Clinical trial NCT04236141
Conditions: Diffuse, Large B-Cell, Lymphoma
Sponsor: Hoffmann-La Roche
Start date: 2020-07-10; Completion date: 2022-02-07
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A study to evaluate the Efficacy and Safety of Polatuzumab Vedotin in combination with BR (Bendamustine and Rituximab) compared with BR alone in Chinese participants with R/R DLBCL. Approximately 42 Chinese participants will be randomised to treatment arms in a 2:1 ratio. Randomisation will be conducted with the aid of an interactive web-based response system (IxRS).

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Polatuzumab Vedotin intervention 2: Bendamustine intervention 3: Rituximab intervention 4: Placebo
Intervention descriptions: intervention 1: Participants will receive a total of 6 cycles (a cycle being 21 days) of 1.8mg/kg Polatuzumab Vedotin (IV infusion) on Day 2 of Cycle 1 and Day 1 of Cycles 2-6. intervention 2: Participants will receive a total of 6 cycles (a cycle being 21 days) of 90 mg/m2 Bendamustine (IV infusion) on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6. intervention 3: Participants will receive a total of 6 cycles (a cycle being 21 days) of 375 mg/m2 Rituximab (IV infusion) on Day 1 of each cycle. intervention 4: Participants will receive a total of 6 cycles (a cycle being 21 days) of Placebo (IV infusion) on Day 2 of Cycle 1 and Day 1 of Cycles 2-6.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A Phase III, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of Polatuzumab 
Vedotin in Combination with Bendamustine and Rituximab Compared 
with Bendamustine and Rituximab Alone in Chinese Patients with 
Relapsed or Refractory Diffuse Large B-Cell Lymphoma  
NCT Number: 
NCT04236141 
Document Date: 
Protocol Version 2: 12 May 2020 
 
 


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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 YO41543, Version 2
PROTOCOL
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF POLATUZUMAB VEDOTIN IN 
COMBINATION WITH BENDAMUSTINE AND 
RITUXIMAB COMPARED WITH BENDAMUSTINE 
AND RITUXIMAB ALONE IN CHINESE PATIENTS 
WITH RELAPSED OR REFRACTORY DIFFUSE 
LARGE B-CELL LYMPHOMA
PROTOCOL NUMBER:
YO41543
VERSION NUMBER:
2
EUDRACT NUMBER:
Not applicable
IND NUMBER:
Not applicable
TEST PRODUCT:
Polatuzumab vedotin, lyophilized
(DCDS4501S, RO5541077)
MEDICAL MONITOR:
, M.D. Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below.
 
12-May-2020 15:28:16
Title
Approver's Name
Date and Time (UTC)


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
2/Protocol YO41543, Version 2
PROTOCOL AMENDMENT, VERSION 2
RATIONALE
Protocol YO41543 has been amended to incorporate changes to diffuse large B-cell 
lymphoma (DLBCL) prognostic biomarkers as highlighted in a recent update of the WHO 
DLBCL Classification, including cell-of-origin subtypes (activated B cell and germinal 
center B cell subtypes) and patients with co-expression of BCL2 and MYC.  Furthermore, 
the Sponsor is planning to investigate the efficacy of polatuzumab vedotin in patients 
with the expression of its target CD79b on DLBCL tumor cell surface.  Efficacy analyses 
in these four biomarker populations are considered important for interpreting the efficacy 
of polatuzumab vedotin in this heterogeneous disease setting with different potential 
underlying molecular biology.  Collectively, given the importance of these analyses, the 
Sponsor proposes to update these analyses from exploratory objective to biomarker 
objectives.
Changes to the protocol, along with a rationale for each change, are summarized below:

Sections 2.2, 2.3, and 2.4 have had mentions of exploratory objectives updated to 
reflect the current analysis plan.

Sections 2.5 and 3.3.4 have been updated to reflect the incorporation of the updated 
WHO DLBCL classifications into biomarker objectives.

Sections 4.1.1 and 4.1.3 have been updated to remove central pathology diagnosis 
to reflect sites’ confirmed ability to diagnose DLBCL.

Section 4.1.1 has been updated to remove requirement for a biopsy to be performed 
at screening if archival tissue is unavailable or inadequate. 

Sections 4.1.2, and 4.4.1.4 have been updated to clarify the instructions of 
monitoring for hepatitis B reactivation.

Section 4.4.1.4 has been updated to reflect HBV assay sensitivity recommended by 
WHO.

Section 4.5.3 has been updated to remove genitourinary component of the physical 
exam.

Section 4.5.6 has been updated to remove bands from hematology test.

Sections 4.5.6, 8.4, and 9.5 have been updated to remove reference to exploratory 
biomarkers. 

Section 6.1 has been updated to further clarify the rationale used in determining 
sample size.

Sections 6.4.1 and 6.4.2 have been updated to further clarify statistical analysis 
methodology.

Section 5.1 and 5.1.1 have been updated in accordance with the Polatuzumab 
Vedotin Investigator Brochure, Version 11. These include updated known and 
potential risks associated with polatuzumab vedotin.

Appendix 1 has been updated to further clarify the need of dedicated CT scans.


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
3/Protocol YO41543, Version 2
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 YO41543, Version 2
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11
PROTOCOL AMENDMENT SYNOPSIS ............................................................ 12
1.
BACKGROUND .......................................................................................... 25
1.1
Background on Diffuse Large B-Cell Lymphoma................... 25
1.2
Background on Polatuzumab Vedotin ................................... 26
1.2.1
Nonclinical Studies with Polatuzumab Vedotin...................... 27
1.2.2
Clinical Studies with Polatuzumab Vedotin............................ 27
1.2.3
Pharmacokinetic and Immunogenicity Properties 
of Polatuzumab Vedotin......................................................... 29
1.3
Study Rationale and Benefit-Risk Assessment...................... 33
2.
OBJECTIVES AND ENDPOINTS ............................................................... 34
2.1
Efficacy Objectives ................................................................ 34
2.1.1
Primary Efficacy Objective..................................................... 34
2.1.2
Secondary Efficacy Objective................................................ 34
2.2
Safety Objectives................................................................... 35
2.3
Pharmacokinetic Objectives .................................................. 36
2.4
Immunogenicity Objectives.................................................... 36
2.5
Biomarker Objective .............................................................. 36
3.
STUDY DESIGN......................................................................................... 37
3.1
Description of the Study......................................................... 37
3.1.1
Overview of Study Design ..................................................... 37
3.1.2
Study Treatment Regimen..................................................... 39
3.1.3
Independent Review Committee............................................ 41
3.2
End of Study and Length of Study......................................... 41
3.3
Rationale for Study Design.................................................... 41
3.3.1
Rationale for Polatuzumab Vedotin Dose and 
Schedule................................................................................ 41
3.3.2
Rationale for Patient Population ............................................ 41
3.3.3
Rationale for Rituximab and Bendamustine Dose 
and Schedule......................................................................... 42
3.3.4
Rationale for Biomarker Assessments................................... 43


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3.3.5
Rationale for Stratification Factors......................................... 43
3.3.6
Rationale for Clinical Outcome Assessments........................ 44
3.3.6.1
PET-Defined Complete Response......................................... 44
3.3.6.2
Patient-Reported Outcomes .................................................. 44
4.
MATERIALS AND METHODS .................................................................... 44
4.1
Patients.................................................................................. 44
4.1.1
Inclusion Criteria.................................................................... 44
4.1.2
Exclusion Criteria................................................................... 46
4.1.3
Criteria for Lymph Node Biopsy Tissue ................................. 49
4.2
Method of Treatment Assignment and Blinding..................... 49
4.2.1
Treatment Assignment........................................................... 49
4.2.2
Blinding.................................................................................. 50
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 51
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 51
4.3.1.1
Polatuzumab Vedotin and Placebo........................................ 51
4.3.1.2
Rituximab............................................................................... 51
4.3.1.3
Bendamustine........................................................................ 51
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 51
4.3.2.1
Polatuzumab Vedotin and Placebo........................................ 52
4.3.2.2
Rituximab............................................................................... 52
4.3.2.3
Bendamustine........................................................................ 54
4.3.3
Premedication........................................................................ 55
4.3.4
Investigational Medicinal Product Accountability ................... 57
4.3.5
Continued Access to Polatuzumab Vedotin and 
Rituximab............................................................................... 57
4.4
Concomitant Therapy ............................................................ 57
4.4.1
Permitted Therapy................................................................. 57
4.4.1.1
Treatment and Prophylaxis of Neutropenia ........................... 58
4.4.1.2
Premedication for Patients at High Risk for 
Tumor Lysis Syndrome.......................................................... 58
4.4.1.3
Prophylaxis for Infections....................................................... 59


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4.4.1.4
Monitoring and Treatment for Hepatitis B 
Reactivation........................................................................... 59
4.4.2
Cautionary Therapy ............................................................... 59
4.4.2.1
Medications Given with Precaution due to Effects 
Related to Cytochrome P450 Enzymes and P-
Glycoprotein .......................................................................... 59
4.4.2.2
Herbal Therapies................................................................... 60
4.4.3
Prohibited Therapy ................................................................ 60
4.4.3.1
Immunizations ....................................................................... 61
4.5
Study Assessments ............................................................... 61
4.5.1
Informed Consent Forms and Screening Log........................ 61
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 62
4.5.3
Physical Examinations........................................................... 62
4.5.4
Vital Signs.............................................................................. 62
4.5.5
Tumor and Response Evaluations......................................... 63
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 64
4.5.7
Electrocardiograms................................................................ 67
4.5.8
Patient-Reported Outcome Assessment................................ 67
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 68
4.6.1
Study Treatment Discontinuation........................................... 68
4.6.2
Patient Discontinuation from the Study.................................. 69
4.6.3
Study Discontinuation............................................................ 70
4.6.4
Site Discontinuation............................................................... 70
5.
ASSESSMENT OF SAFETY....................................................................... 70
5.1
Safety Plan ............................................................................ 70
5.1.1
Risks Associated with Polatuzumab Vedotin......................... 71
5.1.1.1
Known Risks Associated with Polatuzumab 
Vedotin .................................................................................. 71
5.1.1.2
Potential Risks Associated with Polatuzumab 
Vedotin .................................................................................. 73
5.1.2
Risks Associated with Rituximab........................................... 74
5.1.2.1
Infusion-Related Reactions.................................................... 74


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5.1.2.2
Tumor Lysis Syndrome.......................................................... 74
5.1.2.3
Hepatitis B Virus Reactivation ............................................... 75
5.1.2.4
Progressive Multifocal Leukoencephalopathy........................ 75
5.1.2.5
Cardiac Toxicity ..................................................................... 75
5.1.2.6
Infection................................................................................. 75
5.1.2.7
Severe Mucocutaneous Reactions........................................ 76
5.1.2.8
Bowel Obstruction and Perforation........................................ 76
5.1.3
Risks Associated with Bendamustine .................................... 76
5.1.3.1
Myelosuppression.................................................................. 76
5.1.3.2
Infection................................................................................. 76
5.1.3.3
Infusion-Related Reactions and Anaphylaxis ........................ 76
5.1.3.4
Tumor Lysis Syndrome.......................................................... 77
5.1.3.5
Skin Reactions....................................................................... 77
5.1.3.6
Long-Term Stem-Cell Toxicity ............................................... 77
5.1.3.7
Extravasation of Bendamustine............................................. 77
5.1.3.8
Transfusion-Associated Graft versus Host 
Disease.................................................................................. 77
5.1.3.9
Drug Interactions ................................................................... 77
5.1.4
Management of Patients Who Experience 
Specific Adverse Events........................................................ 78
5.1.4.1
Dose Delays and Dose Modifications .................................... 78
5.1.4.2
Treatment Interruption and Schedule 
Modification ........................................................................... 78
5.1.4.3
Non-Hematologic Toxicities................................................... 79
5.2
Safety Parameters and Definitions ........................................ 85
5.2.1
Adverse Events ..................................................................... 85
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 86
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 86
5.2.4
Selected Adverse Events....................................................... 87
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 87
5.3.1
Adverse Event Reporting Period ........................................... 87
5.3.2
Eliciting Adverse Event Information....................................... 88


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
8/Protocol YO41543, Version 2
5.3.3
Assessment of Severity of Adverse Events ........................... 88
5.3.4
Assessment of Causality of Adverse Events ......................... 89
5.3.5
Procedures for Recording Adverse Events............................ 89
5.3.5.1
Infusion-Related Reactions.................................................... 90
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 90
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 90
5.3.5.4
Persistent or Recurrent Adverse Events................................ 90
5.3.5.5
Abnormal Laboratory Values ................................................. 91
5.3.5.6
Abnormal Vital Sign Values ................................................... 92
5.3.5.7
Abnormal Liver Function Tests.............................................. 92
5.3.5.8
Deaths ................................................................................... 92
5.3.5.9
Preexisting Medical Conditions.............................................. 93
5.3.5.10
Lack of Efficacy or Worsening of DLBCL............................... 93
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 93
5.3.5.12
Cases of Accidental Overdose or Medication 
Error....................................................................................... 94
5.3.5.13
Patient-Reported Outcome Data ........................................... 95
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 95
5.4.1
Emergency Medical Contacts................................................ 96
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 96
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 96
5.4.2.2
Events That Occur after Study Drug Initiation........................ 97
5.4.3
Reporting Requirements for Pregnancies.............................. 97
5.4.3.1
Pregnancies in Female Patients............................................ 97
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 97
5.4.3.3
Abortions ............................................................................... 98
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 98
5.5
Follow-Up of Patients after Adverse Events .......................... 98
5.5.1
Investigator Follow-Up........................................................... 98
5.5.2
Sponsor Follow-Up ................................................................ 99


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
9/Protocol YO41543, Version 2
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 99
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 99
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 100
6.1
Determination of Sample Size ............................................. 100
6.2
Summaries of Conduct of Study.......................................... 100
6.3
Summaries of Treatment Group Comparability ................... 100
6.4
Efficacy Analyses ................................................................ 101
6.4.1
Primary Efficacy Endpoint.................................................... 101
6.4.2
Secondary Efficacy Endpoints............................................. 101
6.5
Safety Analyses................................................................... 102
6.6
Pharmacokinetic Analyses................................................... 103
6.7
Immunogenicity Analyses.................................................... 103
6.8
Biomarker Analyses............................................................. 104
7.
DATA COLLECTION AND MANAGEMENT ............................................. 104
7.1
Data Quality Assurance....................................................... 104
7.2
Electronic Case Report Forms............................................. 104
7.3
Source Data Documentation................................................ 105
7.4
Use of Computerized Systems ............................................ 105
7.5
Retention of Records........................................................... 106
8.
ETHICAL CONSIDERATIONS.................................................................. 106
8.1
Compliance with Laws and Regulations .............................. 106
8.2
Informed Consent................................................................ 106
8.3
Institutional Review Board or Ethics Committee.................. 107
8.4
Confidentiality...................................................................... 108
8.5
Financial Disclosure ............................................................ 108
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 108
9.1
Study Documentation .......................................................... 108
9.2
Protocol Deviations.............................................................. 109
9.3
Site Inspections ................................................................... 109


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10/Protocol YO41543, Version 2
9.4
Administrative Structure....................................................... 109
9.5
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 109
9.6
Protocol Amendments ......................................................... 110
10. REFERENCES ......................................................................................... 111
LIST OF TABLES
Table 1
Administration of First and Subsequent Infusions of 
Rituximab.................................................................................... 54
Table 2
Premedication for Rituximab and Blinded Polatuzumab 
Vedotin/Placebo.......................................................................... 56
Table 3
Management of Infusion-Related Symptoms .............................. 80
Table 4
Guidelines for Dose Delay or Modification of Polatuzumab 
Vedotin, Rituximab, or Bendamustine......................................... 81
Table 5
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 88
Table 6
Causal Attribution Guidance ....................................................... 89
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 38
Figure 2
Polatuzumab Vedotin/Placebo plus BR Regimen ....................... 40
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................ 116
Appendix 2
Schedule of Pharmacokinetic and Immunogenicity Samples 
(Polatuzumab Vedotin/Placebo)................................................ 123
Appendix 3
Lugano Response Criteria for Malignant Lymphoma (Cheson 
et al. 2014)................................................................................ 124
Appendix 4
Recommended Anaphylaxis Management ............................... 130
Appendix 5
Functional Assessment of Cancer Therapy/Gynecologic 
Oncology Group-Neurotoxicity (FACT/GOG-NTX).................... 131
Appendix 6
Sample List of Cautionary Medications..................................... 132
Appendix 7
Commonly Used CYP1A2 Inhibitors and Inducers (Drugs, 
Foods, Over the Counter Medications, and Supplements) ....... 133


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
11/Protocol YO41543, Version 2
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
TO EVALUATE THE EFFICACY AND SAFETY OF 
POLATUZUMAB VEDOTIN IN COMBINATION WITH 
BENDAMUSTINE AND RITUXIMAB COMPARED 
WITH BENDAMUSTINE AND RITUXIMAB ALONE IN
CHINESE PATIENTS WITH RELAPSED OR 
REFRACTORY DIFFUSE LARGE B-CELL 
LYMPHOMA
PROTOCOL NUMBER:
YO41543
VERSION NUMBER:
2
EUDRACT NUMBER:
Not applicable
IND NUMBER:
Not applicable
TEST PRODUCT:
Polatuzumab vedotin, lyophilized
(DCDS4501S, RO5541077)
MEDICAL MONITOR:
, M.D. Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name  (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor.


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
12/Protocol YO41543, Version 2
PROTOCOL AMENDMENT SYNOPSIS
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF POLATUZUMAB VEDOTIN IN COMBINATION
WITH BENDAMUSTINE AND RITUXIMAB COMPARED WITH 
BENDAMUSTINE AND RITUXIMAB ALONE IN CHINESE 
PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE 
B-CELL LYMPHOMA
PROTOCOL NUMBER:
YO41543
VERSION NUMBER:
2
EUDRACT NUMBER:
Not applicable
IND NUMBER:
Not applicable
TEST PRODUCT:
Polatuzumab vedotin, lyophilized (DCDS4501S, RO5541077)
PHASE:
Phase III
INDICATION:
Diffuse large B-cell lymphoma
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics of polatuzumab vedotin plus
bendamustine and rituximab (BR) compared with placebo plus BR in Chinese patients with 
relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL).  Specific objectives and 
corresponding endpoints for the study are outlined below.
In this protocol, "study treatment" refers to the combination of treatments assigned to patients 
as part of this study (i.e., polatuzumab vedotin/placebo, bendamustine, and rituximab).
Efficacy Objectives
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of polatuzumab vedotin 
plus BR compared with placebo plus BR in Chinese patients with R/R DLBCL on the basis of 
the following endpoint. This objective is to investigate whether the benefit (in terms of complete 
response [CR] rate at end of treatment assessment) of administrating polatuzumab vedotin plus 
BR in this study is consistent with the benefit observed in the global study, GO29365.

CR at the end of treatment assessment (68 weeks after Cycle 6 Day 1 or final dose of 
study treatment) based on positron emission tomographycomputed tomography (PET-CT), 
as determined by the Independent Review Committee (IRC) according to the Lugano 
Response Criteria for Malignant Lymphoma, hereafter referred to as the "Lugano Response 
Criteria" (Cheson et al. 2014)
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of polatuzumab 
vedotin plus BR compared with placebo plus BR in Chinese patients with R/R DLBCL on the 
basis of the following endpoints:

CR at the end of treatment assessment based on PET-CT, as determined by the 
investigator according to the Lugano Response Criteria


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13/Protocol YO41543, Version 2

Objective response (OR), defined as CR or partial response (PR), at the end of treatment 
assessment based on PET-CT, as determined by the investigator and IRC according to the 
Lugano Response Criteria 

CR at the end of treatment assessment based on computed tomography (CT) only, as 
determined by the investigator and IRC according to the Lugano Response Criteria

OR, defined as CR or PR, at the end of treatment assessment based on CT only, as 
determined by the investigator and IRC according to the Lugano Response Criteria 

Best objective response, defined as CR or PR, while on study based on PET-CT or CT only, 
as determined by the investigator and IRC according to the Lugano Response Criteria

Duration of response (DOR), defined as the time from the first occurrence of a documented 
objective response to disease progression, relapse, or death from any cause based on 
PET-CT or CT only, as determined by the investigator and IRC according to the Lugano 
Response Criteria 

Progression-free survival, defined as the period from date of randomization until the date of 
disease progression, relapse, or death from any cause based on PET-CT or CT only, as 
determined by the investigator and IRC according to the Lugano Response Criteria 

Event-free survival, defined as the time from date of randomization to any treatment failure 
including disease progression, relapse, initiation of new anti-lymphoma treatment, or death 
based on PET-CT or CT only, as determined by the investigator according to the Lugano 
Response Criteria

Overall survival (OS), defined as the time from date of randomization until the date of death 
from any cause  
Safety Objectives
The safety objective for this study is to evaluate the safety of polatuzumab vedotin plus BR 
compared with placebo plus BR in Chinese patients with R/R DLBCL on the basis of the 
following endpoints:

Incidence and severity of adverse events, with severity determined according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 
(NCI CTCAE v5.0)

Incidence and nature of study drug discontinuation, dose reduction, and dose delay due to 
adverse events
Additionally, this study will evaluate the safety of polatuzumab vedotin plus BR compared with 
placebo plus BR from the patient's perspective to better understand treatment impact, 
tolerability, and reversibility on the basis of the following endpoint:

Change from baseline in peripheral neuropathy as assessed through use of the Functional 
Assessment of Cancer Therapy/Gynecologic Oncology GroupNeurotoxicity 
(FACT/GOG-NTX) 
Pharmacokinetic Objectives
The pharmacokinetic (PK) objective for this study is to characterize the PK for total antibody, 
antibody-conjugated monomethyl auristatin E (acMMAE), and unconjugated monomethyl 
auristatin E (MMAE) following polatuzumab vedotin administration, when combined with BR, in 
Chinese patients with R/R DLBCL on the basis of the following endpoints:

Serum concentration of total antibody at specified timepoints

Plasma concentration of acMMAE at specified timepoints

Plasma concentration of unconjugated MMAE at specified timepoints
Additionally, this study will evaluate potential relationships between polatuzumab vedotin 
exposure and the efficacy and safety of polatuzumab vedotin, when combined with BR, in 
Chinese patients with R/R DLBCL on the basis of the following endpoints:

Relationship between plasma concentration or PK parameters for polatuzumab vedotin and 
efficacy endpoints

Relationship between plasma concentration or PK parameters for polatuzumab vedotin and 
safety endpoints


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Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to polatuzumab 
vedotin, when combined with BR, in Chinese patients with R/R DLBCL on the basis of the 
following endpoint:

Prevalence of anti-drug antibodies (ADAs) for polatuzumab vedotin at baseline and 
incidence of ADAs during the study
Additionally, for this study will evaluate potential effects of ADAs on the basis of the following 
endpoint:

Relationship between ADA status for polatuzumab vedotin and efficacy, safety, or PK 
endpoints
Biomarker Objective
The biomarker objective for this study is to evaluate the response to polatuzumab vedotin, when 
combined with BR, in Chinese patients with R/R DLBCL with known prognostic factors, such as 
activated B cell (ABC)-DLBCL or germinal center B cell [GCB]-DLBCL as analyzed through 
use of a centrally performed RNA-based assay, or co-expression of BCL2 and MYC (double-
expressor, [DEL]) as analyzed through use of centrally performed immunohistochemistry 
(IHC) tests.  In addition, the association between response and the expression of the target of 
polatuzumab vedotin, CD79b (as analyzed through use of a centrally performed IHC test) will 
be evaluated.

CR at the end of treatment assessment based on PET-CT, as determined by the IRC 
according to the Lugano Response Criteria in populations of ABC-DLBCL, GCB-DLBCL, 
DEL, and expression of CD79b

OR, defined as CR or PR, at the end of treatment assessment based on PET-CT, as 
determined by the  IRC according to the Lugano Response Criteria in populations of 
ABC-DLBCL, GCB-DLBCL, DEL, and expression of CD79b
Study Design
Description of Study
This is a Phase III, multicenter, randomized, double-blind, placebo-controlled study to evaluate 
the efficacy and safety of polatuzumab vedotin in combination with BR compared with BR alone
in Chinese patients with R/R DLBCL.
Approximately 42 Chinese patients will be randomized to one of the following treatment arms in 
a 2:1 ratio:

Polatuzumab vedotin plus BR (experimental arm)

Placebo plus BR (control arm)
Randomization will be conducted with the aid of an interactive web-based response system 
(IxRS) and will be stratified according to the following factors: 

DOR to most recent prior therapy:  12 months versus 12 months 

Number of prior therapies (1 vs. 2)
For consistency with the pivotal study population (Study GO29365), patients with 
2 prior lines of therapy will be capped within 70% of the whole population.
Refer to the protocol for the study design schema and the schedule of activities.
Study treatment will be administered by IV infusion every 21 days for up to 6 cycles, as 
described in the protocol.  The first day of treatment will constitute Study Day 1.  Refer to the 
protocol for details on study treatment dosage and administration.
All patients will be closely monitored for adverse events and serious adverse events throughout 
the study and for 90 days after the final dose of study treatment.  Adverse events will be graded 
according to NCI CTCAE v5.0. Laboratory safety assessments will include regular monitoring 
of hematology and blood chemistry, and tests of immunological parameters.
Blood samples will be taken at various timepoints during the study to analyze the PK properties 
of polatuzumab vedotin (total antibody, acMMAE, and unconjugated MMAE), as well as the 
immunogenicity of polatuzumab vedotin, when given in combination with BR. 


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Response will be determined by an IRC and investigators using the Lugano Response Criteria 
(Cheson et al. 2014) at the following timepoints:

Screening:  within 35 days of Cycle 1 Day 1

Interim response assessment:  between Cycle 3 Day 15 and Cycle 4 Day 1

End of treatment assessment:  68 weeks after Cycle 6 Day 1 or the final dose of study 
treatment
For patients with disease progression occurring prior to the anticipated date of the end of 
treatment assessment, the visit date with the response assessment showing disease 
progression will be used in replacement of the end of treatment assessment.
Imaging at these timepoints must include PET scans in conjunction with diagnostic-quality CT 
scans with both oral and IV contrast.  An independent review of the responses of all patients will 
also be conducted to confirm the primary CR endpoint.   
Patients who complete the study treatment period will return to the clinic for a treatment 
completion visit 30 (5) days after the final dose of study treatment (Cycle 6 Day 1).  Patients 
who discontinue study treatment prematurely will return to the clinic for a treatment 
discontinuation visit 30 (5) days after the final dose of study treatment.  
Disease Progression and Follow Up
Following completion of treatment, patients who have not progressed will be followed clinically 
every 3 months (14 days) according to the schedule of activities.  Tumor assessments should 
also be performed to confirm clinical suspicion of relapse or disease progression for 
documentation.  Follow-up visit intervals should be determined from the end of treatment 
assessment.  
CT (preferred) or PET-CT scans should be performed during follow-up:

Every 6 months after the end of treatment assessment until disease progression, study 
withdrawal, end of study, or death, whichever comes first; or 

At any time that disease progression is suspected via clinical response assessment
For patients who have disease progression 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 disease progression
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 disease progression, assessments should be followed according to the schedule of 
activities, including response assessments and adverse events.  
Patients who discontinue all components of study treatment prior to disease progression (e.g., 
for toxicity) will continue in the study and will be followed for progressive disease and OS 
(regardless of whether they subsequently receive a new anti-lymphoma therapy). 
Study Treatment Regimen
Patients will receive a total of 6 cycles of polatuzumab vedotin or placebo in combination with 
BR.  A cycle is typically 21 days.
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/placebo IV infusion

Bendamustine 90 mg/m2 IV infusion
Cycle 1 Day 3

Bendamustine 90 mg/m2 IV infusion


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Schedule for Cycles 26
As long as the observed individual patient safety profile of polatuzumab vedotin/placebo and BR 
allows all study treatment infusions to be given on the same day, then the study treatment
infusions will be given sequentially on the same day for Cycles 26 and in the order specified 
below.
Cycles 26 Day 1

Rituximab 375 mg/m2 IV infusion

Polatuzumab vedotin/placebo IV infusion

Bendamustine 90 mg/m2 IV infusion
Cycles 26 Day 2

Bendamustine 90 mg/m2 IV infusion
Independent Review Committee
An IRC composed of certified radiologists and a hematologist or oncologist with experience in 
malignant lymphoma will assess all patients for response on the basis of imaging results and 
biopsy results that are performed related to efficacy evaluation.  Decisions will be guided by a 
Charter specific to the independent review.
Number of Patients
Approximately 42 patients with R/R DLBCL will be enrolled in this study.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form Age 18 years at time of signing Informed Consent Form

Able to comply with the study protocol and procedures, in the investigator’s judgment

Transplant ineligible patients with R/R DLBCL, classified as below:
-
Patients who are ineligible for second-line stem cell transplantation (SCT), with 
progressive disease or no response (stable disease [SD]) 6 months from start of 
initial therapy (second-line refractory)
-
Patients who are ineligible for second-line SCT, with disease relapse after initial 
response 6 months from start of initial therapy (second-line 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 (third-line or beyond refractory)
-
Patients who are ineligible for third-line (or beyond) SCT with disease relapse after 
initial response 6 months from start of prior therapy (third-line or beyond relapsed)

Confirmed DLBCL diagnosis as:
-
DLBCL, not otherwise specified (NOS) (including both GCB and ABC)
-
T-cell/histiocyte-rich large B-cell lymphoma
-
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements 
-
High grade B-cell lymphoma, NOS 
-
Primary mediastinal (thymic) large B-cell lymphoma
-
Epstein-Barr virus positive DLBCL, NOS

For patients who have received prior bendamustine, a response duration 1 year (for 
patients who have relapsed disease after a prior regimen)

At least one bi-dimensionally measurable lesion, defined as >1.5 cm in its longest 
dimension as measured by CT or magnetic resonance imaging

Availability of archival or freshly collected tumor tissue before study enrollment
Formalin-fixed, paraffin-embedded tissue blocks are preferred. 
If a tissue block is not available, at least 11 unstained slides or freshly cut serial 
sections (35 μm in thickness), will be accepted.


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Of note, receipt of tumor samples is not necessary prior to study enrollment. 

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
-
ANC 1.5 109/L
-
Platelet count 75 109/L

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, and agreement to refrain from donating 
eggs, as defined below:
Women must remain abstinent or use single highly effective or combined contraceptive 
methods with a failure rate of 1% per year during the treatment period and for 12 
months after the final dose study treatment.  Women must refrain from donating eggs 
during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or regulations.
Examples of highly effective contraceptive methods with a failure rate of 1% per year 
include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper 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.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.  If required per local guidelines or 
regulations, locally recognized acceptable methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form.

For men who are not surgically sterile:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, and agreement to refrain from donating 
sperm, as defined below:
With a female partner of childbearing potential who is not pregnant, men must 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 final dose of study treatment.  Men must refrain from donating sperm 
during this same period.
With a pregnant female partner, men must remain abstinent or use a condom during 
the treatment period and for 6 months after the final dose of study treatment to avoid 
exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.  If required per local guidelines or 
regulations, locally recognized acceptable methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form.

Residence in the People’s Republic of China


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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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 or rituximab 

History of sensitivity to mannitol (mannitol is an excipient in bendamustine)

Prior use of any MAb, radioimmunoconjugate, or antibody-drug conjugate 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 the protocol.

Completion of autologous SCT within 100 days prior to Cycle 1 Day 1

Prior allogeneic SCT

Prior treatment with CAR T-cell therapy

Eligibility for autologous SCT

Grade 3b FL

History of transformation of indolent disease to DLBCL

Primary or secondary CNS lymphoma

Current Grade 1 peripheral neuropathy

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)


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
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 monthly (or on Day 1 of every 
cycle) during the study and 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 polymerase chain 
reaction is negative for HCV RNA.

Known history of HIV seropositive status
For patients with unknown HIV status, HIV testing will be performed at screening.

Known infection human T-cell leukemia virus 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

Pregnant or breastfeeding or intending to become pregnant during the study or within 
12 months after the final dose of study treatment
Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to initiation of study drug.

Any of the following abnormal laboratory values, unless abnormal laboratory values are due 
to underlying lymphoma per the investigator:
-
Serum creatinine clearance 40 mL/min (using Cockcroft-Gault formula)
-
AST or ALT 2.5 upper limit of normal (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
Criteria for Lymph Node Biopsy Tissue
Patients must meet following criteria for lymph node biopsy tissue:

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 11 serial, freshly cut, unstained slides accompanied by an 
associated pathology report will be requested.  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.


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
20/Protocol YO41543, Version 2
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.  If a tissue block is provided, after necessary sections are cut, the remaining 
specimen will be returned to site upon request.  Tissue collected on study will not be returned to 
sites.
Refer to the laboratory manual for additional details.
End of Study
The end of the study is defined as the timepoint at which approximately two-thirds of enrolled 
patients have experienced deaths, or all patients have discontinued from the study, whichever 
occurs first.
In addition, the Sponsor may decide to terminate the study at any time.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is
expected to be approximately 21 months.
Investigational Medicinal Products
Polatuzumab Vedotin and Placebo
Polatuzumab vedotin and placebo will be supplied by the Sponsor as a sterile, white to grayish-
white, preservative-free lyophilisate in single-use vials. Polatuzumab vedotin or placebo should 
be prepared and administered in the same manner. For information on the formulation and 
handling of polatuzumab vedotin or placebo, see the pharmacy manual and the Polatuzumab 
Vedotin Investigator's Brochure.
Polatuzumab vedotin (1.8 mg/kg) or placebo will be administered by IV infusion on Day 2 of 
Cycle 1 and then Day 1 of Cycles 26.
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 the Rituximab 
Investigator’s Brochure.
Rituximab (375 mg/m2) will be administered by IV infusion on Day 1 of Cycles 16.
Bendamustine
Bendamustine hydrochloride will be supplied by the Sponsor.  For information on the 
formulation, packaging, and handling of bendamustine hydrochloride, see the pharmacy manual.
Bendamustine (90 mg/m2) will be administered by IV infusion over 3060 minutes on 
2 consecutive days of each cycle (Days 2 and 3 in Cycle 1 and then Days 1 and 2 in 
Cycles 26).  
Statistical Methods
Primary Analysis
CR at end of treatment assessment (68 weeks after Cycle 6 Day 1 or the final dose of study 
treatment) based on PET-CT, as determined by the IRC, will be used as the primary efficacy 
endpoint.  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 polatuzumab vedotin plus BR and placebo plus BR randomized
arms will be estimated along with the corresponding 95% CI on the basis of normal 
approximation to the binomial distribution.
Determination of Sample Size
The primary endpoint of CR at the end of treatment assessment was used to determine the 
sample size of the study. 
The primary objective of the study is to investigate whether the benefit (in terms of CR at the 
end of treatment assessment) of administrating polatuzumab vedotin plus BR in this study is 
consistent with the benefit observed in the global study GO29365. CR rate at the end of 
treatment assessment was increased from 17.5% in the BR arm to be 40% in the polatuzumab 
vedotin plus BR arm for study GO29365 (i.e., 22.5% CR rate increase).


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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In this study, 42 patients will be enrolled in a 2:1 randomization allocation to polatuzumab 
vedotin plus BR (experimental arm) or placebo plus BR arm (control arm). A total of 42 
patients will provide an approximate 80% probability of observing at least 50% of the benefit
in the CR rate at the end of treatment assessment observed in the global Study GO29365.
The expected enrollment duration is approximately 9 months and the primary analysis is 
expected to occur approximately 6 months of follow-up after the last patient is enrolled. The 
study will continue after primary analysis until about two-thirds of enrolled patients have 
experienced death or all patients have discontinued from study, whichever occurs earlier.  
Based on the observed median OS in Study GO29365 (4.7 months in the BR arm, 12.4 months 
in the polatuzumab vedotin plus BR arm), the final OS analysis is expected to occur 
approximately 10 months after the last patient is enrolled.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
aa-IPI
age-adjusted International Prognostic Index
ABC
activated B cell
acMMAE
antibody-conjugated monomethyl auristatin E
ADA
anti-drug antibody
ADC
antibody-drug conjugate
AUC
area under the concentrationtime curve
AUCinf
area under the concentration–time curve from Time 0 
to infinity
BOR
best objective response
BR
bendamustine and rituximab
BSA
body surface area
CAR
chimeric antigen receptor
CHOP
cyclophosphamide, doxorubicin, vincristine, and 
prednisone
CHP
cyclophosphamide, doxorubicin, and prednisone
CLL
chronic lymphocytic leukemia
Cmax
maximum plasma concentration
Ctrough
trough concentration
CMH
Cochran Mantel Haenszel
CR
complete response
CT
computed tomography (scan)
CTCAE
Common Terminology Criteria for Adverse Events
DDI
drugdrug interaction
DLBCL
diffuse large B-cell lymphoma
DOR
duration of response
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
DEL
double-expressor lymphoma
EFS
event-free survival
FACT/GOG-NTX  
Functional Assessment of Cancer 
Treatment/Gynecologic Oncology GroupNeurotoxicity
FDA
(U.S.) Food and Drug Administration
FL
follicular lymphoma
GCB
germinal center B cell


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Abbreviation
Definition
G-CSF
granulocyte colony-stimulating factor
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HR
hazard ratio
HRQoL 
health-related quality of life
HSV
herpes simplex virus
ICH
International Council for Harmonisation
IHC
immunohistochemistry
IMP
investigational medicinal product
iNHL
indolent non-Hodgkin lymphoma
IPI
International Prognostic Index
IRB
Institutional Review Board
IRC
Independent Review Committee
IRR
infusion-related reaction
IxRS
interactive voice or web-based response system
MAb
monoclonal antibody
MMAE
monomethyl auristatin E
NALT
new anti-lymphoma treatment
NCA
non-compartmental analysis
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCI CTCAE v5.0
National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0
NHL
non-Hodgkin lymphoma
NOS
not otherwise specified
OR
objective response
OS
overall survival
PCR
polymerase chain reaction
PE
polyethylene
PET
positron emission tomography (scan)
PET-CT
positron emission tomographycomputed tomography 
(scan)
PFS
progression-free survival


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Abbreviation
Definition
P-gp
P-glycoprotein
PK
pharmacokinetic
PML
progressive multifocal leukoencephalopathy
PopPK
population pharmacokinetic
PR
partial response
PRO
patient-reported outcome
PVC
polyvinyl chloride
Q3W
every 3 weeks
R-CHOP
rituximab plus cyclophosphamide, doxorubicin, 
vincristine, and prednisone
R-CHP
rituximab plus cyclophosphamide, doxorubicin, and 
prednisone
R/R
relapsed or refractory
SCT
stem cell transplantation
SD
stable disease
t1/2
terminal half-life
TEN
toxic epidermal necrolysis
TLS
tumor lysis syndrome
ULN
upper limit of normal
vc-MMAE
valine-citrulline-monomethyl auristatin E
VZV
Varicella zoster virus


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
25/Protocol YO41543, Version 2
1.
BACKGROUND
1.1
BACKGROUND ON DIFFUSE LARGE B-CELL LYMPHOMA
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin 
lymphoma (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 c-MYC (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 monoclonal antibody (MAb) rituximab to 
cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone 
(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 8 cycles of rituximab combined with 6 or 8 cycles of CHOP or 
CHOP-like chemotherapy (rituximab plus CHOP [R-CHOP]) is considered to be the 
standard of care for patients with previously untreated DLBCL (Tilly et al. 2012; National 
Comprehensive Cancer Network [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 (OS) (Shipp et al. 1993):

Age (60 vs. 60 years)

Serum 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)
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 progression-
free survival (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 


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was prognostic of response to therapy and OS.  Patients with a higher number of risk 
factors have lower rates of complete response (CR) to therapy, as well as lower rates of 
5-year survival (Ziepert et al. 2010).
For patients who are not cured by first-line therapy, high-dose chemotherapy followed by 
autologous stem cell transplantation (SCT) 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 SCT because of refractory disease 
or frailty have poor outcomes.  Responses to subsequent therapies range from 10% to 
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 POLATUZUMAB VEDOTIN
CD79b is a cell surface antigen whose expression is restricted to all mature B cells 
except plasma cells.  It is expressed in a majority of B-cell derived malignancies, 
including nearly all NHL and chronic lymphocytic leukemia (CLL) samples tested 
(Dornan et al. 2009).  Antibodies bound to CD79b are rapidly internalized, which makes 
CD79b ideally suited for targeted delivery of cytotoxic agents (Polson et al. 2007, 2009).  
Polatuzumab vedotin is an antibody-drug conjugate (ADC) that contains a humanized 
IgG1 anti-human CD79b MAb (MCDS4409A) and a potent anti-mitotic agent, 
mono-methyl auristatin E (MMAE), linked through a protease-cleavable linker, 
maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PAB).  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 


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addition of polatuzumab vedotin to a standard anti-CD20 antibody plus chemotherapy 
regimen will provide enhanced efficacy and safety to patients with NHL.
1.2.1
Nonclinical Studies with Polatuzumab Vedotin
Refer to the Polatuzumab Vedotin Investigator’s Brochure for details on nonclinical 
studies.
1.2.2
Clinical Studies with Polatuzumab Vedotin
Clinical data on polatuzumab vedotin in patients with NHL or CLL are available from four
Phase I/Ib studies (DCS4968g, JO29138, GO27834, and GO29044) and four ongoing 
Phase Ib/II studies (GO29365, GO29833, GO29834, and BO29561) in patients with B-
cell lymphoma: 

DCS4968g evaluated polatuzumab vedotin as a single agent and in combination 
with rituximab in patients with relapsed or refractory (R/R) B-cell lymphoma and CLL.  

JO29138 is evaluating polatuzumab vedotin as a single agent in Japanese patients 
with R/R B-cell lymphoma.

GO27834 evaluated polatuzumab vedotin in combination with either obinutuzumab 
or rituximab in patients with R/R follicular lymphoma (FL) or DLBCL.

GO29044 evaluated polatuzumab vedotin in combination with rituximab plus 
cyclophosphamide, doxorubicin, and prednisone (R-CHP) or obinutuzumab plus 
cyclophosphamide, doxorubicin, and prednisone (CHP) in patients with newly 
diagnosed or R/R B-cell lymphoma.  

GO29365 is evaluating polatuzumab vedotin in combination with bendamustine plus 
rituximab or obinutuzumab in patients with R/R FL or DLBCL.  

GO29833 is evaluating polatuzumab vedotin in combination with venetoclax and 
either obinutuzumab or rituximab in patients with R/R FL or DLBCL, respectively.

GO29834 is evaluating polatuzumab vedotin in combination with lenalidomide and 
either obinutuzumab or rituximab in patients with R/R FL or DLBCL, respectively.

BO29561 is evaluating polatuzumab vedotin in combination with atezolizumab and 
either obinutuzumab or rituximab in patients with R/R FL or DLBCL, respectively.

GO39942 (POLARIX) is evaluating polatuzumab vedotin in combination with R-CHP 
in patients with newly diagnosed DLBCL.
Single-agent safety and efficacy of polatuzumab vedotin was assessed in 
Study DCS4968g.  Polatuzumab vedotin was assessed in patients with B-cell lymphoma 
at doses from 0.1 to 2.4 mg/kg every 3 weeks (Q3W).  Among 86 patients with B-cell 
lymphoma or CLL treated with single-agent polatuzumab vedotin up to 2.4 mg/kg, the 
treatment-emergent events regardless of relationship to study drug reported in 20% of 
patients included neutropenia (38%), diarrhea (37%), pyrexia (31%), nausea (30%), 
peripheral sensory neuropathy (30%), fatigue (23%), and anemia (20%).  Single-agent 
polatuzumab vedotin anti-tumor activity was observed at doses 1.8 mg/kg in patients 
with R/R indolent B-cell lymphoma and DLBCL.  At a dose of 2.4 mg/kg, objective 


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responses were observed in 7 out of 16 patients (44%) with R/R indolent B-cell 
lymphoma and 14 out of 27 patients (52%) with R/R DLBCL.  At a dose of 1.8 mg/kg, 
2 partial responses (PRs) were observed in patients with R/R DLBCL (n4).  Based on 
the overall benefitrisk profile of polatuzumab vedotin, subsequent trials have mainly 
utilized a 1.8 mg/kg dose.   
Clinical data from previous studies describing the safety and activity of polatuzumab 
vedotin combined with immunochemotherapy are summarized below.
Polatuzumab Vedotin, Bendamustine, and Rituximab in Relapsed or 
Refractory DLBCL
In the randomized Phase II study GO29365 (n80), the addition of polatuzumab vedotin 
to bendamustine and rituximab (BR) has been shown to improve outcomes in transplant-
ineligible patients with R/R DLBCL compared with BR alone (data from clinical cutoff 
date, 30 April 2018).  Polatuzumab vedotin plus BR showed clinically meaningful efficacy 
with improvements in response rates that translated to prolongation of survival.  The 
primary efficacy endpoint of CR rate at the primary response assessment based on 
positron emission tomographycomputed tomography (PET-CT), as determined by an 
Independent Review Committee (IRC), was higher in the polatuzumab vedotin plus BR
arm (40.0% [16 out of 40 patients]; 95% CI: 24.9% to 56.7%) compared with the BR arm 
(17.5% [7 out of 40 patients]; 95% CI: 7.3% to 32.8%).  The difference in CR rates 
between arms was significant (22.5% in favor of polatuzumab vedotin plus BR; 
95% CI: 2.6% to 40.2%; p0.0261, Cochran Mantel Haenszel [CMH] 2). Duration of 
response (DOR), event-free survival (EFS), PFS, and OS were all higher with 
polatuzumab vedotin plus BR. The risk of death was reduced by 58% in patients treated 
with polatuzumab vedotin plus BR compared with BR (stratified hazard ration [HR]0.42; 
95% CI: 0.24 to 0.75; p0.0023).  Median OS was extended to 12.4 months 
(95% CI: 9.0 to not estimable) in the polatuzumab vedotin plus BR arm, from 4.7 months 
(95% CI: 3.7 to 8.3) in the BR arm.  The treatment effect for survival was consistently 
observed across all subgroups of patients with R/R DLBCL tested. The safety profile of 
polatuzumab vedotin plus BR was acceptable and in line with that observed for BR.  
Polatuzumab vedotin at 1.8 mg/kg in combination with bendamustine (90 mg/m2) and 
rituximab (375 mg/m2) was assessed in patients with R/R DLBCL or FL.  Among 
89 patients treated with the combination, the treatment-emergent events regardless of 
relationship to study drug reported in 20% of patients included neutropenia (43%), 
diarrhea (38%), nausea (38%), fatigue (36%), thrombocytopenia (29%), pyrexia (27%), 
anemia (26%), decreased appetite (25%), and constipation (20%).  
The results of this study demonstrate that polatuzumab vedotin is an active agent in 
R/R DLBCL when given in combination with chemotherapy and a CD20-targeting MAb.  
This China-only study is bridging the R/R DLBCL randomized portion of Study GO29365.


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Polatuzumab Vedotin in Previously Untreated DLBCL
The Phase Ib/II study GO29044 evaluated the recommended Phase II dose of 
polatuzumab vedotin at 1.8 mg/kg every 21 days with R-CHP in 45 patients with 
previously untreated DLBCL (Tilly et al. 2017).  All 45 patients received at least one dose 
of study drug and 40 patients completed 6 or 8 cycles (23 and 17 patients, respectively). 
The safety profile (including hematologic toxicity, infections, and neurotoxicity) was 
comparable to that seen in the R-CHOP arm of the contemporary study 
BO21005/GOYA.  The patients in Study GO29044 experienced similar rates of Grade 3 
and 4 adverse events (57.8% vs. 60.3%), Grade 5 adverse events (2.2% vs. 4.3%), and 
serious adverse events (37.8% vs. 37.6%) when compared with the R-CHOP arm of 
BO21005/GOYA (Vitolo et al. 2016; Tilly et al. 2017).  
Pharmacokinetic (PK) assessments did not demonstrate alterations to 
cyclophosphamide or doxorubicin PK when combined with polatuzumab vedotin, and 
dose intensity of R-CHP was also maintained with the incorporation of polatuzumab 
vedotin at 1.8 mg/kg.  
Efficacy by positron emission tomography (PET), as measured by investigator-assessed 
response by modified Cheson 2007 criteria, was promising, with 78% achieving CR and 
91% achieving OR at the end of treatment.  In the context of the Phase II patient 
population having higher-risk features, such as 78% having IPI 35 (98% IPI 25) and a 
median age of 69 years, the treatment regimen of R-CHP plus polatuzumab vedotin 
1.8 mg/kg, which is currently being further assessed in Study GO39942, has the 
potential to improve upon the current standard-of-care therapy (R-CHOP).
Refer to the Polatuzumab Vedotin Investigator’s Brochure for details on clinical studies.
1.2.3
Pharmacokinetic and Immunogenicity Properties of 
Polatuzumab Vedotin
The PK characteristics of polatuzumab vedotin three key analytes (conjugate, total 
antibody, and unconjugated MMAE [Gorovits et al. 2013; Kaur et al. 2013]) after 
single-agent treatment in patients with NHL based on a non-compartmental analysis
(NCA) in the Phase I study DCS4968g are summarized below.  Results are based on a 
relatively intensive PK sampling schedule.

The disposition of polatuzumab vedotin conjugate (evaluated as 
antibody-conjugated-MMAE [acMMAE]) appears driven by its antibody component.  
The PK properties of acMMAE and total antibody are largely similar and highly 
correlated, as characterized by a steadystate volume of distribution close to the 
physiological serum/plasma volume, low clearance, and relatively long terminal 
half-life (t1/2).

After the first dose of 1.8 mg/kg polatuzumab vedotin, the acMMAE mean (standard 
deviation) maximum plasma concentration (Cmax) was 803 (233) ng/mL, the area 
under the concentrationtime curve from Time 0 to infinity (AUCinf) was 
1860 (966) day ng/mL, and the t1/2 was 5.05 (1.60) days.


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
After the first dose of polatuzumab vedotin, the Cmax and AUCinf for acMMAE, total 
antibody, and unconjugated MMAE increased approximately dose-proportionally 
over the 0.1 to 2.4 mg/kg dose range.  

Mild increases of plasma acMMAE and serum total antibody pre-dose 
concentrations were observed with repeated Q3W dosing.  The average Cycle 4 
Day 1 pre-dose concentration was approximately 1.5-fold of the average 
concentration at Cycle 2 Day 1 pre-dose for acMMAE and 2.4-fold for total antibody.  

Unconjugated MMAE is a catabolite of polatuzumab vedotin and its 
pharmacokinetics appears to follow formation-rate limited kinetics, as indicated by 
relatively long t1/2 (2.92 to 6.44 days across doses of 0.12.4 mg/kg).  The time to 
maximum plasma concentration was 2.013.41 days across doses of 0.12.4 mg/kg.  
After the first dose of 1.8 mg/kg, the mean (standard deviation) Cmax was 6.82 (4.73)
ng/mL (N6).  

Plasma exposures of unconjugated MMAE were much lower compared with
acMMAE (1% by Cmax, and 3% by AUCinf, at 1.8 mg/kg).  

There was no apparent increase of plasma trough concentrations of unconjugated 
MMAE after repeated Q3W dosing.
The PK profiles and parameters were similar in the absence and presence of rituximab, 
suggesting that rituximab has little impact on polatuzumab vedotin pharmacokinetics in 
the patient population with R/R NHL.  Given the various CYPs involved for metabolism of 
MMAE and bendamustine, the risks of PK interactions between them is low, as 
described below.
Drug-drug interaction (DDI) risk for polatuzumab vedotin given in combination with BR:

There are no clinically meaningful drug interactions for polatuzumab vedotin given in 
combination with BR.  
Based on the population PK analysis, the rituximab combination was 
associated with mildly higher acMMAE Cycle 6 exposures (24% for area under 
the concentrationtime curve [AUC], 5% for Cmax) and moderately lower 
unconjugated MMAE Cycle 6 exposures (37% for AUC, 40% for Cmax).  This 
magnitude of higher acMMAE exposures is not expected to have a clinically 
relevant impact on safety based on the exposure-safety analysis.  
Bendamustine has no impact on acMMAE and unconjugated MMAE exposures.  
Polatuzumab vedotin does not affect the pharmacokinetics of rituximab and 
bendamustine.  Both the observed data and the population PK simulated 
exposures were similar with or without polatuzumab vedotin combination (10% 
difference).  The bendamustine PK parameters estimated by NCA are similar in 
patients who received polatuzumab vedotin plus BR versus BR alone (20% 
differences for each parameter). 


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
DDI potential for unconjugated MMAE with CYP3A substrate, inhibitor, or inducer as 
co-medications
Based on a physiologically based pharmacokinetic model verified with clinical 
DDI data of brentuximab vedotin, an ADC with the same link-payload 
valine-citrulline-MMAE (vc-MMAE), co-administration of polatuzumab vedotin 
with strong CYP3A4 inhibitors (e.g., ketoconazole) and strong CYP3A4 
inducers (e.g., rifampin) may result in changes of unconjugated MMAE 
exposure (48% higher AUC by ketoconazole, 49% lower AUC by rifampin); 
co-administration of polatuzumab vedotin does not appear to affect the 
exposure of midazolam, a CYP3A4 substrate. The 48% higher unconjugated 
MMAE exposures with a strong CYP3A inhibitor is not expected to have a 
clinically relevant impact on safety based on the exposure-safety analysis.  
Thus, no adjustment of starting dose is warranted when given in combination. 
Key summary of ethnic sensitivity analysis in polatuzumab vedotin pharmacokinetics 
among the Asian population compared with the global population are presented below.
Overall, no clinically meaningful difference in the pharmacokinetics of polatuzumab 
vedotin has been observed for patients enrolled from Asia or patients of Asian race.  
Therefore, no adjustment of dose is warranted for Asian patients.  Key PK findings 
relevant to the Asian population, assessed on the basis of both race and region, are 
as follows:

In the pivotal study GO29365, the direct observed mean Cycle 4 acMMAE and total 
antibody Cmax and trough concentration (Ctrough), as well as unconjugated MMAE 
Ctrough, were 9.9%17.5% lower in patients enrolled from Asia (n10, South Korea
being the only country) compared with patients enrolled outside of Asia (n124).

Based on observed monotherapy PK data, when comparing the pharmacokinetics of 
polatuzumab vedotin among Japanese (Study JO29138) and global 
(Study DCS4968g) patients with NHL, no clinically relevant difference was observed.  
With the limited number of evaluable Japanese patients (n6), the dose-normalized 
Cmax and AUCinf were largely similar between the two studies. The dose-normalized 
Cmax and AUCinf for acMMAE, the key analyte of interest for exposure-safety/efficacy 
relationships, were comparable between Japanese and global patients.  Some 
trends were observed toward higher total antibody exposure (~37%) and lower 
unconjugated MMAE exposure (~61%) in Japanese patients.  However, on the 
basis of these results, no dose adjustment has been made for the ongoing 
registration-enabling Japanese Phase II Study JO40762, where a regimen of 
1.8 mg/kg Q3W was selected.

Population pharmacokinetic (PopPK) evaluation on race:  Based on 460 NHL 
patients from Studies GO29365, DCS4968g, GO27834, and GO29044, race (Asian 
vs. non-Asian) was identified as a statistically significant covariate for central volume 
of acMMAE (V1) in the popPK model, but the magnitude of impact on Cmax was small 
(7.3% higher for Asian) based on the sensitivity analysis and thus not clinically 
meaningful.  Asian (n18) and non-Asian (n422) patients showed nearly identical 
(1.2% difference) simulated Cycle 6 acMMAE Cmax and AUC.  For unconjugated 


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MMAE, exposure was numerically lower in Asian patients (18.6% for AUC and 16.9% 
for Cmax) compared with non-Asian patients.

PopPK evaluation on region:  Region was not formally tested as a covariate in the 
popPK model, given that it is highly correlated with race.  The simulated Cycle 6 
exposures of patients enrolled from Asia (n10) and non-Asia regions (n450) 
suggested that acMMAE exposures in patients enrolled from Asia were nearly 
identical (10% difference) to the exposures of patients from non-Asia regions, 
while unconjugated MMAE exposures were numerically lower (25% for AUC and 
23.2% for Cmax) for patients enrolled from Asia.

The prediction-corrected visual predictive check plots by popPK for acMMAE and 
unconjugated MMAE further confirmed there is no clinically meaningful difference by 
race and region.
In conclusion, observed PK data and popPK analyses suggest that there is no clinically 
meaningful difference in polatuzumab vedotin pharmacokinetics among the Asian 
population compared with the global population.  Therefore, no adjustment of dose is 
warranted for Asian patients.
Key summary of anti-drug antibody (ADA) observations from clinical studies: 

As of September 2018, across all patients including Study GO29365 (excluding 
patients in Arm G) and six additional supportive studies, the postbaseline ADA 
incidence is 2.6% (14 out of 536 patients). The low observed incidence of ADAs is 
not unexpected given that the mechanism of action of polatuzumab vedotin is to 
target and kill B-cells and that most patients are co-medicated with rituximab.  

In Study GO29365 (excluding Arm G), the incidence of treatment-emergent (sum of 
treatment-induced and treatment-enhanced) ADA is 6.0% (8 of 134 patients). 

Based on the simulated exposures using individual empirical Bayes estimate 
parameters with partial covariate correction method, for the ADA-positive patients
with NHL (N12 PK-evaluable patients with NHL), the acMMAE exposures are 
similar to the ADA-negative patients (10% difference).  The unconjugated MMAE 
exposures are slightly higher in ADA-positive patients (10% for AUC, 24% for Cmax), 
but the differences were not statistically significant (geometric mean ratios 
included 1).  Thus, positive ADA response is not expected to have a clinically 
relevant impact on polatuzumab vedotin PK exposures.  

Due to the limited number of ADA-positive patients following administration of 
polatuzumab vedotin, no conclusions can be drawn concerning a potential effect of 
immunogenicity on safety or efficacy.  However, no obvious correlation has been 
identified between ADA response and safety, and the emergence of ADAs to 
polatuzumab vedotin did not appear to impact efficacy of ongoing long-term 
responses in the few patients that were antibody positive. 
Refer to the Polatuzumab Vedotin Investigator’s Brochure for details on clinical PK and 
immunogenicity studies.


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1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
DLBCL expresses the CD20 antigen, and anti-CD20 antibody 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 (Coiffier et al. 
2002, 2007, 2010; Feugier et al. 2005; Hiddemann et al. 2005; Habermann et al. 2006; 
Herold et al. 2007; Marcus et al. 2008; Pfreundschuh et al. 2008; Salles et al. 2008).  
Progress has been made in the treatment of 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 
patients who develop refractory disease during or after first-line therapy.
Common regimens used to treat transplant-eligible patients with R/R DLBCL are also 
used to treat transplant-ineligible patients.  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 patients 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 2019).
Three studies have evaluated the combination of BR in R/R DLBCL (Ohmachi et al. 
2013; Vacirca et al. 2014; Dang et al. 2018).  In one of the Phase II trials, the OR rate 
was 63% (37% CR/unconfirmed CR) 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).  In the Phase III trial, in which 137 patients received BR, 
the OR rate was 48% (17% CR, 4% unconfirmed CR) and the median DOR was 
7.2 months (6.510.8 months) (Dang et al. 2018).
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.  Study GO29365 demonstrated a clinically 
meaningful benefit with the addition of the novel ADC, polatuzumab vedotin, to BR 
compared with BR alone. In the randomized comparison, the polatuzumab vedotin
(1.8 mg/kg) plus BR combination showed significantly improved CR rates, PFS, and OS 
compared with BR alone. The risk of death was reduced by 58% in patients treated with 
polatuzumab vedotin plus BR compared with BR (stratified HR 0.42; p0.0023).  Median 
OS was more than 2.5 times longer in patients receiving polatuzumab vedotin plus BR 
compared with BR alone (12.4 vs. 4.7 months). 


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The same trend has been observed within the Asian patient population.  No previously 
reported Phase III randomized study has shown a survival benefit in this population of 
patients (Czuczman et al. 2017; Dang et al. 2018). Study GO29365 is the first
randomized study to show survival benefit in transplant-ineligible patients with 
R/R DLBCL. In addition, currently available PK data from Asian patients treated with 
polatuzumab vedotin did not show clinical meaningful differences.  The safety profile 
between Asia and the global population is consistent on the basis of data from 
Study GO29365.  Considering there is no ethnic difference, the Sponsor believes the 
combination of polatuzumab vedotin plus BR can provide an available treatment option 
worldwide for patients with R/R DLBCL.
This China-only bridging study is designed to demonstrate comparable risk and benefit 
of polatuzumab vedotin plus BR in Chinese patients with R/R DLBCL and support the 
registration of the R/R DLBCL indication in China.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, and pharmacokinetics of polatuzumab 
vedotin plus BR compared with placebo plus BR in Chinese patients with R/R DLBCL.  
Specific objectives and corresponding endpoints for the study are outlined below.
In this protocol, "study treatment" refers to the combination of treatments assigned to 
patients as part of this study (i.e., polatuzumab vedotin/placebo, bendamustine, and 
rituximab).
2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of polatuzumab 
vedotin plus BR compared with placebo plus BR in Chinese patients with R/R DLBCL on 
the basis of the following endpoint. This objective is to investigate whether the benefit (in 
terms of CR rate at end of treatment assessment) of administrating polatuzumab vedotin 
plus BR in this study is consistent with the benefit observed in the global study,
GO29365.

CR at the end of treatment assessment (68 weeks after Cycle 6 Day 1 or final dose 
of study treatment) based on PET-CT, as determined by the IRC according to the 
Lugano Response Criteria for Malignant Lymphoma, hereafter referred to as the 
"Lugano Response Criteria" (Cheson et al. 2014; see Appendix 3)
2.1.2
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of polatuzumab 
vedotin plus BR compared with placebo plus BR in Chinese patients with R/R DLBCL on 
the basis of the following endpoints:

CR at the end of treatment assessment based on PET-CT, as determined by the 
investigator according to the Lugano Response Criteria


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
OR, defined as CR or PR, at the end of treatment assessment based on PET-CT, 
as determined by the investigator and IRC according to the Lugano Response 
Criteria

CR at the end of treatment assessment based on computed tomography (CT) only, 
as determined by the investigator and IRC according to the Lugano Response 
Criteria

OR, defined as CR or PR, at the end of treatment assessment based on CT only, as 
determined by the investigator and IRC according to the Lugano Response Criteria

Best objective response (BOR), defined as CR or PR, while on study based on
PET-CT or CT only, as determined by the investigator and IRC according to the 
Lugano Response Criteria

DOR, defined as the time from the first occurrence of a documented objective 
response to disease progression, relapse, or death from any cause based on 
PET-CT or CT only, as determined by the investigator and IRC according to the 
Lugano Response Criteria

PFS, defined as the period from date of randomization until the date of disease 
progression, relapse, or death from any cause based on PET-CT or CT only, as 
determined by the investigator and IRC according to the Lugano Response Criteria

EFS, defined as the time from date of randomization to any treatment failure 
including disease progression, relapse, initiation of new anti-lymphoma treatment 
(NALT), or death based on PET-CT or CT only, as determined by the investigator 
according to the Lugano Response Criteria

OS, defined as the time from date of randomization until the date of death from 
any cause
  
2.2
SAFETY OBJECTIVES
The safety objective for this study is to evaluate the safety of polatuzumab vedotin plus
BR compared with placebo plus BR in Chinese patients with R/R DLBCL on the basis of 
the following endpoints:

Incidence and severity of adverse events, with severity determined according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0 (NCI CTCAE v5.0)

Incidence and nature of study drug discontinuation, dose reduction, and dose delay 
due to adverse events
Additionally, this study will evaluate the safety of polatuzumab vedotin plus BR 
compared with placebo plus BR from the patient's perspective to better understand 
treatment impact, tolerability, and reversibility on the basis of the following endpoint:

Change from baseline in peripheral neuropathy as assessed through use of the 
Functional Assessment of Cancer Therapy/Gynecologic Oncology 
GroupNeurotoxicity (FACT/GOG-NTX) 


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2.3
PHARMACOKINETIC OBJECTIVES
The PK objective for this study is to characterize the PK for total antibody, acMMAE, and 
unconjugated MMAE following polatuzumab vedotin administration, when combined with 
BR, in Chinese patients with R/R DLBCL on the basis of the following endpoints:

Serum concentration of total antibody at specified timepoints

Plasma concentration of acMMAE at specified timepoints

Plasma concentration of unconjugated MMAE at specified timepoints
Additionally, this study will evaluate potential relationships between polatuzumab 
vedotin exposure and the efficacy and safety of polatuzumab vedotin, when combined 
with BR, in Chinese patients with R/R DLBCL on the basis of the following endpoints:

Relationship between plasma concentration or PK parameters for polatuzumab 
vedotin and efficacy endpoints

Relationship between plasma concentration or PK parameters for polatuzumab 
vedotin and safety endpoints
2.4
IMMUNOGENICITY OBJECTIVES
The immunogenicity objective for this study is to evaluate the immune response to 
polatuzumab vedotin, when combined with BR, in Chinese patients with R/R DLBCL on 
the basis of the following endpoint:

Prevalence of ADAs for polatuzumab vedotin at baseline and incidence of ADAs 
during the study
Additionally, this study will evaluate potential effects of ADAs on the basis of the 
following endpoint:

Relationship between ADA status for polatuzumab vedotin and efficacy, safety, or 
PK endpoints
2.5
BIOMARKER OBJECTIVE
The biomarker objective for this study is to evaluate the response to polatuzumab 
vedotin, when combined with BR, in Chinese patients with R/R DLBCL with known 
prognostic factors, such as activated B cell (ABC)-DLBCL or germinal center B cell 
[GCB]-DLBCL, as analyzed through use of a centrally performed RNA-based assay, or 
co-expression of BCL2 and MYC (double-expressor [DEL]) as analyzed through use of 
centrally performed immunohistochemistry (IHC) tests.  In addition, the association 
between response and the expression of the target of polatuzumab vedotin, CD79b (as 
analyzed through use of a centrally performed IHC test) will be evaluated.

CR at the end of treatment assessment based on PET-CT, as determined by the IRC 
according to the Lugano Response Criteria in populations of ABC-DLBCL, GCB-
DLBCL, DEL, and expression of CD79b


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
OR, defined as CR or PR, at the end of treatment assessment based on PET-CT, as 
determined by the  IRC according to the Lugano Response Criteria in populations 
of ABC-DLBCL, GCB-DLBCL, DEL, and expression of CD79b
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design
This is a Phase III, multicenter, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of polatuzumab vedotin in combination with BR 
compared with BR alone in Chinese patients with R/R DLBCL.
Approximately 42 Chinese patients will be randomized to one of the following treatment 
arms in a 2:1 ratio:

Polatuzumab vedotin plus BR (experimental arm)  

Placebo plus BR (control arm)
Randomization will be conducted with the aid of an interactive web-based response 
system (IxRS) and will be stratified according to the following factors: 

DOR to most recent prior therapy:  12 months versus 12 months 

Number of prior therapies (1 vs. 2)
For consistency with the pivotal study population (Study GO29365), patients 
with 2 prior lines of therapy will be capped within 70% of the whole population.
Figure 1 presents an overview of the study design.  A schedule of activities is provided 
in Appendix 1.
Study treatment will be administered by IV infusion every 21 days for up to 6 cycles, as 
described in Section 3.1.2 and Figure 2.  The first day of treatment will constitute 
Study Day 1.  Refer to Section 4.3.2 for details on study treatment dosage and 
administration.




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Patients who complete the study treatment period will return to the clinic for a treatment 
completion visit 30 (5) days after the final dose of study treatment (Cycle 6 Day 1).  
Patients who discontinue study treatment prematurely will return to the clinic for a 
treatment discontinuation visit 30 (5) days after the final dose of study treatment.  
Disease Progression and Follow Up
Following completion of treatment, patients who have not progressed will be followed 
clinically every 3 months (14 days) according to the schedule of activities (Appendix 1).  
Tumor assessments should also be performed to confirm clinical suspicion of relapse or 
disease progression for documentation. Follow-up visit intervals should be determined 
from the end of treatment assessment.  
CT (preferred) or PET-CT scans should be performed during follow-up:

Every 6 months after the end of treatment assessment until disease progression, 
study withdrawal, end of study, or death, whichever comes first; or 

At any time that disease progression is suspected via clinical response assessment
For patients who have disease progression 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 disease progression 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 disease progression, assessments should 
be followed according to the schedule of activities, including response assessments and 
adverse events.  
Patients who discontinue all components of study treatment prior to disease progression 
(e.g., for toxicity) will continue in the study and will be followed for progressive disease 
and OS (regardless of whether they subsequently receive a new anti-lymphoma therapy). 
3.1.2
Study Treatment Regimen
Patients will receive a total of 6 cycles of polatuzumab vedotin or placebo in combination 
with BR (see Figure 2).  A cycle is typically 21 days.
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/placebo IV infusion

Bendamustine 90 mg/m2 IV infusion


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Cycle 1 Day 3

Bendamustine 90 mg/m2 IV infusion
Schedule for Cycles 26
As long as the observed individual patient safety profile of polatuzumab vedotin/placebo
and BR allows all study treatment infusions to be given on the same day, then the study 
treatment infusions will be given sequentially on the same day for Cycles 26 and in the 
order specified below.
Cycles 26 Day 1

Rituximab 375 mg/m2 IV infusion

Polatuzumab vedotin/placebo IV infusion

Bendamustine 90 mg/m2 IV infusion
Cycles 26 Day 2

Bendamustine 90 mg/m2 IV infusion
Figure 2
Polatuzumab Vedotin/Placebo plus BR Regimen
BR bendamustine and rituximab; C Cycle.


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3.1.3
Independent Review Committee
An IRC composed of certified radiologists and a hematologist or oncologist with 
experience in malignant lymphoma will assess all patients for response (see Appendix 3) 
on the basis of imaging results and biopsy results that are performed related to efficacy 
evaluation.  Decisions will be guided by a Charter specific to the independent review.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of the study is defined as the timepoint at which approximately two-thirds of 
enrolled patients have experienced deaths, or all patients have discontinued from the 
study, whichever occurs first.
In addition, the Sponsor may decide to terminate the study at any time.
The total length of the study, from screening of the first patient to the end of the study, is
expected to be approximately 21 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Polatuzumab Vedotin Dose and Schedule
In Study GO29365, 6 cycles of treatment with polatuzumab vedotin 1.8mg/kg combined 
with rituximab (375mg/m2) and bendamustine (90 mg/m2) was well tolerated with a 
favorable risk and benefit profile. This data (n40) now expands to study Arms G and H 
with an additional 100 patients exposed at this dose level.  There were no ethnic 
differences observed in Study GO29365, which have the same dose levels of study 
treatments that are considered appropriate for this China-only study.
3.3.2
Rationale for Patient Population
As previously stated, there continues to be a high unmet need worldwide for transplant-
ineligible patients with R/R DLBCL. Current treatments available for this patient 
population have demonstrated a median PFS 3 months (1.310 months) (Colosia et al. 
2014); the median OS for non-eligible patients is only 6 months (Crump et al. 2017). For 
patients who relapse within 12 months, rituximab plus gemcitabine in combination with
oxaliplatin (RGemOx) demonstrated median PFS and OS of 3 months and 6 months,
respectively.  In a Phase II study of patients treated with BR in this patient population, 
the CR rate was only 15.3% with a median PFS of 3.6 months (Vacirca et al. 2014).
Although chimeric antigen receptor (CAR) T-cell therapy is a revolutionary breakthrough 
in this area, patients may not be eligible for treatment, and treatment is not readily 
available.  The 6-month response rate for treatment with CAR T-cell therapy is reported 
as 30%54% (Neelapu et al. 2017; Schuster et al. 2017).
In Study GO29365, polatuzumab vedotin plus BR demonstrated a 40% CR rate versus 
the control arm (BR alone; 17.5% CR) in highly refractory patients (80% refractory to last 
prior therapy).  The risk of death was reduced by 58% (stratified HR 0.42; p0.0023)
and median OS was more than 2.5 times longer in patients treated with polatuzumab 


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vedotin plus BR compared with BR alone (12.4 vs. 4.7 months, respectively) (Sehn et al. 
2018). Therefore, polatuzumab vedotin provides a new treatment choice for patients 
with R/R DLBCL.  
Thus, there is an urgent clinical need for the study of new effective and tolerable 
therapies, such as polatuzumab vedotin plus BR, in transplant-ineligible patients with
R/R DLBCL.
3.3.3
Rationale for Rituximab and Bendamustine Dose and Schedule
In Study GO29365, patients with R/R DLBCL receiving polatuzumab vedotin plus BR 
completed a median of 5 cycles with 46.7% completing all 6 treatment cycles and were 
treated for a median treatment duration of approximately 2.42 months for each individual 
component of study treatment.  The majority of patients treated with polatuzumab 
vedotin plus BR received their planned doses of polatuzumab vedotin, bendamustine,
and rituximab. Therefore, in this China-only bridging study of GO29365, the same dose 
level and schedule for bendamustine (90 mg/m2 administered over 2 consecutive days 
on a 21-day cycle in patients with R/R DLBCL) will be used.
Three other studies have evaluated the combination of BR in patients with R/R DLBCL 
(Ohmachi et al. 2013; Vacirca et al. 2014; Dang et al. 2018).  In these studies, rituximab 
was administered at a standard dose of 375 mg/m2 on Day 1, followed by bendamustine 
120 mg/m2 over 2 consecutive days for up to 6 cycles.  Cycles were administered on a 
21-day (Ohmachi et al. 2013) or a 28-day cycle (Vacirca et al. 2014; Dang et al. 2018).
The most frequent Grade 3 or 4 adverse events observed in the Ohmachi and Vacirca 
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). Phase 3 data from the Dang study show that the most frequent 
adverse events occurring in patients receiving either BR or rituximab plus gemcitabine
remain hematologic (thrombocytopenia: 87% any grade, 64% Grade 3; neutropenia: 35%
any grade; 16% Grade 3).
In the Ohmachi study, 29% of patients (15 of 51 patients) who received Cycle 2 and 32% 
(14 of 44 patients) 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, the pivotal 
study GO29365 has used 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 Q3W when combined 
with rituximab for aggressive NHL (Cheson et al. 2010).


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For transplant-ineligible patients with R/R DLBCL, there is no universal standard of care 
regimen used as no prior randomized trials have established the superiority of one 
regimen over another for this population (see Section 1.3).  Guidelines such as those put 
forth by the NCCN include BR, which has shown activity in R/R DLBCL (Ohmachi et al. 
2013; Vacirca et al. 2014; Hong et al. 2018). 
In addition, cross-trial comparisons of survival outcomes between different regimens 
have significant limitations in terms of differences in enrolled or observed populations,
such as numbers of refractory versus relapsed (or early relapsed) patients, numbers of 
prior lines of therapy (e.g., number of patients with one prior line vs. two or more, or if 
there was a maximum number of prior lines allowed in the trial), and when trials were 
conducted (some earlier trials occurred at a time when there were still a significant 
number patients who were not exposed to rituximab in first-line therapy).  Thus, it 
remains difficult to draw definitive conclusions that regimens based on platinum or 
gemcitabine are truly superior to BR in the contemporary setting for the transplant-
ineligible patient population with R/R DLBCL without a randomized trial.  As BR has 
shown efficacy in two prospective single-arm trials and two randomized trials (Ohmachi 
et al. 2013; Vacirca et al. 2014; Dang 2018; Sehn et al. 2018), and is used in many 
centers to treat this population of patients, it is considered a relevant comparator.  
As one of the first chemotherapy combinations explored in the clinical development plan, 
BR was selected to partner with polatuzumab vedotin to avoid potential overlapping of 
peripheral neuropathy that may be seen in platinum-based therapies.  In order to assess 
the individual contribution of polatuzumab vedotin in the polatuzumab vedotin plus BR 
combination, BR was selected as the comparator. 
3.3.4
Rationale for Biomarker Assessments
Biomarkers in the tumor that are associated with drug target, mechanism of action, and 
NHL biology 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 appear to result in 
differential activity in DLBCL prognostic subgroups, including ABC versus GCB and 
DLBCL with co-expression of BCL2 and MYC, all of which were recognized as 
prognostic markers by 2016 WHO DLBCL Classification (Swerdlow et al. 2016).
Therefore, it is of interest to understand the activity of a novel treatment, such as 
polatuzumab vedotin plus BR, in these DLBCL subtypes.  
3.3.5
Rationale for Stratification Factors
For relapsed DLBCL, predictive factors have included initial remission duration of
1 year and the absence of bulky disease at the time of SCT (Sweetenham 2005).


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In addition, in Study GO29365, prior treatment lines have shown a major impact on 
outcome.  As a bridging study, this China-only study will use prior treatment lines 2 and 
remission duration of 1 year as stratification factors.
Given the marked heterogeneity in outcome based on these risk factors, patients will be 
stratified at randomization to take these factors into account.
3.3.6
Rationale for Clinical Outcome Assessments
3.3.6.1
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 
and now is the standard for fluorodeoxyglucose-avid lymphoma (Cheson 2015).
3.3.6.2
Patient-Reported Outcomes
In this study, peripheral neuropathy will be assessed using the FACT/GOG-NTX, as it is 
a treatment-related effect common to polatuzumab vedotin. The FACT/GOG-NTX
evaluates treatment-induced neurologic symptoms (including sensory, hearing, motor, 
and dysfunction) and consists of 11 questions (see Appendix 5).
4.
MATERIALS AND METHODS
Eligible patients must have R/R DLBCL and meet the following inclusion and 
exclusion criteria.
4.1
PATIENTS
Approximately 42 patients with R/R DLBCL will be enrolled in this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Able to comply with the study protocol and procedures, in the investigator’s 
judgment

Transplant ineligible patients with R/R DLBCL, classified as below:
–
Patients who are ineligible for second-line SCT, with progressive disease or no 
response (stable disease [SD]) 6 months from start of initial therapy 
(second-line refractory)
–
Patients who are ineligible for second-line SCT, with disease relapse after initial 
response 6 months from start of initial therapy (second-line 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 (third-line or 
beyond refractory)


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–
Patients who are ineligible for third-line (or beyond) SCT with disease relapse 
after initial response 6 months from start of prior therapy (third-line or 
beyond relapsed)

Confirmed DLBCL diagnosis as:
–
DLBCL, not otherwise specified (NOS) (including both GCB and ABC)
–
T-cell/histiocyte-rich large B-cell lymphoma
–
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements 
–
High grade B-cell lymphoma, NOS 
–
Primary mediastinal (thymic) large B-cell lymphoma
–
Epstein-Barr virus positive DLBCL, NOS

For patients who have received prior bendamustine, a response duration 1 year 
(for patients who have relapsed disease after a prior regimen)

At least one bi-dimensionally measurable lesion, defined as 1.5 cm in its longest 
dimension as measured by CT or magnetic resonance imaging (MRI)

Availability of archival or freshly collected tumor tissue before study enrollment
Formalin-fixed, paraffin-embedded tissue blocks are preferred. 
If a tissue block is not available, at least 11 unstained slides or freshly cut serial 
sections (35 m in thickness), will be accepted.
Of note, receipt of tumor samples is not necessary prior to study enrollment. 

Life expectancy of at least 24 weeks

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 of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, and agreement to refrain from 
donating eggs, as defined below:
Women must remain abstinent or use single highly effective or combined 
contraceptive methods with a failure rate of 1% per year during the treatment 
period and for 12 months after the final dose study treatment.  Women must 
refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 


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permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations.
Examples of highly effective contraceptive methods with a failure rate of 
1% per year include bilateral tubal ligation, male sterilization, hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, 
and copper 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.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  
If required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form.

For men who are not surgically sterile:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, and agreement to refrain from 
donating sperm, as defined below:
With a female partner of childbearing potential who is not pregnant, men must
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 final dose of study treatment. Men must 
refrain from donating sperm during this same period.
With a pregnant female partner, men must remain abstinent or use a condom 
during the treatment period and for 6 months after the final dose of study 
treatment to avoid exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  
If required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form.

Residence in the People’s Republic of China
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


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
Contraindication to bendamustine or rituximab 

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.

Completion of autologous SCT within 100 days prior to Cycle 1 Day 1

Prior allogeneic SCT

Prior treatment with CAR T-cell therapy

Eligibility for autologous SCT

Grade 3b FL

History of transformation of indolent disease to DLBCL

Primary or secondary CNS lymphoma

Current Grade 1 peripheral neuropathy

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.


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
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 monthly (or 
on Day 1 of every cycle) during the study and 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 polymerase chain 
reaction (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.

Known infection human T-cell leukemia virus 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

Pregnant or breastfeeding or intending to become pregnant during the study or 
within 12 months after the final dose of study treatment
Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days prior to initiation of study drug.

Any of the following abnormal laboratory values, unless abnormal laboratory values 
are due to underlying lymphoma per the investigator:
–
Serum creatinine clearance 40 mL/min (using Cockcroft-Gault formula)
–
AST or ALT 2.5 upper limit of normal (ULN)
–
Total bilirubin 1.5 ULN


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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
Patients must meet following criteria for lymph node biopsy tissue:

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 11 serial, freshly cut, unstained slides accompanied by 
an associated pathology report will be requested.  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.  If a tissue block is provided, after necessary sections are 
cut, the remaining specimen will be returned to site upon request.  Tissue collected on 
study will not be returned to sites.
Refer to the laboratory manual for additional details.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
4.2.1
Treatment Assignment
This is a randomized, double-blind study.  After initial written informed consent has been
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient's 
identification number and treatment assignment from an IxRS.
Patients will be randomly assigned to one of two treatment arms:  experimental arm 
(polatuzumab vedotin plus BR) or control arm (placebo plus BR).  Randomization will 
occur in a 2:1 ratio using a permuted-block randomization method to ensure a balanced 
assignment to each treatment arm.  Randomization will be stratified according to the 
following criteria:

DOR to most recent prior therapy (12 months vs. 12 months)


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
Number of prior therapies (1 vs. 2)
4.2.2
Blinding
Study site personnel and patients will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 
exception of individuals who require access to patient treatment assignments to fulfill 
their job roles during a clinical trial. These roles include the clinical supply chain 
managers, sample handling staff, operational assay group personnel, and IxRS service 
provider.
While PK and immunogenicity samples must be collected from patients assigned to the 
comparator arm to maintain the blinding of treatment assignment, PK and ADA assay 
results for these patients are generally not needed for the safe conduct or proper 
interpretation of the study data.  Laboratories responsible for performing study drug PK 
and ADA assays will be unblinded to patient treatment assignments to identify 
appropriate samples for analysis.  PK samples from patients assigned to the comparator 
arm will not be analyzed for study drug PK concentration except by request (e.g., to 
evaluate a possible error in dosing).  Baseline immunogenicity samples will be analyzed 
for all patients.  Postbaseline immunogenicity samples from patients assigned to the 
comparator arm will not be analyzed for ADAs except by request.
To optimize timelines for delivery of PK-related analyses, unblinded PK and ADA data 
may be released to selected clinical pharmacology personnel before the clinical cutoff 
date, prior to study unblinding.
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations.
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.  The 
investigator should document and provide an explanation for any non-emergency 
unblinding.  If the Medical Monitor agrees to patient unblinding, the investigator will be 
able to break the treatment code by contacting the IxRS.
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 


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personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are polatuzumab vedotin,
placebo for polatuzumab vedotin, bendamustine, and rituximab.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Polatuzumab Vedotin and Placebo
Polatuzumab vedotin and placebo will be supplied by the Sponsor as a sterile, white to
grayish-white, preservative-free lyophilisate in single-use vials. Polatuzumab vedotin or
placebo should be prepared and administered in the same manner. For information on 
the formulation and handling of polatuzumab vedotin or placebo, 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 the 
Rituximab Investigator’s Brochure.
4.3.1.3
Bendamustine
Bendamustine hydrochloride will be supplied by the Sponsor.  For information on the 
formulation, packaging, and handling of bendamustine hydrochloride, see the pharmacy 
manual.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimen is summarized in Section 3.1.2.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Any dose modification should be noted on the Study Drug 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 for 
patients who experience adverse events are provided in Section 5.1.4.
The patient weight obtained during screening (Day 28 to Day 1) should be used for 
dose determination for all treatment cycles; if the patient’s weight within 96 hours prior to 
Day 1 of a given treatment cycle 10% from the weight obtained during screening, the 
new weight should be used to calculate the dose.  The weight that triggered a dose 
adjustment will be taken as the new reference weight for future dose adjustments.  All 


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subsequent doses should be modified accordingly.  Sites may calculate the dose based 
on real-time weight.
4.3.2.1
Polatuzumab Vedotin and Placebo 
Polatuzumab vedotin (1.8 mg/kg) or placebo will be administered by IV infusion on Day 2 
of Cycle 1 and then Day 1 of Cycles 26. Refer to Section 3.1.2 and Figure 2 for details 
on the study treatment regimen.
Given the double-blinded nature of this study, site staff will be unaware of the treatment 
assignment of each patient.  The dosage, preparation, administration, and compliance 
for both polatuzumab vedotin and the placebo for polatuzumab vedotin will be identical.
After reconstitution with Sterile Water for Injection and dilution into IV bags that contain
isotonic sodium chloride solution (0.9% NaCl), polatuzumab vedotin/placebo will be 
administered by IV infusion using a dedicated standard administration set with 0.2-m or
0.22-m in-line filters at a final polatuzumab vedotin/placebo concentration determined
by the patient-specific dose. Compatibility of polatuzumab vedotin/placebo with IV bags,
infusion lines, filters, and other infusion aids has been established with items made of
specific materials of construction.  Please consult the pharmacy manual and the
Polatuzumab Vedotin Investigator’s Brochure for a list of compatible materials and
specific dose preparation instructions. 
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/placebo (which may have already been administered as a premedication for 
rituximab).  If infusion-related reactions (IRRs) are observed with the first infusion of 
polatuzumab vedotin in the absence of premedication, premedication must be 
administered before subsequent doses per Table 2.
The polatuzumab vedotin/placebo infusion may be slowed or interrupted for patients who 
experience 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.
4.3.2.2
Rituximab
Rituximab (375 mg/m2) will be administered by IV infusion on Day 1 of Cycles 16.  
Refer to Section 3.1.2 and Figure 2 for details on the study treatment regimen. No dose 
modifications of rituximab are allowed.


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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 
dose of rituximab is split over 2 days, both infusions must occur with appropriate 
premedication and at the first infusion rate (see Table 1).
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).  A 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 1.  If a 
patient tolerates the first cycle of study treatment without significant infusion reactions, 
rituximab may be administered as rapid infusion (over 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 5.1.4.3.
Rituximab should be administered as a slow IV infusion through a dedicated line.  IV 
infusion pumps (such as the B. Braun InfusomatSpace) should be used to control the 
infusion rate of rituximab.  Administration sets with polyvinyl chloride (PVC), 
polyurethane, or polyethylene (PE) as a product contact surface and IV bags with 
polyolefine, polypropylene, 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.


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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.
Table 1
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 the patient tolerates the first cycle of study 
treatment without significant infusion reactions, 
rituximab may be administered as rapid infusion 
(over 90 minutes) in accordance with local 
institutional guidelines.

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).
4.3.2.3
Bendamustine
Bendamustine (90 mg/m2) will be administered by IV infusion over 3060 minutes on 
2 consecutive days of each cycle (Days 2 and 3 in Cycle 1 and then Days 1 and 2 in 
Cycles 26).  Refer to Section 3.1.2 and Figure 2 for details on the study treatment 
regimen.
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 
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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 antiemetics may be administered as per institutional guidelines (see 
Section 4.4).  Granulocyte colony-stimulating factor (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. 
Dose modification and dose delays will be implemented for hematologic toxicities.
4.3.3
Premedication
Patients should receive premedication as outlined in Table 2.


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Table 2
Premedication for Rituximab and Blinded Polatuzumab 
Vedotin/Placebo
Timepoint
Patients Who Require 
Premedication
Premedication
Administration
Cycle 1 
Day 1
All patients
Corticosteroid a
Complete 1 hour prior to rituximab 
infusion.
Antihistamine drug b
Analgesic/antipyretic c
Administer 30 minutes prior to 
rituximab infusion.
Cycle 1,
Day 2
All patients
Corticosteroid a
Permitted at the discretion of the 
treating physician.
Antihistamine drug b
Analgesic/antipyretic c
Administer 30 minutes prior to 
polatuzumab vedotin/placebo
infusion.
Cycles 2
and beyond,
Day 1
Patients with no IRR 
during the previous 
infusion
Corticosteroid a
Complete 1 hour prior to rituximab 
and polatuzumab vedotin/placebo 
infusion. May be omitted at the 
investigator’s discretion.
Antihistamine drug b
Analgesic/antipyretic c
Administer 30 minutes prior to 
infusion.  May be omitted or 
adapted at the investigator’s 
discretion.
Patients with Grade 1 
or 2 IRR during the 
previous infusion
Corticosteroid a
Complete 1 hour prior to rituximab 
and polatuzumab vedotin/placebo 
infusion.
Antihistamine drug b
Analgesic/antipyretic c
Administer 30 minutes prior to 
rituximab and/or polatuzumab 
vedotin/placebo infusion.
Patients with Grade 3 
IRR, wheezing, 
urticaria, or other 
symptoms of 
anaphylaxis during 
the previous infusion
Patients with bulky 
disease
Corticosteroid
(mandatory)
Complete 1 hour prior to rituximab 
and/or polatuzumab 
vedotin/placebo infusion.
Antihistamine drug b
Analgesic/antipyretic c
Administer 30 minutes prior to 
rituximab and/or polatuzumab 
vedotin/placebo infusion.
IRRinfusion-related reaction.
a A 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. Hydrocortisone should not be used, as it has not been effective in 
reducing rates of IRRs.  
b For example, 50100 mg of diphenhydramine.
c For example, 6501000 mg of acetaminophen/paracetamol.


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4.3.4
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (polatuzumab vedotin/placebo, rituximab, 
and bendamustine) 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.
4.3.5
Continued Access to Polatuzumab Vedotin and Rituximab
Currently, the Sponsor does not have any plans to provide Roche IMPs (polatuzumab 
vedotin and rituximab) or any other study treatments to patients who have completed the 
study.  The Sponsor may evaluate whether to continue providing polatuzumab vedotin 
and rituximab in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from 7 days prior to initiation of 
study drug to the treatment completion/discontinuation visit.   All such medications 
should be reported to the investigator and recorded on the Concomitant Medications 
eCRF.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Oral contraceptives will be allowed.

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.

Antiemetic 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., 5HT3) antagonist (i.e., dolasetron, ondansetron, etc.) or 
according to institutional practice.


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
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
–
Premedication before rituximab, polatuzumab vedotin or bendamustine 
–
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)
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, per local standard practice.  Vitamin D substitution is encouraged for 
patients with vitamin D deficiency (Bittenbring et al. 2014).  Patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per local standard practice.  Serious infusion-
associated events manifested by dyspnea, hypotension, wheezing, bronchospasm, 
tachycardia, reduced oxygen saturation, or respiratory distress should be managed with 
supportive therapies as clinically indicated (e.g., supplemental oxygen and 2-adrenergic 
agonists).
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 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 syndrome (TLS) 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.


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4.4.1.3
Prophylaxis for Infections
Given the risk of infections associated with bendamustine and the potential added risk 
with polatuzumab vedotin, antiviral (coverage for herpes simplex virus [HSV] and 
Varicella zoster virus [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.
4.4.1.4
Monitoring and Treatment for Hepatitis B Reactivation
Patients who are both HBsAg negative and HBcAb positive may be included in this study.  
These patients should have HBV DNA levels obtained monthly (or on Day 1 of every 
cycle) 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 
29 IU/mL.
If the HBV-DNA assay becomes positive and is above the 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) 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 within the WHO-recommended range of 
29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) and immediately 
referred to a 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 antiviral 
medication, study treatment will be permanently discontinued (see Section 5.1.4 and 
Table 4).
Prophylactic antiviral medications for hepatitis B reactivation will follow the institution’s 
standard of care.
4.4.2
Cautionary Therapy
4.4.2.1
Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes and P-Glycoprotein
In vitro data suggest that unconjugated MMAE is mainly metabolized by CYP3A4 and, to 
a lesser extent, by CYP2D6.  Based on a validated physiological-based PK model 
simulation and a clinical DDI study of brentuximab vedotin, which contains identical 
maleimidocaproyl-valine-citrulline-MMAE (mc-vc-MMAE) linker/payload as polatuzumab 
vedotin (Han et al 2013), ketoconazole as a strong CYP3A4 inhibitor increases the 
exposure (e.g., AUC) of unconjugated MMAE by approximately 34%, while rifampin as a 
strong CYP3A4 inducer increases the exposure (e.g., AUC) of unconjugated MMAE by 


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approximately 46%. Concomitant medications that are strong CYP3A4 inhibitors 
(see Appendix 6) should be considered cautionary as they may potentially increase 
exposure to unconjugated MMAE leading to adverse reactions, which require close 
monitoring.  
If a patient is taking any of the medications in the categories of strong CYP3A4 inhibitors 
and inducers, the investigator will assess and document the use of these medications 
known or suspected to fall in those categories.
A sample list of cautionary medications that fall into the categories within this section can 
be found in Appendix 6.  The lists of medications are not necessarily comprehensive.  
The investigator should consult the prescribing information when determining whether a 
concomitant medication can be safely administered with study treatment.  In addition, 
the investigator should contact the Medical Monitor if questions arise regarding 
medications not listed in Appendix 6.
MMAE is a P-glycoprotein (P-gp) substrate but not a P-gp inhibitor. Concomitant 
medications that are P-gp inhibitors (see Appendix 6) should be considered cautionary 
as they may potentially increase exposure to unconjugated MMAE leading to adverse 
reactions, which require close monitoring.  If a patient is taking any of the medications in 
the categories of P-gp inhibitors, the investigator will assess and document the use of 
these medications known or suspected to fall in those categories.  A sample list of 
cautionary medications that fall into the categories within this section can be found 
in Appendix 6.  The list of medications is not necessarily comprehensive.
4.4.2.2
Herbal Therapies 
Concomitant use of herbal therapies should not be used because their pharmacokinetics, 
safety profiles, and potential DDIs are generally unknown.  A sample list of cautionary 
medications (including some herbal therapies) is included in Appendix 6.  However, 
herbal therapies not intended for the treatment of cancer may be used during the study 
at the discretion of the investigator.
4.4.3
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 therapies (other than intrathecal CNS prophylaxis and study treatment) 
intended for the treatment of lymphoma whether Center for Drug Evaluation of 
China approved or experimental. 

Immunotherapy or immunosuppressive therapy other than study treatments used for 
the intention of treating lymphoma (e.g., for an adverse event)


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
Any unplanned radiotherapy

Hormone therapy other than contraceptives, hormone-replacement therapy, or 
megestrol acetate

Biologic agents used for the intention of treating lymphoma other than clinically 
indicated hematopoietic growth factors

Pre-phase therapy, other than the use of prednisone (see Table 2 in Section 4.3.3)
4.4.3.1
Immunizations
Patients who participate in this study may not receive either primary or booster 
vaccination with live virus vaccines at any time during study treatment.  Investigators 
should review the vaccination status of potential study patients being considered for this 
study and follow the national guidelines for adult vaccination with non-live vaccines 
intended to prevent infectious diseases before study therapy.
Per the Rituximab Investigator’s Brochure, the safety of immunization with live viral 
vaccines following MabThera/Rituxan therapy has not been studied, and vaccination 
with live virus vaccines is not recommended.  Refer to the Rituximab Investigator’s 
Brochure for additional safety information.
4.5
STUDY ASSESSMENTS 
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. Bone 
marrow biopsies collected within 90 days prior to Day 1 of study treatment are 
acceptable.  Samples obtained more than 90 days prior to Day 1 require prior approval 
by the Medical Monitor before the patient can be randomized.
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
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record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History, Concomitant Medication, 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,
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
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, 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.
4.5.4
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.  Record abnormalities observed at baseline on the General Medical History 
and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.
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.


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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.
4.5.5
Tumor and Response Evaluations
All evaluable or measurable disease must be documented at screening and re-assessed 
at each subsequent tumor evaluation.  Response will be assessed by the IRC and the 
investigator on the basis of physical examinations, CT scans, PET-CT scans, and bone 
marrow examinations using the 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 
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, are required at the following 
visits:

Screening:  within 35 days of Cycle 1 Day 1

Interim response assessment:  between Cycle 3 Day 15 and Cycle 4 Day 1

End of treatment assessment:  68 weeks after Cycle 6 Day 1 or the final dose of 
study treatment
CT (preferred) or PET-CT scans should be performed during follow-up:

Every 6 months after end of treatment assessment until disease progression, study 
withdrawal, end of study, or death, whichever comes first; or 

At any time that disease progression is suspected via clinical response assessment


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The Lugano Response Criteria (see Appendix 3) 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.
At all times during the study, diagnosis of disease progression based on clinical 
examination must be confirmed by imaging (e.g., CT, PET-CT) as soon as feasible 
(maximum, within 30 days) and prior to initiation of non–protocol specified anti-
lymphoma therapy. 
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 (within 3 months of Cycle 1 Day 1) 
for staging purposes in all patients.  In addition, the definition of CR requires clearing of 
previously infiltrated bone marrow in CT based response.  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 only in two circumstances:

To confirm a radiological assessment of CR if there was bone marrow involvement 
with tumor at screening 

If required for confirmation of relapse in the bone marrow 
Any additional (unscheduled) bone marrow examinations performed during the study will 
be at the discretion of the investigator.
4.5.6
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 HBV DNA tests, the option to submit samples for analysis to 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, lymphocytes, eosinophils, basophils, 
and monocytes])


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
Serum chemistry:  sodium, potassium, glucose, BUN or urea, creatinine, calcium, 
total bilirubin, direct bilirubin, total protein, albumin, ALT, AST, ALP, LDH, uric 
acid/urate, hemoglobin A1c (HbA1c), amylase, and lipase
At screening, samples will be obtained in a fasting state for all patients.  
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

HIV serology:  HIV antibody

HBV serology:  HBsAg, total HBcAb, and (if HBsAg test is negative and total HBcAb 
test is positive) HBV DNA
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection.

HCV serology:  HCV antibody 
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has an HCV infection.

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, 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 end of treatment 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 screening.


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Central Laboratory Assessments
Plasma, serum, and tumor tissue samples for biomarker, ADA, and PK analyses 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 
natural killer-cell counts (CD16 and CD56) at screening, end of treatment 
assessment visit, and every 6 months (from the treatment completion visit) until 
end of study or patient discontinuation.

Plasma and serum samples for PK analysis (polatuzumab vedotin/placebo; see
Appendix 2)
–
Serum concentration of total antibody
–
Plasma concentration of acMMAE
–
Plasma concentration of unconjugated MMAE

Serum samples for immunogenicity analysis (polatuzumab vedotin/placebo; see
Appendix 2)

Pretreatment tumor tissue sample is required (archival tissue or fresh pretreatment 
biopsy is acceptable) and to be submitted according to local regulations.  Tumor 
blocks are preferred.  If a tumor block is not available, a minimum of 11 serial freshly 
cut, unstained slides are required. 
Biomarker research in tumor tissue will include analysis of DLBCL prognostic subtype 
(ABC/GCB), and expression of BCL2, MYC, and CD79b.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Biological samples will be destroyed after the final Clinical Study Report has been 
completed:

Plasma and/or serum samples collected for PK or immunogenicity analysis and 
characterization (including domain specificity) will be destroyed after the final study 
results have been reported.

Tumor tissue samples collected for biomarker research will be destroyed after the 
final study results have been reported.

Remaining archival tissue blocks will be returned to local pathology according to 
country-specific procedures.
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 
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samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
4.5.7
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. 
4.5.8
Patient-Reported Outcome Assessment
Patient-reported outcome (PRO) data will be collected to document the treatment benefit 
and more fully characterize the safety profile of polatuzumab vedotin. PRO data will be 
obtained through use of the FACT/GOG-NTX scale (see Appendix 5).
The FACT/GOG-NTX is a validated self-report measure for assessing
platinum/paclitaxel-induced peripheral neuropathy (Huang et al. 2007). This measure 
can be used to assess polatuzumab vedotininduced neuropathy, as symptoms of 
chemotherapy-induced neuropathy caused by microtubule inhibitors do overlap with
those seen in platinum/paclitaxelcontaining regimens. The full measure consists of the
FACT-G physical, social/family, emotional, and functional well-being scales (27 items),
as well as a peripheral neuropathy symptoms scale (11 items). For this study, only the
items that comprise the peripheral neuropathy scale will be administered to patients. 
The scale contains 4 subscales that assess sensory neuropathy (4 items), hearing 
neuropathy (2 items), motor neuropathy (3 items), and dysfunction associated with 
neuropathy (2 items), which can be summed to create a total score.  Each item is rated 
on a 5-point response scale that ranges from "not at all" to "very much," with higher 
scores indicative of more extreme neuropathy.
The scale, translated into the local language as appropriate, should be completed in its
entirety at specified timepoints during the study. To ensure instrument validity and that 
data standards meet health authority requirements, paper versions of the FACT/GOG-
NTX scale will be self-administered or interviewer administered (as appropriate) before 
the patient receives any information on disease status, prior to the performance of non-
PRO assessments, and prior to the administration of study treatment. The data from the 
questionnaires will be entered into the EDC system by site staff.
Study site staff will ensure that the FACT/GOG-NTX scale is provided to the patients for
completion per the schedule of activities (see Appendix 1), and before the patients
complete the visit the site staff will confirm completion or alternatively document any
reasons for not completing the scale.


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The FACT/GOG-NTX will be administered on Day 1 of every cycle, at treatment
completion/discontinuation, at the end of treatment assessment, and at specified 
planned post-treatment visits thereafter until the close of the study (every 3 months after 
the treatment completion visit).
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of 
the following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy

Use of an anti-cancer therapy not required per protocol

Symptomatic deterioration attributed to disease progression

Confirmed disease progression per investigator assessment according to the 
Lugano Response Criteria (Appendix 3)

Unacceptable toxicity (as described in Section 5.1 and Table 4)

Patient/investigator decision  
In these cases, patients should continue to be followed for both resolution of toxicity and 
disease progression as described in Sections 5.5 and 5.6, and in Appendix 1.
The primary reason for early treatment termination should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
Patients will return to the clinic for treatment discontinuation visit 30 (5) days after the 
final dose of study treatment and should obtain tumor response assessments. 
Assessments should continue to follow the schedule as outlined in Appendix 1.
In the case where a patient experiences disease progression, information on survival 
follow-up and new anti-cancer therapy will be collected via telephone calls, patient 
medical records, and/or clinic visits approximately every 6 months until death (unless the 
patient withdraws consent or the Sponsor terminates the study).  
Polatuzumab Vedotin
A patient should permanently discontinue polatuzumab vedotin if any of the 
following occur:

Grade 4 peripheral neuropathy 


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
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 
Rituximab
A patient should permanently discontinue rituximab 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)
Polatuzumab Vedotin/Placebo plus Bendamustine and Rituximab
A patient should permanently discontinue polatuzumab vedotin/placebo plus BR 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

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 antiviral therapy

Disease progression
4.6.2
Patient Discontinuation from the Study
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 discontinuation from the study may include, but are not limited to, the 
following:

Patient withdrawal of consent

Study termination or site closure

Adverse event

Loss to follow-up

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain a reason for patient discontinuation from the study.  
The primary reason for discontinuation from the study should be documented on the 
appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
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end of treatment assessments (see Appendix 1).  Patients who withdraw from the study 
will not be replaced.
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status only if permitted by local 
regulations.
4.6.3
Study 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.  
4.6.4
Site Discontinuation
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 Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Polatuzumab vedotin is not approved in China, and clinical development is ongoing.  
The safety plan for patients in this study is based on clinical experience with 
polatuzumab vedotin in completed and ongoing studies.  The anticipated important 
safety risks for polatuzumab vedotin are outlined below.  Please refer to the 
Polatuzumab Vedotin Investigator's Brochure for a complete summary of safety 
information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for dosage modification and treatment interruption or 
discontinuation, are provided below.


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Safety will be evaluated through the monitoring of the following:

Serious adverse events that are attributed to protocol-mandated interventions from 
the time of signing informed consent until the first dose of study treatment on 
Cycle 1 Day 1

All adverse events, including serious and non-serious adverse events, from Cycle 1 
Day 1 until 90 days after the final dose of study treatment
After this period, the investigator should report all serious adverse events that 
are believed to be related to prior study drug treatment for an indefinite period 
of time (even after the study has been closed).

All adverse events of special interest that the investigator considers related to study 
drug from Cycle 1 Day 1 until 12 months after the final dose of study treatment

Measurements of protocol-specified hematology and clinical chemistry laboratory 
values

Measurements of protocol-specified vital signs

Assessment of ECGs and echocardiogram or multiple-gated acquisition scans if 
clinically indicated

Assessment of physical findings on clinical physical examinations
5.1.1
Risks Associated with Polatuzumab Vedotin
On the basis of clinical data to date, the following known and suspected risks are 
described below.  Guidelines around the management of these risks through dose and 
schedule modifications are described in Section 5.1.4.  Refer to the Polatuzumab 
Vedotin Investigator’s Brochure for complete and updated details.
5.1.1.1
Known Risks Associated with Polatuzumab Vedotin
Based on clinical experience with polatuzumab vedotin in patients treated in the current 
Phase I and II studies, the following are identified risks of polatuzumab vedotin. 
Myelosuppression: Consolidation of Neutropenia (Including Febrile 
Neutropenia), Thrombocytopenia, and Anemia
Neutropenia, neutropenia-associated events (including febrile neutropenia), 
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 Table 4.  
Primary G-CSF prophylaxis is required for neutropenia.  The use of G-CSF for 
neutropenia is described in Section 4.4.1.1.  Transfusion support for anemia and 
thrombocytopenia is permitted at the discretion of the investigator.


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Peripheral Neuropathy (Sensory and/or Motor)
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.  Neuropathy will be monitored by the standard clinical evaluation per 
investigator’s discretion and reported according to NCI CTCAE.
Study treatment dose and schedule modifications for peripheral neuropathy are 
described in Table 4.
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 populations 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.  In addition, neutropenia is a known risk for
polatuzumab vedotin.  Reports in the literature indicate that granulocytopenia is a major 
predisposing factor to infections in patients with B-cell lymphoma (Bishop et al. 1981).  
The reported incidence of infection in chemotherapy courses for B-cell lymphoma 
associated with 500 granulocytes/L was higher than those with 500 granulocytes/L.  
Anti-infective prophylaxis should be considered and is described in Section 4.4.1.3.
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 for polatuzumab vedotin infusion administration are outlined in Table 2.  
Close monitoring throughout the infusion is required, and IRRs should be managed as 
outlined in Table 3.


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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 Associated with Polatuzumab Vedotin
Below are potential risks of polatuzumab vedotin.  See the Polatuzumab Vedotin 
Investigator’s Brochure for full information.
Effects on the Relative-Dose Intensity of Bendamustine and Rituximab
Depending upon the toxicity profile observed with the addition of polatuzumab vedotin to 
BR, there may be a reduction in the relative-dose intensity of BR that is administered.
Tumor Lysis Syndrome 
There is a potential risk of TLS if treatment with polatuzumab vedotin results in the rapid 
destruction of a large number of tumor cells.  If any evidence of TLS occurs during the 
study, tumor lysis prophylaxis measures will be instituted.  Patients who are considered 
to have a high tumor burden (e.g., lymphocyte count 25109/L or bulky 
lymphadenopathy) and who are considered to be at risk for TLS by the investigator will 
receive tumor lysis prophylaxis (e.g., allopurinol 300 mg/day orally or a suitable 
alternative treatment such as rasburicase 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 and adequate hydration, as deemed 
appropriate by the investigator.
Immunogenicity (Anti-Drug Antibodies)
As with any recombinant antibody, polatuzumab vedotin may elicit an immune response, 
and patients may develop antibodies against it.  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.
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. 


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Hyperglycemia
Hyperglycemia has been observed in patients treated with polatuzumab vedotin as well 
as with other ADCs that use the same vc-MMAE platform.  Hyperglycemia has been 
reversible upon holding or discontinuing treatment of the ADCs and/or initiation or 
adjustment of anti-hyperglycemic medications.
Hepatotoxicity
Hepatotoxicity has been observed in patients treated with polatuzumab vedotin in both 
the Phase I and II trials.  Although the relationship between hepatotoxicity and 
polatuzumab vedotin has not been definitively determined, transient, dose-related 
increases in hepatic enzymes were noted in nonclinical rat studies.  No hepatotoxicity 
was noted following administration of the surrogate ADC in cynomolgus monkeys.
Elevations of transaminases have been reported in patients receiving polatuzumab 
vedotin and have ranged in intensity from Grades 1 to 4. These have been reversible 
with and without dose modification/discontinuation.  For additional information, please 
refer to the current Polatuzumab Vedotin Investigator’s Brochure.
For blinded polatuzumab vedotin/placebo dose delay, modification, and discontinuation 
instructions, see Table 4. 
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.
5.1.2
Risks Associated with Rituximab
Please see the current Rituximab Investigator’s Brochure for full information.
For rituximab dose delay, modification, and discontinuation instructions, see Table 4.
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 


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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 Virus 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 antiviral 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 PML should be suspected in any patient who develops new-onset 
neurologic manifestations.  The majority of patients with hematologic malignancies 
diagnosed with PML received rituximab in combination with chemotherapy or as part of a 
hematopoietic SCT.  Most cases of PML were diagnosed within 12 months of the 
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 


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or reactivated viral infections include cytomegalovirus, HSV, parvovirus B19, VZV, West 
Nile virus, HBV, and HCV.
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
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. 
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 5.1.4 for monitoring plans and Table 4 for instructions for dose delay and 
modification of bendamustine.  Antiviral (coverage for HSV, VZV) and anti-pneumocystis
prophylaxis are required per Section 4.4.1.3.  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
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.


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5.1.3.4
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.
5.1.3.5
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 and TEN, some fatal, have been 
reported when bendamustine was administered concomitantly with allopurinol and other 
medications known to cause these syndromes.  Patients with skin reactions should be 
monitored closely.  If skin reactions are severe or progressive, bendamustine should be 
withheld.
5.1.3.6
Long-Term Stem-Cell Toxicity
Premalignant and malignant diseases, including myelodysplastic syndrome, 
myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma, have 
developed in patients treated with bendamustine.
5.1.3.7
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.
5.1.3.8
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.
5.1.3.9
Drug Interactions
Certain medications may interact with bendamustine.  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.  CYP1A2 inhibitors and inducers are not contraindicated.  During treatment with 
bendamustine, patients will be provided with a card to keep with them that provides 


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notification to other health care providers that the patient is taking bendamustine as a 
participant in a clinical study.
5.1.4
Management of Patients Who Experience Specific Adverse 
Events
Guidelines for management of specific adverse events are outlined in Table 4.  
Additional guidelines are provided in the subsections below.
5.1.4.1
Dose Delays and Dose Modifications
Patients should be assessed clinically for toxicity before each dose using 
NCI CTCAE v5.0 unless otherwise stated.  These guidelines pertain to dose delays and 
modifications based on physical examination findings, observed toxicities, and laboratory 
results obtained within 72 hours before study treatment administration.  Dosing will occur 
only if a patient’s clinical assessment and laboratory test values are acceptable.  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 and the approval of the Medical Monitor.
No dose modifications of rituximab (375 mg/m2) are allowed.  
Bendamustine and polatuzumab vedotin doses may be reduced (per the guidelines 
outlined in Table 4) with the approval of the Medical Monitor.
If administration of chemotherapy is delayed, the administration of rituximab and 
polatuzumab vedotin should be delayed for the same time frame (e.g., if bendamustine 
therapy is delayed, administration of rituximab and polatuzumab vedotin should also be 
delayed so that they are given together beginning on Day 1 of the same cycle).
5.1.4.2
Treatment Interruption and Schedule Modification
Study treatment may be temporarily suspended in patients who experience toxicity 
considered to be related to study drug.  Aside from the withholding of blinded 
polatuzumab vedotin for neuropathy per Table 4, study drugs withheld for 14 days
because of toxicity should be discontinued, unless resumption of treatment is approved 
following investigator discussion with the Medical Monitor
Study treatment may be suspended for reasons other than toxicity (e.g., surgical 
procedures) with Medical Monitor approval.  The investigator and the Medical Monitor 
will determine the acceptable length of treatment interruption. If scheduled dosing 
coincides with a holiday that precludes dosing, dosing should commence on the nearest 
following date, with subsequent dosing continuing on a 21-day schedule as applicable.


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Patients 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.
5.1.4.3
Non-Hematologic Toxicities
Infusion-Related Reactions and Anaphylaxis
Medications including epinephrine for SC injection, corticosteroids, diphenhydramine 
hydrochloride for IV injection, and resuscitation equipment should be available for 
immediate use.  Management of infusion-related symptoms for rituximab is summarized 
in Table 3 according to the administration rates in Section 4.3.2.2.  In the event of a 
life-threatening IRR (which may include pulmonary or cardiac events) or IgE-mediated 
anaphylactic reaction, rituximab 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 4 for recommended management of anaphylaxis.
Patients who experience rituximab-associated infusion-related temperature elevations of 
38.5°C or other minor infusion-related symptoms may be treated symptomatically with 
acetaminophen/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 4 for recommended management of anaphylaxis.
Guidelines for the management of IRRs and anaphylaxis are detailed in Table 3.


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Table 3
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.
NCI CTCAE v5.0National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0.
Refer to the NCI-CTCAE v5.0 scale for the grading of symptoms.  Management of IgE-mediated 
allergic reactions should be as directed in the text following this table.
a Supportive treatment:  Patients should be treated with acetaminophen/paracetamol and an 
antihistamine such as diphenhydramine if they have not been received in the previous 4 hours.  
IV saline may be indicated.  For bronchospasm, urticaria, or dyspnea, patients may require 
antihistamines, oxygen, corticosteroids (e.g., 100 mg IV prednisolone or equivalent), and/or 
bronchodilators.  Patients with hypotension who require vasopressor support must be 
permanently discontinued from study drug.
b Infusion rate escalation after re-initiation:  Upon complete resolution of symptoms, 
the infusion may be resumed at 50% of the rate achieved prior to interruption.  In the absence 
of infusion-related symptoms, the rate of infusion may be escalated in increments of 
50 mg/hour every 30 minutes.


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Table 4
Guidelines for Dose Delay or Modification of Polatuzumab Vedotin, Rituximab, 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 

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 bendamustine is 90 mg/m2, 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 two 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.


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Table 4
Guidelines for Dose Delay or Modification of Polatuzumab Vedotin, Rituximab, or Bendamustine (cont.)
Event(s)
Dose Delay or Modification
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 dose level (70 mg/m2).

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 bendamustine is 90 mg/m2, then reduce bendamustine to the next lower 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 two 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 is required.


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Table 4
Guidelines for Dose Delay or Modification of Polatuzumab Vedotin, Rituximab, or Bendamustine (cont.)
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 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 TLS

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 is required.


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Table 4
Guidelines for Dose Delay or Modification of Polatuzumab Vedotin, Rituximab, or Bendamustine (cont.)
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.
BRbendamustine and rituximab; DILIdrug-induced liver injury; G-CSFgranulocyte colony-stimulating factor; HBVhepatitis B virus; 
LMWHlow molecular-weight heparin; TLStumor lysis syndrome; ULNupper limit of normal.
a All based on laboratory test results obtained within 72 hours before infusion of Day 1 of that cycle. 


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Hematologic Toxicity
Note that lymphopenia is not considered to be a hematologic toxicity because it is an 
expected outcome of therapy.  
Dose Discontinuation
Dosing delay exceeding 14 days in the initiation of the next planned cycle of 
polatuzumab vedotin/placebo plus BR 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 the schedule of activities (Appendix 1).
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, 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) (see Sections 5.3.5.9
and 5.3.5.10 for more information)

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


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
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:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs 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)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
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 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7)


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
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

Grade 2 or higher peripheral neuropathy (sensory and/or motor) 

Grade 3 or higher Infections 

HBV reactivation
5.2.4
Selected Adverse Events
Additional data will be collected for the following selected adverse events:

Neutropenia, including febrile neutropenia (all grades)

Peripheral neuropathy (sensory and/or motor, all grades)

Infections (all grades)

Hepatic toxicity (all grades)
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 adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 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 final dose of study treatment.


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Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 5 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 5
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 (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for
reporting instructions), per the definition of serious adverse event in Section 5.2.2.


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5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also
Table 6):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of 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

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 6
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
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.


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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 IRR).
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 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

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.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 


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more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).


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5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol-
specified adverse event reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of DLBCL should be recorded on the Death Attributed 
to Progressive Disease eCRF.  All other deaths that occur during the adverse event 


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reporting period, 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).
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
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 DLBCL
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on the Lugano Response Criteria (Appendix 3).  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., inpatient 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.  


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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
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
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 associated 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; see Section 5.4.2).  For 
polatuzumab vedotin/placebo and rituximab, 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.


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In addition, all special situations associated with polatuzumab vedotin/placebo and 
rituximab, 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.

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
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  Sites are not expected to review the 
PRO data for adverse events.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

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)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 


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than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board or Ethics Committee 
(IRB/EC).
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Medical Monitor/Roche Medical Responsible:
 M.D., Ph.D. (Primary)
Telephone No.:
Mobile Telephone No.:
Medical Monitor:
 M.D. (Secondary)
Telephone No.:
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events 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.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.


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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 final dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 90 days after the final dose 
of study treatment 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 12 months after the final 
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within
6 months after the final dose of study drug.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 


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investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  When 
permitted by the site, the pregnant partner would need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
If the authorization has been signed, the investigator should submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician.
5.4.3.3
Abortions
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 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).
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.


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During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 90 days after the final 
dose of study drug), all deaths, regardless of cause, should be reported through use of 
the Long-Term Survival Follow-Up eCRF.
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study drug, the event should be reported through use 
of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Polatuzumab Vedotin Investigator's Brochure

Rituximab Investigator’s Brochure

Summary of Product Characteristics for bendamustine


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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
6.1
DETERMINATION OF SAMPLE SIZE
The primary endpoint of CR at the end of treatment assessment was used to determine 
the sample size of the study. 
The primary objective of the study is to investigate whether the benefit (in terms of CR at 
the end of treatment assessment) of administrating polatuzumab vedotin plus BR in this 
study is consistent with the benefit observed in the global study GO29365. CR rate at 
the end of treatment assessment was increased from 17.5% in the BR arm to be 40% in 
the polatuzumab vedotin plus BR arm for study GO29365 (i.e., 22.5% CR rate increase).
In this study, 42 patients will be enrolled in a 2:1 randomization allocation to 
polatuzumab vedotin plus BR (experimental arm) or placebo plus BR arm (control arm). 
A total of 42 patients will provide an approximate 80% probability of observing at least 
50% of the benefit in the CR rate at the end of treatment assessment observed in the 
global Study GO29365.
The expected enrollment duration is approximately 9 months and the primary analysis is 
expected to occur approximately 6 months of follow-up after the last patient is enrolled. 
The study will continue after primary analysis until about two-thirds of enrolled patients 
have experienced death or all patients have discontinued from study, whichever occurs 
earlier.  Based on the observed median OS in Study GO29365 (4.7 months in the BR 
arm, 12.4 months in the polatuzumab vedotin plus BR arm), the final OS analysis is 
expected to occur approximately 10 months after the last patient is enrolled.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study discontinuation will be listed and 
summarized.  Major protocol deviations will be listed and evaluated for their potential 
effects on the interpretation of study results.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics (such as age, sex, and duration of malignancy) 
will be summarized using means, standard deviations, medians, and ranges for 
continuous variables and proportions for categorical variables, as appropriate.  
Summaries will be presented overall and by treatment group.


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6.4
EFFICACY ANALYSES
The analysis population for the efficacy analyses will consist of all randomized patients, 
with patients grouped according to their assigned treatment.
6.4.1
Primary Efficacy Endpoint
CR at end of treatment assessment (68 weeks after Cycle 6 Day 1 or the final dose of 
study treatment) based on PET-CT, as determined by the IRC, will be used as the 
primary efficacy endpoint.  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 polatuzumab 
vedotin plus BR and placebo plus BR randomized arms will be estimated along with the 
corresponding 95% CI on the basis of normal approximation to the binomial distribution.  
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 OR, patients without a postbaseline 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 the end of treatment assessment based on PET-CT, as determined by the 
investigator

OR, defined as CR or PR, at the end of treatment assessment based on PET-CT, 
as determined by the investigator and IRC

CR at the end of treatment assessment based on CT only, as determined by the 
investigator and IRC 

OR, defined as CR or PR, at the end of treatment assessment based on CT only, as 
determined by the investigator and IRC

BOR, defined as CR or PR, while on study based on PET-CT or CT only, as 
determined by the investigator and IRC
Among patients with a BOR of CR or PR, DOR, as determined by the investigator and 
IRC, will be defined as the time from the initial CR or PR to the time of disease 
progression, relapse, 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.  Kaplan-Meier methodology will be 
used to estimate median DOR for each treatment group and to construct DOR curves 
for visual descriptions of the difference between the experimental and control arms. The 
Brookmeyer-Crowley methodology will be used to construct the 95% CI for the median 
DOR for each treatment group (Brookmeyer and Crowley 1982).  The unstratified Cox 
proportional hazard model will be used to estimate the DOR HR between the two 
treatment groups and its 95%CI.  


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PFS, as determined by the investigator and IRC, is defined as the period from the date 
of randomization 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.  
EFS, as determined by the investigator, is defined as the time from date of 
randomization 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 postbaseline tumor 
assessments or documentation of NALT, EFS will be censored at the time of 
randomization.
OS is defined as the time from date of randomization 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 PFS, EFS, and OS will be identical to those outlined previously for DOR. 
6.5
SAFETY ANALYSES
The safety analysis population will consist of all randomized patients who received at 
least one dose of study drug, with patients grouped according to treatment received. 
Safety will be assessed through summaries of exposure to study treatment, adverse 
events, changes in laboratory test results, and changes in vital signs and ECGs.
Study treatment exposure (such as treatment duration, total dose received, and number 
of cycles and dose modifications) will be summarized with descriptive statistics.
All verbatim adverse event terms will be mapped to MedDRA thesaurus terms, and 
adverse event severity will be graded according NCI CTCAE v5.0.  All adverse events, 
serious adverse events, adverse events leading to death, adverse events of special 
interest, and adverse events leading to study treatment discontinuation that occur on or 
after the first dose of study treatment (i.e., treatment-emergent adverse events) will be 
summarized by mapped term, appropriate thesaurus level, and severity grade.  For 
events of varying severity, the highest grade will be used in the summaries.  Deaths and 
cause of death will be summarized.
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, pulse 
oximetry, and temperature), and ECG data will be displayed by time, with grades
identified where appropriate.  Additionally, a shift table of selected laboratory tests will be 
used to summarize the baseline and maximum postbaseline severity grade.  Changes in 
vital signs and ECGs will be summarized.


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The FACT/GOG-NTX will be scored using a corresponding user manual.  Summary 
statistics of the FACT/GOG-NTX total and individual items with their changes from 
baseline will be calculated at each assessment timepoint.   
6.6
PHARMACOKINETIC ANALYSES
The PK population for analysis will include all patients who have at least one evaluable 
PK sample postdose for at least one analyte.
Individual and mean serum concentrations of total polatuzumab vedotin antibody (fully 
conjugated, partially deconjugated and fully deconjugated antibody), plasma 
concentrations of polatuzumab vedotin conjugate (evaluated as acMMAE), and 
unconjugated MMAE versus time data will be tabulated and plotted after appropriate 
grouping.  The pharmacokinetics of the above analytes will be summarized after 
appropriate grouping, as the data will allow, by estimating selected PK parameters, such 
as AUC and Cmax. The population PK analysis will investigate the effects of certain 
covariates on the pharmacokinetics of polatuzumab vedotin related analytes, as the data 
will allow and at the Sponsor’s discretion. These covariates may include renal and 
hepatic impairment, as data will allow.
Exposure-response (safety and efficacy) analysis may be conducted using 
plasma/serum concentrations or relevant PK parameters and available drug effect data 
(e.g., CR rate, PFS, and/or toxicity data), per the Sponsor’s discretion and as the data 
will allow.
To assess potential PK drug interactions, PK parameters for each analyte of 
polatuzumab vedotin will be compared with historical data, as the data will allow.
6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients with at least one 
evaluable postbaseline ADA sample.  Patients will be grouped according to treatment 
received or, if no treatment is received prior to study discontinuation, according to 
treatment assigned.
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (postbaseline incidence) 
will be summarized by treatment group.  When determining postbaseline incidence, 
patients are considered to be ADA positive if they are ADA negative or have missing 
data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more postbaseline samples is at least 0.60 titer unit greater than the titer of the 
baseline sample (treatment-enhanced ADA response).  Patients are considered to be 
ADA negative if they are ADA negative or have missing data at baseline and all 
postbaseline samples are negative, or if they are ADA positive at baseline but do not 


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have any postbaseline samples with a titer that is at least 0.60 titer unit greater than the 
titer of the baseline sample (treatment unaffected).
The relationship between ADA status and safety, efficacy, and PK may be analyzed and 
reported via descriptive statistics.
6.8
BIOMARKER ANALYSES
PET-CT CR and OR rate will be analyzed in following subgroups: (1) patients with 
ABC-DLBCL as analyzed through use of a centrally performed RNA-based assay, (2) 
patients with GCB-DLBCL as analyzed through use of a centrally performed RNA-
based assay, (3) patients with co-expression of BCL2 and MYC (double-expressor, DEL) 
as analyzed through use of centrally performed IHC tests, and (4) patients with 
expression of CD79b as analyzed through use of a centrally performed IHC test.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and other 
electronic data will be sent directly to the Sponsor, using the Sponsor's standard
procedures to handle and process the electronic transfer of these data.
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.
PRO data will be collected on paper questionnaires.  The data from the questionnaires 
will be entered into the EDC system by site staff.
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.


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


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7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms, 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 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 Good 
Clinical Practice 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 will comply with applicable local, regional, and 
national laws.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 


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document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
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 
local health authority and IRB/EC.  Investigators may receive written Investigational New 
Drug safety reports or other safety-related communications from the Sponsor.  
Investigators are responsible for ensuring that such reports are reviewed and processed 
in accordance with health authority requirements and the policies and procedures 
established by their IRB/EC, and archived in the site's study file. 


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8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
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 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.


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9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 10 sites in China will participate to enroll approximately 42 patients.  
Enrollment will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in 
Section 4.5.6.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected.
Tumor response and progression will be evaluated by an IRC and the investigator.
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, 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, provided the requirements of Roche's global policy on data sharing have been 
met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
Data at the following website:
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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 any data that are clinically 
meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
111/Protocol YO41543, Version 2
10.
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Appendix 1
Schedule of Activities
Day a
(Window)
Screen
(28 days) b
Treatment
Treatment
Completion/
Discont. d
EOT 
Assessment
e
Follow-
Up f
Cycle 1
Cycle 2
Cycle 3
Cycles 46
30 (5)
days after 
final dose 
68 weeks 
after C6D1 
or final dose 
D1 c
D2
D3
D8 
(1)
D15 
(1)
D1 
(2)
D2 
D1 
(2)
D2 
D15
(1) 
D1 
(2)
D2 
Informed consent g
x
Demographic data
x
General medical history 
and baseline conditions
x
Concomitant 
medications h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events i
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x i
ECOG PS
x
x
x
x
IPI
x
Complete physical 
exam j
x
Targeted physical 
examination k
x
x
x
x
x
x
x
Vital signs l
x
x
x
x
x
x
x
x
x
x
Height, weight, and 
BSA m
x
x
x
x
x
12-lead ECG
x
x
x


Appendix 1: Schedule of Activities (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
117/Protocol YO41543, Version 2
Day a
(Window)
Screen
(28 days) b
Treatment
Treatment
Completion/
Discont. d
EOT 
Assessment
e
Follow-
Up f
Cycle 1
Cycle 2
Cycle 3
Cycles 46
30 (5)
days after 
final dose 
68 weeks 
after C6D1 
or final dose 
D1 c
D2
D3
D8 
(1)
D15 
(1)
D1 
(2)
D2 
D1 
(2)
D2 
D15
(1) 
D1 
(2)
D2 
FACT/GOG-NTX n
x
x
x
x
x
x
(every 
3 mo.)
Clinical response 
assessment o
x
x
x
x
x
x
x
x
CT scan and PET-CT 
scan p
x q
x
x
(x) r
Rituximab s
x
x
x
x
Polatuzumab vedotin or 
placebo t
x
x
x
x
Bendamustine u
x
x
x
x
x
x
x
x
Hematology v
x
x
x
x
x
x
x
x
x
x
Serum chemistry w
x
x
x
x
x
x
x
x
x
x
Coagulation panel x
x
Viral serology y
x
Serum IgA, IgG, and IgM
x
x
x
x
Pregnancy test z
x
x
x
x
x
Bone marrow biopsy and 
aspirate aa
x
(x)
(x)
(x)


Appendix 1: Schedule of Activities (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
118/Protocol YO41543, Version 2
Day a
(Window)
Screen
(28 days) b
Treatment
Treatment
Completion/
Discont. d
EOT 
Assessment
e
Follow-
Up f
Cycle 1
Cycle 2
Cycle 3
Cycles 46
30 (5)
days after 
final dose 
68 weeks 
after C6D1 
or final dose 
D1 c
D2
D3
D8 
(1)
D15 
(1)
D1 
(2)
D2 
D1 
(2)
D2 
D15
(1) 
D1 
(2)
D2 
Tumor tissue sample for 
prognostic biomarker 
studies bb
x
Lymphocyte subsets cc
x
x
x
(every
6 mo.)
Anti-drug antibody 
(polatuzumab vedotin)
See Appendix 2
PK assessment 
(polatuzumab vedotin)
See Appendix 2
Survival follow-up/
status dd
x
x
x
BSAbody surface area; Ccycle; CRcomplete response; CT computed tomography (scan); Dday; Discont.discontinuation; DLBCLdiffuse large 
B-cell lymphoma; ECOG PSEastern Cooperative Oncology Group Performance Status; eCRFelectronic Case Report Form; EOTend of treatment; 
FACT/GOG-NTXFunctional Assessment of Cancer Treatment/Gynecologic Oncology GroupNeurotoxicity; HbA1chemoglobin A1c; HBcAbhepatitis 
B core antibody; HBsAbhepatitis B surface antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; 
IPIInternational Prognostic Index; momonth; PCRpolymerase chain reaction; PET-CTpositron emission tomographycomputed tomography
(scan); PKpharmacokinetic; (x)conditional/optional (refer to footnote).
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 Screening and pretreatment tests and evaluations will be performed within 28 days before first dose, unless otherwise specified.  Results of standard-


Appendix 1: Schedule of Activities (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
119/Protocol YO41543, Version 2
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.  Bone marrow biopsies collected within 90 days prior to Day 1 of study treatment are acceptable. Samples obtained 
more than 90 days prior to Day 1 require prior approval by the Medical Monitor before the patient can be randomized.
c Local laboratory assessments and targeted physical examination may be performed within 72 hours preceding Cycle1 Day 1 administration unless 
otherwise specified; pre-infusion laboratory samples should be drawn 04 hours prior to infusion.
d Patients who complete the study treatment period will return to the clinic for a treatment completion visit 30 (5) days after the final dose of study 
treatment (Cycle 6 Day 1). Patients who discontinue study treatment prematurely will return to the clinic for a treatment discontinuation visit
30 (5) days after the final dose of study treatment. The visit at which response assessment shows progressive disease may be used as the 
treatment discontinuation visit.
e All patients will be asked to return to the clinic for the end of treatment assessment. This visit is to take place between 6 and 8 weeks after Cycle 6 
Day 1 or the final dose of study treatment. For patients with disease progression occurring prior to the anticipated date of the end of treatment 
assessment, the visit date with the response assessment showing progressive disease may be used in replacement of the end of treatment 
assessment.
f Following completion of treatment, patients who have not progressed will be followed clinically every 3 months (14 days). Follow-up visit intervals 
should be determined from treatment completion visit.
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 consists of any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, 
nutritional supplements) used by a patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug to the treatment
completion/discontinuation visit.  All such medications should be reported to the investigator and recorded on the Concomitant Medications eCRF 
(see Section 4.4).
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 final 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 examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, 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.


Appendix 1: Schedule of Activities (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
120/Protocol YO41543, Version 2
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
Vital signs include respiratory rate, pulse rate, pulse oximetry, and systolic and diastolic blood pressures while the patient is in a seated position, and 
temperature.  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.
m 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.
n The FACT/GOG-NTX (see Appendix 5) will be administered on Day 1 of every cycle, at treatment completion/discontinuation, and at specified 
planned post-treatment visits thereafter until the close of the study (every 3 months after the treatment completion visit).  Paper versions of the 
FACT/GOG-NTX scale will be self-administered or interviewer administered (as appropriate) before the patient receives any information on disease 
status, prior to the performance of non-PRO assessments, and prior to the administration of study treatment. The data from the questionnaires will be 
entered into the EDC system by site staff.  See Section 4.5.8 for additional details.  
o Clinical response assessment of tumor conducted via physical examination.
p CT scans and PET-CT scans are required at screening, the interim response assessment (between Cycle 3 Day 15 and Cycle 4 Day 1), and the end 
of treatment assessment (68 weeks after Cycle 6 Day 1 or the final dose of study treatment). Diagnostic contrast enhanced CT scans obtained as 
part of a PET-CT may be used in lieu of dedicated CT scans. All other imaging may be CT only.  The Lugano Response Criteria (see Appendix 3) 
will be used to assess overall response to study treatment.
q Screening PET-CT must be obtained within 35 days of Cycle 1 Day 1.  
r
CT (preferred) or PET-CT scans should be performed during follow-up every 6 months after end of treatment assessment until disease progression, 
study withdrawal, end of study, or death, whichever comes first; or at any time that progression is suspected via clinical response assessment.  
s Rituximab (375 mg/m2) will be administered by IV infusion on Day 1 of Cycles 16.  No dose modifications of rituximab are allowed.  Rituximab should 
be administered after premedication with oral acetaminophen/paracetamol and an antihistamine (see Section 4.3.2.2).
t
Polatuzumab vedotin (1.8 mg/kg) or placebo will be administered by IV infusion on Day 2 of Cycle 1 then Day 1 of Cycles 26 (see Section 4.3.2.1).   
u Bendamustine (90 mg/m2) will be administered by IV infusion over 3060 minutes on 2 consecutive days of each cycle (Days 2 and 3 in Cycle 1, then 
Days 1 and 2 in Cycles 26) (see Section 4.3.2.3).


Appendix 1: Schedule of Activities (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
121/Protocol YO41543, Version 2
v Hematology includes hemoglobin, hematocrit, RBC count, WBC count, platelet count, and percent or absolute differential (neutrophils, lymphocytes, 
eosinophils, basophils, and monocytes).  Results should be obtained within 3 days before study treatment administration.  
w Serum chemistry includes sodium, potassium, glucose, BUN or urea, creatinine, calcium, total bilirubin, direct bilirubin, total protein, albumin, ALT, 
AST, ALP, LDH, uric acid/urate, HbA1c, amylase, and lipase.  At screening, samples 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.
x INR or, PT, and PTT or aPTT.  Results should be obtained within 3 days before study treatment administration.
y At screening, patients will be tested for HIV, HBsAg, total HBcAb, and HCV antibody.  If a patient has a negative HBsAg test and a positive total 
HBcAb test at screening, an HBV DNA test must also be performed at screening and monthly (or on Day 1 of each cycle) during the study treatment 
period, and for at least 12 months after the completion of study treatment to determine if the patient has an HBV infection.  If a patient has a positive 
HCV antibody test at screening, an HCV RNA test must also be performed to determine if the patient has an HCV infection.
z All women of childbearing potential will have a serum pregnancy test at screening within 7 days before Cycle 1 Day 1.  In addition, a serum or urine 
pregnancy test must be performed prior to study treatment on Day 1 of each subsequent cycle (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.
aa 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 end of treatment assessment in patients who achieve radiologic CR 
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.
bb Pretreatment tumor tissue sample is required (archival tissue or fresh pre-treatment biopsy is acceptable) and to be submitted according to local 
regulations.  Tumor blocks are preferred.  If a tumor block is not available, a minimum of 11 serial freshly cut, unstained slides are required.  
Remaining archival tissue blocks will be returned to local pathology according to country-specific procedures.  
cc Whole blood samples will be collected at screening, end of treatment assessment, and every 6 months (from the treatment completion visit) until the 
end of study or patient discontinuation.
dd During the follow-up period (i.e., after treatment completion):  For patients who have disease progression 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.  In the case where a patient experiences disease progression, information on survival follow-up and new anti-cancer therapy will be 
collected via telephone calls, patient medical records, and/or clinic visits approximately every 6 months until death (unless the patient withdraws 
consent or the Sponsor terminates the study).  For patients who started a new anti-lymphoma therapy but do not have disease progression, 


Appendix 1: Schedule of Activities (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
122/Protocol YO41543, Version 2
assessments should be followed according to the schedule of activities, including response assessments and adverse events.


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
123/Protocol YO41543, Version 2
Appendix 2
Schedule of Pharmacokinetic and Immunogenicity Samples
(Polatuzumab Vedotin/Placebo)
Study Visit
Sample Timepoint a
Samples
(polatuzumab vedotin/placebo) b
Cycle 1 Day 2
Pre-polatuzumab vedotin/placebo infusion
ADA (serum), 
PK (serum and plasma) c
End of polatuzumab vedotin/placebo infusion
PK (serum and plasma) c
Cycle 1 Day 8
6 days (1 day) after Day 2 infusion 
PK (serum and plasma) c
Cycle 1 Day 15
13 days (1 day) after Day 2 infusion
PK (serum and plasma) c
Cycle 2 Day 1
Pre-polatuzumab vedotin/placebo infusion
ADA (serum), 
PK (serum and plasma) c
End of polatuzumab vedotin/placebo infusion
PK (serum and plasma) c
Cycle 3 Day 1
Pre-polatuzumab vedotin/placebo infusion
PK (serum and plasma) c
End of polatuzumab vedotin/placebo infusion
PK (serum and plasma) c
Cycle 3 Day 8
7 days (1 day) after Day 1 infusion
PK (serum and plasma) c
Cycle 3 Day 15
14 days (1 day) after Day 1 infusion
PK (serum and plasma) c
Cycle 4 Day 1
Pre-polatuzumab vedotin/placebo dose
ADA (serum), 
PK (serum and plasma) c
End of polatuzumab vedotin/placebo infusion
PK (serum and plasma) c
Treatment Completion/
Discontinuation
Approximately 30 days 5 after final infusion 
ADA (serum), 
PK (serum and plasma) c
Post-treatment 
(Follow-up visit at
Months 3, 6, and 12)
Random sample
ADA (serum) 
Concentration (serum only)
ADAanti-drug antibody; BRbendamustine and rituximab; MMAEmonomethyl auristatin E; 
PKpharmacokinetic.
a
Pre-infusion samples should be drawn 04 hours before the start of polatuzumab vedotin infusion.  
End-of-infusion samples should be drawn 30 minutes (15 minutes) after the end of polatuzumab 
vedotin infusion, unless otherwise specified.
b Up to 11-mL whole-blood samples will be taken for polatuzumab vedotin/placebo PK (conjugate 
[evaluated as antibody-conjugated MMAE], polatuzumab vedotin/placebo total antibody, and 
unconjugated MMAE), polatuzumab vedotin/placebo ADA, and polatuzumab vedotin concentration 
sample at each specified timepoint with separate tubes for plasma or serum samples. 
c Polatuzumab vedotin/placebo PK, including serum PK samples for total antibody and plasma PK 
samples for conjugate (evaluated as antibody-conjugated MMAE) and unconjugated MMAE. Per the 
sampling schedule above, approximately 12 PK sampling points will be pre-specified from each 
patient treated with polatuzumab vedotin/placebo plus 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 ADA 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. 


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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Appendix 3
Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014)
Response should be determined on the basis of radiographic and clinical evidence of disease.  For the end of treatment assessment, 
an FDG-PET (18F fluorodeoxyglucose positron emission tomography)/CT (computed tomography) scan will be performed 68 weeks 
after Cycle 6 Day 1 or the final dose of study treatment, as assessed by an Independent Review Committee and the investigator.  
Assessment of the PET-CT scan should follow the criteria presented below (Cheson et al. 2014).
Target and Non-Target Lesions
Up to six of the largest target nodes, nodal masses, or other lymphomatous lesions that are measurable in two diameters should be 
identified from different body regions representative of the patient’s overall disease burden and include mediastinal and retroperitoneal 
disease, if involved.  At baseline, a measurable node must be greater than 15 mm in longest diameter (LDi).  Measurable extranodal 
disease may be included in the six representative, measured lesions.  At baseline, measurable extranodal lesions should be greater 
than 10 mm LDi. 
All other lesions (including nodal, extranodal, and assessable disease) should be followed as non-measured disease as non-target 
lesions (e.g., cutaneous, gastrointestinal, bone, spleen, liver, kidneys, pleural or pericardial effusions, ascites, bone, bone marrow). 
Split Lesions and Confluent Lesions
Lesions may split or may become confluent over time. In the case of split lesions, the individual product of the perpendicular diameters 
(PPDs) of the nodes should be summed together to represent the PPD of the split lesion; this PPD is added to the sum of the PPDs of 
the remaining lesions to measure response.  If subsequent growth of any or all of these discrete nodes occurs, the nadir of each 
individual node is used to determine progression. In the case of confluent lesions, the PPD of the confluent mass should be 
compared with the sum of the PPDs of the individual nodes, with more than 50% increase in PPD of the confluent mass compared 
with the sum of individual nodes necessary to indicate progressive disease.  The LDi and smallest diameter (SDi) are no longer 
needed to determine progression.


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
125/Protocol YO41543, Version 2
Response and Site
PET-CT–Based Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic response (all of the following)
Lymph nodes and 
extralymphatic sites
Score 1, 2, or 3 a with or without a residual mass on 5PS b
It is recognized that in Waldeyer’s ring or extranodal sites 
with high physiologic uptake or with activation within 
spleen or marrow (e.g., with chemotherapy or myeloid 
colony-stimulating factors), uptake may be greater than 
normal mediastinum and/or liver.  In this circumstance, 
complete metabolic response may be inferred if uptake 
at sites of initial involvement is no greater than 
surrounding normal tissue even if the tissue has high 
physiologic uptake.
Target nodes/nodal masses must regress to ≤1.5 cm 
in LDi
No extralymphatic sites of disease
Non-measured lesion
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in marrow
Normal by morphology; if indeterminate, IHC negative
Appendix 3: Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014) (cont.)


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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Response and Site
PET-CT–Based Response
CT-Based Response
Partial
Partial metabolic response
Partial remission (all of the following)
Lymph nodes and 
extralymphatic sites
Score 4 or 5 b with reduced uptake compared with baseline 
and residual mass(es) of any size
50% decrease in SPD of up to 6 target measurable 
nodes and extranodal sites
At interim, these findings suggest responding disease
When a lesion is too small to measure on CT, assign 
5 mm5 mm as the default value
At end of treatment, these findings indicate residual disease
When no longer visible, 00 mm
For a node 5 mm5 mm, but smaller than normal, 
use actual measurement for calculation
Non-measured lesion
Not applicable
Absent/normal, regressed, but no increase
Organ enlargement
Not applicable
Spleen must have regressed by 50% in length 
beyond normal
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake compatible 
with reactive changes from chemotherapy allowed).  If 
there are persistent focal changes in the marrow in the 
context of a nodal response, consideration should be given 
to further evaluation with MRI or biopsy or an interval scan.
Not applicable
Appendix 3: Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014) (cont.)


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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Response and Site
PET-CT–Based Response
CT-Based Response
No response or stable disease 
No metabolic response
Stable disease
Target nodes/nodal masses, 
extranodal lesions
Score 4 or 5 b with no significant change in FDG uptake 
from baseline at interim or end of treatment
< 50% decrease from baseline in SPD of up to 6 dominant, 
measurable nodes and extranodal sites; no criteria for 
progressive disease are met
Non-measured lesion
Not applicable
No increase consistent with progression
Organ enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Appendix 3: Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014) (cont.)


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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Response and 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 
masses
Score 4 or 5 b with an increase in intensity of uptake from 
baseline and/or
PPD progression:
Extranodal lesions
New FDG-avid foci consistent with lymphoma at interim or 
end-of-treatment assessment
An individual node/lesion must be abnormal with:
LDi1.5 cm and
Increase by50% from PPD nadir and
An increase in LDi or SDi from nadir
0.5 cm for lesions 2 cm
1.0 cm for lesions 2 cm
In the setting of splenomegaly (13 cm), the splenic length 
must increase by50% of the extent of its prior increase 
beyond baseline (e.g., a 15-cm spleen must increase 
to 16 cm).  If no prior splenomegaly, must increase by at least 
2 cm from baseline.
New or recurrent splenomegaly 
Non-measured lesions
None
New or clear progression of preexisting non-measured lesions
New lesions
New FDG-avid foci consistent with lymphoma rather than 
another etiology (e.g., infection, inflammation); if uncertain 
regarding etiology of new lesions, biopsy or interval scan 
may be considered
Regrowth of previously resolved lesions
A new node1.5 cm in any axis
A new extranodal site1.0 cm in any axis; if 1.0 cm in any 
axis, its presence must be unequivocal and must be attributable 
to lymphoma
Assessable disease of any size unequivocally attributable to 
lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
Appendix 3: Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014) (cont.)


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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5PS 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 (scan); PPD cross product of the LDi and perpendicular diameter; SDi shortest 
axis perpendicular to the LDi; SPD sum of the product of the perpendicular diameters for multiple lesions.
a
A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan.  However, in trials involving 
PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment).  Measured 
dominant lesions:  Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two diameters.  
Nodes should preferably be from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas.   Non-nodal 
lesions include those in solid organs (e.g., liver, spleen, kidneys, lungs), gastrointestinal involvement, cutaneous lesions, or those noted on palpation.  Non-
measured lesions:  Any disease not selected as measured; dominant disease and truly assessable disease should be considered not measured.  These 
sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet the requirements for measurability 
but are still considered abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively 
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be 
confirmed and followed by imaging.  In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the 
mediastinum with complete metabolic response, but should be no higher than surrounding normal physiologic uptake (e.g., with marrow activation as a 
result of chemotherapy or myeloid growth factors).
b
PET 5PS:  1 no uptake above background; 2 uptake mediastinum; 3 uptake mediastinum but liver; 4 uptake moderatelyliver; 5 uptake 
markedly higher than liver and/or new lesions; X new areas of uptake unlikely to be related to lymphoma. 
Appendix 3: Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014) (cont.)


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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Appendix 4
Recommended Anaphylaxis Management
These guidelines are intended as a reference and should not supersede pertinent local
or institutional standard operating procedures.
REQUIRED EQUIPMENT AND MEDICATION
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion:

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:
1.
Stop the study treatment infusion.
2.
Call for additional medical assistance.
3.
Maintain an adequate airway.
4.
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible.
5.
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge.
6.
Continue to observe the patient and document observations.


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Appendix 5
Functional Assessment of Cancer Therapy/Gynecologic 
Oncology Group-Neurotoxicity (FACT/GOG-NTX) 


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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Appendix 6
Sample List of Cautionary Medications
(A) Inhibitors
Strong Inhibitors
Moderate Inhibitors
Weak Inhibitors
CYP3A
boceprevir, clarithromycin, 
cobicistat, conivaptan, 
danoprevir/ritonavir, 
elvitegravir/ritonavir, idelalisib,a
indinavir, itraconazole, 
ketoconazole, mibefradil, 
lopinavir/ritonavir, nefazodone, 
nelfinavir, paritaprevir/ritonavir 
combinations, ritonavir, 
posaconazole, saquinavir, 
telaprevir, telithromycin, 
tipranavir/ritonavir, 
troleandomycin, voriconazole
amprenavir, aprepitant, 
atazanavir, cimetidine, 
ciprofloxacin, 
clotrimazole, crizotinib, a
cyclosporine, a
darunavir/ritonavir, 
diltiazem, dronedarone, 
erythromycin, 
fluconazole, fluvoxamine, 
fosamprenavir, imatinib, a
isavuconazole, 
tofisopam, verapamil
chlorzoxazone, 
cilostazol, 
fosaprepitant, 
istradefylline, ivacaftor, 
lomitapide, ranitidine, 
ranolazine, tacrolimus, 
ticagrelor
a These are the anticancer agents; contact Medical Monitor before use.
(B) Inducers
Strong Inducers
Moderate Inducers
Weak Inducers
CYP3A
avasimibe, carbamazepine, 
enzalutamide, mitotane, phenytoin, 
rifampin, St. John’s wort
bosentan, efavirenz, 
etravirine, modafinil, 
nafcillin
armodafinil, rufinamide
(C) Examples of clinical inhibitors for P-gp transporters
Transporter
Gene
Inhibitor
P-gp a
ABCB1
amiodarone, carvedilol, clarithromycin, 
dronedarone, itraconazole, lapatinib, 
lopinavir and ritonavir, propafenone, 
quinidine, ranolazine, ritonavir, 
saquinavir and ritonavir, telaprevir, 
tipranavir and ritonavir, verapamil 
a Most of P-gp inhibitors also inhibit CYP3A.
Source:  U.S. Food and Drug Administration. Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers [resource on the Internet]. 2017 [cited 29 March 2019]. 
Available from: 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsl
abeling/ucm093664.htm#table3-3


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
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Appendix 7
Commonly Used CYP1A2 Inhibitors and Inducers (Drugs, Foods, 
Over the Counter Medications, and Supplements) 
On the basis of the U.S. Package Insert 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.


Appendix 7: Commonly Used CYP1A2 Inhibitors and Inducers (Drugs, Foods, Over the 
Counter Medications, and Supplements) (cont.)
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
134/Protocol YO41543, Version 2
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.

SAP_001.pdf: 
 
Official Title: 
A Phase III, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of Polatuzumab 
Vedotin in Combination with Bendamustine and Rituximab Compared 
with Bendamustine and Rituximab Alone in Chinese Patients with 
Relapsed or Refractory Diffuse Large B-Cell Lymphoma  
NCT Number: 
NCT04236141 
Document Date: 
SAP Version 1: 8 March 2021 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan YO41543
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF POLATUZUMAB VEDOTIN 
IN COMBINATION WITH BENDAMUSTINE AND RITUXIMAB 
COMPARED WITH BENDAMUSTINE AND RITUXIMAB 
ALONE IN CHINESE PATIENTS WITH RELAPSED OR 
REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA
PROTOCOL NUMBER:
YO41543
STUDY DRUG:
Polatuzumab vedotin
VERSION NUMBER:
1
IND NUMBER:
Not applicable
EUDRACT NUMBER:
Not applicable
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
 Ph.D.
DATE FINAL:
See electronic date stamp below
Date and Time(UTC)        Reason for Signing                              Name
08-Mar-2021 03:40:51
Company Signatory


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan YO41543
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 4
2.
STUDY DESIGN........................................................................................... 4
2.1
Protocol Synopsis.................................................................... 5
2.2
Endpoints................................................................................. 5
2.2.1
Primary Efficacy Endpoint........................................................ 5
2.2.2
Secondary Efficacy Endpoints................................................. 5
2.2.3
Safety Endpoints ..................................................................... 6
2.2.4
Pharmacokinetic Endpoints ..................................................... 6
2.2.5
Immunogenicity Endpoints....................................................... 6
2.2.6
Biomarker Endpoints ............................................................... 6
2.3
Determination of Sample Size ................................................. 7
2.4
Analysis Timing ....................................................................... 7
3.
STUDY CONDUCT....................................................................................... 7
3.1
Randomization......................................................................... 7
3.2
Independent Review Committee.............................................. 8
4.
STATISTICAL METHODS ............................................................................ 8
4.1
Analysis Populations ............................................................... 8
4.1.1
Intent-to-Treat Population........................................................ 8
4.1.2
Safety Population .................................................................... 8
4.1.3
Pharmacokinetic-Evaluable Population ................................... 8
4.1.4
Immunogenicity-Evaluable Population..................................... 8
4.1.5
Biomarker-Evaluable Population ............................................. 8
4.2
Analysis of Study Conduct....................................................... 8
4.3
Analysis of Treatment Group Comparability ............................ 9
4.4
Efficacy Analysis...................................................................... 9
4.4.1
Primary Efficacy Endpoint........................................................ 9
4.4.2
Secondary Efficacy Endpoints................................................. 9
4.4.3
Biomarker Analyses............................................................... 11
4.5
Safety Analyses..................................................................... 11
4.5.1
Exposure of Study Medication............................................... 11


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan YO41543
4.5.2
Adverse Events ..................................................................... 11
4.5.3
Peripheral Neuropathy........................................................... 11
4.5.4
Laboratory Data..................................................................... 11
4.5.5
Vital Signs.............................................................................. 12
4.6
Pharmacokinetic Analyses..................................................... 12
4.7
Immunogenicity Analyses...................................................... 12
4.8
Missing Data.......................................................................... 13
4.9
Interim Analyses .................................................................... 13
5.
REFERENCES ........................................................................................... 14
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 5
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ...................................................................... 15
Appendix 2
Schedule of Assessments.......................................................... 25


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan YO41543
1.
BACKGROUND
This Statistical Analysis Plan (SAP) provides details of the planned analyses and
statistical methods for Study YO41543 (Polarose), a Phase III, multicenter, randomized, 
double-blind, placebo-controlled study to evaluate the efficacy and safety of 
polatuzumab vedotin in combination with bendamustine and rituximab (BR) compared 
with BR alone in Chinese patients with relapsed or refractory (R/R) diffuse large B-cell 
lymphoma (DLBCL).
This document is based on the statistical section of the study protocol and will provide 
more details to the planned statistical analyses. 
The detailed background information for the study can be found in the study protocol.
2.
STUDY DESIGN
This is a Phase III, multicenter, randomized, double-blind, placebo-controlled study to
evaluate the efficacy and safety of polatuzumab vedotin in combination with BR
compared with BR alone in Chinese patients with R/R DLBCL.
Approximately 42 Chinese patients will be randomized to one of the following treatment
arms in a 2:1 ratio:

Polatuzumab vedotin plus BR (experimental arm)

Placebo plus BR (control arm)
Randomization will be conducted with the aid of an interactive web-based response
system (IxRS) and will be stratified according to the following factors:

Duration of response (DOR) to most recent prior therapy:  12 months versus 12 
months

Number of prior lines of therapies (1 versus 2)
For consistency with the pivotal study population (Study GO29365), patients with 2 
prior lines of therapy will be capped within 70% of the whole population.
Figure 1 presents an overview of the study design. A schedule of activities is provided in 
Appendix 2.
Patients will receive a total of 6 cycles of polatuzumab vedotin or placebo in combination 
with BR.  A cycle is typically 21 days.


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Figure 1
Study Schema
Notes: The screening period is from Days 28 to 1. Study treatment will be administered every
21 days for 6 cycles.
BR bendamustine and rituximab; CR complete response; DLBCL diffuse large B-cell 
lymphoma; EOT end of treatment; IRC Independent Review Committee; PET-CT = positron
emission tomographycomputed tomography (scan); Pola polatuzumab vedotin; R/R 
relapsed or refractory.
a The end of treatment assessment is 68 weeks after Cycle 6 Day 1 or the final dose of study 
treatment.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2.
2.2
ENDPOINTS
2.2.1
Primary Efficacy Endpoint

Complete response (CR) at the end of treatment assessment (6-8 weeks after Cycle 
6 Day 1 or final dose of study treatment) based on positron emission tomography-
computed tomography (scan) (PET-CT), as determined by the Independent Review 
Committee (IRC) according to the Lugano Response Criteria for Malignant 
Lymphoma, hereafter referred to as the "Lugano Response Criteria" (Cheson et al. 
2014)
2.2.2
Secondary Efficacy Endpoints

CR at the end of treatment assessment based on PET-CT, as determined by the
investigator according to the Lugano Response Criteria

Objective response (OR), defined as CR or partial response (PR), at the end of 
treatment assessment based on PET-CT, as determined by the investigator and 
IRC according to the Lugano Response Criteria

CR at the end of treatment assessment based on computed tomography (CT) only,
as determined by the investigator and IRC according to the Lugano Response
Criteria

OR, defined as CR or PR, at the end of treatment assessment based on CT only, as
determined by the investigator and IRC according to the Lugano Response Criteria

Best objective response (BOR), defined as CR or PR, while on study based on PET-
CT or CT only, as determined by the investigator and IRC according to the Lugano 
Response Criteria


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
DOR, defined as the time from the initial CR or PR until the first occurrence of 
disease progression or relapse based on PET-CT or CT only as determined by the 
investigator and IRC according to the Lugano Response Criteria or death from any 
cause, whichever occurs first

Progression-free survival (PFS), defined as the time from date of randomization until 
the first occurrence of disease progression or relapse based on PET-CT or CT only 
as determined by the investigator and IRC according to the Lugano Response 
Criteria or death from any cause, whichever occurs first

Event-free survival (EFS), defined as the time from date of randomization until the 
first occurrence of disease progression or relapse based on PET-CT or CT only as 
determined by the investigator according to the Lugano Response Criteria, initiation 
of new anti-lymphoma treatment (NALT) or death from any cause, whichever occurs 
first

Overall survival (OS), defined as the time from date of randomization until the date 
of death from any cause
2.2.3
Safety Endpoints

Incidence and severity of adverse events, with severity determined according to the
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 
5.0 (NCI CTCAE v5.0)

Incidence and nature of study drug discontinuation, dose reduction, and dose delay
due to adverse events

Change from baseline in peripheral neuropathy as assessed through use of the
Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-
Neurotoxicity (FACT/GOG-NTX)
2.2.4
Pharmacokinetic Endpoints

Serum concentration of total antibody at specified timepoints

Plasma concentration of acMMAE at specified timepoints

Plasma concentration of unconjugated MMAE at specified timepoints
2.2.5
Immunogenicity Endpoints

Prevalence of anti-drug antibodies (ADAs) for polatuzumab vedotin at baseline and 
incidence of ADAs during the study

Potential relationship between ADA status for polatuzumab vedotin and efficacy, 
safety, or pharmacokinetic (PK) endpoints
2.2.6
Biomarker Endpoints

CR at the end of treatment assessment based on PET-CT, as determined by the 
IRC according to the Lugano Response Criteria in populations of activated B cell 
diffuse large B-cell lymphoma (ABC-DLBCL), germinal center B cell DLBCL (GCB-
DLBCL), double-expressor lymphoma (DEL), and expression of CD79b


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
OR, defined as CR or PR, at the end of treatment assessment based on PET-CT, 
as determined by the IRC according to the Lugano Response Criteria in populations
of ABC-DLBCL, GCB-DLBCL, DEL, and expression of CD79b
2.3
DETERMINATION OF SAMPLE SIZE
The primary endpoint of CR at the end of treatment assessment was used to determine
the sample size of the study.
The primary objective of the study is to investigate whether the benefit (in terms of CR at
the end of treatment assessment) of administrating polatuzumab vedotin plus BR in this
study is consistent with the benefit observed in the global study GO29365. CR rate at
the end of treatment assessment as determined by the IRC was increased from 17.5% 
in the BR arm to be 40% in the polatuzumab vedotin plus BR arm for study GO29365 
(i.e., 22.5% CR rate increase).
In this study, 42 patients will be enrolled in a 2:1 randomization allocation to
polatuzumab vedotin plus BR (experimental arm) or placebo plus BR arm (control arm).
A total of 42 patients will provide an approximate 80% probability of observing at least 50% 
of the benefit in the CR rate at the end of treatment assessment observed in the global 
Study GO29365.
2.4
ANALYSIS TIMING
The expected enrollment duration is approximately 9 months and the primary analysis is
expected to occur approximately 6 months of follow-up after the last patient is enrolled.
The study will continue after primary analysis until about two-thirds of enrolled patients
have experienced death or all patients have discontinued from study, whichever occurs
earlier. Based on the observed median OS in Study GO29365 (4.7 months in the BR
arm, 12.4 months in the polatuzumab vedotin plus BR arm), the final OS analysis is
expected to occur approximately 10 months after the last patient is enrolled.
3.
STUDY CONDUCT
3.1
RANDOMIZATION 
Patients will be randomly assigned to one of two treatment arms: experimental arm
(polatuzumab vedotin plus BR) or control arm (placebo plus BR). Randomization will
occur in a 2:1 ratio using a permuted-block randomization method to ensure a balanced
assignment to each treatment arm. Randomization will be stratified according to the
following criteria:

DOR to most recent prior therapy (12 months vs. 12 months)

Number of prior lines of therapies (1 vs. 2)


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3.2
INDEPENDENT REVIEW COMMITTEE
An IRC composed of certified radiologists and a hematologist or oncologist with
experience in malignant lymphoma will assess all patients for response through use of 
the 2014 Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014) on 
the basis of imaging results and biopsy results that are performed related to efficacy
evaluation. Decisions will be guided by a Charter specific to the independent review.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
4.1.1
Intent-to-Treat Population
The intention-to-treat (ITT) population is defined as all patients randomized, whether or 
not the patients received the assigned treatment. The ITT patients will be analyzed 
according to the treatment assigned at randomization by the interactive web-based 
response system (IxRS).
4.1.2
Safety Population
The safety analysis population will consist of all randomized patients who received at
least one dose of study drug, with patients grouped according to treatment received.
Specifically, a patient will be included in the polatuzumab vedotin plus BR arm in safety 
analyses if the patient receives any amount of polatuzumab vedotin, regardless of the 
initial treatment assignment by IxRS.
4.1.3
Pharmacokinetic-Evaluable Population
The PK population for analysis will include all patients who have at least one evaluable
PK sample post dose for at least one analyte.
4.1.4
Immunogenicity-Evaluable Population
The immunogenicity analysis population will consist of all patients with at least one
evaluable post-baseline ADA sample. Patients will be grouped according to treatment
received or, if no treatment is received prior to study discontinuation, according to
treatment assigned.
4.1.5
Biomarker-Evaluable Population
For each biomarker to be analyzed, the corresponding biomarker-evaluable population
will include all randomized patients who have a valid baseline assessment for that 
specific biomarker. Biomarker-evaluable population will be used for biomarker subgroup 
analyses.
4.2
ANALYSIS OF STUDY CONDUCT
The enrollment, major protocol deviations, and reasons for discontinuation from the 
study will be summarized by treatment arm for the ITT population. Study treatment


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administration and reasons for discontinuation from study treatment will be summarized 
by actual treatment arm for the safety population.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics (such as age, sex, and duration of malignancy)
will be summarized by treatment group for the ITT population. Descriptive summaries of 
continuous data will present the group mean, standard deviation, median, minimum and 
maximum. Descriptive summaries of discrete data will include frequencies and 
percentages.
4.4
EFFICACY ANALYSIS
4.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is CR at end of treatment assessment (6-8 weeks after 
Cycle 6 Day 1 or the final dose of study treatment) based on PET-CT, as determined by 
the IRC. The analysis population for this CR analysis will be the ITT population. Patients 
without the end-of-treatment tumor assessments or if their response at end of treatment 
is not evaluable, will be considered non-CR patients. 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 polatuzumab vedotin plus BR and placebo plus BR randomized arms will 
be estimated along with the corresponding 95% CI on the basis of normal approximation 
to the binomial distribution.
4.4.2
Secondary Efficacy Endpoints
Response rate is defined as the percentage of patients with CR, OR, or BOR as
described below:

CR at the end of treatment assessment based on PET-CT, as determined by the
investigator

OR, defined as CR or PR, at the end of treatment assessment based on PET-CT, as 
determined by the investigator and IRC

CR at the end of treatment assessment based on CT only, as determined by the
investigator and IRC

OR, defined as CR or PR, at the end of treatment assessment based on CT only, as
determined by the investigator and IRC

BOR, defined as CR or PR, while on study based on PET-CT or CT only, as
determined by the investigator and IRC
For the endpoint of CR and OR at end of treatment (EOT), patients without the end-of-
treatment tumor assessments or if their response at end of treatment is not evaluable, 


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will be considered non-CR and non-OR patients. For the endpoint of BOR, patients 
without a post-baseline tumor assessment will be considered non-responders. The 
analysis population for CR at EOT, OR at EOT, and BOR as described above will be the 
ITT population. Analyses of these endpoints will be identical to those described above 
for the primary efficacy endpoint of CR rate measured by PET-CT scan and determined 
by the IRC.
For patients with a BOR of CR or PR, DOR, as determined by the investigator and IRC, 
is defined as the time from the initial CR or PR to the time of disease progression, 
relapse, 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. Kaplan-Meier methodology will be
used to estimate median DOR for each treatment group and to construct DOR curves for 
visual descriptions of the difference between the experimental and control arms. The
Brookmeyer-Crowley methodology will be used to construct the 95% CI for the median
DOR for each treatment group (Brookmeyer and Crowley 1982). The unstratified Cox
proportional hazard model will be used to estimate the DOR HR between the two
treatment groups and its 95%CI.
PFS, as determined by the investigator and IRC, is defined as the period from the date
of randomization until the date of disease progression, relapse, or death from any cause,
whichever occurs first. The analysis population for this PFS analysis will be the ITT 
population. 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.
EFS, as determined by the investigator, is defined as the time from date of
randomization to any treatment failure including disease progression, relapse, initiation
of NALT, or death, whichever occurs first. The analysis population for this EFS analysis 
will be the ITT population. 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.
OS is defined as the time from date of randomization until the date of death from any
cause. The duration of OS will be analyzed in the ITT population. Patients who have not 
died will be censored at the last date known to be alive.
Analyses of PFS, EFS, and OS will be identical to those outlined previously for DOR.
Duration of follow-up will be estimated by reverse Kaplan-Meier method (Schemper and
Smith 1996).


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4.4.3
Biomarker Analyses
As the data will allow, PET-CT CR and OR rate will be analyzed in following subgroups: 
(1) patients with ABC-DLBCL as analyzed through use of a centrally performed RNA-
based assay, (2) patients with GCB-DLBCL as analyzed through use of a centrally 
performed RNA-based assay, (3) patients with co-expression of BCL2 and MYC 
(double-expressor, DEL) as analyzed through use of centrally performed IHC tests, and 
(4) patients with expression of CD79b as analyzed through use of a centrally performed 
IHC test.
4.5
SAFETY ANALYSES
Unless specified otherwise, safety analysis will be performed for the safety population,
with patients grouped according to the study treatment they actually received.
4.5.1
Exposure of Study Medication
Study treatment exposure (such as treatment duration, total dose received, and number
of cycles and dose modifications) will be summarized with descriptive statistics.
4.5.2
Adverse Events
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according NCI CTCAE v5.0. All adverse events, serious adverse events, adverse events 
leading to death, adverse events of special interest, and adverse events leading to study 
treatment discontinuation that occur on or after the first dose of study treatment (i.e., 
treatment-emergent adverse events) will be summarized by mapped term, appropriate 
thesaurus level, and severity grade. For events of varying severity, the highest grade will 
be used in the summaries. Deaths and cause of death will be summarized.
4.5.3
Peripheral Neuropathy
Peripheral neuropathy will be assessed through use of the Functional Assessment of 
Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX).
Visit summary and change from baseline analyses will be performed for the FACT/GOG-
NTX.  Summary statistics (number of patients, mean, standard deviation, median, 
minimum, maximum) of score and score change from baseline to each time point will be 
presented by treatment arm.
4.5.4
Laboratory Data
Laboratory data will be summarized by treatment arm. Values outside the normal ranges 
will be summarized by treatment arm. In addition, selected laboratory data will be 
summarized by treatment arm and NCI CTCAE grade. In addition, shift tables describing 
changes from baseline will be presented using the NCI CTCAE grading scale.


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4.5.5
Vital Signs
Changes in vital signs will be summarized by treatment arm.
Electrocardiograms (ECGs) will also be summarized by treatment arm.
4.6
PHARMACOKINETIC ANALYSES
The PK analysis will be performed in the PK-evaluable population. 
Individual and mean serum concentrations of total polatuzumab vedotin antibody (fully
conjugated, partially deconjugated and fully deconjugated antibody), plasma
concentrations of polatuzumab vedotin conjugate (evaluated as acMMAE), and
unconjugated MMAE versus time data will be tabulated and plotted after appropriate
grouping. The pharmacokinetics of the above analytes will be summarized after
appropriate grouping, as the data will allow, by estimating selected PK parameters, such
as AUC and Cmax. The population PK analysis will investigate the effects of certain
covariates on the pharmacokinetics of polatuzumab vedotin related analytes, as the data
will allow and at the Sponsor’s discretion. These covariates may include renal and
hepatic impairment, as data will allow.
Exposure-response (safety and efficacy) analysis may be conducted using
plasma/serum concentrations or relevant PK parameters and available drug effect data
(e.g., CR rate, PFS, and/or toxicity data), per the Sponsor’s discretion and as the data
will allow.
To assess potential PK drug interactions, PK parameters for each analyte of
polatuzumab vedotin will be compared with historical data, per the Sponsor’s discretion 
and as the data will allow.
4.7
IMMUNOGENICITY ANALYSES
The immunogenicity analysis will be performed in the immunogenicity-evaluable 
population and reported within the Integrated Summary of Immunogenicity (ISI).
The ISI will include an immunogenicity risk assessment, assay strategy, and summary of 
immunogenicity results. The numbers and proportions of ADA-positive patients and 
ADA-negative patients at baseline (baseline prevalence) and after drug administration 
(postbaseline incidence) will be summarized by treatment group. When determining 
postbaseline incidence, patients are considered to be ADA positive if they are ADA 
negative or have missing data at baseline but develop an ADA response following study 
drug exposure (treatment-induced ADA response), or if they are ADA positive at 
baseline and the titer of one or more postbaseline samples is at least 0.60 titer unit 
greater than the titer of the baseline sample (treatment-enhanced ADA response). 
Patients are considered to be ADA negative if they are ADA negative or have missing 
data at baseline and all postbaseline samples are negative, or if they are ADA positive at 
baseline but do not have any postbaseline samples with a titer that is at least 0.60 titer 


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unit greater than the titer of the baseline sample (treatment unaffected). Samples that 
confirm positive for ADA will be further characterized by titer determination and domain 
specificity.
The potential relationship between ADA status and safety, efficacy, and PK may be 
analyzed and reported via descriptive statistics.
4.8
MISSING DATA
See Sections 4.4 and 4.5 for methods for handling missing data for the primary and
secondary endpoints.
4.9
INTERIM ANALYSES
No efficacy interim analyses are planned.


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5.
REFERENCES
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29−41.
Cheson B, Fisher R, Barrington S, et al. Recommendations for initial evaluation, staging 
and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification. J Clin Oncol 2014;32:19.
Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time.
Controlled Clinical Trial 1996;17:3436.


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Appendix 1
Protocol Synopsis
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF POLATUZUMAB VEDOTIN IN COMBINATION 
WITH BENDAMUSTINE AND RITUXIMAB COMPARED WITH 
BENDAMUSTINE AND RITUXIMAB ALONE IN CHINESE 
PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE 
B-CELL LYMPHOMA
PROTOCOL NUMBER:
YO41543
VERSION NUMBER:
2
EUDRACT NUMBER:
Not applicable
IND NUMBER:
Not applicable
TEST PRODUCT:
Polatuzumab vedotin, lyophilized (DCDS4501S, RO5541077)
PHASE:
Phase III
INDICATION:
Diffuse large B-cell lymphoma
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics of polatuzumab vedotin plus
bendamustine and rituximab (BR) compared with placebo plus BR in Chinese patients with 
relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL).  Specific objectives and 
corresponding endpoints for the study are outlined below.
In this protocol, "study treatment" refers to the combination of treatments assigned to patients 
as part of this study (i.e., polatuzumab vedotin/placebo, bendamustine, and rituximab).
Efficacy Objectives
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of polatuzumab vedotin 
plus BR compared with placebo plus BR in Chinese patients with R/R DLBCL on the basis of 
the following endpoint. This objective is to investigate whether the benefit (in terms of complete 
response [CR] rate at end of treatment assessment) of administrating polatuzumab vedotin plus 
BR in this study is consistent with the benefit observed in the global study, GO29365.

CR at the end of treatment assessment (68 weeks after Cycle 6 Day 1 or final dose of 
study treatment) based on positron emission tomographycomputed tomography (PET-CT), 
as determined by the Independent Review Committee (IRC) according to the Lugano 
Response Criteria for Malignant Lymphoma, hereafter referred to as the "Lugano Response 
Criteria" (Cheson et al. 2014)
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of polatuzumab 
vedotin plus BR compared with placebo plus BR in Chinese patients with R/R DLBCL on the 
basis of the following endpoints:


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
CR at the end of treatment assessment based on PET-CT, as determined by the 
investigator according to the Lugano Response Criteria

Objective response (OR), defined as CR or partial response (PR), at the end of treatment 
assessment based on PET-CT, as determined by the investigator and IRC according to the 
Lugano Response Criteria 

CR at the end of treatment assessment based on computed tomography (CT) only, as 
determined by the investigator and IRC according to the Lugano Response Criteria

OR, defined as CR or PR, at the end of treatment assessment based on CT only, as 
determined by the investigator and IRC according to the Lugano Response Criteria 

Best objective response, defined as CR or PR, while on study based on PET-CT or CT only, 
as determined by the investigator and IRC according to the Lugano Response Criteria

Duration of response (DOR), defined as the time from the first occurrence of a documented 
objective response to disease progression, relapse, or death from any cause based on 
PET-CT or CT only, as determined by the investigator and IRC according to the Lugano 
Response Criteria 

Progression-free survival, defined as the period from date of randomization until the date of 
disease progression, relapse, or death from any cause based on PET-CT or CT only, as 
determined by the investigator and IRC according to the Lugano Response Criteria 

Event-free survival, defined as the time from date of randomization to any treatment failure 
including disease progression, relapse, initiation of new anti-lymphoma treatment, or death 
based on PET-CT or CT only, as determined by the investigator according to the Lugano 
Response Criteria

Overall survival (OS), defined as the time from date of randomization until the date of death 
from any cause  
Safety Objectives
The safety objective for this study is to evaluate the safety of polatuzumab vedotin plus BR 
compared with placebo plus BR in Chinese patients with R/R DLBCL on the basis of the 
following endpoints:

Incidence and severity of adverse events, with severity determined according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 
(NCI CTCAE v5.0)

Incidence and nature of study drug discontinuation, dose reduction, and dose delay due to 
adverse events
Additionally, this study will evaluate the safety of polatuzumab vedotin plus BR compared with 
placebo plus BR from the patient's perspective to better understand treatment impact, 
tolerability, and reversibility on the basis of the following endpoint:

Change from baseline in peripheral neuropathy as assessed through use of the Functional 
Assessment of Cancer Therapy/Gynecologic Oncology GroupNeurotoxicity 
(FACT/GOG-NTX) 
Pharmacokinetic Objectives
The pharmacokinetic (PK) objective for this study is to characterize the PK for total antibody, 
antibody-conjugated monomethyl auristatin E (acMMAE), and unconjugated monomethyl 
auristatin E (MMAE) following polatuzumab vedotin administration, when combined with BR, in 
Chinese patients with R/R DLBCL on the basis of the following endpoints:

Serum concentration of total antibody at specified timepoints

Plasma concentration of acMMAE at specified timepoints

Plasma concentration of unconjugated MMAE at specified timepoints
Additionally, this study will evaluate potential relationships between polatuzumab vedotin 
exposure and the efficacy and safety of polatuzumab vedotin, when combined with BR, in 
Chinese patients with R/R DLBCL on the basis of the following endpoints:

Relationship between plasma concentration or PK parameters for polatuzumab vedotin and 
efficacy endpoints


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
Relationship between plasma concentration or PK parameters for polatuzumab vedotin and 
safety endpoints
Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to polatuzumab 
vedotin, when combined with BR, in Chinese patients with R/R DLBCL on the basis of the 
following endpoint:

Prevalence of anti-drug antibodies (ADAs) for polatuzumab vedotin at baseline and 
incidence of ADAs during the study
Additionally, for this study will evaluate potential effects of ADAs on the basis of the following 
endpoint:

Relationship between ADA status for polatuzumab vedotin and efficacy, safety, or PK 
endpoints
Biomarker Objective
The biomarker objective for this study is to evaluate the response to polatuzumab vedotin, when 
combined with BR, in Chinese patients with R/R DLBCL with known prognostic factors, such as 
activated B cell (ABC)-DLBCL or germinal center B cell [GCB]-DLBCL as analyzed through 
use of a centrally performed RNA-based assay, or co-expression of BCL2 and MYC (double-
expressor, [DEL]) as analyzed through use of centrally performed immunohistochemistry 
(IHC) tests.  In addition, the association between response and the expression of the target of 
polatuzumab vedotin, CD79b (as analyzed through use of a centrally performed IHC test) will 
be evaluated.

CR at the end of treatment assessment based on PET-CT, as determined by the IRC 
according to the Lugano Response Criteria in populations of ABC-DLBCL, GCB-DLBCL, 
DEL, and expression of CD79b

OR, defined as CR or PR, at the end of treatment assessment based on PET-CT, as 
determined by the  IRC according to the Lugano Response Criteria in populations of 
ABC-DLBCL, GCB-DLBCL, DEL, and expression of CD79b
Study Design
Description of Study
This is a Phase III, multicenter, randomized, double-blind, placebo-controlled study to evaluate 
the efficacy and safety of polatuzumab vedotin in combination with BR compared with BR alone
in Chinese patients with R/R DLBCL.
Approximately 42 Chinese patients will be randomized to one of the following treatment arms in 
a 2:1 ratio:

Polatuzumab vedotin plus BR (experimental arm)

Placebo plus BR (control arm)
Randomization will be conducted with the aid of an interactive web-based response system 
(IxRS) and will be stratified according to the following factors: 

DOR to most recent prior therapy:  12 months versus 12 months 

Number of prior therapies (1 vs. 2)
For consistency with the pivotal study population (Study GO29365), patients with 
2 prior lines of therapy will be capped within 70% of the whole population.
Refer to the protocol for the study design schema and the schedule of activities.
Study treatment will be administered by IV infusion every 21 days for up to 6 cycles, as 
described in the protocol.  The first day of treatment will constitute Study Day 1.  Refer to the 
protocol for details on study treatment dosage and administration.
All patients will be closely monitored for adverse events and serious adverse events throughout 
the study and for 90 days after the final dose of study treatment.  Adverse events will be graded 
according to NCI CTCAE v5.0. Laboratory safety assessments will include regular monitoring 
of hematology and blood chemistry, and tests of immunological parameters.


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18/Statistical Analysis Plan YO41543
Blood samples will be taken at various timepoints during the study to analyze the PK properties 
of polatuzumab vedotin (total antibody, acMMAE, and unconjugated MMAE), as well as the 
immunogenicity of polatuzumab vedotin, when given in combination with BR. 
Response will be determined by an IRC and investigators using the Lugano Response Criteria 
(Cheson et al. 2014) at the following timepoints:

Screening:  within 35 days of Cycle 1 Day 1

Interim response assessment:  between Cycle 3 Day 15 and Cycle 4 Day 1

End of treatment assessment:  68 weeks after Cycle 6 Day 1 or the final dose of study 
treatment
For patients with disease progression occurring prior to the anticipated date of the end of 
treatment assessment, the visit date with the response assessment showing disease 
progression will be used in replacement of the end of treatment assessment.
Imaging at these timepoints must include PET scans in conjunction with diagnostic-quality CT 
scans with both oral and IV contrast.  An independent review of the responses of all patients will 
also be conducted to confirm the primary CR endpoint.   
Patients who complete the study treatment period will return to the clinic for a treatment 
completion visit 30 (5) days after the final dose of study treatment (Cycle 6 Day 1).  Patients 
who discontinue study treatment prematurely will return to the clinic for a treatment 
discontinuation visit 30 (5) days after the final dose of study treatment.  
Disease Progression and Follow Up
Following completion of treatment, patients who have not progressed will be followed clinically 
every 3 months (14 days) according to the schedule of activities.  Tumor assessments should 
also be performed to confirm clinical suspicion of relapse or disease progression for 
documentation.  Follow-up visit intervals should be determined from the end of treatment 
assessment.  
CT (preferred) or PET-CT scans should be performed during follow-up:

Every 6 months after the end of treatment assessment until disease progression, study 
withdrawal, end of study, or death, whichever comes first; or 

At any time that disease progression is suspected via clinical response assessment
For patients who have disease progression 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 disease progression
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 disease progression, assessments should be followed according to the schedule of 
activities, including response assessments and adverse events.  
Patients who discontinue all components of study treatment prior to disease progression (e.g., 
for toxicity) will continue in the study and will be followed for progressive disease and OS 
(regardless of whether they subsequently receive a new anti-lymphoma therapy). 
Study Treatment Regimen
Patients will receive a total of 6 cycles of polatuzumab vedotin or placebo in combination with 
BR.  A cycle is typically 21 days.
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/placebo IV infusion

Bendamustine 90 mg/m2 IV infusion
Cycle 1 Day 3

Bendamustine 90 mg/m2 IV infusion


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19/Statistical Analysis Plan YO41543
Schedule for Cycles 26
As long as the observed individual patient safety profile of polatuzumab vedotin/placebo and BR 
allows all study treatment infusions to be given on the same day, then the study treatment
infusions will be given sequentially on the same day for Cycles 26 and in the order specified 
below.
Cycles 26 Day 1

Rituximab 375 mg/m2 IV infusion

Polatuzumab vedotin/placebo IV infusion

Bendamustine 90 mg/m2 IV infusion
Cycles 26 Day 2

Bendamustine 90 mg/m2 IV infusion
Independent Review Committee
An IRC composed of certified radiologists and a hematologist or oncologist with experience in 
malignant lymphoma will assess all patients for response on the basis of imaging results and 
biopsy results that are performed related to efficacy evaluation.  Decisions will be guided by a 
Charter specific to the independent review.
Number of Patients
Approximately 42 patients with R/R DLBCL will be enrolled in this study.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form Age 18 years at time of signing Informed Consent Form

Able to comply with the study protocol and procedures, in the investigator’s judgment

Transplant ineligible patients with R/R DLBCL, classified as below:
-
Patients who are ineligible for second-line stem cell transplantation (SCT), with 
progressive disease or no response (stable disease [SD]) 6 months from start of 
initial therapy (second-line refractory)
-
Patients who are ineligible for second-line SCT, with disease relapse after initial 
response 6 months from start of initial therapy (second-line 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 (third-line or beyond refractory)
-
Patients who are ineligible for third-line (or beyond) SCT with disease relapse after 
initial response 6 months from start of prior therapy (third-line or beyond relapsed)

Confirmed DLBCL diagnosis as:
-
DLBCL, not otherwise specified (NOS) (including both GCB and ABC)
-
T-cell/histiocyte-rich large B-cell lymphoma
-
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements 
-
High grade B-cell lymphoma, NOS 
-
Primary mediastinal (thymic) large B-cell lymphoma
-
Epstein-Barr virus positive DLBCL, NOS

For patients who have received prior bendamustine, a response duration 1 year (for 
patients who have relapsed disease after a prior regimen)

At least one bi-dimensionally measurable lesion, defined as >1.5 cm in its longest 
dimension as measured by CT or magnetic resonance imaging

Availability of archival or freshly collected tumor tissue before study enrollment
Formalin-fixed, paraffin-embedded tissue blocks are preferred. 
If a tissue block is not available, at least 11 unstained slides or freshly cut serial 
sections (35 μm in thickness), will be accepted.


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20/Statistical Analysis Plan YO41543
Of note, receipt of tumor samples is not necessary prior to study enrollment. 

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
-
ANC 1.5 109/L
-
Platelet count 75 109/L

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, and agreement to refrain from donating 
eggs, as defined below:
Women must remain abstinent or use single highly effective or combined contraceptive 
methods with a failure rate of 1% per year during the treatment period and for 12 
months after the final dose study treatment.  Women must refrain from donating eggs 
during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or regulations.
Examples of highly effective contraceptive methods with a failure rate of 1% per year 
include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper 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.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.  If required per local guidelines or 
regulations, locally recognized acceptable methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form.

For men who are not surgically sterile:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, and agreement to refrain from donating 
sperm, as defined below:
With a female partner of childbearing potential who is not pregnant, men must 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 final dose of study treatment.  Men must refrain from donating sperm 
during this same period.
With a pregnant female partner, men must remain abstinent or use a condom during 
the treatment period and for 6 months after the final dose of study treatment to avoid 
exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.  If required per local guidelines or 
regulations, locally recognized acceptable methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form.

Residence in the People’s Republic of China


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21/Statistical Analysis Plan YO41543
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 or rituximab 

History of sensitivity to mannitol (mannitol is an excipient in bendamustine)

Prior use of any MAb, radioimmunoconjugate, or antibody-drug conjugate 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 the protocol.

Completion of autologous SCT within 100 days prior to Cycle 1 Day 1

Prior allogeneic SCT

Prior treatment with CAR T-cell therapy

Eligibility for autologous SCT

Grade 3b FL

History of transformation of indolent disease to DLBCL

Primary or secondary CNS lymphoma

Current Grade 1 peripheral neuropathy

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)


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22/Statistical Analysis Plan YO41543

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 monthly (or on Day 1 of every 
cycle) during the study and 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 polymerase chain 
reaction is negative for HCV RNA.

Known history of HIV seropositive status
For patients with unknown HIV status, HIV testing will be performed at screening.

Known infection human T-cell leukemia virus 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

Pregnant or breastfeeding or intending to become pregnant during the study or within 
12 months after the final dose of study treatment
Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to initiation of study drug.

Any of the following abnormal laboratory values, unless abnormal laboratory values are due 
to underlying lymphoma per the investigator:
-
Serum creatinine clearance 40 mL/min (using Cockcroft-Gault formula)
-
AST or ALT 2.5 upper limit of normal (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
Criteria for Lymph Node Biopsy Tissue
Patients must meet following criteria for lymph node biopsy tissue:

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 11 serial, freshly cut, unstained slides accompanied by an 
associated pathology report will be requested.  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.


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23/Statistical Analysis Plan YO41543
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.  If a tissue block is provided, after necessary sections are cut, the remaining 
specimen will be returned to site upon request.  Tissue collected on study will not be returned to 
sites.
Refer to the laboratory manual for additional details.
End of Study
The end of the study is defined as the timepoint at which approximately two-thirds of enrolled 
patients have experienced deaths, or all patients have discontinued from the study, whichever 
occurs first.
In addition, the Sponsor may decide to terminate the study at any time.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is
expected to be approximately 21 months.
Investigational Medicinal Products
Polatuzumab Vedotin and Placebo
Polatuzumab vedotin and placebo will be supplied by the Sponsor as a sterile, white to grayish-
white, preservative-free lyophilisate in single-use vials. Polatuzumab vedotin or placebo should 
be prepared and administered in the same manner. For information on the formulation and 
handling of polatuzumab vedotin or placebo, see the pharmacy manual and the Polatuzumab 
Vedotin Investigator's Brochure.
Polatuzumab vedotin (1.8 mg/kg) or placebo will be administered by IV infusion on Day 2 of 
Cycle 1 and then Day 1 of Cycles 26.
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 the Rituximab 
Investigator’s Brochure.
Rituximab (375 mg/m2) will be administered by IV infusion on Day 1 of Cycles 16.
Bendamustine
Bendamustine hydrochloride will be supplied by the Sponsor.  For information on the 
formulation, packaging, and handling of bendamustine hydrochloride, see the pharmacy manual.
Bendamustine (90 mg/m2) will be administered by IV infusion over 3060 minutes on 
2 consecutive days of each cycle (Days 2 and 3 in Cycle 1 and then Days 1 and 2 in 
Cycles 26).  
Statistical Methods
Primary Analysis
CR at end of treatment assessment (68 weeks after Cycle 6 Day 1 or the final dose of study 
treatment) based on PET-CT, as determined by the IRC, will be used as the primary efficacy 
endpoint.  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 polatuzumab vedotin plus BR and placebo plus BR randomized
arms will be estimated along with the corresponding 95% CI on the basis of normal 
approximation to the binomial distribution.
Determination of Sample Size
The primary endpoint of CR at the end of treatment assessment was used to determine the 
sample size of the study. 
The primary objective of the study is to investigate whether the benefit (in terms of CR at the 
end of treatment assessment) of administrating polatuzumab vedotin plus BR in this study is 
consistent with the benefit observed in the global study GO29365. CR rate at the end of 
treatment assessment was increased from 17.5% in the BR arm to be 40% in the polatuzumab 
vedotin plus BR arm for study GO29365 (i.e., 22.5% CR rate increase).


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24/Statistical Analysis Plan YO41543
In this study, 42 patients will be enrolled in a 2:1 randomization allocation to polatuzumab 
vedotin plus BR (experimental arm) or placebo plus BR arm (control arm). A total of 42 
patients will provide an approximate 80% probability of observing at least 50% of the benefit
in the CR rate at the end of treatment assessment observed in the global Study GO29365.
The expected enrollment duration is approximately 9 months and the primary analysis is 
expected to occur approximately 6 months of follow-up after the last patient is enrolled. The 
study will continue after primary analysis until about two-thirds of enrolled patients have 
experienced death or all patients have discontinued from study, whichever occurs earlier.  
Based on the observed median OS in Study GO29365 (4.7 months in the BR arm, 12.4 months 
in the polatuzumab vedotin plus BR arm), the final OS analysis is expected to occur 
approximately 10 months after the last patient is enrolled.


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
25/Statistical Analysis Plan YO41543
Appendix 2
Schedule of Assessments
Day a
(Window)
Screen
(28 days) b
Treatment
Treatment
Completion/
Discont. d
EOT 
Assessment
e
Follow-
Up f
Cycle 1
Cycle 2
Cycle 3
Cycles 46
30 (5)
days after 
final dose 
68 weeks 
after C6D1 
or final dose 
D1 c
D2
D3
D8 
(1)
D15 
(1)
D1 
(2)
D2 
D1 
(2)
D2 
D15
(1) 
D1 
(2)
D2 
Informed consent g
x
Demographic data
x
General medical history 
and baseline conditions
x
Concomitant 
medications h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events i
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x i
ECOG PS
x
x
x
x
IPI
x
Complete physical 
exam j
x
Targeted physical 
examination k
x
x
x
x
x
x
x
Vital signs l
x
x
x
x
x
x
x
x
x
x
Height, weight, and 
BSA m
x
x
x
x
x
12-lead ECG
x
x
x


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
26/Statistical Analysis Plan YO41543
Appendix 2
Schedule of Assessments (cont.)
Day a
(Window)
Screen
(28 days) b
Treatment
Treatment
Completion/
Discont. d
EOT 
Assessment e
Follow-
Up f
Cycle 1
Cycle 2
Cycle 3
Cycles 46
30 (5)
days after 
final dose 
68 weeks 
after C6D1 or 
final dose 
D1 c
D2
D3
D8 
(1)
D15 
(1)
D1 
(2)
D2 
D1 
(2)
D2 
D15
(1) 
D1 
(2)
D2 
FACT/GOG-NTX n
x
x
x
x
x
x
(every 
3 mo.)
Clinical response 
assessment o
x
x
x
x
x
x
x
x
CT scan and PET-CT scan p
x q
x
x
(x) r
Rituximab s
x
x
x
x
Polatuzumab vedotin or 
placebo t
x
x
x
x
Bendamustine u
x
x
x
x
x
x
x
x
Hematology v
x
x
x
x
x
x
x
x
x
x
Serum chemistry w
x
x
x
x
x
x
x
x
x
x
Coagulation panel x
x
Viral serology y
x
Serum IgA, IgG, and IgM
x
x
x
x
Pregnancy test z
x
x
x
x
x
Bone marrow biopsy and 
aspirate aa
x
(x)
(x)
(x)


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
27/Statistical Analysis Plan YO41543
Appendix 2
Schedule of Assessments (cont.)
Day a
(Window)
Screen
(28 days) b
Treatment
Treatment
Completion/
Discont. d
EOT 
Assessment e
Follow-
Up f
Cycle 1
Cycle 2
Cycle 3
Cycles 46
30 (5)
days after 
final dose 
68 weeks 
after C6D1 or 
final dose 
D1 c
D2
D3
D8 
(1)
D15 
(1)
D1 
(2)
D2 
D1 
(2)
D2 
D15
(1) 
D1 
(2)
D2 
Tumor tissue sample for 
prognostic biomarker 
studies bb
x
Lymphocyte subsets cc
x
x
x
(every
6 mo.)
Anti-drug antibody 
(polatuzumab vedotin)
See Appendix 2 of the protocol
PK assessment 
(polatuzumab vedotin)
See Appendix 2 of the protocol
Survival follow-up/
status dd
x
x
x
BSAbody surface area; Ccycle; CRcomplete response; CT computed tomography (scan); Dday; Discont.discontinuation; DLBCLdiffuse large 
B-cell lymphoma; ECOG PSEastern Cooperative Oncology Group Performance Status; eCRF electronic Case Report Form; EOTend of treatment; 
FACT/GOG-NTXFunctional Assessment of Cancer Treatment/Gynecologic Oncology GroupNeurotoxicity; HbA1chemoglobin A1c; HBcAbhepatitis 
B core antibody; HBsAbhepatitis B surface antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; 
IPIInternational Prognostic Index; momonth; PCRpolymerase chain reaction; PET-CTpositron emission tomographycomputed tomography
(scan); PKpharmacokinetic; (x)conditional/optional (refer to footnote).
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.  


Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd
28/Statistical Analysis Plan YO41543
Appendix 2
Schedule of Assessments (cont.)
b 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. Bone marrow biopsies collected within 90 days prior to Day 1 of study treatment are acceptable.  Samples obtained 
more than 90 days prior to Day 1 require prior approval by the Medical Monitor before the patient can be randomized.
c Local laboratory assessments and targeted physical examination may be performed within 72 hours preceding Cycle1 Day 1 administration unless 
otherwise specified; pre-infusion laboratory samples should be drawn 04 hours prior to infusion.
d Patients who complete the study treatment period will return to the clinic for a treatment completion visit 30 (5) days after the final dose of study 
treatment (Cycle 6 Day 1).  Patients who discontinue study treatment prematurely will return to the clinic for a treatment discontinuation visit 
30 (5) days after the final dose of study treatment.  The visit at which response assessment shows progressive disease may be used as the 
treatment discontinuation visit.
e All patients will be asked to return to the clinic for the end of treatment assessment.  This visit is to take place between 6 and 8 weeks after Cycle 6 
Day 1 or the final dose of study treatment.  For patients with disease progression occurring prior to the anticipated date of the end of treatment
assessment, the visit date with the response assessment showing progressive disease may be used in replacement of the end of treatment 
assessment.
f
Following completion of treatment, patients who have not progressed will be followed clinically every 3 months (14 days).  Follow-up visit intervals 
should be determined from treatment completion visit.
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 consists of any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, 
nutritional supplements) used by a patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug to the treatment 
completion/discontinuation visit.  All such medications should be reported to the investigator and recorded on the Concomitant Medications eCRF.
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 final 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.  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.


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Appendix 2
Schedule of Assessments (cont.)
j
Complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, 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
Vital signs include respiratory rate, pulse rate, pulse oximetry, and systolic and diastolic blood pressures while the patient is in a seated position, and 
temperature.  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.
m 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.
n The FACT/GOG-NTX will be administered on Day 1 of every cycle, at treatment completion/discontinuation, and at specified planned post-treatment 
visits thereafter until the close of the study (every 3 months after the treatment completion visit).  Paper versions of the FACT/GOG-NTX scale will be 
self-administered or interviewer administered (as appropriate) before the patient receives any information on disease status, prior to the performance 
of non-PRO assessments, and prior to the administration of study treatment. The data from the questionnaires will be entered into the EDC system 
by site staff.    
o Clinical response assessment of tumor conducted via physical examination.
p CT scans and PET-CT scans are required at screening, the interim response assessment (between Cycle 3 Day 15 and Cycle 4 Day 1), and the end 
of treatment assessment (68 weeks after Cycle 6 Day 1 or the final dose of study treatment).  Diagnostic contrast enhanced CT scans obtained as 
part of a PET-CT may be used in lieu of dedicated CT scans.  All other imaging may be CT only.  The Lugano Response Criteria will be used to 
assess overall response to study treatment.
q Screening PET-CT must be obtained within 35 days of Cycle 1 Day 1.  


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Appendix 2
Schedule of Assessments (cont.)
r
CT (preferred) or PET-CT scans should be performed during follow-up every 6 months after end of treatment assessment until disease progression, 
study withdrawal, end of study, or death, whichever comes first; or at any time that progression is suspected via clinical response assessment.  
s Rituximab (375 mg/m2) will be administered by IV infusion on Day 1 of Cycles 16.  No dose modifications of rituximab are allowed.  Rituximab should 
be administered after premedication with oral acetaminophen/paracetamol and an antihistamine.
t
Polatuzumab vedotin (1.8 mg/kg) or placebo will be administered by IV infusion on Day 2 of Cycle 1 then Day 1 of Cycles 26.   
u Bendamustine (90 mg/m2) will be administered by IV infusion over 3060 minutes on 2 consecutive days of each cycle (Days 2 and 3 in Cycle 1, then 
Days 1 and 2 in Cycles 26).
v Hematology includes hemoglobin, hematocrit, RBC count, WBC count, platelet count, and percent or absolute differential (neutrophils, lymphocytes, 
eosinophils, basophils, and monocytes).  Results should be obtained within 3 days before study treatment administration.  
w Serum chemistry includes sodium, potassium, glucose, BUN or urea, creatinine, calcium, total bilirubin, direct bilirubin, total protein, albumin, ALT, 
AST, ALP, LDH, uric acid/urate, HbA1c, amylase, and lipase.  At screening, samples 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.
x INR or, PT, and PTT or aPTT.  Results should be obtained within 3 days before study treatment administration.
y At screening, patients will be tested for HIV, HBsAg, total HBcAb, and HCV antibody.  If a patient has a negative HBsAg test and a positive total 
HBcAb test at screening, an HBV DNA test must also be performed at screening and monthly (or on Day 1 of each cycle) during the study treatment 
period, and for at least 12 months after the completion of study treatment to determine if the patient has an HBV infection.  If a patient has a positive 
HCV antibody test at screening, an HCV RNA test must also be performed to determine if the patient has an HCV infection.
z All women of childbearing potential will have a serum pregnancy test at screening within 7 days before Cycle 1 Day 1.  In addition, a serum or urine 
pregnancy test must be performed prior to study treatment on Day 1 of each subsequent cycle (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.
aa 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 end of treatment assessment in patients who achieve radiologic CR 
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. 


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Appendix 2
Schedule of Assessments (cont.)
bb Pretreatment tumor tissue sample is required (archival tissue or fresh pre-treatment biopsy is acceptable) and to be submitted according to local 
regulations.  Tumor blocks are preferred.  If a tumor block is not available, a minimum of 11 serial freshly cut, unstained slides are required.  
Remaining archival tissue blocks will be returned to local pathology according to country-specific procedures.  
cc Whole blood samples will be collected at screening, end of treatment assessment, and every 6 months (from the treatment completion visit) until the 
end of study or patient discontinuation.
dd During the follow-up period (i.e., after treatment completion):  For patients who have disease progression 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.  In the case where a patient experiences disease progression, information on survival follow-up and new anti-cancer therapy will be 
collected via telephone calls, patient medical records, and/or clinic visits approximately every 6 months until death (unless the patient withdraws 
consent or the Sponsor terminates the study).  For patients who started a new anti-lymphoma therapy but do not have disease progression, 
assessments should be followed according to the schedule of activities, including response assessments and adverse events.