutuzumab cohort

Any of the following abnormal laboratory values, unless abnormal laboratory values 
are due to underlying lymphoma per the investigator:
–
Creatinine 1.5ULN or a measured creatinine clearance 40 mL/min
–
AST or ALT 2.5ULN
–
Total bilirubin 1.5ULN
Patients with documented Gilbert disease may be enrolled if total bilirubin is 
3ULN.
–
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 

Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or renders the patient at high risk from treatment 
complications
4.1.3
Criteria for Lymph Node Biopsy Tissue

Eligible patients must have available at the study site a representative formalin-fixed, 
paraffin-embedded tumor specimen that enabled the definitive diagnosis of FL or 
DLBCL.

The specimen must contain adequate evaluable tumor cells (20% for excisional 
biopsy and 50% if sample is a core biopsy) to enable relevant biomarker analysis.

A tissue block (preferred) or 15 serial, freshly cut, unstained slides plus punch 
biopsy of the tissue block accompanied by an associated pathology report will be 
requested.  Punch biopsy is required only with the slide submission.  Cytological or 
fine-needle aspiration samples are not acceptable.  In countries that use a different 
fixative than formalin, available tissue block will be accepted and notation of the type 
of fixative should be included.
If the archival tissue is unavailable or insufficient on the basis of the above criteria, the 
patient may still be eligible if the patient is willing to provide tissue from a pretreatment 
core or excisional/incisional biopsy of the tumor. Cytological or fine-needle aspiration 
samples are not acceptable.  The sample should be shipped according to instructions 
provided in the laboratory manual.  If a tissue block is provided, after necessary sections 
are cut and core for TMA is taken, the remaining specimen will be returned to site upon 
request.  Tissue collected on study will not be returned to sites.


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Patients enrolled into Arm G of the Phase II NF Cohort will only need to submit tissue 
and pathology report for central pathology review to confirm diagnosis; no exploratory 
biomarkers studies will be conducted for this arm. Tissue requirements will be updated 
in the laboratory manual.  Refer to the laboratory manual for more details.
Exploratory biomarker studies will be conducted for patients enrolled in Arm H of the 
Phase II NF Cohort. Tumor tissue samples will be required along with the corresponding 
pathology report for central pathology review to confirm diagnosis. Tissue requirements 
will be updated in the laboratory manual.  Refer to the laboratory manual for more details.
A central pathology review of all DLBCL patients, including those in the main study, will 
be performed to confirm diagnosis.  If needed, additional slides from previously collected 
samples may be requested for DLBCL patients in the main study. Refer to the 
laboratory manual for more details.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
This is an open-label study.  Patients with either R/R FL or R/R DLBCL will be enrolled.  
Following the Phase Ib portion of this study, allocation to the bendamustine plus 
rituximab or the combination of polatuzumab vedotin with bendamustine plus rituximab 
arms will be randomized and stratified by duration of response to prior therapy 
(12 months vs. 12 months) and disease burden (high vs. low) (see Section 3.1.2.1).  
Randomization will be performed by an interactive voice or Web-based response system 
(IxRS) using stratified permuted blocks.  Patients will be assigned in an equivalent ratio 
(1:1) to one of the two treatment arms for each histology group (FL and DLBCL).
After the recommended dose of polatuzumab vedotin in combination with bendamustine 
plus obinutuzumab is determined, the patients will then be enrolled into the dose 
expansion portion (20 patients in each histology group).  
Enrollment tracking will be performed by the IxRS for all arms, including patients in the 
NF Cohort.
After written informed consent has been obtained and preliminary eligibility has been 
established, the study site will submit documentation supporting eligibility to the Sponsor 
and obtain the Sponsor’s approval to enroll the patient.  Once the Sponsor reviews and 
approves the patient for enrollment, the patient number will be assigned and the patient 
will be randomized to the treatment assignment via the IxRS.
4.3
STUDY TREATMENT
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Polatuzumab Vedotin
Polatuzumab vedotin will be supplied by the Sponsor.  The lyophilized formulation of 
polatuzumab vedotin will be used in combination with BR in the NF Cohort (Arm G and 


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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Arm H).  Patients in all the other cohorts (Arms AF) will receive the initial liquid 
formulation.  
The original formulation of polatuzumab vedotin is a single-use liquid formulation 
provided in a 100 mg/10 mL drug product.  It is not stable after dilution into 
saline-containing IV bags, thus requiring a syringe pump for delivery.  Therefore, a 
lyophilized formulation of polatuzumab vedotin has been developed, as 170 mg/vial drug 
product and 140 mg/vial drug product, to improve product stability upon dilution into 
saline-containing IV bags.  The 170 mg/vial drug product and the 140 mg/vial drug 
product yield the same product concentration and composition after reconstitution with 
the intended sterile water for injection reconstitution volumes of 8.8 mL and 7.2 mL, 
respectively.  The 140 mg/vial drug product will be used in this study.
For information on the formulation, packaging, and handling of polatuzumab vedotin, see
the pharmacy manual and the Polatuzumab Vedotin Investigator's Brochure.
4.3.1.2
Rituximab
Rituximab (MabThera®/Rituxan®) will be supplied by the Sponsor.  For information on the 
formulation, packaging, and handling of rituximab, see the pharmacy manual and 
investigator’s brochure for rituximab (MabThera/Rituxan).
4.3.1.3
Bendamustine
Bendamustine hydrochloride will be supplied by the Sponsor.  Bendamustine 
hydrochloride is marketed by Cephalon previously as the licensed product Treanda® and 
now as Bendeka® for the United States and is marketed in Germany by Mundipharma 
International Corporation Ltd under the name Levact®.  For information on the 
formulation, packaging, and handling of bendamustine hydrochloride, refer to the 
pharmacy manual.
4.3.1.4
Obinutuzumab
Obinutuzumab (Gazyva® in the United States) will be supplied by the Sponsor.  For 
information on the formulation, packaging, and handling of obinutuzumab, see the 
pharmacy manual, and investigator’s brochure for obinutuzumab (Gazyva).
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Bendamustine plus Rituximab Regimen
Patients will receive a total of six cycles bendamustine and rituximab (BR) (see Figure 5).  
A cycle is typically 28 days for FL and 21 days for DLBCL.
For the purpose of ensuring consistent PK measurements, treatment will be 
administered sequentially in the order specified below. 


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Schedule for Cycle 1
Cycle 1, Day 1

Rituximab 375 mg/m2 IV infusion
Cycle 1, Day 2 and Day 3

Bendamustine 90 mg/m2 IV infusion
Schedule for Cycles 26
Cycles 26, Day 1

Rituximab 375 mg/m2 IV infusion

Bendamustine 90 mg/m2 IV infusion
Cycles 26, Day 2

Bendamustine 90 mg/m2 IV infusion
Figure 6
Bendamustine plus Rituximab Regimen
CCycle; IVintravenous.
4.3.2.2
Polatuzumab Vedotin plus BR Regimen
Patients will receive a total of six cycles of polatuzumab vedotin in combination with BR 
(see Figure 7).  A cycle is typically 28 days for FL and 21 days for DLBCL.  Patients in 
the NF Cohort (Arm G and Arm H) will follow the same schedule and dosing 
requirements as patients in the other Phase II cohorts (Arms AF).
For the purposes of ensuring consistent PK measurements, treatments will be 
administered sequentially in the order specified below.
Schedule for Cycle 1
Cycle 1, Day 1

Rituximab 375 mg/m2 IV infusion
Cycle 1, Day 2

Polatuzumab vedotin IV infusion




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Schedule for Cycle 1
Cycle 1, Day 1

Obinutuzumab 1000 mg IV infusion
Cycle 1, Day 2

Polatuzumab vedotin 1.8 mg/kg IV infusion

Bendamustine 90 mg/m2 IV infusion
Cycle 1, Day 3

Bendamustine 90 mg/m2 IV infusion
Cycle 1, Day 8 and Day 15

Obinutuzumab 1000 mg IV infusion
Schedule for Cycles 26
As long as the observed individual patient safety profile of polatuzumab vedotin and BG 
allows all study treatment infusions to be given on the same day, then the polatuzumab 
vedotin and BG infusions will be given sequentially on the same day for Cycles 26 in 
the order specified below.
Cycles 26, Day 1

Obinutuzumab 1000 mg IV infusion

Polatuzumab vedotin 1.8 mg/kg IV infusion

Bendamustine 90 mg/m2 IV infusion
Cycles 26, Day 2

Bendamustine 90 mg/m2 IV infusion




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The following administration instructions apply to the liquid and lyophilized formulations.
The initial dose will be administered to patients who are well hydrated over
90 (10) minutes.  Premedication (e.g., 5001000 mg of oral acetaminophen or 
paracetamol and 50100 mg diphenhydramine as per institutional standard practice) 
may be administered to an individual patient before administration of polatuzumab 
vedotin.  Administration of corticosteroids is permitted at the discretion of the treating 
physician.  If IRRs are observed with the first infusion in the absence of premedication, 
premedication must be administered before subsequent doses.
The polatuzumab vedotin infusion may be slowed or interrupted for patients 
experiencing infusion-associated symptoms.  Following the initial dose, patients will be 
observed for 90 minutes for fever, chills, rigors, hypotension, nausea, or other infusion 
associated symptoms.  If prior infusions have been well tolerated, subsequent doses of 
polatuzumab vedotin may be administered over 30 (10) minutes, followed by a 
30-minute observation period after the infusion.
Any dose modification should be noted on the Polatuzumab Vedotin Administration 
electronic Case Report Form (eCRF).  Cases of accidental overdose or medication error, 
along with any associated adverse events, should be reported as described in
Section 5.3.5.12.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.
4.3.2.5
Rituximab
Rituximab 375 mg/m2 will be administered by IV infusion with bendamustine alone or in 
combination with polatuzumab vedotin and bendamustine, as outlined in Section 4.3.2.1
and Section 4.3.2.2.  Rituximab will be administered on Day 1 of Cycles 16.  No dose
modifications of rituximab are allowed.
The patient’s body surface area (BSA) calculated at screening 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, there is no BSA cap 
and actual body weight, not adjusted weight, is recommended.  Empiric dose adjustment 
for obese patients (obesity defined as body mass index 30, as measured in kilograms
divided by meters squared) may be implemented per institutional guidelines.
The rituximab administration should be completed at least 30 minutes before 
administration of other study treatments.  The infusion of rituximab may be split over 
2 days if the patient is at increased risk for an IRR (high tumor burden, high peripheral 
lymphocyte count).  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 


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dose of rituximab is split over 2 days, both infusions must occur with appropriate 
premedication and at the first infusion rate (see Table 3).
All rituximab infusions should be administered to patients after premedication with oral 
acetaminophen (e.g., 6501000 mg) and an antihistamine such as diphenhydramine 
hydrochloride (50100 mg) 3060 minutes before starting each infusion (unless 
contraindicated).  An additional glucocorticoid (e.g., 100 mg IV prednisone or 
prednisolone or equivalent) is allowed at the investigator’s discretion.  For patients who 
did not experience infusion-related symptoms with their previous infusion, premedication 
at subsequent infusions may be omitted at the investigator’s discretion.
Rituximab infusions will be administered according to the instructions in Table 3.  If a 
patient tolerates the first cycle of study treatment without significant infusion reactions, 
rituximab may be administered as rapid infusion (e.g., over 6090 minutes) 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.  For the management of IRRs 
and anaphylaxis, see Section 5.1.5.5.
Rituximab should be administered as a slow IV infusion through a dedicated line.  IV 
infusion pumps (such as the Braun Infusomat Space) should be used to control the 
infusion rate of rituximab.  Administration sets with polyvinyl chloride (PVC), 
polyurethane (PUR), or polyethylene (PE) as a product contact surface and IV bags with 
polyolefine, polypropylene (PP), PVC, or PE as a product contact surface are compatible 
and can be used.  Additional in-line filters should not be used because of potential 
adsorption.  The in-line filter used for the administration of polatuzumab vedotin should 
not be used for the administration of rituximab.
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 3
Administration of First and Subsequent Infusions of Rituximab
First Infusion (Cycle 1, Day 1)
Subsequent Infusions
Begin infusion at an initial rate of 50 mg/hr
If no infusion-related or hypersensitivity 
reaction occurs, increase the infusion rate in 
50-mg/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 
resolves, resume the infusion at a 
50% reduction in rate (i.e., 50% of rate used 
at the time the reaction occurred).
If the patient experienced an 
infusion-related or hypersensitivity reaction 
during the prior infusion, begin infusion at 
an initial rate of 50 mg/hr and follow 
instructions for first infusion.
If the patient tolerated the prior infusion well 
(defined by absence of Grade 2 reactions 
during a final infusion rate of 100 mg/hr), 
begin infusion at a rate of 100 mg/hr.
If no reaction occurs, increase the infusion 
rate in 100-mg/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 
resolves, resume the infusion at a 50% 
reduction in rate (i.e., 50% of rate used at 
the time the reaction occurred).
Any dose modification should be noted on the Rituximab Administration electronic Case 
Report Form (eCRF).  Cases of accidental overdose or medication error, along with any 
associated adverse events, should be reported as described in Section 5.3.5.12.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.
4.3.2.6
Obinutuzumab
Obinutuzumab will be administered by IV infusion as an absolute (flat) dose of 1000 mg 
in combination with polatuzumab vedotin and bendamustine, as outlined in 
Section 4.3.2.3.  Obinutuzumab will be administered on Days 1, 8, and 15 of Cycle 1 and
on Day 1 of Cycles 26 (see Table 4).  No dose modifications of obinutuzumab are 
allowed.
All obinutuzumab infusions should be administered after premedication with oral 
acetaminophen and an antihistamine (see Section 4.4.1.2).  The prophylactic use of 
corticosteroids (e.g., 100 mg of IV prednisolone or equivalent) may also be considered 
for patients thought to be at high risk for IRRs if deemed appropriate by the investigator 
and should be administered prior to the obinutuzumab infusion.  Premedication with 
prednisone/prednisolone is mandatory in patients who had an IRR and should continue 
until IRRs no longer occur during antibody infusion.  For the management of IRRs and 
anaphylaxis, see Section 5.1.5.5.


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The administration of obinutuzumab should be completed at least 30 minutes before 
administration of other study treatments.  If it is the strong preference of the investigator 
or of the site (e.g., for logistical reasons) or if the patient is at increased risk for an IRR 
(high tumor burden, high peripheral lymphocyte count), the administration of 
obinutuzumab infusion can be split over 2 days.  If the dose of obinutuzumab is split over 
2 days, patients may receive 100 mg on Day 1 and 900 mg on Day 2.
Table 4
Administration of First and Subsequent Infusions of 
Obinutuzumab
First Infusion (Cycle 1, Day 1)
Subsequent Infusions
Begin infusion at an initial rate of 50 mg/hr
If no infusion-related or hypersensitivity 
reaction occurs, increase the infusion rate in 
50-mg/hour increments every 30 minutes to a 
maximum of 400 mg/hr.
If a reaction develops, stop or slow the 
infusion.  Administer medications and 
supportive care in accordance with 
institutional guidelines.  If reaction has 
resolved, resume the infusion at a 
50% reduction in rate (i.e., 50% of rate used 
at the time the reaction occurred).

If the patient experienced an 
infusion-related or hypersensitivity 
reaction during the prior infusion, use 
full premedication including 100 mg 
prednisone/prednisolone (until no 
further infusion-related reaction 
occurs), begin infusion at an initial rate 
of 50 mg/hr, and follow instructions for 
first infusion.

If the patient tolerated the prior infusion 
well (defined by absence of Grade 2 
reactions during a final infusion rate of 
100 mg/hr), begin infusion at a rate of 
100 mg/hr.

If no reaction occurs, increase the 
infusion rate in 100-mg/hour increments 
every 30 minutes, to a maximum of 
400 mg/hr.

If a reaction develops, stop or slow the 
infusion.  Administer medications and 
supportive care in accordance with 
institutional guidelines.  If reaction has 
resolved, resume the infusion at a 
50% reduction in rate (i.e., 50% of rate 
used at the time the reaction occurred).
In all parts of the study, obinutuzumab must be administered in a clinical (inpatient or 
outpatient) setting.  Full emergency resuscitation facilities should be immediately 
available and patients should be under the close supervision of the investigator at all 
times.  For the management of IRRs and anaphylaxis, see Section 5.1.5.5.
Obinutuzumab should be administered as a slow IV infusion through a dedicated line.  IV 
infusion pumps should be used to control the infusion rate of obinutuzumab.  Do not 
administer as an IV push or bolus.  Administration sets with PVC, PUR, or PE as a 
product contact surface and IV bags with polyolefin, PP, PVC, or PE as a product 
contact surface are compatible and can be used.  Do not use an additional in-line filter 
because of potential adsorption.


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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.
For further details, refer to the label of Gazyva.
Any dose modification should be noted on the Obinutuzumab Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along 
with any associated adverse events, should be reported as described in Section 5.3.5.12.
4.3.2.7
Bendamustine
All patients will receive bendamustine administered intravenously on 2 consecutive days 
of each 21-day or 28-day cycle for up to six cycles.  The dose and schedule of 
bendamustine administered will depend on whether the patient has R/R FL or R/R 
DLBCL.
R/R Follicular NHL:

Bendamustine at 90 mg/m2 administered IV over 3060 minutes on 2 consecutive 
days (Days 2 and 3 in Cycle 1, then Days 1 and 2 in Cycles 26) of each cycle, for 
up to six cycles.  Each cycle is 28 days.
R/R DLBCL:

Bendamustine at 90 mg/m2 administered IV over 3060 minutes on 2 consecutive 
days (Days 2 and 3 in Cycle 1, then Days 1 and 2 in Cycles 26) of each cycle, for 
up to six cycles.  Each cycle is 21 days.
BSA will be calculated at screening and should be used to calculate the dose of 
bendamustine 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, there is no BSA cap and actual body weight, not 
adjusted weight, is recommended.  Empiric dose adjustment for obese patients (obesity 
defined as body mass index 30 kg/m2) may be implemented per institutional guidelines.
Administration of bendamustine should follow any rituximab and polatuzumab vedotin 
administration, if applicable. The administration rate of bendamustine may be 
implemented per institutional guidelines.
Premedication with anti-emetics may be administered as per institutional guidelines (see 
Section 4.4).  G-CSF will be required as primary prophylaxis during each cycle of 
therapy. The decision not to administer G-CSF as primary prophylaxis should be made 
in consultation with and following the approval of the Medical Monitor.


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Dose modification and dose delays will be implemented for hematologic toxicities.  
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.5.5.2.
Any dose modification should be noted on the Bendamustine Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along 
with any associated adverse events, should be reported as described in Section 5.3.5.12.
4.3.3
Investigational Medicinal Product Accountability
All investigational medical products (IMPs) required for completion of this study
(polatuzumab vedotin, rituximab, bendamustine, and obinutuzumab) will be provided by 
the Sponsor where required by local health authority regulations.  The study site will 
acknowledge receipt of IMPs to confirm the shipment condition and content.  Any 
damaged shipments will be replaced.
IMPs will be either disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Trial Access to Polatuzumab Vedotin
The Sponsor will offer post-trial access to the study drug (polatuzumab vedotin), free of 
charge, to eligible patients in accordance with the Roche Global Policy on Continued 
Access to IMP, as outlined below.
A patient will be eligible to receive study drug after the end of the study if all of the 
following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive study drug after the end of the study if any of the 
following conditions are met:

The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., covered by the patient's insurance or otherwise does 
not create a financial hardship for the patient)


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
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for FL or DLBCL

The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for FL or DLBCL

Provision of study drug is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to IMP is available at the following 
Internet site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
4.4.1
Permitted Therapy
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to screening to the study treatment completion visit, which is 30 (5) days 
after the last dose of study treatment.  All such medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF.
Patients may continue to use oral contraceptives, hormone-replacement therapy, or 
other maintenance therapies.
MMAE is a substrate of the cytochrome P450 (CYP450) enzymes, specifically CYP3A.  
Published data suggest that MMAE is neither an inhibitor nor inducer of CYP3A.  
Patients who are receiving strong CYP3A inhibitors should be closely monitored for 
adverse reactions when given polatuzumab vedotin (Han et al. 2013).
4.4.1.1
Treatment and Prophylaxis of Neutropenia
The administration of G-CSF is required as a primary prophylaxis in each cycle of 
therapy.  The dose and form of G-CSF will be at the discretion of the investigator.  The 
use of additional G-CSF is allowed for the treatment of neutropenia per investigator 
discretion. The decision not to administer G-CSF as primary prophylaxis should be 
made in consultation with and following the approval of the Medical Monitor.
4.4.1.2
Premedication before Rituximab and Obinutuzumab
All rituximab and obinutuzumab infusions should be administered to patients after 
premedication.  The following premedication is required before rituximab and 
obinutuzumab therapy:

Acetaminophen/paracetamol (6501000 mg) orally at least 3060 minutes before 
the start of all infusions

Antihistamine, such as diphenhydramine (2550 mg), approximately 3060 minutes 
before the start of each infusion (unless contraindicated)


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On Cycle 1, Day 1, it is recommended that glucocorticoids (e.g., 100 mg prednisone or 
prednisolone or equivalent) be given within 12 hours as pre-medication, but at least 
60 minutes prior to the obinutuzumab infusion.  After the first obinutuzumab infusion, 
additional glucocorticoids are allowed at the investigator’s discretion.  For patients who 
did not experience infusion related symptoms with their previous infusion, premedication 
at subsequent infusions may be omitted at the investigator’s discretion.
4.4.1.3
Premedication for Patients at High Risk for Tumor Lysis 
Syndrome
Patients with high tumor burden and considered by the investigator to be at risk for 
tumor lysis should also receive tumor lysis prophylaxis prior to the initiation of treatment.  
Patients should be well hydrated.  Starting 12 days prior to the first dose of study 
treatment, it is desirable to maintain a fluid intake of approximately 3 L/day.  In addition, 
all patients with high tumor burden and considered to be at risk for tumor lysis should be 
treated with 300 mg/day of allopurinol orally or a suitable alternative treatment (i.e., 
rasburicase), starting 4872 hours prior to Cycle 1, Day 1 of treatment and hydration.  
Patients should continue to receive repeated prophylaxis with allopurinol if deemed 
appropriate by the investigator and adequate hydration prior to each subsequent cycle of 
treatment.
4.4.1.4
Prophylaxis for Infections
Given the risk of infections associated with bendamustine and the potential added risk 
with polatuzumab vedotin, antiviral (coverage for HSV and VZV), and anti-pneumocystis 
prophylaxis are required beginning at the initiation of study treatment and continuing for 
at least 6 months after the completion of study treatment.  If clinically indicated, anti-
infective prophylaxis for other infectious agents is permitted.
4.4.1.5
Monitoring and Treatment for Hepatitis B Reactivation
Patients who are both HBsAg negative and anti-HBc positive may be included in this 
study.  These patients should have HBV DNA levels obtained monthly during the study 
and for at least 12 months after the last cycle of therapy by means of real time PCR with 
the use of an assay that has a sensitivity of at least 10 IU/mL.
If the HBV-DNA assay becomes positive and is above the World Health Organization’s 
(WHO) cutoff of 100 IU/mL, study treatment will be held and the patient should be 
treated (for at least 1 year after the last dose of rituximab or obinutuzumab) with an 
appropriate nucleoside analogue and immediately referred to a gastroenterologist or 
hepatologist for management.  Patients may resume study treatment once HBV DNA 
levels decrease to undetectable levels.
If the HBV DNA assay becomes positive and is 100 IU/mL, the patient should be 
retested within 2 weeks.  If the assay is still positive, study treatment will be held and the 
patient should be treated with an appropriate nucleoside analogue (for at least 1 year 
after the last dose of rituximab or obinutuzumab) and immediately referred to a 


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gastroenterologist or hepatologist for management.  Patients may resume study 
treatment once the HBV DNA levels decrease to undetectable levels.
If a patient’s HBV DNA level exceeds 100 IU/mL while the patient is receiving anti-viral 
medication, study treatment will be permanently discontinued (see Section 5.1.5, 
Table 7).
Patients in countries where prophylactic anti-viral medications for hepatitis B reactivation 
are the standard of care may be treated prophylactically.
4.4.1.6
Other Concomitant Medications
Necessary supportive measures for optimal medical care will be given throughout the 
study according to institutional standards, including the use of growth factors (e.g., 
erythropoietin), if clinically indicated.
Anti-emetic therapy may be instituted for any patient if clinically indicated.  
Bendamustine has a moderate risk of emesis (Cheson et al. 2010).  It is recommended 
that bendamustine infusions be administered following premedication with a serotonin 
(e.g., 5-HT3) antagonist (i.e., dolasteron, ondansetron, etc.) or according to institutional 
practice.
Systemic steroid therapy will not be allowed either during or within 7 days before the first 
dose of study treatment with the exception of the following:

Inhaled corticosteroids for the treatment of asthma or chronic obstructive pulmonary 
disease (COPD)

Premedication before rituximab, obinutuzumab, polatuzumab vedotin or 
bendamustine (see Section 4.4.1.2)

Topical steroids

Stable replacement corticosteroid therapy for an inherited or acquired deficiency

Ongoing corticosteroid use for lymphoma symptom control 

Corticosteroid treatment 30 mg/day of prednisone or equivalent on a stable dose 
prior to study enrollment and initiation of therapy (see Section 4.1.2)
4.4.2
Prohibited Therapy
Treatment with other concomitant anti-tumor agents not defined in this protocol as study 
treatment, radiotherapy, or other concurrent investigational agents of any type will result 
in withdrawal of patients from study treatment.
Use of the following therapies is prohibited during the study:

Cytotoxic chemotherapy, other than bendamustine and intrathecal chemotherapy for 
CNS prophylaxis

Immunotherapy or immunosuppressive therapy, other than study treatments

Radioimmunotherapy


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
Hormone therapy, other than contraceptives, stable hormone-replacement therapy, 
or megestrol acetate

Biologic agents other than hematopoietic growth factors, which are allowed if 
clinically indicated and used in accordance with instructions provided in the package 
inserts

Any therapy (other than intrathecal CNS prophylaxis) intended for the treatment of 
lymphoma whether it is approved by the European Medicines Agency (EMA) or the 
U.S. Food and Drug Administration (FDA) or is experimental

Radiotherapy
4.4.2.1
Immunizations
Patients who participate in this study may not receive either primary or booster 
vaccinations with live virus vaccines for at least 28 days before initiation of rituximab or 
obinutuzumab, at any time during study treatment, or until B-cell recovery.  Investigators 
should review the vaccination status of potential study patients being considered for this 
study and follow the U.S. Centers for Disease Control and Prevention guidelines for 
adult vaccination with non-live vaccines intended to prevent infectious diseases before 
study therapy.
Patients who require the use of any of these agents will be discontinued from study 
treatment.
4.5
STUDY ASSESSMENTS
Unless otherwise stated, the baseline measurement for any given assessment will be 
defined as the last value obtained before the first dose of study drug.  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.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations. ICFs 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 randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies, reason for transplant ineligibility, 2016 WHO
classification, current Ann Arbor stage, and procedures), ECOG performance status,


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reproductive status, smoking history, alcohol and drugs abuse, and all medications (e.g., 
prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 7 days prior to the screening visit.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Prognostic Indices
FLIPI and FLIPI2 clinical factors obtained at diagnosis and at enrollment will be collected 
for patients with FL.  IPI clinical factors at diagnosis and at enrollment will be collected 
for patients with DLBCL.  See Appendix 10 for description of the FLIPI, FLIPI2, and IPI.
4.5.4
Physical Examinations
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, 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, physical examinations should include evaluation of the 
presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly 
(clinical response assessment).  These will be recorded on the appropriate Tumor 
Assessment eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Targeted physical examinations should be limited to 
systems of primary relevance (i.e., cardiovascular, respiratory, those associated with 
symptoms, and those associated with tumor assessment [lymph nodes, liver, and 
spleen]).  Changes from baseline abnormalities should be recorded in patient notes.  
New or worsened clinically significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF.
4.5.5
Total Neuropathy Score Clinical Assessment
All patients participating in the study should undergo a Clinical Total Neuropathy 
Assessment (Cavaletti et al. 2006; Cavaletti et al. 2007) as shown in the schedule of 
assessments (see Appendix 1).  The neuropathy assessments include subjective 
sensory symptoms, motor symptoms, and autonomic symptoms and objective pinprick 
sensitivity, vibration sensitivity, strength testing, and deep tendon reflex testing to 
determine the total neuropathy score (see Appendix 7). 
Patients enrolled in the NF Cohort (Arm G and Arm H), receiving polatuzumab vedotin 
(lyophilized) in combination with BR, will be exempt from the Clinical Total Neuropathy 
Assessment.  Investigators will assess neuropathy per usual clinical practices and 
document neuropathy as an adverse event.


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4.5.6
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, pulse oximetry, and 
systolic and diastolic blood pressures while the patient is in a seated position, and 
temperature.  Weight, height, and BSA will also be recorded.  Height and BSA are 
required at screening only, unless there has been 10% change in body weight since the 
last BSA assessment, in which case BSA should be recalculated and documented in the 
eCRF.
During 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 30 (10) minutes following completion of dosing in subsequent cycles.
During rituximab administration visits, vital signs are to be measured prior to the start of 
the infusion of rituximab as well as at the end of the rituximab infusion. Additional vital 
sign measurements that are obtained as per the institution’s standard of care are to be 
recorded on the eCRF.
During the administration of obinutuzumab in Cycle 1, vital signs are to be obtained 
before infusion of obinutuzumab, then after the start of the infusion, approximately every 
15 (5) minutes for 90 minutes, then every 30 (10) minutes until 1 hour after the end of 
the infusion.  During administration of obinutuzumab in subsequent cycles, vital signs 
are to be recorded before infusion of obinutuzumab, then after the start of infusion, and 
approximately every 30 (10) minutes until 1 hour after the end of infusion.
4.5.7
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 IRC and the 
investigator on the basis of physical examinations, CT scans, PET-CT scans, and bone 
marrow examinations using the Modified Lugano Response Criteria (Cheson et al. 2014).
Radiographic Assessments
PET-CT scans should include skull-base to mid-thigh.  Full-body PET-CT scan should 
be performed when clinically appropriate.
CT scans with oral and IV contrast should include chest, abdomen, and pelvic scans; CT 
scans of the neck should be included if clinically indicated.  CT scans for response 
assessment may be limited to areas of prior involvement only if required by local 
regulatory authorities.  At the investigator’s discretion, CT scans may be repeated at any 
time if progressive disease is suspected.
In patients for whom contrast is contraindicated (e.g., patients with contrast allergy or 
impaired renal clearance), CT or combined PET-CT scans without contrast are permitted 
so long as they permit consistent and precise measurement of target lesions during the 


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study treatment period.  Details regarding imaging procedures in these cases will be 
provided in the Imaging Manual.
PET scans, in conjunction with diagnostic-quality CT scans, will be obtained in this study.  
PET and diagnostic-quality CT scans are required at screening, after Cycle 3 of study 
treatment (i.e., between Cycle 3, Day 15, and Cycle 4, Day 1), and at the primary 
response assessment visit.  CT scans without PET scans will be obtained every 
6 months until approximately 2 years after the treatment completion visit.  The Modified
Lugano Response Criteria (see Appendix 4) will be used to assess overall response to 
study treatment.
The same radiographic assessment modality should be used for all response 
evaluations to ensure consistency across different timepoints.
A full tumor assessment including radiographic assessment must be performed any time 
disease progression or relapse is suspected.
Bone Marrow Assessments
Bone marrow examinations are required at screening for staging purposes in all patients.  
In addition, the definition of CR requires clearing of previously infiltrated bone marrow.  
Bone marrow examinations should include a biopsy for morphology and an aspirate for 
local hematology (optional if standard of care at the site).
Repeat bone marrow examinations are required in two circumstances. 
If there was bone marrow infiltration at screening, then a subsequent bone marrow 
biopsy (trephine) at the primary response assessment visit is required for clinical 
response evaluation for all patients who may have achieved a CR.  In patients with a PR 
and continued bone marrow involvement, a subsequent bone marrow examination may 
be required to confirm a CR at a later timepoint.
An optional biopsy should be done at the time of relapse or transformation if bone 
marrow involvement is suspected.  A tissue sample should be collected at that time.  A 
formalin-fixed, paraffin-embedded tissue block over 1520 unstained sections on coated 
slides is preferred.
Any additional (unscheduled) bone marrow examinations performed during the study will 
be at the discretion of the investigator.
4.5.8
Laboratory, Biomarker, and Other Biological Samples
Local Laboratory Assessments
Samples for hematology, serum chemistry, pregnancy, hepatitis B and C serology, and 
quantitative immunoglobulin assessments will be analyzed at the study site’s local 
laboratory.  In the event the study site’s local laboratory cannot adhere to protocol 
requirements for hepatitis B serology tests, the option to submit samples for analysis to 


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the central laboratory is available.  Laboratory samples may be obtained up to 72 hours 
before start of study treatment administration on Day 1 of the treatment cycle.
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology (hemoglobin, hematocrit, RBC count, WBC count, platelet count, and 
percent or absolute differential [neutrophils, bands, lymphocytes, eosinophils, 
basophils, and monocytes])

Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, BUN/urea, 
creatinine, calcium, magnesium, phosphorus, total bilirubin, direct bilirubin, total 
protein, albumin, ALT, AST, alkaline phosphatase, LDH, uric acid/urate, hemoglobin 
A1c (HbA1c), amylase, and lipase.  At screening, all samples for laboratory test will be 
obtained in a fasting state for all patients according to local guidelines.  Subsequent 
laboratory tests can be non-fasting.  HbA1c will be measured only at screening and 
at Cycle 4, Day 1 and can be obtained in a non-fasting state.  Only at screening, 
obtain -2 microglobulin.

Coagulation:  INR or PT, and PTT or aPTT

Viral serology:
–
Hepatitis B surface antibody (HBsAb), HBsAg, and total HBcAb
–
HBV-DNA by PCR if the patient is HBcAb positive 
–
HCV antibody 
–
HCV RNA by PCR if the patient is HCV antibody positive

Quantitative immunogloblulins:  IgG, IgA, and IgM

Pregnancy test
All women of childbearing potential will have a serum pregnancy test within 
7 days before Cycle 1, Day 1 of study treatment.  In addition, for women of 
childbearing potential, a serum or urine pregnancy test must be performed prior 
to study treatment on Day 1 of each subsequent cycle of study treatment 
(laboratory samples may be obtained up to 72 hours before start of study 
treatment administration on Day 1 of the treatment cycle).  If any urine pregnancy 
test is positive, study treatment will be delayed until the patient pregnancy status 
is confirmed by a serum pregnancy test.  If serum pregnancy test is positive, the 
patient will be permanently discontinued from study treatment.

Bone marrow biopsy and aspirate
Bone marrow biopsy and aspirate are required at screening in all patients and at 
the primary response assessment for all patients who have achieved a 
radiographic CR in whom bone marrow involvement was diagnosed by 
morphology at screening.  Bone marrow biopsy is optional, but strongly 
recommended, for responders without documented bone marrow involvement at 
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Central Laboratory Assessments
Blood and tumor tissue samples for biomarker, ADA, and PK analyses and for the 
Roche Clinical Repository (RCR) will be sent to one or several Roche-designated central 
laboratories or to the Sponsor for analysis.  Instruction manuals and supply kits will be 
provided for all central laboratory assessments.

Lymphocyte subsets
Whole blood samples will be collected and analyzed by flow cytometry for B cells 
(CD19 positive), T-cell counts (positive for CD3, CD4, and CD8), and NK-cell 
counts (CD16 and CD56) at baseline, primary response assessment visit, and
every 6 months (counting from the treatment completion visit) until end of study 
or patient discontinuation.

PK assessments (see Appendix 2) 
–
Immunogenicity assessment (see Appendix 2)
–
Plasma and serum samples for anti-polatuzumab vedotin antibody
–
Plasma and serum samples for anti-obinutuzumab antibody
Serum samples collected for PK and ADA analysis which may be used for 
additional method development, including but not limited to, assay validation 
and characterization, will be destroyed no later than 5 years after the final 
Clinical Study Report has been completed.
When a patient withdraws from the study, samples collected prior to the date 
of withdrawal may still be analyzed, unless the patient specifically requests 
that the samples be destroyed or local laws require destruction of the samples.

Central pathology review for confirmation of diagnosis
Central review of pathology reports and tissue samples will be performed to 
confirm diagnosis for all DLBCL patients in the study.  For DLBCL patients that 
are in the main study, additional slides may be requested. Refer to the 
laboratory manual for more details.

Required samples for exploratory biomarker research are as follows:
Tumor tissue sample is required at baseline (archival tissue or fresh 
pre-treatment biopsy is acceptable).  Biopsy at the time of 
progression/transformation is optional.  Tumor blocks are preferred.  If a tumor 
block is not available, a minimum of 15 serial freshly cut, unstained slides and a 
punch biopsy of the tumor block are required.  Tumor block or punch biopsy is 
required for construction of a tissue microarray.  The remainders of the tissue 
blocks will be returned to local pathology according to country-specific 
procedures.
A peripheral blood sample for MRD analysis is required for all patients at 
screening, between Cycle 3, Day 15, and Cycle 4, Day 1, and at the Primary 
Response Assessment Visit.
A whole blood and plasma sample will be collected for the analysis of prognostic 
factors. 


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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Patients enrolled in the NF Cohort (Arm G), receiving polatuzumab vedotin 
(lyophilized) plus BR, will be exempt from exploratory biomarker research 
samples.
Optional Exploratory Biomarkers for Roche Clinical Repository (see Section 4.5.11)

Patients may give consent to the acquisition blood samples by signing the Optional 
Research ICF.  Optional samples for exploratory biomarker research are as follows:
Residual tumor tissue specimens from biopsy samples at baseline and at 
progression. 
Leftover blood samples from MRD analysis and exploratory whole blood and 
plasma samples
If patients consent to participate in the optional exploratory biomarker research, 
residual blood, plasma, tissue samples, and their derivatives (e.g., including but 
not limited to RNA, DNA, tissue microarrays, unstained sections, etc.) will be 
stored in the RCR for up to 15 years after the date of final closure of the 
associated clinical database to enable future research.
4.5.9
Electrocardiograms
A resting 12-lead ECG is required at screening, on Cycle 3, Day 1, at the treatment 
completion visit, and as clinically indicated.  ECGs for each patient should be obtained 
with the use of the same machine when possible.  Interpretation of the ECG should be 
performed by a qualified investigator or sub-investigator. 
4.5.10
Patient-Reported Outcomes
The TINAS is an 11-item questionnaire focused on symptoms of neuropathy related to 
treatment that is scored on a 0 to 10 scale, with 0 being the symptom is not present to 
10 being the symptom is as bad as the patient can imagine.  The questionnaire will be 
analyzed for the individual neuropathy symptoms experienced by a patient as well as the 
calculation of an overall neuropathy severity score.  Additionally, a single item asking 
patients to rate when numbness and tingling was at the worst will be used to predict the 
onset of peripheral neuropathy.  The measure takes less than 5 minutes to complete.
The TINAS will be completed weekly over the course of study treatment, either while on 
site or at home.  Additionally, to collect information about the reversibility of peripheral 
neuropathy following treatment completion, the TINAS will be completed once a week for 
the first 2 months following treatment, then once a month for the next 10 months.
The TINAS, translated as required into the local language, will be completed by the 
patient on his or her own electronic devices (i.e., mobile phone, tablet, or home 
computer) or on a device provided to the patient for the purpose of this study to allow for 
the secure access and transmission of the questionnaire.  The eDiary software and 


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instructions for completing the TINAS electronically will be provided by the Investigator 
Staff. All measures are to be completed in their entirety by the patient.  The data will be 
transmitted automatically via Web or wireless to a centralized database at the ePRO 
vendor.  To ensure instrument validity and that data standards meet health authority 
requirements, the TINAS should be completed prior to the completion of other study 
assessments and the administration of study treatment.
Patients enrolled in the NF Cohort (Arm G and Arm H), receiving polatuzumab vedotin 
(lyophilized) plus BR, will be exempt from completing the TINAS.
4.5.11
Samples for Roche Clinical Repository
4.5.11.1
Overview of the Roche Clinical Repository
The RCR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients in the future.
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives:

Study the association of biomarkers with efficacy, adverse events, or disease 
progression

Increase knowledge and understanding of disease biology

Study drug response, including drug effects and the processes of drug absorption 
and disposition

Develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.11.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the ICF 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 4.5.11) will not be applicable at that site.
4.5.11.3
Sample Collection
The following samples will be collected at specific timepoints (see Table 5) for research 
purposes, including but not limited to research on dynamic (non-inherited) biomarkers:
Residual tumor samples from collection site lymph node biopsy may be submitted at the 


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screening visit or at disease progression for DNA, RNA, or protein extraction.

Whole blood and plasma samples for DNA, RNA, or protein extraction will be drawn 
at the baseline visit and at the end of treatment.

Residual samples of peripheral blood from MRD analysis.
Table 5
Sample Collection
Sample
Timepoint
Residual whole blood and plasma and 
their derivatives (e.g., DNA, RNA, 
protein, etc.)
Baseline
Primary Response Assessment
Residual tissue (i.e., unstained sections, 
progression tissue blocks, tissue 
microarrays), and tissue derivatives 
(e.g., tumor RNA and DNA)
Baseline
Progression/transformation
Residual plasma and DNA extracted 
from samples of peripheral blood 
(remaining DNA after analysis of 
[minimal residual disease])
Baseline between Cycle 3, Day 15 and Cycle 4,
Day 1 
Primary Response Assessment (peripheral 
blood)
Dates of consent should be recorded on the associated RCR page of the eCRF.  See 
the laboratory manual for sampling procedures, storage conditions, and shipment 
instructions.
Roche Clinical Repository 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 ICF and applicable laws (e.g., health authority 
requirements).
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.
4.5.11.4
Confidentiality
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is double-coded by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A linking key between the 
patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 


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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 the Legal Department at Roche, as applicable.
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the ICF (or separate authorization for use 
and disclosure of personal health information) signed by the patient, unless permitted or 
required by law.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise.
4.5.11.5
Consent to Participate in the Roche Clinical Repository
The ICF 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.
A separate, specific signature is not required for the mandatory RCR blood samples 
collected at baseline.
4.5.11.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining 
samples will be destroyed or will no longer be linked to the patient.  However, if RCR 
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remain as part of the overall research data.  If a patient wishes to withdraw consent to 
the testing of his or her RCR samples during the study, the investigator must inform the 
Medical Monitor in writing of the patient's wishes through use of the appropriate RCR 
Subject Withdrawal Form and must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent 
to the testing of his or her RCR samples after closure of the site, the investigator must 
inform the Sponsor by emailing the study number and patient number to the following 
email address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from Study GO29365 does not, by itself, constitute withdrawal of 
content for testing of RCR samples.  Likewise, a patient's withdrawal of consent for 
testing of RCR samples does not constitute withdrawal from Study GO29365.
4.5.11.7
Monitoring and Oversight
Roche Clinical Repository 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 ICF.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples.
4.5.12
Timing of Study Assessments
4.5.12.1
Screening and Pretreatment Assessments
A signed ICF for participation in the study must be obtained before performing any 
study-specific screening tests or evaluations.
Screening and pretreatment tests and evaluations will be performed within 28 days 
before first dose, unless otherwise specified.  Results of standard-of-care tests or 
examinations performed before obtaining informed consent and within 28 days before 
first dose may be used; such tests do not need to be repeated for screening.  All 
screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before randomization.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
See Appendix 1 for the schedule of screening and pretreatment assessments.
4.5.12.2
Assessments during Treatment
All assessments must be performed on the day of the specified visit unless a time 
window is specified in the schedule of assessments (see Appendix 1).  Assessments 


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scheduled on the day of study treatment administration should be performed before 
administration of study treatment, unless otherwise noted in the schedule of 
assessments.
See Appendix 1 for the schedule of assessments performed during the treatment period.
4.5.12.3
Follow-Up Assessments
Month 0 in follow-up is considered to be the treatment completion visit.
Treatment Completion Visit
Patients who complete the study treatment period (defined as completion of six cycles of 
study treatment) or discontinue from the study treatment early (e.g., if they terminated 
treatment early because of an adverse event) will be asked to return to the clinic within 
30 days (5 days) after the last dose of study treatment for a treatment completion visit.  
The visit at which response assessment shows progressive disease may be used as the 
treatment completion visit.
See Appendix 1 for the schedule of assessments performed at the treatment completion 
visit.
Primary Response Assessment Visit
All patients will be asked to return to the clinic for the primary response assessment visit.  
This visit is to take place between 6 and 8 weeks after the last dose of study treatment.  
For patients with disease progression occurring prior to the anticipated date of the 
Primary Response Assessment visit, the visit date with the response assessment 
showing PD may be used in replacement of the Primary Response Assessment Visit.
See Appendix 1 for the schedule of assessments performed at the primary response 
assessment visit.
Every 3Month Visit or Every 6-Month Visit until End of Study
For patients without disease progression, assessments will be performed every 
3 months 14 days after the treatment completion visit, until Month 24 and then every 
6 months (14 days) thereafter until the end of study (i.e., the last patient in completes
follow-up of 2 years), patient withdraws consent or Sponsor closes the study.  Other 
assessments are indicated in Appendix 1.
Disease Progression and No New Treatment
If response assessment shows PD during the follow-up period, subsequent visits will 
have assessments limited to recording of any new anti-lymphoma therapy, the 
occurrence of adverse events (per Section 5.3 and Section 5.4), and survival.  Diagnosis 
of disease progression based on clinical examination must be confirmed by CT scan as 
soon as possible (maximum, within 4 weeks) and prior to any new anti-lymphoma 


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therapy.  If no new treatment is started, the subject will be followed per the usual 
follow-up schedule described above.
Disease Progression and New Treatment
After a patient has PD during follow-up and starts a new anti-lymphoma therapy, contact 
will be made with patients by telephone on at least an annual basis for survival.
No Disease Progression and New Treatment
Patients who discontinue study treatment early because of adverse event and start a 
new anti-lymphoma therapy in the absence of PD should be followed according to the 
protocol schedule, including the response assessments and the reporting of adverse 
events until 90 days after the last dose of study drug (see Section 5.3 and Section 5.4) 
unless they withdraw consent.  
See the schedule of assessments provided in Appendix 1 for specified follow-up 
assessments.
4.5.12.4
Assessments at Unplanned Visits
See Appendix 1 for assessments that are required in the event of an unplanned visit.
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 (i.e., consistent failure to show up for scheduled visits, 
consistent missed treatment, etc.)
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced.
4.6.2
Study Treatment Discontinuation
A patient must discontinue study treatment permanently if any of the following occurs:

Grade 4 IRR:  The patient should be withdrawn from study treatment immediately 
and rituximab or obinutuzumab and bendamustine treatment should be permanently 
discontinued.


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
Recurrence of Grade 3 IRR at re-challenge:  Treatment should be permanently 
discontinued.

Patients with infusion-related Grade 3 wheezing, hypoxia, or generalized urticaria
must be permanently discontinued from study drug on the first occurrence. 

Grade 3 toxicity that does not resolve to Grade 2 or baseline value within 
3 weeks after last dose and that has a reasonable possibility of being related to the 
administration of polatuzumab vedotin, rituximab, or obinutuzumab, and/or 
bendamustine

Recurrent Grade 4 neutropenia with infection, despite G-CSF support

Grade 4 neurotoxicity including peripheral neuropathy (polatuzumab vedotin only)

Grade 3 neurotoxicity that leads to a treatment delay of 14 days or more and does 
not improve to Grade 2 within 14 days

Disease progression

Any dose delay of 4 weeks

Pregnancy
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
In the event that a patient discontinues from study treatment early for reasons other than 
documented disease progression/relapse, that patient will proceed into the follow-up 
period until progression.
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

Inaccurate or incomplete data recording

Non-compliance with the International Conference for Harmonisation (ICH) guideline 
for GCP


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
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Polatuzumab vedotin is approved by the U.S. Food and Drug Administration (FDA),
European Medicines Agency (EMA), and other health authority regulatory agencies for 
use in patients with transplant-ineligible R/R DLBCL.  The safety plan for this study is 
designed to ensure patient safety and will include specific eligibility criteria and 
monitoring assessments as detailed below.
Safety will be evaluated through the monitoring of the following:

Serious adverse events that are attributed to protocol-mandated interventions from 
the time of signing informed consent until the first dose of study treatment on 
Cycle 1, Day 1

All adverse events, including serious adverse events, from Cycle 1, Day 1, 
regardless of relationship to study drug, will be reported until 90 days after the last 
dose of study drug.  After this period, the Sponsor should be notified of any 
post-study serious adverse events or non-serious adverse events of special 
interest, regardless of attribution (see Section 5.3.1 for reporting details).  

Measurements of protocol-specified hematology and clinical chemistry laboratory 
values

Measurements of protocol-specified vital signs

Assessment of ECGs and physical findings on clinical physical examinations
5.1.1
Risks Associated with Polatuzumab Vedotin
The clinical safety profile of polatuzumab vedotin is based on clinical data obtained in 
ongoing and completed studies.  This profile is summarized in Section 1.2.1.  On the 
basis of clinical data to date, the known and suspected risks are described below.  
Polatuzumab vedotin (170 mg/vial lyophilized) is currently in use in other clinical trials 
with an observed safety profile that is consistent with the known safety profile.  
Guidelines around the management of these risks through dose and schedule
modifications are described in Section 5.1.5.  Refer also to the current Investigator’s 
Brochure for complete and updated details.
5.1.1.1
Known Risks
On the basis of clinical experience with polatuzumab vedotin in patients treated in the 
current Phase I and Phase II studies, the following are identified risks of polatuzumab 
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Myelosuppression: Consolidation of Neutropenia (including Febrile 
Neutropenia), Thrombocytopenia, and Anemia
Neutropenia, neutropenia-associated events, thrombocytopenia, and anemia, including 
serious and severe cases, have been reported in patients receiving polatuzumab vedotin.  
Adequate hematologic function should be confirmed before initiation of study treatment.  
Patients receiving study treatment will be regularly monitored for evidence of marrow 
toxicity with complete blood counts.  Study treatment for hematologic toxicities may be 
delayed or modified as described in Section 5.1.5.  The use of G-CSF for neutropenia is 
described in Section 4.4.1.1. G-CSF primary prophylaxis is required for neutropenia.  
The decision not to administer G-CSF as primary prophylaxis should be made in 
consultation with and following the approval of the Medical Monitor. Transfusion 
support for anemia and thrombocytopenia is permitted at the discretion of the 
investigator.
Peripheral Neuropathy
Patients receiving polatuzumab vedotin may develop peripheral neuropathy, including 
peripheral sensory and/or motor neuropathy.  These events have generally been 
reversible to varying degrees as much as available, but it is not known if full reversibility 
can be expected or predicted.  Patients in clinical trials with polatuzumab vedotin should 
be monitored for symptoms of neuropathy, including hypoesthesia, hyperesthesia, 
paresthesia, dysesthesia, discomfort, a burning sensation, weakness, gait disturbance, 
loss of balance, orthostatic hypotension, syncope, 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.  Monitoring will include the use of the Total Neuropathy Score (TNS) except in 
the NF Cohort, which will be monitored by the standard clinical evaluation per 
investigator’s discretion.
Study treatment dose and schedule modifications for peripheral neuropathy are 
described in Section 5.1.5.
Infections
Patients receiving polatuzumab vedotin may be at a higher risk of developing infections.  
Serious infections, including opportunistic infections, such as pneumonia (including 
pneumocystis jirovecii and other fungal pneumonia), bacteremia, sepsis, herpes 
infection, and cytomegalovirus infection have been reported in patients treated with 
polatuzumab vedotin.  Several other risk factors in the patient population under study 
influencing patients’ vulnerability to a higher risk of infections, particularly serious 
and opportunistic infection, include predisposition of the indication disease to 
infections, elderly population, and comorbidity. The use of anti-infective prophylaxis is 
required for patients on study and is described in Section 4.4.1.4.
Given the risk of infections associated with bendamustine and the potential added risk 
with polatuzumab vedotin, antiviral (coverage for HSV and VZV), and 


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anti-pneumocystis prophylaxis are required beginning at the initiation of study 
treatment and continuing for at least 6 months after the completion of study treatment.  
If clinically indicated, antiinfective prophylaxis for other infectious agents is 
permitted.
Infusion-Related Reactions
IRRs have been reported in patients receiving polatuzumab vedotin. Commonly 
experienced events included nausea, vomiting, chills, fever, pruritus, hypotension, 
flushing, and other symptoms.  In the majority of the patients, the events were 
Grade 12.
Premedication and monitoring procedures for polatuzumab vedotin infusion 
administration are outlined in Section 4.3.2.4.  
Gastrointestinal Toxicity (Diarrhea, Nausea, Vomiting, Constipation, and
Anorexia)
Diarrhea, nausea, vomiting, constipation, and abdominal pain are reported frequently, 
with diarrhea and nausea being the most common (20%) treatment-emergent adverse 
events in Phase I and II clinical studies with polatuzumab vedotin.  Diarrhea has been 
responsible for study drug modification and discontinuation.  Most cases were low 
grade, with more serious cases being confounded by polypharmacy, comorbidities, or 
disease under study.
5.1.1.2
Potential Risks
Below are potential risks of polatuzumab vedotin. See the Investigator’s Brochure for 
polatuzumab vedotin for full information.
5.1.1.2.1
Effects on the Relative-Dose Intensity of BR or BG
Depending upon the toxicity profile observed with the addition of polatuzumab vedotin to 
BR or BG, there may be a reduction in the relative-dose intensity of BR or BG that is 
administered.
5.1.1.2.2
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) is a risk 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 taken.  Patients who are considered 
to have a high tumor burden (e.g., lymphocyte count 25109/L or bulky 
lymphadenopathy) and who are considered to be at risk for 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 at Cycle 1, Day 1.  These patients should continue to receive repeated 
prophylaxis with allopurinol and adequate hydration before each subsequent infusion, as 
deemed appropriate by the investigator.


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5.1.1.2.3
Immunogenicity (Anti-Drug Antibodies)
As with any recombinant antibody, polatuzumab vedotin may elicit an immune response 
and patients may develop antibodies against polatuzumab vedotin.  Patients will be 
closely monitored for any potential immune response to polatuzumab vedotin.  
Appropriate screening, confirmatory, and characterization assays will be employed to 
assess ADAs before, during, and after the treatment with polatuzumab vedotin.  Given 
the historically low immunogenicity rate of rituximab in patients with NHL, ADAs against 
rituximab will not be monitored in this study.
5.1.1.2.4
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. 
5.1.1.2.5
Hyperglycemia
Hyperglycemia has been observed in patients treated with polatuzumab vedotin and 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 
standard-of-care anti-hyperglycemic medications.
5.1.1.2.6
Hepatotoxicity
Hepatotoxicity has been observed in patients treated with polatuzumab vedotin in both 
the Phase I and Phase II trials.  Although the relationship between hepatotoxicity and 
polatuzumab vedotin has not been definitively determined, transient, dose-related 
increases in hepatic enzymes were noted in nonclinical rat studies.  No hepatotoxicity 
was noted following administration of the surrogate ADC in cynomolgus monkeys. 
Transient elevations of transaminases have been reported in patients receiving 
polatuzumab vedotin and have ranged in intensity from Grade 1 to Grade 2.  These have 
been reversible with and without dose modification.  Two patients treated with 
polatuzumab vedotin have experienced serious adverse events, including fatty infiltration 
of the liver (steatosis) in one patient and hepatic cytolysis in the other.  Both were 
deemed “related” to polatuzumab vedotin and both patients fully recovered following 
discontinuation of the polatuzumab vedotin.  The relationship between polatuzumab 
vedotin and these two events is not known.
5.1.1.2.7
Carcinogenicity
Polatuzumab vedotin may have carcinogenic potential given the mechanism of action of 
MMAE, the cytotoxic component of polatuzumab vedotin.  Myelodysplastic syndrome 
and other second malignancies have been reported in Phase I and II clinical studies with 
polatuzumab vedotin.  The majority of these patients had received multiple prior lines 
of anti-cancer therapy, and this was considered as a significant contributory factor.


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5.1.2
Risks Associated with Rituximab Therapy
Please see the current Rituximab Investigator’s Brochure for full information.
5.1.2.1
Infusion-Related Reactions
Patients treated with rituximab are at risk for IRRs.  Fatal infusion reactions within 
24 hours of rituximab infusion can occur; approximately 80% of fatal reactions occurred 
with the first infusion.  Severe reactions to rituximab typically occurred during the first 
infusion with time to onset of 30120 minutes.  Rituximab-induced infusion reactions and 
sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, 
pulmonary infiltrates, adult respiratory distress syndrome, myocardial infarction, 
ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death.
5.1.2.2
Tumor Lysis Syndrome
Patients treated with rituximab may be at risk for TLS.  With rituximab treatment, acute 
renal failure, hyperkalemia, hypocalcaemia, hyperuricemia, or hyperphosphatemia from 
tumor lysis, some fatal, can occur within 1224 hours after the first infusion of rituximab 
in patients with NHL.  A high number of circulating malignant cells (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 treated as clinically indicated.
5.1.2.3
Hepatitis B Reactivation
HBV reactivation with subsequent fulminant hepatitis, hepatic failure, and death can 
occur in patients with hematologic malignancies treated with rituximab.  The median time 
to diagnosis of hepatitis was approximately 4 months after the initiation of rituximab 
treatment and approximately 1 month after the last dose. 
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 et al. 2009).  In a review of 57 patients who developed 
PML after rituximab administration, all patients had received prior therapies with 
alkylating agents, corticosteroids, purine analogs, or drugs to prevent allogeneic stem 
cell or solid-organ graft rejection.  The diagnosis of PML in any patient treated with 
rituximab is rare, but should be suspected in any patient who develops new-onset 
neurologic manifestations.  The majority of patients with hematologic malignancies 
diagnosed with PML received rituximab in combination with chemotherapy or as part of a 


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hematopoietic SCT.  Most cases of PML were diagnosed within 12 months of the 
patient’s last infusion of rituximab.
5.1.2.5
Cardiac Toxicity
Angina and cardiac arrhythmias have occurred with rituximab treatment and can be 
life-threatening.  Infusions should be discontinued in the event of serious or 
life-threatening cardiac arrhythmias.  Patients who develop clinically significant 
arrhythmias should undergo cardiac monitoring during and with subsequent infusions of 
rituximab.  Patients with preexisting cardiac conditions, including angina and arrhythmias, 
and who have had recurrences of these events during rituximab therapy should be 
monitored throughout the infusion and in the post-infusion period.
5.1.2.6
Infection
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.  New 
or reactivated viral infections include cytomegalovirus, herpes simplex virus, parvovirus 
B19, Varicella zoster virus, West Nile virus, and hepatitis B and C viruses.
5.1.2.7
Severe Mucocutaneous Reactions
Severe reactions, including fatal mucocutaneous reactions, can occur in patients 
receiving rituximab.  These reactions include paraneoplastic pemphigus, 
Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic 
epidermal necrolysis (TEN).  The onset of these reactions in patients treated with 
rituximab has varied from 1 to 13 weeks following rituximab exposure.
5.1.2.8
Bowel Obstruction and Perforation
Abdominal pain, bowel obstruction, and perforation, in some cases leading to death, can 
occur in patients receiving rituximab in combination with chemotherapy.  In 
postmarketing reports of rituximab, the mean time to documented gastrointestinal 
perforation was 6 days (range 177 days) in patients with NHL.
5.1.3
Risks Associated with Bendamustine
Please see the United Kingdom Summary of Product Characteristics for Bendamustine 
for full information.
5.1.3.1
Myelosuppression
Patients treated with bendamustine are likely to experience myelosuppression.  Blood 
counts will be monitored weekly during the first cycle and then frequently throughout 
subsequent cycles of treatment.  Patients who experience Grade 3 or 4 neutropenia or 
thrombocytopenia should be monitored until neutrophil and platelet values return to at 
least Grade 2.  The use of G-CSF for the primary prophylaxis is required. The decision 
not to administer G-CSF as primary prophylaxis should be made in consultation with and 
following the approval of the Medical Monitor. 


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5.1.3.2
Infection
Infection, including pneumonia and sepsis, has been reported.  Patients with 
myelosuppression after treatment with bendamustine are more susceptible to infections.  
The study physician will treat patients with clinical evidence of infection appropriately.  
See Section 5.1.5 for monitoring plans and Table 7 for instructions for dose delay and 
modification of bendamustine.  Antiviral (coverage for HSV, VZV) and anti-pneumocystis 
prophylaxis are required beginning at the initiation of study treatment and continuing for 
at least 6 months after the completion of study treatment.  Opportunistic infections have 
occurred with treatment of bendamustine. Evaluation for opportunistic infections is 
recommended in cases of unexplained and prolonged fever, unexplained transaminitis,
or unexplained/ongoing symptoms such as diarrhea, nausea, and neurological changes.
5.1.3.3
Hepatitis B Reactivation
Reactivation of hepatitis B in patients who are chronic carriers of this virus has 
occurred after these patients received bendamustine hydrochloride. Some cases resulted 
in acute hepatic failure or a fatal outcome. Patients should be tested for HBV infection 
before initiating treatment with bendamustine hydrochloride. Carriers of HBV who 
require treatment with bendamustine hydrochloride should be closely monitored for 
signs and symptoms of active HBV infection throughout therapy and for several months 
following termination of therapy.
5.1.3.4
Infusion-Related Reactions and Anaphylaxis
Infusion reactions to bendamustine have occurred commonly in clinical trials.  Symptoms 
include fever, chills, pruritus, and rash.  In rare instances, severe anaphylaxis and 
anaphylactoid reactions have occurred, particularly in the second and subsequent cycles 
of therapy.  Patients should be monitored clinically and discontinue drug for every 
reaction.
5.1.3.5
Tumor Lysis Syndrome
TLS has been reported in association with bendamustine treatment in clinical trials and 
in postmarketing reports.  The onset tends to be within the first treatment cycle of 
bendamustine and, without intervention, may lead to acute renal failure and death.  
Preventive measures include maintaining adequate volume status and close monitoring 
of blood chemistry, particularly potassium and uric acid levels.  Allopurinol has also been 
used during the beginning of bendamustine therapy.  However, there may be an 
increased risk of severe skin toxicity when bendamustine and allopurinol are 
administered concomitantly.
5.1.3.6
Skin Reactions
A number of skin reactions have been reported with bendamustine treatment, including 
rash, toxic skin reactions, and bullous exanthema.  In a study of bendamustine in 
combination with rituximab, one case of TEN occurred.  TEN has been reported for 
rituximab.  Cases of Stevens-Johnson syndrome, TEN and Drug Reaction with 
Eosinophila and Systemic Symptoms (DRESS), some fatal, have been reported with the 


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use of bendamustine.  Patients with skin reactions should be monitored closely.  If skin 
reactions are severe or progressive, bendamustine should be withheld.
5.1.3.7
Long-Term Stem-Cell Toxicity
Premalignant and malignant diseases, including myelodysplastic syndrome, 
myeloproliferative disorders, acute myeloid leukemia (AML), and bronchial carcinoma, 
have developed in patients treated with bendamustine.
5.1.3.8
Extravasation of Bendamustine
Erythema, marked swelling, and pain from bendamustine extravasation have resulted in 
hospitalization.  Precautions should be taken to avoid extravasation, including monitoring 
of the IV infusion site for redness, swelling, pain, infections, and necrosis during and 
after administration of bendamustine.
5.1.3.9
Transfusion-Associated Graft versus Host Disease
Rare cases of transfusion-associated graft-versus-host disease have been reported 
following treatment of low-grade B-cell malignancies with purine analogues (i.e., 
fludarabine or cladribine).  The situation with newer purine antagonists such as 
bendamustine is unclear.  Transfusions, if required, should be performed according to 
national guidelines.
5.1.3.10
Drug Interactions
Certain medications may interact with bendamustine.  Caution should be used or 
alternative treatments should be considered if concomitant treatment with CYP1A2 
inhibitors or inducers is needed.  CYP1A2 inhibitors and inducers are not contraindicated.  
During treatment with bendamustine, patients will be provided with a card to keep with 
them that provides notification to other health care providers that the patient is taking 
bendamustine as a participant in a clinical study (see Appendix 9).
5.1.4
Risks Associated with Obinutuzumab
Please see the current Obinutuzumab Investigator’s Brochure for full information.
5.1.4.1
Infusion-Related Reactions and Hypersensitivity Reactions 
(Including Anaphylaxis)
The commonly experienced IRRs have been characterized by fever, chills, flushing, 
nausea, vomiting, hypotension, hypertension, fatigue, and other symptoms.  Patients 
with pre-existing cardiac conditions may experience worsening of their cardiac disease.
Respiratory infusion-related symptoms, such as hypoxia, dyspnea, bronchospasm, 
larynx and throat irritation, and laryngeal edema, have also been reported.  These IRRs 
were mostly mild or moderate (NCI CTCAE, v3.0, Grade 1 and 2 events), and 10% of
the events were severe (Grade 3 events), occurring predominantly during the first hour 
of the infusion or shortly after the first infusion had finished.  The events resolved with 
the slowing or interruption of the infusion and supportive care.  The incidence and 
severity of IRRs decreased with subsequent infusions.  Extensive tumor burden 


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predominantly localized in the blood circulation (e.g., high peripheral lymphocyte count in 
patients with CLL) may be a predisposing factor for the development of IRRs.
Hypersensitivity reactions with immediate (e.g. anaphylaxis) and delayed onset (e.g., 
serum sickness) have been reported in patients treated with obinutuzumab.
IRRs may be clinically indistinguishable from IgE-mediated allergic or anaphylactic 
reactions.
5.1.4.2
Tumor Lysis Syndrome
TLS has been reported with obinutuzumab administration.  Patients with a high tumor 
burden, including patients with a lymphocyte count 25109/L, particularly patients with 
B-cell CLL and mantle cell lymphoma, are at increased risk for TLS and severe IRRs.  
All patients with peripheral blood lymphocyte counts of 25109/L or bulky adenopathy 
must receive prophylaxis for TLS prior to the initiation of study treatment.  This includes 
appropriate hydration, consisting of fluid intake of approximately 3 L/day, starting 
12 days prior to the first dose of obinutuzumab, and administration of allopurinol 
(300 mg/day orally) or a suitable alternative (i.e., rasburicase) treatment, starting at 
1224 hours prior to the first infusion of obinutuzumab (Cycle 1, Day 1).  All patients 
should then be carefully monitored during the initial weeks of treatment.  Patients still 
considered at risk for TLS because of persistently high tumor burden (i.e., peripheral 
blood lymphocyte counts 25109/L) before the second and subsequent infusions of 
obinutuzumab should receive continuous TLS prophylaxis with allopurinol or a suitable 
alternative (i.e., rasburicase) and adequate hydration until the risk is abated, as 
determined by the investigator.  For treatment of TLS, correct electrolyte abnormalities, 
monitor renal function and fluid balance, and administer supportive care, including 
dialysis as indicated.  For further details please refer to the label of Gazyva.
5.1.4.3
Neutropenia
Cases of Grade 3 or 4 neutropenia, including febrile neutropenia, have been reported 
with obinutuzumab administration.  Grade 3 or 4 neutropenia has predominantly been 
observed in patients with CLL.  Patients who experience Grade 3 or 4 neutropenia 
should be monitored until neutrophil values return to at least Grade 2.  Use of G-CSF 
has been found to result in a rapid normalization of neutrophils, similar to what has been 
observed in patients treated with rituximab.  The use of G-CSF is allowed for treatment 
of neutropenia in this study.  Primary prophylaxis with G-CSF is required. The decision 
not to administer G-CSF as primary prophylaxis should be made in consultation with and 
following the approval of the Medical Monitor. 
5.1.4.4
Thrombocytopenia
Severe and life-threatening thrombocytopenia, including acute thrombocytopenia 
(occurring within 24 hours after the infusion), has been observed during treatment with 
obinutuzumab.  Fatal hemorrhagic events have also been reported in patients treated 
with obinutuzumab.  It seems that the first cycle is the greatest risk of hemorrhage in 


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patients treated with obinutuzumab.  A clear relationship between thrombocytopenia and 
hemorrhagic events has not been established.  Patients treated with concomitant 
medication, which could possibly worsen thrombocytopenia-related events (e.g., platelet 
inhibitors and anticoagulants), may be at greater risk of bleeding.  Patients should be 
closely monitored for thrombocytopenia, especially during the first cycle; regular 
laboratory tests should be performed until the event resolves, and dose delays should be 
considered in case of severe or life-threatening thrombocytopenia.  Transfusion of blood 
products (i.e., platelet transfusion) according to institutional practice is at the discretion 
of the treating physician. 
5.1.4.5
Infection
On the basis of its anticipated mode of action, resulting in profound B-cell depletion, 
obinutuzumab may be associated with an increased risk of infections.  Infections, 
including some fatal infections, have been reported in patients receiving obinutuzumab.  
Therefore, obinutuzumab should not be administered to patients with active severe 
infections.
In the FL studies, a high incidence of infections was observed in all phases of the 
studies, including follow-up, with the highest incidence seen in maintenance.  
Reactivation of hepatitis B as well as other serious viral infections (e.g., infections
caused by cytomegalovirus, Varicella zoster virus, herpes simplex virus, 
John Cunningham [JC] virus, and HCV) that were new, reactivated, or exacerbated have 
been reported with the B cell–depleting antibody rituximab mainly in patients who had 
received the drug in combination with chemotherapy or as part of a hematopoietic SCT.  
Particular attention should be given to patients who have previously received significant 
immunosuppressive treatment, such as high-dose chemotherapy and SCT.
JC viral infections (including fatal) that resulted in PML with destructive infection of 
oligodendrocytes of the CNS white matter) have been reported in patients treated with 
anti-CD20 therapies, including rituximab and obinutuzumab.
The diagnosis of PML should be considered in any patient presenting with new-onset 
neurologic manifestations.  The symptoms of PML are unspecific and can vary 
depending on the affected region of the brain.  Motor involvement with corticospinal tract 
findings, sensory involvement, cerebellar deficits, and visual field defects are common.  
Some syndromes regarded as cortical (e.g., aphasia or visual-spatial disorientation) can 
occur.
Evaluation of PML includes but is not limited to consultation with a neurologist, brain MRI, 
and lumbar puncture (cerebrospinal fluid testing for JC viral DNA):

Therapy with obinutuzumab should be withheld during the investigation of potential 
PML and permanently discontinued in case of confirmed PML.  Discontinuation or 
reduction of any concomitant chemotherapy or immunosuppressive therapy should 


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also be considered.  The patient should be referred to a neurologist for the 
diagnosis and management of PML.
5.1.4.6
Impaired Immunization Response
The safety of immunization with live virus vaccines following obinutuzumab therapy has 
not been studied.  Thus, vaccination with live virus vaccines is not recommended during 
treatment and until B-cell recovery.
5.1.4.7
Worsening of Preexisting Cardiac Condition
In patients with underlying cardiac disease and treated with obinutuzumab, adverse 
events such as angina pectoris, acute coronary syndrome, myocardial infarction, heart
failure, and arrhythmias, including atrial fibrillation and tachyarrhythmia, have been 
observed.  These events may occur as part of an IRR and can be fatal.  Therefore, 
patients with a history of cardiac disease should be monitored closely.  In addition, these 
patients should be hydrated with caution to prevent a potential fluid overload.
5.1.4.8
Gastrointestinal Perforation
Gastrointestinal perforation has been reported in patients treated with obinutuzumab 
including fatal events.  Patients with gastrointestinal involvement should be monitored for 
signs of gastrointestinal perforation. 
5.1.5
Management of Specific Adverse Events
Guidelines for management of specific adverse events are outlined in Table 7.  
Additional guidelines are provided in the subsections below.
5.1.5.1
Dose Delays and Dose Modifications
Patients should be assessed clinically for toxicity before each dose using NCI CTCAE 
v4.03 unless otherwise stated.  These guidelines pertain to dose delays and 
modifications based on physical examination findings, observed toxicities, and laboratory 
results obtained within 72 hours before study treatment administration.  Dosing will occur 
only if a patient’s clinical assessment and laboratory test values are acceptable.  Dose 
delays and dose modifications due to adverse events not specified in this section should 
proceed on the principle of maintaining the dose intensity of bendamustine.  The 
determination of all dose and schedule modifications will be made on the basis of the 
investigator’s assessment of ongoing clinical benefit with continuing study treatment in 
consultation with the Medical Monitor and with the approval of the Medical Monitor.
5.1.5.2
Dose Modifications
No dose modifications of rituximab (375 mg/m2) or obinutuzumab (1000 mg) are allowed.
Bendamustine and polatuzumab vedotin doses may be reduced (per the guidelines 
outlined in Table 8) with the approval of the Medical Monitor.


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5.1.5.3
Dose Delay
If administration of chemotherapy is delayed, the administration of rituximab or 
obinutuzumab and polatuzumab vedotin should be delayed for the same time frame 
(e.g., if bendamustine therapy is delayed, administration of rituximab or obinutuzumab 
and polatuzumab vedotin should also be delayed so that they are given together 
beginning on Day 1 of the same cycle).  
For guidelines for dose delay for obinutuzumab for febrile neutropenia or neutropenia 
with infection or thrombocytopenia at Cycle 1, Day 8, and Cycle 1, Day 15, see Table 8.
5.1.5.4
Schedule Modifications
Patients with DLBCL who have received Cycle 1 treatment may have the dosing 
schedule changed to a 28-day cycle if it is considered by the investigator that changing a 
patient’s dosing regimen from 21-day to 28-day cycles would provide sufficient time for 
recovery from a transient and reversible toxicity (e.g., cytopenia without requiring 
repeated treatment delays).  Modifications of this type to the dosing schedule must be 
made in consultation with the Medical Monitor and have the approval of the Medical 
Monitor.
5.1.5.5
Non-Hematologic Toxicities
5.1.5.5.1
Infusion-Related Reactions and Anaphylaxis
Medications including epinephrine for SC injections, corticosteroids, diphenhydramine 
hydrochloride for IV injection, and resuscitation equipment should be available for 
immediate use.  Management of infusion-related symptoms for both rituximab and 
obinutuzumab are summarized in Table 6 according to the administration rates in 
Section 4.3.2.5 and Section 4.3.2.6.  In the event of a life-threatening IRR (which may
include pulmonary or cardiac events) or IgE-mediated anaphylactic reaction, rituximab or 
obinutuzumab should be discontinued and no additional drug should be administered.  
Patients who experience any of these reactions should receive aggressive symptomatic 
treatment and will be discontinued from study treatment.  See Appendix 6 for 
recommended management of anaphylaxis.
Patients who experience rituximab- or obinutuzumab-associated infusion-related 
temperature elevations of 38.5°C or other minor infusion-related symptoms may be 
treated symptomatically with acetaminophen/paracetamol (5001000 mg) and/or H1- and 
H2- histamine receptor antagonists (e.g., diphenhydramine hydrochloride) and ranitidine.  
Serious infusion-related events, manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress, should 
be managed with additional supportive therapies (e.g., supplemental oxygen, 2-agonists, 
epinephrine, and/or corticosteroids) as clinically indicated according to standard clinical 
practice.  See Appendix 6 for recommended management of anaphylaxis.
Guidelines for the management of IRRs and anaphylaxis are detailed in Table 6.


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Table 6
Management of Infusion-Related Symptoms
Infusion-Related Symptoms
Guidance
Grade 12

Slow or hold infusion.

Give supportive treatment a

Upon symptom resolution, may resume infusion-rate 
escalation at the investigator’s discretion.

Note:  For Grade 2 wheezing or urticaria, patient must be 
premedicated for any subsequent doses.  If symptoms recur, 
the infusion must be stopped immediately and study drug 
permanently discontinued.
Grade 3

Discontinue infusion.

Give supportive treatment a

Upon symptom resolution, may resume infusion-rate 
escalation, at investigator discretion b

Note:  If the same adverse event recurs with same severity, 
treatment must be permanently discontinued.

Note:  For Grade 3 hypotension or fever, patient must be 
premedicated before re-treatment.  If symptoms recur, then 
study drug must be permanently discontinued.

Note:  If patient has Grade 3 wheezing, bronchospasm, or 
generalized urticaria at first occurrence, study drug must be
permanently discontinued.
Grade 4

Discontinue infusion immediately, treat symptoms 
aggressively, and permanently discontinue study drug.
IVintravenous; NCI CTCAE v4.03National Cancer Institute Common Terminology Criteria for 
Adverse Events, version 4.03.
Refer to the NCI-CTCAE v4.03 scale for the grading of symptoms.  Management of IgE-mediated 
allergic reactions should be as directed in the text following this table.
a Supportive treatment:  Patients should be treated with acetaminophen/paracetamol and an 
antihistamine such as diphenhydramine if they have not been received in the previous 4 hours.  
IV saline may be indicated.  For bronchospasm, urticaria, or dyspnea, patients may require 
antihistamines, oxygen, corticosteroids (e.g., 100 mg IV prednisolone or equivalent), and/or 
bronchodilators.  Patients with hypotension who require vasopressor support must be 
permanently discontinued from study drug.
b Infusion rate escalation after re-initiation:  Upon complete resolution of symptoms, 
the infusion may be resumed at 50% of the rate achieved prior to interruption.  In the absence 
of infusion-related symptoms, the rate of infusion may be escalated in increments of 
50 mg/hour every 30 minutes.


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Table 7
Guidelines for Dose Delay or Modification of Polatuzumab Vedotin, Rituximab, Obinutuzumab, or 
Bendamustine
Event(s)
Dose Delay or Modification
Grade 3 or 4 neutropenia on 
Day 1 of any Cycle with or 
without infection or fever a
First delay

Delay all study treatment.  Treatment cannot be delayed for more than 2 weeks.

Administer growth factors as appropriate; (e.g., G-CSF for neutropenia as indicated and for all subsequent 
cycles).

If ANC recovers to 1000/L by Day 7 of the scheduled date for the next cycle, administer full dose of 
polatuzumab vedotin, bendamustine, and rituximab or obinutuzumab.

If ANC recovers to 1000/L on or after Day 8 of the scheduled date for the next cycle, reduce the dose of 
bendamustine to 70 mg/m2.

If the primary cause of neutropenia is thought to be lymphoma infiltration into the bone marrow, the 
investigator may elect not to reduce the dose of bendamustine.  Decisions must be made in consultation with 
and with approval of the Medical Monitor. 
Recurrent Grade 3 or 4 
neutropenia on Day 1 of any 
Cycle

Delay doses of all study treatment.  Treatment cannot be delayed for more than 2 weeks.

If ANC recovers to 1000/L by Day 7 of the scheduled date for the next cycle, administer full dose of study 
treatment.

If ANC recovers to 1000/L on or after Day 8 of the scheduled date for the next cycle, then:

If the dose of polatuzumab vedotin is 1.8 mg/kg, then reduce bendamustine to the next lowest dose 
level of 70 mg/m2 (1st dose reduction) and maintain polatuzumab vedotin dose of 1.8 mg/kg.  If there 
was a prior dose reduction, then reduce bendamustine to the next lowest dose level of 50 mg/m2
(2nd dose reduction) and maintain polatuzumab vedotin dose at 1.8 mg/kg.

No dose reductions of polatuzumab vedotin for neutropenia are allowed.

No more than 2 dose reductions of bendamustine are allowed.  If patient develops persistent Grade 3 or 
4 neutropenia despite growth factor support and after bendamustine dose reductions, permanently 
discontinue all study treatment.
Severe thrombocytopenia 
(platelets 10,000/µL) and/or 
symptomatic bleeding in 
patients who are not receiving 
concomitant anticoagulants or 
platelet inhibitors

Hold obinutuzumab in case of severe thrombocytopenia (platelets 10,000/L) or symptomatic bleeding 
(irrespective of platelet count) until it resolves.  For guidelines for dose delay for obinutuzumab on Cycle 1,
Day 8 and Cycle 1, Day 15, see Table 8. 


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Event(s)
Dose Delay or Modification
Thrombocytopenia with 
platelets 20,000/L and/or 
symptomatic bleeding in 
patients who are receiving 
concomitant anticoagulants or 
platelet inhibitors b, c

Hold obinutuzumab in case of platelets 20.000/L or symptomatic bleeding (irrespective of platelet count) 
until it resolves.  For guidelines for dose delay for obinutuzumab on Cycle 1, Day 8, and Cycle 1, Day 15, see 
Table 8.

For patients who are on LMWH, when thrombocytopenia with platelets 20,000/L develops, reduce the dose 
of LMWH used. b

For patients who are on platelet inhibitors, when thrombocytopenia with platelets 20.000/L develops, 
consideration should be given to temporarily pause their use.b
Grade 3 or 4 thrombocytopenia 
on Day 1 of any cycle, first 
episode

Delay doses of all study treatment.

If platelet count recovers to 75,000/L by Day 7 of the scheduled date of the next cycle, administer full dose 
of study treatment.

If platelet count recovers to 75,000/L on or after Day 8 of the scheduled date of the next cycle, reduce the 
dose of bendamustine to the next (lowest) dose level (70 mg/m2).  Full dose of BR may be given to patients on 
Arm B and Arm D (BR only arms).

If the patient had baseline thrombocytopenia and the primary cause of thrombocytopenia is thought to be 
lymphoma infiltration into the bone marrow, the investigator may elect not to reduce the dose of bendamustine.
Recurrent Grade 3 or 4 
thrombocytopenia

Delay doses of all study treatment.

If platelet count recovers to 75,000/L by Day 7 of the scheduled date of the next cycle, administer full dose 
of study treatment

If platelet count recovers to 75,000/L on or after Day 8 of the scheduled date of the next cycle, then:

If the dose of polatuzumab vedotin is 1.8 mg/kg, then reduce bendamustine to the next lowest dose 
level of 70 mg/m2 (1st dose reduction) and maintain polatuzumab vedotin dose of 1.8 mg/kg.  If there 
was a prior dose reduction, then reduce bendamustine to the next lowest dose level of 50 mg/m2
(2nd dose reduction) and maintain polatuzumab vedotin dose at 1.8 mg/kg.  

No more than 2 dose reductions of bendamustine are allowed.  

If patient develops Grade 4 thrombocytopenia following polatuzumab vedotin and bendamustine dose 
reductions, discontinue all study treatment permanently.
Grade 1 or 2 neutropenia 
and/or thrombocytopenia

No dose reduction or delay 


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Event(s)
Dose Delay or Modification
Grade 2 or 3 peripheral 
neuropathy (including its signs 
and symptoms)

Delay all study treatment

If recovered to Grade 1 within 14 days of the scheduled date of the next cycle:

If the dose of polatuzumab vedotin is 1.8 mg/kg, then reduce polatuzumab vedotin to 1.4 mg/kg (permanent 
dose reduction).  BR or BG may be administered at their full doses.

If there was a prior dose reduction of polatuzumab vedotin to 1.4 mg/kg for Grade 2 or 3 neurotoxicity, all 
study treatment must be permanently discontinued. 

If not recovered to Grade 1 until 14 days or after the scheduled date for the next cycle, all study treatment 
must be permanently discontinued. 
Grade 4 peripheral neuropathy 
(including its signs and 
symptoms)

Discontinue polatuzumab vedotin permanently and discontinue all other treatment.
Total Bilirubin 3.0 mg/dL

Delay treatment until resolution to 1.5 mg/dL within 14 days.  Evaluate for causality.

Any case involving an increase in hepatic transaminase 3baseline AND an increase in direct bilirubin 
2ULN, WITHOUT any findings of cholestasis or jaundice or signs of hepatic dysfunction AND in the 
absence of other contributory factors (e.g., worsening of metastatic disease or concomitant exposure to known 
hepatotoxic agent or of a documented infectious etiology) is suggestive of potential DILI, and drug should be 
discontinued.
Grade 3 or 4 tumor 
lysis syndrome

Hold all study treatment.  The patient’s next dose may be delayed for up to 14 days. 

Following complete resolution TLS, study treatment may be re-administered at the full dose during next 
scheduled infusion, in conjunction with prophylactic therapy.
Grade 3 or 4 non-hematologic 
toxicity not specifically 
described above (excluding 
alopecia, nausea, and 
vomiting)

Delay study treatment for a maximum of 14 days

If improvement to Grade 1 or baseline, continue study therapy at full dose, or dose reduce at the discretion of 
the investigator per site’s standard after discussion with the Medical Monitor.
Grade 2 
non-hematologic toxicity

Delay study treatment for a maximum of 14 days.

If improvement to Grade 1 or baseline, administer previous doses of study treatment.  
Grade 1 
non-hematologic toxicity

No dose reduction or delay


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Event(s)
Dose Delay or Modification
Hepatitis B reactivation (as 
noted by new detectable 
HBV-DNA levels)

HBV-DNA levels between WHO-recommended range of 29 and 100 IU/mL:  Re-test within 2 weeks.  If still 
positive, hold all study treatment and treat patient with an appropriate nucleoside analogue.  Immediately refer 
patient to a gastroenterologist or hepatologist.

HBV-DNA levels at WHO-recommended cutoff of 100 IU/mL:  hold all study treatment and treat the patient 
with an appropriate nucleoside analogue.  Immediately refer patient to a gastroenterologist or hepatologist.

Rising HBV-DNA viral load (exceeding 100 IU/mL) while on an appropriate anti-viral therapy:  Discontinue all 
study treatment immediately.
ANCabsolute neutrophil count; BGbendamustine and obinutuzumab; BRbendamustine and rituximab; DILIdrug-induced liver injury; 
G-CSFgranulocyte colony stimulating factor; HBVhepatitis B virus; LMWHlow molecular-weight heparin; Rrituximab; ULNupper limit of 
normal; WHOWorld Health Organization.
a All based on laboratory test results obtained within 72 hours before infusion of Day 1 of that cycle. 
b If the clinical condition of patient requires the use of concomitant anticoagulants, the patients are at increased risk of bleeding when 
thrombocytopenia with platelets 20.000/L develops.  When possible, replace prior therapy with vitamin K antagonists with LMWH before 
Cycle 1, Day 1. 
c Clinical decision-making may be adjusted depending on the patient-specific assessment of benefit and risk.


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


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5.1.5.5.2
Hematologic Toxicity
Note that lymphopenia is not considered to be a hematologic toxicity because it is an 
expected outcome of therapy.  See Table 4 for specific guidance. 
5.1.5.5.3
Dose Discontinuation
Dosing delay exceeding 14 days in the initiation of the next planned cycle of BR, 
polatuzumab vedotinBR, or polatuzumab vedotinBG and will require study treatment
discontinuation unless Medical Monitor approval is obtained to continue on study 
treatment.
If scheduled dosing coincides with a holiday that precludes dosing, commence dosing on 
the nearest following date, with subsequent dosing continuing on a 21- or 28-day 
schedule as applicable.
Patients who discontinue all study treatment for adverse events should remain in the 
study and continue to have disease assessments until progression and standard follow 
up per Section 4.5.
5.1.5.6
Treatment Discontinuation Criteria
5.1.5.6.1
Polatuzumab Vedotin
A patient should permanently discontinue polatuzumab vedotin if any of the following 
occur:

Grade 4 peripheral neuropathy 

Grade 3 peripheral neuropathy that leads to a treatment delay of 14 days or more 
and does not improve to Grade 1 within 14 days

Recurrence of a Grade 2 peripheral neuropathy at the reduced dose 
5.1.5.6.2
Rituximab or Obinutuzumab
A patient should permanently discontinue rituximab or obinutuzumab if any of the 
following occur:

Grade 4 infusion-related symptom or anaphylaxis.  The patient should be withdrawn 
from study treatment immediately and supportive treatment given.

Recurrence of Grade 3 infusion-related symptoms at re-challenge, regardless of 
timing (e.g., within same session or at the next session) 

If patient has Grade 3 wheezing, bronchospasm, or generalized urticaria at first 
occurrence.
5.1.5.6.3
BR, Polatuzumab Vedotin Plus BR, or Polatuzumab Vedotin 
plus BG 
A patient should permanently discontinue BR, polatuzumab vedotinBR, or polatuzumab 
vedotin BG if any of the following occur:

Grade 3 or 4 hematologic toxicity that does not resolve to Grade 2 and delays 
treatment by 14 days despite administration of growth factors


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
Grade 2 non-hematologic toxicity that does not resolve to Grade 1 or baseline 
value and delays treatment by 14 days

Hepatitis B reactivation despite initiation of the appropriate anti-viral therapy

Disease progression
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest, 
measurement of protocol-specified safety laboratory assessments, measurement of 
protocol-specified vital signs, and other protocol-specified tests that are deemed critical 
to the safety evaluation of the study.
Certain types of events require immediate reporting to the Sponsor as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH 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

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 drug

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 serious adverse event is any adverse event that meets any of the following criteria:

Fatal (i.e., the adverse event actually causes or leads to death)

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.


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
Requires or prolongs inpatient 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)

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

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 
AE (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE criteria) 
(see Section 5.3.3); the event itself may be of relatively minor medical significance (e.g., 
severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following:

Potential DILI that includes 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 drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection 
in a patient exposed to a medicinal product.  This term applies only when a 
contamination of the study drug is suspected.

TLS of any grade (irrespective of causality)

Second malignancies
Adverse events that meet the definition of a safety event during the safety run-in 
observation period (see Section 3.1.1.2) will be recorded on the Adverse Event eCRF 
and reported immediately to the Medical Monitor as described in Section 3.1.1.2.  If a 


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safety event also meets the definition of an SAE, the event will also qualify for expedited 
reporting to the Sponsor (see Section 5.4.2 for reporting instructions).
Real time safety monitoring will be employed for safety run-in assessment and dose 
expansion decisions.
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.
For each AE recorded on the Adverse Event eCRF, the investigator will make an 
assessment of seriousness (see Section 5.2.2), severity (see Section 5.3.3), and 
causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported (see 
Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until 90 days after the last dose of study drug.  After this period, 
the investigator is not required to actively monitor patients for adverse events; however, 
the Sponsor should be notified if the investigator becomes aware of any post-study 
serious adverse events or adverse events of special interest, regardless of attribution 
(see Section 5.6).  Secondary malignancies will be recorded indefinitely (even if the 
study has ended) for all enrolled subjects.
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? 


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5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v 4.03) will be used for 
assessing adverse event severity.  Table 9 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 9
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 (v4.03), 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 an 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 event (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 or 
not an adverse event is considered to be related to the study drug, indicating yes or no 
accordingly.  The following guidance should be taken into consideration (see Table 10):

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study


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
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 
occurrence of the event
Table 10 Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon rechallenge. 
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after first 
dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
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 study drug administration 
should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of infusion-related reaction or anaphylactic reaction).
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than IRRs (see Section 5.3.5.1), 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 


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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.  Examples of this type of event are the following:

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.

If a severe gastrointestinal 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.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  For more information regarding the reporting requirements for 
persistent or recurrent adverse events, please refer to the eCRF Completion Guidelines 
document.
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:

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


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
Clinically significant in the investigator’s judgment
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., 
alkaline phosphatase and bilirubin 5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 if the test result is above or below the normal range (e.g., elevated 
potassium, as opposed to abnormal potassium).  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as hyperkalemia.
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
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:

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

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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 


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changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.7
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 the abnormal laboratory values (if a diagnosis cannot 
be established) 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 serious adverse event or a non-serious 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 drug, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.4.2).  The 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").
During survival follow-up, deaths attributed to progression of lymphoma should be 
recorded only on the Survival eCRF.


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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 
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 Revised Response Criteria for Malignant Lymphoma and 
Modified Lugano Response Criteria (see Appendix 4).  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 serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug 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


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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
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event assocatied with a special situation should be recorded 
separately 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).  For polatuzumab vedotin, 
rituximab, and obinutuzumab, adverse events associated with special situations should 
be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
In addition, all special situations associated with polatuzumab vedotin, rituximab, or 
obinutuzumab, regardless of whether they result in an adverse event, should be 
recorded on the Adverse Event eCRF as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.


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
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.3.5.13
Patient-Reported Outcome Data
The PRO measurements are described in Section 4.5.10.  The methods for collecting 
and analyzing PRO data are different from those for the ascertainment of observed or 
volunteered adverse events.  Because of these differences, PRO data will not be 
reported as adverse events and no attempt will be made to resolve any noticeable 
discrepancies between PRO data and observed or volunteered adverse events.  The 
PRO data will be presented in separate tables, figures, and data listings from the 
adverse event data, and will be included in the appropriate section of the final study 
report.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures and address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Any death not due to progression of lymphoma, regardless of relationship to 
study drug

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
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


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
Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Medical Monitors and Emergency Medical Contacts
Medical Monitor Contact Information
Medical Monitor:
, Pharm.D.
Mobile Telephone No.:  
Emergency Medical Contact:
                             
, M.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 
Monitor, 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 the Medical Monitor contact information will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
A paper Serious Adverse Event Reporting Form and fax cover sheet should be 
completed and faxed to Roche Safety Risk Management or its designee immediately 
(i.e., no more than 24 hours after learning of the event), using the fax numbers provided 
to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study drug with the exception 
of second malignancies.  Second malignancies will be recorded indefinitely (even if the 
study has ended) and irrespective of new anti-lymphoma treatment (NALT) for all 
enrolled subjects.  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, a paper Serious Adverse Event 
Reporting Form and fax cover sheet should be completed and faxed to Roche Safety 
Risk Management or its designee immediately (i.e., no more than 24 hours after learning 


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of the event), using the fax numbers 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 poststudy 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 1 year after the last dose 
of study treatment.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Roche Safety Risk Management.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.
In the event that the EDC system is unavailable, a paper Clinical Trial Pregnancy
Reporting Form and fax cover sheet should be completed and faxed to Roche Safety 
Risk Management or its designee immediately (i.e., no more than 24 hours after learning 
of the pregnancy), using the fax numbers provided to investigators (see Protocol 
Administrative and Contact Information and List of Investigators).  Once the EDC system 
is available, all information will need to be entered and submitted via the EDC system.
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the ICF to immediately inform the investigator if 
their partner becomes pregnant during the study or within 6 months after the last dose of 
study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  Attempts should be made to collect and report details of the course 
and outcome of any pregnancy in the partner of a male patient exposed to study drug.  
The pregnant partner will need to sign an Authorization for Use and Disclosure of 
Pregnancy Health Information to allow for follow-up on her pregnancy.  Once the 
authorization has been signed, the investigator will update the Pregnancy Report eCRF 
with additional information on the course and outcome of the pregnancy.  An investigator 
who is contacted by the male patient or his pregnant partner may provide information on 
the risks of the pregnancy and the possible effects on the fetus, to support an informed 
decision in cooperation with the treating physician and/or obstetrician.
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1.


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5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as an serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2).
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 serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF. 
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1.
5.5.2
Sponsor Follow-Up
For serious adverse events, non-serious 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., 


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from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case. 
5.6
POST-STUDY ADVERSE EVENTS
The investigator is not required to actively monitor patients for serious adverse events 
after the end of the adverse event reporting period (defined as 90 days after the last 
dose of study drug).  However, the Sponsor should be notified if the investigator 
becomes aware of any death or other serious adverse event that occurs after the end of 
the adverse event reporting period, regardless of causality.  Second malignancies will be 
recorded indefinitely (even if the study has ended) and irrespective of NALT for all 
enrolled subjects.
The investigator should report these events directly to Roche Safety Risk Management 
via telephone or via fax machine using the Serious Adverse Event Reporting Form and 
fax cover sheet.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Polatuzumab Vedotin Investigator's Brochure

Rituximab Investigator’s Brochure

Obinutuzumab Investigator’s Brochure

Summary of Product Characteristics (United Kingdom) for bendamustine
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 Phase Ib part of this study is designed to assess the safety and tolerability of the 
combination of polatuzumab vedotin with BR or BG in patients with R/R FL or R/R 
DLBCL.  Once the safety and tolerability of polatuzumab vedotin in combination with BR 
or BG is confirmed, the Phase II part of the study will begin.  


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The Phase II part of the study has a randomized component that is designed to assess 
the safety and efficacy of the combination of polatuzumab vedotin with BR compared 
with that of BR alone in patients with R/R FL or R/R DLBCL.  In addition, the Phase II 
part of the study has a non-randomized component that is designed to assess the safety 
and efficacy of the RP2D of polatuzumab vedotin with BG in each of two independent 
cohorts of patients, one enrolling patients with R/R FL and the other enrolling patients 
with R/R DLBCL.
Furthermore, the Phase II part of the study has an additional two non-randomized arms
within the NF Cohort (Arms G and H).  Arm G was designed primarily to assess the 
pharmacokinetics and safety of the new formulation in patients with R/R DLBCL, which 
uses the new lyophilized formulation of polatuzumab vedotin plus BR. Arm H was 
designed to further assess the clinical efficacy and safety of using the new lyophilized 
formulation of polatuzumab vedotin in combination with BR in patients with R/R DLBCL.
The safety and efficacy data from each phase will be summarized separately by 
treatment arm.  Safety analyses will include all treated patients (i.e., patients who 
received any amount of study medication) according to actual treatment received. 
Efficacy analyses for the randomized component of the Phase II will be conducted in 
accordance with the intent-to-treat principle (i.e., according to randomized treatment 
assignment) and separately for each histology.  Efficacy analyses for the 
non-randomized component of the Phase II will be done separately for each histological 
cohort (i.e., FL or DLBCL), including the arms in the NF Cohort. Additionally, efficacy 
analyses for Arm G and Arm H in the NF Cohort will be summarized individually and in a 
pooled fashion (see Section 6.4).
6.1
DETERMINATION OF SAMPLE SIZE
The purpose of this study is to evaluate the safety, tolerability, and efficacy of 
polatuzumab vedotin in combination with BR or BG.
6.1.1
Phase Ib: Safety Run-In Stage
In this study, approximately 24 patients will be enrolled during the safety run-in portion of 
the study (see Section 3.1).  This corresponds to treating a minimum 6 FL and 6 DLBCL 
patients with polatuzumab vedotin in combination with BR and 6 FL and 6 DLBCL 
patients with polatuzumab vedotin in combination with BG.  A combination will be 
deemed safe for the purpose of moving to the Phase II part of the study as long as 
2 safety events are observed in a given 6-patient cohort as this is consistent with 
requirements for identification of a candidate RP2D based upon a standard 33 design.
6.1.2
Phase II: Randomized and Expansion Stage
A total of 200 patients will be enrolled in Phase II (40 patients for each treatment arm 
and histology in the rituximab-containing regimens and 20 patients for each histology 
group in the obinutuzumab-containing regimen).  In total, enrollment of approximately 


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224 patients is planned in order to evaluate the safety and efficacy of polatuzumab 
vedotin when combined with BR or BG.  The expected enrollment duration is 
approximately 25 months and the total study duration is anticipated to be approximately 
50 months.
The primary efficacy endpoint is CR rate as determined by PET-CT scan at the primary 
response assessment (68 weeks after Cycle 6, Day 1 or last dose of study medication)
as assessed by IRC.  The primary analysis will be estimation of treatment-specific 
PET-CT CR rates as well as the difference in PET-CT CR rates between patients 
randomized to treatment with polatuzumab vedotin in combination with BR and those 
randomized to treatment with BR alone for each histological subtype.  
With 40 patients per arm, 95% exact Clopper-Pearson CIs (Clopper and Pearson 1934) 
for estimation of the true CR rate for would have a margin of error not exceeding17%.  
Table 11 and Table 12 show Clopper-Pearson exact 95% CIs corresponding to
observed CR rates ranging from 60% to 80% based on sample sizes of 40 and 20, 
respectively.  With 40 patients and an observed CR rate of at least 60%, a true CR rate 
below 43% can be ruled out with 95% confidence.  With 20 patients and an observed CR 
rate of at least 60%, a true CR rate below 36% can be ruled out with 95% confidence.  In 
addition, with 40 patients in each arm, assuming a 40% CR rate in the BR arm, and a 
25% increase in CR rate when polatuzumab vedotin is added to BR, the 95% CI for the 
difference in CR rates is (3.8%, 46.2%).
Table 11 Clopper-Pearson Exact 95% Confidence Intervals for Assumed 
Observed CR Rates based on Sample Size of 40 Patients
Polatuzumab VedotinBR
CR rate
No. of Patients with CR
(95% CI for rate)
80%
32 (64%, 91%)
75%
30 (59%, 87%)
70%
28 (53%, 83%)
65%
26 (48%, 79%)
60%
24 (43%, 75%)
BRbendamustine rituximab; CRcomplete 
response.


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Table 12 Clopper-Pearson Exact 95% Confidence Intervals for Assumed 
Observed CR Rates based on Sample Size of 20 Patients
Polatuzumab VedotinBG
CR rate
No. of Patients with CR
(95% CI for rate)
80%
16 (56%, 94%)
75%
15 (51%, 91%)
70%
14 (46%, 88%)
65%
13 (41%, 85%)
60%
12 (36%, 81%)
BGbendamustine obinutuzumab; CRcomplete response.
With respect to assessment of safety based on a sample size of 20 in each of the BG 
arms, the chance of observing at least one adverse event with true incidence of 10% is 
at least 88%.  With 40 patients in each of the BR arms, there is at least an 87% chance 
of observing at least one adverse event with true incidence of 5%.
6.1.3
Phase II: New Formulation Cohort
6.1.3.1
Arm G
For the NF Cohort (Arm G), the original sample size was approximately 2030 patients.  
The objective of this cohort is to gain clinical PK experience with polatuzumab vedotin 
(lyophilized) in combination with BR in R/R DLBCL patients. The currently proposed PK 
sampling scheme (see Appendix 2) is considered sufficient to characterize the 
pharmacokinetics of polatuzumab vedotin related analytes by using the population PK 
analysis approach. PK and safety outcomes will be descriptive.  Safety will be analyzed 
as described for the other cohorts.
The sample size for Arm G was initally planned to be approximately 2030 patients with 
the goal of obtaining 20 PK-evaluable patients. PK evaluable is defined as the patient 
having at minimum PK data of all three analytes collected from Cycle 1 until Cycle 2,
Day 1 after dosing of polatuzumab vedotin. Since this evaluation is not a comparison of 
two randomized arms, it is not appropriate to prespecify the criteria of PK comparability.  
However, when compared to the available data for patients that received Phase I/II 
material, 20 patients would achieve >80% power to obtain a 90% confidence interval for 
the geometric mean ratio (GMR) that falls within the 80%125% range, assuming that
the true GMR equals 1.05 and the inter-individual variability of acMMAE AUC equals 
20%.  
In order to provide confirmatory support of the efficacy observed in the polatuzumab 
vedotinBR arm in the randomized cohort, an additional 10 patients with one prior line 
of therapy will be enrolled into this NF Cohort to achieve similar representation of 
patients by lines of therapy.


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The total sample size of 40 (3010) patients from Arm G would provide at least 87% 
power to detect PET CR of 40% under the hypotheses below, with one-sided 2.5% 
for exact binomial one-sample test:
H0: PET CR rate17.5%, H1: PET CR rate 17.5%
6.1.3.2
Arm H
In order to further evaluate the clinical efficacy among patients with R/R DLBCL who are 
ineligible for transplant who received the new lyophilized formulation of polutuzumab 
vedotin in combination with BR, an additional arm (Arm H) has been added to the 
NF Cohort, which includes approximately an additional 60 patients with R/R DLBCL. 
Under the assumption of 40% PET-assessed CR rate at Primary Response Assessment, 
combining the 40 patients in Arm G of the NF Cohort with the 60 patients in Arm H 
(100 patients [4060]) will provide a more precise 95% CI (Clopper-Pearson exact CI) of 
(30%, 50%) (see Table 13). Furthermore, this 95% CI completely excludes the 95% CI 
[17.5% (11%, 26%)] of the CR rate observed in the randomized BR arm with an
assumed number of 100 patients.


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Table 13 Estimated Polatuzumab Vedotin plus BR Complete Response
Rate in R/R DLBCL
CR Rate
n40
n60
n100
No. of 
Patients 
with CRs
95% CI of 
Rate
No. of 
Patients 
with
CRs
95% CI of 
Rate
No. of 
Patients 
with CRs
95% CI of 
Rate
60%
24
(43%, 75%)
36
(47%, 72%)
60
(50%, 70%)
55%
22
(38%, 71%)
33
(42%, 68%)
55
(45%, 65%)
50%
20
(34%, 66%)
30
(37%, 63%)
50
(40%, 60%)
45%
18
(29%, 62%)
27
(32%, 58%)
45
(35%, 55%)
40%
16
(25%, 57%)
24
(28%, 53%)
40
(30%, 50%)
35%
14
(21%, 52%)
21
(23%, 48%)
35
(26%, 45%)
30%
12
(17%, 47%)
18
(19%, 43%)
30
(21%, 40%)
BRbendamustine and rituximab; CIconfidence interval; CRcomplete response; 
DLBCLdiffuse large B-cell lymphoma; R/Rrelapsed or refractory.
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, major protocol violations, and discontinuations from the study will be 
summarized separately by treatment arm.  The incidence of treatment discontinuation for 
reasons other than disease progression will be tabulated by treatment arm.  Major 
protocol violations, including violations of inclusion/exclusion criteria, will be summarized 
by treatment arm.
Study drug administration data will be listed by dose level and any dose modifications 
will be flagged.  The number of doses, treatment cycles, and average dose received for 
each study drug for the schedule/treatment arm will be summarized using means, SDs, 
medians, and ranges by treatment arms.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics, such as age, sex, race, and duration of 
malignancy, will be summarized using means, SDs, medians, and ranges for continuous 
variables by treatment arms.  For discrete data, descriptive summaries as frequencies 
and percentages by treatment arms will be presented.
6.4
EFFICACY ANALYSES
The efficacy analyses will include all randomized patients, with patients grouped 
according to the treatment assigned at randomization (Phase II polatuzumab vedotin 
plus BR and BR alone).  For the Phase II expansion, patients assigned to polatuzumab 
vedotin plus BG will be grouped by histology (i.e., FL or DLBCL). The efficacy analyses 
will also include the Phase II non-randomized NF cohort in patients with R/R DLBCL.


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NF Cohort:  Pooled Efficacy Analysis
In addition to the efficacy analyses as outlined in the objectives (see Section 2.3) for the 
individual arms of the NF Cohort, efficacy analysis will also be pooled for the following 
endpoints:

Primary efficacy endpoint: CR at the Primary Response Assessment based on 
PET-CT, as determined by the IRC

Secondary efficacy endpoints:
-
CR at the Primary Response Assessment based on PET-CT, as determined by 
the investigator
-
OR (CR or PR) at the Primary Response Assessment based on PET-CT, as 
determined by the investigator and IRC
-
BOR (CR or PR) while on study either by PET-CT or CT only, as determined by 
the investigator and IRC
-
DOR based on PET-CT or CT only, as determined by the investigator and IRC 
-
PFS based on PET-CT or CT only, as determined by the investigator and IRC 
-
EFS based on PET-CT or CT only, as determined by the investigator
-
OS
6.4.1
Primary Efficacy Endpoint
CR at Primary Response Assessment (68 weeks after Cycle 6, Day 1 or last dose of 
study drug) as measured by PET-CT scan and as determined by an IRC will be used as
the primary efficacy endpoint.  This primary efficacy endpoint applies to the Phase II 
randomized cohorts treated with polatuzumab vedotin plus BR versus BR, as well as 
Arm H of the NF Cohort (individually and together with Arm G). The CR rate, defined as 
the percentage of patients with CR, will be estimated and the corresponding 
Clopper-Pearson exact 95% CI will be constructed for each treatment arm.  The 
difference in CR rates between the combination of polatuzumab vedotinBR and BR 
randomized arms will be estimated along with the corresponding 95% CI on the basis of 
normal approximation to the binomial distribution.  An exploratory comparison of CR 
rates for the BR-containing regimens will be conducted using the Cochran Mantel 
Haenszel 2 test adjusted for randomization stratification factors (Agresti 2002).
Response assessment is determined using the Modified Lugano Response Criteria 
(Cheson et al. 2014) specified in Appendix 4.


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6.4.2
Secondary Efficacy Endpoints
Response rate is defined as the percentage of patients with CR, OR, or BOR as 
described below.  For the endpoint of objective response, patients without a 
post-baseline tumor assessment will be considered non-responders. 
Analyses of these endpoints will be identical to those described above for the primary 
efficacy endpoint of CR rate measured by PET-CT scan.

CR at Primary Response Assessment based on PET-CT, as determined by the 
investigator

CR at Primary Response Assessment based on PET-CT, as determined by IRC (for 
Phase II expansion (polatuzumab vedotin plus BG cohorts) and NF Cohort (Arm G
only)

OR (CR or PR) at Primary Response Assessment based on PET-CT, as determined 
by the investigator and IRC

CR at Primary Response Assessment based on CT only, as determined by the 
investigator and IRC

OR (CR or PR) at Primary Response Assessment based on CT only, as determined 
by the investigator and IRC

BOR (CR or PR) while on study based on PET-CT or CT only, as determined by the 
investigator

DLBCL cohorts only: BOR, DOR and PFS based on PET-CT or CT only, as 
determined by IRC and investigator (see Section 6.4.3 for a description of DOR and 
PFS determination)

NF cohort only:  OS and EFS based on PET-CT or CT only, as determined by the 
investigator
6.4.3
Exploratory Efficacy Endpoints
Among patients with a best overall response of CR or PR, DOR will be defined as the 
time from the initial CR or PR to the time of disease progression, relapsed or death from 
any cause, whichever occurs first.  If a patient does not experience death or disease 
progression before the end of the study, DOR will be censored on the date of the last 
tumor assessment.  DOR will be summarized descriptively with use of the Kaplan-Meier 
method (Kaplan and Meier 1958).  If analytically possible, median DOR will be estimated, 
along with the corresponding 95% CI using the method of Brookmeyer and Crowley 
(1982).  No formal comparisons of DOR across treatment arms will be conducted.
PFS is defined as the period from the date of randomization or first treatment for 
non-randomized arms until the date of disease progression, relapse, or death from any 
cause, whichever occurs first.  For patients who have not progressed, relapsed, or died 
at the time of analysis, PFS will be censored on the date of last tumor assessment.  If no 
tumor assessments were performed after the Screening Visit, PFS will be censored at 
the date of randomization/first treatment.  The distribution of times for PFS will be 


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summarized descriptively using the Kaplan-Meier method (Kaplan and Meier 1958) to 
estimate median (if analytically possible), 1-year, and 2-year PFS and 95% CIs using 
Greenwood’s formula. 
EFS is defined as the time from date of randomization or first treatment for 
non-randomized arms to any treatment failure including disease progression, relapse, 
initiation of NALT, or death, whichever occurs first.  If the specified event (disease 
progression/relapse, death, start of an NALT) does not occur, patients will be censored 
at the date of last tumor assessment. For patients who do not have post-baseline tumor 
assessments or documentation of NALT, EFS will be censored at the time of 
randomization/first treatment.
OS is defined as the time from date of randomization or first treatment for 
non-randomized arms until the date of death from any cause.  Patients who have not 
died will be censored at the last date known to be alive.  
Analyses of EFS and OS will be identical to those outlined previously for PFS. 
Duration of follow-up will be estimated by reverse Kaplan-Meier method (Schemper and 
Smith 1996).
6.5
SAFETY ANALYSES
Safety will be assessed through summaries of adverse events, summaries of changes 
from screening assessments in laboratory test results, ECGs, and changes in vital signs.
All collected adverse event data will be summarized by phase of the study, treatment 
arm, and histological subtype.  All adverse events occurring on or after first study 
treatment will be summarized by mapped term, appropriate thesaurus levels, and 
NCI CTCAE v4.03 toxicity grade.  All serious adverse events will be listed separately 
and summarized.
Deaths reported during the study treatment period and those reported during follow-up 
after treatment discontinuation will be listed.
Relevant laboratory and vital sign (temperature, heart rate, respiratory rate, pulse 
oximetry, and blood pressure) data will be displayed by time, with NCI CTCAE v4.03
Grade 3 and 4 values identified where appropriate.
6.6
PHARMACOKINETIC ANALYSES
Individual and mean serum and plasma concentrations of polatuzumab vedotin, 
bendamustine, rituximab, and obinutuzumab versus time data will be tabulated and 
plotted.  Summary statistics of concentration data will be computed for each scheduled 
sampling time for each analyte.  PK parameters, such as AUC, Cmax, systemic CL, and 
Vss may be estimated (as appropriate for the data collected).  Estimates for these 


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parameters will be tabulated and summarized (mean and SD).  PK parameters will be 
determined using the appropriate technique based on available data.  
Non-compartmental analysis and/or population PK analysis method may be applied for 
PK parameter estimation.  Potential drug interactions may be assessed by comparison 
of PK in the current study with historical data.  Potential correlations between PK 
variability and demographic and pathophysiological covariates may be explored by 
population PK analysis.  Potential correlations between PK variability and 
pharmacodynamic, efficacy, and safety outcome may be explored by exploratory 
graphical analysis and PK-pharmacodynamic modeling.  The assessment of PK 
parameters and related analysis will be performed per Sponsor’s discretion, based on 
the appropriateness of the PK data collected, the trial outcome, and the future 
development path for polatuzumab vedotin.
6.7
PATIENT-REPORTED OUTCOME ANALYSES
The TINAS will be scored using a corresponding user manual.  Summary statistics of the 
TINAS total and individual items with their changes from baseline will be calculated at 
each assessment timepoint.
Patients enrolled in the NF Cohort (Arm G and Arm H), receiving polatuzumab vedotin 
(lyophilized) plus BR, will be exempt from completing the TINAS.
6.8
EXPLORATORY ANALYSES
Exploratory analyses of biomarkers (see Section 2.2.5) related to tumor biology and the 
mechanisms of action of polatuzumab vedotin and rituximab or obinutuzumab will be 
conducted.  Analyses will assess prognostic and/or predictive value of candidate 
biomarkers separately for each histological subtype and both investigator and IRC 
assessed outcomes.  Specifically, the association between candidate biomarkers and 
PET-CT CR rate and OR rate and potentially other measures of efficacy and safety, 
independent of treatment, will be explored to assess potential prognostic value.  In 
addition, the potential effect modification of treatment effect on PET-CT CR rate and OR 
rate and potentially other measures of efficacy and safety, by biomarker status, will be 
explored to assess potential predictive value.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and other 


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electronic data will be sent directly to the Sponsor, using the Sponsor’s standard 
procedures to handle and process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
ePRO data will be collected through use of an electronic device.  This device will be the 
patient’s own electronic devices (i.e., mobile phone, tablet, or home computer) to ensure 
the secure collection and transmission of the data.  The software is designed for entry of 
data in a way that is attributable, secure, accurate, and in compliance with U.S. FDA 
regulations for electronic records (21 Code of Federal Regulations [CFR] Part 11).  The 
ePRO device data are available for view access only via secure access to a Web server.  
Only identified and trained users may view the data, and their actions become part of the 
audit trail.  The Sponsor will have view access only.  System backups for data stored by 
the Sponsor and records retention for the study data will be consistent with the 
Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
Patients will use an ePRO device to capture PRO data.  This device will be the patient’s 
own electronic devices (i.e., mobile phone, tablet, or home computer) to ensure the 
secure collection and transmission of the data.  The data will be transmitted via Web or 
wireless automatically to a centralized database at the ePRO vendor.
Once the study is complete, the ePRO data, audit trail, and trial and system 
documentation will be archived.  The investigator will receive patient data for the site in 
both human- and machine-readable formats on an archival-quality compact disc that 
must be kept with the study records as source data at the end of study.  
Acknowledgement of receipt of the compact disc is required.  In addition, the Sponsor 
will receive all patient data in a machine-readable format on a compact disc.


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7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.
Source documents (paper or electronic) are 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, 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 7.6.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of 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.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), ICFs, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for 15 years 
after completion or discontinuation of the study, or for the length of time required by 


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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.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki, or the applicable 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 or European Economic Area will comply 
with the E.U. Clinical Trial Directive (2001/20/EC) and applicable local, regional, and 
national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample ICF (and ancillary sample ICFs such as a Child’s Assent or 
Caregiver's ICF, 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 ICFs or 
any alternate consent forms proposed by the site (collectively, the Consent Forms) 
before IRB/EC submission.  The final IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research.  The investigator or authorized designee will 
explain to each patient the objectives of the exploratory research.  Patients will be told 
that they are free to refuse to participate and may withdraw their specimens at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to allow any remaining specimens to be 
used for exploratory research.  Patients who decline to participate will not provide a 
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The ICFs 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 ICFs 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 ICFs must be provided to the Sponsor 
for health authority submission purposes.
If the consent forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative
must re-consent by signing the most current version of the ICFs or to the addendum, in 
accordance with applicable laws and IRB/EC policy.  For any updated or revised ICFs, 
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 ICFs 
for continued participation in the study.
A copy of each signed ICF must be provided to the patient or the patient’s legally 
authorized representative.  All signed and dated ICFs 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 ICF 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 ICFs, any information to be given to the patient, and relevant 
supporting information must be submitted to the IRB/EC by the Principal Investigator and 
reviewed and approved by the IRB/EC before the study is initiated.  In addition, any 
patient recruitment materials must be approved by the IRB/EC.
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 


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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 ICF (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.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted clinical study reports and other summary reports will be provided upon 
request (see Section 9.5).
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 


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course of the study and for 1 year after completion of the study (i.e., last patient last visit 
[LPLV]).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, ICF, 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
In the United States, this trial will be sponsored and managed by Genentech, Inc.  
F. Hoffmann-La Roche Ltd will sponsor this trial outside of the United States, with 
management responsibilities shared by Genentech and Roche.  Genentech and Roche 
have authorized Roche Registrations Ltd, a company formed under the laws of England, 
to act as their legally authorized representative for the purposes of Article 19 of Directive 
2001/20/EC relating to the implementation of GCP in the conduct of clinical trials on 
medicinal products for human use.  Reference to Sponsor in this protocol will mean 
Genentech for the United States and F. Hoffmann-La Roche Ltd for countries outside of 
the United States.
Electronic data capture 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 4.5.8; otherwise, local laboratories will be used.  A central 


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independent review facility will be used to collect CT and PET-CT scans, and the IRC 
will perform independent assessments of response for all patients enrolled in the study.
9.5
DISSEMINATION 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, in clinical trial registries and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical
Trials Data at the following website:
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.


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9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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Appendix 1
Schedule of Activities (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
164/Protocol GO29365, Version 8
BGbendamustineobinutuzumab; BRbendamustinerituximab; BSAbody surface area; Ccycle; CRcomplete response; DLBCL diffuse 
large B-cell lymphoma; ECOG PSEastern Cooperative Oncology Group Performance Status; eCRFelectronic Case Report Form; 
FLIPIFollicular Lymphoma International Prognostic Index; FUfollow-up; IPIInternational Prognostic Index; MRDminimal residual disease; 
NAnot applicable; NFnew formulation; PET-CTpositron emission tomography/computed tomography; PKpharmacokinetic; R/R relapsed or 
refractory; TINASTherapy-Induced Neuropathy Assessment Scale; (x) conditional/optional (refer to footnote).
Notes: Assessments shaded in gray should be performed as scheduled for patients with FL on Cycle 1, Day 22 because treatment is administered 
on a 28-day cycle.  Patients with DLBCL will not need the Cycle 1, Day 22 assessment because treatment is administered on a 21-day cycle.  With 
consent to optional research, residual tissue and blood samples will be stored in the RCR (see Section 4.5.11).  Arm GNF Cohort of R/R DLBCL 
treated with lyophilized polatuzumab vedotin plus BR. Arm HNF Cohort of R/R DLBCL treated with lyophilized polatuzumab vedotin plus BR.
a On treatment days, all assessments must be performed on the day of the specified visit unless a time window is specified in this schedule of 
assessments.  On treatment days, pre-infusion laboratory samples should be drawn 0–4 hours before the start of infusion, and post-infusion 
laboratory samples should be drawn 030 minutes after the end of infusion, unless otherwise specified.  
b Local laboratory assessments and targeted physical examination may be performed within 72 hours preceding Cycle 1, Day 1 administration 
unless otherwise specified; pre-infusion laboratory samples should be drawn 04 hours prior to infusion.
c Visit not specified by the protocol.  Assessments (possibly including hematology and/or chemistry sample collection) should be performed as 
clinically indicated.
d Patients who complete the treatment period will return to the clinic for a treatment completion visit at 30 (5) days after Cycle 6, Day 1.  Patients 
who discontinue study drug prematurely will return to the clinic for a treatment discontinuation visit 30 (5) days after the last dose of study drug.  
The visit at which response assessment shows progressive disease may be used as the treatment discontinuation visit.
e Following completion of treatment, patients who have not progressed will be followed clinically every 3 months (14 days) until the end of Year 2 
from treatment completion visit.  Patients will then be followed every 6 months until disease progression, study withdrawal, end of study, or death, 
whichever comes first.  Follow-up visit intervals should be determined from treatment completion visit.
f
If the study completion/discontinuation visit is simultaneous with other visits in the schedule of assessments, do not duplicate assessments that
are common in both of the visits.  These assessments should be entered in the study completion or early discontinuation visit only.
g Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained no more than 28 days 
before initiation of study treatment.
h 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 screening to the study treatment completion visit, which is 30 (5) days after the last dose of 
study treatment.  All such medications should be reported to the investigator and recorded on the Concomitant Medications eCRF.  Please see 
Section 4.4.1.


Appendix 1
Schedule of Activities (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
165/Protocol GO29365, Version 8
i
After informed consent has been obtained, but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 90 days after the last dose of study drug.  
After this period, the investigator is not required to actively monitor patients for adverse events; however, the Sponsor should be notified if the 
investigator becomes aware of any post-study serious adverse events or non-serious adverse events of special interest (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 study drug or trial-related procedures until a final outcome can be reported.
j
Complete physical exam 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.  As part of tumor assessment, physical examinations should also include the evaluation of the presence and 
degree of enlarged lymph nodes, hepatomegaly, and splenomegaly (clinical response assessment), which will be recorded on the appropriate 
Tumor Assessment eCRF.  At subsequent visits (or as clinically indicated), limited, symptom-directed (targeted) physical examinations should be 
performed.  
k Targeted physical examinations should be limited to systems of primary relevance (i.e., cardiovascular, respiratory, those associated with 
symptoms, and those associated with tumor assessment [lymph nodes, liver, and spleen]).  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
l
All patients, except those in Arm G and Arm H, should undergo a Total Neuropathy Score Clinical Assessment (to include subjective sensory 
symptoms, motor symptoms, autonomic symptoms; to include objective pinprick sensitivity, vibration sensitivity, strength testing and deep tendon 
reflex testing) to determine their total neuropathy score on all indicated visits prior to administration of study treatment. 
m Vital signs to include respiratory rate, pulse rate, pulse oximetry, and systolic and diastolic blood pressures while the patient is in a seated 
position, and temperature.  On polatuzumab vedotin infusion days, 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 
30 (10) minutes following completion of dosing in subsequent cycles.  On rituximab infusion days, vital signs should be obtained before the 
infusion of rituximab and at the end of the rituximab infusion. Additional vital signs measurements are to be obtained as per each institution’s 
standard of care and as clinically indicated. On obinutuzumab infusion days, vital signs are to be obtained before infusion of obinutuzumab, then 
after the start of the infusion approximately every 15 (5) minutes for 90 minutes, then every 30 (10) minutes until 1 hour after the end of the 
infusion for Cycle 1.  During administration of obinutuzumab in subsequent cycles, vital signs are to be obtained before infusion of obinutuzumab, 
then after the start of the infusion, approximately every 30 minutes (10) minutes until 1 hour after the end of infusion.
n Height is required at screening only.  BSA is required at screening only unless there has been 10% change in body weight since the last BSA 
assessment, in which case BSA should be recalculated and documented on the eCRF.  It is recommended that the Mosteller BSA formula 
(Mosteller et al.1987) be used; however, BSA may be calculated using the investigator’s preferred formula.


Appendix 1
Schedule of Activities (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
166/Protocol GO29365, Version 8
o The Therapy-Induced Neuropathy Assessment Scale (TINAS) is the patient-reported outcomes instrument.  TINAS should be completed weekly 
during the course of study treatment.  On study visit days, TINAS should be completed before all other assessments during the study visit.  
Following the study treatment period, the TINAS will be completed once a week for the first 2 months, then once per month for the next 10 
months.  Patients in Arm G and Arm H will be exempt.
p Clinical response assessment of tumor conducted via physical examination.
q Imaging should be PET-CT at screening, Interim Response Assessment (between Cycle 3, Day 15 and Cycle 4, Day 1) and Primary Response
Assessment Visit.  All other imaging may be CT only.  Response assessment will be performed using the Revised Response Criteria for 
Malignant Lymphoma and Modified Lugano Response Criteria (see Appendix 4).
r
Screening PET-CT must not be obtained more than 35 days prior to Cycle 1, Day 1.  
s Scan (CT or PET-CT) should be performed during follow up every 6 months for 2 years or until study end or at any time that progression is 
suspected via clinical response assessment.  
t
Scan not necessary if patient has already had a scan within the last 30 days.
u For patients who will receive either polatuzumab vedotinBR or BR alone, rituximab 375 mg/m2 will be administered on Day 1 of each cycle.  
Rituximab should be administered after premedication with oral acetaminophen/paracetamol and an antihistamine. 
v For patients who will receive polatuzumab vedotinBG, obinutuzumab 1000 mg will be administered on Days 1, 8, and 15 of Cycle 1, then on 
Day 1 of each subsequent cycle.  Obinutuzumab should be administered after premedication with oral acetaminophen/paracetamol and an
antihistamine. 
w Polatuzumab vedotin will be administered on Day 2 of Cycle 1.  If well tolerated, then all study treatment may be administered on the same day 
(Day 1 of subsequent cycles) during subsequent cycles. 
x Bendamustine 90 mg/m2 will administered on Days 2 and 3 of Cycle 1, then on Days 1 and 2 of each subsequent cycle.  
y Hematology includes hemoglobin, hematocrit, RBC count, WBC count, platelet count, and percent or absolute WBC count differential 
(neutrophils, bands, lymphocytes, eosinophils, basophils, and monocytes).  Results should be obtained within 3 days before study treatment 
administration.  
z Serum chemistry includes sodium, potassium, chloride, bicarbonate, glucose, BUN/urea, creatinine, calcium, magnesium, phosphorus, total 
bilirubin, direct bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, LDH, uric acid/urate, hemoglobin A1c (HbA1c), amylase and 
lipase.  At screening, all samples for laboratory test will be obtained in a fasting state for all patients.  HbA1c will only be measured at screening 
and at Cycle 4, Day 1 and can be obtained in a non-fasting state.  Only at screening, obtain -2 microglobulin.  Results should be obtained within 
3 days before study treatment administration.
aa INR and/or, PT, and PTT or aPTT.  Results should be obtained within 3 days before study treatment administration.


Appendix 1
Schedule of Activities (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
167/Protocol GO29365, Version 8
bb Hepatitis B (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [HBsAb], and total hepatitis B core antibody [HBcAb]) and hepatitis 
C virus (HCV) antibody serology required. Patients with positive [HBcAb and negative HBsAg) must undergo monthly HBV-DNA testing by 
polymerase chain reaction (PCR) on day 1 of each cycle during study treatment and for at least 12 months after the study treatment completion.  
If the patient is HCV-antibody positive, then HCV RNA by PCR is required.  HIV testing will be performed at screening if required by the health 
authority overseeing the study site.
cc All women who are not postmenopausal (12 months of non-therapyinduced amenorrhea) or surgically sterile will have a serum pregnancy test 
at screening within 7 days before Cycle 1, Day 1.  In addition, for women of childbearing potential, a serum or urine pregnancy test must be 
performed prior to Day 1 of each subsequent cycle of study treatment (laboratory samples may be obtained up to 72 hours before start of study 
treatment administration on Day 1 of the treatment cycle).  If any urine pregnancy test is positive, study treatment will be delayed until the patient 
pregnancy status is confirmed by a serum pregnancy test.  If serum pregnancy test is positive, the patient will be permanently discontinued from 
study treatment.
dd Bone marrow biopsy and aspirate are mandatory in all patients at screening and should include biopsy for morphology.  The bone marrow 
assessment must be performed within 3 months of the Cycle 1, Day 1.  For patients with bone marrow involvement (presence of lymphoma) at 
screening, a repeat bone marrow biopsy and aspirate should be repeated at the primary response assessment in patients who achieve 
radiologic complete response or if there is clinical suspicion of progressive disease in the bone marrow in the absence of progressive disease as 
demonstrated by radiographic imaging.  Bone marrow assessments will be performed locally.
ee Availability of archival or freshly biopsied tumor tissue samples should be confirmed at screening.  For construction of a tissue microarray, tumor 
block or punch biopsy of the tumor block are required.  Fresh tissue sections will be generated from tissue microarrays to study proteins that 
have limited stability in tissue sections.  Remainders of archival tissue blocks will be returned to sites upon request according to country-specific 
procedures.  Tumor tissue biopsy at disease progression is optional.  See Section 4.1.3.  Patients in Arm G will be exempt.
ff Peripheral blood sample (10-mL per sample) for MRD analysis in all patients at Cycle 1, Day 1 (prior to dosing), between Cycle 3, Day 15 and 
Cycle 4, Day 1, and at the Primary Response Assessment Visit.  Patients in Arm G and Arm H will be exempt.
gg Lymphocyte subsets at baseline, Primary Response Assessment Visit, and every 6 months (counting from the treatment completion visit) until 
the end of study or patient discontinuation.
hh During the follow-up period (i.e., after treatment completion):  For patients who have progressive disease and have not started new 
anti-lymphoma therapy, follow-up should consist of recording of first new anti-lymphoma therapy, adverse events, and survival and continue to 
follow the above schedule.  For patients who have progressive disease and started a new anti-lymphoma therapy, contact will be made by 
telephone on at least an annual basis for survival.  For patients who started a new anti-lymphoma therapy but do not have progressive disease, 
assessments should be followed according to schedule.  See Section 4.5.11.3.


Appendix 1
Schedule of Activities (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
168/Protocol GO29365, Version 8
ii Tissue sample applies only to Arm G and Arm H, and will be submited prior to starting Cycle 1, Day 1.  Central pathology review of pathology 
reports and previously collected tissue samples will be performed for all DLBCL patients.  If needed, additional slides may be requested for 
patients in the main study.  
jj For patients who progress prior to the anticipated Primary Response Assessment visit, the visit at which response assessment shows 
progressive disease may be used as the Primary Response Assessment.


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
169/Protocol GO29365, Version 8
Appendix 2
Pharmacokinetic and Anti-Drug Antibody Sampling Schedule
Table 1
Phase Ib Pharmacokinetic and Anti-Drug Antibody Sampling Schedule for Patients Treated with 
Polatuzumab Vedotin plus BR
The pharmacokinetic (PK) sampling schedule below is applicable to patients who receive the rituximab-containing regimen in the 
Phase Ib portion of the study.  Per the sampling schedule (see below), 21 PK samples will be collected from each patient treated with 
polatuzumab vedotin plus bendamustine and rituximab (BR). Ideally, all PK samples and anti-drug antibody samples will be drawn 
from the arm opposite from the infusion arm.  In patients with indwelling catheters, a PK sample may be drawn from the catheter after 
sample flushing.
Study Visit
Sample Timepoint
Samples a
Cycle 1, Day 2
Pre-polatuzumab vedotin infusion
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) b
End of polatuzumab vedotin infusion
Polatuzumab vedotin PK (serum and plasma) b
Cycle 1, Day 8
6 days (1 day) after Day 2 infusion 
Polatuzumab vedotin PK (serum and plasma) b
Cycle 1, Day 15
13 days (1 day) after Day 2 infusion
Polatuzumab vedotin PK (serum and plasma) b
Cycle 2, Day 1
Pre-polatuzumab vedotin infusion
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) b
End of polatuzumab vedotin infusion
Polatuzumab vedotin PK (serum and plasma) b
Cycle 4, Day 1
Pre-polatuzumab vedotin dose
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) b
End of polatuzumab vedotin infusion
Polatuzumab vedotin PK (serum and plasma) b
Post-treatment 
(Follow-up visit at Months 3, 6, 12, 18, and 24)
Random sample
Polatuzumab vedotin ADA (serum)
Polatuzumab vedotin concentration (serum)


Appendix 2
Pharmacokinetic and Anti-Drug Antibody Sampling Schedule (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
170/Protocol GO29365, Version 8
ADAanti-drug antibody; MMAEmonomethyl auristatin E; PKpharmacokinetic.
Notes:  Pre-infusion samples should be drawn 04 hours before the start of infusion.  End-of-infusion samples should be drawn 30 minutes 
(15 minutes) unless otherwise specified.
a Up to 11-mL whole-blood samples will be taken for polatuzumab vedotin PK (polatuzumab vedotin total antibody, unconjugated MMAE, and 
conjugate [evaluated as antibody-conjugated MMAE), polatuzumab vedotin ADA, and polatuzumab vedotin concentration sample at each 
specified timepoint with separate tubes for plasma or serum samples. 
b Polatuzumab vedotin PK, including serum PK samples for total antibody and plasma PK samples for conjugate (evaluated as antibody-conjugated 
MMAE) and unconjugated MMAE.


Appendix 2
Pharmacokinetic and Anti-Drug Antibody Sampling Schedule (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
171/Protocol GO29365, Version 8
Table 2
Phase Ib Pharmacokinetic and Anti-Drug Antibody Sampling Schedule for Patients Treated with 
Polatuzumab Vedotin plus BG
The pharmacokinetic (PK) sampling schedule below is applicable to patients who receive the obinutuzumab-containing regimen in the 
Phase Ib portion of the study.  Per the sampling schedule (see below), 37 samples will be collected from each patient treated with 
polatuzumab vedotin plus bendamustine and obinutuzumab (BG).  Ideally, all PK samples and anti-drug antibody samples will be 
drawn from the arm opposite from the infusion arm.  In patients with indwelling catheters, a PK sample may be drawn from the 
catheter after sample flushing.
Study Visit
Sample Timepoint
Samples a
Cycle 1, Day 1
Pre-obinutuzumab infusion
Obinutuzumab ADA (serum), 
Obinutuzumab concentration (serum)
Cycle 1, Day 2
Pre-polatuzumab vedotin infusion
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) b
End of polatuzumab vedotin infusion
Polatuzumab vedotin PK (serum and plasma) b
Cycle 1, Day 8
6 days (1 day) after Day 2 infusion
Polatuzumab vedotin PK (serum and plasma) b
Cycle 1, Day 15
13 days (1 day) after Day 2 infusion
Polatuzumab vedotin PK (serum and plasma) b
Cycle 2, Day 1
Pre-obinutuzumab infusion
Obinutuzumab ADA (serum), 
Obinutuzumab concentration (serum)
Pre-polatuzumab vedotin infusion 
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) b
End of polatuzumab vedotin infusion
Polatuzumab vedotin PK (serum and plasma) b
Cycle 4, Day 1 
Pre-obinutuzumab infusion
Obinutuzumab ADA (serum), 
Obinutuzumab concentration (serum)


Appendix 2
Pharmacokinetic and Anti-Drug Antibody Sampling Schedule (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
172/Protocol GO29365, Version 8
Study Visit
Sample Timepoint
Samples a
Pre-polatuzumab vedotin dose
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) b
End of polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b
Post-treatment (Follow-up 
visit at Months 3, 6, 12, 
18, and 24)
Random sample
Obinutuzumab ADA (serum), 
Obinutuzumab concentration sample (serum), 
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin concentration sample (serum)
ADAanti-drug antibody; MMAEmonomethyl auristatin E; PKpharmacokinetic.
Notes:  Pre-infusion samples should be drawn 04 hours before the start of infusion.  End-of-infusion samples should be drawn 30 minutes 
(15 minutes) unless otherwise specified.
a Up to 19-mL whole-blood samples will be taken for polatuzumab vedotin PK (polatuzumab vedotin total antibody, unconjugated MMAE, and 
conjugate [evaluated as antibody-conjugated MMAE), polatuzumab vedotin ADA, polatuzumab vedotin concentration, obinutuzumab ADA, 
and obinutuzumab concentration at each specified timepoint with separate tubes for plasma or serum samples.
b Polatuzumab vedotin PK, including serum PK samples for total antibody and plasma PK samples for conjugate (evaluated as antibody-
conjugated MMAE) and unconjugated MMAE.


Appendix 2
Pharmacokinetic and Anti-Drug Antibody Sampling Schedule (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
173/Protocol GO29365, Version 8
Table 3
Phase II Pharmacokinetic and Anti-Drug Antibody Sampling Schedule for Patients Treated with 
Polatuzumab Vedotin plus BR
The pharmacokinetic (PK) sampling schedule below is applicable to all patients who receive polatuzumab vedotin plus BR in the
Phase II randomized portion of the study.  Approximately 30 samples will be collected per patient treated with polatuzumab vedotin 
plus BR during Phase II.  Ideally, all PK samples and anti-drug antibody samples will be drawn from the arm opposite from the infusion 
arm.  In patients with indwelling catheters, a PK sample may be drawn from the catheter after sample flushing.
Study Visit
Sample Timepoint
Samples a
Cycle 1, Day 1
Pre-rituximab infusion
Rituximab PK (serum) b
End of rituximab infusion
Rituximab PK (serum) b
Cycle 1, Day 2
Pre-polatuzumab vedotin infusion
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) b
End of polatuzumab vedotin infusion
Polatuzumab vedotin PK (serum and plasma) b 
Pre-bendamustine infusion
Bendamustine PK (plasma)
Immediately after end of bendamustine 
infusion (5 minutes)
Bendamustine PK (plasma)
1 hour post-bendamustine infusion 
(5 minutes)
Bendamustine PK (plasma)
2 hour post-bendamustine infusion 
(5 minutes)
Bendamustine PK (plasma)
3 hour post-bendamustine infusion 
(5 minutes)
Bendamustine PK (plasma)
4 hour post-bendamustine infusion 
(5 minutes)
Bendamustine PK (plasma)


Appendix 2
Pharmacokinetic and Anti-Drug Antibody Sampling Schedule (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
174/Protocol GO29365, Version 8
Study Visit
Sample Timepoint
Samples a
Cycle 2, Day 1
Pre-rituximab infusion 
Rituximab PK (serum) b
Pre-polatuzumab vedotin infusion 
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) b
Cycle 4, Day 1 
Pre-rituximab dose
Rituximab PK (serum)
Pre-polatuzumab vedotin infusion
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) b
End of polatuzumab vedotin infusion
Polatuzumab vedotin PK (serum and plasma) b
Treatment Completion Visit 
Approximately 1530 days after last infusion Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) b
Post-treatment 
(Follow-up visit at Months 3, 6, 12, 18, and 24)
Random sample
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin concentration (serum)
ADAanti-drug antibody; MMAEmonomethyl auristatin E; PKpharmacokinetic. 
Notes:  Pre-infusion samples should be drawn 0-4 hours before the start of infusion.  End-of-infusion samples should be drawn 30 minutes 
(15 minutes) unless otherwise specified.
a Up to 11-mL whole-blood samples will be taken for rituximab PK, polatuzumab vedotin PK (polatuzumab vedotin total antibody, unconjugated 
MMAE and conjugate [evaluated as antibody-conjugated MMAE), polatuzumab vedotin anti-drug antibody, polatuzumab vedotin 
concentration, and bendamustine PK at each specified timepoint with separate tubes for plasma or serum samples.
b Polatuzumab vedotin PK, including serum PK samples for total antibody and plasma PK samples for conjugate (evaluated as antibody-
conjugated MMAE) and unconjugated MMAE.


Appendix 2
Pharmacokinetic and Anti-Drug Antibody Sampling Schedule (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
175/Protocol GO29365, Version 8
Table 4
Phase II Pharmacokinetic Sampling Schedule for Patient Treated with BR Alone
The pharmacokinetic (PK) sampling schedule below is applicable to all patients who receive BR in the Phase II randomized portion of 
the study.  Approximately 10 samples will be collected per patient treated with BR during Phase II.  Ideally, all PK samples and 
anti-drug antibody samples will be drawn from the arm opposite from the infusion arm.  In patients with indwelling catheters, a PK 
sample may be drawn from the catheter after sample flushing.
Study Visit
Sample Timepoint
Samples a
Cycle 1, Day 1
Pre-rituximab infusion
Rituximab PK (serum)
End of rituximab infusion
Rituximab PK (serum)
Cycle 1, Day 2
Pre-bendamustine infusion
Bendamustine PK (plasma)
Immediately after end of bendamustine infusion (5 minutes)
Bendamustine PK (plasma)
1 hour post-bendamustine infusion (5 minutes)
Bendamustine PK (plasma)
2 hour post-bendamustine infusion (5 minutes)
Bendamustine PK (plasma)
3 hour post-bendamustine infusion (5 minutes)
Bendamustine PK (plasma)
4 hour post-bendamustine infusion (5 minutes)
Bendamustine PK (plasma)
Cycle 2, Day 1
Pre-rituximab infusion
Rituximab PK (serum)
Cycle 4, Day 1 
Pre-rituximab dose
Rituximab PK (serum)
PKpharmacokinetic. 
Notes:  Pre-infusion samples should be drawn 04 hours before the start of infusion.  End of infusion samples should be drawn 30 minutes 
(15 minutes) unless otherwise specified.
Up to 5-mL whole-blood samples will be taken for rituximab PK and bendamustine PK at each specified timepoint with separate tubes for plasma or 
serum sample


Appendix 2
Pharmacokinetic and Anti-Drug Antibody Sampling Schedule (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
176/Protocol GO29365, Version 8
Table 5
Phase II Pharmacokinetic Sampling and Anti-Drug Antibody Schedule for Patients Treated with 
Polatuzumab Vedotin plus BG
The pharmacokinetic (PK) sampling schedule below is applicable to all patients who receive polatuzumab vedotin plus BG in the 
Phase II expansion portion of the study.  Approximately 46 samples will be collected per patient treated with polatuzumab vedotin plus 
BG during Phase II.  Ideally, all PK samples and anti-drug antibody samples will be drawn from the arm opposite from the infusion arm.  
In patients with indwelling catheters, a PK sample may be drawn from the catheter after sample flushing.
Study Visit
Sample Timepoint
Samples a
Cycle 1, Day 1
Pre-obinutuzumab infusion
Obinutuzumab ADA (serum), 
Obinutuzumab PK (serum) b
End of obinutuzumab infusion
Obinutuzumab PK (serum) b
Cycle 1, Day 2
Pre-polatuzumab vedotin infusion 
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) b
End of polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b
Pre-bendamustine infusion
Bendamustine PK (plasma)
Immediately after end of bendamustine infusion (5 minutes)
Bendamustine PK (plasma)
1 hour post-bendamustine infusion (5 minutes)
Bendamustine PK (plasma)
2 hour post-bendamustine infusion (5 minutes)
Bendamustine PK (plasma)
3 hour post-bendamustine infusion (5 minutes)
Bendamustine PK (plasma)
4 hour post-bendamustine infusion (5 minutes)
Bendamustine PK (plasma)


Appendix 2
Pharmacokinetic and Anti-Drug Antibody Sampling Schedule (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
177/Protocol GO29365, Version 8
Study Visit
Sample Timepoint
Samples a
Cycle 2, Day 1
Pre-obinutuzumab infusion
Obinutuzumab ADA (serum), 
Obinutuzumab PK (serum) b
Pre-polatuzumab vedotin infusion 
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) b
Cycle 4, Day 1 
Pre-obinutuzumab infusion
Obinutuzumab ADA (serum), 
Obinutuzumab PK (serum) b
End of obinutuzumab infusion
Obinutuzumab PK (serum) b
Pre-polatuzumab vedotin infusion
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) b
End of polatuzumab vedotin infusion 
Polatuzumab vedotin PK (serum and plasma) b
Treatment Completion Visit
Approximately 1530 days after last infusion Obinutuzumab ADA (serum), 
Obinutuzumab PK (serum), b
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) b
Post-treatment 
(Follow-up visit at Months 3, 6, 12, 18, and 
24)
Random sample
Obinutuzumab ADA (serum), 
Obinutuzumab concentration (serum), 
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin concentration (serum)


Appendix 2
Pharmacokinetic and Anti-Drug Antibody Sampling Schedule (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
178/Protocol GO29365, Version 8
ADAanti-drug antibody; MMAEmonomethyl auristatin E; PKpharmacokinetic.
Notes:  Pre-infusion samples should be drawn 04 hours before the start of infusion.  End of infusion samples should be drawn 30 minutes 
(15 minutes) unless otherwise specified.
a Up to 19-mL whole-blood samples will be taken for obinutuzumab PK, obinutuzumab ATA, obinutuzumab concentration, polatuzumab 
vedotin PK (polatuzumab vedotin total antibody, unconjugated MMAE and conjugate [evaluated as antibody-conjugated MMAE]), 
polatuzumab vedotin ATA, polatuzumab vedotin concentration, bendamustine PK at each specified point with separate tubes for plasma or 
serum samples.
b Polatuzumab vedotin PK, including serum PK samples for total antibody and plasma PK samples for conjugate (evaluated as antibody-
conjugated MMAE) and unconjugated MMAE.


Appendix 2
Pharmacokinetic and Anti-Drug Antibody Sampling Schedule (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
179/Protocol GO29365, Version 8
Table 6
Phase II Pharmacokinetic Sampling and Anti-Drug Antibody Schedule for the NF Cohort (Arm G) for 
Patients Treated with Polatuzumab Vedotin (Lyophilized) plus BR
Study Visit
Sample Timepoint a
Samples b
Cycle 1, Day 2
Pre-polatuzumab vedotin infusion
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) c
End of polatuzumab vedotin infusion
Polatuzumab vedotin PK (serum and plasma) c
Cycle 1, Day 8
6 days (1 day) after Day 2 infusion 
Polatuzumab vedotin PK (serum and plasma) c
Cycle 1, Day 15
13 days (1 day) after Day 2 infusion
Polatuzumab vedotin PK (serum and plasma) c
Cycle 2, Day 1
Pre-polatuzumab vedotin infusion
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) c
End of polatuzumab vedotin infusion
Polatuzumab vedotin PK (serum and plasma) c
Cycle 3, Day 1
Pre-polatuzumab vedotin infusion
Polatuzumab vedotin PK (serum and plasma) c
End of polatuzumab vedotin infusion
Polatuzumab vedotin PK (serum and plasma) c
Cycle 3, Day 8
7 days (1 day) after Day 1 infusion
Polatuzumab vedotin PK (serum and plasma) c
Cycle 3, Day 15
14 days (1 day) after Day 1 infusion
Polatuzumab vedotin PK (serum and plasma) c
Cycle 4, Day 1
Pre-polatuzumab vedotin dose
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) c
End of polatuzumab vedotin infusion
Polatuzumab vedotin PK (serum and plasma) c
Treatment Completion/Early 
Termination Visit
Approximately 30 days 5 after last infusion 
Polatuzumab vedotin ADA (serum), 
Polatuzumab vedotin PK (serum and plasma) c
Post-treatment 
(Follow-up visit at Months 3, 6, and 
12)
Random sample
Polatuzumab vedotin ADA (serum) 
Polatuzumab vedotin concentration (serum only)
ADAanti-drug antibody; MMAEmonomethyl auristatin E; PKpharmacokinetic.


Appendix 2
Pharmacokinetic and Anti-Drug Antibody Sampling Schedule (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
180/Protocol GO29365, Version 8
a
Pre-infusion samples should be drawn 04 hours before the start of infusion.  End-of-infusion samples should be drawn 30 minutes 
(15 minutes) after the end of infusion unless otherwise specified.
b Up to11-mL whole-blood samples will be taken for polatuzumab vedotin PK (polatuzumab vedotin total antibody, unconjugated MMAE, and 
conjugate [evaluated as antibody-conjugated MMAE]), polatuzumab vedotin ADA, and polatuzumab vedotin concentration sample at each 
specified timepoint with separate tubes for plasma or serum samples. 
c Polatuzumab vedotin PK, including serum PK samples for total antibody and plasma PK samples for conjugate (evaluated as 
antibody-conjugated MMAE and unconjugated MMAE). The pharmacokinetic (PK) and anti-drug antibody (ADA) sampling schedule below is 
applicable to patients with R/R DLBCL who are participating in Arm G of the NF cohort treated with polatuzumab vedotin (lyophilized) plus BR.  
Per the sampling schedule above, approximately 12 PK sampling points will be pre-specified from each patient treated with polatuzumab vedotin 
plus bendamustine and rituximab (BR) up to Cycle 4, Day 1, and additional PK sampling points will be at treatment completion/termination visit 
and follow-up visits.  All PK samples and anti-drug antibody samples should be drawn from the arm opposite from the infusion arm.  In patients 
with indwelling catheters, a PK sample may be drawn from the catheter after sample flushing.


Appendix 2
Pharmacokinetic and Anti-Drug Antibody Sampling Schedule (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
181/Protocol GO29365, Version 8
Table 7
Phase II Pharmacokinetic Sampling and Anti-Drug Antibody Schedule for the NF Cohort (Arm H) for 
Patients Treated with Polatuzumab Vedotin (Lyophilized) plus BR
Study Visit
Sample Timepoint a
Samples b
Cycle 1, Day 2
Pre-polatuzumab vedotin infusion
Polatuzumab vedotin ADA (serum) 
Polatuzumab vedotin PK (serum and plasma) c
End of polatuzumab vedotin infusion
Polatuzumab vedotin PK (serum and plasma) c
Cycle 2, Day 1
Pre-polatuzumab vedotin dose
Polatuzumab vedotin ADA (serum) 
Polatuzumab vedotin PK (serum and plasma) c
End of polatuzumab vedotin infusion
Polatuzumab vedotin PK (serum and plasma) c
Cycle 4, Day 1
Pre-polatuzumab vedotin dose
Polatuzumab vedotin ADA (serum) 
Polatuzumab vedotin PK (serum and plasma) c
End of polatuzumab vedotin infusion
Polatuzumab vedotin PK (serum and plasma) c
Treatment Completion/Early 
Termination Visit 
Approximately 30 days 5 after last infusion 
Polatuzumab vedotin ADA (serum)
Polatuzumab vedotin PK (serum)
Post-treatment 
(Follow-up visit at Month 3)
Random sample
Polatuzumab vedotin ADA (serum)
Polatuzumab vedotin PK (serum)
ADAanti-drug antibody; BRbendamustine rituximab; MMAEmonomethyl auristatin E; NFnew formulation; PKpharmacokinetic.
a Pre-infusion samples should be drawn 04 hours before the start of infusion.  End-of-infusion samples should be drawn 30 minutes 
(15 minutes) after the end of infusion unless otherwise specified.
b Up to11-mL whole-blood samples will be taken for polatuzumab vedotin PK (polatuzumab vedotin total antibody, conjugate [evaluated as 
antibody-conjugated MMAE], and unconjugated MMAE), polatuzumab vedotin ADA, and polatuzumab vedotin concentration sample at each 
specified timepoint with separate tubes for plasma or serum samples. 
c All PK samples and anti-drug antibody samples should be drawn from the arm opposite the infusion arm.  In patients with indwelling catheters, a 
PK sample may be drawn from the catheter after sample flushing. 


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
182/Protocol GO29365, Version 8
Appendix 3
Response Criteria for Malignant Lymphoma
Response should be determined on the basis of radiographic and clinical evidence of 
disease.  For the Primary Response Assessment, an FDG-PET (18F fluorodeoxyglucose 
positron emission tomography) scan will be performed 68 weeks after Cycle 6 Day 1.  
Assessment of the PET scan should follow the criteria described by Juweid et al. 2007, 
which is presented in the table below.
COMPLETE REMISSION

Complete disappearance of all detectable clinical evidence of disease and disease 
related symptoms if present before therapy

Typically FDG avid lymphoma:  in patients with no pre-treatment PET scan or when 
the PET scan was positive before therapy, a post-treatment residual mass of any 
size is permitted as long as it is PET negative.

Variably FDG-avid lymphomas/FDG avidity unknown:  in patients without a 
pre-treatment PET scan, or if a pre-treatment PET scan was negative, all lymph 
nodes and nodal masses must have regressed on CT to normal size (1.5 cm in 
their greatest transverse diameter for nodes 1.5 cm before therapy).  Previously 
involved nodes that were 1.1 to 1.5 cm in their long axis and 1.0 cm in their short 
axis before treatment must have decreased to 1.0 cm in their short axis after 
treatment.

The spleen and/or liver, if considered enlarged before therapy on the basis of a 
physical examination or computed tomography (CT) scan, should not be palpable 
on physical examination and should be considered normal size by imaging studies, 
and nodules related to lymphoma should disappear.  However, determination of 
splenic involvement is not always reliable because a spleen considered normal in 
size may still contain lymphoma, whereas an enlarged spleen may reflect variations 
in anatomy, blood volume, the use of hematopoietic growth factors, or causes other 
than lymphoma.

If the bone marrow was involved by lymphoma before treatment, the infiltrate must 
have cleared on repeat bone marrow biopsy.  The biopsy sample on which this 
determination is made must be adequate (with a goal of 20 mm unilateral core).  If 
the sample is indeterminate by morphology, it should be negative by 
immunohistochemistry.  A sample that is negative by immunohistochemistry but that 
demonstrates a small population of clonal lymphocytes by flow cytometry will be 
considered a complete response (CR) until data become available demonstrating a 
clear difference in patient outcome.


Appendix 3
Response Criteria for Malignant Lymphoma (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
183/Protocol GO29365, Version 8
PARTIAL REMISSION

At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of 
the largest dominant nodes or nodal masses.  These nodes or masses should be 
selected according to all of the following:  they should be clearly measurable in at 
least two perpendicular dimensions; if possible they should be from disparate 
regions of the body; and they should include mediastinal and retroperitoneal areas 
of disease whenever these sites are involved.

No increase should be observed in the size of other nodes, liver, or spleen.

Splenic and hepatic nodules must regress by 50% in their SPD or, for single 
nodules, in the greatest transverse diameter (GTD).

With the exception of splenic and hepatic nodules, involvement of other organs is 
usually assessable and no measurable disease should be present.

Bone marrow assessment is irrelevant for determination of a partial response (PR) if 
the sample was positive before treatment.  However, if positive, the cell type should 
be specified (e.g., large-cell lymphoma or small neoplastic B cells).  Patients who 
achieve a CR by the above criteria but who have persistent morphologic bone 
marrow involvement will be considered partial responders.  If the bone marrow was 
involved before therapy and a clinical CR is achieved, but with no bone marrow 
assessment after treatment, patients should be considered partial responders.

No new sites of disease should be observed.

Typically FDG-avid lymphoma:  for patients with no pre-treatment PET scan or if the 
PET scan was positive before therapy, the post-treatment PET should be positive in 
at least one previously involved site.

Variably FDG-avid lymphomas/FDG-avidity unknown:  for patients without a pre-
treatment PET scan, or if a pre-treatment PET scan was negative, CT criteria should 
be used.
In patients with follicular lymphoma, a PET scan is only indicated with 1 or at most 2 
residual masses that have regressed by more than 50% on CT; those with more than 2 
residual lesions are unlikely to be PET negative and should be considered partial 
responders.


Appendix 3
Response Criteria for Malignant Lymphoma (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
184/Protocol GO29365, Version 8
STABLE DISEASE

A patient is considered to have stable disease when that patient fails to attain the 
criteria needed for a CR or PR but does not fulfill those for progressive disease (PD) 
(see Relapsed Disease [after Complete Remission] or PD [after Partial Remission or 
Stable Disease]). 

Typically FGD-avid lymphomas:  the PET should be positive at prior sites of disease 
with no new areas of involvement on the post-treatment CT or PET.

Variably FDG-avid lymphomas/FDG-avidity unknown:  for patients without a pre-
treatment PET scan or if the pre-treatment PET was negative, there must be no 
change in the size of the previous lesions on the post-treatment CT scan.
RELAPSED DISEASE (AFTER COMPLETE REMISSION) OR PROGRESSIVE 
DISEASE (AFTER PARTIAL REMISSION OR STABLE DISEASE)
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm, 
regardless of the short axis.  If a lymph node has a long axis of 1.1 to 1.5 cm, it should 
only be considered abnormal if its short axis is more than 1.0.  Lymph nodes 
1.01.0 cm will not be considered as abnormal for relapse or PD.

Appearance of any new lesion 1.5 cm in any axis during or at the end of therapy, 
even if other lesions are decreasing in size.  Increased FDG uptake in a previously 
unaffected site should only be considered relapsed or PD after confirmation with 
other modalities.  In patients with no prior history of pulmonary lymphoma, new lung 
nodules identified by CT are mostly benign.  Thus, a therapeutic decision should not 
be made solely on the basis of the PET without histologic confirmation.

At least a 50% increase from nadir in the SPD of any previously involved nodes, or 
in a single involved node, or the size of other lesions (e.g., splenic or hepatic 
nodules).  To be considered PD, a lymph node with a diameter of the short axis 
1.0 cm must increase by 50% and to a size of 1.51.5 cm or 1.5 cm in the long 
axis.

At least a 50% increase in the longest diameter of any single previously identified 
node 1 cm in its short axis.

Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected 
with current PET systems (1.5 cm in its long axis by CT).
Measurable extranodal disease should be assessed in a manner similar to that for nodal 
disease.  For these recommendations, the spleen is considered nodal disease.  Disease 
that is only assessable (e.g., pleural effusions, bone lesions) will be recorded as present 
or absent only, unless, while an abnormality is still noted by imaging studies or physical 
examination, it is found to be histologically negative.


Appendix 3
Response Criteria for Malignant Lymphoma (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
185/Protocol GO29365, Version 8
In clinical trials where PET is unavailable to the vast majority of participants, or where 
PET is not deemed necessary or appropriate for use (e.g., a study in patients with 
mucosa-associated lymphoid tissue lymphoma), response should be assessed as above 
but only using CT scans.  However, residual masses should not be assigned 
unconfirmed CR status but should be considered PRs.
Response
Definition
Nodal Masses
Spleen, Liver
Bone Marrow
CR
Disappearance 
of all evidence of 
disease
a) FDG-avid or PET-positive 
before therapy; mass of any 
size permitted if PET-negative 
b) Variably FDG-avid or 
PET-negative; regression to 
normal size on CT
No palpable, 
nodules; nodules 
disappeared
Infiltrate cleared on 
repeat biopsy; if 
indeterminate on 
morphology and 
IHC; bone marrow 
should be negative
PR
Regression of 
measurable 
disease and no 
new sites
A 50% decrease in SPD of 
up to six largest dominant 
masses; no increase in size of 
other nodes
a) FDG-avid or PET-positive 
before therapy; one or more 
PET-positive at previously 
involved site
b) Variably FDG-avid or 
PET-negative; regression on 
CT
A 50% decrease 
in SPD of nodules 
(for single nodule 
in the greatest 
transverse 
diameter); 
no increase in size 
of liver or spleen
Irrelevant if 
positive before 
therapy; cell type 
should be 
specified
SD
Failure to attain 
CR/PR or PD
a) FDG-avid or PET-positive 
before therapy; PET-positive at 
prior sites of disease and no 
new sites on CT or PET 
b) Variably FDG-avid or 
PET-negative; no change in 
size of previous lesions on CT
Relapsed 
disease or 
PD
Any new lesion 
or increase by 
50% of 
previously 
involved sites 
from nadir
Appearance of a new lesion(s) 
1.5 cm in any axis, 50% 
increase in SPD of more than 
one node, or 50% increase in 
longest diameter of previously 
identified node 1 cm in short 
axis.  Lesions PET-positive if 
FDG-avid lymphoma or 
PET-positive before therapy
50% increase from 
nadir in the SPD of 
any previous 
lesions
New or recurrent 
involvement
CRcomplete response; CTcomputed tomography; FDG 18F fluorodeoxyglucose positron 
emission tomography; IHC immunohistochemistry; PDprogressive disease; PET positron 
emission tomography; PRpartial response; SDstable disease; SPDsum of product 
diameters.


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
186/Protocol GO29365, Version 8
Appendix 4
Revised Criteria for Response Assessment:  Modified Lugano Classification
Response should be determined on the basis of radiographic and clinical evidence of disease.  For the Primary Response 
Assessment, an FDG-PET (18F fluorodeoxyglucose positron emission tomography)/CT (computed tomography) scan will be performed 
68 weeks after Cycle 6 Day 1 as assessed by IRC and by investigator.  Assessment of the PET-CT scan should follow the criteria 
described by Cheson BD 2014 presented below.
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin 
and Non-Hodgkin lymphoma:  The Lugano Classification. J Clin Oncol. 2014 
Selection of measured dominant (indicator) lesions:

Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two diameters
A measurable node must have an LDi greater than 1.5 cm.
A measurable extranodal lesion should have an LDi greater than 1.0 cm.

Nodes should preferably be from disparate regions of the body and should include, where applicable, mediastinal and 
retroperitoneal areas. 

Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, and lungs), GI involvement, cutaneous lesions, or 
those noted on palpation. 

If possible, they should be from disparate regions of the body.

Should include mediastinal and retroperitoneal areas of disease whenever these sites are involved


Appendix 4
Revised Criteria for Response Assessment:  Modified Lugano Classification (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
187/Protocol GO29365, Version 8
Selection of non-measured (non-indicator) lesions:

Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured.  
These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet 
the requirements for measurability but are still considered abnormal, as well as truly assessable disease, which is any site of 
suspected disease that would be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone 
lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging.
In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, and bone marrow), FDG uptake may be greater than in the mediastinum 
with complete metabolic response, but should be no higher than surrounding normal physiologic uptake (e.g., with marrow activation 
as a result of chemotherapy or myeloid growth factors).


Appendix 4
Revised Criteria for Response Assessment:  Modified Lugano Classification (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
188/Protocol GO29365, Version 8
Response
Site
PET-CT-based Response
CT-based Response
Complete
Complete metabolic response
Complete radiologic response (all of the following)
Lymph nodes and 
extralymphatic sites
Score 1, 2, or 3a with or without a residual mass on 5PSb
It is recognized that in Waldeyer’s ring or extranodal sites 
with high physiologic uptake or with activation within 
spleen or marrow (e.g., with chemotherapy or myeloid 
colony-stimulating factors), uptake may be greater than 
normal mediastinum and/or liver.  In this circumstance, 
complete metabolic response may be inferred if uptake at 
sites of initial involvement is no greater than surrounding 
normal tissue even if the tissue has high physiologic 
uptake
Target nodes/nodal masses must regress to 1.5 cm 
in LDi
No extralymphatic sites of disease
Nonmeasured 
lesion
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in marrow
Normal by morphology; if indeterminate, IHC negative
Normal by morphology;  if indeterminate, IHC negative
Partial
Partial metabolic response
Partial remission (all of the following)
Lymph nodes and 
extralymphatic sites
Score of 4 or 5b with reduced uptake compared with 
baseline and residual mass(es) of any size
at interim, these findings suggest responding disease
at end of treatment, these findings indicate residual 
disease
50% decrease in SPD of up to 6 target measureable 
nodes and extranodal sites
When a lesion is too small to measure on CT, assign 
5 mm 5 mm as the default value
When no longer visible, 00 mm
For a node 5 mm 5 mm, but smaller than normal, 
use actual measurement for calculation


Appendix 4
Revised Criteria for Response Assessment:  Modified Lugano Classification (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
189/Protocol GO29365, Version 8
Response
Site
PET-CTbased Response
CT-based Response
Partial (cont.)
Nonmeasured 
lesions
Not applicable
Absent/normal, regressed, but no increase
Organ enlargement
Not applicable
Spleen must have regressed by 50% in length 
beyond normal
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake 
compatible with reactive changes from chemotherapy 
allowed).  If there are persistent focal changes in the 
marrow in the context of a nodal response, consideration 
should be given to further evaluation with MRI or biopsy or 
an interval scan
Not applicable
None or 
Stable 
Disease
No metabolic response
Stable disease
Target nodes/nodal 
masses, extranodal 
lesions
Score 4 or 5 b with no significant change in FDG uptake 
from baseline at interim or end of treatment
50% decrease from baseline in SPD for up to 
6 dominant, measurable nodes and extranodal sites; 
no criteria for progressive disease are met
Nonmeasured 
lesions
Not applicable
No increase consistent with progression
Organ enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable


Appendix 4
Revised Criteria for Response Assessment:  Modified Lugano Classification (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
190/Protocol GO29365, Version 8
Response
Site
PET-CTbased Response
CT-based Response
Progressive 
Disease
Progressive metabolic disease
Progressive disease (requires at least 1 of the following)
Individual target 
nodes/nodal 
lesions
Extranodal lesions
Score 4 or 5b with an increase in intensity of 
uptake from baseline and/or
New FDG-avid foci consistent with lymphoma 
at interim or end-of-treatment assessment.
PPD progression:
An individual node/lesion must be abnormal with: 

LDi1.5 cm AND

Increase by50% from PPD nadir AND 

An increase in LDi or SDi from nadir

0.5 cm for lesions 2 cm

1.0 cm for lesions 2 cm
Nonmeasured 
lesions
None
New or clear progression of preexisting nonmeasured lesions
Organ 
enlargement
In the setting of splenomegaly, the splenic length must increase by 
50% of the extent of its prior increase beyond baseline (e.g., 15-cm 
spleen must increase to 16 cm).  If no prior splenomegaly, must 
increase by at least 2 cm from baseline.
New or recurrent splenomegaly
New lesions
New FDG-avid foci consistent with lymphoma 
rather than another etiology (e.g., infection, 
inflammation).  If uncertain regarding etiology 
of new lesions, biopsy or interval scan may be 
considered
Regrowth of previously resolved lesions
A new node 1.5 cm in any axis
A new extranodal site 1.0 cm in any axis; if 1.0 cm in any axis, its 
presence must be unequivocal and must be attributable to lymphoma
Assessable disease of any size unequivocally attributable to 
lymphoma
Bone marrow
New or recurrent FDG-acid foci
New or recurrent involvement


Appendix 4
Revised Criteria for Response Assessment:  Modified Lugano Classification (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
191/Protocol GO29365, Version 8
5-PS5-point scale; CT computed tomography; FDG fluorodeoxyglucose; IHCimmunohistochemistry; LDi longest transverse diameter of a lesion; 
MRImagnetic resonance imaging; PET positron emission tomography; PPDcross product of the LDi and perpendicular diameter; SDishortest axis 
perpendicular to the LDi; SPDsum of the product of the perpendicular diameters for multiple lesions.
a A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan.  However, in trials involving 
PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment). 
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.


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
192/Protocol GO29365, Version 8
Appendix 5
Recommendations for the Use of White Blood Cell Growth 
Factors
PRIMARY PROPHYLACTIC G-CSF ADMINISTRATION (FIRST AND 
SUBSEQUENT-CYCLE USE)
Primary prophylaxis with growth-colony stimulating factor (G-CSF) is required. The 
decision not to administer G-CSF as primary prophylaxis should be made in consultation 
with and following the approval of the Medical Monitor. 
THERAPEUTIC USE OF G-CSF
G-CSF administration should be considered for the following patients:

Patients with febrile neutropenia who are at high risk for infection-associated 
complications; or

Patients who have prognostic factors that are predictive of poor clinical outcome, 
e.g., prolonged (10 days) and profound (100/L) neutropenia, age 65 years, 
uncontrolled primary disease, pneumonia, hypotension and multi-organ dysfunction 
(sepsis), invasive fungal infection, being hospitalized at the time of fever 
development
Source:  Smith et al. 2006 Update of recommendations for the use of white blood cell 
growth factors: an evidence-based clinical practice guideline. J Clin Oncol 
2006;24:3187205.


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
193/Protocol GO29365, Version 8
Appendix 6
Recommended Anaphylaxis Management
The following equipment is needed in the event of a suspected anaphylactic 
reaction during study drug infusion:

Appropriate monitors (electrocardiogram, blood pressure, pulse oximetry

Oxygen and masks for oxygen delivery

Airway management devices per standard of care

Epinephrine for intravenous, intramuscular, and/or endotracheal administration in 
accordance with institutional guidelines 

Salbutamol (or albuterol or equivalent)

Antihistamines (H1 and H2 blockers)

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
The following are the procedures to follow in the event of a suspected 
anaphylactic reaction during study drug infusion:

Stop the study drug infusion.

Call for additional assistance!

Maintain an adequate airway.

Provide oxygen

Ensure that appropriate monitoring is in place, with continuous electrocardiogram 
and pulse oximetry monitoring, if possible.

Administer epinephrine first, followed by antihistamines, albuterol, or other 
medications as required by patient status and directed by the physician in charge.

Continue to observe the patient and document observations.


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
194/Protocol GO29365, Version 8
Appendix 7
Total Neuropathy Score Clinical Assessment 
Total Neuropathy Score-Nurse (TNSn)
TNSn
0
1
2
3
4
Sensory 
symptoms
None
Symptoms 
limited to 
fingers or toes
Symptoms 
extend to 
ankle or wrist
Symptoms 
extend to knee 
or elbow
Symptoms 
extend above 
knees or 
elbows
Motor 
symptoms
None
Slight difficulty
Moderate 
difficulty
Require help/ 
assistance
Paralysis
Autonomic 
symptoms
None
1 yes
2 yes
3 yes
4 or 5 yes
Pin sensibility
Normal
Reduced in 
fingers/toes
Reduced up to 
wrist/ankle
Reduced up to 
elbow/knee
Reduced to 
above 
elbow/knee
Vibration 
sensibility
Normal
Reduced in 
fingers/toes
Reduced up to 
wrist/ankle
Reduced up to 
elbow/knee
Reduced to 
above 
elbow/knee
TNSn
0
1
2
3
4
Copyright Johns Hopkins University 2008, all rights reserved.
Sources:  
Cavaletti G, Frigeni B, Lanzani F, et al. The total neuropathy score as assessment tool for 
grading the course of chemotherapy-induced peripheral neurotoxicity: comparison with the 
National Cancer Institute-Common Toxicity Scale. J Peripher Nerv Syst 2007;12:2105. 
Cavaletti G, Jann S, Pace A, et al. Multi-center assessment of the total neuropathy score for 
chemotherapy-induced peripheral neurotoxicity. J Peripher Nerv Syst 2006;11:13541.


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
195/Protocol GO29365, Version 8
Appendix 8
Therapy-Induced Neuropathy Assessment Scale (TINAS)
Source:  Thomas SK, Mendoza TR, Vichaya EG, et al. Validation of the chemotherapy-induced 
neuropathy scale. J Clin Oncol 2012;30(15 suppl):9140.


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
196/Protocol GO29365, Version 8
Appendix 9
Commonly Used CYP1A2 Inhibitors and Inducers (Drugs, Foods, 
Over the Counter Medications, and Supplements)
On the basis of the U.S. Package Insert (USPI) for bendamustine, no formal clinical 
assessments of pharmacokinetic drug drug interactions between bendamustine and 
other drugs have been conducted.  Bendamustine's active metabolites, gamma hydroxy 
bendamustine (M3) and N-desmethyl-bendamustine (M4), are formed via cytochrome 
P450 CYP1A2.  Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) have potential to 
increase plasma concentrations of bendamustine and decrease plasma concentrations 
of active metabolites.  Inducers of CYP1A2 (e.g., omeprazole, smoking) have potential 
to decrease plasma concentrations of bendamustine and increase plasma 
concentrations of its active metabolites.
The medications listed below are not contraindicated; however, caution should be used 
or alternative treatments with medications that are not CYP1A2 inhibitors or inducers 
should be considered if concomitant treatment with CYP1A2 inhibitors or inducers is 
needed for the patient's medical condition.  This list is not exhaustive.


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
197/Protocol GO29365, Version 8
Appendix 9
Commonly Used CYP1A2 Inhibitors and Inducers (Drugs, Foods, 
Over the Counter Medications, and Supplements) (cont.)
CYP1A2 Inhibitors
Amiodarone
Imipramine
Amitriptyline
Isoniazid
Amlodipine
Ketoconazole
Anastrozole
Lidocaine
Caffeine
Losartan
Cimetidine (Tagamet)
Erythromycin
Ciprofloxacin (Cipro)
Estrogens
Citalopram
Mexiletine
Clarithromycin
Mexiletine
Clotrimazole
Modafenil
Clozapine
Nifedipine
Diclofenac
Olanzapine
Diltiazem
Omeprazole
Echinacea 
Ondansetron
Ethinyl Estradiol
Paroxetinee
Fluoroquinolones
Propafenone
Fluconazole
Propanolol
Fluvoxamine
Ranitidine
Gemfibrozil
Rofecoxib
Ginseng
Sertraline
CYP1A2 Inducers
Barbiturates (e.g., Phenobarbital)
Rifampin (e.g., Rifadin)
Cruciferous vegetables (broccoli, 
cauliflower, arugula, brussel sprouts, 
cabbage, kale, chard, turnips, radishes, 
wasabi, bok choy, watercress, collard 
greens)
Smoking
Char-grilled meat
Triamterene (Dyrenium)
Carbamazepine (e.g., Tegretol)
Zolmitriptan (Zomig)
Primidone
Adapted from ctep.cancer.gov/protocolDevelopment/docs/cyp1a2.doc.


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
198/Protocol GO29365, Version 8
Appendix 9
Commonly Used CYP1A2 Inhibitors and Inducers (Drugs, Foods, 
Over the Counter Medications, and Supplements) (cont.)
Sample card to be handed to patients in the GO29365 study.  This card may be adapted 
to comply with local guidelines.
During this clinical study, I am receiving a drug called bendamustine.  This drug is 
approved for the treatment of lymphoma in the United States of America and a number 
of the European Union member states.  The following medications and substances are 
examples of drugs and substances that may alter blood levels of bendamustine:
Fluvoxamine
Ciprofloxacin
Omeprazole
Smoking
Caution must be used or alternative treatments be considered if treatment with one of 
these listed drugs or substances or another CYP1A2 inhibitor or inducer is needed.  If 
you have further questions, please contact the study doctor whose name and contact 
number are indicated on the other side of this card. 


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
199/Protocol GO29365, Version 8
Appendix 10
Follicular Lymphoma International Prognostic Index and 
International Prognostic Index
Follicular Lymphoma International Prognostic Index (FLIPI)
Risk Factors
Ann-Arbor Stage III or IV
Age 60 years
Serum LDH 1ULN
Anemia (hemoglobin120 g/L)
Involved nodal areas 4
FLIPI Risk Group
Number of FLIPI Risk Factors
Low
0 or 1
Intermediate
2
High
35
FLIPIFollicular Lymphoma International Prognostic Index; LDHlactate dehydrogenase; 
ULNupper limit of normal.
The results of FDG-PET should not be taken into account for calculation of FLIPI as this 
prognostic score was established without FDG-PET.
Adapted from: Solal-Celigny P, Roy P, Colombat P, et al. Follicular Lymphoma International 
Prognostic Index. Blood 2004;104:1258–64


Appendix 10
Follicular Lymphoma International Prognostic Index and 
International Prognostic Index (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
200/Protocol GO29365, Version 8
Follicular Lymphoma International Prognostic Index (FLIPI) Nodal Areas
Reference modified from: Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma 
international prognostic index. Blood 2004;104:1258–64.


Appendix 10
Follicular Lymphoma International Prognostic Index and 
International Prognostic Index (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
201/Protocol GO29365, Version 8
Follicular Lymphoma International Prognostic Index (FLIPI) 2
Risk Factors
Bone marrow involvement
Age 60 years
2 microglobulin 1ULN
Anemia (hemoglobin 120 g/L)
Longest diameter of largest involved node 6 cm
FLIPI2 Risk Group
Number of FLIPI2 Risk Factors
Low
0
Intermediate
1 or 2
High
35
FLIPI2Follicular Lymphoma International Prognostic Index 2; LDH lactate dehydrogenase; 
ULNupper limit of normal.
The results of FDG-PET should not be taken into account for calculation of FLIPI2 as 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.


Appendix 10
Follicular Lymphoma International Prognostic Index and 
International Prognostic Index (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
202/Protocol GO29365, Version 8
International Prognostic Index (IPI)
Risk Factors
Ann-Arbor Stage III or IV
Age 60 years
Serum LDH 1ULN
ECOG Performance Status 2
Extranodal involvement 2
IPI Risk Group
Number of IPI Risk Factors
Low
0 or 1
Low-intermediate
2
High-intermediate
3
High
4 or 5
ECOGEastern Cooperative Oncology Group; IPIInternational Prognostic Index; 
LDHlactate dehydrogenase; ULNupper limit of normal.
The results of FDG-PET should not be taken into account for calculation of IPI as this 
prognostic score was established without FDG-PET.
Adapted from: Shipp MA, Harrington DP, Anderson JR, et al. A predictive model for aggressive 
Non-Hodgkin’s Lymphoma. N Engl J Med 1993;329:98794.