A Phase III, Open-Label, Multicenter, Randomized, Study Evaluating the Safety and Efficacy of Polatuzumab Vedotin in Combination With Rituximab Plus Gemcitabine Plus Oxaliplatin (R-GEMOX) Versus R-GEMOX Alone in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Phase: PHASE3
Conditions: Diffuse Large B-Cell Lymphoma
Sponsor: Hoffmann-La Roche

Official Title: 
A Phase III, Open-Label, Multicenter, Randomized, Study Evaluating 
the Safety and Efficacy of Polatuzumab Vedotin in Combination with 
Rituximab Plus Gemcitabine Plus Oxaliplatin (R-GEMOX) Versus R-
GEMOX Alone in Patients with Relapsed/Refractory Diffuse Large B-
Cell Lymphoma 
NCT Number: 
NCT04182204 
Document Date: 
Protocol Version 8: 06-May-2025 

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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 MO40598, Version 8 
 
PROTOCOL 
TITLE: 
A PHASE III, OPEN-LABEL, MULTICENTER, 
RANDOMIZED STUDY EVALUATING THE SAFETY 
AND EFFICACY OF POLATUZUMAB VEDOTIN IN 
COMBINATION WITH RITUXIMAB PLUS 
GEMCITABINE PLUS OXALIPLATIN (R-GEMOX) 
VERSUS R-GEMOX ALONE IN PATIENTS WITH 
RELAPSED/REFRACTORY DIFFUSE LARGE 
B-CELL LYMPHOMA 
PROTOCOL NUMBER: MO40598 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2018-003727-10 
IND NUMBER: 
109409 
TEST PRODUCT: 
Polatuzumab vedotin (RO5541077; 
anti‑CD79b‑VC‑MMAE; DCDS4501S) 
MEDICAL MONITOR: 
 Pharm.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
See electronic signature and date stamp on final page 
of this document 
 
 

Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
Protocol MO40598, Version 8 
2 
PROTOCOL HISTORY 
 
Protocol 
Version 
Date Final 
8 
See electronic date stamp on the final page of this document 
7 
24 March 2021 
6 
24 February 2021 
5 
12 June 2020 
4 
27 November 2019 
3 
5 September 2019 
2 
16 April 2019 
1 
24 January 2019 
 

Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
Protocol MO40598, Version 8 
3 
PROTOCOL AMENDMENT, VERSION 8: 
RATIONALE 
  
Protocol MO40598 has been primarily amended to increase the sample size as a 
consequence of the change in the median overall survival (mOS) assumptions based on 
the availability of newer subsequent therapies in the relapsed/refractory (R/R) diffuse 
large B-cell lymphoma (DLBCL) therapy landscape.  Risks and management guidelines 
for polatuzumab vedotin have also been updated to align with the latest effective 
Polatuzumab Vedotin Investigator’s Brochure (Version 13).  Changes to the protocol, 
along with a rationale for each change, are summarized below: 
 
Determination of sample size (Section 6.1) has been updated due to a shift in the 
treatment landscape for R/R DLBCL, which has changed markedly since the 
authoring of this protocol in 2019.  Assumptions of mOS have been updated based 
on the availability of newer treatments such as CAR T-cell therapy subsequent to 
POLARGO study treatment (Study MO40598).  The new assumptions for mOS 
increased the number of events for the primary endpoint of overall survival from 
 
to 
 events in order to maintain an 
 power with a two-sided alpha of 
.  As 
a result of the increase in number of events, the total sample size has been 
increased to approximately 250 patients.  Sections 1.3, 3.1, 3.2, 4.1, 4.2, 6.1, and 
9.5 have been updated accordingly. 
 
Language has been edited to clarify the assessments required during long-term 
follow-up and the methods for collection of information (Sections 3.1 and 4.6.1; 
Appendices 1 and 2). 
 
The definition of refractory has been clarified to include patients who did not 
respond to their last line of therapy (stable disease) in addition to those who 
experienced disease progression within 6 months of their last relapse (Sections 3.1, 
3.3.2, and 4.1.1). 
 
Language has been added to clarify the end of study and length of study 
(Section 3.2). 
 
Inclusion criteria were clarified to include patients with newly transformed DLBCL 
from indolent lymphoma (no treatment received for the transformed lymphoma) if 
the patient has received an anthracycline containing chemotherapy regimen (such 
as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) for the 
indolent lymphoma (Section 4.1.1). 
 
To address the coronavirus disease 2019 (COVID-19) pandemic COVID-19 
vaccines have been added as permitted therapy (Section 4.4.1.4). 
 
Risks for polatuzumab vedotin have been updated to align with the latest 
Polatuzumab Vedotin Investigator’s Brochure (Version 13) (Section 5.1.1.1). 
 
Risks for rituximab, gemcitabine, and oxaliplatin have been removed from the 
protocol and references to the Rituximab Investigator’s Brochure and Package 
Insert/Summary of Product Characteristics for gemcitabine and oxaliplatin have 
been added. 

Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
Protocol MO40598, Version 8 
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 
Management guidelines for adverse events have been edited to clarify: 
– 
Recommendations for management of Grade 2 or 3 peripheral neuropathy 
(Sections 4.6.1 and 5.1.2.3) and Grade 2 non-hematologic toxicity 
(Section 5.1.2.3) 
– 
Study treatment can be delayed for a maximum of 14 days after the scheduled 
date of the next cycle (Section 5.1.2.2). 
 
Guidelines for recording special situations and adverse events associated with 
special situations in the Adverse Event electronic Case Report Form have been 
updated (Section 5.3.5.12). 
 
Additional minor changes were made to clarify and align different sections and 
documents: 
– 
Language was added to clarify how to count salvage and conditioning 
chemotherapies in prior lines of therapy (Sections 3.1, 3.3.2, and 4.1.1). 
– 
Language was edited to include abstinence/contraception time periods for all 
drugs (Section 4.1.1). 
– 
The time period to record concomitant medications was clarified (Section 4.5.2, 
Appendices 1 and 2). 
– 
Magnetic resonance imaging scans were added as an imaging modality for 
patients in whom contrast is contraindicated (Section 4.5.8). 
– 
The names of samples and study visits for pharmacokinetics were clarified 
(Appendix 4).  
– 
Language has been added to indicate that the Informed Consent Form will 
instruct female patients to inform the investigator if they become pregnant 
(Section 5.4.3.1). 
– 
Language regarding investigator reporting of pregnancies has been clarified 
(Section5.4.3.2). 
 
Personal identifiable information (i.e., name and telephone number) for the Medical 
Monitors has been removed from the protocol (Section 5.4.1).  Medical Monitor 
contact information has been replaced with a sentence indicating that this 
information will be provided separately to sites. 
 
Language has been added to indicate that sites can confirm that appropriate 
temperature conditions have been maintained during investigational medicinal 
product transit either by time monitoring (shipment arrival date and time) or 
temperature monitoring (Section 4.3.3). 
 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with the EU’s Clinical Trials Regulation 
requirements (Section 8.4). 
 
Due to certain local requirements and an alignment of Sponsor process, it has been 
clarified that summaries of clinical study results may be available in health authority 
databases for public access in addition to redacted Clinical Study Reports.  The 
name of a Roche policy on data sharing has been corrected (Section 9.6). 

Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
Protocol MO40598, Version 8 
5 
 
Appendix 15 has been added to designate all protocol-mandated therapies as an 
investigational medicinal product or a non-investigational medicinal product. 
 
Additional minor changes have been made to repair typographical errors and to improve 
clarity and consistency.  Substantive new information appears in Book Antigua italics 
(Book Antigua italics) in the amended protocol.  This amendment represents cumulative 
changes to the original protocol. 
 
 

Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
Protocol MO40598, Version 8 
6 
 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................. 14 
PROTOCOL SYNOPSIS .................................................................................... 15 
1. 
BACKGROUND .......................................................................................... 37 
1.1 
Background on Relapsed/Refractory Diffuse 
Large B-Cell Lymphoma ........................................................ 37 
1.1.1 
First-Line Treatment of Diffuse Large B-Cell 
Lymphoma ............................................................................. 37 
1.1.2 
Treatment of Relapsed/Refractory Diffuse Large 
B-Cell Lymphoma .................................................................. 38 
1.1.3 
Prognostic Risk Groups ......................................................... 39 
1.2 
Background on Polatuzumab Vedotin ................................... 39 
1.2.1 
Polatuzumab Vedotin Mechanism of Action .......................... 39 
1.2.2 
Polatuzumab Vedotin Clinical Studies ................................... 40 
1.2.2.1 
Efficacy .................................................................................. 40 
1.2.2.2 
Safety .................................................................................... 44 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 47 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 50 
3. 
STUDY DESIGN ......................................................................................... 54 
3.1 
Description of the Study......................................................... 54 
3.1.1 
Internal Monitoring Committee ............................................... 63 
3.1.2 
Independent Data Monitoring Committee .............................. 63 
3.1.3 
Independent Review Committee ............................................ 63 
3.2 
End of Study and Length of Study ......................................... 63 
3.3 
Rationale for Study Design .................................................... 64 
3.3.1 
Rationale for Patient Population ............................................ 64 
3.3.2 
Rationale for Stratification Factors ......................................... 64 
3.3.3 
Rationale for Polatuzumab Vedotin Dose and 
Schedule ................................................................................ 64 
3.3.4 
Rationale for Rituximab Plus Gemcitabine Plus 
Oxaliplatin as the Control Therapy and for its 
Dose and Schedule ............................................................... 65 
3.3.5 
Rationale for Biomarker Assessments ................................... 66 

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3.3.6 
Rationale for the Functional Assessment of 
Cancer Therapy/Gynecologic Oncology Group-
Neurotoxicity 12-Item Scale (FACT/GOG-NTX-
12) ......................................................................................... 67 
3.3.7 
Rationale for EQ-5D-5L, EORTC QLQ-C30 and 
FACT-Lym Patient-Reported Outcome 
Assessments ......................................................................... 68 
3.3.8 
Rationale for the Independent Data Monitoring 
Committee ............................................................................. 68 
4. 
MATERIALS AND METHODS .................................................................... 69 
4.1 
Patients .................................................................................. 69 
4.1.1 
Inclusion Criteria .................................................................... 69 
4.1.2 
Exclusion Criteria ................................................................... 71 
4.2 
Method of Treatment Assignment .......................................... 73 
4.3 
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 74 
4.3.1 
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 74 
4.3.1.1 
Polatuzumab Vedotin ............................................................ 74 
4.3.1.2 
Rituximab ............................................................................... 75 
4.3.1.3 
Gemcitabine .......................................................................... 75 
4.3.1.4 
Oxaliplatin .............................................................................. 75 
4.3.2 
Study Treatment Dosage, Administration, and 
Compliance ............................................................................ 75 
4.3.2.1 
Polatuzumab Vedotin ............................................................ 76 
4.3.2.2 
Rituximab ............................................................................... 77 
4.3.2.3 
Gemcitabine .......................................................................... 79 
4.3.2.4 
Oxaliplatin .............................................................................. 79 
4.3.3 
Investigational Medicinal Product Accountability ................... 79 
4.3.4 
Continued Access to Polatuzumab Vedotin, 
Rituximab, Oxaliplatin, and Gemcitabine ............................... 80 
4.4 
Concomitant Therapy ............................................................ 80 
4.4.1 
Permitted Therapy ................................................................. 80 
4.4.1.1 
Premedication Before Polatuzumab Vedotin ......................... 81 
4.4.1.2 
Premedication Before Rituximab ........................................... 81 

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4.4.1.3 
Premedication for Patients at High Risk for 
Tumor Lysis Syndrome .......................................................... 81 
4.4.1.4 
Prophylaxis for Infections....................................................... 81 
4.4.1.5 
Treatment and Prophylaxis of Neutropenia ........................... 82 
4.4.1.6 
Monitoring and Treatment for Hepatitis B 
Reactivation ........................................................................... 82 
4.4.1.7 
Other Concomitant Medications ............................................ 83 
4.4.2 
Cautionary Therapy ............................................................... 83 
4.4.2.1 
Medications Given with Precaution due to Effects 
Related to Cytochrome P450 Enzymes ................................. 83 
4.4.2.2 
Herbal Therapies ................................................................... 84 
4.4.3 
Prohibited Therapy ................................................................ 84 
4.5 
Study Assessments ............................................................... 85 
4.5.1 
Informed Consent Forms and Screening Log ........................ 85 
4.5.2 
Medical History, Concomitant Medication, and 
Demographic Data ................................................................. 85 
4.5.3 
Physical Examinations ........................................................... 85 
4.5.4 
Vital Signs .............................................................................. 86 
4.5.5 
Assessment of the International Prognostic Index ................. 86 
4.5.6 
Assessment of Eastern Cooperative Oncology 
Group Performance Status .................................................... 86 
4.5.7 
Assessment of the Functional Assessment of 
Cancer Therapy/Gynecologic Oncology Group-
Neurotoxicity 12-Item Scale ................................................... 87 
4.5.8 
Tumor and Response Evaluations ......................................... 87 
4.5.9 
Laboratory, Biomarker, and Other Biological 
Samples ................................................................................. 88 
4.5.10 
Electrocardiograms ................................................................ 91 
4.5.11 
Clinical Outcome Assessment ............................................... 91 
4.5.11.1 
Data Collection Methods for Clinical Outcome 
Assessments ......................................................................... 92 
4.5.11.2 
Description of Clinical Outcome Assessments 
Instruments ............................................................................ 93 
4.6 
Treatment, Patient, Study, and Site 
Discontinuation ...................................................................... 94 
4.6.1 
Study Treatment Discontinuation ........................................... 94 

Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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4.6.2 
Patient Discontinuation from Study ........................................ 95 
4.6.3 
Study Discontinuation ............................................................ 96 
4.6.4 
Site Discontinuation ............................................................... 96 
5. 
ASSESSMENT OF SAFETY ....................................................................... 96 
5.1 
Safety Plan ............................................................................ 96 
5.1.1 
Risks Associated with Study Treatment................................. 97 
5.1.1.1 
Risks Associated with Polatuzumab Vedotin ......................... 97 
5.1.1.2 
Risks Associated with Rituximab ......................................... 100 
5.1.1.3 
Risks Associated with Gemcitabine and 
Oxaliplatin .......................................................................... 100 
5.1.1.4 
Risks Associated with Pola-R-GemOx and R-
GemOx Combination Therapy ............................................. 100 
5.1.2 
Management of Patients Who Experience 
Adverse Events ................................................................... 100 
5.1.2.1 
Dose Modifications .............................................................. 100 
5.1.2.2 
Dose Delays/Treatment Interruption .................................... 101 
5.1.2.3 
Management Guidelines ...................................................... 102 
5.2 
Safety Parameters and Definitions ...................................... 106 
5.2.1 
Adverse Events ................................................................... 106 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) .................................................................... 106 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................. 107 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters .............................................. 108 
5.3.1 
Adverse Event Reporting Period ......................................... 108 
5.3.2 
Eliciting Adverse Event Information ..................................... 108 
5.3.3 
Assessment of Severity of Adverse Events ......................... 109 
5.3.4 
Assessment of Causality of Adverse Events ....................... 109 
5.3.5 
Procedures for Recording Adverse Events .......................... 110 
5.3.5.1 
Infusion-Related Reactions .................................................. 110 
5.3.5.2 
Diagnosis versus Signs and Symptoms............................... 110 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events.................................................................................. 111 
5.3.5.4 
Persistent or Recurrent Adverse Events .............................. 111 

Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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5.3.5.5 
Abnormal Laboratory Values ............................................... 112 
5.3.5.6 
Abnormal Vital Sign Values ................................................. 112 
5.3.5.7 
Abnormal Liver Function Tests ............................................ 113 
5.3.5.8 
Deaths ................................................................................. 113 
5.3.5.9 
Preexisting Medical Conditions ............................................ 114 
5.3.5.10 
Lack of Efficacy or Worsening of Diffuse Large B-
Cell Lymphoma .................................................................... 114 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ........................ 114 
5.3.5.12 
Cases of Accidental Overdose or Medication 
Error..................................................................................... 115 
5.3.5.13 
Patient-Reported Outcome Data ......................................... 116 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor ........................................................ 116 
5.4.1 
Emergency Medical Contacts .............................................. 117 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ................... 117 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................. 117 
5.4.2.2 
Events That Occur after Study Drug Initiation ...................... 117 
5.4.3 
Reporting Requirements for Pregnancies ............................ 118 
5.4.3.1 
Pregnancies in Female Patients .......................................... 118 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ............... 118 
5.4.3.3 
Abortions ............................................................................. 119 
5.4.3.4 
Congenital Anomalies/Birth Defects .................................... 119 
5.5 
Follow-Up of Patients after Adverse Events ........................ 119 
5.5.1 
Investigator Follow-Up ......................................................... 119 
5.5.2 
Sponsor Follow-Up .............................................................. 120 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 120 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ............................................................... 120 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ..................... 121 
6.1 
Determination of Sample Size ............................................. 121 
6.2 
Summaries of Conduct of Study .......................................... 122 
6.3 
Summaries of Treatment Group Comparability ................... 122 

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6.4 
Efficacy Analyses ................................................................ 122 
6.4.1 
Primary Efficacy Endpoint .................................................... 122 
6.4.2 
Secondary Efficacy Endpoints ............................................. 123 
6.4.2.1 
Complete Response Rate .................................................... 123 
6.4.2.2 
Objective Response Rate .................................................... 124 
6.4.2.3 
Best Overall Response ........................................................ 124 
6.4.2.4 
Progression-Free Survival ................................................... 125 
6.4.2.5 
Duration of Response .......................................................... 125 
6.4.2.6 
Event-Free Survival ............................................................. 125 
6.4.2.7 
Patient-Reported Outcomes ................................................ 126 
6.5 
Safety Analyses ................................................................... 128 
6.6 
Pharmacokinetic Analyses ................................................... 129 
6.7 
Immunogenicity Analyses .................................................... 129 
6.8 
Biomarker Analyses ............................................................. 129 
6.9 
Subgroup Analyses ............................................................. 130 
................ 130 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 130 
7.1 
Data Quality Assurance ....................................................... 130 
7.2 
Electronic Case Report Forms ............................................. 131 
7.3 
Source Data Documentation ................................................ 131 
7.4 
Use of Computerized Systems ............................................ 132 
7.5 
Retention of Records ........................................................... 132 
8. 
ETHICAL CONSIDERATIONS .................................................................. 132 
8.1 
Compliance with Laws and Regulations .............................. 132 
8.2 
Informed Consent ................................................................ 133 
8.3 
Institutional Review Board or Ethics Committee .................. 134 
8.4 
Confidentiality ...................................................................... 134 
8.5 
Financial Disclosure ............................................................ 135 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 135 
9.1 
Study Documentation .......................................................... 135 
9.2 
Protocol Deviations .............................................................. 135 

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9.3 
Management of Study Quality ............................................. 135 
9.4 
Site Inspections ................................................................... 136 
9.5 
Administrative Structure....................................................... 136 
9.6 
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 136 
9.7 
Protocol Amendments ......................................................... 137 
10. REFERENCES ......................................................................................... 138 
 
 
LIST OF TABLES 
Table 1 
Efficacy of R-CHOP and EPOCH  Rituximab for First-Line 
Treatment of Diffuse Large B-Cell Lymphoma ............................ 38 
Table 2 
Efficacy of Polatuzumab Vedotin (Alone or in Combination) 
in Patients with DLBCL in Studies DCS4968g, GO27834, 
and GO29044 ............................................................................. 41 
Table 3 
Overview of Efficacy of Polatuzumab Vedotin in Combination 
with Bendamustine/Rituximab in Patients with DLBCL 
(Study GO29365) ........................................................................ 42 
Table 4 
Adverse Events Occurring in  20% of Patients Treated with 
Single-Agent Polatuzumab Vedotin, by Pooled Dose Cohorts 
and Histology, in Study DCS4968g ............................................. 44 
Table 5 
Adverse Events Occurring in  20% of B-Cell Lymphoma 
Patients Treated with Polatuzumab Vedotin Plus Rituximab 
in Study GO27834 ...................................................................... 45 
Table 6 
Summary of Peripheral Neuropathy in Patients with R/R 
DLBCL in the Safety Population of Study GO29365 ................... 47 
Table 7 
Efficacy of GemOx  Rituximab for Second-Line Treatment 
of B-Cell Lymphoma ................................................................... 48 
Table 8 
Objectives and Corresponding Endpoints: Safety Run-In  
(Stage 1) ..................................................................................... 51 
Table 9 
Objectives and Corresponding Endpoints: Randomized 
Controlled Trial (Stage 2) ............................................................ 52 
......................... 58 
......................... 60 
Table 12 
Biomarkers for Retrospective Exploratory Research (Stage 
2) ................................................................................................. 62 
Table 13 
Administration of First and Subsequent Infusions of 
Rituximab .................................................................................... 79 
Table 14 
 Guidelines for Management of Patients Who Experience 
Adverse Events ......................................................................... 102 
Table 15 
Management of Infusion-Related Symptoms: Rituximab and 
Polatuzumab Vedotin ................................................................ 105 

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Table 16 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE v5.0 ...................................... 109 
Table 17 
Causal Attribution Guidance ..................................................... 110 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 55 
Figure 2 
Safety Run-In Schema (Stage 1) ................................................ 57 
Figure 3 
Regimen in the Experimental Treatment Group: 
Polatuzumab Vedotin Plus Rituximab Plus Gemcitabine Plus 
Oxaliplatin ................................................................................... 75 
Figure 4 
Regimen in the Control Group: Rituximab Plus Gemcitabine 
Plus Oxaliplatin ........................................................................... 76 
 
 
LIST OF APPENDICES 
 
Appendix 1 
 Schedule of Activities: Safety Run-In (Stage 1) ....................... 143 
Appendix 2 Schedule of Activities: Randomized Controlled Trial (Stage 2) ...... 148 
Appendix 3 
 Schedule of Biomarker Samples: Randomized Controlled 
Trial (Stage 2) ........................................................................... 154 
Appendix 4 
 Schedule for Serum and Plasma Pharmacokinetic Samples: 
Safety Run-In (Stage 1) and RCT (Stage 2) ............................. 155 
Appendix 5 
 Lugano Response Assessment Criteria ................................... 156 
Appendix 6 
 Recommendations for the Use of White Blood Cell Growth 
Factors ...................................................................................... 161 
Appendix 7 
 Recommended Anaphylaxis Management .............................. 162 
Appendix 8 
 Eastern Cooperative Oncology Group Performance Status ..... 163 
Appendix 9 
 International Prognostic Index .................................................. 164 
Appendix 10 
 Functional Assessment of Cancer Therapy/Gynecologic 
Oncology Group-Neurotoxicity 12-Item Questionnaire .............. 165 
Appendix 11 
 Functional Assessment of Cancer Therapy–Lymphoma .......... 166 
Appendix 12 
 EuroQol Group 5-Dimension 5-Level Questionnaire ................ 169 
Appendix 13 
 European Organisation for Research and Treatment of 
Cancer Quality-of-Life Questionnaire:  EORTC QLQ-C30 ........ 172 
Appendix 14 
 Sampson’s Clinical Criteria for Diagnosing Anaphylaxis .......... 174 
Appendix 15  Investigational Medicinal Product and Non-Investigational 
Medicinal Product Designations (for Use in European 
Economic Area and United Kingdom) ...................................... 175 
 

 
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
Protocol MO40598, Version 8 
14 
PROTOCOL ACCEPTANCE FORM 
TITLE: 
A PHASE III, OPEN-LABEL, MULTICENTER, 
RANDOMIZED STUDY EVALUATING THE SAFETY 
AND EFFICACY OF POLATUZUMAB VEDOTIN IN 
COMBINATION WITH RITUXIMAB PLUS 
GEMCITABINE PLUS OXALIPLATIN (R-GEMOX) 
VERSUS R-GEMOX IN PATIENTS WITH 
RELAPSED/REFRACTORY DIFFUSE LARGE B-
CELL LYMPHOMA 
PROTOCOL NUMBER: MO40598 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2018-003727-10 
IND NUMBER: 
109409 
TEST PRODUCT: 
Polatuzumab vedotin (RO5541077; anti-CD79b-
VC‑MMAE; DCDS4501S) 
MEDICAL MONITOR: 
, Pharm.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor. 
 

 
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
Protocol MO40598, Version 8 
15 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, OPEN-LABEL, MULTICENTER, RANDOMIZED 
STUDY EVALUATING THE SAFETY AND EFFICACY OF 
POLATUZUMAB VEDOTIN IN COMBINATION WITH RITUXIMAB 
PLUS GEMCITABINE PLUS OXALIPLATIN (R-GEMOX) VERSUS 
R-GEMOX IN PATIENTS WITH RELAPSED/REFRACTORY 
DIFFUSE LARGE B-CELL LYMPHOMA 
PROTOCOL NUMBER: 
MO40598 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2018-003727-10 
IND NUMBER: 
109409 
TEST PRODUCT: 
Polatuzumab vedotin (RO5541077; anti-CD79b-VC-MMAE; 
DCDS4501S) 
PHASE: 
Phase III 
INDICATION: 
Relapsed/refractory diffuse large B-cell lymphoma 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
Study MO40598 will evaluate the safety and efficacy of polatuzumab vedotin in combination 
with rituximab, gemcitabine, and oxaliplatin (Pola-R-GemOx) compared to rituximab, 
gemcitabine, and oxaliplatin alone (R-GemOx) in patients with relapsed or refractory diffuse 
large B cell lymphoma (DLBCL).  Treatment will occur in two stages: 1) an initial safety run-in 
stage assessing Pola-R-GemOx; and 2) an RCT stage comparing Pola-R-GemOx versus 
R‑GemOx. 
Specific objectives and corresponding endpoints for each stage of the study are outlined in 
Synopsis Table 1 and Synopsis Table 2.  
 
Synopsis Table 1. 
Objectives and Corresponding Endpoints: Safety Run-In (Stage 1) 
Primary Safety Objective 
Corresponding Endpoints 
 
To evaluate the safety and tolerability 
of Pola-R-GemOx as a combination 
therapy 
 
Incidence, nature and severity of physical 
findings and AEs, with a specific focus on 
PN, according to the NCI CTCAE v5.0  
 
Secondary Safety Objectives 
Corresponding Endpoints 
 
To evaluate the safety and tolerability 
of Pola-R-GemOx as a combination 
therapy and to assess the 
immunogenicity of polatuzumab 
vedotin 
 
Incidence and assessment of PN, as 
measured by FACT/GOG‑NTX‑12 
 
Tolerability, as measured by dose 
interruptions, dose reductions and dose 
intensity 
 
Prevalence of ADAs at baseline and 
incidence of ADAs during the study 
 

 
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Secondary Efficacy Objective 
Corresponding Endpoints 
 
To evaluate the efficacy of 
Pola‑R‑GemOx 
 
CR, defined as the proportion of patients 
who achieve complete metabolic response 
based on PET-CT, according to Lugano 
2014 response criteria, at the end of 
treatment as determined by the investigator 
 
ORR, defined as the proportion of patients 
who achieve complete or partial metabolic 
responses, according to Lugano 2014 
response criteria, at end of treatment as 
determined by the investigator 
 
BOR, defined as the best response while on 
study, according to Lugano 2014 response 
criteria, as determined by the investigator 
 
PFS, defined as the time from enrollment to 
the first occurrence of disease progression 
as determined by the investigator according 
to Lugano 2014 response criteria or death 
from any cause  
 
OS, defined as time from enrollment to 
death from any cause 
 
EFSeff, defined as time from enrollment to the 
earliest occurrence of the below cases: 
- 
Disease progression or relapse  
- 
Death due to any cause 
 
Initiation of any NALT 
Exploratory Pharmacokinetic 
Objective 
Corresponding Endpoints 
 
To further evaluate the PK of 
polatuzumab vedotin  
 
 
PK of polatuzumab vedotin in combination 
with R-GemOx in patients with relapsed or 
refractory DLBCL 
AE  adverse event; ADA  anti-drug antibody; BOR  best overall response; CR  complete 
response; DLBCL   diffuse large B-cell lymphoma; EFSeff   event-free survival; 
FACT/GOG‑NTX‑12   Functional Assessment of Cancer Therapy/Gynecologic Oncology 
Group-Neurotoxicity 12-Item Scale; NALT  non-protocolspecified anti-lymphoma treatment; 
NCI CTCAE v5.0  National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0; ORR  objective response rate; OS  overall survival; PET-CT   positron emission 
tomography-computed tomography; PFS  progression-free survival; PK  pharmacokinetics; 
PN  peripheral neuropathy; Pola-R-GemOx  polatuzumab vedotin, rituximab, gemcitabine, and 
oxaliplatin; R‑GemOx  rituximab plus gemcitabine plus oxaliplatin. 
 
 

 
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Synopsis Table 2. 
Objectives and Corresponding Endpoints: Randomized Controlled 
Trial (Stage 2) 
Primary Efficacy Objective 
Corresponding Endpoint 
 
To evaluate the efficacy of 
Pola‑R‑GemOx compared with 
R‑GemOx alone 
 
 
OS, defined as time from randomization to 
death from any cause 
Secondary Efficacy Objective 
Corresponding Endpoints 
 
To evaluate the efficacy of 
Pola‑R‑GemOx compared with 
R‑GemOx alone 
Key secondary endpoints included in the 
hierarchical testing procedure: 
 
PFS, defined as the time from randomization 
to the first occurrence of disease 
progression, as determined by the 
investigator according to Lugano 2014 
response criteria, or death from any cause 
 
CR, defined as the proportion of patients 
who achieve complete metabolic response 
based on PET-CT, according to Lugano 
2014 response criteria, at the end of 
treatment as determined by an IRC 
 
ORR, defined as the proportion of patients 
who achieve complete or partial metabolic 
responses, based on PET-CT according to 
Lugano 2014 response criteria, at the end of 
treatment as determined by an IRC 
Secondary endpoints that will not be adjusted for 
testing multiplicity: 
 
BOR, defined as the best response while on 
study, according to Lugano 2014 response 
criteria, as determined by the investigator 
 
CR, defined as the proportion of patients 
who achieve complete metabolic response 
based on PET-CT, according to Lugano 
2014 response criteria, at the end of 
treatment as determined by the investigator 
 
ORR, defined as the proportion of patients 
who achieve complete or partial metabolic 
responses, according to Lugano 2014 
response criteria, at the end of treatment as 
determined by the investigator 
 
DOR, defined as the time from the first 
occurrence of a documented objective 
response to disease progression, as 
determined by the investigator according to 
Lugano 2014 response criteria, or death from 
any cause, whichever occurs first 
 
EFSeff, defined as time from randomization to 
the earliest occurrence of the below cases: 
- 
Disease progression or relapse  
- 
Death due to any cause 
 
Initiation of any NALT 
 

 
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Secondary PRO Objective 
Corresponding Endpoint 
 
To evaluate impact of treatment and 
disease on aspects of health-related 
quality of life 
 
Time to deterioration in physical functioning 
and fatigue as measured by the 
EORTC QLQ‑C30 
 
Time to progression in lymphoma symptoms 
as measured by the FACT-Lym subscale 
 
Change from baseline in PN as measured by 
the FACT/GOG-NTX-12 subscale score 
 
Safety Objective 
Corresponding Endpoints 
 
To evaluate the safety and 
tolerability of Pola-R-GemOx 
compared with R-GemOx and to 
assess the immunogenicity of 
polatuzumab vedotin 
 
Incidence, nature, and severity of AEs 
(including PN) according to 
NCI CTCAE v5.0 and physical findings 
 
Tolerability, as assessed by dose 
interruptions, dose reductions and dose 
intensity 
 
Prevalence of ADAs at baseline and 
incidence of ADAs during the study 
 
Exploratory Biomarker Objectives 
Corresponding Endpoints 
 
To identify biomarkers that: 
- 
Are prognostic of response to 
polatuzumab vedotin 
(i.e., predictive biomarkers)  
- 
Are associated with progression to 
a more severe disease 
(i.e., prognostic biomarkers) 
- 
Can provide evidence of 
polatuzumab vedotin activity, or 
can increase the knowledge and 
understanding of disease biology 
 
To explore MRD as a prognostic 
marker in R/R DLBCL 
 
 
Associations between efficacy endpoints, 
including OS, PFS and CR rate, and 
exploratory biomarkers, which may include 
but are not limited to histological and 
molecular prognostic markers and profiles of 
circulating immune 
Exploratory Pharmacokinetic 
Objective 
Corresponding Endpoints 
 
To further evaluate the PK of 
polatuzumab vedotin  
 
 
PK of polatuzumab vedotin in combination 
with R-GemOx in patients with relapsed or 
refractory DLBCL 
Exploratory PRO Objectives 
Corresponding Endpoints 
 
To evaluate impact of treatment and 
disease on aspects of health-related 
quality of life 
 
Descriptive summary statistics and the 
change from baseline for: 
- 
All scales for the EORTC QLQ-C30 
- 
FACT-Lym subscale 
- 
FACT/GOG-NTX-12 
- 
EQ-5D-5L 
 
AE  adverse event; ADA  anti-drug antibody; BOR  best overall response; CR  complete 
response; DLBCL   diffuse large B-cell lymphoma; DOR  duration of response; EFSeff   event-
free survival; EORTC QLQ-C30  European Organisation for Research and Treatment of 
Cancer Quality-of-Life Questionnaire, Core 30; EQ-5D-5L  EuroQol 5-Dimension 

 
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Treatment Period 
The Treatment Period will occur in two stages.  Stage 1 will comprise a safety run-in, where 
approximately 10 patients will receive experimental study treatment with Pola-R-GemOx.  The 
purpose of Stage 1 is to provide a preliminary safety assessment of the study treatment, prior to 
entering Stage 2 of the study.  Stage 2 will comprise an RCT, where approximately 250 patients 
will be randomly assigned in a 1:1 ratio to receive either experimental study treatment with Pola-
R-GemOx or control study treatment with R-GemOx.  In both stages of the Treatment Period, 
patients will receive up to 8 cycles of Pola-R-GemOx or 8 cycles of R-GemOx, each 
administered on 21‑day cycles.  Dosing regimens are described in detail in Section 4.3.2.  Dose 
delays/reductions will be permitted, as detailed in the protocol (Section 5.1.2).  
 
Stage 1: Safety Run-In (Figure 2)  
 
At a limited number of sites (approximately 18 centers), approximately 13 patients will be 
treated with Pola-R-GemOx 
 
Accrual of these patients will be staggered across three cohorts until the number of 
evaluable patients required for each cohort (mentioned below) is reached.  Evaluable 
patients are patients who complete at least 4 cycles of treatment or are discontinued 
because of Grade  3 PN: 
– 
Cohort 1: 3 evaluable patients 
– 
Cohort 2: 3 evaluable patients 
– 
Cohort 3: 4 evaluable patients 
Approximately 7 patients will be recruited in Cohort 3, with the aim of having at 
least 4 evaluable patients. 
 
Cohort 2 and Cohort 3 will not begin enrolling patients until all safety evaluations have been 
completed in Cohort 1 and Cohort 2, respectively, and recruitment of the next cohort has 
been approved (see below for how approval occurs).  Patients who discontinue prior to 
Cycle 4 of treatment due to disease progression, death or any other reason that is not 
directly attributable to PN will be replaced until the required number of evaluable patients is 
reached. 
 
Once 3 evaluable patients from Cohort 1 complete 4 cycles or discontinue because of 
Grade  3 PN, the IMC, in collaboration with the Steering Committee (SC) (if necessary), will 
evaluate the total safety profile of Pola‑R‑GemOx, with a particular focus on PN.  They will 
then approve or disapprove enrollment into the next cohort.  This recommendation will be 
released to the Sponsor responsible.  Cohort 2 will follow the same process. 
 
 
 
In addition to the above, all patients from previous cohorts who proceeded beyond the 
fourth cycle of therapy will be re-evaluated by the IMC to assess the potential of cumulative 
neurotoxicity with Pola-R-GemOx, as well as the course of PN resolution. 
 

 
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 
 
 
 
 
 

 
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 
 
 
The objectives and endpoints of the two stages are provided in Section 2. Safety will be 
assessed by adverse events per NCI CTCAE v5.0, patient-reported FACT/GOG‑NTX‑12 score 
(Stage 1), clinical laboratory test results, ECG, and vital signs.  Response assessments will be 
according to Lugano 2014 criteria, based on positron emission tomography–computed 
tomography (PET-CT) scans at screening and the end of treatment.  All response assessments 
will be carried out by the investigator.  In addition, the secondary outcomes of objective 
response rate (ORR) and CR rate in Stage 2 will be assessed by an Independent Review 
Committee, based on primary imaging data collected by the Sponsor. 
Stage 1 and Stage 2 of the Treatment Period will also assess anti-drug antibodies (ADAs) and 
the sparse pharmacokinetic (PK) profile of polatuzumab vedotin in combination with R-GemOx.  
Stage 2 of the Treatment Period will also assess biomarkers (as per Synopsis Table 5) and 
additional patient-reported outcomes (EuroQol 5‑Dimension Questionnaire, 5‑Level Version 
[EQ-5D-5L], FACT/GOG-NTX-12, Functional Assessment of Cancer TherapyLymphoma 
[FACT-Lym], and EORTC QLQ‑C30). 

 
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Synopsis Table 5  
Biomarkers for Retrospective Exploratory Research (Stage 2) 
Sample Type 
Timing (All Mandatory) 
Proposed Biomarkers 
DLBCL tumor tissue 
(fresh or archival) 
Baseline 
 RNA-based gene expression 
profiling, including but not 
limited to cell-of-origin gene 
signature analysis 
 IHC and proteomic profiling, 
including BCL2 and MYC 
 Translocation profiles, 
including BCL2 and MYC 
 Mutation profiling by NGS, 
including but not limited to 
CD79b 
Blood for MRD assays 
Baseline, subsequent time 
points during treatment, and 
end of treatment (or 
discontinuation, whichever 
comes first) 
 ctDNA level and clonal 
mutation profile 
 ctDNA as a peripheral 
measure of disease biology, 
prognosis, subsets, and 
treatment response 
Blood for flow cytometry a 
Baseline, subsequent time 
points during treatment, and 
end of treatment (or 
discontinuation, whichever 
comes first) 
 Flow-cytometry–based 
profiling of circulating immune 
cells 
 To evaluate the prognostic 
value of patient immune 
fitness and investigate the 
effect of treatment regimen on 
circulating immune cells 
ctDNA  circulating tumor DNA; IHC  immunohistochemistry; NGS  next-generation sequencing; 
MRD  minimal residual disease. 
a The first 100 patients at selected sites will undergo flow cytometry. 
 
Post-Treatment Period 
Patients who complete study treatment per protocol (see Section 4.3.2) or discontinue from the 
study treatment early (e.g., if they terminated treatment early because of an adverse event) will 
enter the Post-Treatment Period, which will consist of an End of Treatment Visit occurring 
28 (  7) days after the last dose of study treatment and then a Long-term Follow-Up Period.  
Assessments carried out at the End of Treatment Visit and during the Long-term Follow-Up 
Period are described in the Schedules of Activities in Appendix 1, Appendix 2, Appendix 3, and 
Appendix 4.  
Patients in the Follow-Up Period will be assessed as follows via clinic visits, telephone calls, 
and/or patient medical records approximately every 2 months until death, loss to follow-up, or 
study termination by the Sponsor: 
 
Patients who complete treatment or discontinue all study treatment prematurely due to 
reasons other than disease progression will continue standard long-term follow-up 
assessments including required ADA sampling and radiographic assessments until 
disease progression and will be followed for NALT and survival. 
 
Patients who initiate NALT in the absence of progressive disease will continue to be 
followed for progression (including radiographic assessments), additional NALT, and 
survival. 
 
Patients with disease progression will be followed for NALT and survival. 
 

 
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Internal Monitoring Committee 
An IMC will be established to monitor patient safety during the safety run-in and provide 
recommendations on whether the next cohorts or RCT should open.  The IMC will include 
Sponsor representatives who are not associated with study conduct, at a minimum, 
representatives from Clinical Science, Safety Science and Biometrics.  The IMC will review all 
necessary cumulative data at regular intervals during the study.  The IMC will evaluate the total 
safety profile of Pola-R-GemOx, with a particular focus on PN.  Ad hoc meetings may be called 
in addition to scheduled meetings, as necessary, to provide recommendations on management 
of any new safety issues.  Specific operational details, such as the committee's composition, 
frequency and timing of meetings, and members' roles and responsibilities, will be detailed in an 
IMC Charter. 
 
Independent Data Monitoring Committee 
An iDMC will evaluate safety data periodically during the RCT (see Section 6.10).  The analysis 
supporting iDMC review will be conducted by an independent Data Coordinating Center (iDCC) 
and provided to the iDMC.  The iDMC will follow a charter that outlines the iDMC roles and 
responsibilities. 
The guidelines for safety monitoring and predefined stopping rules for treatment-related deaths, 
PN events, and treatment delays that lead to treatment discontinuation will be provided in the 
iDMC charter. 
Independent Review Committee 
An Independent Review Committee (IRC) composed of board-certified radiologists and an 
oncologist with experience in malignant lymphoma will assess all patients for response (see 
Appendix 5) until end of treatment on the basis of imaging results and bone marrow biopsy 
results for all patients during the RCT.  Decisions will be guided by a Charter specific to the 
independent review. 
 
Number of Patients 
Approximately 10 patients will be enrolled in the safety run-in phase, and approximately 
250 patients will be enrolled in the randomized portion, for a total of approximately 260 patients. 
 
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 
 
Ability to comply with the study protocol, in the investigator’s judgment 
 
Histologically-confirmed diffuse large B-cell lymphoma, not otherwise specified or history of 
transformation of indolent disease to DLBCL 
 
Relapsed or refractory disease, defined as follows: 
– 
Relapsed:  Disease that has recurred following a response that lasted  6 months from 
completion of the last line of therapy. 
– 
Refractory: Disease that did not respond to or that progressed during therapy or 
progressed within 6 months ( 6 months) of prior therapy. 
 
 
At least one ( 1) line of prior systemic therapy: 
– 
Patients may have undergone autologous HSCT prior to recruitment.  In such cases, 
salvage chemotherapy (e.g., rituximab, dexamethasone, cytarabine, and cisplatin 
[R-DHAP] and rituximab, ifosfamide, carboplatin, and etoposide phosphate [R-ICE]) 
will be counted as one line of therapy and conditioning chemotherapy (e.g., BEAM) 
followed by consolidative autologous HSCT will be counted as a separate line of 
therapy. 

 
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– 
Patients may have undergone allogeneic HSCT prior to recruitment, so long as they 
are off all immunosuppressive therapy and have no active GVHD.  In such cases, 
salvage chemotherapy (e.g., R-DHAP and R-ICE) will be counted as one line of 
therapy and conditioning chemotherapy (e.g., carmustine, etoposide, cytarabine, and 
melphalan [BEAM]) followed by allogeneic HSCT will be counted as a separate line of 
therapy. 
– 
Patients may have undergone CAR Tcell therapy prior to recruitment.  In such 
cases, cell collection, conditioning chemotherapy, and infusion will be counted as one 
line of therapy. 
– 
Local therapies (e.g., radiotherapy) will not be considered as lines of treatment. 
– 
For patients with history of transformation of indolent disease to DLBCL, it is 
preferred that patients have received at least one treatment for the transformed 
lymphoma.  However, if there are cases where the patient has received an 
anthracycline-containing chemotherapy regimen (such as R-CHOP) for the indolent 
lymphoma only, then these patients can be considered as. 
 
At least one bi-dimensionally measurable lesion, defined as  1.5 cm in its longest 
dimension as measured by computed tomography (CT) or magnetic resonance imaging 
(MRI) 
 
ECOG performance status of 0,1, or 2 
– 
Patients with an ECOG performance status of 3 can be considered in the RCT stage, 
but only if this status is DLBCL-related and if after a prephase of a 7-day steroid 
treatment during the screening phase (e.g., 1 mg/kg prednisone) an improvement in 
ECOG performance status to 2 or less is observed prior to enrolment. 
 
Adequate hematological function, as defined by: 
– 
Hemoglobin  8 g/dL  
– 
ANC  1.5  109/L or  0.5  109 if the neutropenia is attributable to underlying disease 
and before the administration of steroids 
– 
Platelet count  75  109/L or  50  109 if the thrombocytopenia is attributable to 
underlying disease 
 
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 contraceptive methods with a failure rate of  1% 
per year during the treatment period and for 12 months after the final dose of 
polatuzumab vedotin, rituximab, gemcitabine, or oxaliplatin.  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 
requirements. 
– 
Examples of 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. 
– 
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. 

 
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 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below 
(the patient should receive advice on the possibility of opting for cryoconservation of sperm 
prior to start of study treatment due to the possibility of irreversible infertility following 
therapy with gemcitabine, oxaliplatin, or polatuzumab vedotin): 
– 
With a female partner of childbearing potential who is not pregnant, men who are not 
surgically sterile must remain abstinent or 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 6 months after the final dose of polatuzumab vedotin, 
rituximab, oxaliplatin, and/or gemcitabine.  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 polatuzumab vedotin, 
rituximab, oxaliplatin, and/or gemcitabine 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. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
History of severe allergic or anaphylactic reactions to humanized or murine monoclonal 
antibodies (or recombinant antibody-related fusion proteins) or known sensitivity or allergy 
to murine products 
 
Contraindication to rituximab, gemcitabine, or oxaliplatin 
 
PN assessed to be Grade  1 according to NCI CTCAE v5.0 at enrollment 
 
Prior use of polatuzumab vedotin or a gemcitabine  platinum-based agent combination 
 
Enrollment in any previous or ongoing polatuzumab vedotin trial 
 
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. 
 
Planned autologous or allogeneic stem cell transplantation or CAR Tcell therapy at time 
of recruitment 
– 
Patients with only one prior therapy who are appropriate for stem cell transplantation 
are excluded from this trial.  Reasons for transplant-ineligibility may include age, 
performance status, comorbidities, transplant failure or failed procedure, insufficient 
response to salvage therapy, patient refusal, or logistical reasons. 
 
Primary or secondary CNS lymphoma at the time of recruitment 
 
Richter’s transformation or prior CLL 
 
Any of the following abnormal laboratory values, unless abnormal laboratory values are due 
to underlying lymphoma per the investigator: 
– 
Creatinine  1.5   upper limit of normal (ULN) or a measured creatinine clearance  30 
mL/min 
– 
AST or ALT  2.5 x 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 

 
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– 
PTT or aPTT  1.5  ULN in the absence of a lupus anticoagulant 
 
History of other malignancy that could affect compliance with the protocol or interpretation 
of results.  Exceptions include: 
– 
Patients with a history of curatively-treated basal or squamous cell carcinoma of the 
skin or in situ carcinoma of the cervix at any time prior to the study are eligible. 
– 
A patient with any other malignancy appropriately treated with curative intent and the 
malignancy has been in remission without treatment for  2 years prior to enrollment is 
eligible. 
– 
Patients with low-grade, early-stage prostate cancer (Gleason score 6 or below, 
Stage 1 or 2) with no requirement for therapy at any time prior to study are eligible. 
 
Evidence of significant, uncontrolled concomitant diseases that could affect compliance with 
the protocol or interpretation of results, including significant cardiovascular disease (such as 
New York Heart Association Class III or IV cardiac disease, myocardial infarction within the 
last 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary disease 
(including obstructive pulmonary disease and history of bronchospasm) 
 
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding 
fungal infections of nail beds) at study enrollment or any major episode of infection (as 
evaluated by the investigator) within 4 weeks prior to Cycle 1 Day 1 
 
Patients with suspected or latent tuberculosis 
– 
Latent tuberculosis needs to be confirmed by positive interferon-gamma release assay 
 
Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive 
hepatitis B surface antigen [HBsAg] serology) 
– 
Patients with occult or prior HBV infection (defined as negative HBsAg and positive 
hepatitis B core antibody [HBcAb]) may be included if HBV DNA is undetectable, 
provided that they are willing to undergo DNA testing on Day 1 of every cycle and 
monthly for at least 12 months after the last cycle of study treatment. 
 
Positive test results for hepatitis C virus (HCV) antibody 
– 
Patients who are positive for HCV antibody are eligible only if PCR is negative for HCV 
RNA. 
 
Known history of HIV seropositive status 
– 
For patients with unknown HIV status, HIV testing will be performed at Screening if 
required by local regulations. 
 
Vaccination with a live vaccine within 4 weeks prior to treatment 
 
Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) other than for 
diagnosis 
 
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 
render the patient at high risk from treatment complications 
 
Pregnant or breastfeeding, or intending to become pregnant during the study or within 
12 months after the last dose of study drug 
– 
Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to initiation of study drug. 
End of Study and Length of Study 
The end of this study is defined as the date when the last patient, last visit, occurs which will 
be the timepoint at which all patients enrolled in the study have either had at least 2  years of 
follow-up from the time of the treatment-completion visit or have discontinued the study.  The 
end of the study is expected to occur approximately 2.5 years after the last patient is enrolled. 
After an initial safety-run in, the randomized stage for recruitment is expected to occur over 
approximately 19 months. 

 
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This is an event-driven trial.  The clinical cut-off date for the primary OS analysis will be 
confirmed when the targeted number of mortality events 
deaths) have occurred, which is 
expected approximately
months after the first patient is randomized (first patient in) in the 
RCT stage of the study. 
In addition, the Sponsor may decide to terminate the study at any time. 
 
Investigational Medicinal Products 
The investigational medicinal product (IMP) for this study is Pola-R-GemOx.  The control 
therapy is R-GemOx. 
Polatuzumab Vedotin 
Polatuzumab vedotin 1.8 mg/kg will be administered intravenously on Day 1 of each 21-day 
cycle for up to 8 cycles.  Polatuzumab vedotin should be administered after rituximab on the 
same day or, in the event of a dose delay for rituximab, the following day (see below). 
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 is greater or less than 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 subsequent doses 
should be modified accordingly.  Dose adjustments for body weight changes  10% are also 
acceptable should this be local standard of care.  Due to limited clinical experience in patients 
treated with 1.8 mg/kg polatuzumab vedotin at a total dose  240 mg, it is recommended not to 
exceed a dose of 240 mg per cycle. 
The initial dose will be administered to patients who are well hydrated (as per local guidelines) 
over 90  10 minutes.  Premedication (e.g., 5001000 mg of oral acetaminophen or paracetamol 
and approximately 50100 mg diphenhydramine as per institutional standard practice) may be 
administered to an individual patient  30 minutes before starting administration of polatuzumab 
vedotin.  Administration of corticosteroids is permitted at the discretion of the treating physician.  
If infusion-related reactions (IRRs) are observed with the first infusion in the absence of 
premedication, premedication must be administered before subsequent doses. 
The polatuzumab vedotin infusion may be slowed or interrupted for patients experiencing 
infusion-associated symptoms.  Following the initial dose, patients will be observed for 90 
minutes for fever, chills, rigors, hypotension, nausea, or other infusion associated symptoms.  If 
prior infusions have been well tolerated, subsequent doses of polatuzumab vedotin may be 
administered over 30  10 minutes, followed by a 30-minute observation period after the 
infusion. 
During administration of polatuzumab vedotin, vital signs should be assessed before the start of 
the infusion, every 30  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. 
Please refer to the Pharmacy Manual for detailed instructions on administration of polatuzumab 
vedotin. 
 
Rituximab 
Rituximab (Mabthera/Rituxan®) 375 mg/m2 will be administered intravenously on Day 1 of each 
21-day cycle for up to 8 cycles.  Rituximab should be administered before polatuzumab vedotin 
on the same day; in the event of a dose delay for rituximab, polatuzumab vedotin may be 
administered on the following day. 
No dose modifications of rituximab are allowed. 
During the administration of rituximab in Cycle 1, vital signs are to be obtained before infusion, 
then after the start of the infusion, approximately every 30  5 minutes for 90 minutes, then 
every 30  10 minutes until 1 hour after the end of the infusion.  During administration of 
rituximab in subsequent cycles, vital signs are to be recorded before infusion, then after the 
start of infusion, and approximately every 30  10 minutes until 1 hour after the end of infusion. 
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 

 
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 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 Synopsis 
Table 6). 
All rituximab infusions should be administered to patients after premedication with oral 
acetaminophen (e.g., 5001000 mg) and an antihistamine such as diphenhydramine 
hydrochloride (e.g., 50100 mg)  30 minutes before starting each infusion (unless 
contraindicated).  An additional glucocorticoid (e.g., 100 mg IV prednisone or prednisolone or 
equivalent) is allowed at the investigator’s discretion.  For patients who did not experience 
infusion-related symptoms with their previous infusion, premedication at subsequent infusions 
may be omitted at the investigator’s discretion. 
Rituximab infusions will be administered according to the instructions in Synopsis Table 6.  
If a patient tolerates the first cycle of study treatment without significant infusion reactions, 
rituximab may be administered as rapid infusion in accordance with local institutional guidelines. 
During the treatment period, rituximab must be administered to patients in a setting where full 
emergency resuscitation facilities are immediately available.  Patients should be under close 
supervision of the investigator at all times.  For the management of IRRs and anaphylaxis, see 
Section 5.1.2. 
Rituximab should be administered as a slow IV infusion through a dedicated line.  IV infusion 
pumps (such as the Braun Infusomat Space) should be used to control the infusion rate of 
rituximab.  Administration sets with polyvinyl chloride (PVC), polyurethane (PUR), or 
polyethylene (PE) as a product contact surface and IV bags with polyolefine, polypropylene 
(PP), PVC, or PE as a product contact surface are compatible and can be used.  Additional in-
line filters should not be used because of potential adsorption.  The in-line filter used for the 
administration of polatuzumab vedotin should not be used for the administration of rituximab. 
After the end of the first infusion, the IV line or central venous catheter should remain in place 
for  2 hours in order to administer IV drugs if necessary.  If no adverse events occur after 2 
hours, the IV line may be removed or the central venous catheter may be de-accessed.  For 
subsequent infusions, the IV line or central venous catheter should remain in place for at least 1 
hour after the end of the infusion.  If no adverse events occur after 1 hour, the IV line may be 
removed or the central venous catheter may be de‑accessed. 
 

 
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Synopsis Table 6  
Administration of First and Subsequent Infusions of Rituximab 
First Infusion (Cycle 1 Day 1) 
Subsequent Infusions 
 
Begin infusion at an initial rate of 50 mg/hr 
 
If no infusion-related or hypersensitivity 
reaction occurs, increase the infusion rate 
in 50-mg/hr increments every 30 minutes, 
to a maximum of 400 mg/hr. 
 
If a reaction develops, stop or slow the 
infusion.  Administer medications and 
supportive care in accordance with 
institutional guidelines.  If the reaction 
resolves, resume the infusion at a 
50% reduction in rate (i.e., 50% of rate 
used at the time the reaction occurred). 
 
If the patient experienced an 
infusion-related or hypersensitivity 
reaction during the prior infusion, begin 
infusion at an initial rate of 50 mg/hr and 
follow instructions for first infusion. 
 
If the patient tolerated the prior infusion 
well (defined by absence of Grade 2 
reactions during a final infusion rate of 
 100 mg/hr), begin infusion at a rate of 
100 mg/hr. 
 
If no reaction occurs, increase the 
infusion rate in 100-mg/hr increments 
every 30 minutes, to a maximum of 400 
mg/hr. 
 
If a reaction develops, stop or slow the 
infusion.  Administer medications and 
supportive care in accordance with 
institutional guidelines.  If the reaction 
resolves, resume the infusion at a 50% 
reduction in rate (i.e., 50% of rate used 
at the time the reaction occurred). 
 
Gemcitabine 
Gemcitabine 1000 mg/m2 will be administered intravenously on Day 2 of each 21-day cycle for 
up to 8 cycles.  Gemcitabine should be administered before oxaliplatin on the same day.  In the 
event that rituximab dosing is split across two days, gemcitabine may be administered on Day 2 
(i.e., the same day rituximab dosing is completed) or on the following day (see Section 4.3.2.2. 
Dose modifications for gemcitabine are described in Section 5.1.2.1. 
The method of administering gemcitabine is described in the local prescribing information. 
Oxaliplatin 
Oxaliplatin 100 mg/m2 will be administered intravenously on Day 2 of each 21-day cycle for up 
to 8 cycles.  Oxaliplatin should be administered after gemcitabine on the same day.  In the 
event that rituximab dosing is split across two days, oxaliplatin may be administered on Day 2 
(i.e., the same day rituximab dosing is completed) or on the following day (see Section 4.3.2.2). 
Dose modifications for oxaliplatin are described in Section 5.1.2.1. 
The method for administering oxaliplatin is described in local prescribing information. 
 
Statistical Methods 
Primary Analysis 
The primary efficacy objective for the randomized part of this study is to evaluate the efficacy of 
Pola-R-GemOx compared with R-GemOx in patients with relapsed or refractory DLBCL on the 
basis of the following endpoint: 
 
OS, defined as the time from randomization to the death from any cause during the study 
 
The primary efficacy analysis will be completed on the ITT population, with patients grouped 
according to their treatment assigned at randomization. 
Data for patients without death will be censored at the date at which the patient was last known 
to be alive.  Otherwise, data will be censored at the date of randomization. 
Kaplan-Meier methodology will be used to estimate the OS for each treatment arm, and Kaplan-
Meier curves will be produced.  Overall survival will be compared between treatment arms by 
stratified logrank test.  The hazard ratio (HR) for death will be estimated using a stratified Cox 

 
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proportional hazards model; the stratification factors will be the same as the randomization 
stratification factors by IxRS.  The 95% confidence interval (CI) for the HR will be provided.  
Brookmeyer-Crowley methodology will be used to construct the 95% CI for the median OS for 
each treatment arm (Brookmeyer and Crowley 1982). 
The type I error () for this study is 0.05 (two-sided).  Further details will be included in the SAP. 
In case patients become eligible for HSCT and undergo a transplant (in their best interest), 
sensitivity analyses will be performed for OS and PFS to assess the impact this may have.  For 
this, patient data will be censored at the time of transplant. 
 
Determination of Sample Size 
The primary objective of the randomized part of this study is to evaluate the efficacy of Pola-R-
GemOx versus R-GemOx in patients with relapsed or refractory DLBCL as measured by OS.  
Assuming a median OS of 
 months in the R-GemOx arm and a randomization ratio of 1:1, 
 events are required to detect a between-group difference of 
 months in the median OS 
(HR  
) with 
 power and a 2-sided  of 
.  Based on the above statistical 
assumptions, and anticipating a recruitment period of approximately 19 months and a follow-up 
of 12 months after the last patient was randomized, a total of approximately 250 patients will be 
randomized, taking into account an estimated drop-out rate of 
. 
In addition, approximately 10 patients will be enrolled in the safety run-in stage. 
 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
aa-IPI 
age-adjusted International Prognostic Index 
ABC 
activated Bcell-like 
ADA 
anti-drug antibody 
ADC 
antibody-drug conjugate 
AE 
adverse event 
ASR 
age-standardized risk 
BCR 
B-cell receptor 
BEAM 
carmustine, etoposide, cytarabine, and melphalan 
BP 
blood pressure 
BR 
bendamustine plus rituximab 
BSA 
body surface area 
CHOP 
cyclophosphamide, doxorubicin, vincristine, and prednisone 
CLL 
chronic lymphocytic leukemia 
COO 
cell of origin 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRO 
contract research organization 
CT 
computed tomography 
ctDNA 
circulating tumor DNA 
DAR 
drug-to-antibody ratio 
DLBCL 
diffuse large B-cell lymphoma 
DOR 
duration of objective response 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EFSeff 
event-free survival 
EPOCH 
etoposide, prednisone, vincristine, cyclophosphamide, and 
doxorubicin 
EORTC QLQ-C30 
European Organisation for the Research and Treatment of 
Cancer Quality-of-Life Questionnaire, Core 30 
EQ-5D-5L 
EuroQol 5-Dimension Questionnaire, 5-Level Version 
EWB 
emotional well-being 
FACT-G 
Functional Assessment of Cancer Therapy–General 
Questionnaire 
FACT/GOG-NTX-12 
Functional Assessment of Cancer Therapy/Gynecologic 
Oncology Group-Neurotoxicity 12-Item Scale 

 
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Abbreviation 
Definition 
FACT-Lym 
Functional Assessment of Cancer Therapy–Lymphoma 
FDA 
Food and Drug Administration 
FPI 
first patient in 
FWB 
functional well-being 
GCB 
germinal center B-celllike 
G-CSF 
granulocyte colony-stimulating factor 
GemOx 
gemcitabine plus oxaliplatin 
GVHD 
graft versus host disease 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HBC 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQoL 
health-related quality of life 
HSCT 
hematopoietic stem cell transplantation 
ICH 
International Conference on Harmonisation 
iDMC 
independent Data Monitoring Committee  
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IPI 
International Prognostic Index 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRR 
infusion-related reaction 
IxRS 
interactive voice or Web-based response system 
LDH 
lactate dehydrogenase 
MAb 
monoclonal antibody 
MMAE 
mono-methyl auristatin E 
MRI 
magnetic resonance imaging 
NALT 
non-protocolspecified anti-lymphoma treatment 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE v5.0 
National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 5.0 
NGS 
next-generation sequencing 
NHL 
Non-Hodgkin lymphoma 
ORR 
objective response rate 
OS 
overall survival 
PE 
Polyethylene 
PEF 
peak expiratory flow 

 
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Abbreviation 
Definition 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PML 
progressive multifocal leukoencephalopathy 
PN 
peripheral neuropathy 
Pola-R-GemOx 
polatuzumab vedontin plus rituximab, gemcitabine, and 
oxaliplatin 
PP 
polypropylene 
PRO 
patient-reported outcome 
PUR 
polyurethane 
PVC 
polyvinyl chloride 
PWB 
physical well-being 
R-CHOP 
rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone 
RCT 
randomized controlled trial 
R-DHAP 
rituximab, dexamethasone, cytarabine, and cisplatin 
R-ICE 
rituximab, ifosfamide, carboplatin, and etoposide phosphate 
R-GemOx 
rituximab plus gemcitabine plus oxaliplatin 
R/R 
relapsed or refractory 
SC 
Steering Committee 
SmPC 
Summary of Product Characteristics from the European 
Medicines Agency 
SoC 
standard of care 
SWB 
social/family well-being 
TOI 
trial outcome index 
ULN 
upper limit of normal 

 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON RELAPSED/REFRACTORY DIFFUSE 
LARGE B-CELL LYMPHOMA 
Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in the 
world and the thirteenth most common cancer overall (Bray et al. 2018).  It is estimated 
that 509,590 new cases of NHL were diagnosed worldwide in 2018 (2.8% of total new 
cancer cases) and 248,724 people died of the disease (2.6% of total cancer-related 
deaths).  The age-standardized risks (ASRs) of newly diagnosed NHL across Northern, 
Southern, Eastern and Western Europe ranged from 280.1–363.5 per 
100,000 person‑years for males and 216.5–292.1 per 100,000 person-years for females.  
The ASRs of mortality from NHL across the same European regions were 118.4–171.0 
and 76.2–92.0 per 100,000 person years, respectively.  In the United States, it is 
estimated that 74,680 people were diagnosed with NHL in 2018 (incidence, 19.4 per 
100,000) and 19,910 patients died from the disease (National Cancer Institute 2018). 
NHL comprises a heterogeneous group of lymphoproliferative disorders but most 
commonly presents as a defect in B-lymphocytes.  Thus, the most common subtypes of 
NHL, all of B-cell origin, include diffuse large B-cell lymphoma (DLBCL; 32.5% of total 
NHL cases), chronic lymphocytic leukemia (CLL; 18.6%), follicular lymphoma (17.1%), 
marginal zone lymphoma (8.3%), and mantle cell lymphoma (4.1%) 
(Al‑Hamadani et al. 2015).  NHL can be divided into indolent and aggressive forms 
based on subtype. 
Originating from mature B-cells, DLBCL is an aggressive NHL with a median survival of 
 1 year in untreated patients (Rovira et al. 2015).  A majority of DLBCL cells express 
CD20, a membrane antigen that is important in cell cycle initiation and differentiation 
(Anderson et al. 1984).  Several genetic abnormalities have been identified in patients 
with DLBCL, including defects in BCL6 (35%–40%), BCL2 (translocation 15%, 
amplification 24%), and cMYC (15%). 
1.1.1 
First-Line Treatment of Diffuse Large B-Cell Lymphoma 
According to guidelines from the National Comprehensive Cancer Network (NCCN) 
(National Comprehensive Cancer Network 2018), first-line treatment of DLBCL in 
non-frail patients with adequate cardiovascular capacity should consist of the anti-CD20 
monoclonal antibody rituximab in combination with a multi-agent chemotherapy.  
Typically, the multi-agent chemotherapy is comprised of individual agents with 
non‑cross‑resistant mechanisms of action, e.g., cyclophosphamide, doxorubicin, 
vincristine and prednisone (CHOP), or etoposide, prednisone, vincristine, 
cyclophosphamide and doxorubicin (EPOCH).  Efficacy outcomes for rituximab  CHOP 
(R-CHOP) or EPOCH  rituximab in this setting are summarized in Table 1. 

 
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Table 1 
Efficacy of R-CHOP and EPOCH  Rituximab for First-Line 
Treatment of Diffuse Large B-Cell Lymphoma 
 
R-CHOP 
% (95% CI) 
CHOP 
% (95% CI) 
P-value 
LNH-98.5 Study a 
 
 
 
 
CR/CRu 
76 
63 
0.005 
 
2-year EFS b 
57 (50, 64) 
38 (32, 45) 
  0.001 
 
10-year PFS 
36.5 (29.7, 43.3) 
20.1 (14.6, 26.2) 
  0.0001 
 
2-year OS 
70 (63, 77) 
57 (50, 64) 
0.007 
 
10-year OS 
43.5 (36.4, 50.4) 
27.6 (21.4, 34.3) 
  0.0001 
 
EPOCH  Rituximab 
% (95% CI) 
 
 
MabThera International Trial c 
 
 
 
 
CR/CRu 
94 
– 
– 
 
5-year PFS 
79 (68, 87) 
– 
– 
 
10-year EFS 
47.8 (34.2, 61.4) 
– 
– 
 
5-year OS 
80 (69, 88) 
– 
– 
 
10-year OS 
63.6 (52.8, 74.4) 
– 
– 
CHOP  cyclophosphamide, doxorubicin, vincristine, and prednisone; CR  complete response; 
CRu  unconfirmed complete response; EFS  event-free survival; EPOCH  etoposide, 
prednisone, vincristine, cyclophosphamide, and doxorubicin; IPI  International Prognostic 
Index; PFS  progression-free survival; OS  overall survival; R-CHOP  rituximab, doxorubicin, 
vincristine, and prednisone. 
a (Coiffier et al. 2002; Coiffier et al. 2010). 
b An event was defined as disease progression or relapse, initiation of a new (unplanned) 
anticancer treatment (e.g., radiation therapy), or death from any cause without progression. 
c (Wilson et al. 2008; Purroy et al. 2015). NB:  Subjects treated median age 50 with majority 
low IPI). 
 
1.1.2 
Treatment of Relapsed/Refractory Diffuse Large B-Cell 
Lymphoma 
For patients who are not cured by first-line therapy, high-dose chemotherapy followed by 
autologous stem cell transplantation offers a second chance for long term remission.  
For relapsed or refractory (R/R) DLBCL patients who are not eligible for stem cell 
transplantation due to age, comorbidities or other factors, there are different treatment 
options including various chemoimmunotherapies (bendamustine/rituximab; rituximab 
plus gemcitabine plus oxaliplatin [R-GemOx]; gemcitabine, dexamethasone and cisplatin 
[GDP]).  These chemoimmunotherapies tend to be used with the goal of palliation rather 
than long-term survival.  Recently approved treatments in the relapsed/refractory setting 
include CAR-T therapies and polatuzumab vedotin in combination with 
bendamustine/rituximab. 

 
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Approximately half of patients with relapsed DLBCL fail to respond to second-line 
therapy because of refractory disease (Gisselbrecht et al. 2010), and a significant 
number are ineligible for aggressive therapy because of age or comorbidities.  
Furthermore, patients who either relapse after or are ineligible for stem cell 
transplantation because of refractory disease or frailty have poor outcomes.  Thus, a 
significant clinical need exists for new therapeutic approaches in patients with 
R/R DLBCL. 
1.1.3 
Prognostic Risk Groups 
Although there is currently no way to prospectively identify individual patients with NHL 
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 predictive of overall survival (OS) 
(International Non-Hodgkin's Lymphoma Prognostic Factors 1993) (Appendix 9): 
 
Age (  60 vs.  60 years) 
 
Serum lactate dehydrogenase (LDH, normal vs. elevated) level 
 
Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs. 2–4) 
 
Stage (I or II vs. III or IV) 
 
Extranodal-site involvement (0 or 1 vs. 2–4) 
 
The IPI defines four distinct prognostic subgroups depending on the number of negative 
prognostic factors at diagnosis.  Patients with DLBCL and 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 
(International Non-Hodgkin's Lymphoma Prognostic Factors 1993).  The aa-IPI is based 
on stage, serum LDH, and ECOG performance status and 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). 
1.2 
BACKGROUND ON POLATUZUMAB VEDOTIN 
1.2.1 
Polatuzumab Vedotin Mechanism of Action 
CD79b is a cell surface antigen that is expressed solely on mature B cells, except for 
plasma cells.  It is also expressed in a majority of Bcell-derived malignancies, including 
nearly all NHL and CLL samples tested (Dornan et al. 2009).  Antibodies bound to 
CD79b are rapidly internalized, which makes CD79b ideally suited for targeted delivery 
of cytotoxic agents (Polson et al. 2007; Polson et al. 2009). 

 
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Polatuzumab vedotin (DCDS4501A [liquid formulation] and DCDS4501S [lyophilized 
formulation]) is an antibody-drug conjugate (ADC) that contains a humanized 
immunoglobulin G1 anti-human CD79b monoclonal antibody (MAb; MCDS4409A) and a 
potent anti-mitotic agent, mono-methyl auristatin E (MMAE), linked through a protease 
labile linker, maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl. 
Mono-methyl auristatin E has a mechanism 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 of polatuzumab vedotin at the cell-surface epitope and 
internalization of the ADC by the targeted cell, MMAE is released after cleavage of the 
linker by lysosomal enzymes.  Mono-methyl auristatin E then binds to tubulin and 
disrupts the microtubule network, resulting in inhibition of cell division and cell growth 
(Doronina et al. 2003). 
Thus, therapy with polatuzumab vedotin takes advantage of the specific targeting 
capability of the antibody and the cytotoxic activity of MMAE, which has increased 
potency compared to vincristine.  It is hypothesized that the addition of 
polatuzumab vedotin to a standard anti-CD20 antibody plus chemotherapy regimen will 
provide enhanced efficacy and safety to patients with NHL. 
Refer to the Polatuzumab Vedotin Investigator's Brochure for further details on 
polatuzumab vedotin nonclinical studies. 
1.2.2 
Polatuzumab Vedotin Clinical Studies 
Polatuzumab vedotin is currently being investigated in patients with B-cell hematological 
malignancies in nine clinical trials, including one completed study (DCS4968g) and eight 
ongoing studies (GO27834, GO29044, GO29365, JO29138, GO29833, GO29834, 
BO29561, and GO39942).  These trials have evaluated or are evaluating 
polatuzumab vedotin as a single agent or in combination with rituximab and other 
anti‑cancer agents. 
Key objectives of the current study are to compare the safety and efficacy of 
polatuzumab vedotin in combination with R-GemOx versus R-GemOx alone in patients 
with relapsed or resistant DLBCL (see Section 1.3).  Data from earlier 
polatuzumab vedotin studies most relevant to the current study are summarized below. 
1.2.2.1 
Efficacy 
Data from Phase I Study DCS4968g, Phase II Study GO27834, and Phase Ib/II 
Study GO29044 showed that therapy with polatuzumab vedotinalone or in 
combination with either rituximab or rituximab plus cyclophosphamide, doxorubicin, and 
prednisoneresulted in significant anticancer responses in patients with relapsed or 
refractory B-cell lymphomas (Table 2; Polatuzumab Vedotin Investigator’s Brochure).  
This conclusion was confirmed and extended by recently published data from another 
Phase Ib/II study (GO29365), which directly assessed whether polatuzumab vedotin 

 
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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could enhance the efficacy of a standard rituximab-containing regimen (Table 3).  
Notably, the latter study found that the addition of polatuzumab vedotin to bendamustine 
plus rituximab (BR) significantly extended survival time relative to BR alone (median 
overall survival [95% CI]: 12.4 [9.0–NE] months vs. 4.7 [3.7–8.3] months) in patients with 
relapsed or refractory DLBCL, consistent with expectation and, thus, validation of the 
clinical rationale for polatuzumab vedotin. 
Table 2 
Efficacy of Polatuzumab Vedotin (Alone or in Combination) in 
Patients with DLBCL in Studies DCS4968g, GO27834, and 
GO29044 
 
DCS4968g 
GO27834 
GO29044 a 
Pola dose, mg/kg 
 1.8 
1.8 
2.4 
2.4 
2.4 
1.0–1.8 
Backbone 
– 
– 
– 
R 
R 
R-CHP 
BOR, n (%) 
 
 
 
 
 
 
 
n 
8 
4 
27 
1 
39 
50 
 
CR 
0 
0 
4 (14.8) 
0 
8 (20.5) 
38 (76.0) 
 
PR 
1 (12.5) 
2 (50.0) 
10 (37.0) 
1 (100) 
13 (33.3) 
7 (14.0) 
 
SD 
0 
1 (25.0) 
4 (14.8) 
0 
5 (12.8) 
0 (0.0) 
 
PD 
7 (87.5) 
1 (25.0) 
8 (29.6) 
0 
11 (28.2) 
3 (6.0) 
 
Missing 
0 
0 
1 (3.7) 
0 
2 (5.1) 
2 (4.0) 
PFS 
 
 
 
 
 
 
 
n 
– 
4 
27 
– 
39 
– 
 
Median (months) 
– 
4.6 
5.0 
– 
5.6 
– 
 
95% CI 
– 
(1.4–13.9) 
(2.3–6.8) 
– 
(4.3–12.8) 
– 
BOR  best overall response; BR  bendamustine, rituximab; CR  complete response; 
DLBCL  diffuse large B-cell lymphoma; PFS  progression-free survival; PD  progressive 
disease; pola  polatuzumab vedotin; PR  partial response; R  rituximab; R-CHP  rituximab, 
cyclophosphamide, doxorubicin, prednisone/prednisolone; SD  stable disease. 
a Patients had newly diagnosed or relapsed/resistant disease. 
 
 
 

 
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1.2.2.2 
Safety 
Adverse events (AEs) associated with polatuzumab vedotin as a single agent and in 
combination with rituximab are summarized in Table 4 and Table 5, respectively. 
Table 4 
Adverse Events Occurring in  20% of Patients Treated with 
Single-Agent Polatuzumab Vedotin, by Pooled Dose Cohorts and 
Histology, in Study DCS4968g 
Histology 
B-cell lymphoma a 
CLL 
ALL 
Dose cohort (mg/kg) 
 1.8 
n  17 b 
1.8 
n  6 
2.4 
n  45 
 1.8 
n  18 b 
n  86 
Adverse event 
 
 
 
 
 
 Neutropenia 
5 (29%) 
4 (67%) 
20 (44%) 
4 (22%) 
33 (38%) c 
 Diarrhea 
4 (24%)) 
3 (50%) 
20 (44%) 
5 (28%) 
32 (37%) 
 Pyrexia 
5 (29%) 
2 (33%) 
13 (29%) 
7 (39%) 
27 (31%) 
 Nausea 
5 (29%) 
3 (50%) 
16 (36%) 
2 (11%) 
26 (30%) 
 Peripheral sensory neuropathy 
5 (29%) 
4 (67%) 
17 (38%) 
0 
26 (30%) d 
 Fatigue 
7 (41%) 
3 (50%) 
5 (11%) 
5 (28%) 
20 (23%) 
 Anemia 
2 (12%) 
1 (17%) 
9 (20%) 
5 (28%) 
17 (20%) 
 Decreased appetite 
5 (29%) 
2 (33%) 
4 (9%) 
5 (28%) 
16 (19%) 
 Headache 
1 (6%) 
1 (17%) 
3 (7%) 
5 (28%) 
10 (12%) 
 Rash 
0 
1 (17%) 
6 (13%) 
4 (22%) 
11 (13%) 
 Constipation 
5 (29%) 
2 (33%) 
7 (16%) 
2 (11%) 
16 (19%) 
 Cough 
6 (35%) 
3 (50%) 
5 (11%) 
2 (11%) 
16 (19%) 
ALL  acute lymphoblastic leukemia; CLL  chronic lymphocytic leukemia; 
DLBCL  diffuse large B-cell lymphoma. 
Clinical cutoff: 25 February 2015. 
a Aggregated histology of diffuse large B-cell lymphoma, indolent B-cell lymphoma and 
Mantle cell lymphoma. 
b Aggregate of 0.1, 0.5 and 1.0 mg/kg dose cohorts for indolent B-cell lymphoma patients and 
0.1, 0.25, 0.5 and 1.0 mg/kg dose cohorts for DLBCL patients, 0.25, 0.5, 1.0, and 1.8 mg/kg 
for CLL patients. 
c Preferred terms:  neutropenia (n  33 [38%]) and febrile neutropenia (n  2 [2%]). 
d Preferred terms:  peripheral sensory neuropathy (n  26 [30%]), peripheral motor neuropathy 
(n  5 [6%]), and neuropathy peripheral (n  1 [1%]).  Overall resolved, including all 
Peripheral Neuropathy Preferred terms  35.8%. 
 
 

 
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Table 5 
Adverse Events Occurring in  20% of B-Cell Lymphoma Patients 
Treated with Polatuzumab Vedotin Plus Rituximab in 
Study GO27834 
Histology 
FL 
DLBCL 
Combined 
Treatment 
Pola-R 
Pola-R 
Pola-R 
Pola-R 
Pola dose (mg/kg) 
1.8 
n  20 
2.4 
n  20 
2.4 
n  39 
All  
n  79 
Adverse Event 
 
 
 
 
 
Fatigue 
13 (65%) 
12 (60%) 
23 (59%) 
48 (61%) 
 
Nausea 
11 (55%) 
11 (55%) 
14 (36%) 
36 (46%) 
 
Peripheral neuropathy 
6 (30%) 
13 (65%) 
14 (36%) 
33 (42%) a 
 
Diarrhea 
6 (30%) 
11 (55%) 
15 (39%) 
32 (41%) 
 
Peripheral sensory neuropathy 
11 (55%) 
8 (40%) 
9 (23%) 
28 (35%) b 
 
Neutropenia 
8 (40%) 
5 (25%) 
10 (26%) 
23 (29%) 
 
Decreased appetite 
4 (20%) 
5 (25%) 
12 (31%) 
21 (27%) 
 
Constipation 
5 (25%) 
5 (25%) 
9 (23%) 
19 (24%) 
 
Cough 
3 (15%) 
3 (15%) 
12 (31%) 
18 (23%) 
 
Arthralgia 
5 (25%) 
5 (25%) 
6 (15%) 
16 (20%) 
 
Asthenia 
0 
7 (35%) 
9 (23%) 
16 (20%) 
 
Pain in extremity 
4 (20%) 
5 (25%) 
7 (18%) 
16 (20%) 
 
Pyrexia 
6 (30%) 
3 (15%) 
7 (18%) 
16 (20%) 
 
Vomiting 
3 (15%) 
5 (25%) 
8 (21%) 
16 (20%) 
DLBCL  diffuse large B-cell lymphoma; FL  follicular lymphoma; Pola-R  polatuzumab 
vedotin combined with rituximab (375 mg/m2 q3w). 
Note:  Patients were treated for 17 cycles, until PD or unacceptable toxicity. 
Clinical cutoff:  21 April 2016. 
a Overall 18 patients (55%) reported at least one event resolved. 
b Overall 22 patients (79%) reported at least one event resolved. 
 
Peripheral neuropathy (PN) was assessed in Study GO29365 in patients with 
R/R DLBCL who received polatuzumab vedotin in combination with bendamustine and 
rituximab.  The overall incidence of PN in patients treated with pola-BR in Phase Ib/II 
combined was 40.0% (18/45 patients with 29 PN events) (see Table 6).  The most 
frequently reported PN event by preferred term in patients treated with pola-BR was 
neuropathy peripheral (9 patients) followed by peripheral sensory neuropathy 
(6 patients).  Six of the 18 patients with PN events had Grade 2 events (preferred terms:  
neuropathy peripheral (5 patients), peripheral sensory neuropathy, and muscular 
weakness (1 patient each).  No Grade  3 or serious events of PN were reported in 
patients with R/R DLBCL treated with pola-BR.  Ten of the 18 patients with R/R DLBCL 

 
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who had a PN event during treatment with pola-BR had a history of prior PN, and of 
these, 8 patients had ongoing Grade 1 PN at baseline. 
One patient discontinued all study treatments due to loss of muscle mass, reported as 
the preferred term muscle atrophy (Grade 1), which was included under the conservative 
analysis of PN using the wide SMQ for PN.  Polatuzumab vedotin dose was reduced in 
2 patients, in both cases due to Grade 2 PN.  In both cases, the event had resolved by 
the time of the clinical cutoff.  Overall, the PN events had resolved in 10/18 patients 
without the need, in most cases, for delays or any change in dose of study treatment. 
The median time to onset of PN in patients with R/R DLBCL treated with pola-BR was 
1.8 months (0.0–4.9 months), and the median time to resolution was 1.2 months 
(0.022.4 months). 
In the randomized Phase II, the incidence of all grade PN events was higher in the 
pola-BR arm compared to the BR arm (43.6% [17/39 patients with 26 events] vs. 
7.7% [3/39 patients with 4 events]).  The PN events reported in the BR arm were 
Grade 2 neuralgia, PN, muscular weakness, and decreased vibratory sense. 
Based on these and other safety data, PN (both serious and non-serious) and 
neutropenia (both serious and non-serious) have been identified as potential risks of 
polatuzumab vedotin treatment. 

 
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Table 6 
Summary of Peripheral Neuropathy in Patients with R/R DLBCL 
in the Safety Population of Study GO29365 
Study Phase 
Phase Ib 
Phase II (randomized) 
Phase Ib/II 
Treatment 
Pola  BR 
BR 
Pola  BR 
Pola  BR 
(total) 
Sample size 
N  6 
N  39 
N  39 
N  45 
Total no. of PN events 
3 
4 
26 
29 
Patients with at least one: 
 
 
 
 
any grade PN event 
1 (16.7%) 
3 (7.7%) 
17 (43.6%) 
18 (40.0%) 
Grade 2 PN event 
0 
2 (5.1%) 
6 (15.4%) 
6 (15.4%) 
Serious PN event 
0 
0 
0 
0 
PN event leading to any study 
drug discontinuation 
0 
0 
1 (2.6%) 
1 (2.2%) 
PN event leading to any study 
drug reduction 
0 
0 
2 (5.1%) 
a 
2 (4.4%)
a 
PN event leading to any study 
drug interruption 
0 
0 
2 (5.1%)
a 
2 (4.4%)
a 
BR  bendamustine and rituximab; DLBCL   diffuse large B-cell lymphoma; PN  peripheral 
neuropathy; pola   polatuzumab; R/R  relapsed/refractory. 
Note:  Analyses of PN events were based on all preferred terms captured under the standardized 
MedDRA query “Peripheral Neuropathy [wide]” (20000034w). 
Notes:  PN event categories with  10% difference between pola  BR and BR arms in the 
randomized Phase II are shown in bold and underlined. 
a  Polatuzumab vedotin dose was reduced and bendamustine and rituximab dose was delayed in 
2 patients. 
 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
The clinical development program for polatuzumab vedotin is based on the hypothesis 
that adding an anti-CD79b antibody to a standard regimen of anti-CD20 antibody 
(rituximab) plus chemotherapy will provide enhanced efficacy in patients with 
B‑cell lymphomas.  Prior clinical studies have supported this hypothesis 
(see Section 1.2.2 and the Polatuzumab Vedotin Investigator’s Brochure).  For instance, 
Study GO29365 directly compared polatuzumab vedotin plus BR to BR alone in patients 
with R/R DLBCL.  Results showed that the addition of polatuzumab vedotin significantly 
improved objective response, PFS and, most notably, survival.  Thus, early studies have 
validated the overall rationale for polatuzumab vedotin in the treatment of B-cell 
malignancies and encourage further studies on this potentially important therapeutic 
antibody. 
Central to the development of polatuzumab vedotin as a clinical agent is assessment of 
its efficacy and safety profiles when used in combination with other 
rituximab‑chemotherapy regimens.  Consistent with its favorable 
NCCN recommendation (National Comprehensive Cancer Network 2018), gemcitabine 
plus oxaliplatin (GemOx)  rituximab is one such second-line treatment for DLBCL and 

 
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one that is commonly used in the clinic.  Efficacy outcomes for GemOx  rituximab 
(R‑GemOx) in relapsed or refractory DLBCL are summarized in Table 7. 
Table 7 
Efficacy of GemOx  Rituximab for Second-Line Treatment of 
B-Cell Lymphoma 
 
R-GemOx 
% (95% CI) 
GemOx 
% (95% CI) 
El Gnaoui et al. a 
 
 
 
2-year PFS 
62 (44, 81) 
 
 
2-year EFS 
43 (27, 60) 
 
 
2-year OS 
66 (50, 82) 
 
Lopez et al. b 
 
 
 
ORR 
43 
 
 
 
CR 
34 
 
 
 
PR 
9 
 
 
1-year PFS 
29 (12, 46) 
 
 
1-year OS 
41 (22, 60) 
 
Mounier et al. c 
 
 
 
5-year PFS 
13 (5, 24) 
 
 
5-year OS 
14 (6, 26) 
 
Corazzelli et al. d 
 
 
 
3.5-year FFS 
28 (9, 47) 
7 (0, 16) 
 
3.5-year OS 
37 (20, 55) 
7 (0, 16) 
aa-IPI  age-adjusted International Prognostic Index; CR  complete response; DLBCL  diffuse 
large B-cell lymphoma; EFS  event-free survival; FFS  failure-free survival; 
GemOx  gemcitabine plus oxaliplatin; IPI  International Prognostic Index; ORR  objective 
response rate; OS  overall survival; PFS  progression-free survival; PR  partial response. 
R‑GemOx  rituximab, gemcitabine, and oxaliplatin. 
a Includes patients with DLBCL, follicular cell lymphoma, and mantle cell lymphoma 
(El Gnaoui et al. 2007). 
b Only includes patients with DLBCL; 69% of patients had an aa-IPI of 2 or 3; median 
follow-up   13 (95% CI: 5 to 25) months (Lopez et al. 2008). 
c Only includes patients with DLBCL; 71% of patients had IPI  2 at baseline 
(Mounier et al. 2013). 
d Includes patients with DLBCL, follicular cell lymphoma, and mantle cell lymphoma 
(Corazzelli et al. 2009). 
 
As with other treatments in this setting, data from Table 7 demonstrates that R-GemOx 
provides encouraging efficacy in patients with relapsed or refractory DLBCL.  
Nonetheless, a high percentage of patients still fails to respond to the combination.  It 
therefore becomes of significant interest to assess whether the addition of 

 
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polatuzumab vedotin to R-GemOx can provide additional efficacy in a safe and tolerable 
fashion in patients with relapsed or refractory DLBCL. 
To address this issue, Study MO40598 will be a phase III, multicenter, open-label, 
randomized controlled trial comparing experimental therapy, polatuzumab vedontin plus 
R-GemOx (Pola-R-GemOx), versus control therapy, R-GemOx, in patients with relapsed 
or refractory DLBCL.  A total of approximately 250 patients will be enrolled, allowing for 
the detection of a between-group difference of 
 months in the median OS (hazard 
ratio [HR] 
), with 
 power and a two-sided  of 
 (see Section 6.1 for 
assumptions underlying sample size estimations).  R-GemOx will be administered under 
standard clinical conditions as described in local prescribing information so that 
potentially positive results from this trial can be applied in the future to standard clinical 
practice. 
Because this is the first study to assess the Pola-R-GemOx combination, particular 
attention will be paid to addressing potential safety concerns for enrolled patients.  As 
described in Section 1.2.2, PN (both serious and non-serious) has been identified as a 
risk of polatuzumab vedotin treatment.  This risk could be especially relevant in the 
current trial, as 30% to 40% of patients treated with oxaliplatin, one of the agents in the 
GemOx backbone, may also experience PN during and following treatment (Johnson et 
al. 2015).  In addition to chronic neurotoxicities (Shahriari-Ahmadi et al. 2015), oxaliplatin 
may cause transient acute neuropathic pain, manifesting as cold-induced dysesthesia in 
the hands, face, and oral cavity (Staff et al. 2017).  See Section 5.1.1.3 (Risks 
Associated with Gemcitabine and Oxaliplatin) for further information regarding 
oxaliplatin-associated PN. 
Study MO40598 has a number of design features that address this potential PN risk.  
These include: 
 
Patients with baseline PN greater than Grade 1, as assessed by National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 5.0 
(NCI CTCAE v5.0), will be excluded from enrollment. 
 
The study will have a safety run-in stage with a particular focus on PN as described 
in Section 3.1. 
 
Per current guidance (Polatuzumab Vedotin Investigator’s Brochure), treatment with 
polatuzumab vedotin will be limited to 8 cycles of therapy to minimize risk for the 
potential development of PN. 
 
Polatuzumab vedotin will be administered at 1.8 mg/kg, which is the recommended 
dose (Polatuzumab Vedotin Investigator’s Brochure). 
 
Appropriate guidance for managing Grade  2 PN events, which includes an initial 
dose delay and subsequent mandatory reduction, is provided in the protocol. 
 
To further confirm the safety profile of Pola-R-GemOx, Study MO40598 has specific 
objectives to assess PN among the participants, based on the Functional Assessment of 

 
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Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity Subscale (FACT/GOG-
NTX-12; see Section 3.3.6) (Calhoun et al. 2003; Huang et al. 2007). 
Clinical studies on polatuzumab vedotin have also identified neutropenia (both serious 
and non-serious) as another potential risk of polatuzumab vedotin therapy.  In an effort 
to manage this risk in Study MO40598, investigators will monitor absolute neutrophil 
counts throughout the Treatment Period (see Appendix 1 and Appendix 2).  Any patient 
who develops new or worsening neutropenia will be managed as described in 
Section 4.4.1.5 and Section 5.1, which may include dose modification or discontinuation.  
Treatment for emergent neutropenia will be in accordance with local guidelines and 
protocol; prophylactic and therapeutic administration of granulocyte colony-stimulating 
factors will be required as per protocol and standard of care.  Any signs of infection will 
be managed immediately, as appropriate. 
Beyond the prior strategies for monitoring and managing adverse events of special 
interest (PN and neutropenia), several additional steps will be taken to ensure the safety 
of participants in Study MO40598.  First, eligibility criteria have been chosen judiciously 
to select for an appropriate study population that is most likely able to tolerate study 
treatment.  Second, administration of all study treatments will be performed in a 
monitored setting where there is immediate access to trained personnel and adequate 
equipment and medicine to manage potentially serious reactions.  (Section 4.3).  Third, 
adverse events will be closely monitored throughout the study (Section 5.1.1 and 
Section 5.1.2).  Finally, the study will have an Internal Monitoring Committee (IMC) 
during the safety run-in stage and an independent Data Monitoring Committee (iDMC) 
during the randomized controlled trial (RCT) stage to assess safety signals on an 
ongoing basis. 
With the above safety precautions in place, risks potentially associated with study 
treatment will be managed carefully in Study MO40598.  Thus, given the strong clinical 
need for better therapies in the setting of relapsed or refractory DLBCL 
(see Section 1.1.2), it is deemed that comparing the benefits of Pola-R-GemOx 
combination therapy to current standard of care (R-GemOx) outweigh the risks in this 
study. 
2. 
OBJECTIVES AND ENDPOINTS 
Study MO40598 will evaluate the safety and efficacy of polatuzumab vedotin in 
combination with rituximab, gemcitabine, and oxaliplatin (Pola-R-GemOx) compared to 
rituximab, gemcitabine, and oxaliplatin alone (R-GemOx) in patients with relapsed or 
refractory DLBCL.  Treatment will occur in two stages: 1) an initial safety run-in stage 
assessing Pola-R-GemOx; and 2) an RCT stage comparing Pola-R-GemOx versus 
R‑GemOx. 

 
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Specific objectives and corresponding endpoints for each stage of the study are outlined 
in Table 8 and Table 9. 
Table 8 
Objectives and Corresponding Endpoints: Safety Run-In  
(Stage 1) 
Primary Safety Objective 
Corresponding Endpoints 
 
To evaluate the safety and tolerability of 
Pola-R-GemOx as a combination 
therapy 
 
Incidence, nature and severity of physical 
findings and AEs, with a specific focus on PN, 
according to the NCI CTCAE v5.0  
 
Secondary Safety Objectives 
Corresponding Endpoints 
 
To evaluate the safety and tolerability of 
Pola-R-GemOx as a combination 
therapy and to assess the 
immunogenicity of polatuzumab vedotin 
 
Incidence and assessment of PN, as 
measured by FACT/GOG‑NTX‑12 
 
Tolerability, as measured by dose 
interruptions, dose reductions and dose 
intensity 
 
Prevalence of ADAs at baseline and incidence 
of ADAs during the study 
 
Secondary Efficacy Objective 
Corresponding Endpoints 
 
To evaluate the efficacy of 
Pola‑R‑GemOx 
 
CR, defined as the proportion of patients who 
achieve complete metabolic response based 
on PET-CT, according to Lugano 2014 
response criteria (Appendix 5), at the end of 
treatment as determined by the investigator 
 
ORR, defined as the proportion of patients 
who achieve complete or partial metabolic 
responses, according to Lugano 2014 
response criteria (Appendix 5), at end of 
treatment as determined by the investigator 
 
BOR, defined as the best response while on 
study, according to Lugano 2014 response 
criteria (Appendix 5), as determined by the 
investigator 
 
PFS, defined as the time from enrollment to 
the first occurrence of disease progression as 
determined by the investigator according to 
Lugano 2014 response criteria (Appendix 5) or 
death from any cause  
 
OS, defined as time from enrollment to death 
from any cause 
 
EFSeff, defined as time from enrollment to the 
earliest occurrence of the below cases: 
- 
Disease progression or relapse  
- 
Death due to any cause 
 
Initiation of any NALT 

 
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Table 8 
Objectives and Corresponding Endpoints: Safety Run-In  
(Stage 1), contd. 
Exploratory Pharmacokinetic Objective 
Corresponding Endpoints 
 
To further evaluate the PK of 
polatuzumab vedotin  
 
 
PK of polatuzumab vedotin in combination 
with R-GemOx in patients with relapsed or 
refractory DLBCL 
AE  adverse event; ADA  anti-drug antibody; BOR  best overall response; CR  complete 
response; DLBCL   diffuse large B-cell lymphoma; EFSeff   event-free survival; 
FACT/GOG‑NTX‑12   Functional Assessment of Cancer Therapy/Gynecologic Oncology 
Group-Neurotoxicity 12-Item Scale; NALT  non-protocolspecified anti-lymphoma treatment; 
NCI CTCAE v5.0  National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0; ORR  objective response rate; OS  overall survival; PET-CT   positron emission 
tomography-computed tomography; PFS  progression-free survival; PK  pharmacokinetics; 
PN  peripheral neuropathy; Pola-R-GemOx  polatuzumab vedotin, rituximab, gemcitabine, and 
oxaliplatin; R‑GemOx  rituximab plus gemcitabine plus oxaliplatin. 
 
Table 9 
Objectives and Corresponding Endpoints: Randomized 
Controlled Trial (Stage 2) 
Primary Efficacy Objective 
Corresponding Endpoint 
 
To evaluate the efficacy of 
Pola‑R‑GemOx compared with 
R‑GemOx alone 
 
 
OS, defined as time from randomization to 
death from any cause 
Secondary Efficacy Objective 
Corresponding Endpoints 
 
To evaluate the efficacy of 
Pola‑R‑GemOx compared with 
R‑GemOx alone 
Key secondary endpoints included in the 
hierarchical testing procedure: 
 
PFS, defined as the time from randomization 
to the first occurrence of disease 
progression, as determined by the 
investigator according to Lugano 2014 
response criteria (Appendix 5 
), or death 
from any cause 
 
CR, defined as the proportion of patients 
who achieve complete metabolic response 
based on PET-CT, according to Lugano 
2014 response criteria (Appendix 5 
), at 
the end of treatment as determined by an 
IRC 
 
ORR, defined as the proportion of patients 
who achieve complete or partial metabolic 
responses, based on PET-CT according to 
Lugano 2014 response criteria (Appendix 5
 
), at the end of treatment as determined 
by an IRC 
 

 
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Table 9 
Objectives and Corresponding Endpoints: Randomized 
Controlled Trial (Stage 2), contd. 
Secondary Efficacy Objective 
Corresponding Endpoints 
 
Secondary endpoints that will not be adjusted for 
testing multiplicity: 
 
BOR, defined as the best response while on 
study, according to Lugano 2014 response 
criteria (Appendix 5), as determined by the 
investigator 
 
CR, defined as the proportion of patients 
who achieve complete metabolic response 
based on PET-CT, according to Lugano 
2014 response criteria (Appendix 5 
), at 
the end of treatment as determined by the 
investigator 
 
ORR, defined as the proportion of patients 
who achieve complete or partial metabolic 
responses, according to Lugano 2014 
response criteria (Appendix 5 
), at the 
end of treatment as determined by the 
investigator 
 
DOR, defined as the time from the first 
occurrence of a documented objective 
response to disease progression, as 
determined by the investigator according to 
Lugano 2014 response criteria, or death 
from any cause, whichever occurs first 
 
EFSeff, defined as time from randomization to 
the earliest occurrence of the below cases: 
- 
Disease progression or relapse  
- 
Death due to any cause 
- 
Initiation of any NALT 
Secondary PRO Objective 
Corresponding Endpoint 
 
To evaluate impact of treatment and 
disease on aspects of health-related 
quality of life 
 
Time to deterioration in physical functioning 
and fatigue as measured by the 
EORTC QLQ‑C30 
 
Time to progression in lymphoma symptoms 
as measured by the FACT-Lym subscale 
 
Change from baseline in PN as measured by 
the FACT/GOG-NTX-12 subscale score 
 
Safety Objective 
Corresponding Endpoints 
 
To evaluate the safety and tolerability 
of Pola-R-GemOx compared with 
R-GemOx and to assess the 
immunogenicity of polatuzumab 
vedotin 
 
Incidence, nature, and severity of AEs 
(including PN) according to NCI CTCAE v5.0 
and physical findings 
 
Tolerability, as assessed by dose 
interruptions, dose reductions and dose 
intensity 
 
Prevalence of ADAs at baseline and 
incidence of ADAs during the study 
 

 
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Table 9 
Objectives and Corresponding Endpoints: Randomized 
Controlled Trial (Stage 2), contd. 
Exploratory Biomarker Objectives 
Corresponding Endpoints 
 
To identify biomarkers that: 
- 
Are prognostic of response to 
polatuzumab vedotin 
(i.e., predictive biomarkers)  
- 
Are associated with progression 
to a more severe disease 
(i.e., prognostic biomarkers) 
- 
Can provide evidence of 
polatuzumab vedotin activity, or 
can increase the knowledge and 
understanding of disease biology 
 
To explore MRD as a prognostic 
marker in R/R DLBCL 
 
 
Associations between efficacy endpoints, 
including OS, PFS and CR rate, and 
exploratory biomarkers, which may include 
but are not limited to histological and 
molecular prognostic markers and profiles of 
circulating immune cells (see Table 12 for a 
description of proposed exploratory 
biomarkers) 
Exploratory Pharmacokinetic Objective 
Corresponding Endpoints 
 
To further evaluate the PK of 
polatuzumab vedotin  
 
 
PK of polatuzumab vedotin in combination 
with R-GemOx in patients with relapsed or 
refractory DLBCL 
Exploratory PRO Objectives 
Corresponding Endpoints 
 
To evaluate impact of treatment and 
disease on aspects of health-related 
quality of life 
 
Descriptive summary statistics and the 
change from baseline for: 
- 
All scales for the EORTC QLQ-C30 
- 
FACT-Lym subscale 
- 
FACT/GOG-NTX-12 
- 
EQ-5D-5L 
 
AE  adverse event; ADA  anti-drug antibody; BOR  best overall response; CR  complete 
response; DLBCL   diffuse large B-cell lymphoma; DOR  duration of response; EFSeff   event-
free survival; EORTC QLQ-C30  European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire, Core 30; EQ-5D-5L  EuroQol 5-Dimension Questionnaire, 5-Level 
Version; FACT/GOG-NTX-12   Functional Assessment of Cancer Therapy/Gynecologic 
Oncology Group-Neurotoxicity 12-Item Scale; FACT-Lym Functional Assessment of Cancer 
Therapy-Lymphoma; IRC  Independent Review Committee; MRD  minimal residual disease; 
NALT  non-protocolspecified anti-lymphoma treatment; NCI CTCAE v5.0  National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 5.0; ORR  objective 
response rate; OS  overall survival; PET-CT   positron emission tomography-computed 
tomography; PFS  progression-free survival; PK  pharmacokinetics; PN  peripheral neuropathy; 
Pola-R‑GemOx  polatuzumab vedotin, rituximab, gemcitabine, and oxaliplatin; 
R/R  relapsed/refractory; R-GemOx  rituximab plus gemcitabine plus oxaliplatin. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
Study MO40598 is a Phase III, multicenter, open-label RCT in patients with relapsed or 
refractory DLBCL.  The study will consist of a Screening Period, a Treatment Period, and 

 
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Treatment Period 
The Treatment Period will occur in two stages.  Stage 1 will comprise a safety run-in, 
where approximately 10 patients will receive experimental study treatment with 
Pola-R-GemOx.  The purpose of Stage 1 is to provide a preliminary safety assessment 
of the study treatment, prior to entering Stage 2 of the study.  Stage 2 will comprise an 
RCT, where approximately 250 patients will be randomly assigned in a 1:1 ratio to 
receive either experimental study treatment with Pola-R-GemOx or control study 
treatment with R-GemOx.  In both stages of the Treatment Period, patients will receive 
up to 8 cycles of Pola-R-GemOx or 8 cycles of R-GemOx, each administered on 
21‑day cycles.  Dosing regimens are described in detail in Section 4.3.2.  
Dose delays/reductions will be permitted, as detailed in the protocol (Section 5.1.2). 
Stage 1: Safety Run-In (Figure 2)  
 
At a limited number of sites (approximately 18 centers), approximately 13 patients 
will be treated with Pola-R-GemOx 
 
Accrual of these patients will be staggered across three cohorts until the number of 
evaluable patients required for each cohort (mentioned below) is reached.  
Evaluable patients are patients who complete at least 4 cycles of treatment or are 
discontinued because of Grade  3 PN: 
– 
Cohort 1: 3 evaluable patients 
– 
Cohort 2: 3 evaluable patients 
– 
Cohort 3: 4 evaluable patients 
Approximately 7 patients will be recruited in Cohort 3, with the aim of 
having at least 4 evaluable patients. 
 
Cohort 2 and Cohort 3 will not begin enrolling patients until all safety evaluations 
have been completed in Cohort 1 and Cohort 2, respectively, and recruitment of the 
next cohort has been approved (see below for how approval occurs).  Patients who 
discontinue prior to Cycle 4 of treatment due to disease progression, death or any 
other reason that is not directly attributable to PN will be replaced until the required 
number of evaluable patients is reached. 
 
Once 3 evaluable patients from Cohort 1 complete 4 cycles or discontinue because 
of Grade  3 PN, the IMC, in collaboration with the Steering Committee (SC) (if 
necessary), will evaluate the total safety profile of Pola‑R‑GemOx, with a particular 
focus on PN.  They will then approve or disapprove enrollment into the next cohort.  
This recommendation will be released to the Sponsor responsible.  Cohort 2 will 
follow the same process. 
 

 
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 
 
In addition to the above, all patients from previous cohorts who proceeded beyond 
the fourth cycle of therapy will be re-evaluated by the IMC to assess the potential of 
cumulative neurotoxicity with Pola-R-GemOx, as well as the course of PN 
resolution. 
 
Figure 2 Safety Run-In Schema (Stage 1) 
 
EOT  end of treatment; evaluable  treated for at least 4 cycles of therapy or discontinued due to 
Grade  3 peripheral neuropathy; pts  patients; RCT  randomized controlled trial. 
 
The Formal Go/No-Go Decision at the End of Stage 1 
 
When a minimum of 10 evaluable patients in the Treatment Period of Stage 1 have 
received the last dose of Pola-R-GemOx (i.e., completed Cycle 8 or discontinued 
between Cycle 5 and Cycle 8), the IMC will review the safety profile of the Stage 1 
study population up to this point, focusing in particular on the frequency, course and 
reversibility of Grade  3 PN events. 
– 
 
Based on the preceding information, the IMC will provide a recommendation, with 
the advice of the SC (if necessary), to the Sponsor responsible whether to continue 
to the RCT Stage. 
 
 
 
Stage 2: Randomized Controlled Trial  
If Pola-R-GemOx combination therapy is deemed to be tolerable in the safety run-in, 
enrollment into the RCT stage will begin.  Approximately 250 eligible patients will be 
randomized in a 1:1 ratio to receive either Pola-R-GemOx or R-GemOx.  Randomization 
will be stratified by three factors: number of previous lines of systemic treatment 

 
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(1 vs.  2), outcome of last systemic therapy (relapsed vs. refractory), and age 
(  70 years vs.  70 years). 
 
 
 
 

 
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 
 
 
 
 

 
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 
 
 
 
 
The objectives and endpoints of the two stages are provided in Section 2.  Safety will be 
assessed by adverse events per NCI CTCAE v5.0, patient-reported 
FACT/GOG‑NTX‑12 score (Stage 1), clinical laboratory test results, ECG, and vital 
signs.  Response assessments will be according to Lugano 2014 criteria (Appendix 5), 
based on positron emission tomography–computed tomography (PET-CT) scans at 
screening and the end of treatment.  All response assessments will be carried out by the 
investigator.  In addition, the secondary outcomes of objective response rate (ORR) and 
CR rate in Stage 2 will be assessed by an Independent Review Committee, based on 
primary imaging data collected by the Sponsor. 
Stage 1 and Stage 2 of the Treatment Period will also assess anti-drug antibodies 
(ADAs) and the sparse pharmacokinetic (PK) profile of polatuzumab vedotin in 
combination with R-GemOx.  Stage 2 of the Treatment Period will also assess 
biomarkers (as per Table 12) and additional patient-reported outcomes 
(EuroQol 5‑Dimension Questionnaire, 5‑Level Version [EQ-5D-5L], FACT/GOG-NTX-12, 
Functional Assessment of Cancer TherapyLymphoma [FACT-Lym], and 
EORTC QLQ‑C30). 

 
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Table 12 Biomarkers for Retrospective Exploratory Research (Stage 2) 
Sample Type 
Timing (All Mandatory) 
Proposed Biomarkers 
DLBCL tumor tissue 
(fresh or archival) 
Baseline 
 RNA-based gene expression 
profiling, including but not 
limited to cell-of-origin gene 
signature analysis 
 IHC and proteomic profiling, 
including BCL2 and MYC 
 Translocation profiles, 
including BCL2 and MYC 
 Mutation profiling by NGS, 
including but not limited to 
CD79b 
Blood for MRD assays 
Baseline, subsequent time 
points during treatment, and 
end of treatment (or 
discontinuation, whichever 
comes first) 
 ctDNA level and clonal 
mutation profile 
 ctDNA as a peripheral 
measure of disease biology, 
prognosis, subsets, and 
treatment response 
Blood for flow cytometry a 
Baseline, subsequent time 
points during treatment, and 
end of treatment (or 
discontinuation, whichever 
comes first) 
 Flow-cytometry–based 
profiling of circulating immune 
cells 
 To evaluate the prognostic 
value of patient immune 
fitness and investigate the 
effect of treatment regimen on 
circulating immune cells 
ctDNA  circulating tumor DNA; IHC  immunohistochemistry; NGS  next-generation 
sequencing; MRD  minimal residual disease. 
a The first 100 patients at selected sites will undergo flow cytometry. 
 
Post-Treatment Period 
Patients who complete study treatment per protocol (see Section 4.3.2) or discontinue 
from the study treatment early (e.g., if they terminated treatment early because of an 
adverse event) will enter the Post-Treatment Period, which will consist of an 
End of Treatment Visit occurring 28 (  7) days after the last dose of study treatment and 
then a Long-term Follow-Up Period.  Assessments carried out at the End of Treatment 
Visit and during the Long-term Follow-Up Period are described in the Schedules of 
Activities in Appendix 1, Appendix 2, Appendix 3 
, and Appendix 4 . 
Patients in the Follow-Up Period will be assessed as follows via clinic visits, telephone 
calls, and/or patient medical records approximately every 2 months until death, loss to 
follow-up, or study termination by the Sponsor: 
 
Patients who complete treatment or discontinue all study treatment prematurely 
due to reasons other than disease progression will continue standard long-term 

 
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follow-up assessments including required ADA sampling and radiographic 
assessments until disease progression and will be followed for NALT and survival. 
 
Patients who initiate NALT in the absence of progressive disease will continue to be 
followed for progression (including radiographic assessments), additional NALT, 
and survival. 
 
Patients with disease progression will be followed for NALT and survival. 
 
3.1.1 
Internal Monitoring Committee 
An IMC will be established to monitor patient safety during the safety run-in and provide 
recommendations on whether the next cohorts or RCT should open.  The IMC will 
include Sponsor representatives who are not associated with study conduct, at a 
minimum, representatives from Clinical Science, Safety Science and Biometrics.  The 
IMC will review all necessary cumulative data at regular intervals during the study.  The 
IMC will evaluate the total safety profile of Pola-R-GemOx, with a particular focus on PN.  
Ad hoc meetings may be called in addition to scheduled meetings, as necessary, to 
provide recommendations on management of any new safety issues.  Specific 
operational details, such as the committee's composition, frequency and timing of 
meetings, and members' roles and responsibilities, will be detailed in an IMC Charter. 
3.1.2 
Independent Data Monitoring Committee 
An iDMC will evaluate safety data periodically during the RCT (see Section 6.10).  The 
analysis supporting iDMC review will be conducted by an independent Data 
Coordinating Center (iDCC) and provided to the iDMC.  The iDMC will follow a charter 
that outlines the iDMC roles and responsibilities. 
The guidelines for safety monitoring and predefined stopping rules for treatment-related 
deaths, PN events, and treatment delays that lead to treatment discontinuation will be 
provided in the iDMC charter. 
3.1.3 
Independent Review Committee 
An Independent Review Committee (IRC) composed of board-certified radiologists and 
an oncologist with experience in malignant lymphoma will assess all patients for 
response (see Appendix 5) until end of treatment on the basis of imaging results and 
bone marrow biopsy results for all patients during the RCT.  Decisions will be guided by 
a Charter specific to the independent review. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit, occurs  
which will be the timepoint at which all patients enrolled in the study have either had 
at least 2 years of follow-up from the time of the treatment-completion visit or have 
discontinued the study.  The end of the study is expected to occur approximately 
2.5 years after the last patient is enrolled. 

 
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After an initial safety-run in, the randomized stage for recruitment is expected to occur 
over approximately 19 months. 
This is an event-driven trial.  The clinical cut-off date for the primary OS analysis will be 
confirmed when the targeted number of mortality events (
 deaths) have occurred, 
which is expected approximately 
 months after the first patient is randomized (first 
patient in) in the RCT stage of the study. 
In addition, the Sponsor may decide to terminate the study at any time. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Patient Population 
Please see Section 1.3 (Study Rationale and Benefit Risk Assessment). 
3.3.2 
Rationale for Stratification Factors 
Participants in this trial will be stratified at the time of randomization for the following 
factors: 
 
Number of previous lines of systemic therapy for DLBCL (1 vs.  2) 
– 
Conditioning chemotherapy followed by consolidative autologous HSCT will be 
counted as one line of therapy.  Conditioning chemotherapy followed by 
allogeneic HSCT will be counted as one line of therapy.  Local therapies 
(e.g., radiotherapy) will not be considered as lines of treatment. 
 
Outcome of last systemic therapy (relapsed vs. refractory) 
– 
Relapsed disease in this study is defined as disease that has recurred 
 6 months after completion of the last line of treatment. 
– 
Refractory disease is defined as disease that did not respond to or that  
progressed during therapy or progressed within 6 months ( 6 months) of prior 
therapy. 
 
Age ( 70 years vs.  70 years) 
 
The preceding stratification will produce treatment groups that are roughly equivalent in 
terms of disease progression and disease status, thereby ensuring comparability 
between the experimental (Pola-R-GemOx) and control (R-GemOx) arms. 
3.3.3 
Rationale for Polatuzumab Vedotin Dose and Schedule 
The dose and schedule of polatuzumab vedotin in this study have been chosen based 
on experience from the Phase I Study DCS4968g, as well as other studies across the 
development program.  In DCS4968g, administration of single-agent 
polatuzumab vedotin in patients with relapsed/refractory indolent NHL or DLBCL at 
doses ranging from 0.1 to 2.4 mg/kg resulted in approximately linear dose‑proportional 
pharmacokinetics for antibody-conjugate, total antibody, and unconjugated MMAE.  
Furthermore, co-administration of rituximab had no effect on the PK of 

 
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polatuzumab vedotin, and vice versa.  General safety profiles of polatuzumab vedotin 
alone and in combination with rituximab across this range of doses are summarized in 
Section 1.3 and described below in relation to dose and schedule choice. 
From prior studies, PN and neutropenia have been identified as risks associated with 
polatuzumab vedotin therapy (Section 1.3, Section 5.1.1.1, and the 
Polatuzumab Vedotin Investigator’s Brochure).  These are also important risks for 
R-GemOx therapy (Section 3.1), necessitating caution in choice of dose and schedule of 
experimental study treatment in the current trial.  Consequently, to optimize the safety of 
study participants, a dose and schedule of polatuzumab vedotin have been chosen that 
provide the lowest exposure to therapeutic antibody while still providing nearly maximal 
clinical effect.  Specifically, polatuzumab vedotin will be administered at 1.8 mg/kg per 
dose for up to eight 21-day treatment cycles (corresponding to 6 months of total 
treatment).  This dosing regimen is currently recommended by internal Roche guidance 
for all polatuzumab vedotin clinical trials as the optimal balance between safety and 
efficacy.  Due to limited clinical experience in patients treated with 1.8 mg/kg 
polatuzumab vedotin at a total dose  240 mg, it is recommended not to exceed a dose 
of 240 mg per cycle. 
Because this is the first study to evaluate Pola-R-GemOx therapy, Study MO40598 will 
also have a safety run-in period to assess PN risk, thereby validating initial safety, as 
well as continued assessments of PN and neutropenia throughout the Treatment Period 
(Section 1.3).  The study also has dose reduction criteria designed to manage adverse 
events (Section 5.1.2). 
3.3.4 
Rationale for Rituximab Plus Gemcitabine Plus Oxaliplatin as 
the Control Therapy and for its Dose and Schedule 
The clinical development program for polatuzumab vedotin is based on the hypothesis 
that adding an anti-CD79b antibody to a standard regimen of anti-CD20 antibody plus 
chemotherapy will provide enhanced efficacy in patients with B-cell lymphomas.  Prior 
clinical studies are consistent with this hypothesis (see Section 1.3 and the Polatuzumab 
Vedotin Investigator’s Brochure), although the number of rituximab-containing backbone 
therapies evaluated to date in combination with polatuzumab vedotin is relatively limited. 
As R-GemOx is commonly used in the clinic for relapsed/refractory DLBCL and is 
recommended by the NCCN in this setting (National Comprehensive Cancer Network 
2018), it is of significant interest to assess whether adding polatuzumab vedotin to 
R-GemOx provides the expected efficacy enhancement.  Thus, the current prospective, 
randomized comparative trial will compare patients treated with experimental therapy 
(i.e., Pola-R-GemOx) versus those treated with control therapy (i.e., R-GemOx).  
In order that potentially positive results from this trial can be applied directly to clinical 
practice in the future, R-GemOx will be administered under standard clinical conditions, 
(i.e., as described in local prescribing information). 

 
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Control patients will receive R-GemOx at the currently recommended dosage and 
schedule for up to 8 cycles.  An identical regimen consisting of 8 cycles of R-GemOx has 
been shown in published clinical studies to be effective and well tolerated in the setting 
of relapsed or refractory DLBCL, with Grade 3–4 infectious episodes observed in 22% 
of cycles (Mounier et al. 2013).  Given that 8 cycles are also considered to be optimal for 
polatuzumab vedotin therapy based on current clinical studies (Section 3.3 and 
Polatuzumab Vedotin Investigators Brochure), it was deemed that 8 cycles of therapy in 
both treatment arms (R-GemOx and Pola-R-GemOx) would be used in this study. 
3.3.5 
Rationale for Biomarker Assessments 
Diffuse large B-cell lymphoma is a heterogeneous disease and, consequently, a number 
of distinct proteomic and molecular profiles have been identified in patients who exhibit 
different prognoses and responses to standard-of-care (SoC) treatments (Lenz et al. 
2008; Johnson et al. 2009; Johnson et al. 2012; Scott et al. 2015; Chapuy et al. 2018; 
Schmitz et al. 2018).  The most established DLBCL biomarker subsets to date are 
molecularly-defined profiles consistent with developmental stage or cell of origin (COO) 
of the B-celloriginating tumor (i.e., the activated B-celllike [ABC] profile) the germinal 
center B-celllike (GCB) or unclassified profile, the BCL2/MYC double-expressor profile 
(characterized by elevated expression of both MYC and BCL2), and the BCL2/MYC 
double-hit profile (translocation in both BCL2 and MYC).  In the recent revision of the 
WHO classification, a new molecular subgroup was defined, the high-grade B‑cell 
lymphoma with MYC and BCL2 and/or BCL6 rearrangements (Swerdlow et al. 2016).  In 
addition to their distinct molecular profiles, these DLBCL signatures have varied 
prognostic outcomes in front-line DLBCL patients when treated with the SoC therapy 
R‑CHOP; for COO, the ABC subgroup characteristically has an inferior prognosis 
relative to GCB with R-CHOP treatment in front-line DLBCL (Alizadeh et al. 2000; 
Lenz et al. 2008; Nowakowski et al. 2016).  For BCL2/MYC, the double-expressor and 
the double-hit patients also have reported inferior prognosis (Johnson et al. 2009; 
Johnson et al. 2012). More recently, molecular subtypes have been identified that 
transcend the categories aforementioned, with distinct genotypic, epigenetic and clinical 
characteristics.  Examples include the four genetic subtypes described by Schmitz et al., 
and the five DLBCL subsets as described by Chapuy et al.  It is likely that further work in 
this realm may redefine new treatment combinations in the future treatment regimens.  
The clinical implications of these DLBCL subsets have almost exclusively been studied 
in first-line DLBCL and are likely to be important in the development of new treatment 
regimens.  However, the prognostic implication of these subsets in the relapsed or 
refractory setting is less clear, except that there are certain higher-risk subsets that tend 
to have higher rates of treatment failure with R-CHOP (Thieblemont et al. 2011; 
Camicia et al. 2015; Nowakowski et al. 2016). 
CD79b is the molecular target of polatuzumab vedotin.  In vivo, CD79b heterodimerizes 
with CD79a, thereby forming an essential component of the multi-protein B-cell receptor 
(BCR) complex, which is critical for functional BCR expression and B-cell signaling.  

 
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CD79b is consistently expressed in mature B-cells and in mature B-cell malignancies 
(Chu and Arber 2001; Olejniczak et al. 2006; Polson et al. 2009). 
Exploratory biomarkers for this study may include, but are not limited to:  the target of 
polatuzumab vedotin (CD79b), established prognostic biomarkers in DLBCL (cell-of-
origin, BCL2/MYC double-expression and BCL2/MYC double-translocation), gene 
expression analysis, and tumor mutation profiling by next-generation sequencing (NGS).  
These biomarkers will be tested in Stage 2 of the study (RCT).  Serial or longitudinal 
collection of plasma samples will be collected in Stage 2 of this study.  Non-invasive, 
blood collection will enable the assessment of circulating tumor DNA (ctDNA), which is 
believed to come from apoptotic remains of tumor cells.  The ctDNA can be quantified 
and also assessed for its genomic mutations.  Beyond associating this information at 
baseline with clinical efficacy for prognostic and treatment effect evaluation, this 
information will also allow for monitoring of residual disease at the molecular level and 
for tracking clonal evolution. 
3.3.6 
Rationale for the Functional Assessment of Cancer 
Therapy/Gynecologic Oncology Group-Neurotoxicity 12-Item 
Scale (FACT/GOG-NTX-12) 
Peripheral neuropathy has been identified as a potential risk of polatuzumab vedotin 
treatment (Section 3.1, Section 5.1.1.1, and Polatuzumab Vedotin Investigator’s 
Brochure).  Therefore, to ensure patient safety, PN will be monitored throughout the 
study using the NCI CTCAE v5.0 (see Appendix 1 and Appendix 2).  However, while the 
sensory section of the NCI CTCAE v5.0 has good validity, it has been shown to be fairly 
insensitive in predicting chemotherapy-induced PN (Shimozuma et al. 2012).  In light of 
this, several neuropathy-specific scales have been developed that capture aspects of 
chemotherapy-induced PN frequently missed by simple and more general toxicity 
scales, such as the NCI CTCAE v5.0 (Curcio 2016). 
The FACT/GOG-NTX contains 11 items scored from 0–4, and scores are summed for a 
range of 11–44 (Curcio KR 2016).  The FACT/GOG-NTX was initially developed with the 
input of expert clinicians and patients who reported symptoms of chemotherapy-induced 
PN within the past month (Calhoun et al. 2003).  The questionnaire was validated with 
women diagnosed with gynecologic malignancies who received taxanes and platinum 
compounds, well-known neurotoxic drugs (Calhoun et al. 2003; Huang et al. 2007). 
Kopec et al. (2006) modified the FACT/GOG-NTX by adding one item specific to 
oxaliplatin, which is of particular interest given that one of the members of the 
chemotherapy backbone in this study is oxaliplatin.  This version has been renamed the 
FACT/GOG-NTX-12 (Appendix 10).  The revised version was tested in patients with 
colon cancer.  Reliability was good (Cronbach alpha  0.85), and the questionnaire 
scores were correlated with the National Cancer Institute-Sanofi criteria.  The 
FACT/GOG-NTX-12 was also shown to be sensitive to changes in chemotherapy-
induced PN over time.  Combined with its relative ease of administration, these features 

 
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make the FACT/GOG-NTX-12 ideally suited to clinical studies and will be used in this 
study to assess chemotherapy-induced PN. 
3.3.7 
Rationale for EQ-5D-5L, EORTC QLQ-C30 and FACT-Lym 
Patient-Reported Outcome Assessments 
Patient-reported outcome (PRO) assessments provide a unique perspective on disease 
and treatment burden and complement the evaluation of clinical benefits associated with 
specific therapies.  Patient-relevant outcomes are now integral components of treatment, 
regulatory and reimbursement decision-making, as well as important considerations in 
many of today’s quality initiatives (Institute of Medicine [U.S.], Committee on Quality of 
Health Care in America 2001).  Consequently, to supplement the growing database of 
information on the health-related quality of life (HRQoL) effects of polatuzumab vedotin 
therapy in combination with rituximab plus chemotherapy, patients in Stage 2 of 
Study MO40598 (randomized controlled trial) will complete the following 
PRO instruments, according to the Schedule of Activities in Appendix 2: 
 
The EuroQol 5-Dimension Questionnaire, 5-level version: The EQ-5D-5L is a widely 
used validated self-report health status questionnaire that is used to calculate a 
health status utility score for health economic analyses (EuroQol 1990; 
Brooks 1996; Herdman et al. 2011; Janssen et al. 2013) (Appendix 12).  There are 
two components to the EQ-5D-5L: a five-item health state profile that assesses 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, as well 
as a visual analog scale (VAS) that measures health state.  Published weighting 
systems allow for creation of a single composite score of the patient's health status. 
 
European Organisation for the Research and Treatment of Cancer Quality of Life 
Questionnaire, Core 30: The EORTC QLQ-C30 is a validated, reliable self-report 
measure (Aaronson et al. 1993; Fitzsimmons et al. 1999) (see Appendix 13).  It 
consists of 30 questions that assess five aspects of patient functioning (physical, 
emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and 
vomiting, pain), global health/quality of life, and six single items (dyspnea, insomnia, 
appetite loss, constipation, diarrhea, and financial difficulties) with a recall period of 
the previous week.  Scale scores can be obtained for the multi-item scales.  The 
EORTC QLQ C30 module takes approximately 10 minutes to complete. 
 
The Functional Assessment of Cancer Therapy–Lymphoma: The FACT-Lym is a 
validated HRQoL instrument used specifically in patients with lymphoma 
(Appendix 11).  The FACT-Lym is composed of the 27-item Functional Assessment 
of Cancer TherapyGeneral Questionnaire (FACT‑G), which measures 
health-related quality of life in patients undergoing any type of cancer therapy, plus 
the 15-item Lymphoma Subscale, which assesses how lymphoma-specific 
symptoms impact HRQoL (Cella et al. 1993; Cella  et  al. 2005).  Each item of the 
FACT-Lym is answered using a 5-point Likert scale. 
 
3.3.8 
Rationale for the Independent Data Monitoring Committee 
An iDMC will be incorporated to monitor patient safety during the RCT instead of the 
IMC.  As a result, although this is an open‑label study and the investigators and patients 

 
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are unblinded, the Sponsor and study team performing the primary analysis will not have 
access to aggregated statistical outputs by treatment arm indicating treatment.  An 
unblinded iDMC will facilitate evaluation of the safety profile during the RCT.  The iDMC 
will provide recommendations to the Sponsor whether to continue, modify or terminate 
the trial. 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
Approximately 10 patients will be enrolled in the safety run-in phase, and approximately 
250 patients will be enrolled in the randomized portion, for a total of approximately 
260 patients. 
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 
 
Ability to comply with the study protocol, in the investigator’s judgment 
 
Histologically-confirmed diffuse large B-cell lymphoma, not otherwise specified or 
history of transformation of indolent disease to DLBCL 
 
Relapsed or refractory disease, defined as follows: 
– 
Relapsed:  Disease that has recurred following a response that lasted 
 6 months from completion of the last line of therapy. 
– 
Refractory: Disease that did not respond to or that progressed during therapy 
or progressed within 6 months ( 6 months) of prior therapy. 
 
 
At least one (  1) line of prior systemic therapy: 
– 
Patients may have undergone autologous HSCT prior to recruitment.  In such 
cases, salvage chemotherapy (e.g., rituximab, dexamethasone, cytarabine, and 
cisplatin [R-DHAP] and rituximab, ifosfamide, carboplatin, and etoposide 
phosphate [R-ICE]) will be counted as one line of therapy and conditioning 
chemotherapy (e.g., BEAM) followed by consolidative autologous HSCT will be 
counted as a separate line of therapy. 
– 
Patients may have undergone allogeneic HSCT prior to recruitment, so long as 
they are off all immunosuppressive therapy and have no active GVHD.  In such 
cases, salvage chemotherapy (e.g., R-DHAP and R-ICE) will be counted as one 
line of therapy and conditioning chemotherapy (e.g., carmustine, etoposide, 
cytarabine, and melphalan [BEAM]) followed by allogeneic HSCT will be 
counted as a separate line of therapy. 
– 
Patients may have undergone CAR T-cell therapy prior to recruitment.  In 
such cases, cell collection, conditioning chemotherapy, and infusion will be 
counted as one line of therapy. 

 
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– 
Local therapies (e.g., radiotherapy) will not be considered as lines of treatment. 
– 
For patients with history of transformation of indolent disease to DLBCL, it is 
preferred that patients have received at least one treatment for the transformed 
lymphoma.  However, if there are cases where the patient has received an 
anthracycline-containing chemotherapy regimen (such as R-CHOP) for the 
indolent lymphoma only, then these patients can be considered as eligible. 
 
At least one bi-dimensionally measurable lesion, defined as  1.5 cm in its longest 
dimension as measured by computed tomography (CT) or magnetic resonance 
imaging (MRI) 
 
ECOG performance status of 0,1, or 2 
– 
Patients with an ECOG performance status of 3 can be considered in the RCT 
stage, but only if this status is DLBCL-related and if after a prephase of a 7-day 
steroid treatment during the screening phase (e.g., 1 mg/kg prednisone) an 
improvement in ECOG performance status to 2 or less is observed prior to 
enrolment. 
 
Adequate hematological function, as defined by: 
– 
Hemoglobin  8 g/dL  
– 
ANC  1.5  109/L or  0.5  109 if the neutropenia is attributable to underlying 
disease and before the administration of steroids 
– 
Platelet count  75  109/L or  50  109 if the thrombocytopenia is attributable to 
underlying disease 
 
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 contraceptive methods with a failure rate 
of  1% per year during the treatment period and for 12 months after the final 
dose of polatuzumab vedotin, rituximab, gemcitabine, or oxaliplatin.  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 requirements. 
– 
Examples of 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. 
– 
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 

 
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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:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below (the patient should receive advice on the possibility of opting for 
cryoconservation of sperm prior to start of study treatment due to the possibility of 
irreversible infertility following therapy with gemcitabine, oxaliplatin, or polatuzumab 
vedotin): 
– 
With a female partner of childbearing potential who is not pregnant, men who 
are not surgically sterile must remain abstinent or 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 6 months after the final dose of 
polatuzumab vedotin, rituximab, oxaliplatin, and/or gemcitabine.  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 
polatuzumab vedotin, rituximab,oxaliplatin, and/or gemcitabine 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. 
 
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 
monoclonal antibodies (or recombinant antibody-related fusion proteins) or known 
sensitivity or allergy to murine products 
 
Contraindication to rituximab, gemcitabine, or oxaliplatin 
 
PN assessed to be Grade  1 according to NCI CTCAE v5.0 at enrollment 
 
Prior use of polatuzumab vedotin or a gemcitabine  platinum-based agent 
combination 
 
Enrollment in any previous or ongoing polatuzumab vedotin trial 
 
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 

 
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– 
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. 
 
Planned autologous or allogeneic stem cell transplantation or CAR T-cell therapy at 
time of recruitment 
– 
Patients with only one prior therapy who are appropriate for stem cell 
transplantation are excluded from this trial.  Reasons for transplant-ineligibility 
may include age, performance status, comorbidities, transplant failure or failed 
procedure, insufficient response to salvage therapy, patient refusal, or logistical 
reasons. 
 
Primary or secondary CNS lymphoma at the time of recruitment 
 
Richter’s transformation or prior CLL 
 
Any of the following abnormal laboratory values, unless abnormal laboratory values 
are due to underlying lymphoma per the investigator: 
– 
Creatinine  1.5   upper limit of normal (ULN) or a measured creatinine 
clearance  30 mL/min 
– 
AST or ALT  2.5 x 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 
 
History of other malignancy that could affect compliance with the protocol or 
interpretation of results.  Exceptions include: 
– 
Patients with a history of curatively-treated basal or squamous cell carcinoma 
of the skin or in situ carcinoma of the cervix at any time prior to the study are 
eligible. 
– 
A patient with any other malignancy appropriately treated with curative intent 
and the malignancy has been in remission without treatment for  2 years prior 
to enrollment is eligible. 
– 
Patients with low-grade, early-stage prostate cancer (Gleason score 6 or 
below, Stage 1 or 2) with no requirement for therapy at any time prior to study 
are eligible. 
 
Evidence of significant, uncontrolled concomitant diseases that could affect 
compliance with the protocol or interpretation of results, including significant 
cardiovascular disease (such as New York Heart Association Class III or IV cardiac 
disease, myocardial infarction within the last 6 months, unstable arrhythmias, or 
unstable angina) or significant pulmonary disease (including obstructive pulmonary 
disease and history of bronchospasm) 
 
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection 
(excluding fungal infections of nail beds) at study enrollment or any major episode of 
infection (as evaluated by the investigator) within 4 weeks prior to Cycle 1 Day 1 

 
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 
Patients with suspected or latent tuberculosis 
– 
Latent tuberculosis needs to be confirmed by positive interferon-gamma 
release assay 
 
Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive 
hepatitis B surface antigen [HBsAg] serology) 
– 
Patients with occult or prior HBV infection (defined as negative HBsAg and 
positive hepatitis B core antibody [HBcAb]) may be included if HBV DNA is 
undetectable, provided that they are willing to undergo DNA testing on Day 1 of 
every cycle and monthly for at least 12 months after the last cycle of study 
treatment. 
 
Positive test results for hepatitis C virus (HCV) antibody 
– 
Patients who are positive for HCV antibody are eligible only if PCR is negative 
for HCV RNA. 
 
Known history of HIV seropositive status 
– 
For patients with unknown HIV status, HIV testing will be performed at 
Screening if required by local regulations. 
 
Vaccination with a live vaccine within 4 weeks prior to treatment 
 
Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) other than 
for diagnosis 
 
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 render the patient at high risk from treatment 
complications 
 
Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 12 months after the last dose of study drug 
– 
Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days prior to initiation of study drug. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
Study MO40598 is an open-label trial.  The Principal Investigator (PI) may consult with 
the Medical Monitor/Sponsor for advice or clarification of any eligibility criteria and 
may share risk factor information pertinent to the patient but the decision of whether a 
patient meets the eligibility criteria to enroll to the protocol is the responsibility of the 
PI.  The study site will obtain the patient number and treatment assignment from an 
interactive voice or Web-based response system (IxRS). 
The Treatment Period will occur in two stages:  
Stage 1:  Safety Run-In 
 
During the safety run-in (Figure 2), approximately 13 patients will be treated with 
Pola-R-GemOx. 

 
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 
Accrual of these patients will be staggered across three cohorts: 
– 
Cohort 1:  3 evaluable patients 
– 
Cohort 2:  3 evaluable patients 
– 
Cohort 3:  4 evaluable patients 
Approximately 7 patients will be recruited in Cohort 3, with the aim of 
having at least 4 evaluable. 
 
Within each cohort, safety will be evaluated when the number of intended evaluable 
patients complete 4 cycles of treatment, with a focus on acute PN toxicities.  Once 
all safety evaluations have been conducted within a cohort and further subject 
accrual is cleared, the next cohort will open to recruitment. 
 
Once at least 10 evaluable patients in the safety run-in have received the last dose 
of Pola-R-GemOx, the safety and tolerability of the Pola-R-GemOx regimen will be 
assessed by the IMC, and a decision will be made whether to continue into the RCT 
stage of the study.  The SC will be available for consultation during this time. 
 
Only a limited number of sites (approximately 18 centers) will be open for accrual 
into the safety run-in. 
 
Stage 2:  Randomized Control Trial 
 
If Pola-R-GemOx combination therapy is deemed tolerable in Stage 1, newly 
enrolled patients will be randomized in a 1:1 ratio to receive either Pola-R-GemOx 
or R-GemOx. 
 
Randomization will be performed by IxRS using stratified permuted blocks.  
Stratification factors will include: 1) number of previous lines of therapy for DLBCL; 
2) relapsed versus refractory status; and 3) age. 
 
Approximately 250 eligible patients are expected to enroll in this stage of the study. 
 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal product (IMP) for this study is Pola-R-GemOx.  The control 
therapy is R-GemOx. 
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
Polatuzumab Vedotin 
Polatuzumab vedotin will be supplied by the Sponsor as a lyophilized formulation 
(140 mg/vial).  Prior to administration, the lyophilized powder will be reconstituted with 
sterile water for injection to a volume of 7.2 mL. 
For information on the formulation, packaging, and handling of polatuzumab vedotin, see 
the pharmacy manual and the Polatuzumab Vedotin Investigator's Brochure. 

 
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4.3.1.2 
Rituximab 
Rituximab 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 
Gemcitabine 
Gemcitabine will be supplied by the Sponsor.  For information on the formulation, 
packaging, and handling of gemcitabine, see the pharmacy manual and the Gemcitabine 
Summary of Product Characteristics (SmPC). 
4.3.1.4 
Oxaliplatin 
Oxaliplatin will be supplied by the Sponsor.  For information on the formulation, 
packaging, and handling of oxaliplatin, see the pharmacy manual and the Oxaliplatin 
SmPC. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
Any overdose or incorrect administration of any of the study treatments should be noted 
on the Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of any of the study treatments 
should be recorded on the Adverse Event eCRF. 
Therapeutic regimens in this study are summarized in Figure 3 and Figure 4 and 
described in more detail in the following sections.  Guidelines for dosage modification 
and treatment interruption or discontinuation for patients who experience adverse events 
are provided in Section 5.1.2. 
Figure 3 Regimen in the Experimental Treatment Group: 
Polatuzumab Vedotin Plus Rituximab Plus Gemcitabine Plus 
Oxaliplatin 
 
C  cycle; D  day. 
a Rituximab should be administered before polatuzumab vedotin. 
b Gemcitabine should be administered before oxaliplatin. 
 

 
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Figure 4 Regimen in the Control Group: Rituximab Plus Gemcitabine Plus 
Oxaliplatin 
 
C  cycle; D  day. 
a 
Gemcitabine should be administered before oxaliplatin. 
 
4.3.2.1 
Polatuzumab Vedotin 
Polatuzumab vedotin 1.8 mg/kg will be administered intravenously on Day 1 of each 
21-day cycle for up to 8 cycles.  Polatuzumab vedotin should be administered after 
rituximab on the same day or, in the event of a dose delay for rituximab, the following 
day (see below). 
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 is greater or less than 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 subsequent doses should be modified accordingly.  Dose adjustments 
for body weight changes  10% are also acceptable should this be local standard of 
care.  Due to limited clinical experience in patients treated with 1.8 mg/kg 
polatuzumab vedotin at a total dose  240 mg, it is recommended not to exceed a dose 
of 240 mg per cycle. 
The initial dose will be administered to patients who are well hydrated (as per local 
guidelines) over 90  10 minutes.  Premedication (e.g., 5001000 mg of oral 
acetaminophen or paracetamol and approximately 50100 mg diphenhydramine as per 
institutional standard practice) may be administered to an individual patient  30 minutes 
before starting administration of polatuzumab vedotin.  Administration of corticosteroids 
is permitted at the discretion of the treating physician.  If infusion-related reactions 
(IRRs) are observed with the first infusion in the absence of premedication, 
premedication must be administered before subsequent doses. 
The polatuzumab vedotin infusion may be slowed or interrupted for patients 
experiencing infusion-associated symptoms.  Following the initial dose, patients will be 

 
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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. 
During administration of polatuzumab vedotin, vital signs should be assessed before the 
start of the infusion, every 30  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. 
Please refer to the Pharmacy Manual for detailed instructions on administration of 
polatuzumab vedotin. 
4.3.2.2 
Rituximab 
Rituximab (Mabthera/Rituxan®) 375 mg/m2 will be administered intravenously on Day 1 
of each 21-day cycle for up to 8 cycles.  Rituximab should be administered before 
polatuzumab vedotin on the same day; in the event of a dose delay for rituximab, 
polatuzumab vedotin may be administered on the following day. 
No dose modifications of rituximab are allowed. 
During the administration of rituximab in Cycle 1, vital signs are to be obtained before 
infusion, then after the start of the infusion, approximately every 30  5 minutes for 
90 minutes, then every 30  10 minutes until 1 hour after the end of the infusion.  During 
administration of rituximab in subsequent cycles, vital signs are to be recorded before 
infusion, then after the start of infusion, and approximately every 30  10 minutes until 
1 hour after the end of infusion. 
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 13 ). 

 
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All rituximab infusions should be administered to patients after premedication with oral 
acetaminophen (e.g., 5001000 mg) and an antihistamine such as diphenhydramine 
hydrochloride (e.g., 50100 mg)  30 minutes before starting each infusion (unless 
contraindicated).  An additional glucocorticoid (e.g., 100 mg IV prednisone or 
prednisolone or equivalent) is allowed at the investigator’s discretion.  For patients who 
did not experience infusion-related symptoms with their previous infusion, premedication 
at subsequent infusions may be omitted at the investigator’s discretion. 
Rituximab infusions will be administered according to the instructions in Table 13.  
If a patient tolerates the first cycle of study treatment without significant infusion 
reactions, rituximab may be administered as rapid infusion in accordance with local 
institutional guidelines. 
During the treatment period, rituximab must be administered to patients in a setting 
where full emergency resuscitation facilities are immediately available.  Patients should 
be under close supervision of the investigator at all times.  For the management of IRRs 
and anaphylaxis, see Section 5.1.2. 
Rituximab should be administered as a slow IV infusion through a dedicated line.  
IV infusion pumps (such as the Braun Infusomat Space) should be used to control the 
infusion rate of rituximab.  Administration sets with polyvinyl chloride (PVC), 
polyurethane (PUR), or polyethylene (PE) as a product contact surface and IV bags with 
polyolefine, polypropylene (PP), PVC, or PE as a product contact surface are compatible 
and can be used.  Additional in-line filters should not be used because of potential 
adsorption.  The in-line filter used for the administration of polatuzumab vedotin should 
not be used for the administration of rituximab. 
After the end of the first infusion, the IV line or central venous catheter should remain in 
place for  2 hours in order to administer IV drugs if necessary.  If no adverse events 
occur after 2 hours, the IV line may be removed or the central venous catheter may be 
de-accessed.  For subsequent infusions, the IV line or central venous catheter should 
remain in place for at least 1 hour after the end of the infusion.  If no adverse events 
occur after 1 hour, the IV line may be removed or the central venous catheter may be 
de‑accessed. 

 
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Table 13 Administration of First and Subsequent Infusions of Rituximab 
First Infusion (Cycle 1 Day 1) 
Subsequent Infusions 
 Begin infusion at an initial rate of 50 mg/hr 
 If no infusion-related or hypersensitivity 
reaction occurs, increase the infusion rate in 
50-mg/hr increments every 30 minutes, 
to a maximum of 400 mg/hr. 
 If a reaction develops, stop or slow the 
infusion.  Administer medications and 
supportive care in accordance with 
institutional guidelines.  If the reaction 
resolves, resume the infusion at a 
50% reduction in rate (i.e., 50% of rate used 
at the time the reaction occurred). 
 If the patient experienced an 
infusion-related or hypersensitivity reaction 
during the prior infusion, begin infusion at 
an initial rate of 50 mg/hr and follow 
instructions for first infusion. 
 If the patient tolerated the prior infusion 
well (defined by absence of Grade 2 
reactions during a final infusion rate of 
 100 mg/hr), begin infusion at a rate of 
100 mg/hr. 
 If no reaction occurs, increase the infusion 
rate in 100-mg/hr increments every 
30 minutes, to a maximum of 400 mg/hr. 
 If a reaction develops, stop or slow the 
infusion.  Administer medications and 
supportive care in accordance with 
institutional guidelines.  If the reaction 
resolves, resume the infusion at a 50% 
reduction in rate (i.e., 50% of rate used at 
the time the reaction occurred). 
 
4.3.2.3 
Gemcitabine 
Gemcitabine 1000 mg/m2 will be administered intravenously on Day 2 of each 21-day 
cycle for up to 8 cycles.  Gemcitabine should be administered before oxaliplatin on the 
same day.  In the event that rituximab dosing is split across two days, gemcitabine may 
be administered on Day 2 (i.e., the same day rituximab dosing is completed) or on the 
following day (see Section 4.3.2.2). 
The method of administering gemcitabine is described in the local prescribing 
information. 
4.3.2.4 
Oxaliplatin 
Oxaliplatin 100 mg/m2 will be administered intravenously on Day 2 of each 21-day cycle 
for up to 8 cycles.  Oxaliplatin should be administered after gemcitabine on the same 
day.  In the event that rituximab dosing is split across two days, oxaliplatin may be 
administered on Day 2 (i.e., the same day rituximab dosing is completed) or on the 
following day (see Section 4.3.2.2). 
The method for administering oxaliplatin is described in local prescribing information. 
4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (polatuzumab vedotin, rituximab, 
gemcitabine, and oxaliplatin) will be provided by the Sponsor.  The study site will 
acknowledge receipt of IMPs supplied by the Sponsor using the IxRS to confirm the 

 
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shipment condition and content.  Any damaged shipments will be replaced.  The 
investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit, either by time monitoring (shipment arrival date and 
time) or temperature monitoring, for all IMPs received and that any discrepancies have 
been reported and resolved before use of the IMPs.  All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions, with access limited to the investigator and 
authorized staff. 
Investigational medicinal products will either be disposed of at the study site according to 
the study site’s institutional standard operating procedure or be returned to the Sponsor 
(if supplied by the Sponsor) with the appropriate documentation.  The site’s method of 
destroying Sponsor-supplied IMPs must be agreed to by the Sponsor.  The site must 
obtain written authorization from the Sponsor before any Sponsor-supplied IMP is 
destroyed, and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Continued Access to Polatuzumab Vedotin, Rituximab, 
Oxaliplatin, and Gemcitabine  
Currently, the Sponsor does not have any plans to provide Sponsor study drugs 
(polatuzumab vedotin, rituximab, oxaliplatin, and gemcitabine) or any other study 
treatments or interventions to patients who have completed the study.  The Sponsor may 
evaluate whether to continue providing polatuzumab vedotin or 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 treatment to the study 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 
 
Hormone-replacement therapy 

 
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 
Other maintenance therapies 
 
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, per local standard practice.  Guidelines for specific supportive 
therapies are provided in the following subsections. 
4.4.1.1 
Premedication Before Polatuzumab Vedotin 
Per protocol, polatuzumab vedotin infusions should immediately follow rituximab 
infusions.  Consequently, as premedication is required before all rituximab infusions (see 
Section 4.4.1.2), additional premedication for polatuzumab vedotin is not required. 
However, if there is a delay in dosing of polatuzumab vedotin, then polatuzumab vedotin 
should be administered following premedication.  Premedication will consist of 
approximately 5001000 mg of oral acetaminophen or paracetamol and approximately 
50100 mg diphenhydramine (as per institutional standard practice) administered 
 30 minutes before starting administration of polatuzumab vedotin.  Administration of 
corticosteroids is permitted at the discretion of the treating physician. 
4.4.1.2 
Premedication Before Rituximab 
All rituximab infusions should be administered to patients after premedication.  The 
following premedication is required before rituximab therapy: 
 
Acetaminophen/paracetamol (e.g., 500–1000 mg) orally at  30 minutes before the 
start of all infusions 
 
Antihistamine, such as diphenhydramine (e.g., 50–100 mg),  30 minutes before the 
start of each infusion (unless contraindicated) 
 
4.4.1.3 
Premedication for Patients at High Risk for Tumor Lysis 
Syndrome 
Patients with high tumor burden and considered by the investigator to be at risk for 
tumor lysis should also receive tumor lysis prophylaxis prior to the initiation of treatment.  
Patients should be well hydrated.  Starting 1–2 days prior to the first dose of study 
treatment, it is desirable to maintain a fluid intake of approximately 3 L/day.  In addition, 
all patients with high tumor burden and considered to be at risk for tumor lysis should be 
treated with 300 mg/day of allopurinol orally or a suitable alternative treatment 
(e.g., rasburicase), starting approximately 48–72 hours prior to Cycle 1 Day 1 of 
treatment and hydration.  Patients should continue to receive repeated prophylaxis if 
deemed appropriate by the investigator and adequate hydration prior to each 
subsequent cycle of treatment. 
4.4.1.4 
Prophylaxis for Infections 
Anti-infective prophylaxis for pneumocystis and herpesvirus infections is mandatory and 
should be instituted per institutional practice or investigator preference based on 
individual patient risk factors.  Patients in countries where prophylactic anti-viral 
medications for hepatitis B reactivation are the standard of care, patients should be 

 
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treated prophylactically (Flowers et al. 2013; NCCN 2017).  All anti-infective prophylaxis 
should be recorded appropriately in the eCRF. 
With reference to coronavirus disease 2019 (COVID-19) vaccines, an assessment was 
conducted to determine whether there is any impact of the COVID-19 vaccines on the 
benefit-risk assessment of this study protocol.  Given the mechanism of action of 
rituximab, it is expected that the efficacy of COVID-19 vaccines may be diminished in 
patients who are B-cell depleted.  The investigator should use clinical judgement to 
decide on the most suitable timing of vaccination, and where possible, COVID-19 
vaccines should be administered to patients before they start immunosuppressive 
therapy.  The COVID-19 vaccines may also be administered at any time during the 
study provided they are non-live vaccines.  If administered during the study, the 
COVID-19 vaccines are considered concomitant medications.  The COVID-19 vaccines 
must be administered in accordance with the approved/authorized vaccine label (or 
equivalent) and official immunization instructions.  Based on this assessment, no 
additional risk mitigation measures related to COVID-19 vaccination are proposed at 
this time.  The recommendations listed above and the current safety monitoring and 
management guidelines and risk-mitigation measures provided in the study protocol are 
considered adequate. 
4.4.1.5 
Treatment and Prophylaxis of Neutropenia 
The administration of granulocyte colony-stimulating factor (G-CSF) as a primary 
prophylaxis in each cycle of therapy is required and should be administered as per 
local/institutional guidelines.  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. 
4.4.1.6 
Monitoring and Treatment for Hepatitis B Reactivation 
Patients with occult or prior HBV infection (defined as negative HBsAg and positive 
hepatitis B core antibody [HBcAb]) may be included in this study if HBV DNA is 
undetectable.  These patients should have HBV DNA levels obtained on Day 1 of every 
cycle and for at least 12 months after the last cycle of study treatment 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’s 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  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 

 
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hepatologist for management.  Patients may resume study treatment once the HBV DNA 
levels decrease to undetectable levels. 
If a patient’s HBV DNA level exceeds 100 IU/mL while the patient is receiving anti-viral 
medication, study treatment will be permanently discontinued (see Section 5.1.2.3, 
Table 14). 
Patients in countries where prophylactic anti-viral medications for hepatitis B reactivation 
are the standard of care may be treated prophylactically. 
4.4.1.7 
Other Concomitant Medications 
Necessary supportive measures for optimal medical care will be given throughout the 
study according to institutional standards, including the use of growth factors 
(e.g., erythropoietin or G-CSF), if clinically indicated. 
Anti-emetic therapy may be instituted for any patient if clinically indicated. 
4.4.2 
Cautionary Therapy 
Caution should be exercised in the administration of oxaliplatin in patients with a history 
or a predisposition for prolongation of QT, those who are taking medicinal products 
known to prolong QT interval, and those with electrolyte disturbances such as 
hypokalemia, hypocalcemia, or hypomagnesemia.  The QT interval should be closely 
monitored on a regular basis before and after administration of oxaliplatin.  
Electrocardiogram recordings will be obtained at specified timepoints, as outlined in the 
Schedule of Activities (see Appendix 1  and Appendix 2), and as clinically indicated.  In 
case of QT prolongation, oxaliplatin treatment should be discontinued, as per the SmPC. 
4.4.2.1 
Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes 
Mono-methyl auristatin E is a substrate of the CYP450 enzymes, specifically CYP3A.  
Published data suggest that MMAE is neither an inhibitor nor inducer of CYP3A.  
Patients who are receiving strong CYP3A inhibitors should be closely monitored for 
adverse reactions when given polatuzumab vedotin (Han et al. 2013). 
Mono-methyl auristatin E is a P-glycoprotein (P-gp) substrate, but not a P-gp inhibitor.  
Concomitant medications that are P-gp inhibitors should be considered cautionary, as 
they may potentially lead 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. 
Other medications that are not prespecified study treatments may need to be used with 
caution in this study.  The investigator should consult the prescribing information and 
contact the Medical Monitor if questions arise regarding the safe use of any concomitant 
medication. 

 
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4.4.2.2 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles and potential drug-drug interactions are generally 
unknown.  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 concomitant therapies is prohibited as described below: 
 
Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 2 weeks prior to initiation of study treatment and during study treatment. 
 
Cytotoxic chemotherapy, other than gemcitabine, oxaliplatin, and intrathecal 
chemotherapy for CNS prophylaxis 
 
Immunotherapy or immunosuppressive therapy for the purpose of treating 
lymphoma, other than study treatments 
 
Radioimmunotherapy 
 
Hormone therapy, other than contraceptives, stable hormone-replacement therapy, 
or megestrol acetate 
 
Biologic agents for the treatment of lymphoma 
– 
Biological agents that are supportive therapies, such as hematopoietic growth 
factors, are allowed if clinically indicated and used in accordance with 
instructions provided in the package inserts. 
 
Any therapy (other than intrathecal CNS prophylaxis) intended for the treatment of 
lymphoma, whether it is approved by the European Medicines Agency or the 
U.S. Food and Drug Administration (FDA) or is experimental 
 
Radiotherapy 
 
Immunizations 
– 
Patients who participate in this study may not receive either primary or booster 
vaccinations with live virus vaccines for at least 28 days before initiation of 
rituximab, at any time during study treatment, or until B-cell recovery.  
Investigators should review the vaccination status of potential study patients 
being considered for this study and follow the U.S. Centers for Disease Control 
and Prevention guidelines for adult vaccination with non-live vaccines intended 
to prevent infectious diseases before study therapy. 
 
Patients who require the use of any of these agents will be discontinued from study 
treatment. 

 
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4.5 
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study are provided in Appendix 1 
and Appendix 2.  All activities must 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 
all eligibility criteria before enrollment.  The investigator will maintain a detailed record of 
all patients screened and to document eligibility or record reasons for screening failure, 
as applicable. 
4.5.2 
Medical History, Concomitant Medication, and Demographic 
Data 
Medical history, including 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, and reproductive status will be recorded at baseline.  In addition, all 
medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 7 days prior 
to initiation of study treatment until 28 days after the last dose of study drug will be 
recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity, since this is a 
global study and Non-Hodgkin's lymphoma, in epidemiological studies, has been shown 
to vary in incidence, histological subtypes, age of presentation and responses to 
treatment based on race and 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, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems (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).  Any abnormality identified at baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF. 

 
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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. 
Limited, symptom-directed physical examinations should be performed at specified post 
baseline visits and as clinically indicated.  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]).  Limited physical exam should also monitor 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.  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, 
systolic and diastolic blood pressure while the patient is in a seated or supine position, 
and temperature.  Weight, height, and BSA will also be recorded.  Height and BSA are 
required at screening only, unless there has been  10% change in body weight since 
the last BSA assessment, in which case BSA should be recalculated and documented in 
the eCRF. 
4.5.5 
Assessment of the International Prognostic Index 
The IPI is a clinician-assessed tool that is prognostic of OS in patients with NHL 
(International Non-Hodgkin's Lymphoma Prognostic Factors 1993) (Section 1.1.3).  The 
instrument is based on measurements of five clinical factors, including age, 
serum LDH level, ECOG performance status, cancer stage, and extra-nodal site 
involvement. 
The method for assessing IPI is described in Appendix 9. 
4.5.6 
Assessment of Eastern Cooperative Oncology Group 
Performance Status 
The ECOG performance status is a clinician-assessed tool that describes a patient’s 
level of functioning in terms of their ability to care for themselves, daily activity, and 
physical ability (walking, working, etc.) (ECOG-ACRIN Cancer Research Group 2018). 
The method for assessing ECOG performance status is described in Appendix 8. 

 
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4.5.7 
Assessment of the Functional Assessment of Cancer 
Therapy/Gynecologic Oncology Group-Neurotoxicity 12-Item 
Scale 
The FACT/GOG-NTX-12 is a 12-item patient-reported outcome instrument that was 
designed to measure chemotherapy-induced PN (Kopec et al. 2006).  Individual items 
on the subscale assess sensory neuropathy, motor neuropathy, hearing neuropathy, and 
dysfunction associated with neuropathy; in addition, there is one item specific to 
oxaliplatin.  The FACT/GOG-NTX-12 takes approximately 5 minutes to complete. 
The FACT/GOG-NTX-12 is provided in Appendix 10. 
4.5.8 
Tumor and Response Evaluations 
Response will be assessed by the investigator and, for CR and ORR in Stage 2, by an 
Independent Review Committee on the basis of physical examinations and PET-CT 
scans using Lugano Response Criteria (Cheson et al. 2014) (Appendix 5).  Scans will be 
carried out as follows (see also Appendix 1 and Appendix 2): 
 
Screening:  PET-CT scan 
 
Mid-Treatment:  PET-CT scan or CT scan 
– 
Completed between Cycle 4, Day 15 and Cycle 5, Day 1 
 
End of Treatment:  PET-CT scan 
 
Long-Term Follow-up:  CT scans or PET-CT (if indicated) 
– 
Completed every 6 months until progression or the end of the study, whichever 
comes first 
 
All primary imaging data used for tumor assessments until end of treatment will be 
collected by the Sponsor to enable centralized, independent review of response 
endpoints by an IRC; IRC assessments of CR and ORR in Stage 2 are mandated in this 
study (see Section 2). 
Positron emission tomographycomputed tomography scans should include skull-base 
to mid-thigh.  Full-body PET-CT scan should be performed when clinically appropriate.  
Image enhancement systems (such as GE Healthcare’s Q.Clear or similar) must not be 
used. 
Computed tomography scans with IV contrast should include chest, abdomen, and 
pelvic scans; CT scans of the neck should be included if clinically indicated.  Computed 
tomography 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, or MRI 

 
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scans are permitted so long as they permit consistent and precise measurement of target 
lesions during the study treatment period. 
Positron emission tomography scans, in conjunction with diagnostic-quality CT scans, 
will be obtained in this study at the times indicated in the Schedule of Activities 
(Appendix 1 and Appendix 2).  Computed tomography scans without PET scans will also 
be obtained at the times indicated in the Schedule of Activities (Appendix 1 and 
Appendix 2).  Lugano Response Criteria (Appendix 5) will be used to assess overall 
response to study treatment. 
The same CT/MRI assessment modality should be used for all response evaluations to 
ensure consistency across different timepoints (Note:  PET-CT is mandatory at the 
screening and end-of-treatment assessments). 
A full tumor assessment including radiographic assessment must be performed any time 
disease progression or relapse is suspected. 
Patients with a response of PR or CR for whom subsequent therapy is indicated 
(e.g., CAR-T therapy or autologous stem cell transplantation) will continue on study and 
remain evaluable. 
Bone marrow biopsies: As noted in guidelines from the National Comprehensive 
Cancer Network and the European Society for Medical Oncology, focal uptake of FDG 
into bone marrow during PET-CT is more sensitive than bone marrow biopsy for 
assessing infiltration in DLBCL and is highly specific.  Thus, bone marrow biopsies are 
not mandated in this study.  However, bone marrow biopsies prior to treatment should 
be mandatory for transformed DLBCL patients to check for occult bone marrow 
involvement by follicular lymphoma, which may not show on PET-CT.  Moreover, at the 
discretion of the investigator, bone marrow biopsies may be conducted in patients with 
negative bone signal on PET-CT if he or she feels the results could change prognosis 
and treatment. 
If bone marrow biopsies are conducted, the results will be collected on the eCRF. 
4.5.9 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
 
Hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes) 
 
Serum or plasma chemistry: sodium, potassium, chloride, bicarbonate (or CO2), 
glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total 
and (if available) direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, and 
LDH 
 
Coagulation: INR or PT, and PTT or aPTT 

 
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 
Viral serology: 
– 
HIV 
For patients with unknown HIV status, HIV testing will be performed at 
Screening if required by local regulations. 
– 
Hepatitis B surface antibody, HBsAg, and total HBcAb 
– 
HBV-DNA by PCR if the patient is HBcAb positive 
– 
HCV antibody 
– 
HCV RNA by PCR if the patient is HCV antibody positive 
 
Pregnancy test 
– 
All women of childbearing potential will have a serum pregnancy test at 
screening.  Monthly pregnancy testing should be performed for medicinal 
products (IMPs or protocol-mandated NIMPs) that are genotoxic or have 
demonstrated or suspected teratogenicity. 
 
The following samples will be sent to the Sponsor or a designee for analysis: 
 
Stage 1 and Stage 2 in Pola-R-GemOx Patients: 
– 
PK blood samples 
Blood samples for PK analysis of polatuzumab vedotin:  Serum 
polatuzumab vedotin total antibody (which includes all drug-to-antibody 
ratio [DAR] species, including DAR 0 and DAR  1), plasma 
polatuzumab vedotin conjugate (evaluated as antibody-conjugated MMAE), 
and plasma unconjugated MMAE concentrations will be quantified with the 
use of validated methods.  At the discretion of the Sponsor, these samples 
may also be analyzed for other potential catabolites, if considered 
necessary. 
Depending on the ongoing assessment of study data, the frequency of 
polatuzumab vedotin PK sampling may be halted or reduced later in the 
study.  Pharmacokinetic samples may be used for additional exploratory 
biomarker analyses. 
– 
ADA blood samples 
Serum samples for anti-polatuzumab vedotin antibody:  A validated 
antibody-bridging ELISA will be used to screen for and confirm the 
presence of anti-polatuzumab vedotin antibodies in patient samples, as 
well as to characterize and determine the titer of confirmed ADA-positive 
samples. 
Depending on the ongoing assessment of study data, the frequency of 
polatuzumab vedotin ADA sampling may be halted or reduced later in the 
study. 

 
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 
Stage 2 ONLY: 
– 
Exploratory biomarker research may include, but will not be limited to, analysis 
of protein expression, analysis of genes or gene signatures, analysis of 
circulating tumor DNA, analysis of circulating lymphocytes.  Research may 
involve extraction of DNA, ctDNA, or RNA; analysis of mutations, single 
nucleotide polymorphisms, and other genomic variants; and genomic profiling 
through use of NGS of a comprehensive panel of genes.  Next‑generation 
sequencing methods may include whole genome sequencing (WGS) or whole 
exome sequencing (WES) of tissue.  DNA extracted from blood may be used to 
identify somatic variants by distinguishing germline variants from somatic 
variants.  Analysis will be focused on genome variations that are not inherited. 
– 
Mandatory, newly-collected DLBCL tumor tissue sample at baseline (or 
archival sample if fresh sample not available) and blood and plasma samples 
for biomarker research (see Appendix 3) 
Analysis of biomarker testing on DLBCL tumor tissue and plasma samples 
will be performed at central laboratories. 
Exploratory biomarker research may include but will not be limited to the 
biomarkers listed in Table 12 .  Results from biomarker research will not 
be shared with investigators or study participants unless required by law, 
given the complexity and exploratory nature of these analyses. 
Biological samples, if not used up, will be destroyed within 5 years after the 
final clinical study report has been completed. 
For enrolled patients, remaining archival tissue blocks will be returned to 
the site upon request or 18 months after final closure of the study 
database, whichever occurs first.  For patients who are not enrolled, 
remaining archival tissue blocks will be returned to the site no later than 6 
weeks after eligibility determination.  Availability of archival or freshly 
biopsied DLBCL tumor tissue samples should be confirmed at screening.  
If the patient has had anti-lymphoma treatment between the time of the 
prior biopsy and the time of study treatment initiation, a core-needle biopsy 
is recommended, if feasible and safe by investigator judgment.  
Formalin-fixed paraffin-embedded tissue blocks are preferred over slides.  
If a tissue block is not available, a minimum of 1015 slides (15 preferred, 
or in accordance with local regulatory requirements) serial, freshly cut, 
unstained slides is acceptable. 
If archival tissue is unavailable or unacceptable according to above criteria, 
a pretreatment core needle, excisional, or incisional tumor biopsy is 
required if feasible and safe by investigator judgment.  Cytological or fine-
needle aspiration samples are not acceptable. 
For sampling procedures, storage conditions, and shipment instructions, 
see the laboratory manual. 
 

 
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Biological samples will be destroyed no later than the time of completion of the final 
Clinical Study Report, with the following exceptions:  screening DLBCL tumor tissue, 
plasma and/or serum samples collected for PK, ADA, and biomarker analyses may be 
needed for assay development, validation, additional characterization (such as 
neutralizing antibody analysis) and additional safety and immunogenicity assessments, 
as appropriate;  therefore, these samples will be destroyed no later than 5 years after 
the final Clinical Study Report has been completed. 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
4.5.10 
Electrocardiograms 
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
Schedule of Activities (see Appendix 1 and Appendix 2) and as clinically indicated. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site. 
Caution should be exercised in the administration of oxaliplatin in patients with a history 
or a predisposition for prolongation of QT, those who are taking medicinal products 
known to prolong QT interval, and those with electrolyte disturbances such as 
hypokalemia, hypocalcemia, or hypomagnesemia.  The QT interval should be closely 
monitored on a regular basis before and after administration of oxaliplatin.  In case of QT 
prolongation, oxaliplatin treatment should be discontinued, as per the SmPC. 
4.5.11 
Clinical Outcome Assessment 
Patient-reported outcome PRO instruments will be completed to assess the treatment 
benefit and more fully characterize the safety profile of polatuzumab vedotin.  In addition, 
PRO instruments will enable the capture of each patient’s direct experience with 
polatuzumab vedotin. 
PRO data will be collected through use of the following instruments:  
FACT/GOG‑NTX‑12, EQ-5D-5L, EORTC QLQ-C30, and FACT/Lym.  Details about 
these instruments are provided in Section 4.5.11.2. 
The questionnaires, translated into the local language as appropriate, will be completed 
in their entirety at specified timepoints during the study.  To ensure instrument validity 
and that data standards meet health authority requirements, questionnaires will be self-
administered before the patient receives any information on disease status, prior to the 

 
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performance of non-PRO assessments, and prior to the administration of study 
treatment, unless otherwise specified. 
4.5.11.1 
Data Collection Methods for Clinical Outcome Assessments 
PRO instruments will be self-administered at the clinic at specified timepoints during the 
study (see schedule of activities in Appendix 1) and at home every second month during 
the long term follow up.  At the clinic, instruments will be administered 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, unless otherwise 
specified. 
PRO instruments, translated into the local language as appropriate, will be provided by 
the Sponsor in preprinted booklets to enable the instrument to be administered at each 
specified timepoint. 
During clinic visits, PRO instruments should be administered as outlined below: 
 
Patients' health status should not be discussed prior to administration of the 
instruments. 
 
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol. 
 
Sites should allow sufficient time for patients to complete the instruments, estimated 
to be approximately 30 minutes at each specified visit. 
 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
 
Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers. 
 
Site staff should not interpret or explain questions but may read questions verbatim 
upon request. 
 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
 
Site staff should review all completed instruments and should ask the patient to 
rectify any response that is not clearly marked in the appropriate location.  If a 
response is missing, site staff should ask the patient to complete the item or confirm 
that the item was intentionally left blank. 
 
During the follow up period, PRO questionnaires may be completed at home and 
returned to the clinic.  Patients should be given the following instructions for completing 
PRO instruments at home: 
 
Patients should complete the instruments in a quiet area with minimal distractions 
and disruptions. 
 
Patients should answer questions to the best of their ability; there are no right or 
wrong answers. 

 
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 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
 
4.5.11.2 
Description of Clinical Outcome Assessments Instruments 
The FACT/GOG-NTX-12 (Appendix 10) is a 12-item patient-reported outcome 
instrument that was designed to measure chemotherapy-induced PN (Kopec et al. 
2006).  Individual items on the subscale assess sensory neuropathy, motor neuropathy, 
hearing neuropathy, and dysfunction associated with neuropathy; in addition, there is 
one item specific to oxaliplatin.  The FACT/GOG-NTX-12 takes approximately 5 minutes 
to complete. 
The EQ-5D-5L is a validated self-report health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses (EuroQol 1990; 
Brooks 1996; Herdman et al. 2011; Janssen et al. 2013) (Appendix12).  There are two 
components to the EQ-5D-5L:  a five-item health state profile that assesses mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression, as well as a visual 
analogue scale (VAS) that measures health state.  Published weighting systems allow 
for creation of a single composite score of the patient's health status.  The EQ-5D-5L 
takes approximately 5 minutes to complete.  It will be used in this study for informing 
pharmacoeconomic evaluations. 
The EORTC QLQ-C30 is a validated, reliable self-report measure (Aaronson et al. 1993; 
Fitzsimmons et al. 1999) (Appendix 13).  It consists of 30 questions that assess five 
aspects of patient functioning (physical, emotional, role, cognitive, and social), three 
symptom scales (fatigue, nausea and vomiting, pain), global health/quality of life, and six 
single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties) with a recall period of the previous week.  Scale scores can be obtained for 
the multi-item scales.  The EORTC QLQ C30 module takes approximately 10 minutes to 
complete. 
The FACT-Lym is a validated HRQoL instrument used specifically in patients with 
lymphoma.  It is composed of the 27-item FACT-G, which measures health-related 
quality of life in patients undergoing any type of cancer therapy, plus the 15-item 
Lymphoma-Specific Subscale (FACT-Lym LYMS; range 0–60), which assesses the 
HRQoL impacts of more lymphoma-specific symptoms (Cella et al. 1993; Cella et al. 
2005) (Appendix 11).  Functional Assessment of Cancer Therapy–General 
Questionnaire items are divided into four primary HRQoL domains: physical well-being 
(PWB; seven items; range, 0–28), social/family wellbeing (SWB; seven items; range, 0–
28), emotional well-being (EWB; six items; range, 0–24), and functional well-being 
(FWB; seven items; range, 0–28).  The FACT‑Lym LYMS consists of common 
lymphoma disease and/or treatment-related symptoms (e.g., pain, fever, swelling, night 
sweats, insomnia, itching, weight loss, fatigue, and loss of appetite).  Three summary 
scales: FACT-Lym trial outcome index (FACT-Lym TOI; range, 0–116; composed of the 
PWB, FWB, and FACT-Lym LYMS scales); FACT-G (range, 0–108; composed of the 

 
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PWB, FWB, SWB, and EWB), and the FACT-Lym total score (FACT-Lym TOT, range, 
0–168; composed of all of the scales) can also be calculated.  Higher scores are 
reflective of better HRQoL.  Each item of the FACT-Lym is answered using a 5-point 
Likert scale ranging from 0  “not at all” to 4  “very much”.  The FACT-Lym takes 
approximate 5–10 minutes to complete. 
Clinically meaningful minimally important differences (i.e., the smallest amount of 
change considered important to patients) at the individual subscale and FACT-Lym TOT 
level are prespecified and will be used to define the proportion of patients reporting 
meaningful changes on the FACT-Lym LYMS (  3 points), FACT-Lym TOI (  6 points), 
and FACT-Lym TOT (  7 points) as a result of treatment (Carter et al. 2008). 
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 determines it is in the best interest of the patient 
 
Grade 4 IRR 
– 
The patient should be withdrawn from study treatment immediately and 
polatuzumab vedotin, rituximab, gemcitabine, and oxaliplatin treatment should 
be permanently discontinued. 
 
Recurrence of Grade 3 IRR at rechallenge 
 
Infusion-related Grade  3 wheezing, hypoxia, or generalized urticaria 
 
Grade  3 hematological toxicity that does not resolve to Grade  2 or baseline value 
within  14 days after last dose and that has a reasonable possibility of being related 
to the administration of any of the study drugs for both arms following the 
recommended dose reduction (Table 14) 
 
Multiple recurrences of Grade 4 neutropenia with infection despite G-CSF support, 
at clinician’s discretion 
 
Grade 4 PN 
 
Discontinue polatuzumab vedotin and oxaliplatin if patient develops Grade  2 PN 
that does not improve to Grade  1 by Day 15 after the scheduled date for next 
cycle (Table 1) 
 
Discontinue polatuzumab vedotin if patient previously had Grade 2 PN that 
resulted in dose reduction of polatuzumab vedotin or oxaliplatin and Grade  ≥ 2 PN 
recurs and improves to Grade ≤ 1 within 14 days after scheduled date of next cycle 
(Table 1) 
 
Discontinue oxaliplatin if patient previously had a dose reduction of oxaliplatin 
and a discontinuation of polatuzumab vedotin and Grade ≥ 2 PN recurs (Table 1) 

 
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 
Discontinue all study treatment if patient previously had Grade 3 PN and 
Grade ≥ 2 PN recurs (Table 1)   
 
Disease progression 
 
Pregnancy 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  During Stage 2, patients who discontinue study treatment 
prematurely will not be replaced. 
All patients will return to the clinic for an End of Treatment/Discontinuation Visit 28 days 
after the last dose of study drug (see Appendix 1 and Appendix 2 for additional details).  
After treatment discontinuation, information on survival follow-up and new anti-cancer 
therapy will be collected via clinic visits, telephone calls, and/or patient medical records 
approximately every 2 months until the end of the study (unless the patient withdraws 
consent or the Sponsor terminates the study). 
4.6.2 
Patient Discontinuation from 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 patient 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 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Patient non-compliance, 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 
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. 
At least three documented attempts to contact a patient is required before considering a 
patient lost to follow up. Of these three attempts two should involve calls to the patient or 

 
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the patients’ primary care provider at different times of the day and one should include 
written communication to the patients’ home address. 
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 
 
Noncompliance 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 
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 in Section 5.1.1.1.  Please refer 
to the Polatuzumab Vedotin Investigator's Brochure for a complete summary of safety 
information. 
Please refer to the Rituximab Investigator’s Brochure for a complete summary of safety 
information for rituximab.  Please refer to the gemcitabine SmPC and the oxaliplatin 
SmPC for complete summaries of safety information for gemcitabine and oxaliplatin. 
Finally, a potentially important safety risk (thrombocytopenia) for Pola-R-GemOx and 
R-GemOx combination therapy is outlined below in Section 5.1.1.4. 
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.  A safety run-in will assess PN risk of Pola-R-GemOx combination therapy 
prior to randomization to the two study treatments.  Patients will undergo safety 

 
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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. 
5.1.1 
Risks Associated with Study Treatment 
5.1.1.1 
Risks Associated with Polatuzumab Vedotin 
The clinical safety profile of polatuzumab vedotin is based on clinical data obtained in 
ongoing and completed studies.  On the basis of clinical data to date, the risks are 
described below.  Guidelines for management of these risks through dose and schedule 
modifications are described in Table 14  of Section 5.1.2.3 (Management Guidelines).  
See the Polatuzumab Vedotin Investigator’s Brochure for full information on the risks 
associated with polatuzumab vedotin. 
Peripheral Neuropathy (Sensory and/or Motor) 
Patients receiving polatuzumab vedotin may develop PN, including peripheral sensory 
and/or motor neuropathy.  These events have generally been reversible to varying 
degrees, 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 PN may require 
a dose delay, dose reduction, or discontinuation of treatment and should be managed 
according to the protocol.  Monitoring will include the use of the NCI CTCAE v5.0 and 
the FACT/GOG‑NTX‑12 (Appendix 10). 
Study treatment dose and schedule modifications for PN are described in Section 5.1.2. 
Myelosuppression:  Consolidation of Neutropenia (Including Febrile 
Neutropenia), Thrombocytopenia, and Anemia 
Neutropenia and neutropenia-associated events (e.g., febrile neutropenia, 
thrombocytopenia, and anemia, including serious and severe cases) have generally 
been reversible but in some cases have resulted in protocol-mandated dose reductions 
and/or delays.  Adequate hematologic function, including RBCs and platelets, should be 
confirmed before initiation of study treatment.  Patients receiving study treatment will be 
regularly monitored for evidence of marrow toxicity with complete blood counts.  Study 
treatment for hematologic toxicities may be delayed or modified as described in Section 
5.1.2.  The use of G-CSF for neutropenia is described in Section 5.1.2.3 (Table 14).  
G-CSF primary prophylaxis is required for neutropenia.  The decision not to administer 
G-CSF as primary prophylaxis should be discussed with the Medical Monitor.  
Transfusion support for anemia and thrombocytopenia is permitted at the discretion of 
the investigator. 

 
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Infections 
Patients receiving polatuzumab vedotin may be at a higher risk of developing infections.  
Serious infections, including opportunistic infections, such as pneumonia (including 
pneumocystis jirovecii and other fungal pneumonia), bacteremia, sepsis, herpes 
infection, and cytomegalovirus infection have been reported in patients treated with 
polatuzumab vedotin.  Several other risk factors in the patient population under study 
influencing patients’ vulnerability to a higher risk of infections, particularly serious and 
opportunistic infection, include predisposition of the indication disease to infections, 
elderly population, and comorbidity.  The use of anti-infective prophylaxis is required for 
patients on study and is described in Section 4.4.1.4.  
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. 
Infusion-Related Events 
Infusion-related events 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. 
All patients will be monitored for infusion reactions during the infusions and immediately 
afterwards (for additional instructions on the monitoring and management of infusion 
reactions, see Section 5.1.2).  Recommended management of suspected anaphylactic 
reactions during study drug infusions is provided in Appendix 7.  For premedication 
guidance for polatuzumab vedotin infusion, see to Section 4.3.2.1. 
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. 
Progressive Multifocal Leukoencephalopathy 
One case of progressive multifocal leukoencephalopathy (PML) has been reported with 
polatuzumab vedotin treatment.  Patients should be monitored closely for new or 
worsening neurological, cognitive, or behavioral changes suggestive of PML.  
Polatuzumab vedotin and any concomitant chemotherapy should be held if PML is 
suspected and permanently discontinued if the diagnosis is confirmed. 

 
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Tumor Lysis Syndrome 
Tumor lysis syndrome is a risk if treatment with polatuzumab vedotin results in the rapid 
destruction of a large number of tumor cells.  If any evidence of this occurs during the 
study, tumor lysis prophylaxis measures will be taken.  Patients who are considered to 
have a high tumor burden (e.g., lymphocyte count  25 × 109/L or bulky 
lymphadenopathy) and who are considered to be at risk for tumor lysis by the 
investigator will receive tumor lysis prophylaxis (e.g., allopurinol  300 mg/day orally or a 
suitable alternative treatment [according to institutional practice] starting 12–24 hours 
before study treatment) and must be well hydrated before the initiation of study 
treatment at Cycle 1 Day 1.  These patients should continue to receive repeated 
prophylaxis with allopurinol and adequate hydration before each subsequent infusion, as 
deemed appropriate by the investigator. 
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.  Given the possibility of 
irreversible infertility with polatuzumab vedotin, advice should be provided to patients 
regarding the option of cryopreservation of sperm prior to the start of study treatment. 
Hyperglycemia 
Hyperglycemia has been observed in patients treated with polatuzumab vedotin and with 
other ADCs that use the same vc-MMAE platform.  Hyperglycemia has been reversible 
upon holding or discontinuing treatment of the ADCs and/or initiation or adjustment of 
standard-of-care antihyperglycemic medications. 
Hepatotoxicity 
Hepatotoxicity has been observed in patients treated with polatuzumab vedotin in both 
Phase I and Phase II trials.  Although the relationship between hepatotoxicity and 
polatuzumab vedotin has not been definitively determined, transient, dose-related 
increases in hepatic enzymes were noted in nonclinical rat studies.  No hepatotoxicity 
was noted following administration of the surrogate ADC in cynomolgus monkeys. 

 
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Elevations of transaminases have been reported in patients receiving polatuzumab 
vedotin and have ranged in intensity from Grades 14.  These have been reversible with 
and without dose modification/discontinuation.  Liver enzymes and bilirubin level should 
be monitored.  For additional information, please refer to the current 
Polatuzumab Vedotin Investigator’s Brochure. 
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. 
5.1.1.2 
Risks Associated with Rituximab 
See the current Rituximab Investigator’s Brochure for full information on the risks 
associated with rituximab. 
For rituximab dose delay and discontinuation instructions, see Table 1. 
5.1.1.3 
Risks Associated with Gemcitabine and Oxaliplatin 
See the Package Insert/SmPC for gemcitabine and oxaliplatin for full information. 
For gemcitabine and oxaliplatin dose delay, modification, and discontinuation 
instructions, see Table 1.  
5.1.1.4 
Risks Associated with Pola-R-GemOx and R-GemOx 
Combination Therapy 
Pola-R-GemOx and R-GemOx may have the potential to lead to severe 
thrombocytopenia due to the cumulative hematologic toxicities of component agents.  
Patients treated with concomitant anticoagulants may therefore be at a greater risk for 
bleeding. 
Treating physicians should consider switching patients already on oral anticoagulation to 
LMWH prior to Cycle 1 Day 1, if possible.  Decisions on treatment and dose of 
anticoagulants and anti-platelet agents in patients with severe thrombocytopenia 
( 50 g/L) should be made on a case-by-case basis.  More frequent monitoring of the 
complete blood count (CBC) or platelet transfusions may be required at the discretion of 
the treating physician. 
5.1.2 
Management of Patients Who Experience Adverse Events 
5.1.2.1 
Dose Modifications 
Patients should be assessed clinically for toxicity before each dose of study treatment 
(Pola-R-GemOx or R-GemOx) using NCI CTCAE v5.0, unless otherwise stated.  
Dose modifications should be based on physical examination findings, observed 
toxicities, and laboratory results obtained within 72 hours before study treatment 

 
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administration.  Dosing will occur only if a patient’s clinical assessment and laboratory 
test values are acceptable.  Dose modifications due to adverse events not specified in 
this protocol should proceed on the principle of maintaining a dose intensity of 100%.  
The determination of all dose modifications will be made on the basis of the 
investigator’s assessment of ongoing clinical benefit with continuing study treatment.  All 
decisions regarding dose delays, modifications, and discontinuations may be discussed 
with the Medical Monitor if desired. 
Polatuzumab vedotin 
Polatuzumab vedotin doses may be reduced per the guidelines in Table 14 . 
Peripheral neuropathy is consistent with the mechanism of action of antibody-conjugated 
MMAE and was frequently reported across all polatuzumab vedotin regimens.  
Cumulative toxicity was observed as the incidence and severity of PN events increased 
when polatuzumab vedotin was dosed beyond 6 cycles or dosed higher than 1.8 mg/kg.  
When polatuzumab vedotin was administered up to 6 cycles in the regimen of pola  BR, 
PN events were almost entirely Grade 1–2 in severity, with most events reaching only 
Grade 1 in peak severity.  Peripheral neuropathy events were effectively managed with 
dose delay/interruption and dose reductions of polatuzumab vedotin if necessary with 
few treatment discontinuations from refractory PN observed. 
A guidance for the management of PN is described in Section 5.1.2.3 (Table 14 ). 
Rituximab 
No dose modifications of rituximab (375 mg/m2) are allowed. 
Gemcitabine 
Gemcitabine may be reduced per the guidelines in Table 14. 
Oxaliplatin 
Oxaliplatin may be reduced per the guidelines in Table 14 . 
5.1.2.2 
Dose Delays/Treatment Interruption 
Patients should be assessed clinically for toxicity before each dose of study treatment 
(Pola-R-GemOx or R-GemOx) using NCI CTCAE v5.0, unless otherwise stated.  
Dose delays/treatment interruptions should be 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 or treatment interruption will occur according to the guidance in Table 14
 
.  Toxicity that leads to a delay of  14 days in the initiation of the next planned 
treatment cycle should require study treatment discontinuation unless the investigator 
assesses an ongoing clinical benefit with continuing study treatment (may discuss with 

 
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the Medical Monitor).  Study treatment may continue with the remaining study drugs 
in the event that one or more study drugs are discontinued. 
5.1.2.3 
Management Guidelines 
Guidelines for management of specific adverse events are outlined in Table 14 .  
Additional guidelines are provided in the subsections below.  Note:  Lymphopenia is not 
considered to be a hematologic toxicity, as it is an expected outcome of therapy. 
Table 14  Guidelines for Management of Patients Who Experience 
Adverse Events 
Event(s) a 
Dose Delay or Modification 
Grade 3 or 4 neutropenia 
 Hold all study treatment until ANC recovers to  1000/µL 
 Administer growth factors, if necessary, per the 
recommendations in Appendix 6 
 If ANC recovers to  1000/µL on or before Day 7, resume all 
study treatment without any additional dose reductions 
 If ANC recovers to  1000/μL after Day 7: 
– 
Restart all study treatment, with dose reduction of 
gemcitabine to 750 mg/m2 for current and subsequent 
cycles 
– 
If gemcitabine dose reduction has already occurred, then 
consider dose reduction of polatuzumab vedotin to 
1.4 mg/kg for current and subsequent cycles 
– 
If both gemcitabine and polatuzumab vedotin have 
already been dose reduced, then discontinue all study 
treatment 
Grade 3 or 4 
thrombocytopenia 
 Hold all study treatment until platelets recover to  75,000/µL 
 If platelets recover to  75,000/µL on or before Day 7, resume 
all study treatment without any additional dose reductions 
 If platelets recover to  75,000/μL after Day 7: 
– 
Restart all study treatment, with dose reduction of 
gemcitabine to 750 mg/m2 for current and subsequent 
cycles 
– 
If gemcitabine dose reduction has already occurred, then 
consider dose reduction of polatuzumab vedotin to 1.4 
mg/kg for current and subsequent cycles 
 If both gemcitabine and polatuzumab vedotin have already 
been dose reduced, then discontinue all study treatment 
 
 
 

 
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Table 14  Guidelines for Management of Patients Who Experience 
Adverse Events, contd. 
Event(s) a 
Dose Delay or Modification 
Grade 2 or 3 PN 
 Delay all study treatment until improvement to Grade  1 
 If recovered to Grade  1 within  14 days after the scheduled 
date of the next cycle:  
– 
Restart study treatment with polatuzumab vedotin at a 
permanently reduced dose of 1.4 mg/kg and oxaliplatin at 
a dose of 75 mg/m2 
– 
If a prior dose reduction to 1.4 mg/kg for polatuzumab 
vedotin or 75 mg/m2 for oxaliplatin has occurred, 
discontinue polatuzumab vedotin alone if the patient 
previously had Grade 2 PN. 
 If not recovered to Grade  1 by Day 15 after the scheduled 
date for the next cycle, oxaliplatin and polatuzumab vedotin 
must be permanently discontinued 
 If the patient previously had Grade 3 PN, discontinue all 
study treatment. 
 If oxaliplatin has been dose reduced and polatuzumab 
vedotin has been discontinued previously, discontinue 
oxaliplatin 
Grade 4 PN (including its 
signs and symptoms) 
 Discontinue all study treatment 
Pharyngolaryngeal 
dysesthesia 
 Prolong oxaliplatin infusion to 6 hours 
Total bilirubin  3.0 mg/dL 
 Delay all 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 all 
study treatment should be discontinued 
Grade 3 or 4 tumor lysis 
syndrome 
 Hold all study treatment.  The patient’s next dose may be 
delayed for up to 14 days. 
 Following complete resolution of TLS, study treatment may 
be re-administered at the full dose during next scheduled 
infusion, in conjunction with prophylactic therapy. 

 
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Table 14  Guidelines for Management of Patients Who Experience 
Adverse Events, contd. 
Event(s) a 
Dose Delay or Modification 
QT-interval prolongation 
 If the QTcF interval increases by  500 msec, or if it 
increases by  60 msec from baseline, oxaliplatin should be 
discontinued. 
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 and may be discussed with 
the Medical Monitor 
Grade 2 non-hematologic 
toxicity 
 Consider delaying study treatment for a maximum of 14 days 
 If improvement to Grade  1 or baseline, continue study 
therapy at full dose, or reduce dose at the discretion of the 
investigator per site’s standard and may be discussed with 
the Medical Monitor 
Grade 1 non-hematologic 
toxicity 
 No dose reduction or delay 
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. 
DILI  drug-induced liver injury; HBV  hepatitis B virus; NCI CTCAE v5.0  National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 5.0; PN  peripheral 
neuropathy; QTcF  QT interval corrected through use of Fridericia’s formula TLS  tumor lysis 
syndrome; ULN  upper limit of normal. 
Notes:  Refer to the NCI CTCAE v5.0 for the grading of symptoms.  Management of 
IgE-mediated allergic reactions should be as directed in the text following this table. 
Note:  All decisions regarding dose delays, modifications, and discontinuations may be discussed 
with the Medical Monitor if desired. 
a All based on laboratory test results obtained within 72 hours before infusion of Day 1 of that 
cycle. 
 
 

 
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Table 15 Management of Infusion-Related Symptoms: Rituximab and 
Polatuzumab Vedotin 
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 patient 
permanently discontinued from study drug. 
Grade 3 
 Discontinue infusion 
 Give supportive treatment a 
 Upon symptom resolution, may resume 
infusion‑rate escalation at the investigator’s discretion. b 
 
Note:  If the same adverse event recurs with same severity, 
treatment must be permanently discontinued. 
 
Notes:  For Grade 3 hypotension or fever, patient must be 
premedicated before re-treatment.  If symptoms recur, then 
patient must be permanently discontinued from study drug. 
 
Note:  If patient has Grade 3 wheezing, bronchospasm, or 
generalized urticaria at first occurrence, patient must be 
permanently discontinued from study drug. 
Grade 4 
 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. 
Notes:  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/hr 
every 30 minutes. 
 

 
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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 5.3.5.13. 
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 Section 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 
 
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) 

 
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 
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 v5.0; 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: 
 
PN Grade  3 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7) 
 
Suspected transmission of an infectious agent by the study 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. 
 
Tumor lysis syndrome of any grade (irrespective of causality) 
 
Progressive multifocal leukoencephalopathy 
 
Systemic hypersensitivity reactions/anaphylactic and anaphylactoid reactions, as 
defined by Sampson’s criteria (see Appendix 14) 

 
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 
Second malignancies 
 
Real time safety monitoring will be employed throughout the trial. 
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 5.3.5.13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 will be reported until 90 days or the 
initiation of NALT after the last dose of study drug. 
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?"  
 

 
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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 16 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE v5.0. 
Table 16 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE v5.0 
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 v5.0  National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0. 
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. 
 
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 17): 
 
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 

 
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 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 17 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. 
5.3.5.1 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study drug administration 
should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of infusion-related reaction). 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events other than infusion-related reactions (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 

 
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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 
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. 

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

 
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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 
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).  The 
IMC in Stage 1 or iDMC in Stage 2 will monitor the frequency of deaths from all causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 

 
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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 Diffuse Large B-Cell 
Lymphoma 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on Lugano 2014 response criteria (see Appendix 5) 
(Cheson et al. 2014).  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. 
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) 

 
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 
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 and adverse events associated with a special situations are to be 
reported separately on the Adverse Event eCRF as outlined in the sections below. 
Reporting Special Situations  
In addition, all special situations associated with polatuzumab vedotin 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. 
 

 
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Reporting Adverse Events Associated with Special Situations 
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 or 
qualifies as an adverse event of special interest, 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 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.  
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF pages, one entry to report the accidental overdose 
(special situation) and one entry to report the adverse event (headache).  The 
"Accidental overdose" and "Medication error" boxes would need to be checked on both 
eCRF pages. 
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) 
 
Accidental overdoses or medication errors (see Section 5.3.5.12 for details on 
reporting requirements) 
 

 
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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 
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/Ethics Committee 
(IRB/EC). 
5.4.1 
Emergency Medical Contacts 
 
To ensure the safety of study participants, access to the Medical Monitors is available 
24 hours per day, 7 days per week.  An Emergency Medical Call Center will also be 
available 24 hours per day, 7 days per week. The Emergency Medical Call Center will 
connect the investigator with an Emergency Medical Contact, provide medical 
translation service if necessary, and track all calls.  Contact information, including 
toll-free numbers for the Emergency Medical Call Center, 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 Adverse Event/Special Situations Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study drug or the initiation 
of NALT.  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. 

 
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In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations 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 last dose 
of study treatment or the initiation of NALT 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 through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during the 
study or within 1 year after the last 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 last dose of study drug.  The investigator should report the 
pregnancy on the paper Clinical Trial Pregnancy Reporting Form and submit the form to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study 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 with additional 
information on the pregnant partner and the course and outcome of the pregnancy 
becomes available.  

 
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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 in a female patient exposed to study treatment or the female 
partner of a male participant exposed to study treatment 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. 
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. 
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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 last 
dose of study drug or the initiation of NALT), 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 Adverse Event/ Special 
Situations Form using the fax number or email address provided to investigators. 
All patients with AEs of PN should be followed up after discontinuation of study 
treatment for possible deterioration (Coasting phenomenon) and thereafter until 
resolution or stabilization. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 
Drug 
Document 
Polatuzumab vedotin 
Polatuzumab Vedotin Investigator's Brochure 
Rituximab 
Rituximab Investigator’s Brochure 
Gemcitabine 
Gemcitabine U.K. Summary of Product Characteristics 
Oxaliplatin 
Oxaliplatin U.K. Summary of Product Characteristics 
 

 
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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. 
The sponsor will monitor the incidence of the above-listed anticipated events during the 
study.  An aggregate report of any clinically relevant imbalances that do not favor the 
test product will be submitted to health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
This is a Phase III, multicenter, open-label, randomized controlled trial designed to 
evaluate safety and efficacy of polatuzumab vedotin administered by IV infusion in 
combination with rituximab, gemcitabine, and oxaliplatin in patients with relapsed or 
refractory DLBCL. 
The analysis populations are defined as follows: 
 
ITT population:  all randomized patients, grouped according to their assigned 
treatment arm, whether or not the assigned study treatment was received 
 
Safety run-in population:  patients who received any amount of any study drug 
during safety run-in phase 
 
Safety population:  patients who received any amount of any study drug during the 
randomized part 
 
PRO-evaluable population:  PRO-evaluable population will include all randomized 
patients who have a baseline and at least 1 post-baseline assessment.  All PRO 
analyses will be performed based on the treatment arm assigned at randomization. 
 
Pharmacokinetic-Evaluable Population:  The PK population includes all patients who 
have received at least one dose of polatuzumab vedotin and have at least one post-
dose polatuzumab vedotin concentration result. 
 
For all efficacy analyses, patients will be grouped according to the treatment assigned at 
randomization.  For all safety analyses, patients will be grouped according to the 
treatment actually received. 
Hypothesis tests will be two-sided, unless otherwise indicated.  The type I error () for 
this study is 0.05 (two-sided). 
Further details of the analyses will be provided in the Statistical Analysis Plan (SAP). 
6.1 
DETERMINATION OF SAMPLE SIZE 
The primary objective of the randomized part of this study is to evaluate the efficacy of 
Pola-R-GemOx versus R-GemOx in patients with relapsed or refractory DLBCL as 

 
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measured by OS.  Assuming a median OS of 
 months in the R-GemOx arm and a 
randomization ratio of 1:1, 
events are required to detect a between-group difference 
of 
 months in the median OS (HR  
) with 
 power and a 2-sided  of 
.  
Based on the above statistical assumptions, and anticipating a recruitment period of 
approximately 19 months and a follow-up of 12 months after the last patient was 
randomized, a total of approximately 250 patients will be randomized, taking into 
account an estimated drop-out rate of 
. 
In addition, approximately 10 patients will be enrolled in the safety run-in stage. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, major protocol deviations including major deviations of inclusion/exclusion 
criteria, and discontinuation from the study will be summarized by treatment arm for all 
randomized patients.  The reasons for study discontinuation will be tabulated. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic variables such as age, sex, race/ethnicity, and baseline characteristics (in 
particular, stratification variables) will be summarized by treatment arm for all 
randomized patients.  Continuous variables will be summarized with use of means, 
standard deviations, medians, ranges, and inter-quartile ranges.  Categorical variables 
will be summarized by proportions. 
The baseline value of any variable will be defined as the last available value prior to the 
first administration of study treatment. 
6.4 
EFFICACY ANALYSES 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy objective for the randomized part of this study is to evaluate the 
efficacy of Pola-R-GemOx compared with R-GemOx in patients with relapsed or 
refractory DLBCL on the basis of the following endpoint: 
 
OS, defined as the time from randomization to the death from any cause during the 
study 
 
The primary efficacy analysis will be completed on the ITT population, with patients 
grouped according to their treatment assigned at randomization. 
Data for patients without death will be censored at the date at which the patient was last 
known to be alive.  Otherwise, data will be censored at the date of randomization. 
Kaplan-Meier methodology will be used to estimate the OS for each treatment arm, and 
Kaplan-Meier curves will be produced.  Overall survival will be compared between 
treatment arms by stratified logrank test.  The hazard ratio (HR) for death will be 
estimated using a stratified Cox proportional hazards model; the stratification factors will 
be the same as the randomization stratification factors by IxRS.  The 95% confidence 

 
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interval (CI) for the HR will be provided.  Brookmeyer-Crowley methodology will be used 
to construct the 95% CI for the median OS for each treatment arm (Brookmeyer and 
Crowley 1982). 
The type I error () for this study is 0.05 (two-sided).  Further details will be included in 
the SAP. 
In case patients become eligible for HSCT and undergo a transplant (in their best 
interest), sensitivity analyses will be performed for OS and PFS to assess the impact this 
may have.  For this, patient data will be censored at the time of transplant. 
6.4.2 
Secondary Efficacy Endpoints 
The following sections detail the analysis planned for the secondary endpoints of the 
randomized part of the study.  Similar analyses will be performed for the safety run-in 
phase, but will be restricted to descriptive statistics. 
To control the overall type I error rate at a two-sided 0.05 level of significance, a 
hierarchical testing procedure will be used to adjust for multiple statistical testing of the 
primary and key secondary efficacy endpoints.  Key secondary endpoints will be tested 
in the following order: 
 
PFS 
 
CRR at end of treatment (based on response including PET-CT data) as determined 
by an IRC 
 
ORR at end of treatment (based on response including PET-CT data) as determined 
by an IRC 
 
A given hypothesis in the bulleted list above will only be rejected once all previous 
hypotheses have been rejected at a 2-sided 0.05 level of significance. 
No multiplicity adjustment will be performed for the testing of other endpoints and should 
be interpreted with caution. 
6.4.2.1 
Complete Response Rate 
Complete response rate is defined as the proportion of patients who had a complete 
metabolic response (based on response including PET-CT data) according to Lugano 
2014 response criteria (Appendix 5) at the end of treatment, as determined by IRC.  
Patients not meeting these criteria, including patients without any post-baseline tumor 
assessment, will be considered non-responders. 
Complete response rate will be analyzed using the intent-to-treat population. 
An estimate of CRR will be calculated for each treatment arm, and its 95% CI will be 
calculated using the Clopper-Pearson method.  The difference in CRR between 
treatment arms will be calculated, and its 95% CI will be calculated using the normal 

 
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approximation to the binomial distribution.  CRR will be compared between treatment 
arms using the stratified Cochran-Mantel-Haenszel test.  The stratification factors will be 
the same as those described for the analysis of the primary endpoint OS. 
The same analysis will be repeated for the CRR using the response not including PET 
data, and therefore considering patients who had complete response instead of 
complete metabolic response, as determined by the investigator and IRC. 
6.4.2.2 
Objective Response Rate 
An objective response is defined as either a complete or partial metabolic responses 
(based on response including PET-CT data) according to Lugano 2014 response criteria 
at end of treatment, as determined by IRC.  Patients not meeting these criteria, including 
patients without any post-baseline tumor assessment, will be considered non-
responders. 
Objective response rate is defined as the proportion of patients who had an objective 
response.  
Objective response rate will be analyzed using the intent-to-treat population. 
An estimate of ORR will be calculated for each treatment arm, and its 95% CI will be 
calculated using the Clopper-Pearson method.  The difference in ORR between 
treatment arms will be calculated, and its 95% CI will be calculated using the normal 
approximation to the binomial distribution.  Objective response rate will be compared 
between treatment arms using the stratified Cochran-Mantel-Haenszel test.  The 
stratification factors will be the same as those described for the analysis of the primary 
endpoint OS. 
The same analysis will be repeated for the ORR using the response not including PET 
data, objective response (based on response not including PET data) being then defined 
as either a complete or partial response (based on response not including PET data) at 
end of treatment, as determined by the investigator and IRC. 
6.4.2.3 
Best Overall Response 
Best overall response (BOR) is defined as the best response while on study (based on 
response including PET-CT or CT data) according to Lugano 2014 response criteria 
(Appendix 5), as determined by investigator. 
Best overall response will be analyzed using the ITT population. 
An estimate of BOR rates will be calculated for each treatment arm, and its 95% CI will 
be calculated using the Clopper-Pearson method. 

 
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6.4.2.4 
Progression-Free Survival 
Progression-free survival will be defined as the time from randomization to the first 
occurrence of disease progression, as determined by the investigator, or death due to 
any cause, whichever occurs first.  Patients who die without a reported disease 
progression will be considered as an event on the date of death.  Patients who have 
neither progressed nor died at the time of analysis (clinical-cut off) and patients who are 
lost to follow-up will be censored on the date of the last evaluable tumor assessment.  
Patients who did not undergo a post-baseline tumor assessment will be censored at the 
time of randomization.  Kaplan-Meier estimates and the associated 95% CIs of the 
median, 25th and 75th percentile will be presented.  The Kaplan-Meier curve will provide 
a visual description of the differences across treatment arms.  Estimates of the treatment 
effect will be expressed as hazard ratios, using a stratified Cox proportional-hazards 
analysis including 95% confidence limits. 
6.4.2.5 
Duration of Response  
Duration of response (DOR) will be assessed in patients who had an objective response, 
as determined by the investigator, using Lugano 2014 response criteria (Appendix 5).  
Duration of response is defined as the time interval from the date of the first occurrence 
of a complete or partial response (whichever status is recorded first) until the first date 
that progressive disease or death is documented, whichever occurs first.  Patients who 
have not progressed and who have not died at the time of analysis will be censored at 
the time of last tumor assessment date.  If no tumor assessments were performed after 
the date of the first occurrence of a complete or partial response, DOR will be censored 
at the date of the first occurrence of a complete or partial response.  Duration of 
response is based on a non-randomized subset of patients (specifically, patients who 
achieved an objective response), therefore, comparisons between treatment arms will be 
made for descriptive purposes.  The methodologies detailed for the PFS analysis will be 
used for the DOR analysis, except that the analysis will not be stratified. 
6.4.2.6 
Event-Free Survival 
Event free survival (EFSeff) is defined as the time from randomization to first to the 
earliest occurrence of the below cases: 
 
Disease progression or relapse  
 
Death due to any cause 
 
Initiation of any NALT 
 
Patients with no EFSeff events will be censored at the time of the last evaluable tumor 
assessment.  Patients who did not undergo a post-baseline tumor assessment will be 
censored at the time of randomization.  The methodologies detailed for the PFS analysis 
will be used for the EFSeff analysis. 

 
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6.4.2.7 
Patient-Reported Outcomes 
The PRO-evaluable population will be used for descriptive analyses of visit summary 
and change from baseline, responder analyses, and mixed-effects model repeated 
measures (MMRM) modeling, unless specified otherwise.  ITT population will be used 
for completion analyses and time-to-deterioration analyses. 
EORTC QLQ-C30 
For EORTC QLQ-C30 questionnaire, summary statistics at each visit and change from 
baseline of linear-transformed scores will be reported for all the items and the subscales. 
Time to deterioration is defined as the time from randomization to the first documentation 
of a 10-point decrease in EORTC QLQ-C30 physical functioning scale from baseline.  
For fatigue, time to deterioration is defined as the time from randomization to the first 
documentation of a 10-point increase from baseline.  Patients who do not have an 
observed deterioration at the time of clinical data cut-off will be censored i) at the last 
non-missing assessment date if post-baseline assessment ii) on the date of 
randomization if no post-baseline assessment.  The hazard ratio for time to deterioration 
will be estimated using a stratified Cox proportional hazards model.  The 95% CI for the 
hazard ratio will be provided.  Kaplan-Meier methodology will be used to estimate the 
time to deterioration for each treatment arm, and Kaplan-Meier curves will be produced.  
Median and 95% CI will be estimated. 
The EORTC QLQ-C30 data will be scored according to the EORTC scoring manual 
(Fayers 2001).  Missing data will be assessed and reported by time point. In the event of 
incomplete data, for all questionnaire subscales, if more than 50% of the constituent 
items are completed, a pro-rated score will be computed consistent with the scoring 
manuals and published validation reports.  For subscales with less than 50% of the 
items completed, the subscale will be considered as missing.  Completion rates will be 
summarized by number and proportion of patients among those expected to complete 
the EORTC QLQ-C30 at each timepoint. 
FACT-Lym Subscale 
For each of the FACT-Lym questionnaire scales, descriptive statistics at each visit and 
changes from baseline will be reported by treatment arm. 
Time to deterioration is defined as the time from randomization to the first documentation 
of a  3-point decrease from baseline (Carter et al. 2008; Hlubocky et al. 2013).  Patients 
who do not have an observed deterioration at the time of clinical data cut-off will be 
censored i) at the last non-missing assessment date if post-baseline assessment ii) on 
the date of randomization if no post-baseline assessment.  The hazard ratio for time to 
deterioration will be estimated using a stratified Cox proportional hazards model. The 
95% CI for the hazard ratio will be provided.  Kaplan-Meier methodology will be used to 
estimate the time to deterioration for each treatment arm, and Kaplan-Meier curves will 
be produced.  Median and 95% CI will be estimated.  Supplemental item-level analyses 

 
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will be conducted with the individual B-symptom items of the FACT-Lym LymS using a 
raw 1-point worsening.  
For missing items within the questionnaire, prorated scores will be calculated according 
to developer guidance (Webster et al. 2003).  PRO completion rates will be summarized 
at each timepoint by treatment arm. 
FACT/GOG-NTX-12 
FACT/GOG-NTX scores will be reported throughout the trial, including during Stage 1 
(Safety Run-In) and Stage 2 (RCT). 
For each of the FACT/GOG-NTX-12 questionnaire scales, descriptive statistics at each 
visit and changes from baseline will be reported by treatment arm. 
For missing items within the questionnaire, prorated scores will be calculated according 
to developer guidance (Calhoun et al. 2003).  PRO completion rates will be summarized 
at each timepoint by treatment arm. 
For neurotoxicity subscale, descriptive statistics at each visit and changes from baseline 
will also be reported on the safety run-in population. 
EQ-5D-5L 
The EQ-5D-5L Questionnaire is a health utility measure to assess patients’ health status 
using 5 dimensions.  All five dimensions can be combined in a five-digit number which 
then describes the patient’s health state.  This descriptive number is converted to a 
single summary index utility score by using published weights; in this study we use the 
UK crosswalk value set (as published by the EuroQol Research Foundation at 
http://www.euroqol.org/about-eq-5d/valuation-of-eq-5d, Devlin et al 2017). 
Additionally, in the second part of the questionnaire, the current health status is 
measured by the visual analog scale (VAS) with values ranging from 0 to 100. 
For each of the EQ-5D-5L assessments over time, the number and percentage of 
patients in each of the five categories for each question will be evaluated.  A summary of 
the EQ-5D-5L index utility score at each visit and the associated change from baseline 
will also be provided by treatment arm.  Similar analysis will be performed for EuroQoL 
visual analog scale (EQ-VAS). 
The index utility score and VAS will be analyzed by mixed linear models.  In addition, the 
proportion of patients who report changes that exceed the clinically meaningful threshold 
on the EQ-5D-5L index and the EQ-VAS scores will be reported.  A clinically meaningful 
improvement threshold is defined as a change of  0.07 points in the index utility score 
and  7 points in the VAS score. 
Further analysis might be conducted separately. 

 
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6.5 
SAFETY ANALYSES 
The safety analysis will be completed on the safety analysis population. The safety 
analysis population will consist of all randomized patients who received at least one 
dose of study drug. 
As described in Section 3.1, the safety run-in will evaluate the benefit-risk profile of 
polatuzumab vedotin plus R-GemOx, with a particular focus on PN, in a stage-gated 
recruitment process.  The decision to continue to the randomized phase of the study will 
be determined on the basis of how many patients have Grade  3 PN after 4 cycles of 
therapy that does not resolve within 14 days (see Section 3.1).  Safety will be assessed 
through summaries of adverse events and study treatment exposures and will be 
presented by treatment arm. 
Verbatim descriptions of adverse events will be summarized by mapped term, 
appropriate thesaurus level, and toxicity grade.  For each patient, if multiple incidences 
of the same adverse events occur, the maximum severity reported will be used in the 
summaries. 
The following treatment-emergent adverse events will be summarized separately: 
adverse events leading to withdrawal of study drug, adverse events leading to dose 
reduction or interruption, Grade  3 adverse events, adverse events leading to death, 
serious adverse events, and adverse events of special interest, see Section 5.2.3.  In 
addition, exposure-adjusted analyses, as well as analysis of recurrent AEs, will be 
provided as appropriate. 
All deaths and causes of death will be summarized. 
Relevant laboratory values will be summarized by time, with NCI CTCAE v5.0 Grade 3 
and Grade 4 values identified, where appropriate.  Changes in NCI CTCAE v5.0 grade 
will be tabulated by treatment arm. 
For Stage 1, PN, as measured by FACT/GOG-NTX-12 score, will be summarized.  In 
addition, the rate of PN based on AE will be calculated, including all patients that have 
completed Cycle 2 or reported this type of event before. 
Descriptive statistics will be presented for cumulative study medication doses, dose 
modifications/interruptions, and duration of exposure.  Electrocardiograms will be 
analyzed descriptively.  Changes in vital signs will be analyzed using descriptive 
statistics for continuous variables. 
Further details of any additional analyses will be provided in the Statistical analysis plan 
(SAP). 

 
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6.6 
PHARMACOKINETIC ANALYSES 
This study incorporates sparse PK sampling of polatuzumab vedotin to enable 
population PK analysis and to potentially enable additional exploratory correlative 
analyses of PK with pharmacodynamic, safety and/or efficacy endpoints.  These 
analyses will be performed at the Sponsor’s discretion as appropriate and may involve 
pooling of data from other clinical studies.  If performed, the results of these analyses 
may be reported separately from the Clinical Study Report. 
6.7 
IMMUNOGENICITY ANALYSES 
The immunogenicity analysis population will consist of all patients who received at least 
one dose of polatuzumab vedotin 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. 
The numbers and proportions of ADA-positive and ADA-negative patients at baseline 
(baseline prevalence) and after baseline (postbaseline incidence) will be summarized by 
treatment group.  When determining post-baseline incidence, patients are considered to 
be ADA positive if they are ADA negative or have missing data at baseline but are tested 
positive for ADAs following study drug exposure (treatment-induced ADA response); or if 
they are ADA positive at baseline and the titer of one or more post-baseline samples is 
at least 
 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 post baseline 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 
 titer unit greater than the titer of the baseline sample (treatment unaffected). 
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported using standard language/terminology.  Further details of 
any additional analyses will be provided in the Statistical Analysis Plan (SAP). 
6.8 
BIOMARKER ANALYSES 
Exploratory analyses of biomarkers related to tumor biology and the mechanisms of 
action of polatuzumab vedotin and rituximab will be conducted.  Analyses will assess 
prognostic and/or predictive value of candidate biomarkers.  The association between 
candidate biomarkers and OS, PFS and PET-CT CR rate and potentially other measures 
of efficacy and safety, with treatment and independent of treatment, will be explored to 
assess potential predictive and prognostic value, respectively.  The effects of baseline 
prognostic characteristics, including DLBCL subtypes (i.e., COO) and mutation profiles 
on efficacy, will be evaluated using univariate and/or multivariate statistical methods.  
Further details of any additional analyses will be provided in the Statistical Analysis Plan 
(SAP). 

 
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6.9 
SUBGROUP ANALYSES 
To assess the consistency of treatment benefit study results in subgroups defined by 
demographic and relevant baseline characteristics, OS, PFS, and response rate in these 
subgroups will be evaluated. 
Consistency of treatment benefit will be assessed using stratified Cox Proportional 
hazards models, and hazard ratios with 95% confidence intervals will be estimated.  
Forest plots will be used to summarize the results.  
 
 
 
 
 
 
 
 
 
 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
A contract research organization (CRO) will be responsible for the 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 CRO will request data clarification 
from the sites, which the sites will resolve electronically in the EDC system. 
The Sponsor will perform oversight of the data management of this study.  The CRO will 
produce eCRF Specifications for the study based on Sponsor’s templates, including 
quality checking to be performed on the data. 
Electronic Case Report Forms and correction documentation will be maintained in the 
EDC system’s audit trail.  System backups for data stored by the Sponsor and records 
retention for the study data will be consistent with the Sponsor’s standard procedures. 

 
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Patient-reported outcome data will be collected on paper questionnaires.  The data from 
the questionnaires will be entered into the EDC system by site staff.  Paper copies of 
each questionnaire are source documents (see Section 7.3) and will be maintained at 
the study site. 
7.2 
ELECTRONIC CASE REPORT FORMS  
Electronic Case Report Forms 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.  Electronic Case Report Forms will be submitted electronically to the 
Sponsor and should be handled in accordance with instructions from the CRO. 
All eCRFs should be completed by designated, trained site staff.  Electronic Case Report 
Forms should be reviewed and electronically signed and dated by the investigator or a 
designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification 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 

 
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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. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, paper PRO data, Informed Consent Forms, laboratory test 
results, and medication inventory records, must be retained by the Principal Investigator 
for at least 15 years after completion or discontinuation of the study or for the length of 
time required by relevant national or local health authorities, whichever is longer.  After 
that period of time, the documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
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 in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
or Clinical Trials Regulation (536/2014) and applicable local, regional, and national 
laws. 

 
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8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a 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 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 

 
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health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.7). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
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. 
Given the complexity and exploratory nature of biomarker analyses, data derived from 
these analyses will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Roche policy on study data publication (see Section 9.6). 

 
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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.  
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
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. 
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 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 
to study initiation, the Sponsor will identify potential risks associated with critical trial 
processes and data and will implement plans for evaluating and controlling these risks.  

 
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Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan. 
9.4 
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. 
9.5 
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 80–95 sites globally will participate to enroll approximately 250 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.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected. 
An IMC will be employed to monitor and evaluate patient safety during the safety run-in 
(Stage 1).  An iDMC will be employed during the randomized clinical trial part of the 
study (Stage 2).  Further details will be given in the IMC and iDMC charters. 
An IRC will assess tumor response during Stage 2, following a specific charter. 
9.6 
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/or other summaries of clinical study results may be 
available in health authority databases for public access, as required by local regulation, 
and will be made available upon request, provided the requirements of Roche's global 

 
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policy on data sharing have been met.  For more information, refer to the Roche Global 
Policy on Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/  
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 

 
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10. 
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predictor of outcome than the standard IPI for patients with diffuse large B-cell 
lymphoma treated with R-CHOP. Blood 2007;109:185761. 
Shahriari-Ahmadi A, Fahimi A, et al. Prevalence of Oxaliplatin-induced Chronic 
Neuropathy and Influencing Factors in Patients with Colorectal Cancer in Iran. 
Asian Pac J Cancer Prev 2015;16:76036. 
Shimozuma K, Ohashi Y, et al. Taxane-induced peripheral neuropathy and health-
related quality of life in postoperative breast cancer patients undergoing adjuvant 
chemotherapy: N-SAS BC 02, a randomized clinical trial. Support Care Cancer 
2012;20:335564. 
Staff NP, Grisold A, et al. Chemotherapy-induced peripheral neuropathy: A current 
review. Ann Neurol 2017;81:77281. 
Swerdlow SH, Campo E, et al. The 2016 revision of the World Health Organization 
classification of lymphoid neoplasms. Blood 2016;127:237590. 
Thieblemont C, Briere J, et al. The germinal center/activated B-cell subclassification has 
a prognostic impact for response to salvage therapy in relapsed/refractory diffuse 
large B-cell lymphoma: a bio-CORAL study. J Clin Oncol 2011;29:407987. 
Webster K, Cella D, et al. The Functional Assessment of Chronic Illness Therapy 
(FACIT) Measurement System: properties, applications, and interpretation. 
Health Qual Life Outcomes 2003;1:79. 
Wilson WH, Dunleavy K, et al. Phase II study of dose-adjusted EPOCH and rituximab in 
untreated diffuse large B-cell lymphoma with analysis of germinal center and 
post-germinal center biomarkers. J Clin Oncol 2008;26:271724. 
Ziepert M, Hasenclever D, et al. Standard International prognostic index remains a valid 
predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the 
rituximab era. J Clin Oncol 2010;28:237380. 
 

Appendix 1  
Schedule of Activities: Safety Run-In (cont.) 
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145 
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 7 days prior to Day 1 may be used; 
such tests do not need to be repeated for screening.   
b Visit not specified by the protocol.  Assessments should be performed as clinically indicated. 
c Patients who discontinue study drug will return to the clinic for an end of treatment visit 28 days after the last dose of study drug.  The visit at 
which response assessment shows progressive disease may be used as the treatment discontinuation visit, with additional follow-up (e.g., by 
telephone) at a time that corresponds to the time needed to eliminate the drug.  If subsequent lymphoma treatment is planned, this visit can 
occur earlier than 28 days.  Patients who complete a full course of therapy should return to the clinic 28 days after the last dose of study drug for 
assessments of vital signs, weight, hematology, chemistry, pregnancy, response, concomitant medications, and adverse events, as well as to 
receive a complete physical examination and an ECG reading. 
d Required follow-up information will be collected via clinic visits, telephone calls, and/or patient medical records approximately every 2 months 
from the End of Treatment/Discontinuation Visit until death, loss to follow-up, or study termination by the Sponsor.  Patients in the Follow-Up 
Period will be assessed as follows: 
– 
Patients who complete treatment or discontinue all study treatment prematurely due to reasons other than disease progression will 
continue standard long-term follow-up assessments including required ADA sampling and radiographic assessments until disease 
progression and will be followed for NALT and survival. 
– 
Patients who initiate NALT in the absence of progressive disease will continue to be followed for progression (including radiographic 
assessments), additional NALT, and survival. 
– 
Patients with disease progression will be followed for NALT and survival. 
e Informed consent must be documented before any study-specific screening procedure is performed and may be obtained more than 28 days 
before initiation of study treatment. 
f 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, and reproductive status. 
g For patients with unknown HIV status, HIV testing will be performed at Screening if required by local regulations in accordance with national 
and/or institutional guidelines.  HBV serology includes HBsAb, HBsAg, and total HBcAb and, if indicated due to anti-HBcAb antibody positivity, 
PCR testing for HBV DNA.  Patients with occult or prior HBV infection may be included in this study if HBV DNA is undetectable, provided they 
are willing to undergo DNA testing on Day 1 of every cycle and monthly for at least 12 months after the last cycle of study treatment by means of 
real-time PCR, with the use of an assay that has a sensitivity of at least 29 IU/mL.  See Section 4.4.1.6.  HCV serology includes anti-HCV 
antibody testing and, if indicated due to anti-HCV antibody positivity, PCR testing for HCV RNA.  See Section 4.5.8. 
h INR or PT, and PTT or aPTT.  See Section 4.5.8. 
i 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. 

Appendix 1  
Schedule of Activities: Safety Run-In (cont.) 
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
Protocol MO40598, Version 8 
146 
j Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems (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).  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. 
k Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Limited physical exam should also monitor 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.  Record new or worsened clinically significant abnormalities 
on the Adverse Event eCRF. 
l Only on visits where CT is planned. 
m Caution should be exercised in the administration of oxaliplatin in patients with a history or a predisposition for prolongation of QT, those who are 
taking medicinal products known to prolong QT interval, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or 
hypomagnesemia (see Section 4.4.2).  The QT interval should be closely monitored on a regular basis before and after administration of 
oxaliplatin and as clinically indicated. Record clinically significant abnormalities on the Adverse Event eCRF.  
n Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes).  Laboratory assessments required by protocol should be performed within 72 hours before D1 of each cycle.  
If  screening laboratory assessments are performed within 72 hours before C1D1, they are not required to be repeated at C1D1. 
o Chemistry panel (serum or plasma) includes sodium, potassium, chloride, bicarbonate (or CO2), glucose, BUN or urea, creatinine, total protein, 
albumin, phosphorus, calcium, total and (if available) direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, and LDH.  Laboratory 
assessments required by protocol should be performed within 72 hours before D1 of each cycle.  If screening laboratory assessments are 
performed within 72 hours before C1D1, they are not required to be repeated at C1D1. 
p All women who are not postmenopausal (   12 months of non-therapyinduced amenorrhea) or surgically sterile will have a serum pregnancy 
test at screening within 7 days before Cycle 1 Day 1.  In addition, for women of childbearing potential, a serum or urine pregnancy test must be 
performed prior to Day 1 of each subsequent cycle of study treatment (laboratory samples may be obtained up to 72 hours before start of study 
treatment administration on Day 1 of the treatment cycle).  If any urine pregnancy test is positive, study treatment will be delayed until the patient 
pregnancy status is confirmed by a serum pregnancy test.  If serum pregnancy test is positive, the patient will be permanently discontinued from 
study treatment. 
q Radiographic assessment must occur by PET-CT scan at screening, PET-CT scan or CT scan at mid-treatment, PET-CT scan at end 
of treatment, and CT scan during long-term follow-up. 
r Radiographic assessment  28 days prior to treatment is permissible, so long as the radiographic assessment is made prior to C1D1 and after 
the last line of therapy.  In the event of a contraindication to CT contrast agents, MRI assessments are permissible. 
s A full tumor assessment including radiographic assessment must be performed any time disease progression or relapse is suspected. 

Appendix 1  
Schedule of Activities: Safety Run-In (cont.) 
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
Protocol MO40598, Version 8 
147 
t CT scans every 6 months until progression or until the end of the study, whichever occurs first. 
u Bone marrow biopsies are not mandated in this study (see Section 4.5.8).  However, bone marrow biopsies prior to treatment should be 
mandatory for transformed DLBCL patients to check for occult bone marrow involvement by follicular lymphoma, which may not show on 
PET‑CT.  Moreover, at the discretion of the investigator, bone marrow biopsies may be conducted in patients with negative bone signal on 
PET‑CT if he or she feels the results could change prognosis and treatment.  If bone marrow biopsies are conducted, the results will be collected 
on the eCRF. 
v Medications (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 until 28 days after the last dose of study drug. 
w 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 or the initiation of NALT after the 
last dose of study drug.  After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6).  The 
investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the 
investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events 
considered to be related to study drug or trial-related procedures until a final outcome can be reported. 
 

Appendix 2  
Schedule of Activities: Randomized Controlled Trial (cont.) 
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Protocol MO40598, Version 8 
151 
d Required follow-up information will be collected via clinic visits, telephone calls, and/or patient medical records every 2 months from the End of 
Treatment/Discontinuation Visit until death, loss to follow-up, or study termination by the Sponsor.  Patients in the Follow-Up Period will be 
assessed as follows: 
– 
Patients who complete treatment or discontinue all study treatment prematurely due to reasons other than disease progression will 
continue standard long-term follow-up assessments including required ADA sampling and radiographic assessments until disease 
progression and will be followed for NALT and survival. 
– 
Patients who initiate NALT in the absence of progressive disease will continue to be followed for progression (including radiographic 
assessments), additional NALT, and survival. 
– 
Patients with disease progression will be followed for NALT and survival. 
e Informed consent must be documented before any study-specific screening procedure is performed and may be obtained more than 28 days 
before initiation of study treatment. 
f 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, and reproductive status. 
g Questionnaires will be administered before the patient receives any information on disease status, prior to the performance of 
non‑PRO/ClinRO assessments, and prior to the administration of study treatment.  After cycle 3, these will be done every other cycle (i.e. 
Cycle 5 would be the next cycle). 
h For patients with unknown HIV status, HIV testing will be performed at Screening if required by local regulations in accordance with national 
and/or institutional guidelines.  HBV serology includes HBsAb, HBsAg, and total HBcAb and, if indicated due to anti-HBcAb antibody positivity, 
PCR testing for HBV DNA.  Patients with occult or prior HBV infection may be included in this study if HBV DNA is undetectable, provided they 
are willing to undergo DNA testing on Day 1 of every cycle and monthly for at least 12 months after the last cycle of study treatment by means of 
real-time PCR, with the use of an assay that has a sensitivity of at least 29 IU/mL.  See Section 4.4.1.6.  HCV serology includes anti-HCV 
antibody testing and, if indicated due to anti-HCV antibody positivity, PCR testing for HCV RNA.  See Section 4.5.8. 
i INR or PT, and PTT or aPTT.  See Section  4.5.8. 
j 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. 
k Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems (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).  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. 

Appendix 2  
Schedule of Activities: Randomized Controlled Trial (cont.) 
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
Protocol MO40598, Version 8 
152 
l Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Limited physical exam should also monitor 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.  Record new or worsened clinically significant abnormalities 
on the Adverse Event eCRF. 
m Only on visits where CT is planned. 
n Caution should be exercised in the administration of oxaliplatin in patients with a history or a predisposition for prolongation of QT, those who are 
taking medicinal products known to prolong QT interval, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or 
hypomagnesemia (see Section 4.4.2).  The QT interval should be closely monitored on a regular basis before and after administration of 
oxaliplatin and as clinically indicated.  Record clinically significant abnormalities on the Adverse Event eCRF. 
o Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes).  Laboratory assessments required by protocol have to be performed within 72 hours before D1 of each cycle.  
If screening laboratory assessments are performed within 72 hours before C1D1, they are not required to be repeated at C1D1. 
p Chemistry panel (serum or plasma) includes sodium, potassium, chloride, bicarbonate (or CO2), glucose, BUN or urea, creatinine, total protein, 
albumin, phosphorus, calcium, total and (if available)direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, and LDH.  Laboratory 
assessments required by protocol have to be performed within 72 hours before D1 of each cycle.  If screening laboratory assessments are 
performed within 72 hours before C1D1, they are not required to be repeated at C1D1. 
q All women who are not postmenopausal (  12 months of non-therapyinduced amenorrhea) or surgically sterile will have a serum pregnancy test 
at screening within 7 days before Cycle 1 Day 1.  In addition, for women of childbearing potential, a serum or urine pregnancy test must be 
performed prior to Day 1 of each subsequent cycle of study treatment (laboratory samples may be obtained up to 72 hours before start of study 
treatment administration on Day 1 of the treatment cycle).  If any urine pregnancy test is positive, study treatment will be delayed until the patient 
pregnancy status is confirmed by a serum pregnancy test.  If serum pregnancy test is positive, the patient will be permanently discontinued from 
study treatment. 
r Radiographic assessment must occur by PET-CT scan at screening, PET-CT scan or CT scan at mid-treatment, PET-CT scan at end of 
treatment, and CT scan during long-term follow-up. 
s Radiographic assessment  28 days prior to treatment is permissible, so long as the radiographic assessment is made prior to C1D1 and after 
the last line of therapy.  In the event of a contraindication to CT contrast agents, MRI assessments are permissible. 
t A full tumor assessment including radiographic assessment must be performed any time disease progression or relapse is suspected. 
u CT scans every 6 months until progression or until the end of the study, whichever occurs first. 
v Bone marrow biopsies are not mandated in this study (see Section 4.5.8).  However, bone marrow biopsies prior to treatment should be 
mandatory for transformed DLBCL patients to check for occult bone marrow involvement by follicular lymphoma, which may not show on 
PET‑CT.  Moreover, at the discretion of the investigator, bone marrow biopsies may be conducted in patients with negative bone signal on 

Appendix 2  
Schedule of Activities: Randomized Controlled Trial (cont.) 
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
Protocol MO40598, Version 8 
153 
PET‑CT if he or she feels the results could change prognosis and treatment.  If bone marrow biopsies are conducted, the results will be collected 
on the eCRF. 
w Medications (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 until 28 days after the last dose of study drug. 
x 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 or the initiation of NALT after the 
last dose of study drug.  After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6).  The 
investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the 
investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events 
considered to be related to study drug or trial-related procedures until a final outcome can be reported. 
 

 
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
Protocol MO40598, Version 8.0 
 
154 
Appendix 3  
Schedule of Biomarker Samples: Randomized Controlled Trial (Stage 2) 
 
Biosample 
Screening 
Treatment period 
EOT / 
Discontinuation 
Days 
  28 to 1 
C1, D1 
C2, D1 
C3, D1 
C4, D1 
C5, D1 
C6, D1 
C7, D1 
C8, D1 
Mandatory collection a 
Fresh (or archival) DLBCL 
tumor tissue sample b 
x 
 
 
 
 
 
 
 
 
 
Blood for MRD assay 
(predose) c 
 
x 
x 
x 
 
x 
 
 
 
x 
Blood for flow cytometry 
(predose) d 
 
x 
 
x 
 
 
 
 
 
x 
C  cycle; D  day; EOT  end of treatment; MRD  minimal residual disease. 
a Up to 20 ml of whole blood sample will be collected at each specified time point. 
b Availability of archival or freshly biopsied DLBCL tumor tissue samples should be confirmed at screening.  If the patient has had anti-lymphoma 
treatment between the time of the prior biopsy and the time of study treatment initiation, a core-needle biopsy is recommended, if feasible and 
safe by investigator judgment.  Formalin-fixed paraffin-embedded tissue blocks are preferred over slides.  If a tissue block is not available, a 
minimum of 1015 slides (15 preferred, or in accordance with local regulatory requirements) serial, freshly cut, unstained slides is acceptable, 
with an associated pathology report, obtained at any time before study entry.  If archival tissue is unavailable or unacceptable according to above 
criteria, a pretreatment core needle, excisional, or incisional tumor biopsy is required if feasible and safe by investigator judgment.  Cytological or 
fine-needle aspiration samples are not acceptable  
c Peripheral whole-blood sample may be obtained up to 3 days before the study visit. 
d Approximately the first 100 patients at participating sites will undergo flow cytometry assessments. 
 

 
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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155 
Appendix 4  
Schedule for Serum and Plasma Pharmacokinetic Samples: 
Safety Run-In (Stage 1) and RCT (Stage 2) 
 
Study Visit 
Sample Time Points a 
Samples  
Cycle 1 Day 1 
Pre-pola infusion 
Pola acMMAE & unconjugated 
MMAE PK (plasma) b 
Pola ADA & total antibody PK (serum) 
End of Pola infusion 
Pola acMMAE & unconjugated 
MMAE PK (plasma) b 
Cycle 4 Day 1 
Pre-pola infusion 
Pola acMMAE & unconjugated 
MMAE PK (plasma) b 
Pola ADA & total antibody PK (serum) 
End of Pola infusion 
Pola acMMAE & unconjugated 
MMAE PK (plasma) b 
Treatment Completion /  
Early Termination 
End of Treatment visit 
Pola ADA & total antibody PK (serum) 
Long-Term Follow-up  
(2 months) c 
Anytime during visit 
Pola ADA & total antibody PK (serum) 
acMMAE  antibody-conjugated monomethyl auristatin E; ADA  anti-drug antibody; 
MMAE  monomethyl auristatin E; PK  pharmacokinetics; pola  polatuzumab vedotin; 
RCT  randomized controlled trial. 
Notes:  Pre-infusion samples should be drawn 0−4 hours before the start of infusion. 
End−of−infusion samples should be drawn 30 minutes (  15 minutes) unless otherwise specified. 
a Up to 11-mL whole-blood samples will be taken for polatuzumab vedotin ADA and PK 
(polatuzumab vedotin total antibody, acMMAE, and unconjugated MMAE) at each specified 
time point, with separate tubes for plasma or serum samples. 
b Polatuzumab vedotin PK, including PK samples for acMMAE and unconjugated MMAE. 
c ADA and total antibody sample collection at Month 2 of the Post-Treatment Follow-Up Period 
may be replaced instead with a collection at Month 4.  It is not necessary to carry out ADA and 
total antibody sample collection at both Month 2 and Month 4 of the Post-Treatment Follow-Up 
Period. 
 

 
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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156 
Appendix 5  
Lugano Response Assessment Criteria 
Response should be determined on the basis of radiographic and clinical evidence of 
disease according to Lugano response assessment criteria, as summarized below. 
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 nonmeasured disease as non-target lesions (e.g. cutaneous, GI, 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. 

Appendix 5 
Lugano Response Assessment Criteria (cont.) 
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
Protocol MO40598, Version 8 
157 
Revised Criteria for Response Assessment 
Response and Site 
PET-CT–Based Response 
CT-Based Response 
Complete 
Complete metabolic response 
Complete radiologic response 
(all of the following) 
 Lymph nodes and 
extralymphatic 
sites 
Score 1, 2, or 3 a with or without 
a residual mass on 5PS b 
It is recognized that in 
Waldeyer’s ring or extranodal 
sites with high physiologic 
uptake or with activation within 
spleen or marrow (e.g., with 
chemotherapy or myeloid 
colony-stimulating factors), 
uptake may be greater than 
normal mediastinum and/or 
liver.  In this circumstance, 
complete metabolic response 
may be inferred if uptake at 
sites of initial involvement is no 
greater than surrounding 
normal tissue even if the tissue 
has high physiologic uptake. 
Target nodes/nodal masses must 
regress to  1.5 cm in LDi 
No extralymphatic sites of 
disease 
 Nonmeasured lesion 
Not applicable 
Absent 
 Organ enlargement 
Not applicable 
Regress to normal 
 New lesions 
None 
None 
 Bone marrow 
No evidence of FDG-avid 
disease in marrow 
Normal by morphology; if 
indeterminate, IHC negative 
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 
At interim, these findings 
suggest responding disease 
At end of treatment, these 
findings indicate residual 
disease 
  50% decrease in SPD of up to 
6 target measurable nodes and 
extranodal sites 
When a lesion is too small to 
measure on CT, assign 
5 mm  5 mm as the default 
value 
When no longer visible, 0  0 mm 
For a node  5 mm  5 mm, but 
smaller than normal, use actual 
measurement for calculation 
 Nonmeasured 
lesions 
Not applicable 
Absent/normal, regressed, but no 
increase 
 Organ enlargement 
Not applicable 
Spleen must have regressed by 
 50% in length beyond normal 
 New lesions 
None 
None 

Appendix 5 
Lugano Response Assessment Criteria (cont.) 
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
Protocol MO40598, Version 8 
158 
Revised Criteria for Response Assessment 
Response and Site 
PET-CT–Based Response 
CT-Based Response 
 Bone marrow 
Residual uptake higher than 
uptake in normal marrow but 
reduced compared with 
baseline (diffuse uptake 
compatible with reactive 
changes from chemotherapy 
allowed).  If there are 
persistent focal changes in the 
marrow in the context of a 
nodal response, consideration 
should be given to further 
evaluation with MRI or biopsy 
or an interval scan. 
Not applicable 
No response or stable 
disease 
No metabolic response 
Stable disease 
 Target nodes/nodal 
masses, extranodal 
lesions 
Score 4 or 5 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 
 Nonmeasured 
lesions 
Not applicable 
No increase consistent with 
progression 
 Organ enlargement 
Not applicable 
No increase consistent with 
progression 
 New lesions 
None 
None 
 Bone marrow 
No change from baseline 
Not applicable 
Progressive disease 
Progressive metabolic response 
Progressive disease requires at 
least 1 of the following 
 Individual target 
nodes/nodal 
masses 
Score 4 or 5 with an increase in 
intensity of uptake from 
baseline and/or 
PPD progression; 

Appendix 5 
Lugano Response Assessment Criteria (cont.) 
Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
Protocol MO40598, Version 8 
159 
Revised Criteria for Response Assessment 
Response and Site 
PET-CT–Based Response 
CT-Based Response 
 Extranodal lesions 
New FDG-avid foci consistent 
with lymphoma at interim or 
end-of-treatment assessment 
An individual node/lesion must 
be abnormal with: 
LDi  1.5 cm and 
Increase by  50% from PPD 
nadir and 
An increase in LDi or SDi from 
nadir 
0.5 cm for lesions  2 cm 
1.0 cm for lesions  2 cm 
In the setting of splenomegaly, 
the splenic length must 
increase by  50% of the extent 
of its prior increase beyond 
baseline (e.g., a 15-cm spleen 
must increase to  16 cm). If no 
prior splenomegaly, must 
increase by at least 2 cm from 
baseline 
New or recurrent splenomegaly 
 Nonmeasured 
lesions 
None 
New or clear progression of 
preexisting nonmeasured 
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 
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; 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. 

Appendix 5 
Lugano Response Assessment Criteria (cont.) 
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a A score of 3 in many patients indicates a good prognosis with standard treatment, especially if 
at the time of an interim scan.  However, in trials involving PET where de-escalation is 
investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid 
undertreatment).  Measured dominant lesions:  up to six of the largest dominant nodes, nodal 
masses, and extranodal lesions selected to be clearly measurable in two diameters.  Nodes 
should preferably be from disparate regions of the body and should include, where applicable, 
mediastinal and retroperitoneal areas.  Non-nodal lesions include those in solid organs 
(e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on 
palpation.  Nonmeasured lesions:  any disease not selected as measured, dominant disease, 
and truly assessable disease should be considered not measured.  These sites include any 
nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do 
not meet the requirements for measurability but are still considered abnormal, as well as truly 
assessable disease, which is any site of suspected disease that would be difficult to follow 
quantitatively with measurement, including pleural effusions, ascites, bone lesions, 
leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and 
followed by imaging.  In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, bone 
marrow), FDG uptake may be greater than in the mediastinum with complete metabolic 
response, but should be no higher than surrounding normal physiologic uptake (e.g., with 
marrow activation as a result of chemotherapy or myeloid growth factors). 
b PET 5PS:  1, no uptake above background; 2, uptake  mediastinum; 3, uptake  mediastinum 
but  liver; 4, uptake moderately  liver; 5, uptake markedly higher than liver and/or new 
lesions; X, new areas of uptake unlikely to be related to lymphoma. 
 
Reference:  Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial 
evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: 
The Lugano Classification. J Clin Oncol 2014;32:305967.

 
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Appendix 6  
Recommendations for the Use of 
White Blood Cell Growth Factors 
 
Primary Prophylactic G-CSF Administration  
(First and Subsequent Cycle Use) 
Primary prophylaxis with growth-colony stimulating factor (G-CSF) is required. 
Therapeutic Use of G-CSF 
G-CSF administration should be considered for the following patients: 
 
Patients with febrile neutropenia who are at high risk for infection-associated 
complications; or 
 
Patients who have prognostic factors that are predictive of poor clinical outcome, 
e.g., prolonged (  10 days) and profound (  100/L) neutropenia, age  65 years, 
uncontrolled primary disease, pneumonia, hypotension and multi-organ dysfunction 
(sepsis), invasive fungal infection, being hospitalized at the time of fever 
development 
 
Reference:  Smith et al. 2006 Update of recommendations for the use of white blood cell 
growth factors: an evidence-based clinical practice guideline. J Clin Oncol 
2006;24:3187205. 

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

 
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Appendix 9  
International Prognostic Index 
How to Score 
 
Prognostic Factor 
Parameters 
Score 
Age 
  60 years 
0 
  60 years 
1 
ECOG performance status 
0 or 1 
0 
2–4 
1 
Stage 
1 or 2 
0 
3 or 4 
1 
Serum LDH 
  1   ULN 
0 
  1   ULN 
1 
Extranodal involvement a 
  1 site 
0 
  1 site 
1 
ECOG  Eastern Cooperative Oncology Group; LDH  lactate dehydrogenase; ULN  upper limit 
of normal. 
a Extranodal involvement per Cheson et al. 2014 can include sites that have focal uptake by 
PET-CT (e.g., spleen, liver, bone, thyroid, cutaneous, GI, bone, kidneys, pleural or pericardial 
effusions, and ascities). 
 
Prognostic Risk Group Definitions 
 
No. of Risk Factors a 
Risk Group 
0 or 1 
Low 
2 
Low intermediate 
3 
High intermediate 
4 or 5 
High 
No. of risk factors  total score based on the first table in this appendix. 
 
Reference:  International Non-Hodgkin's Lymphoma Prognostic Factors, P. A predictive 
model for aggressive non-Hodgkin's lymphoma. N Engl J Med 1993;329:98794. 
 

Appendix 11 
Functional Assessment of Cancer Therapy–Lymphoma (cont.) 
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Appendix 12  
EuroQol Group 5-Dimension 5-Level Questionnaire 
Do not reproduce or distribute.  The Sponsor will provide 
sites with all instruments to be completed in this study. 
 

Appendix 12 
EuroQol Group 5-Dimension 5-Level Questionnaire (cont.) 
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Appendix 12 
EuroQol Group 5-Dimension 5-Level Questionnaire (cont.) 
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Appendix 13  
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire:  EORTC QLQ-C30 
Do not reproduce or distribute.  The Sponsor will provide 
sites with all instruments to be completed in this study. 
 

Appendix 13  
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire:  EORTC QLQ-C30 (cont.) 
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Appendix 14  
Sampson’s Clinical Criteria for Diagnosing Anaphylaxis 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 
1. 
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen 
lips‑tongue-uvula) 
 
AND AT LEAST ONE OF THE FOLLOWING: 
– 
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia) 
– 
Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (e.g., hypotonia [collapse], syncope, incontinence) 
 
2. 
Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
– 
Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula) 
– 
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia) 
– 
Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence) 
– 
Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
 
3. 
 Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
– 
Systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline PEF 
 
Source:  Sampson, H. A., A. Munoz-Furlong, et al. Second symposium on the definition 
and management of anaphylaxis: summary report--Second National Institute of Allergy 
and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy 
Clin Immunol 2006;117:3917.

 
 
 
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Appendix 15  
Investigational Medicinal Product and Non-Investigational Medicinal Product 
Designations (for Use in European Economic Area and United Kingdom) 
 
Product Name 
IMP/NIMP Designation 
Marketing 
Authorization Status in 
EEA and U.K. 
Used within 
Marketing 
Authorization 
Polatuzumab vedotin  
(RO5541077) 
IMP (test product) 
Approved 
No a 
Rituximab 
(RO452294) 
IMP b  
Approved 
No  
Gemcitabine  
Non-Roche IMP b  
Not Approved c 
Not Applicable d 
Oxaliplatin  
Non-Roche IMP b  
Not Approved c 
Not Applicable d 
EEA  European Economic Area; GemOx  gemcitabine plus oxaliplatin; IMP  investigational 
medicinal product; NIMP  non-investigational medicinal product; LPI  local product information; 
U.K.  United Kingdom.  
a Polatuzumab vedotin is not approved in combination with R-GemOx. 
b  Rituximab, Gemcitabine, and Oxaliplatin are each considered to be an IMP test product as well as 
an IMP comparator. 
c Gemcitabine and Oxaliplatin are not approved in all participating countries. 
d Rituximab, Gemcitabine, and Oxaliplatin are used for an indication not included in the LPI for that 
product. 
 

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