A Phase II Study Evaluating Safety and Efficacy of Polatuzumab Vedotin in Combination With Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone in Patients With Previously Untreated Double and Triple Hit Lymphoma, Double Expressor Lymphoma and High-Grade B Cell Lymphoma
Phase: PHASE2
Conditions: Diffuse Large B-Cell Lymphoma, High Grade B-Cell Lymphoma w/MYC & BCL2 or BCL6 Rearrangements, High Grade B-Cell Lymphoma w/MYC, BCL2 & BCL6 Rearrangements, Double Expressor Lymphoma, High-grade B-cell Lymphoma
Sponsor: Barbara Ann Karmanos Cancer Institute

2019-135:  v11 February 4, 2025 
 
 
   
ML41185 
PROTOCOL 
TITLE: 
A Phase II Study Evaluating Safety and Efficacy of 
Polatuzumab Vedotin in Combination with 
Rituximab, Cyclophosphamide, Doxorubicin, and 
Prednisone in Patients with Previously Untreated 
Double and Triple Hit Lymphoma, Double 
Expressor Lymphoma, and High-Grade B Cell 
Lymphoma 
PROTOCOL NUMBER: 
2019-135 
VERSION NUMBER: 
11 
IND NUMBER: 
147622 
TEST PRODUCTS: 
Funding and Drug 
Supply: 
Polatuzumab vedotin  
Genentech 
PRINCIPAL 
INVESTIGATOR: 
 
 
Dipenkumar Modi, M.D. 
Karmanos Cancer Institute 
4100 John R, Detroit, MI 48201 
Modid@karmanos.org 
313-576-8739 

 
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CO-INVESTIGATORS 
KCI: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PARTICIPATING 
SITES: 
Abhinav Deol, M.D. 
Andrew Kin, M.D.  
Ali Gabali, M.D  
Jay Yang, M.D 
Melissa Runge-Morris, M.D. 
Suresh Balasubramanian, M.D. 
Jeffrey Zonder, M.D. 
Vijendra Singh, M.D. 
Craig Cole, M.D. 
Indryas Woldie, M.D. 
Jose Larios, M.D. 
 
 
   
TBD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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LEAD STUDY 
COORDINATOR: 
 
 
 
 
 
 
LEAD REGULATORY 
COORDINATOR: 
 
 
 
 
 
STATISTICIAN: 
 
 
 
 
 
SPONSOR: 
Nathan DeLuca, BS, 
CCRC 
Ph: 313-576-9689 
delucan@karmanos.org 
 
 
 
 
Kathy Reichel, BS, CCRP 
Ph: 313-576-9374 
reichelk@karmanos.org 
 
 
Seongho Kim, Ph.D. 
Ph: 313-576-8653 
kimse@karmanos.org 
 
 
Karmanos Cancer Institute 
4100 John R 
Detroit, MI 48201 
www.karmanos.org 
1-800-KARMANOS 

 
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Signature Page 
 
 
Protocol Number: 2019-135 
 
 
Protocol Title: 
A Phase II Study Evaluating Safety and Efficacy of Polatuzumab 
Vedotin in Combination with Rituximab, Cyclophosphamide, Doxorubicin, and 
Prednisone in Patients with Previously Untreated Double and Triple Hit 
Lymphoma, Double Expressor Lymphoma, and High-Grade B Cell Lymphoma 
 
 
 
 
 
 
 
Approved By: 
 
 
 
 
 
 
 
 
 
 
 
 
Dipenkumar Modi, MD                       Date: February 4, 2025 
 Principal Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Page 5 of 135 
 
 
 
Protocol Acceptance Page 
Protocol Number: 2019-135 
 
 
 
Protocol Title: 
A Phase II Study Evaluating Safety and Efficacy of Polatuzumab 
Vedotin in Combination with Rituximab, Cyclophosphamide, Doxorubicin, and 
Prednisone in Patients with Previously Untreated Double and Triple Hit 
Lymphoma, Double Expressor Lymphoma, and High-Grade B Cell Lymphoma 
 
 
 
By signing this protocol acceptance page, I confirm I have read, understood, and 
agree to conduct the study in accordance with the current protocol. 
 
 
 
 
 
 
 
 
Principal Investigator Name (Printed) 
 
 
 
 
Principal Investigator Signature 
Date 
 
 
 
This clinical study was designed and shall be implemented and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical 
Practice, with applicable local regulations (including European Directive 
2001/20/EC and US Code of Federal Regulations Title 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
 
 
The study protocol and any amendments are to be reviewed by an Institutional 
Review Board (IRB) before implementation. 
 
 
Confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without 
the prior written consent. 

 
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TABLE OF CONTENTS 
 
• 
TABLE OF CONTENTS   
 
PROTOCOL SYNOPSIS ................................................................................................11 
1.1 
Primary Objective ............................................................................11 
1.2 
Secondary Objectives .....................................................................11 
1.2.1 
Safety Objectives ............................................................................11 
1.2.2 
Secondary Efficacy Objectives ......................................................11 
1.2.3 
Exploratory Objectives ...................................................................12 
1.2.4 
Target Population ............................................................................12 
1. 
BACKGROUND .......................................................................................................20 
1.1.               Background on Disease State .......................................................20 
1.2. 
Background on Polatuzumab Vedotin..........................................22 
1.3. 
Study Rationale and Benefit-Risk Assessment ..........................30 
2. 
OBJECTIVES ..........................................................................................................32 
2.1. 
Primary Objective ............................................................................32 
2.2. 
Secondary Objectives .....................................................................32 
2.2.1. 
Safety Objectives ............................................................................32 
2.2.2. 
Secondary Efficacy Objectives ......................................................32 
2.2.3. 
Exploratory Objectives ...................................................................32 
3. 
STUDY DESIGN .....................................................................................................33 
3.1. Description of the Study .................................................................................33 
3.2. Safety and Study Oversight ...........................................................................38 
3.3. End of Study ....................................................................................................39 
3.4. Rationale for Study Design ............................................................................39 
3.5. 
Outcome Measures ........................................................................39 
3.5.1. Safety Outcome Measures ............................................................39 
3.5.2   Efficacy Outcome Measures  .................................................. 39 
3.5.3. Exploratory Outcome Measures ...................................................40 

 
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4. 
MATERIALS AND METHODS ..............................................................................40 
4.1. 
Patients .............................................................................................40 
4.1.1. 
Inclusion Criteria ..............................................................................40 
4.1.2. 
Exclusion Criteria ............................................................................42 
4.1.3. 
Criteria for Tissue submission .......................................................44 
4.2. 
Study Treatment ..............................................................................45 
4.2.1          Polatuzumab Vedotin plus R-CHP Regimen ........................... 45 
4.2.2. 
Dosage and Administration ...........................................................45 
4.2.3. 
Study Treatment Formulation, Temperature Conditions, 
Packaging and Handling ................................................................48 
4.2.4. 
Investigational Medicinal Product Accountability ........................59 
4.3. 
Concomitant Therapy .....................................................................59 
4.3.1. 
Permitted Therapy ..........................................................................59 
4.3.2. 
CNS Prophylaxis… .........................................................................60 
4.3.3. 
Prophylaxis for Hemorrhagic Cystitis ...................................... 60 
4.3.4. 
Transfusions for Cytopenias ................................................... 60 
4.3.5. 
Treatment and Prophylaxis of Neutropenia ............................ 60 
4.3.6. 
Premedications for Rituximab ................................................. 60 
4.3.7. 
Premedications for Patients at High Risk for Tumor Lysis 
Syndrome ............................................................................... 61 
4.3.8. 
Prophylaxis for Infections........................................................ 61 
4.3.9. 
Monitoring and Treatment for Hepatitis B Reactivation .......... 61 
4.3.10         Other Concomitant Medications ............................................. 62 
4.3.11. 
Prohibited Therapy ..........................................................................62 
4.3.12. 
Immunizations ..................................................................................63 
4.3.13 
    Use of SARS-CoV-2 vaccines in patients who are receiving   
Polivy® (polatuzumab vedotin-piiq)……………………………….63 
4.4. 
Study Assessments ........................................................................64 
4.4.1. 
Informed Consent Forms and Screening.....................................65 
4.4.2. 
Medical History and Demographic Data ......................................65 
4.4.3. 
Prognostic Indices ...........................................................................65 
4.4.4. 
Physical Examinations ...................................................................65 
4.4.5. 
Vital Signs ........................................................................................66 
4.4.6. 
Tumor and Response Evaluations ...............................................66 

 
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4.4.7. 
Laboratory, Biomarker, and Other Biological Samples .............68 
4.4.8. 
Electrocardiogram and Echocardiogram or MUGA ...................69 
4.4.9. 
Timing of Study Assessments ......................................................69 
4.5. 
Patient, Treatment, Study, and Site Discontinuation ................. 
71 
4.5.1. 
Patient Discontinuation ................................................................... 71 
4.5.2. 
Study Treatment Discontinuation.................................................. 72 
4.5.3. 
Study and Site Discontinuation ..................................................... 73 
5. 
ASSESSMENT OF SAFETY .................................................................................73 
5.1. 
Safety Plan .......................................................................................... 73 
5.1.1. 
Risks Associated with Polatuzumab Vedotin ..............................74 
5.1.2. 
Risks Associated with Rituximab Therapy ..................................79 
5.1.3. 
Risks Associated with Cyclophosphamide, Doxorubicin, and 
Prednisone  ......................................................................................81 
5.1.4. 
Management of Specific Adverse Events ....................................81 
5.2. 
Adverse Event Reporting ...............................................................90 
5.3. 
Expedited Reporting Requirements for Serious Adverse Events
 ...........................................................................................................97 
Emergency Medical Contacts........................................................97 
                     Case Transmission Verification of Single Case Reports ..........100 
5.4. 
Expedited Reporting to Regulatory Agencies .............................. 
103 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ...........................103 
6.1. 
Determination of Sample Size .......................................................103 
6.2. 
Summary of conduct of study ........................................................104 
6.3. 
Efficacy Analyses ............................................................................104 
6.3.1. 
Primary Efficacy Endpoint and Analysis ......................................104 
6.3.2. 
Secondary Efficacy Endpoints and Analyses .............................104 
6.4. 
Safety Analyses ..............................................................................105 
6.5. 
Exploratory Analyses ......................................................................105 
6.6. 
Interim and Final Analyses ............................................................106 
7. 
DATA COLLECTION AND MANAGEMENT .....................................................106 
7.1. 
Data and Safety Monitoring .........................................................106 

 
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7.2. 
Data Quality Assurance ...............................................................107 
7.3. 
Source Data Documentation .......................................................107 
7.4. 
Retention of Records ....................................................................107 
8. 
ETHICAL CONSIDERATIONS ...........................................................................108 
8.1. 
Compliance with Laws and Regulations ....................................108 
8.2. 
Institutional Review Board or Ethics Committee ......................108 
8.3. 
Confidentiality ................................................................................108 
8.4. 
Financial Disclosure ......................................................................109 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ...............................................................................................109 
9.1. 
Study Documentation ...................................................................109 
9.2. 
Protocol Deviations .......................................................................109 
9.3. 
Administrative Structure ...............................................................109 
9.4. 
Publication of Data and Protection of Trade Secrets ...............109 
9.5. 
Protocol Amendments ..................................................................110 

 
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10. REFERENCES ......................................................................................................111 
 
APPENDIX 1.        SCHEDULE OF ASSESSMENTS .............................................118 
APPENDIX 2.        REVISED CRITERIA FOR RESPONSE ASSESSMENTS:     
                               LUGANO CLASSIFICATION  ....................................................122 
APPENDIX 3.        RECOMMENDATIONS FOR THE USE OF WHITE BLOOD        
CELL GROWTH FACTORS   ......................................................................................129 
APPENDIX 4.        RECOMMENDED ANAPHYLAXIS MANAGEMENT ..............130 
APPENDIX 5. 
COMMONLY USED CYP1A2 INHIBITORS AND 
INDUCERS (DRUGS, FOODS, OVER THE COUNTER 
MEDICATIONS, AND SUPPLEMENTS) (CONT.) ...........................................131 
APPENDIX 6.        INTERNATIONAL PROGNOSTIC INDEX (IPI) FOR DLBCL           
..........................................................................................................................................133 
APPENDIX 7.         DATA AND SAFETY MONITORING REPORT .........               134 
 
 
 
 
 
LIST OF TABLES 
Table 1      Administration of First and Subsequent Infusions of Rituximab 
   56 
Table 2      Premeds for Rituximab and Polatuzumab Vedotin                                57                       
Table 3      Recommended steps of Dose Reduction for Polatuzumab Vedotin    82 
Table 4      Recommended steps of Dose Reduction for Cyclophosphamide 
   83 
Table 5      Recommended steps of Dose Reduction for Doxorubicin                   83   
Table 6      Management of Infusion-Related Symptoms: Rituximab and PoV ......85 
Table 7      Guidelines for Dose Delay or Modification of Polatuzumab 
Vedotin and R-CHP ..............................................................................86 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 37 
Figure 2 
Schematic of Polatuzumab Vedotin plus RCHP .......................... 47 

 
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PROTOCOL SYNOPSIS 
TITLE: 
A Phase II Study Evaluating Safety and Efficacy of 
Polatuzumab Vedotin in Combination with Rituximab, 
Cyclophosphamide, Doxorubicin, and Prednisone in 
Patients with Previously Untreated Double and Triple 
Hit Lymphoma, Double Expressor Lymphoma, and 
High-Grade B Cell Lymphoma 
 
 
 
Objectives 
1.1 PRIMARY OBJECTIVE 
To determine the rate of complete remission (CR) with polatuzumab vedotin (PoV) plus 
R-CHP in patients with newly diagnosed previously untreated double or triple hit 
lymphoma, double expressor lymphoma (DEL), and high-grade B cell lymphoma 
(HGBL) as measured by PET-defined CR rate using the Lugano Response Criteria at 
the time of primary response assessment (6−8 weeks after Cycle 6 Day 1 or last dose 
of study medication) 
1.2 SECONDARY OBJECTIVES 
1.2.1 Safety Objectives 
• 
To evaluate the safety and tolerability of the combination of PoV plus R-CHP as 
defined by CTCAE 5.0. 
1.2.2 Secondary Efficacy Objectives 
The secondary efficacy objectives for this study are: 
• 
To assess the progression free survival (PFS) with PoV plus R-CHP in the 
above-mentioned patient population 
• 
To assess the overall survival (OS) with PoV plus R-CHP in the above- 
mentioned patient population 
• 
To assess the overall response rate (ORR: CR plus PR) at the time of Primary 
Response Assessment, based on Lugano PET-CT criteria, as determined by the 
investigator 
• 
To assess the duration of response (DOR) to PoV plus R-CHP based on PET- 
CT, as determined by the investigators in the above-mentioned patient 
population 

 
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1.2.3 Exploratory Objectives 
• 
To explore the relationship between protein expression of CD79b and response 
to treatment with PoV plus R-CHP 
• 
To explore the relationship between protein expression of MYC and response to 
treatment with PoV plus R-CHP 
• 
To explore the relationship of CD79b inhibition on MYC protein expression 
Study Design  
Description of Study 
This is a Phase II, multicenter, open label study of polatuzumab vedotin administered by 
IV infusion in combination with standard doses of rituximab, cyclophosphamide, 
doxorubicin, prednisone in patients with untreated double or triple hit lymphoma, double 
expressor lymphoma, and high-grade B cell lymphoma (HGBL). 
 
A total of 49 patients will be enrolled per a Simon’s two-stage optimal design. In the first 
stage, 13 patients will be treated. If there are 2 or fewer complete responses (CR) in 
these 13 patients, the study accrual will be suspended. If there are 3 or more complete 
response, 33 additional patients will be treated for a total of 46. Estimated drop-out rate 
(including nonevaluable patients) will be 5% and the calculated sample size will be a 
total of 49. 
Number of Patients: 49  
1.2.4 Target 
Population 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for study entry: 
• 
Signed informed consent form (ICF) 
• 
Age ≥ 18 years 
• 
Previously untreated patients (except for one prior cycle of CHOP+R) with 
DLBCL as determined by local pathology with histology below: 
o Double hit lymphoma (DHL) or triple hit lymphoma (THL) confirmed by 
FISH testing by local pathology (defined as high grade B-cell lymphoma 
with MYC and BCL2 and/or BCL6 rearrangements). 
o Double expressor lymphoma (DEL) defined as overexpression of MYC 
(≥40%) and BCL2 (>50%) identified by immunohistochemistry (IHC). 
o High grade B-cell lymphoma (HGBL), NOS subtype. 
• 
NOTE: Patients who received anti-lymphoma treatment for prior indolent 
lymphoma are eligible to participate. Availability of archival formalin-fixed paraffin-
embedded (FFPE) tissue blocks or 15 unstained slides serial sections (3−5 μm in 
thickness) must be confirmed prior to study enrollment. The pathology report must 
be available for review and a tissue block sent for retrospective central 

 
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confirmation of diagnosis. See case selection. In materials and methods provided 
in Section 4.4.7.2. 
If central confirmation is unable to be performed on submitted material, stained 
slides used for diagnosis and/or additional tumor tissue specimens may also be 
requested. 
For clarification: Only availability of tumor sample must be verified prior to C1D1 
however treatment can commence prior to completion of central review. The 
adequacy of the tissue will be confirmed if possible (i.e. if it will not delay 
treatment), however, treatment can commence prior to completion of central 
review. 
 
• 
ECOG Performance Status of 0, 1, or 2 
• 
Life expectancy of at least 24 weeks 
• 
At least one bi-dimensionally measurable lesion > 1.5 cm in its longest dimension 
as measured by CT or MRI 
• 
Ability and willingness to comply with the study protocol procedures 
• 
Left ventricular ejection fraction (LVEF) ≥ 45% on cardiac multiple-gated 
acquisition (MUGA) scan or cardiac echocardiogram (ECHO) 
• 
Adequate hematologic function (unless due to underlying disease, as established 
by extensive bone marrow involvement or due to hypersplenism secondary to the 
involvement of the spleen by DLBCL per the investigator), defined as follows: 
o Hemoglobin ≥ 8.0 g/dL without packed RBC transfusion during 14 days 
before first treatment 
o ANC ≥ 1,000/μL 
o Platelet count ≥ 75,000/μL 
• 
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of < 1% per year during the treatment period and for at least 12 months after the 
last dose of study treatment. 
o A woman is considered to be of childbearing potential if she is post- 
menarcheal, has not reached a postmenopausal state (≥ 12 continuous 
months of amenorrhea with no identified cause other than menopause), 
and has not undergone surgical sterilization (removal of ovaries and/or 
uterus). 
o 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. 
o Women must refrain from donating eggs during the same period. 
o 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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post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
• 
For women of childbearing potential, a negative serum pregnancy test result within 
7 days prior to commencement of dosing. Women who are considered not to be of 
childbearing potential are not required to have a pregnancy test. 
• 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below: 
o With female partners of childbearing potential or pregnant female partners, 
men must remain abstinent or use a condom during the treatment period 
and for at least 5 months after the last dose of polatuzumab 
vedotin, 3 months after the last dose of rituximab, and for at least 6 
months after the last dose of cyclophosphamide to avoid exposing 
the embryo for the duration of the pregnancy. Men must refrain 
from donating sperm during this same period. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. Male 
patients considering preservation of fertility should bank sperm before study 
treatment 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Diffuse large B-cell lymphoma, NOS subtype 
• 
Contraindication to any of the individual components of R-CHOP or any component 
of PoV, including prior receipt of anthracyclines or history of severe allergic or 
anaphylactic reactions to humanized or murine MAbs (or recombinant antibody- 
related fusion proteins) or known sensitivity or allergy to murine products 
• 
Contraindication to rituximab or prior administration of an anti CD 20 antibody 
• 
Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive 
therapy, or any investigational agent for the purposes of treating DLBCL prior to 
Cycle 1 Day 1 with the following exceptions: 
o One prior treatment cycle of CHOP+R is allowed. Patients who received one 
prior R-CHOP will still receive 6 cycles of R-CHP plus Polatuzumab Vedotin 
per protocol treatment. 
o Glucocorticoid treatment required for lymphoma symptom control prior to 
the start of study treatment, prednisone 100 mg or equivalent can be 
given for a maximum of 13 days as a prephase treatment, with all tumor 
assessments completed prior to starting prednisone 
o One dose of prophylactic intrathecal (IT) chemotherapy with 
methotrexate 
• 
Grade 3b follicular lymphoma without concurrent DLBCL (evidence of prior grade 3b 
FL and currently with DLBCL are eligible to participate) 
• 
Primary mediastinal (thymic) large B-cell lymphoma 

 
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• 
Burkitt lymphoma 
• 
Primary or secondary CNS lymphoma (primary or secondary involvement), 
primary effusion DLBCL, and primary cutaneous DLBCL 
• 
Current Grade 2 peripheral neuropathy per CTCAE 5.0 
• 
History of other malignancy that could affect compliance with the protocol or 
interpretation of results. Exceptions include, but are not limited to: 
Patients with a history of curatively treated basal or squamous cell carcinoma of 
the skin, in situ carcinoma of the cervix or ductal carcinoma in situ of the 
breast at any time prior to the study are eligible. 
Patients with prior indolent lymphoma are eligible. 
A patient with any other malignancy that has been treated with surgery alone 
with curative intent and the malignancy has been in remission without treatment 
for ≥ 3 years prior to enrollment is eligible. 
Patients with low-grade, early-stage prostate cancer with no requirement for 
therapy at any time prior to study are eligible. 
Additional malignant conditions may be approved pending a written approval by 
the sponsor/medical monitor. 
• 
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) 
• 
History or presence of an abnormal ECG that is clinically significant in the 
investigator’s opinion, including complete left bundle branch block, second- or 
third-degree heart block. 
• 
No evidence of systemic bacterial, viral, or fungal infection at the time of C1D1 
Patients with clinical suspicion active or latent tuberculosis (to be confirmed by 
a positive interferon gamma release assay) 
• 
Positive test results for chronic hepatitis B virus (HBV) infection (defined as 
positive hepatitis B surface antigen [HbsAg]) 
Patients with occult or prior HBV infection (defined as negative HbsAg and 
positive hepatitis B core antibody [HbcAb]) may be included if HBV DNA PCR is 
undetectable, provided that they are willing to undergo DNA testing on Day 1 of 
every cycle and every 3 months for at least 12 months after the last cycle of 
study treatment.  Patients who have protective titers of hepatitis B surface 
antibody (HbsAb) after vaccination or prior but cured hepatitis B are eligible. 
• 
Known history of HIV seropositive status 
For patients with unknown HIV status, HIV testing will be performed at 
Screening 
• 
Vaccination with a live vaccine within 28 days prior to treatment 

 
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• 
Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) other than 
for diagnosis 
• 
Women who are pregnant or lactating or who intend to become pregnant within a 
year of the last dose of study treatment 
• 
Patients with a history of progressive multifocal leukoencephalopathy 
• 
Any of the following abnormal laboratory values, unless abnormal laboratory 
values are due to underlying lymphoma per the investigator: 
 
– Creatinine > 1.5 × ULN or a measured creatinine clearance < 40 mL/min 
– AST or ALT > 2.5 × ULN 
– Total bilirubin ≥ 1.5 × ULN 
Patients with documented Gilbert disease may be enrolled if total bilirubin is 
≤ 3 × ULN. 
– INR or PT > 1.5 × ULN in the absence of therapeutic anticoagulation 
– PTT or aPTT > 1.5 × ULN in the absence of a lupus anticoagulant 
• 
Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk from treatment 
complications 
• 
The use of Evusheld or other post-exposure anti-viral medications against 
COVID19 does not affect study eligibility. 
 
 
End of Study 
The end of the study is defined as the time point at which all patients enrolled in the 
study have completed 5 years of follow-up from the time of the treatment-completion 
visit or have discontinued the study. 
Length of Study: 5 years post last dose of Polatuzumab vedotin and R-CHP 
 
Study Treatment:  Polatuzumab Vedotin, Rituximab, CHP 
Patients will receive prednisone 100 mg on Day 1 of Cycle 1 
Rituximab (or biosimilar) 375 mg/m2 intravenously on Day 1 of Cycle 1 and on Day 1 of 
each subsequent cycle for up to six cycles. 
Following rituximab infusion, polatuzumab vedotin 1.8 mg/kg will be administered on 
Day 1 of each cycle 
The patient weight obtained during screening (Day -28 to Day -1) 
should be used for dose determination for all treatment cycles; if the 
patient’s weight within 96 hours prior to Day 1 of a given treatment 

 
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cycle > 10% from the weight obtained during screening, the new 
weight should be used to 
calculate the dose.  The weight that triggered a dose adjustment will 
be taken as the new reference weight for future dose adjustments.  All 
subsequent doses should be modified accordingly.  Dose recalculation 
for polatuzumab vedotin for weight changes <10% are allowed at 
investigator discretion. 
Cyclophosphamide 750 mg/m2 administered IV on Day 1 of each cycle, Doxorubicin 50 
mg/m2 administered IV on Day 1 of each cycle for a total of 6 cycles. 
Prednisone 100mg daily days 2 through 5 of each cycle 
Intrathecal methotrexate 12 mg as CNS prophylaxis on day 1, 2 or 3 of each 
cycle of therapy Colony/growth factor support on day 3 of each cycle: 
Neulasta/Udenyca 6mg or Neupogen 300- 400mcg daily for 5-10 days 
 
*Patients who received one prior R-CHOP chemotherapy will still receive 6 cycles of R-CHP 
plus Polatuzumab vedotin.  
Statistical Methods 
Determination of Sample Size 
The sample size is justified using Simon’s two-stage optimal design. The null hypothesis that the 
true CR rate is 20%) will be tested against the alternative CR rate of 35%. In  the first 
stage, 13 patients will be accrued. If there are 2 or fewer complete responses in these 
13 patients, the study will be stopped. Otherwise, 33 additional patients will be accrued 
for a total of 46. The null hypothesis will be rejected if 13 or more complete responses 
are observed in 46 patients. This design yields a 1-sided type I error rate of 10% and 
power of 80% when the true response rate is 35%. Considering the drop-out rate 
(including nonevaluable patients) of 5%, the required sample size would be 49 patients. 
 
Primary Efficacy Endpoint 
Complete remission (CR) rate as measured by PET-CT using the Lugano Response 
Criteria. 
 
Secondary Efficacy Endpoints 
• Progression free survival (PFS) 
• Overall survival (OS) 
• Overall response rate (ORR) 
• Duration of response (DOR) 
 
Safety Analyses 
Data from all patients who receive at least one study drug will be included in the safety 
analysis. Safety will be assessed through summaries of adverse events, summaries of 
changes from screening assessments in laboratory test results, ECGs, and changes in 
vital signs. All adverse events occurring on or after first study treatment will be 
summarized by mapped term, appropriate thesaurus levels, and NCI CTC Adverse 
Event v5.0 toxicity grade.  All serious adverse events will be listed separately and 
summarized. Deaths reported during the study treatment period and those reported 

 
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during follow-up after treatment discontinuation will be listed. Relevant laboratory and 
vital sign (temperature, heart rate, respiratory rate, , and blood pressure) data will be 
displayed by time, with NCI CTCAE v5.0 Grade 3 and 4 values identified where 
appropriate. 
 
Exploratory Analyses 
Exploratory analyses of biomarkers related to tumor biology and the mechanisms of 
action of polatuzumab vedotin and rituximab will be conducted. Specifically, the 
association between candidate biomarkers and PET-CT CR rate and ORR and 
potentially other measures of efficacy and safety, independent of treatment, will be 
explored to assess potential prognostic value.  In addition, the potential effect 
modification of treatment effect on PET-CT CR rate and ORR and potential other 
measures of efficacy and safety, by biomarker status, will be explored to assess 
potential predictive value. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
   Definition 
ADA 
anti-drug antibody 
ADC 
antibody drug conjugate 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AML 
acute myeloid leukemia 
ASCO 
American Society of Clinical Oncology 
BOR 
best objective response 
BSA 
body surface area 
CHOP 
cyclophosphamide, doxorubicin, vincristine, and prednisone 
CL 
Clearance 
CR 
complete response 
Cru 
complete response unconfirmed 
CT 
computed tomography 
DEL 
Double Expressor Lymphoma 
DILI 
drug-induced liver injury 
DLBCL 
diffuse large B-cell lymphoma 
DOR 
duration of response 
EC 
Ethics Committee 
EFS 
event-free survival 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
FDA 
U.S. Food and Drug Administration 
FDG 
18F-flurodeoxyglucose 
G-CSF 
granulocyte colony-stimulating factor 
 
 

 
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Abbreviation 
   Definition 
HbcAb 
hepatitis B core antibody 
HbsAg 
hepatitis B surface antigen 
HGBL 
High grade B cell Lymphoma 
HIPAA 
U.S. Health Insurance Portability and Accountability Act 
ICH 
International Council for Harmonisation 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug Application 
iNHL 
indolent non-Hodgkin’s lymphoma 
IPI 
International Prognostic Index 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRR 
infusion-related reaction 
IV 
Intravenous 
LMWH 
low molecular-weight heparin 
LPLV 
Last patient last visit 
Mab 
monoclonal antibody 
MC-VC-PABC 
maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl 
MMAE 
mono-methyl auristatin E 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NALT 
new anti-lymphoma treatment 
NF 
New Formulation 
NHL 
non-Hodgkin lymphoma 
OR 
objective response 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission topography 
PFS 
progression-free survival 
PK 
Pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PR 
partial response 
PRO 
patient-reported outcome 
R 
Rituximab 

 
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Abbreviation 
   Definition 
R/R 
relapsed or refractory 
SCT 
stem cell transplant 
SD 
stable disease 
TEN 
toxic epidermal necrolysis 
TLS 
tumor lysis syndrome 
TMA 
tissue microarray 
ULN 
upper limit of normal 
 
 
 
 
 
1. 
BACKGROUND 
1.1. 
BACKGROUND ON DISEASE STATE 
Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin 
Lymphoma (NHL) accounting for 32,750 new cases every year, and 25% of all cases of 
NHL in North America and Europe (Swerdlow et al, 2016). It is aggressive lymphoma with 
male predominance. The incidence increases with age, with the median age of 64 years 
at diagnosis. 
DLBCL is a clinically and biologically heterogeneous disease. Patients present with 
lymphadenopathy and B symptoms (fever, night sweats, weight loss, and fatigue). 
Approximately 60% of patients present with advanced stage (stage III or IV disease) 
disease with 30% of patients harboring bone marrow involvement. 
 
Double hit lymphoma (DHL) is a particularly virulent subset of DLBCL, representing 
approximately 14% of the newly diagnosed cases. It is defined by simultaneous 
translocation of MYC gene on chromosome 8 to 14 and a concomitant BCL2 or BCL6 
translocation as determined by FISH analysis. When all three abnormalities exist, the 
nomenclature Triple hit lymphoma (THL) is utilized. The prognosis is DHL and THL is 
particularly poor when compared to DLBCL regardless of other prognostic features with 
median PFS and OS of 10.9 months and 21.9 months, respectively. 
 
MYC is a proto-oncogene that produces the transcription factor C-MYC. MYC, located on 
the long arm of chromosome 8 (8q24), plays an important role in metabolism, protein 
synthesis, differentiation, stem cell renewal, stress response, messenger RNA (mRNA) 
regulation, and micro RNA regulation (Sesques and Johnson et al, Blood 2017). MYC 
controls cell cycle progression and proliferation in part by affecting the transcription of 
cyclin-dependent kinases. It is a transcriptional amplifier and increases the transcription 
of genes. BCL2 is located on the chromosome arm 18q21. The primary function of BCL2 
is to promote cell survival by inhibiting apoptosis. BCL6 is a transcription factor that 
suppresses MYC and BCL2 expression in normal GCB cells. 
 
RCHOP given every 21 days remains the standard of care for patients with DLBCL. This 

 
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evidence was based on three randomized prospective studies consisting of 
approximately 2000 older patients (>65 years of age) with advanced stage DLBCL 
(Coiffier et al 2002; Coiffier et al 2010; Feugier et al 2005). 
 
However, there are no prospective trials evaluating the efficacy of chemotherapies in DHL 
or THL. RCHOP has been frequently used based on its promising activity in DLBCL. 
Unfortunately, patients with DHL have dismal outcomes with standard induction 
chemoimmunotherapy with RCHOP. In a retrospective study of DLBCL patients treated 
with R-CHOP demonstrated significantly poor outcomes compared to non double hit 
DLBCL with 5-year PFS of 18% vs 65%, respectively and 5-year OS of 27% vs. 71%, 
respectively (Johnson et al 2012). These disappointing figures are mirrored in other 
studies as well, with most Double and THL patients dying of disease within 2 years of 
diagnosis. In a retrospective study evaluating different chemotherapy regimens, the CR 
rate in double hit lymphoma after RCHOP was 20% (Oki et al 2014; Petrich et al 2014). 
Due to advanced age at diagnosis, medical comorbidities and treatment related toxicities, 
more intensive therapies are utilized only in a minority of patients. Thus, identifying novel 
agents that can be used in combination with RCHOP, with manageable toxicity profile are 
critical to improving outcomes in DHL/THL. 
 
Double expressor lymphoma (DEL), defined as overexpression of MYC (≥ 40%) and 
BCL2 (>50%) proteins by immunohistochemistry (IHC), accounts for 30% of all DLBCL 
cases and experiences lower complete response rate, and shorter progression-free and 
overall survival (Johnson et al 2012, Green et al 2012, Savage et al 2016). Furthermore, 
in an analysis of 893 patients with de novo DLBCL treated with R-CHOP, multivariate 
analysis demonstrated that co-expression of MYC/BCL2 was associated with inferior OS 
(hazard ratio [HR] 2.52; 95% CI 1.73-3.67) and PFS (HR 2.45; 95% CI 1.71-3.51) (Hu et 
al 2013). 
 
High-grade B-cell lymphoma not otherwise specified (HGBL, NOS) is a recently 
introduced diagnostic category for aggressive B-cell lymphomas (Swerdlow et al 2017). 
It includes tumors with Burkitt-like or blastoid morphology that do not have double-hit 
cytogenetics and that cannot be classified as other well-defined lymphoma subtypes. 
HGBL, NOS are rare and heterogeneous. Most have germinal center B-cell phenotype, 
and up to 45% carry a single-hit MYC rearrangement, but otherwise they have no unifying 
immunophenotypic or cytogenetic characteristics. Recent analyses utilizing gene 
expression profiling (GEP) revealed that up to 15% of tumors currently classified as 
diffuse large B-cell lymphoma display a HGBL-like GEP signature, indicating a potential 
to significantly expand the HGBL category using more objective molecular criteria. 
Optimal treatment of HGBL, NOS is poorly defined due to its rarity and inconsistent 
diagnostic patterns. A minority of patients have early-stage disease which can be 
managed with standard RCHOP-based approaches with or without radiation. For 
advanced-stage HGBL, NOS, which often presents with aggressive, disseminated 
disease, high lactate dehydrogenase, and involvement of extranodal organs (including 
the central nervous system [CNS]), intensified Burkitt lymphoma-like regimens with CNS 

 
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prophylaxis may be appropriate. However, many patients diagnosed at age > 60 years 
are not eligible for intensive immunochemotherapy. 
 
DH and TH lymphoma, DEL, and HGBL patients represent the greatest unmet clinical 
need in DLBCL according to a recent clinical trials planning meeting from the National 
Cancer Institute National Clinical Trials Network. R-CHOP is not sufficient induction 
therapy for this group of patients, as the majority of patients will experience disease 
progression after standard treatment (Friedberg et al 2017). Therefore, there is an urgent 
need for novel therapeutic strategies in this high-risk patient population. 
 
1.2. 
BACKGROUND ON POLATUZUMAB VEDOTIN 
1.2.1. Polatuzumab Vedotin Background and Nonclinical Data 
CD79b is a cell surface antigen whose expression is restricted to all mature B cells except 
plasma cells. It is expressed in a majority of B-cell−derived malignancies, including nearly 
all NHL and chronic lymphocytic leukemia (CLL) samples tested (Dornan et al. 2009). 
Antibodies bound to CD79b are rapidly internalized, which makes CD79b ideally suited 
for targeted delivery of cytotoxic agents (Polson et al. 2007; Polson et al. 2009). 
 
Polatuzumab vedotin (DCDS4501A [liquid formulation] and DCDS4501S [lyophilized 
formulation]) is an antibody drug conjugate (ADC) that contains a humanized 
immunoglobulin G1 (IgG1) anti-human CD79b MAb (MCDS4409A) and a potent anti-
mitotic agent, mono-methyl auristatin E (MMAE), linked through a protease labile linker, 
maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl 
(MC-VC-PABC). MMAE 
has a mode of action similar to that of vincristine, which is a component of standard 
chemotherapy (e.g., R-CHOP used for treatment of lymphoma). Following binding at 
the cell-surface epitope and internalization of the ADC by the targeted cell, MMAE is 
released following cleavage of the linker by lysosomal enzymes. MMAE then binds to 
tubulin and disrupts the microtubule network, resulting in inhibition of cell division and cell 
growth (Doronina et al. 2003). This therapeutic approach takes advantage of the specific 
targeting capability of the antibody and the cytotoxic activity of MMAE and the increased 
potency of MMAE compared with vincristine. It is hypothesized that the addition of 
polatuzumab vedotin to a standard anti-CD20 antibody plus chemotherapy regimen will 
provide enhanced efficacy and safety to patients with NHL. 
 
Comprehensive 
pharmacologic, 
pharmacokinetic 
(PK), 
pharmacodynamic, 
and 
toxicological studies were conducted to support the entry of polatuzumab vedotin into 
clinical trials. Because polatuzumab vedotin specifically recognizes CD79b on B cells of 
humans−but not on those of the cynomolgus monkey, rat, or mouse−a surrogate ADC 
(DCDS5017A) that binds to cynomolgus monkey CD79b was generated to assess the 
antigen-dependent activities in cynomolgus monkeys. The structure, binding epitope, 
and binding affinity of the surrogate ADC are similar to that of polatuzumab vedotin. 
Polatuzumab vedotin has demonstrated efficacy in nonclinical mouse xenograft models 
of human CD79b-positive NHL. Additionally, polatuzumab vedotin when combined with 

 
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rituximab plus chemotherapy (rituximab  in combination  with  cyclophosphamide, 
doxorubicin, and prednisone [CHP] or bendamustine) demonstrated better anti-tumor 
activity compared with polatuzumab vedotin as single agent or compared with a current 
standard of care regimen (R-CHOP or rituximab plus bendamustine [BR]) in xenograft 
models of NHL. The pharmacokinetics and safety of polatuzumab vedotin and the 
surrogate ADC were characterized in repeat-dose toxicity studies in rats and cynomolgus 
monkeys. Polatuzumab vedotin and the surrogate ADC were well tolerated in both 
species at the tested doses. The predominant antigen-independent findings associated 
with polatuzumab vedotin or surrogate ADC exposure were reversible bone marrow 
toxicity and associated peripheral blood cell effects in both monkeys and rats. The PK 
profiles of polatuzumab vedotin and the surrogate ADC suggested that the 
pharmacokinetics of the ADC was driven mainly by the antibody component (similar 
serum concentration-time profile between ADC and total MAb). 
 
Refer to the Investigator’s Brochure for complete details of the biochemical composition 
and nonclinical studies of polatuzumab vedotin. 
1.2.1.1. 
Polatuzumab Vedotin Clinical Data 
The original formulation of polatuzumab vedotin is a liquid formulation and was used in 
the main study (i.e., Phase Ib, Phase II expansion, and Phase II randomized cohorts) in 
patients with either R/R FL or R/R DLBCL. The liquid formulation is not stable after 
dilution into saline-containing IV bags, thus requiring a syringe pump for delivery. 
Therefore, a lyophilized formulation of polatuzumab vedotin has been developed to 
improve product stability upon dilution into saline-containing IV bags.  An initial 
170 mg/vial lyophilized configuration was developed and manufactured for a potentially 
higher dose configuration, which is no longer planned, and is currently in use in other 
clinical trials only for dosing up to 1.8 mg/kg.  A 140 mg/vial drug product was 
subsequently developed to support a target dose of 1.8 mg/kg. The 170 mg/vial and  
the 140 mg/vial drug product differ in only the fill volume and yield the same product 
concentration and composition when reconstituted as prescribed. The lyophilized 
formulation of polatuzumab vedotin, referred to as “polatuzumab vedotin (lyophilized)” in 
this protocol, will be used in combination with R-CHP in a Phase II single arm cohort 
enrolling patients with newly diagnosed double or triple hit lymphoma subtypes of 
DLBCL. 
 
Complete and updated details of these data are provided in the Polatuzumab Vedotin 
Investigator’s Brochure. 
 
Clinical data on polatuzumab vedotin in patients with NHL or CLL are available from 
seven Phase I/Ib studies (DCS4968g, JO29138, GO27834, GO29044, GO29365, 
GO29834, and BO29561) and one ongoing Phase Ib/II studies (, GO29833) in patients 
with 
B- cell lymphoma: 
 
 

 
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• 
DCS4968g evaluating safety and tolerability and anti-tumor activity of 
polatuzumab vedotin and determining the maximum tolerated dose (MTD)/RP2D 
as a single agent and in combination with rituximab in R/R (Phase I study) 
• 
JO29138 is evaluating polatuzumab vedotin as a single agent in Japanese 
patients with R/R B-cell lymphoma. 
• 
GO27834 is evaluating polatuzumab vedotin in combination with either 
obinutuzumab or rituximab in patients with R/R follicular lymphoma (FL) or 
DLBCL (Phase II study). 
• 
GO29044 is evaluating polatuzumab vedotin in combination with R-CHP or 
obinutuzumab plus CHP in patients with newly diagnosed or R/R B-cell 
lymphoma. 
• 
GO29365 is evaluating polatuzumab vedotin in combination with bendamustine 
plus rituximab or obinutuzumab in patients with R/R FL or DLBCL. 
• 
GO29833 is evaluating polatuzumab vedotin in combination with venetoclax and 
either obinutuzumab or rituximab in patients with R/R FL or DLBCL,  
respectively. 
• 
GO29834 is evaluating polatuzumab vedotin in combination with lenalidomide 
and either obinutuzumab or rituximab in patients with R/R FL or DLBCL, 
respectively. 
• 
BO29561 is evaluating polatuzumab vedotin in combination with atezolizumab 
and either obinutuzumab or rituximab in patients with R/R FL or DLBCL, 
respectively. 
• 
Phase Ib/II study:  Polatuzumab Vedotin in Combination with Rituximab, 
Cyclophosphamide, Doxorubicin and Prednisone (R-CHP) for patients with 
previously untreated Diffuse Large B-cell Lymphoma 
 
Study DCS4968g (Phase I):  Polatuzumab Vedotin Monotherapy and 
Polatuzumab Vedotin in Combination with Rituximab 
A total of 95 patients have been enrolled into the Phase I study (Study DCS4968g), of 
whom 32 patients with NHL (indolent NHL [iNHL] or DLBCL) were enrolled in 
single-agent dose escalation, 11 patients were enrolled in an iNHL single-agent 
expansion cohort, 23 patients were enrolled in the DLBCL single-agent expansion 
cohort, and 9 patients were enrolled in the Phase Ib polatuzumab vedotin plus rituximab 
combination treatment cohort.  Enrollment of patients with NHL into the study has been 
completed. 
 
The remaining 20 patients, all with CLL, were enrolled into single-agent dose escalation 
cohorts.  For details regarding the clinical data in patients with CLL, refer to the 
Polatuzumab Vedotin Investigator’s Brochure. 

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

 
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discontinuation (Grade 2 hyperesthesia, Grade 2 asthenia, Grade 3 anemia, Grade 3 
thrombocytopenia, and Grade 4 thrombocytopenia). 
Adverse Events with Single-Agent Polatuzumab Vedotin 
Adverse events, regardless of relationship to study drug, were reported in all 66 patients 
(100%) with NHL (iNHL + DLBCL) who were treated with single-agent polatuzumab 

 
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vedotin.  Treatment-emergent adverse events reported in > 20% of patients included 
neutropenia (44%), diarrhea (38%), pyrexia (32%), nausea (32%), peripheral 
neuropathy (30%), fatigue (23%), and cough (21%). 
 
Grade ≥ 3 adverse events, regardless of relationship to study drug, were reported in 
48 of 66 patients (72.7%) with NHL (iNHL or DLBCL).  Neutropenia was the most 
common adverse event experienced by more than 35% of the 66 patients with NHL. 
Thirty-one of 45 patients (68.8%) treated at the RP2D of 2.4 mg/kg experienced a 
Grade 3−5 adverse event. Grade 3−4 adverse events of neutropenia were experienced 
by > 10% of the patients. Three Grade 5 events were reported:  1 patient died of sepsis, 
1 patient died of pulmonary vascular disorder, and 1 patient died from an unknown 
cause.  None of the deaths was assessed by the investigator as related to study 
treatment. 
Adverse Events with Polatuzumab Vedotin Combined with Rituximab 
In the Phase Ib cohort of Study DCS4968g, adverse eventsregardless of relationship 
to study drugwere reported in 9 of 9 patients (100%) who received polatuzumab 
vedotin (2.4 mg/kg) plus rituximab (375 mg/m²). The most common adverse events 
reported in ≥ 2 patients were neutropenia, pyrexia, nausea, diarrhea, hyperuricemia, 
bone pain, fatigue, peripheral neuropathy, decreased appetite, chills, pain in extremity, 
pruritus, arthralgia, night sweats, hypokalemia, dysgeusia, increased blood creatinine, 
infusion-related reactions (IRRs), cough, constipation, thrombocytopenia, anemia, 
hyperglycemia, rash, alopecia, hypomagnesemia, upper abdominal pain, hyperhidrosis, 
myalgia, peripheral motor neuropathy, febrile neutropenia, hyperbilirubinemia, and tooth 
fracture. 
 
Grade ≥ 3 adverse events, regardless of relationship to study drug, were reported in 7 of 
9 patients (77.8%) receiving polatuzumab vedotin in combination with rituximab in the 
Phase Ib cohort of Study DCS4968g.  Grade 3−4 neutropenia was reported in 5 
patients, Grade 3−4 anemia in 2 patients, Grade 3−4 febrile neutropenia in 2 patients, 
and Grade 3−4 hyperglycemia in 2 patients.  No Grade 5 adverse events were reported. 
 
Serious Adverse Events 
From ongoing Phase I Study DCS4968g, a total of 44 serious adverse events were 
reported among 22 patients in the single-agent NHL (iNHL plus DLBCL) cohorts, 
19 serious adverse events were reported in 11 patients in the CLL cohort, and 
15 serious adverse events were reported in 4 patients treated with polatuzumab vedotin 
plus rituximab.  Among all patients, the most common serious adverse events (occurring 
in ≥ 2% of patients) were:  Grade 1−2 pyrexia (6 patients), Grade 3−4 febrile  
neutropenia (4 patients), Grade 4−5 lung infection (3 patients), Grade 3−4 diarrhea (3 
patients), Grade 3−4 hyperglycemia (2 patients), Grade 3−4 hyponatremia (2 patients), 
Grade 2−3 mental status changes (2 patients), Grade 3−4 peripheral neuropathy (2 
patients), Grade 3−4 neutropenia (2 patients), Grade 4−5 pneumonia (2 patients), and 
acute renal failure (Grade 1 in 1 patient and Grade 4 in 1 patient). 

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

 
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Phase Ib/II study:  Polatuzumab Vedotin in Combination with Rituximab, 
Cyclophosphamide, Doxorubicin and Prednisone (R-CHP) for patients with 
previously untreated Diffuse Large B-cell Lymphoma 
Safety 
As of data cut off February 5, 2016, clinical safety data are available for all 36 evaluable 
patients. The most common adverse events in > 20% of patients were fatigue (36%), 
and diarrhea (30%), nausea (31%), and neutropenia (25%). 
 
Forty-four percent of patients had at least one grade 3/4 adverse events including 
neutropenia (22%), febrile neutropenia (14%), hypertension (8%),  thrombocytopenia 
(4%), leukopenia (4%), oral fungal infection (4%), dysphagia (4%), vomiting (4%), 
asthenia (4%), fatigue (4), decreased appetite (4%), hyponatremia (4%), malnutrition 
(4%), chylothorax (4%), back pain (4%), motor dysfunction (4%), and confusional state 
(4%). 
 
Serious adverse events were reported in 33% of patients, with 17 different events. 
These included 4 episodes of febrile neutropenia, 2 of neutropenia, 2 of pneumonia, 
and 1 each of E. coli UTI, oral fungal infection, hyponatremia, malnutrition, chylothorax, 
pulmonary embolism, pyrexia, pathologic femur fracture, and worsening of rheumatoid 
arthritis. 
 
Thirty-three percent of patients experienced peripheral neuropathy (PN). The reported 
terms included PN, paresthesia, muscular weakness, neuralgia, and motor dysfunction. 
All neurologic adverse events attributed to PoV were Grade 1 except one PN that was 
Grade 2 and improved to Grade 1 after PoV dose reduction. There were 2 patients that 
discontinued study treatment due to adverse events (one with a Grade 2 tremor who is 
still in CR, and the other with Grade 2 UTI who ultimately progressed) while 5 (14%) 
had PoV dose reductions (2 PN, 2 neutropenia, 1 weight decrease and asthenia). No 
Grade 5 adverse events were reported among the expansion cohort. 
 
Anti-tumor activity 
At the time of data cutoff (February 5, 2016), response assessments were available in 
26 pts. All pts in the escalation phase have completed study treatment and 8 in 
expansion cohort have completed study treatment. In dose escalation phase of the 
study, end of treatment PET/CT showed complete remission in 80% of patients and 
partial remission in 20% of patients, while the end of treatment PET/CT revealed 
complete remission in 54% of patients, partial remission in 23% of patients and 
progressive disease in 15% of patients in dose expansion phase of the study. 
 
Given these findings, the dose of PoV was recommended to be 1.8 mg/kg in 
combination with R-CHP. 

 
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1.2.1.2. 
Pharmacokinetic and Pharmacodynamic Properties of 
Polatuzumab Vedotin 
The PK properties of polatuzumab vedotin conjugate (evaluated as antibody-conjugated 
MMAE [acMMAE]), total antibody, and unconjugated MMAE after the first dose of 
polatuzumab vedotin in patients with NHL, either as a single agent or in combination 
with rituximab, are summarized below. 
 
In patients with NHL, polatuzumab vedotin demonstrated a trend of linear 
pharmacokinetics for each measurement across the dose range from 0.1 to 2.4 mg/kg. 
On the basis of the results from DCS4968g, 2.4 mg/kg in patients with NHL, serum 
concentrations of total antibody and acMMAE reached peak values at the end of 
infusion. The distribution of total antibody and acMMAE appears to be restricted to the 
serum compartment, with mean steady-state volume of distribution (Vss) values of 
approximately 70−87 mL/kg and approximately 93−109 mL/kg for acMMAE and total 
antibody, respectively.  Mean clearance (CL) of acMMAE (approximately 
15−21 mL/day/kg) was similar to CL of total antibody (approximately 11−19 mL/day/kg), 
suggesting that acMMAE CL was largely dominated by its antibody component.  Mean 
terminal half-life for acMMAE was approximately 5.1−6.4 days and total antibody, 
approximately 8.1 days. 
 
Unconjugated MMAE reached maximal concentrations at 2.01−3.42 days after the first 
dose, suggesting a delayed formation due to catabolism of the conjugate. There was a 
trend of increased Cmax and AUCinf values with conjugate dose increase. At each dose 
level, Cmax and AUCinf values for unconjugated MMAE were substantially lower 
compared with its parent analyte acMMAE, suggesting that the total MMAE level in the 
systemic circulation after conjugate administration was mainly composed of conjugated 
MMAE.  The t½ values ranged from 2.93−5.81 days, which are relatively long for a small 
molecule and similar to the t½ value for conjugate, suggesting that the kinetics of 
unconjugated MMAE could be dominated by its formation from the conjugate. On the 
basis of the t½ values, a small amount of accumulation was expected upon every 
3-week dosing. 
 
The PK profiles and parameters were similar in the absence and presence of rituximab, 
suggesting that rituximab has little impact on polatuzumab vedotin PK in the R/R NHL 
patient population.  Given the various CYPs involved for metabolism of MMAE and 
bendamustine, the risks of PK interactions between them is low. 
 
See the Polatuzumab Vedotin Investigator’s Brochure for additional details on 
nonclinical and clinical studies. 
1.3. 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
RCHOP is the standard first line treatment for untreated DLBCL. Unfortunately, DHL and 
THL, D E L ,  a n d  H G B L ,  N O S  subtypes of DLBCL characterized by aggressive 
disease, are typically chemo- refractory and are associated with short survival and poor 

 
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prognosis independent of the International Prognostic Index. The complete response 
rate with standard R-CHOP is very poor at 20%, with dismal long term PFS and OS. 
Therefore, aggressive chemotherapy regimens including R-EPOCH, R-HyperCVAD/MA, 
and R-CODOX- M/IVAC have been evaluated in retrospective studies; however, these 
chemotherapy regimens can not be used in a substantial proportion due to age and 
comorbidities and have not demonstrated better outcomes prospectively in double/triple 
hit lymphoma, and double expressor lymphoma (Wilson et al 2016) (ASH abstract 469 
2016) Therefore, new therapeutic modalities, are indeed needed to improve outcomes 
in this high-risk population. 
 
Polatuzumab vedotin, an antibody drug conjugate (ADC) that delivers the microtubule 
inhibitor mono-methyl auristatin E (MMAE)in a targeted fashion to cells expressing 
CD79b, has been evaluated in previously untreated DLBCL as a replacement strategy 
for the microtubule inhibitor vincristine. CD79b is a cell surface antigen that is expressed 
ubiquitously on DLBCL tumor cells, as well as other mature B cells (Olejniczak et al. 2006; 
Pfeifer et al. 2015). The expression pattern of this surface antigen enables the application 
of polatuzumab vedotin in all DLBCL subtypes (Pfeifer et al. 2015). The use of a 
replacement strategy enables continuation of the dosing regimen of R-CHP every 21 
days. 
 
Polatuzumab vedotin at doses between 1.8 mg/kg and 2.4 mg/kg has demonstrated 
promising anti-tumor efficacy in R/R DLBCL as a single agent and in combination with an 
anti-CD20 monoclonal antibody. However, in this patient population, the higher 2.4 mg/kg 
dose administered for up to seventeen 21-day cycles resulted in hematologic, infectious, 
and neurologic toxicity. In the Phase Ib/II study GO29044 evaluating the recommended 
Phase II dose of polatuzumab vedotin at 1.8 mg/kg every 21 days with RCHP in patients 
with previously untreated DLBCL, the safety profile was comparable to that seen in the 
RCHOP arm of the contemporary study BO21005/GOYA (Vitolo et al. 2016). These 
patients in GO29044 experienced similar rates of Grade 3 and 4 adverse events (57.8% 
vs. 60.3%), Grade 5 adverse events (2.2% vs. 4.3%), and severe adverse events (37.8% 
vs. 37.6%) when compared with the R-CHOP arm of BO21005/GOYA. This dosing 
schedule is consistent with an analysis performed by the FDA in which the recommended 
Phase II human dose across eight ADC development programs using the same protease- 
cleavable valine-citrulline-MMAE platform, which is between 1.8 mg/kg and 2.4 mg/kg 
when the ADC is given every 21 days (Saber and Leighton 2015). 
 
Pharmacokinetic studies did not demonstrate alterations to cyclophosphamide or 
doxorubicin pharmacokinetics when combined with polatuzumab vedotin, and dose 
intensity of R-CHP was also maintained with the incorporation of polatuzumab vedotin at 
1.8 mg/kg. Efficacy by positron emission tomography (PET), as measured by investigator- 
assessed response by Cheson 2007 criteria, was promising, with 78% achieving CR and 
91% achieving overall response at the end of treatment (10). 
 
Given the promising activity and favorable safety profile of PoV in combination with R- 
CHP in R/R DLBCL, it may be beneficial to evaluate this regimen in double or triple hit 

 
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Lymphoma, double expressor lymphoma, and HGBL, NOS subtype. The objective of the 
current single arm phase II study is to evaluate the safety and efficacy of PoV plus R-
CHP in 49 patients with previously untreated DHL and THL, double expressor 
lymphoma, and HGBL, NOS subtype. 
 
2. OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
To determine the rate of complete remission (CR) with polatuzumab vedotin plus R- 
CHP in patients with newly diagnosed previously untreated double or triple hit  
lymphoma, double expressor lymphoma, and high-grade B cell lymphoma (HGBL) as 
measured by PET-defined CR rate using the Lugano Response Criteria at the time of 
primary response assessment (6−8 weeks after Cycle 6 Day 1 or last dose  of study 
medication) 
2.2. 
SECONDARY OBJECTIVES 
2.2.1. Safety Objectives 
• 
To evaluate the safety and tolerability of the combination of PoV plus R-CHP as 
defined by CTCAE 5.0. 
2.2.2. Secondary Efficacy Objectives 
The secondary efficacy objectives for this study are: 
• 
To assess the progression free survival (PFS) with PoV plus R-CHP in the 
above-mentioned patient population 
• 
To assess the overall survival (OS) with PoV plus R-CHP in the above- 
mentioned patient population 
• 
To assess the overall response rate (ORR; CR or PR) at the time of Primary 
Response Assessment, based on Lugano PET-CT criteria, as determined by the 
investigator 
• 
To assess the duration of response (DOR) to PoV plus R-CHP based on PET- 
CT, as determined by the investigators in the above-mentioned patient 
population 
2.2.3. Exploratory Objectives 
• 
To explore the relationship between CD79b expression and response to 
treatment with PoV plus R-CHP 
• 
To explore the relationship between MYC expression and response to treatment 
with PoV plus R-CHP 
• 
To explore polatuzumab vedotin treatment on Myc protein expression 

 
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3. STUDY DESIGN 
3.1. 
DESCRIPTION OF THE STUDY 
 
This is a Phase II, multicenter, open label study of polatuzumab vedotin administered by 
IV infusion in combination with standard doses of rituximab, cyclophosphamide, 
doxorubicin, prednisone in patients with untreated double or triple hit lymphoma, double 
expressor lymphoma (DEL), and high-grade B cell lymphoma (HGBL). 
 
A total of 49 patients will be enrolled per a Simon’s two-stage optimal design. In the first 
stage, 13 patients will be treated. If there are 2 or fewer responses in these 13 patients, 
the study accrual will be suspended. If there are 3 or more response, 33 additional 
patients will be treated for a total of 46. The estimated drop-out rate (including 
nonevaluable patients) is 5% and the calculated sample size includes 49 total patients. 
 
3.1.1. SCREENING 
WITHIN 28 DAYS PRIOR TO REGISTRATION FOR PROTOCOL THERAPY: 
• 
Informed consent obtained 
• 
Patient must satisfy all the inclusion criteria and absence of any exclusion 
criterion. 
• 
Confirmation of diagnosis of DHL or THL by local pathology testing and 
submission of pathology and FISH reports confirming diagnosis to KCI 
• 
Confirmation of availability of tissue sample 
• 
Physical exam and ECOG PS 
• 
Vital signs: temperature, blood pressure, pulse rate, respiratory rate, weight, 
height, and body surface area (BSA) (screen only). 
• 
Complete blood count with differential (CBC): to include basophils, eosinophils, 
hematocrit, hemoglobin, lymphocytes, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, mean corpuscular volume, monocytes, 
neutrophils, platelet count, red blood cell count, total white cell count. 
• 
Comprehensive metabolic panel (CMP): to include albumin, alkaline 
phosphatase, alanine aminotransferase, amylase, aspartate aminotransferase, 
bicarbonate, calcium, chloride, creatinine, glucose, lactate dehydrogenase 
(LDH), magnesium, phosphorus, uric acid, potassium, sodium, total bilirubin, , 
total protein, BUN/urea or blood urea nitrogen (depending on local practice).  
• 
B2-microglobulin 
• 
HBA1C 
• 
Coagulation: INR or PT, and PTT or aPTT 
• 
Viral serology: 
Hepatitis B surface antibody (HBsAb), HBsAg, and total HBcAb 
HBV-DNA by PCR if the patient is HBcAb positive 
HCV antibody 

 
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HCV RNA by PCR if the patient is HCV antibody positive 
• 
Calculated creatinine clearance using the Cockcroft-Gault formula or by 24-hour 
urine collection for determination of creatinine clearance. 
• 
[Within 7 days prior to Cycle 1 Day 1 of treatment] Serum pregnancy test for 
women of childbearing potential 
• 
Electrocardiogram (EKG) 
• 
Echocardiogram or MUGA to evaluate left ventricular ejection function 
• 
Baseline signs and symptoms; concomitant medications. 
• 
PET scan and CT scan with contrast with measurable disease per protocol. 

 
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3.1.2. TREATMENT 
Patients will receive six cycles of polatuzumab vedotin plus R-CHP at 21-day intervals. The first 
day of treatment will constitute Study Day 1 and patients will be treated up to a total of 
six cycles. 
*Patients who received one prior R-CHOP chemotherapy will still receive 6 cycles of R-
CHP plus Polatuzumab vedotin. 
 
R-CHP + Polatuzumab vedotin: Prednisone 100 mg/day orally given first on days 1 
through 5 of every cycle, followed by Rituximab (or biosimilar) 375 mg/m2 IV infusion, 
Polatuzumab Vedotin 1.8 mg/kg IV, Cyclophosphamide 750 mg/m2 IV infusion and 
Doxorubicin 50 mg/m2 IV push each given on Day 1 of every 21-day cycle for 6 cycles. 
 
Intrathecal methotrexate 12 mg as CNS prophylaxis on day 1, 2 or 3 of each cycle of 
therapy 
All patients will be evaluated for safety and efficacy according to the schedules of 
assessments (Appendix 1). 
 
All patients will be assessed for response to treatment by the investigator with the use 
of standard criteria according to the Lugano Response Criteria (Cheson et al. 2014; see 
Appendix 2) at screening and at the following time points: 
 
• 
Interim response assessment (between Cycle 3 Day 15 and Cycle 4 Day 15) by 
PET/CT 
• 
Primary response assessment:  6−8 weeks after completion of study treatment 
(i.e., Day 1 of Cycle 6 or after last dose of study medication) by PET/CT 
 
Imaging at interim and primary response assessment must include FDG-PET (18F 
fluorodeoxyglucose-positron emission tomography) and a diagnostic-quality CT scan 
with both oral and IV contrast. A combined PET-CT scan is encouraged if feasible. 
 
After discontinuation of therapy, all patients will be followed for 5 years at clinic visits 
conducted every 3 months for the first 2 years of treatment discontinuation and then every 
6 months for the remaining 3 years of follow up until disease progression, death, 
withdrawal of consent, or initiation of another anti-cancer therapy.  CT neck, chest, 
abdomen and pelvis with contrast will be performed every 6 months for the first year or 
sooner if clinical suspicion of progression. MRI with contrast can be performed if CT 
contrast is contraindicated as determined by the treating physician. Tumor assessments 
should also be performed to confirm disease status including clinical suspicion of 
relapse or disease progression for documentation. If there is a clinical concern for 
disease progression, a PET-CT to confirm progression is recommended. 
 
Patients who terminate study treatment prior to 6 cycles of therapy without progressive 
disease will complete the treatment termination visit and then will be followed for 
progression, new anti-lymphoma therapy, and OS. Patients who initiate new anti- 
lymphoma therapy in the absence of progressive disease will be censored at the last 

 
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visit. But these patients will be followed for progression, additional new anti-lymphoma 
therapy, and OS. 
Safety will be evaluated by monitoring all adverse events, serious adverse events, and 
abnormalities identified through physical examinations, vital signs, and laboratory 
assessments. Such events will be graded using the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0). Laboratory 
safety assessments will include routine monitoring of hematology and blood chemistry, 
and tests of immunologic parameters. 
 
 
 

 
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Figure 1 Study Schema 
 
A Phase II Study Evaluating Safety and Efficacy of Polatuzumab Vedotin in 
Combination with Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone in 
Patients with Previously Untreated Double and Triple Hit Lymphoma, Double 
Expressor Lymphoma, and High-Grade B Cell Lymphoma  
 
Confirmation of eligibility, registration and procurement of archival or fresh tissue per 
protocol. Patients with confirmed untreated double or triple hit lymphoma 
Baseline: PET/CT, CBC, CMP, hepatitis serologies, HIV, LDH, PTT, 
PT/INR, B2-microglobulin, HbA1C, EKG and Echo/MUGA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of treatment PET/CT 6-8 weeks upon completion of therapy 
History and physical examination every 3 months for 12 months 
after treatment completion 
CT neck, thorax, abdomen and pelvis every 6 months for one 
year 
After 1 year, follow-up clinically every 3 months for the first 2 
years then every 6 months for 3 more years for a total of 5 years 
PoV + R-CHP* every 21 days for 3 cycles 
Intrathecal methotrexate 12 mg as CNS prophylaxis 
on day 1, 2 or 3 of each cycle of therapy 
Interim Scan: Disease Assessment by PET/CT 
between cycle 3 day 15 and cycle 4 day 15 
Post treatment 
follow up 
Screening phase 
Day-28 to day1 
Treatment phase  
Day 1 to End of treatment 
No evidence of disease 
progression (i.e. CR, 
PR) 
Continue treatment for 
additional 3 cycles for 
a total of 6 cycles 
Disease progression 
or Stable disease 
Off study 

 
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R-CHP + polatuzumab vedotin: 
Day 1: Prednisone 100 mg PO  Rituximab (or biosimilar) 375 mg/m2 IV 
infusion  PoV 1.8 mg/kg IV  Cyclophosphamide 750 mg/m2 IV infusion 
 Doxorubicin 50 mg/m2 IV push 
Day 2-5: Prednisone 100mg/day PO 
Cycle repeated every 21 days 
 
 
3.2. 
Safety and Study Oversight 
 
1. 
Scheduled investigator teleconferences will be held monthly or more frequently 
depending on the activity of the protocol. These meetings will include the 
protocol investigators and research staff involved with the conduct of the 
protocol. 
 
a. During these meetings the investigators will discuss: 
 
1. Safety of protocol participants (adverse events and reporting) 
 
2. Validity and integrity of the data (data completeness on case report 
forms and complete source documentation) 
 
3. Enrollment rate relative to expectation of target accrual, (eligible and 
ineligible participants) 
 
4. Retention of participants, adherence to the protocol and protocol 
deviations 
 
5. Protocol amendments 
 
3.2.1. Internal Monitoring Committee 
1. Data and Safety Monitoring Reports (DSMR) will be completed by the Study 
Coordinator at Karmanos and reflect reported safety data from all sites. The 
DSMR will be submitted to the Karmanos Data and Safety Monitoring 
Committee (DMSC) monthly for review. The DSMC will review safety of all study 
subjects and will recommend continuation or closure of the study. The DSMC 
will review the safety data monthly and will recommend termination if they judge 
the rate and severity of AEs to be unacceptable. The DSMC’s recommendations 
will guide study conduct. 
 
2. The Barbara Ann Karmanos Cancer Institute, Data and Safety Monitoring 
Committee (DSMC) is composed of medical providers, pharmacists and 
research staff and provides the primary oversight of data and safety monitoring 
for KCI Investigator-initiated trials. 

 
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3.3. 
END OF STUDY 
 
The end of the study is defined as the time point at which all patients enrolled in the 
study have completed 60 months (5-years) of follow-up from the time of the treatment-
completion visit or have discontinued the study. 
 
3.4. 
RATIONALE FOR STUDY DESIGN 
 
3.4.1. Rationale for Polatuzumab Vedotin Dose and Schedule 
Polatuzumab vedotin dosing for this study was based on the experience from the Phase 
I Study DCS4968g with single-agent polatuzumab vedotin in relapsed and refractory 
patients with indolent NHL and DLBCL.  Most evidence of anti-tumor activity was 
observed at doses ≥ 1.8 mg/kg. To date, over 500 patients have been enrolled in eight 
trials administering polatuzumab vedotin in B-cell malignancies. At the dose of 1.8 
mg/kg every 21 days, polatuzumab vedotin has been well tolerated as monotherapy and 
in combination with an anti-CD20 monoclonal antibody in patients with R/R B-cell    
NHL, with expected toxicities including cytopenias and peripheral neuropathy. In 
patients with previously untreated DLBCL, polatuzumab vedotin at 1.8 mg/kg in 
combination with R-CHP was administered to 45 patients, and polatuzumab vedotin at 
1.8 mg/kg in combination with CHP and another anti-CD20 monoclonal antibody 
(obinutuzumab) was administered to 17 patients. This constitutes the patient population 
targeted in this study and provides the rationale for the recommended dose and 
schedule of PoV, R-CHP in this study. 
 
3.4.2. Rationale for PET-Defined Complete Response 
PET scanning has been shown in multiple settings to be a more accurate tool for 
assessing activity of lymphoma than CT imaging. In aggressive lymphomas, such as 
DLBCL, PET-defined CR is a better predictor of PFS than response as defined by CT 
(Barrington et al 2014; Cheson et al 2014). 
 
3.4.3. Rationale for collecting tissue samples for biomarker analysis 
Tumor tissue samples will be submitted in all cases prior to starting therapy and at the 
time of progression/inadequate response if biopsy is obtained. Archival tissue may be 
submitted. Tissue will be evaluated for CD79 and MYC expression by the sponsor 
(KCI). 
3.5. 
OUTCOME MEASURES 
3.5.1. Safety Outcome Measures 
Safety will be a secondary end point in our study and will be assessed by CTCAE 5.0 
criteria. 
 
3.5.2. Efficacy Outcome Measures 

 
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Response assessment will be determined according to Lugano Response Criteria for 
Malignant Lymphoma (Lugano Classification; Cheson et al. 2014; see Appendix 2). 
• 
CR at primary response assessment (6−8 weeks after Cycle 6 Day 1 or last 
dose of study medication) based on PET-CT, as determined by the 
investigator 
• 
Progression-free survival (PFS) defined as the duration from the start date of 
the treatment until the date of progression or death from any cause, whichever 
occurs first 
• 
Overall response (OR) defined as CR or PR at primary response assessment 
based on PET-CT as determined by the investigator 
• 
Duration of response (DOR) measured from the date of CR or PR (whichever 
is first recorded) until the first date that recurrent or progressive disease is 
documented among all treated subjects who had a confirmed CR or PR 
 
 
3.5.3. Exploratory Outcome Measures 
The exploratory biomarker outcome measures for this study are as follows: 
• 
Biomarkers will be assessed  retrospectively  using  a  tissue  block  (preferred)  or 15 
serial freshly cut, unstained slides plus punch biopsy of the tissue block from the time 
of initial diagnosis and, if possible, at the time of disease progression. Samples should 
be submitted in all cases prior to initiation of therapy as a baseline sample and 
subsequently at the time of progression/inadequate response if biopsy is performed. 
 
4. MATERIALS AND METHODS 
4.1. 
PATIENTS 
Eligible patients must have previously untreated double or triple hit lymphoma and meet 
the following inclusion and exclusion criteria. 
 
4.1.1. Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for study entry: 
• 
Signed informed consent form (ICF) 
• 
Age ≥ 18 years 
• 
Previously untreated patients (except for one prior cycle of CHOP+R) with DLBCL as 
determined by local pathology. WHO histologies will include: 
o Double hit lymphoma (DHL) or triple hit lymphoma (THL) confirmed by 
FISH testing by local pathology (defined as high grade B-cell lymphoma 
with MYC and BCL2 and/or BCL6 rearrangements) 
o Double expressor lymphoma (DEL) defined as overexpression of MYC ( 
≥ 40%) and BCL2 (> 50%) identified by immunohistochemistry (IHC). 
o High grade B-cell lymphoma (HGBL), NOS subtype. 

 
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o NOTE: Patients who received anti-lymphoma treatment for prior 
indolent lymphoma are eligible to participate 
Availability of archival formalin-fixed paraffin-embedded (FFPE) tissue blocks or 
15 unstained slides serial sections (3−5 μm in thickness) must be confirmed 
prior to study enrollment. The pathology report must be available for review and 
a tissue block sent for retrospective central confirmation of diagnosis. See case 
selection. In materials and methods provided in Section 4.4.7.2. 
If central confirmation is unable to be performed on submitted material, stained 
slides used for diagnosis and/or additional tumor tissue specimens may also be 
requested 
For clarification: Only availability of tumor sample must be verified prior to C1D1 
however treatment can commence prior to completion of central review. The 
adequacy of the tissue will be confirmed if possible (ie. if it will not delay treatment). 
• 
ECOG Performance Status of 0, 1, or 2 
• 
Life expectancy of at least 24 weeks 
• 
At least one bi-dimensionally measurable lesion > 1.5 cm in its longest dimension 
as measured by CT or MRI 
• 
Ability and willingness to comply with the study protocol procedures 
• 
Left ventricular ejection fraction (LVEF) ≥ 45% on cardiac multiple-gated 
acquisition (MUGA) scan or cardiac echocardiogram (ECHO) 
• 
Adequate hematologic function (unless due to underlying disease, as established 
by extensive bone marrow involvement or due to hypersplenism secondary to the 
involvement of the spleen by DLBCL per the investigator), defined as follows: 
o Hemoglobin ≥ 8.0 g/dL without packed RBC transfusion during 14 days 
before first treatment 
o ANC ≥ 1,000/μL 
o Platelet count ≥ 75,000/μL 
• 
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of < 1% per year during the treatment period and for at least 12 months after the 
last dose of study treatment. 
o A woman is considered to be of childbearing potential if she is post- 
menarcheal, has not reached a postmenopausal state (≥ 12 continuous 
months of amenorrhea with no identified cause other than menopause), 
and has not undergone surgical sterilization (removal of ovaries and/or 
uterus). 
o 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. 
o Women must refrain from donating eggs during the same period. 

 
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o 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 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
• 
For women of childbearing potential, a negative serum pregnancy test result within 
7 days prior to commencement of dosing. Women who are considered not to be of 
childbearing potential are not required to have a pregnancy test. 
• 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below: 
o With female partners of childbearing potential or pregnant female partners, 
men must remain abstinent or use a condom during the treatment period 
and for at least 5 months after the last dose of polatuzumab vedotin, 3 
months after the last dose of rituximab, and for at least 6 months after the 
last dose of cyclophosphamide to avoid exposing the embryo for the 
duration of the pregnancy. Men must refrain from donating sperm during 
this same period. 
• 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. Male 
patients considering preservation of fertility should bank sperm before study 
treatment. 
 
 
4.1.2. Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Diffuse large B-cell lymphoma, NOS subtype 
• 
Contraindication to any of the individual components of R-CHOP or any 
component of PoV, including prior receipt of anthracyclines or history of severe 
allergic or anaphylactic reactions to humanized or murine MAbs (or recombinant 
antibody-related fusion proteins) or known sensitivity or allergy to murine products 
• 
Contraindication to rituximab or prior administration of an anti CD 20 antobody. 
• 
Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive 
therapy, or any investigational agent for the purposes of treating DLBCL prior to 
Cycle 1 Day 1 with the following exceptions: 
o One prior treatment cycle of CHOP+R is allowed. Patients who received one 
prior R-CHOP will receive 6 cycles of R-CHP plus Polatuzumab Vedotin per 
protocol treatment.  
o Glucocorticoid treatment required for lymphoma symptom control prior to 
the start of study treatment, prednisone 100 mg or equivalent can be 
given for a maximum of 13 days as a prephase treatment, with all tumor 
assessments completed prior to starting prednisone 
o One dose of prophylactic intrathecal chemotherapy with methotrexate. 
• 
Grade 3b follicular lymphoma without concurrent DLBCL (evidence of prior grade 3b 

 
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FL and currently with DLBCL are eligible to participate) 
• 
Primary mediastinal (thymic) large B-cell lymphoma 
• 
Burkitt lymphoma 
• 
Primary or secondary CNS lymphoma (primary or secondary involvement), 
primary effusion DLBCL, and primary cutaneous DLBCL 
• 
Current Grade 2 peripheral neuropathy per CTCAE 5.0 
• 
History of other malignancy that could affect compliance with the protocol or 
interpretation of results. Exceptions include, but are not limited to: 
Patients with a history of curatively treated basal or squamous cell carcinoma of 
the skin, in situ carcinoma of the cervix or ductal carcinoma in situ of the 
breast at any time prior to the study are eligible. 
Patients with prior indolent lymphoma are eligible. 
A patient with any other malignancy that has been treated with surgery alone 
with curative intent and the malignancy has been in remission without treatment 
for ≥ 3 years prior to enrollment is eligible. 
Patients with low-grade, early-stage prostate cancer with no requirement for 
therapy at any time prior to study are eligible. 
Additional malignant conditions may be approved pending a written approval by 
the sponsor/medical monitor. 
• 
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) 
• 
History or presence of an abnormal ECG that is clinically significant in the 
investigator’s opinion, including complete left bundle branch block, second- or 
third-degree heart block, 
• 
No evidence of systemic bacterial, viral, or fungal infection at the time of C1D1 
Patients with clinical suspicion of active or latent tuberculosis (to be confirmed by 
a positive interferon gamma release assay) 
• 
Positive test results for chronic hepatitis B virus (HBV) infection (defined as 
positive hepatitis B surface antigen [HBsAg]) 
Patients with occult or prior HBV infection (defined as negative HBsAg and 
positive hepatitis B core antibody [HBcAb]) may be included if HBV DNA PCR is 
undetectable, provided that they are willing to undergo DNA testing on Day 1 of 
every cycle and monthly for at least 12 months after the last cycle of study 
treatment.  Patients who have protective titers of hepatitis B surface antibody 
(HBsAb) after vaccination or prior but cured hepatitis B are eligible. 
• 
Known history of HIV seropositive status 
For patients with unknown HIV status, HIV testing will be performed at 

 
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Screening 
• 
Vaccination with a live vaccine within 28 days prior to treatment 
• 
Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) other than 
for diagnosis 
• 
Women who are pregnant or lactating or who intend to become pregnant within a 
year of the last dose of study treatment 
• 
Patients with a history of progressive multifocal leukoencephalopathy 
• 
Any of the following abnormal laboratory values, unless abnormal laboratory 
values are due to underlying lymphoma per the investigator: 
– Creatinine > 1.5 × ULN or a measured creatinine clearance < 40 mL/min 
– AST or ALT > 2.5 × ULN 
– Total bilirubin ≥ 1.5 × ULN 
Patients with documented Gilbert disease may be enrolled if total bilirubin is 
≤ 3 × ULN. 
– INR or PT > 1.5 × ULN in the absence of therapeutic anticoagulation 
– PTT or aPTT > 1.5 × ULN in the absence of a lupus anticoagulant 
• 
Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk from treatment 
complications 
• 
The use of Evusheld or other post-exposure anti-viral medications against 
COVID19 does not affect study eligibility. 
4.1.3. Criteria for Tissue submission 
Eligible patients must have available at the study site a representative formalin-fixed, 
paraffin-embedded tumor specimen that enabled the definitive diagnosis of DLBCL. 
• 
The specimen must contain adequate evaluable tumor cells (≥ 20% for excisional 
biopsy and ≥ 50% if sample is a core biopsy) to enable relevant biomarker 
analysis. 
• 
A tissue block (preferred) or 15 serial, freshly cut, unstained slides plus punch 
biopsy of the tissue block accompanied by an associated pathology report will be 
requested.  Punch biopsy is required only with the slide submission. Cytological or 
fine-needle aspiration samples are not acceptable. 
If the archival tissue is unavailable or insufficient on the basis of the above criteria, the 
patient may still be eligible if the patient is willing to provide tissue from a pretreatment 
core or excisional/incisional biopsy of the tumor. Cytological or fine-needle aspiration 
samples are not acceptable. Tissue collected on study will not be returned to sites. If 
needed, additional slides from previously collected samples may be requested. 
 
Cases received from each of the participating institutes should be histological confirmed 

 
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according to the 2016 WHO classification of tumors of hematopoietic and lymphoid 
neoplasm. The evaluation process by immunohistochemistry (IHC) and fluorescent in situ 
hybridization (FISH) requires the possession of representative amount of tissues in a 
paraffin embedded block to be sent to the primary testing institution (Karmanos Cancer 
Center, Detroit Michigan). 
Shipped slides should be placed in proper containers to avoid breakage during shipping. 
Blocks of paraffin embedded tissue or slides should be sent with a tracking number the 
address below. In addition, the participation institution should call the laboratory at 313- 
576-8351 (Julie Boerner) for any sample that they ship and provide tracking number. 
 
Julie Boerner 
Karmanos Cancer Institute 
4100 John R. St 816 HWCRC 
Detroit MI 48201 
313-576-8351 
 
4.2. 
STUDY TREATMENT 
4.2.1. Polatuzumab Vedotin plus R-CHP regimen 
Polatuzumab vedotin will be administered by IV infusion at 1.8 mg/kg on Day 1 of each 
21-day cycle for 6 cycles; Rituximab (or biosimilar), cyclophosphamide, doxorubicin 
and prednisone (R-CHP) chemoimmunotherapy at standard doses will be administered 
concurrently every 21 days for each 21-day cycle. 
 
4.2.2. Dosage, and Administration 
Schedule for Cycle 1 
Cycle 1 Day 1 (± 2 days) 
• 
Prednisone 100 mg oral 
• 
Rituximab 375 mg/m2 IV infusion 
• 
Polatuzumab Vedotin 1.8 mg/kg IV 
• 
Cyclophosphamide 750 mg/m2 IV infusion 
• 
Doxorubicin 50 mg/m2 IV push 
• 
Intrathecal methotrexate 12 mg as CNS prophylaxis (acceptable to administer on 
day 1, 2 or 3 of each cycle, please see the calendar) 
Cycle 1 Day 3 
• 
Colony/growth factor support 
o Neulasta/Udenyca 6mg day 3 or Neupogen 300-480 mcg daily for 5-10 
days per institutional guidelines beginning on day 3 
Cycle 1 Days 2 through 5 
• 
Prednisone 100 mg oral daily 
 

 
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Schedule for Cycles 2−6 
Cycles 2−6 Day 1 (± 2 days) 
• 
Prednisone 100 mg oral 
• 
Rituximab 375 mg/m2 IV infusion 
• 
Polatuzumab Vedotin 1.8 mg/kg IV 
• 
Cyclophosphamide 750 mg/m2 IV infusion 
• 
Doxorubicin 50 mg/m2 IV push 
• 
Intrathecal methotrexate 12 mg as CNS prophylaxis (acceptable to administer on 
day 1, 2 or 3 of each cycle, please see the calendar) 
Cycle 2-6 Days 2 though 5 
• 
Prednisone 100 mg oral daily 
Cycle 2-6 Day 3 
• 
Colony/growth factor support 
o Neulasta/Udenyca 6mg day 3 or Neupogen 300-480 mcg daily for 5-10 
days per institutional guidelines beginning on day 3 
 
A pre-phase treatment of prednisone at a dose of up to 100 mg PO every day for up to 
13 days prior to Cycle 1, Day 1 is permitted for tumor related symptom control, at the 
discretion of the investigator. Vincristine is not permitted at any time on study. The pre- 
phase treatment is not considered part of study treatment but will be recorded in the 
electronic Case Report Form (eCRF). Staging study assessments (i.e., bone marrow 
biopsy, CT/MRI, PET-CT scan, tumor biopsy) must be performed prior to initiation of 
pre-phase treatment. 
 
The dose of each agent should be calculated on the basis of a patient’s body weight at 
the screening assessment (within 28 days of Cycle 1, Day 1). For changes >10% in body 
weight from screening for all subsequent doses, the doses of all agents should be 
modified accordingly to the new weight/body surface area (BSA). The weight that 
triggered a dose adjustment will be taken as the new reference weight for future dose 
adjustments. 
 
As noted in Section 4.3.5. the use of granulocyte colony-stimulating factor (G-CSF) 
primary prophylaxis is REQUIRED for all patients in this study during all cycles, with 
dosing per institutional guidelines. All patients will receive herpesvirus prophylaxis 
throughout the treatment with Polatuzumab Vedotin 

 
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Figure 2 Schematic of Polatuzumab Vedotin plus R-CHP Regimen Cycles 1-6 
D1 
2 
3 
4 
5 
cycle 2 D1 
 
 
 
 
Prednisone, 100 mg/day on 
days 1 through 5 
 
Rituximab, 375 mg/m2 
 
 
Polatuzumab 1.8 mg/kg 
 
 
Cyclophosphamide, 750 mg/m2 
 
Doxorubicin, 50 mg/m2 
 
Intrathecal Methotrexate 12mg 
on either day 1, 2 or 3 of each 
cycle 
 
 
Neulasta/Udenyca 6mg on day 
3 or Neupogen 300-480 mcg 
daily for 5-10 days 
Days 6-21 

 
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Notes: Order of administration on Day 1 of each cycle will be: first prednisone, 
second rituximab, and third polatuzumab vedotin. Subsequent infusions of 
cyclophosphamide, and doxorubicin should be administered according to institutional 
preference. Neulasta or Neupogen will be administered on Day 3 of each cycle. 
 
Rituximab may be split between Day 1 and Day 2 per Section 4.2.3.2. On Cycle 1, 
polatuzumab vedotin may be administered on Day 2 per investigator preference due to 
the longer infusion times for the first dose of rituximab and polatuzumab vedotin. In this 
instance, cyclophosphamide, and doxorubicin may be administered on Day 1, and 
polatuzumab vedotin may be administered on Day 2 after prednisone. 
 
4.2.3. Study Treatment Formulation, Temperature Conditions, Packaging, 
and Handling 
4.2.3.1 Polatuzumab Vedotin 
The dose of polatuzumab vedotin for each patient will be 1.8 mg/kg. 
 
The study drug is supplied in 20-cc single use glass vials with 20 mm stoppers. Each 
drug product vial delivers 140 mg [7.0 mL] of study drug after reconstitution with 7.2 mL 
sterile water for injection (SWFI). Upon reconstitution with 7.2 mL of SWFI, the 
concentration of Polatuzumab Vedotin is 20 mg/mL in a solution containing sodium 
succinate, sucrose, and polysorbate-20 at pH 5.3. Density of study drug following 
reconstitution is 1.02 g/mL. 
 
Vial Storage Condition and Precautions: 
• 
Store at 2°- 8°C (36°F–46°F). 
• 
Do not freeze. 
• 
Do not shake. 
• 
Protect from light. 
• 
For single use only. 
• 
Do not use beyond expiration date 
Dose solutions should be prepared in an IV infusion bag containing 0.9% 
sodium chloride, 0.45% sodium chloride, or 5% dextrose and constructed with 
product contacting materials of polyvinyl chloride (PVC), polyolefin (PO), 
polyethylene (PE), and/or polypropylene (PP). 
 
Equipment Required for Infusion: 
Do not use infusion bags containing other diluents (e.g.Ringers’ solution, etc.). 
Use a PVC, PO, PE, PP, polyurethane (PU), or polybutadiene (PBD) infusion line 
equipped with a 0.2 or 0.22 μm polyethersulfone (PES) or polysulfone (PSU) filter. 

 
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Reconstitution of the drug product must occur under appropriate aseptic conditions in 
accordance with local regulations and institutional policy, as the study drug contains no 
preservatives. 
Reconstitution Instructions: 
 
• 
Reconstitute immediately before dilution 
 
• 
More than one vial may be needed for a full dose. Calculate the dose, the total 
volume of reconstituted Polatuzumab solution required, and the number of 
Polatuzumab vials needed. 
• 
Reconstitute each 140 mg Polatuzumab vial by using a sterile syringe to slowly 
inject 7.2 mL of Sterile Water for Injection, USP, with the stream directed toward 
the inside wall of the vial to obtain a concentration of 20 mg/mL of polatuzumab 
vedotin-piiq. 
• 
Swirl the vial gently until completely dissolved. Do not shake. 
 
• 
Inspect the reconstituted solution for discoloration and particulate matter. The 
reconstituted solution should appear colorless to slightly brown, clear to slightly 
opalescent, and free of visible particulates. Do not use if the reconstituted 
solution is discolored, is cloudy, or contains visible particulates. Do not freeze or 
expose to direct sunlight. 
• 
If needed, store unused reconstituted Polatuzumab solution refrigerated at 2°C 
to 8°C (36°F to 46°F) for up to 48 hours or at room temperature (9°C to 25°C, 
47°F to 77°F) up to a maximum of 8 hours prior to dilution. Discard vial when 
cumulative storage time prior to dilution exceeds 48 hours. 
 
Dilution 
• 
Dilute polatuzumab vedotin-piiq to a final concentration of 0.72–2.7 mg/mL in an 
intravenous infusion bag with a minimum volume of 50 mL containing 0.9% 
Sodium Chloride Injection, USP, 0.45% Sodium Chloride Injection, USP, or 
5% Dextrose Injection, USP. 
• 
Determine the volume of 20 mg/mL reconstituted solution needed based on 
the required dose. 
• 
Withdraw the required volume of reconstituted solution from the 
Polatuzumab vial using a sterile syringe and dilute into the intravenous 
infusion bag. Discard any unused portion left in the vial. 

 
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• 
Gently mix the intravenous bag by slowly inverting the bag. Do not shake. 
 
• 
Inspect the intravenous bag for particulates and discard if present. 
 
• 
If not used immediately, store the diluted Polatuzumab solution as specified 
in in the table below. Discard if storage time exceeds these limits. Do not 
freeze or expose to direct sunlight. 
• 
Limit transportation to 30 minutes at 9°C to 25°C or 12 hours at 2°C to 8°C 
(refer to instructions below). The total storage plus transportation times of 
the diluted product should not exceed the storage duration specified as 
below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* To ensure product stability, do not exceed specified storage durations 
 
Agitation stress can result in aggregation. Limit agitation of diluted product  
during preparation and transportation to administration site. Do not transport 
diluted product through an automated system (e.g., pneumatic tube or 
automated cart). If the prepared solution will be transported to a separate facility, 
remove air from the infusion bag to prevent aggregation. If air is removed, an 
infusion set with a vented spike is required to ensure accurate dosing during the 
infusion. 
• 
No incompatibilities have been observed between Polatuzumab and intravenous 
infusion bags with product-contacting materials of polyvinyl chloride (PVC) or 
polyolefins (PO) such as polyethylene (PE) and polypropylene (PP). No 
incompatibilities have been observed with infusion sets or infusion aids with 
product-contacting materials of PVC, PE, polyurethane (PU), polybutadiene 
(PBD), acrylonitrile butadiene styrene (ABS), polycarbonate (PC), 
polyetherurethane (PEU), fluorinated ethylene propylene (FEP), or 
Diluent Used to Prepare Solution for 
Infusion 
Diluted Polatuzumab Vedotin Solution 
Storage Conditions* 
0.9% Sodium Chloride Injection, USP 
Up to 24 hours at 2°C to 8°C (36°F to 
46°F) or up to 4 hours at room temperature 
(9 to 25°C, 47 to 77°F) 
0.45% Sodium Chloride Injection, USP 
Up to 18 hours at 2°C to 8°C (36°F to 
46°F) or up to 4 hours at room temperature 
(9 to 25°C, 47 to 77°F) 
5% Dextrose Injection, USP 
Up to 36 hours at 2°C to 8°C (36°F to 
46°F) or up to 6 hours at room temperature 
(9 to 25°C, 47 to 77°F) 

 
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polytetrafluorethylene (PTFE), or with filter membranes composed of polyether 
sulfone (PES) or polysulfone (PSU). 
 
Administration 
• 
Administer Polatuzumab as an intravenous infusion only. 
 
• 
Polatuzumab must be administered using a dedicated infusion line equipped 
with a sterile, non-pyrogenic, low-protein-binding in-line or add-on filter (0.2- or 
0.22-micron pore size) and a catheter. 
• 
Do not mix Polatuzumab with or administer as an infusion with other drugs. 
 
Determination of Patient’s weight: The total dose of Polatuzumab Vedotin 
for each  patient will depend on the patient’s body weight at the screening 
assessment (within 28 days of Cycle 1, Day 1).; If the patient’s weight within 
96 hours prior to Day 1 of a given  treatment cycle > 10% from the weight 
obtained during screening, the new weight should be used to calculate the 
dose. The weight that triggered a dose adjustment will be taken as  the new 
reference weight for future dose adjustments. All subsequent doses should 
be modified accordingly. Dose recalculation for polatuzumab vedotin for 
weight changes 
<10% are allowed at investigator discretion. 
 
 
 
Dose solution preparation: Dose solution preparation must occur under appropriate 
aseptic conditions in accordance with local regulations and institutional policy, as the 
Polatuzumab Vedotin contains no preservatives. 
 
Calculate the appropriate volume of undiluted study drug to the infusion bag using the 
equations below. 
 
[Required dose (mg)] = [Patient weight (kg)] x [Dose per 
kilogram (mg/kg)] 
 
 
 
As an example, a 72 kg patient at the 1.8 mg/kg dose level would require a dose of 130 
mg. The required volume of reconstituted drug product would be 6.5 mL in this 

 
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example. 
Please note: Any deviation of the actual dose from the calculated dose by more than ± 
5% is considered a protocol deviation. 
 
Use the patient-specific required dose to select an appropriate size infusion bag to 
ensure that the final concentration of Polatuzumab Vedotin in the bag is between 0.72 
mg/mL and 2.70 mg/mL. Use the bag’s labeled volume to calculate concentration 
(ignore overfill). 
 
 
Required Polatuzumab 
Vedotin Dose (mg) 
Recommended IV Infusion Bag 
Volume (mL) 
<72 
50 
72-270 
100 
>270 
250 
 
Using a new syringe and needle, withdraw the required volume of the reconstituted drug 
product from the vial, slowly add the required volume of drug product to the IV bag, and 
gently mix the IV bag by slowly rotating the bag. Do not shake. Inspect the bag for 
particulates and discard if present. 
 
Dose Solution Handling and Storage: Do not shake or freeze infusion bags 
containing dose solution. Protect from direct sunlight. The reconstituted Polatuzumab 
Vedotin drug product and the dose solution should be used immediately to limit product 
degradation and microbial growth in case of potential accidental contamination. 
If not used immediately, the reconstituted study drug solution may be stored refrigerated 
at 2-8°C (36-46°F) for up to 24 hours prior to dose solution preparation. Within this 24- 
hour storage period, the reconstituted study drug solution may be temporarily held at 9- 
25°C (47-77°F) up to a maximum of 4 hours. The reconstituted drug solution should be 
discarded if the cumulative storage time prior to the preparation of the dose solution 
exceeds 24 hours. 
 
Similarly, the dose solution (resulting from dilution of the reconstituted product into an IV 
bag) may also be stored refrigerated at 2-8°C (36-46°F) for up to 24 hours prior to 
administration. Within this 24-hour storage period, the dose solution may be temporarily 
held at 9-25°C (47-77°F) up to a maximum of 4 hours. The dose solution should be 
discarded if the cumulative storage time prior to administration exceeds 24 hours. 
 
Agitation stress can result in aggregation. Limit agitation of the dose solution during 
preparation and transportation to administration site. Transporation of the dose solution 
using an automated system (e.g. pneumatic tube or automated cart) have 
not been assessed. If transportation using automated system is unavoidable, site 
should be aware that their use may increase the risk for protein aggregation. If the dose 

 
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solution will be transported through automated system or to a separate facility, remove 
air from the infusion bag to reduce the risk for aggregation. If air is removed, an infusion 
set with a vented spike is required to ensure accurate dosing during the infusion. Limit 
transportation to 30 minutes at 9°C to 25°C or 12 hours at 2°C to 8°C. The total storage 
plus transportation times of the dose solution should not exceed the storage durations 
as indicated above. 
 
Additional Instructions and Information: No incompatibilities have been observed 
between Polatuzumab Vedotin and IV infusion bags with product contacting materials of 
polyvinyl chloride (PVC), or polyolefins (PO) such as polyethylene (PE) and 
polypropylene (PP). In addition, no incompatibilities have been observed with infusion 
sets or infusion aids with product contacting materials of PVC, PE, polyurethane (PU), 
polybutadiene (PBD), acrylonitrile butadiene styrene (ABS), polycarbonate (PC), 
fluorinated ethylene propylene (FEP), polytetrafluorethylene (PTFE), polyether urethane 
(PEU), and with filter membranes composed of polyether sulfone (PES) or polysulfone 
(PSU). The use of administration items constructed of other product-contacting 
materials is not recommended. 
 
Compatibility between Polatuzumab Vedotin and closed system transfer devices 
(CSTDs) or needle free transfer devices has not been assessed. If CSTDs or needle 
free transfer devices must be used to comply with site regulations, the site should be 
aware that their use may lead to the introduction of particles and may not allow 
the withdrawal of the labeled quantity of drug from the vial. Sites should perform a 
thorough visual inspection of the IV bag for particulates. In addition, sites must use a 
0.2 or 0.22 μm polyethersulfone (PES) or polysulfone (PSU) filter during infusion. 
The preparation should be discarded if particulates are observed in the IV bag. 
 
A dedicated infusion line and catheter should be used for the administration of 
Polatuzumab Vedotin. The compatibility of Polatuzumab Vedotin with other drugs as 
well as in-dwelling catheters such as peripherally inserted central catheters (PICCs) 
or other central venous access devices (CVADs) has not been established. If the 
treating health care provider determines that the use of a dedicated infusion line and 
catheter is not feasible, infusion lines and catheters must be flushed before and after 
administration of Polatuzumab to ensure that Polatuzumab does not contact other 
drug solutions. 
Drug administration and pre-treatment recommendation: For Cycles 1-6, 
polatuzumab vedotin should be administered after the prednisone and rituximab 
components of R-CHP have been administered, as infusion reactions due to rituximab 
are typically more common than those for polatuzumab vedotin. The initial dose will be 
administered to patients who are well hydrated over 90 (± 10) minutes. Premedication 
(e.g., 500−1000 mg of oral acetaminophen or paracetamol and 50−100 mg 
diphenhydramine as per institutional standard practice) may be administered to an 
individual patient before administration of polatuzumab vedotin.  Administration of 

 
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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. For infusion rate escalation after infusion related reactions, 
subsequent cycle of Polatuzumab Vedotin should be infused over 90 minutes.  If prior 
infusions have been well tolerated, subsequent doses of polatuzumab vedotin may be 
administered over 30 (± 10) minutes, followed by a 30-minute observation period after 
the infusion. 
 
Any dose modification should be noted on the Polatuzumab Vedotin 
Administration electronic Case Report Form (eCRF).  Cases of accidental 
overdose or medication error, along with any associated adverse events, 
should be reported as described in Section 5.2. 
 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.4.1. 
4.2.3.2 Rituximab 
Rituximab 375 mg/m2 will be administered by IV infusion in combination with 
polatuzumab vedotin, as outlined in Section 4.2. Rituximab will be administered on Day 
1 of Cycles 1−6.  No dose modifications of rituximab are allowed. Rituximab biosimilar 
will be allowed. 
 
The patient’s body surface area (BSA) calculated at screening should be used to 
calculate the dose of rituximab throughout the study unless the patient’s weight 
increases or decreases by > 10% from screening, in which case BSA should be 
recalculated and used for subsequent dosing.  In obese patients, there is no BSA cap 
and actual body weight, not adjusted weight, is recommended.  Empiric dose 
adjustment for obese patients (obesity defined as body mass index ≥ 30, as measured 
in kilograms divided by meters squared) may be implemented per institutional 
guidelines. 
 
The rituximab administration should be completed at least 30 minutes (during cycle 1 
and 15 minutes for subsequent cycles) before administration of other study 
treatments. The infusion of rituximab may be split over 2 days if the patient is at 
increased risk for an IRR (high tumor burden, high peripheral lymphocyte count).  
Administration of rituximab may be continued on the following day, if needed, for 
patients who experience an adverse event during the rituximab infusion. If a dose of 
rituximab is split over 2 days, both infusions must occur with appropriate 
premedication and at the first infusion rate (see Table 1). 
 

 
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All rituximab infusions should be administered to patients after premedication with oral 
acetaminophen (e.g., 650−1000 mg) and an antihistamine such as diphenhydramine 
hydrochloride (50−100 mg) 30−60 minutes before starting each infusion (unless 
contraindicated).  An additional glucocorticoid (e.g., 100 mg IV prednisone or 
prednisolone or equivalent) is allowed at the investigator’s discretion.  For patients who 
did not experience infusion-related symptoms with their previous infusion, 
premedication at subsequent infusions may be omitted at the investigator’s discretion. 
 
Rituximab infusions will be administered according to the instructions in Table 1.  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 first cycle of treatment, rituximab must be administered to patients in a setting 
where full emergency resuscitation facilities are immediately available.  Patients should 
be under close supervision of the investigator at all times.  For the management of IRRs 
and anaphylaxis, see Section 5.1.4.3 
 
Rituximab should be administered as a slow IV infusion through a dedicated line. IV 
infusion pumps (such as the 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. Refer to the specific 
package inserts for preparation, administration, and storage conditions. 
 
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 1. Administration of First and Subsequent Infusions of Rituximab 
 
First Infusion (Cycle 1 Day 1) 
Subsequent Infusions 
• Begin infusion at an initial rate of 50 mg/hr 
• If no infusion-related or hypersensitivity 
reaction occurs, increase the infusion rate in 
50-mg/hr increments every 30 minutes, to a 
maximum of 400 mg/hr. 
• If a reaction develops, stop or slow the 
infusion. Administer medications and 
supportive care in accordance with 
institutional guidelines. If the reaction 
resolves, resume the infusion at a 
50% reduction in rate (i.e., 50% of rate used 
at the time the reaction occurred). 
• If the patient experienced an 
infusion-related or hypersensitivity reaction 
during the prior infusion, begin infusion at 
an initial rate of 50 mg/hr and follow 
instructions for first infusion. 
• If the patient tolerated the prior infusion 
well (defined by absence of Grade 2 
reactions during a final infusion rate of 
≥ 100 mg/hr), begin infusion at a rate of 
100 mg/hr. 
• If no reaction occurs, increase the infusion 
rate in 100-mg/hr increments every 
30 minutes, to a maximum of 400 mg/hr. 
• If a reaction develops, stop or slow the 
infusion. Administer medications and 
supportive care in accordance with 
institutional guidelines. If the reaction 
resolves, resume the infusion at a 50% 
reduction in rate (i.e., 50% of rate used at 
the time the reaction occurred). 
 
 
Any dose modification should be noted on the Rituximab Administration 
electronic Case Report Form (eCRF).  Cases of accidental overdose or 
medication error, along with any associated adverse events, should be 
reported as described in Section 5.2. 
 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.4.1. 
4.2.3.3. Cyclophosphamide, Doxorubicin, and Prednisone Dosage and 
Administration 
CHP chemotherapy consists of cyclophosphamide and doxorubicin administered via IV 
and oral prednisone. Doxorubicin and cyclophosphamide should be administered after 
both rituximab and polatuzumab vedotin infusions. 
 
The dosages are based on the standard CHOP doses: 
• 
Cyclophosphamide 750 mg/m2 administered IV on Day 1 of Cycles 1-6 
 
• 
Doxorubicin 50 mg/ m2 administered IV on Day 1 of Cycles 1-6 
• 
Prednisone 100 mg/day PO on Days 1 through 5 of each Cycle 1-6 
Note: Prednisone may be replaced with prednisolone (100 mg/day) or IV 
methylprednisolone (80 mg/day). Hydrocortisone may not be used as a substitute. 

 
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If glucocorticoid treatment is urgently required for lymphoma symptom control prior to the start 
of study treatment, prednisone 100 mg or equivalent could be given for a maximum of 13 days 
as a prephase treatment, but all tumor assessments must be completed prior to starting 
glucocorticoid treatment. 
Refer to the specific package inserts for preparation, administration, and storage guidelines. 
Cyclophosphamide is stored at 25C or below. Cyclophosphamide is available in 3 vial strengths (2 
gm, 1 gm, and 500 mg). Use sterile water to reconstitute vial per package directions. Doxorubicin is 
stored at 2-8C with 2 different vial strengths. Refer to the specific package inserts for preparation, 
administration, and storage guidelines. BSA may be capped at 2 m2 per institutional standards. If 
CHP is started later than Day 1 of the cycle, then planned Day 1 of the next cycle should be 
calculated from the day when CHP was actually initiated, in order to maintain the regular 
chemotherapy interval of 21 days. 
For details regarding storage, handling and formulation of Cyclophosphamide, Doxorubicin and 
Prednisone, please refer it package insert and institutional standards. 
 
 
4.2.3.4. 
Premedications 
Patients should receive premedications as outlined in Table 2. 
Table 2. Premedication for Rituximab and Polatuzumab Vedotin 
 
Timepoint 
Patients who require pre- 
medication 
Pre-medication 
Administration 
Cycle 1, Day 1 
All patients 
• 
Corticosteroid 
Complete ≥ 1 hour prior 
to rituximab infusion. 
• 
Anti-histamine 
Administer ≥ 30 
minutes prior to 
rituximab infusion; may 
be 
administered to 
patients prior to 
administration of any 
polatuzumab vedotin 
as well. 
• 
Analgesic/Antipyretic 
Cycles 2 and 
beyond, 
Day 1 
Patients with no IRR 
during the previous 
infusion 
• 
Corticosteroid 
Complete ≥ 1 hour prior 
to rituximab and 
polatuzumab 
vedotin infusion. 
• 
Antihistamine drug 
• 
Analgesic/Anti-pyretic 
Administer ≥ 30 
minutes prior to 
infusion. These may be 
omitted at the 
investigator’s 
discretion. 

 
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Patients with Grade 1 
or 2 IRR during the 
previous infusion 
• 
Corticosteroid 
Complete ≥ 1 hour prior 
to rituximab and 
polatuzumab vedotin 
infusion. 
• 
Antihistamine drug 
• 
Analgesic/Anti- 
pyretic 
Administer ≥ 30 
minutes prior to 
rituximab and/or 
polatuzumab vedotin 
infusion. 
Patients with Grade 3 
IRR, wheezing, 
urticaria, or other 
symptoms of 
anaphylaxis during 
the previous infusion 
Patients with bulky 
disease 
• 
Corticosteroid 
Complete ≥ 1 hour prior 
to rituximab and/or 
polatuzumab 
Vedotin infusion. 
• 
Antihistamine drug 
• 
Analgesic/anti-pyretic 
Administer ≥ 30 
minutes prior to 
rituximab and/or 
polatuzumab 
Vedotin infusion. 

 
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4.2.4. Investigational Medicinal Product Accountability 
All investigational medical products (IMPs) required for completion of this study 
(polatuzumab vedotin) will be provided by Roche/Genentech where required by local 
health authority regulations. The study site will acknowledge receipt of IMPs to confirm 
the shipment condition and content.  Any damaged shipments will be replaced. 
 
IMPs will be either disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed to by the 
Sponsor. The site must obtain written authorization from the Sponsor before any IMP is 
destroyed, and IMP destruction must be documented on the appropriate form. 
 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. 
 
Rituximab Cyclophosphamide Adriamycin and Prednisone (RCHP) will be provided by 
the institutions as standard of care therapy. A refrigerator log to maintain appropriate 
storage conditions will be maintained by the site. Any temperature excursions should be 
reported to the sponsor. 
 
4.3. 
CONCOMITANT THERAPY 
4.3.1. Permitted Therapy 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to screening to the study treatment completion visit, which is 30 (± 5) days 
after the last dose of study treatment.  All such medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF. 
 
Patients may continue to use oral contraceptives, hormone-replacement therapy, or 
other maintenance therapies. 
 
MMAE is a substrate of the cytochrome P450 (CYP450) enzymes, specifically CYP3A. 
Published data suggest that MMAE is neither an inhibitor nor inducer of CYP3A. 
Patients who are receiving strong CYP3A inhibitors should be closely monitored for 
adverse reactions when given polatuzumab vedotin (Han et al. 2013). 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
at the discretion of the investigator. Other than the prednisone given as study treatment 
and prednisone that may be given as pre-phase treatment at the discretion of the 
treating investigator physician (see Section 4.2.3.4.), corticosteroids may be used only 
for the treatment of conditions other than lymphoma (e.g., asthma). 
 
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, per local standard practice. Patients who experience infusion- 

 
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associated symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, cimetidine), or 
equivalent medications per local standard practice. Serious infusion-associated events 
manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced 
oxygen saturation, or respiratory distress should be managed with supportive therapies 
as clinically indicated (e.g., supplemental oxygen and a2-adrenergic agonists). 
 
IMPORTANT NOTE: The use of Evusheld or other post-exposure anti-viral 
medications against COVID19 does not affect study eligibility. Patients who have 
received Evusheld can be enrolled and patients who are already on study who receive 
Evusheld can remain on study. Receipt of Evusheld during or after study treatment 
will be documented. To capture side effects associated with individual agents, we 
would advise to maintain at least 1 week of gap between Evusheld and 
chemotherapeutic agents administration if possible. As new agents become available 
for patients, the study team will discuss best practices for administration of these 
agents and provide general guidelines with consideration for the integrity of the 
protocol. 
 
4.3.2.  CNS Prophylaxis 
CNS prophylaxis with intrathecal methotrexate 12 mg as CNS prophylaxis on day 1, 2 
or 3 of each cycle of therapy is required and its use must be documented in the eCRF. 
CNS prophylaxis using systemic IV methotrexate (e.g., 1 g/m2 per cycle) is not 
permitted. 
 
4.3.3. Prophylaxis for Hemorrhagic Cystitis 
Patients should be adequately hydrated before and after cyclophosphamide 
administration and should be instructed to void frequently. Mesna may be used as 
prophylaxis according to institutional practice. 
4.3.4.  Transfusions for cytopenias 
Patients may receive supportive platelet and blood transfusions per institutional 
guidelines once on active study therapy 
 
4.3.5. Treatment and Prophylaxis of Neutropenia 
G-CSF is required as primary prophylaxis in each cycle of therapy. Dosing of G-CSF should 
follow each site’s institutional standards or may be at the investigator’s discretion. 
For patients who develop neutropenia despite prophylaxis, G-CSF is not routinely 
recommended for the treatment of uncomplicated neutropenia. However, G-CSF may 
be considered in patients with fever and neutropenia who are at high risk for infection- 
associated complications or who have prognostic factors predictive of poor clinical 
outcomes (Smith et al. 2015). 
 
4.3.6. Premedications before Rituximab 
All rituximab infusions should be administered to patients after premedication.  The 

 
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following premedication is required before rituximab therapy: 
• 
Acetaminophen/paracetamol (650−1000 mg) orally at least 30−60 minutes before 
the start of all infusions 
• 
Antihistamine, such as diphenhydramine (25−50 mg), approximately 30−60 
minutes before the start of each infusion (unless contraindicated) 
 
On Cycle 1 Day 1, it is recommended that glucocorticoids (e.g., 100 mg prednisone or 
prednisolone or equivalent) be given within 12 hours as pre-medication. For patients 
who did not experience infusion related symptoms with their previous infusion, 
premedication at subsequent infusions may be omitted at the investigator’s discretion. 
 
4.3.7. Premedication for Patients at High Risk for Tumor Lysis Syndrome 
Patients with high tumor burden and considered by the investigator to be at risk for 
tumor lysis should also receive tumor lysis prophylaxis prior to the initiation of treatment. 
Patients should be well hydrated.  Starting 1−2 days prior to the first dose of study 
treatment, it is desirable to maintain a fluid intake of approximately 3 L/day.  In addition, 
all patients with high tumor burden and considered to be at risk for tumor lysis should be 
treated with 300 mg/day of allopurinol orally or a suitable alternative treatment (i.e., 
rasburicase), starting 48−72 hours prior to Cycle 1 Day 1 of treatment and hydration. 
Patients should continue to receive repeated prophylaxis with allopurinol if deemed 
appropriate by the investigator and adequate hydration prior to each subsequent cycle 
of treatment. 
 
4.3.8. Prophylaxis for Infections 
All patints will receive herpesvirus prophylaxis as per institutional standards throughout 
the treatment with Polatuzumab Vedotin. Anti-infective prophylaxis for viral, fungal, 
bacterial, is permitted and should be instituted per institutional practice or investigator 
preference based on individual patient risk factors. All anti-infective prophylaxis used 
should be recorded appropriately in the eCRF. 
 
4.3.9. Monitoring and Treatment for Hepatitis B Reactivation 
Patients who are both HBsAg negative and anti-HBc positive may be included in this 
study.  These patients should have HBV DNA levels obtained monthly during the study 
and for at least 12 months after the last cycle of therapy by means of real time PCR with 
the use of an assay that has a sensitivity of at least 10 IU/mL. 
 
If the HBV-DNA assay becomes positive and is above the World Health Organization’s 
(WHO) cutoff of 100 IU/mL, study treatment will be held, and the patient should be 
treated (for at least 1 year after the last dose of rituximab) 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. 

 
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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 
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 5.1.4,  7). 
4.3.10. Other Concomitant Medications 
Necessary supportive measures for optimal medical care will be given throughout the 
study according to institutional standards, including the use of growth factors (e.g., 
erythropoietin), if clinically indicated. 
 
Anti-emetic therapy may be instituted for any patient if clinically indicated. Systemic 
steroid therapy will not be allowed either during or within 7 days before the first dose of 
study treatment with the exception of the following: 
• 
Inhaled corticosteroids for the treatment of asthma or chronic obstructive 
pulmonary disease (COPD) 
• 
Pre-medication before rituximab or polatuzumab vedotin 
• 
Topical steroids 
• 
Stable replacement corticosteroid therapy for an inherited or acquired deficiency 
• 
Ongoing corticosteroid use for lymphoma symptom control (13 days of prednisone 
is allowed) 
 
 
4.3.11. Prohibited Therapy 
Treatment with other concomitant anti-tumor agents not defined in this protocol as study 
treatment, radiotherapy, or other concurrent investigational agents of any type will result 
in withdrawal of patients from study treatment. 
 
Use of the following therapies is prohibited during the study: 
• 
Cytotoxic chemotherapy, other than intrathecal chemotherapy for CNS prophylaxis 
• 
Immunotherapy or immunosuppressive therapy, other than study treatments 
• 
Radioimmunotherapy 
• 
Hormone therapy, other than contraceptives, stable hormone-replacement 
therapy, or megestrol acetate 
• 
Biologic agents other than hematopoietic growth factors, which are allowed if 
clinically indicated and used in accordance with instructions provided in the 
package inserts 
• 
Any therapy (other than intrathecal CNS prophylaxis) intended for the treatment of 

 
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lymphoma whether it is approved by the European Medicines Agency (EMA) or 
the U.S. Food and Drug Administration (FDA) or is experimental 
• 
Radiotherapy 
 
4.3.12. 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. 
 
 
4.3.13. Use of SARS-CoV-2 vaccines in patients who are receiving Polivy® 
(polatuzumab vedotin-piiq). 
 
As of January 22, 2021, there is insufficient experience with the use of the SARS-CoV-
2 mRNA vaccine in patients receiving Polivy.1 The decision to administer a SARS-CoV-
2 mRNA vaccine should be individualized based on a patient’s SARS-CoV-2 
infection/complication risk, the general condition of the patient, the severity and 
seriousness of the underlying disease/condition for which the patient is receiving 
Polivy as well as the epidemiology of COVID-19 in the patient's geographical location. 
SARS-CoV-2 mRNA vaccines must be given in accordance with the  
approved/authorized vaccine label and official immunization guidance. 
 
Based on the published mechanism of action of the mRNA technology based SARS-
CoV-2 vaccines and the known mechanism of action of Polivy, there is no scientific 
rationale to expect that the mRNA based SARS-CoV-2 vaccines will affect the efficacy 
or safety of Polivy.2 Vaccine studies have not been performed in patients treated with 
Polivy. Studies of traditional non-live vaccines in patients receiving rituximab show a 
diminished antibody response to those vaccines (influenza, varicella zoster, hepatitis B, 
pneumocccus, hemophillus influenzae B, tetanus). Similar attenuation of humoral 
immune response to vaccines is also expected in patients treated with Polivy.1 
Based on the data available to date regarding the adverse events reported in patients 
enrolled in the COVID-19 vaccines trials, a potential for overlapping side effects with 
Polivy should be considered.3 
Per American Society of Hematology (ASH), American Society of Clinical Oncology 
(ASCO) and other organizations’ recommendation, the oncology patients can receive 
the currently available non-live vaccines. For patients enrolled in this particular study, 
per our institutional guidelines, administration of an authorized Covid-19 vaccine, as a 

 
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supportive care measure is acceptable. The use of investigational vaccines is not 
recommended. 
• The timing of vaccination is at the discretion of the investigator. 
• COVID vaccination will not affect patient’s eligibility for the trial. 
• Administration of COVID-19 vaccine, should be appropriately documented and must 
be recorded in the Prior and Concomitant Medications form in the eCRF. 
• If a patient receives the concomitant COVID vaccine, please capture each dose, 
indicate the manufacturer of the vaccine, the date of vaccination, and if this is the first 
or second dose of the vaccine. 
• Please refer to the respective prescribing information of the authorized COVID 
vaccines. 
• Please record all adverse events, including their causalities, as well as noted 
laboratory abnormalities. 
• There may be concurrent known adverse events-- such as fatigue, body ache, fever, 
nausea-- associated with the authorized COVID- vaccines and other components of 
drugs used in this trial. 
• All causalities associated with the treatment emergent events should be reported 
according to the clinical discretion of the investigator. 
• Based on our current limited clinical information, there are no known contraindications 
associated with PoV or R-CHP and the available authorized COVID- vaccines. Please 
also consider contacting the manufacturer of the SARS-CoV-2 mRNA vaccine for 
additional information. 
 
Clinicians interested in further information regarding vaccines for COVID-19 for the 
general population and in the cancer care community may find the following websites 
useful: 
https://www.cdc.gov/vaccines/covid-19/index.html (US Centers for Disease Control and 
Prevention) 
https://www.nccn.org/covid-19/ (National Comprehensive Cancer Network) 
 
Polivy and SARS-CoV-2 Vaccines References 
 
1. Data on file (37qhcmn57te4v5geru3qi8eld0). 
 
2. Pardi N, Hogan MJ, Porter FW, et al. mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov. 
E-pub Date: ppublish April 2018. DOI # 10.1038/nrd.2017.243 . 
https://www.ncbi.nlm.nih.gov/pubmed/29326426 
 
3. Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine 
[supplementary appendix appears online]. N Engl J Med. E-pub Date: [published online ahead of print] 
December 2020. DOI # 10.1056/NEJMoa2034577. 
https://www.ncbi.nlm.nih.gov/pubmed/33301246 
 
4.4. 
STUDY ASSESSMENTS 
Unless otherwise stated, the baseline measurement for any given assessment will be 

 
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defined as the last value obtained before the first dose of study drug.  Changes from 
baseline abnormalities should be recorded in patient notes.  New or worsened clinically 
significant abnormalities should be recorded as adverse events on the Adverse Event 
eCRF. 
 
 
 
4.4.1. Informed Consent Forms and Screening 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
(ICFs) for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
 
4.4.2. Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies, reason for transplant ineligibility, 2016 WHO 
classification, current Ann Arbor stage, and procedures), ECOG performance status, 
reproductive status, smoking history, alcohol and drugs abuse, and all medications 
(e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) used by the patient within 7 days prior to the screening visit. At 
the time of each follow-up physical examination, an interval medical history should be 
obtained and any changes in medications and allergies should be recorded. B- 
symptoms (i.e., weight loss, night sweats, or fever) will be assessed according to 
Appendix 1. Demographic data will include age, sex, and self-reported race/ethnicity. 
 
4.4.3. Prognostic Indices 
IPI clinical factors at diagnosis and at enrollment will be collected.  Please see Appendix 
6 6 for description of the IPI. 
 
4.4.4. Physical Examinations 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions 
eCRF. 
 
As part of tumor assessment, physical examinations should include evaluation of the 
presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly 
(clinical response assessment). While it is important that these findings are documented 
in the notes from the physical exam, we do not intend to capture this data on the CRFs 

 
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as the measurements are not reliable.     
 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Targeted physical examinations should be limited 
to systems of primary relevance (i.e., cardiovascular, respiratory, those associated with 
symptoms, and those associated with tumor assessment [lymph nodes, liver, and 
spleen]).  Clinical assessments of peripheral neuropathy should be performed at 
screening, at Day 1 of each cycle, and at the treatment completion visit and recorded on 
the appropriate eCRF. 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. 
 
4.4.5. Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressures while the patient is in a seated position, and temperature. 
Weight, height, and BSA will also be recorded.  Height and BSA are required at 
screening only, unless there has been > 10% change in body weight since the last BSA 
assessment, in which case BSA should be recalculated and documented  in the eCRF. 
 
During the administration of polatuzumab vedotin, vital signs should be assessed before 
the start of the infusion, every 15 (± 5) minutes during the infusion, at the end of the 
infusion and every 30 (± 10) minutes for 90 minutes following completion of dosing at 
Cycle 1 and 30 (± 10) minutes following completion of dosing in subsequent cycles. 
 
During the administration of rituximab in Cycle 1, vital signs are to be obtained before 
infusion of rituximab, then 15  minutes after the start of infusion. Vital signs will be 
measured approximately every 15 (± 5) minutes for 90 minutes, then every 30 (± 10) 
minutes until 1 hour after the end of the infusion.  During administration of rituximab in 
subsequent cycles, vital signs are to be recorded before infusion of rituximab, then 15 
minutes after the start of infusion, and approximately every 30 (± 10) minutes until 1 
hour after the end of infusion. 
 
4.4.6. Tumor and Response Evaluations 
All evaluable or measurable disease must be documented at screening and re-  
assessed at each subsequent tumor evaluation. An Independent Review Committee 
with the participation of the study Principal Investigator and other participating site 
investigator, during interim analysis and at the completion of the study, will assess 
responses on the basis of physical examinations, CT scans, PET-CT scans, and bone 
marrow examinations using the Lugano Response Criteria (Cheson et al. 2014). 
 
Radiographic Assessments 
PET-CT scans should include skull-base to mid-thigh. Full-body PET-CT scan should 
be performed when clinically appropriate. 
 

 
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CT scans with oral and IV contrast should include chest, abdomen, and pelvic scans; 
CT scans of the neck should be included if clinically indicated. CT scans for response 
assessment may be limited to areas of prior involvement only if required by local 
regulatory authorities. At the investigator’s discretion, CT scans may be repeated at 
any time if progressive disease is suspected. 
 
In patients for whom contrast is contraindicated, (e.g., patients with contrast allergy or 
impaired renal clearance), CT or combined PET-CT scans without contrast are 
permitted so long as they permit consistent and precise measurement of target lesions 
during the study treatment period. 
 
PET-CT scans in conjunction with diagnostic CT scans will be obtained in this study at 
screening, interim assessment (between cycle 3 day 15 and cycle 4 day 15), and at the 
end of treatment (6-8 weeks after the last dose of treatment). If disease progression 
upon completion of therapy is identified, confirmation by PET-CT is recommended. If 
local practice prohibits obtaining both assessments after Cycle 4, PET-CT alone 
(preferred) or CT alone may be obtained at this time. The Lugano Response Criteria 
(Appendix 2) will be used to assess overall response to study treatment. 
The same radiographic assessment modality should be used for all response 
evaluations to ensure consistency across different time points. 
 
At all times during the study, diagnosis of disease progression based on clinical 
examination must be confirmed on CT scan (or MRI scan if CT scan is contraindicated) 
as soon as feasible (maximum, within 30 days) and prior to initiation of non–protocol 
specified anti-lymphoma therapy. 
 
Bone Marrow Assessments 
Bone marrow examinations are optional at screening for staging purposes in all patients 
dependent on physician discretion. Bone marrow examinations should include a biopsy 
for morphology and an aspirate for local hematology (optional if standard of care at the 
site). 
 
Repeat bone marrow examinations are required in two circumstances: 
If there was bone marrow infiltration at screening, then a subsequent bone marrow 
biopsy (trephine) at the primary response assessment visit is required for clinical 
response evaluation for all patients who may have achieved a CR.  In patients with a 
PR and continued bone marrow involvement, a subsequent bone marrow examination 
may be required to confirm a CR at a later time point. 
 
Any additional (unscheduled) bone marrow examinations performed during the study 
will be at the discretion of the investigator. 
 
 
 

 
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4.4.7. Laboratory, Biomarker, and Other Biological Samples 
4.4.7.1. 
Local Laboratory Assessments 
Samples for hematology, serum chemistry, pregnancy, hepatitis B and C serology will 
be analyzed at the study site’s local laboratory. Laboratory samples may be obtained up 
to 72 hours (within 7 days for pregnancy testing) before start of study treatment 
administration on Day 1 of the treatment cycle. 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• Hematology (CBC with differential to include basophils, eosinophils, 
hematocrit, hemoglobin, lymphocytes, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, mean corpuscular volume, monocytes, 
neutrophils, platelet count, red blood cell count, total white cell count). 
• 
Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, BUN/urea, 
creatinine, calcium, magnesium, phosphorus, total bilirubin, total protein, albumin, 
ALT, AST, alkaline phosphatase, uric acid/urate, hemoglobin A1c. HbA1c will be 
measured only at Screening and at Cycle 4 Day 1 and can be obtained in a non-
fasting state.  Only at screening, obtain beta-2 microglobulin. 
• 
Lactate dehydrogenase (LDH) 
• 
Coagulation: INR or PT, and PTT or aPTT 
• 
Amylase 
• 
HIV  
• 
Viral serology: 
– 
Hepatitis B surface antibody (HBsAb), HbsAg, and total HbcAb 
– 
HBV-DNA by PCR if the patient is HbcAb positive 
– 
HCV antibody 
– 
HCV RNA by PCR if the patient is HCV antibody positive 
• 
CSF assessment, as clinically indicated, for detection of CNS lymphoma 
• 
Pregnancy test 
All women of childbearing potential will have a serum pregnancy test within 7 days 
before Cycle 1 Day 1 of study treatment.  In addition, for women of childbearing 
potential, a serum or urine pregnancy test must be performed prior to study 
treatment on Day 1 of each subsequent cycle of study treatment (laboratory 
samples may be obtained up to 72 hours before start of study treatment 
administration on Day 1 of the treatment cycle).  If any urine pregnancy test is 
positive, study treatment will be delayed until the patient pregnancy status is 
confirmed by a serum pregnancy test.  If serum pregnancy test is positive, the 
patient will be permanently discontinued from study treatment. 
4.4.7.2. 
Central Pathology submission for correlative tissue evaluation 
Tumor tissue samples and the corresponding pathology report, for retrospective central 

 
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confirmation of the diagnosis of DLBCL and for exploratory analyses. The specimen 
must contain adequate evaluable tumor cells (≥20% for excisional biopsy and ≥50% for 
core biopsy). 
• 
Formalin-fixed paraffin-embedded tissue blocks are preferred over slides. Tissue 
blocks that are not formalin fixed will be accepted in countries that use a fixative 
other than paraformaldehyde, but information on the type of fixative should be 
included. If a tissue block is not available, a minimum of 15 serial, freshly cut, 
unstained slides accompanied by a tumor block punch may be sent. A tumor block 
or tumor block punch is required for construction of a tissue microarray. 
• 
If archival tissue is unavailable or unacceptable according to above criteria, a 
pretreatment core needle, excisional, or incisional tumor biopsy is required. 
Cytological or fine-needle aspiration samples are not acceptable. Tumor tissue 
from bone metastases that have been decalcified is not acceptable. 
The sample should be shipped according to instructions provided in section 4.1.3. 
For sampling procedures, storage conditions, and shipment instructions, see section 
4.1.3. 
 
4.4.8. Electrocardiograms and Echocardiogram or MUGA 
A resting 12-lead ECG is required at screening and as clinically indicated.  ECGs for 
each patient should be obtained with the use of the same machine when possible. 
Interpretation of the ECG should be performed by a qualified investigator or sub- 
investigator. 
 
Lead placement should be as consistent as possible. Circumstances that may induce 
changes in heart rate, including environmental distractions (e.g., television, radio, 
conversation, should be avoided during the pre-ECG resting period and during ECG 
recording. 
 
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. Clinically significant events should be reported as adverse events. 
 
For assessment of cardiac function (LVEF), an ECHO or MUGA scan should also be 
obtained at screening. An ECHO or MUGA scan may also be obtained as clinically 
indicated. During infusion of doxorubicin, ECG monitoring should be performed per 
clinical practice. 
 
4.4.9. Timing of Study Assessments 
4.4.9.1. 
Screening and Pretreatment Assessments 
A signed ICF for participation in the study must be obtained before performing any 
study-specific screening tests or evaluations. 
 
Screening and pretreatment tests and evaluations will be performed within 28 days 

 
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before first dose, unless otherwise specified.  Results of standard-of-care tests or 
examinations performed before obtaining informed consent and within 28 days before 
first dose may be used; such tests do not need to be repeated for screening.  All 
screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before randomization.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
 
See Appendix 1 for the schedule of screening and pretreatment assessments. 
 
4.4.9.2. 
Assessments during Treatment 
All assessments must be performed on the day of the specified visit unless a time 
window is specified in the schedule of assessments (see Appendix 1).  Assessments 
scheduled on the day of study treatment administration should be performed before 
administration of study treatment, unless otherwise noted in the schedule of 
assessments. 
 
See Appendix 1 for the schedule of assessments performed during the treatment 
period. 
 
NOTE:  participants with diabetes must have weekly comprehensive metabolic 
panels (including glucose) during the first 3 cycles of study treatment and will be 
counseled to ensure anti-diabetic medication adherence. The research nurse will 
ensure compliance with anti-diabetic medications and assist in monitoring blood 
glucose to keep levels below 300 mg/dL throughout study treatment.  
 
4.4.9.3. 
Follow-Up Assessments 
Month 0 in follow-up is considered to be the treatment completion visit. 
 
4.4.9.3.1. Treatment Completion Visit 
Patients who complete the study treatment period (defined as completion of six cycles 
of study treatment) or discontinue from the study treatment early (i.e., if they terminated 
treatment early because of an adverse event) will be asked to return to the clinic within 
30 days (± 5 days) after the last dose of study treatment for a treatment completion visit. 
The visit at which response assessment shows progressive disease may be used as  
the treatment completion visit. 
 
See Appendix 1 for the schedule of assessments performed at the treatment completion 
visit. 
 
4.4.9.3.2. Suspected Progression 
Patients who demonstrate clinical concern for progression should be evaluated by 
appropriate scans as (described in section 4.4.6), laboratory assessments, and physical 
exam.   This visit is to take place at any time when progression is suspected. 

 
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See Appendix 1 for the schedule of assessments performed at the time of suspected 
progression. 
 
4.4.9.3.3. Primary Response Assessment Visit 
All patients will be asked to return to the clinic for the primary response assessment 
visit.  This visit is to take place between 6 to 8 weeks after the last dose of study 
treatment. 
 
See Appendix 1 for the schedule of assessments performed at the primary response 
assessment visit. 
4.4.9.3.4. Every 3-Month Visit until End of Study 
For patients without disease progression, assessments will be performed every 
3 months ± 14 days after the treatment completion visit, until 5 years. Other 
assessments are indicated in Appendix 1. Disease Progression and No New 
Treatment 
If response assessment shows PD during the follow-up period, subsequent visits will 
have assessments limited to recording of any new anti-lymphoma therapy, the 
occurrence of adverse events (per Section 5.2.), and survival.  Diagnosis of disease 
progression based on clinical examination must be confirmed by CT scan as soon as 
possible (maximum, within 4 weeks) and prior to any new anti-lymphoma therapy.   If no 
new treatment is started, the subject will be followed per the usual follow-up schedule. 
4.4.9.3.5. Disease Progression and New Treatment 
After a patient has PD during follow-up and starts a new anti-lymphoma therapy, 
contact will be made with patients by telephone on at least an annual basis for survival. 
4.4.9.3.6. No Disease Progression and New Treatment 
Patients who discontinue study treatment early because of adverse event and start a 
new anti-lymphoma therapy in the absence of PD should be followed according to the 
protocol schedule, including the response assessments and the reporting of adverse 
events until 30 days after the last dose of study drug (see Section 5.2.) unless they 
withdraw consent. 
 
See the schedule of assessments provided in Appendix 1 for specified follow-up 
assessments. 
 
4.4.9.3.7. Assessments at Unplanned Visits 
See Appendix 1 for assessments that are required in the event of an unplanned visit. 
 
4.5. 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.5.1. Patient Discontinuation 

 
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Patients have the right to voluntarily withdraw from the study at any time for any reason. 
In addition, the investigator has the right to withdraw a patient from the study at any 
time.  Reasons for withdrawal from the study may include but are not limited to the 
following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient. 
• 
Patient non-compliance (i.e., consistent failure to show up for scheduled visits, 
consistent missed treatment, etc.) 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 
4.5.2. Study Treatment Discontinuation 
A patient must discontinue study treatment permanently if any of the following occurs: 
• 
Grade 4 Infusion related reaction (IRR). The patient should be withdrawn from 
study treatment immediately and rituximab treatment should be permanently 
discontinued. 
• 
Recurrence of Grade 3 IRR at re-challenge. Treatment should be permanently 
discontinued. 
• 
Patients with infusion-related Grade ≥ 3 wheezing, hypoxia, or generalized 
urticaria must be permanently discontinued from study drug on the first 
occurrence. 
• 
Grade ≥ 3 toxicity that does not resolve to Grade ≤ 2 or baseline value within 
2 
weeks after last dose and that has a reasonable possibility of being related to the 
administration of polatuzumab vedotin, or rituximab. 
• 
Recurrent Grade 4 neutropenia with infection, despite G-CSF support 
• 
Grade 4 neurotoxicity including peripheral neuropathy 
• 
Grade 3 neurotoxicity that leads to a treatment delay of 14 days or more and does 
not improve to Grade ≤ 2 within 14 days 
• 
Disease progression 
• 
Any dose delay of ≥ 4 weeks 
• 
Pregnancy 
• 
Use of an anti-cancer therapy not required per protocol 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 

 
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In the event that a patient discontinues from study treatment early for reasons other 
than documented disease progression/relapse, that patient will proceed into the follow- 
up period until progression. 
 
All patients will return to the clinic for an early treatment termination visit within 4-8 
weeks after the last dose of study drug and should obtain tumor response assessments. 
Assessments should continue to follow the schedule outlined in Appendix 1 and 
Appendix 2. 
 
 
 
4.5.3. Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference for Harmonisation (ICH) 
guideline for GCP 
• 
No study activity (i.e., all patients have completed, and all obligations have been 
fulfilled) 
 
5. 
ASSESSMENT OF SAFETY 
5.1. 
SAFETY PLAN 
Polatuzumab vedotin is not approved in front line setting in combination with R-CHP 
and is currently in clinical development; the entire safety profile is not known at this 
time. The safety plan for this study is designed to ensure patient safety and will include 
specific eligibility criteria and monitoring assessments as detailed below. 
 
Safety will be evaluated through the monitoring of the following: 
• 
Serious adverse events that are attributed to protocol-mandated interventions from 
the time of signing informed consent until the first dose of study treatment on  
Cycle 1 Day 1 
• 
All adverse events, including serious adverse events, from Cycle 1 Day 1, 

 
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regardless of relationship to study drug, will be reported until 30 days after the last 
dose of study drug.  After this period, the Sponsor should be notified of any 
post-study SAEs or non-SAEs of special interest, regardless of attribution (see 
Section 5.2. for reporting details). 
• 
Measurements of protocol-specified hematology and clinical chemistry laboratory 
values 
• 
Measurements of protocol-specified vital signs 
• 
Assessment of ECGs and physical findings on clinical physical examinations 
 
5.1.1. Risks Associated with Polatuzumab Vedotin 
The clinical safety profile of polatuzumab vedotin is based on clinical data obtained in 
the ongoing Phase I and Phase II studies. This profile is summarized in Section 1.2.  
On the basis of clinical data to date, the known and suspected risks are described 
below.  Polatuzumab vedotin (170 mg/vial lyophilized) is currently in use in other clinical 
trials with an observed safety profile that is consistent with the known safety profile. 
Guidelines around the management of these risks through dose and schedule 
modifications are described in Section 5.1.4.  Refer also to the Investigator’s Brochure 
for complete and updated details. 
 
5.1.1.1. 
Known Risks: Myelosuppression and Peripheral Neuropathy: 
 
5.1.1.1.1 Myelosuppression: this is an identified risk that is a consolidation of 
three adverse drug reactions: neutropenia, thrombocytopenia, and anemia . 
Neutropenia 
Neutropenia and neutropenia-associated events (including febrile neutropenia) have 
generally been reversible, but in some cases resulted in protocol-mandated dose 
reductions and/or delays.  Adequate hematologic function should be confirmed before 
initiation of study treatment.  Patients receiving study treatment will be regularly 
monitored for evidence of marrow toxicity with complete blood counts.  Study treatment 
for hematologic toxicities may be delayed or modified as described in Section 5.1.4. and 
Table 7. The use of G-CSF for neutropenia is described in Section 4.3.5. 
 
Thrombocytopenia: thrombocytopenia is an adverse drug reaction of polatuzumab 
vedotin. It can occur in patients receiving polatuzumab vedotin as monotherapy and in 
combination with rituximab, obinutuzumab chemotherapy, atezolizumab, lenalidomide, 
or venetoclax. Grade 3−4 thrombocytopenia has been reported in patients treated with 
polatuzumab vedotin. Patients receiving polatuzumab vedotin should be regularly 
monitored with complete blood counts. Dose delays or modifications should be 
considered as outlined in the protocol for patients with Grade 3−4 thrombocytopenia. 
Transfusion support for thrombocytopenia can be provided in accordance with the local 
guidelines. 
 
Anemia: anemia is an adverse reaction of polatuzumab vedotin. It can occur in patients 

 
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receiving polatuzumab vedotin as monotherapy or in combination with other 
chemotherapeutic agents. Grade 3−4 anemia has been reported in patients treated with 
polatuzumab vedotin. Patients receiving polatuzumab vedotin should be regularly 
monitored with complete blood counts. Transfusion support for anemia can be provided 
in accordance with the local guidelines. 
 
5.1.1.1.2 Peripheral Neuropathy 
Patients receiving polatuzumab vedotin may develop peripheral neuropathy, including 
peripheral sensory and/or motor neuropathy. These events have generally been 
reversible to varying degrees as much as available, but it is not known if full reversibility 
can be expected or predicted.  Patients in clinical trials with polatuzumab vedotin should 
be monitored for symptoms of neuropathy, including hypoesthesia, hyperesthesia, 
paresthesia, dysesthesia, discomfort, a burning sensation, weakness, gait disturbance, 
loss of balance, orthostatic hypotension, syncope, or neuropathic pain.  Patients 
experiencing new or worsening peripheral neuropathy may require a dose delay, 
change in dose, or discontinuation of treatment and should be managed according to 
the protocol. Study treatment dose and schedule modifications for peripheral 
neuropathy are described in Section 5.1.4. and Table 7. Supportive care measures may 
be implemented per investigator preference (e.g., gabapentin). 
 
5.1.1.1.3 Infections 
Infection is an identified risk (both serious and non-serious), and an adverse 
drug reaction (ADR) of polatuzumab vedotin. Serious, life threatening, or fatal 
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. Patients should be closely monitored during 
treatment for signs of bacterial, fungal, or viral infections. Anti-infective 
prophylaxis should be considered. Polatuzumab vedotin and any concomitant 
chemotherapy should be discontinued in patients who develop serious 
infections. 
 
 
5.1.1.1.4 Polatuzumab Vedotin Infusion-Related Events 
Some Mabs may be associated with the development of allergic or anaphylactic 
reactions to either the active protein or excipients. True allergic/anaphylactic reactions 
are rare after the first dose of a product, because they require prior sensitization. 
Patients with true allergic/anaphylactic reactions should not receive further doses of the 
product. 
 
Mabs may also be associated with reactions that are clinically indistinguishable from 
true allergic/anaphylactic reactions, but that are mediated through direct release of 
cytokines or other pro-inflammatory mediators.  Such reactions are often termed IRRs. 
IRRs typically occur with the first infusion of a Mab product and are generally less 

 
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frequent and/or less severe with subsequent infusions. They can often be managed by 
slowing the infusion rate and/or pretreatment with various medications. 
 
Allergic/anaphylactic reactions and IRRs typically begin during or within several hours 
after completing the infusion.  The onset of symptoms may be rapid, and some 
reactions may be life threatening. 
 
Because of the potential for infusion reactions with protein drugs, administration of 
polatuzumab vedotin will be performed in a setting ready with access to emergency 
equipment and staff who are trained to monitor and respond to medical emergencies.  
All patients will be monitored for infusion reactions during the infusions and immediately 
afterwards (for additional instructions on the monitoring and management of infusion 
reactions, see Section 5.1.4.3. and Table 6).  Recommended management of suspected 
anaphylactic reactions during study drug infusions is provided in Appendix 4.               
The initial dose of polatuzumab vedotin may be administered with premedication with 
acetaminophen/paracetamol, antihistamines, or corticosteroids per institutional standard 
practice at the discretion of the Investigator.  Premedication should be used for 
subsequent doses if IRRs are observed in patients who receive their first dose of 
polatuzumab vedotin without premedications.  Significant issues with polatuzumab 
vedotin IRRs have not been observed. 
 
Similar considerations regarding infusion reactions are applicable for rituximab.  Refer 
to Section 4.2.3.2 for additional information. 
 
5.1.1.1.5 Gastrointestinal Toxicity 
Gastrointestinal toxicities are among the most commonly reported adverse events in 
patients being treated with polatuzumab vedotin and include diarrhea, nausea, vomiting, 
constipation, and abdominal pain. These events have been responsible for dose 
modifications and drug discontinuation and are managed with standard-of-care 
treatment. 
 
5.1.1.1.6 Summary of Adverse Drug Reactions Occurring in Patients with 
Previously Untreated DLBCL Treated with Polatuzumab Vedotin in Combination 
with R-CHP 
 
Infections and Infestations:  upper respiratory tract infection, pneumonia, urinary tract 
infection, herpes virus infection, sepsis, and cytomegalovirus infection. 
 
Blood and Lymphatic System Disorders:  neutropenia, anemia, febrile neutropenia, 
leukopenia, thrombocytopenia, lymphopenia, and pancytopenia. 
 
Metabolism and Nutrition Disorders:  decreased appetite, hypokalemia, 
hypoalbuminemia, and hypocalcemia. 
 
Nervous System Disorders:  neuropathy peripheral and dizziness. 
 

 
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Respiratory, Thoracic, and Mediastinal Disorders:  cough, dyspnea, and pneumonitis. 
 
Gastrointestinal Disorders:  nausea, diarrhea, constipation, abdominal pain, and 
vomiting. 
 
Skin and Subcutaneous Tissue Disorders:  alopecia, rash, pruritis, skin infections, and 
dry skin. 
 
Musculoskeletal Disorders:  myalgia and arthralgia. 
 
General Disorders and Administration Site Conditions:  fatigue, mucositis, pyrexia, 
asthenia, peripheral edema, and chills. 
 
Investigations:  weight decreased, transaminases increased, and hypophosphatemia. 
 
Injury, Poisoning, and Procedural:  infusion related reaction. 
 
5.1.1.2. 
Potential Risks Associated with Polatuzumab Vedotin 
See the Investigator’s Brochure for polatuzumab vedotin for full information. 
 
 
Progressive Multifocal Leukoencephalopathy (PML): one case of 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. 
 
 
 
Hepatic Toxicity (Hyperbilirubinemia, Transaminase [AST or ALT] Elevation) 
Evidence exists of hepatic toxicity with similar ADCs using the cytotoxic agent MMAE in 
both nonclinical and clinical studies. This class effect is usually described as mild and 
reversible. Preexisting liver disease, elevated baseline liver enzymes, and concomitant 
medications may also increase the risk. 
 
5.1.1.2.1. Tumor Lysis Syndrome 
Tumor lysis syndrome (TLS) is a risk if treatment with polatuzumab vedotin results in  
the rapid destruction of a large number of tumor cells.  If any evidence of this occurs 
during the study, tumor lysis prophylaxis measures will be taken.  Patients who are 
considered to have a high tumor burden (e.g., lymphocyte count ≥ 25 × 109/L or bulky 
lymphadenopathy) and who are considered to be at risk for tumor lysis by the 
investigator will receive tumor lysis prophylaxis (e.g., allopurinol ≥ 300 mg/day orally or a 
suitable alternative treatment [according to institutional practice] starting 12−24 hours 
before study treatment) and must be well hydrated before the initiation of study 
treatment at Cycle 1 Day 1. These patients should continue to receive repeated 
prophylaxis with allopurinol and adequate hydration before each subsequent infusion, 

 
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as deemed appropriate by the investigator. 
5.1.1.2.2. Immunogenicity 
As with any recombinant antibody, polatuzumab vedotin may elicit an immune response 
and patients may develop antibodies against polatuzumab vedotin.  Patients will be 
closely monitored for any potential immune response to polatuzumab vedotin. 
Appropriate screening, confirmatory, and characterization assays will be employed to 
assess ADAs before, during, and after the treatment with polatuzumab vedotin.  Given 
the historically low immunogenicity rate of rituximab in patients with NHL, ADAs against 
rituximab will not be monitored in this study. 
5.1.1.2.3. Reproductive Toxicity 
Adverse effects on human reproduction and fertility are anticipated with the 
administration of polatuzumab vedotin given the mechanism of action of MMAE 
and the cytotoxic component of polatuzumab vedotin as a microtubule inhibitor. 
No clinical studies assessing the reproductive and embryo-fetal toxicity of polatuzumab 
vedotin have been conducted to date. It is not known whether polatuzumab vedotin can 
cross the placenta or cause harm to the fetus when administered to pregnant women or 
whether it affects reproductive capacity. It is not known whether polatuzumab vedotin can 
be found in sperm. 
5.1.1.2.4. Hyperglycemia 
Hyperglycemia has been observed in patients treated with polatuzumab vedotin and 
with other ADCs that use the same vc-MMAE platform.  Hyperglycemia has been 
reversible upon holding or discontinuing treatment of the ADCs and/or initiation or 
adjustment of standard-of-care anti-hyperglycemic medications. 
 
 
 
Genotoxicity/Carcinogenicity (Myelodysplastic Syndrome) 
MMAE, the cytotoxic component of polatuzumab vedotin, is a microtubule inhibitor 
targeting rapidly dividing cells and is expected to be carcinogenic. Patients who received 
chemotherapy with vincristine sulfate in combination with anticanceranti-cancer drugs 
known to be carcinogenic have developed second malignancies, although the 
contributing role of vincristine sulfate has not been determined. 
 
Renal Toxicity (Increased Serum Creatinine) 
Preliminary safety observations in clinical trials with ADCs using the same linker and 
MMAE have suggested that some patients experience reduction of renal function during 
clinical trials. Most events occurred in the setting of dehydration or other inciting illnesses. 
 
Cardiac Arrhythmias 
While not observed in the nonclinical GLP studies, several SAEs of cardiac toxicities have 
been experienced by patients receiving an ADC-vc-MMAE, which is in the same class as 
polatuzumab vedotin. 
 
Ocular Toxicity 

 
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While not observed in nonclinical GLP studies, treatment-emergent AEs of ocular toxicities 
have been experienced by patients receiving antibody drugs with the same drug conjugate 
(ADC-vc-MMAEs) as polatuzumab vedotin. 
 
Dysgeusia 
While not observed in the nonclinical GLP studies, treatment-emergent AEs of dysgeusia 
or alteration of taste have been experienced by patients receiving ADC-vc-MMAEs which 
are in the same class as polatuzumab vedotin. 
 
 
5.1.2 Risks Associated with Rituximab Therapy 
See the Package Insert/Summary of Product Characteristics for rituximab for full 
information. 
Possible Side Effects of Rituximab (Table Version Date: August 30, 2019) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Rituximab, more than 20 and up to 100 may have: 
• Infection, especially when white blood cell count is low 
• Anemia which may require blood transfusion 
• Nausea 
• Reaction during or following infusion of the drug 
• Chills, fever 
• Tiredness 
 
 
5.1.2.1. 
Infusion-Related Reactions 
Patients treated with rituximab are at risk for IRRs.  Fatal infusion reactions within 
24 hours of rituximab infusion can occur; approximately 80% of fatal reactions occurred 
with the first infusion.  Severe reactions to rituximab typically occurred during the first 
infusion with time to onset of 30−120 minutes.  Rituximab-induced infusion reactions 
and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, 
pulmonary infiltrates, adult respiratory distress syndrome, myocardial infarction, 
ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. 
5.1.2.2. 
Tumor Lysis Syndrome 
Patients treated with rituximab may be at risk for TLS. With rituximab treatment, acute 
renal failure, hyperkalemia, hypocalcaemia, hyperuricemia, or hyperphosphatemia from 
tumor lysis, some fatal, can occur within 12−24 hours after the first infusion of rituximab 
in patients with NHL.  A high number of circulating malignant cells (≥ 25,000/mm3) or 
high tumor burden confers a greater risk of TLS. For patients with evidence of TLS, 
rituximab should be discontinued, and the patient treated as clinically indicated. 
 
5.1.2.3. 
Hepatitis B Reactivation 
HBV reactivation with subsequent fulminant hepatitis, hepatic failure, and death can 
occur in patients with hematologic malignancies treated with rituximab. The median  
time to diagnosis of hepatitis was approximately 4 months after the initiation of rituximab 
treatment and approximately 1 month after the last dose. 

 
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Patients with chronic hepatitis B (HbsAg-positive) viral infection are at risk for 
reactivation and will be excluded from the study.  Patients with evidence of prior 
hepatitis B exposure or who are carriers (defined as HbsAg-negative and 
anti-HbcAb-positive) are at a lower risk for reactivation.  Patients who demonstrate 
evidence of reactivation while receiving an appropriate anti-viral therapy will be 
discontinued from study treatment. 
5.1.2.4. 
Progressive Multifocal Leukoencephalopathy 
Rare cases of progressive multifocal leukoencephalopathy (PML) have also been 
reported in patients treated with rituximab alone or in combination with other 
immunosuppressive medications (Goldberg et al. 2002; Calabrese et al. 2007;  
Carson et al. 2009).  In a review of 57 patients who developed PML after rituximab 
administration, all patients had received prior therapies with alkylating agents, 
corticosteroids, purine analogs, or drugs to prevent allogeneic stem cell or solid-organ 
graft rejection. The diagnosis of PML in any patient treated with rituximab is rare but 
should be suspected in any patient who develops new-onset neurologic manifestations. 
The majority of patients with hematologic malignancies diagnosed with PML received 
rituximab in combination with chemotherapy or as part of a hematopoietic SCT.  Most 
cases of PML were diagnosed within 12 months of the patient’s last infusion of 
rituximab. 
5.1.2.5. 
Cardiac Toxicity 
Angina and cardiac arrhythmias have occurred with rituximab treatment and can be 
life-threatening. Infusions should be discontinued in the event of serious or 
life-threatening cardiac arrhythmias.  Patients who develop clinically significant 
arrhythmias should undergo cardiac monitoring during and with subsequent infusions of 
rituximab.  Patients with pre-existing cardiac conditions, including angina and 
arrhythmias, and who have had recurrences of these events during rituximab therapy 
should be monitored throughout the infusion and in the post-infusion period. 
5.1.2.6. 
Infection 
Serious infections, including fatal bacterial, fungal, and new or reactivated viral 
infections, can occur during and up to 1 year following completion of rituximab-based 
therapy.  New or reactivated viral infections include cytomegalovirus, herpes simplex 
virus, parvovirus B19, Varicella zoster virus, West Nile virus, and hepatitis B and C 
viruses. 
5.1.2.7. 
Severe Mucocutaneous Reactions 
Severe reactions, including fatal mucocutaneous reactions, can occur in patients 
receiving rituximab. These reactions include paraneoplastic pemphigus, 
Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic 
epidermal necrolysis (TEN). The onset of these reactions in patients treated with 
rituximab has varied from 1 to 13 weeks following rituximab exposure. 

 
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5.1.2.8. 
Bowel Obstruction and Perforation 
Abdominal pain, bowel obstruction, and perforation, in some cases leading to death, 
can occur in patients receiving rituximab in combination with chemotherapy.  In 
postmarketing reports of rituximab, the mean time to documented gastrointestinal 
perforation was 6 days (range 1−77 days) in patients with NHL. 
 
5.1.3. 
Risks Associated with Cyclophosphamide, Doxorubicin and 
Prednisone 
Please see the Package Insert/Summary of Product Characteristics for 
Cyclophosphamide, Doxorubicin, and Prednisone for full information. 
Possible Side Effects of Cyclophosphamide (Table Version Date: May 4, 2021) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Cyclophosphamide, more than 20 and up to 100 may have: 
• Infection, especially when white blood cell count is low 
• Anemia which may cause tiredness, or may require transfusion 
• Bruising, bleeding 
• Blood in urine 
• Nausea, vomiting, diarrhea, loss of appetite, pain in belly 
• Sores in mouth which may cause difficulty swallowing 
• Absence of menstrual period which may decrease the ability to have children 
• Hair loss, skin changes, rash, change in nails 
 
   Possible Side Effects of Doxorubicin (Table Version Date: October 15, 2020) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Doxorubicin, more than 20 and up to 100 may have: 
• Nausea, vomiting 
• Red colored urine, saliva, or sweat 
• Hair loss 
 
Possible Side Effects of Prednisone (Table Version Date: February 4, 2022) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Prednisone, more than 20 and up to 100 may have: 
• High blood pressure which may cause headaches, dizziness, blurred vision 
• Swelling of the body, tiredness, bruising 
• In children and adolescents: decreased height 
• Increased appetite and weight gain in the belly, face, back and shoulders 
• Pain in belly 
• Loss of bone tissue 
• Difficulty sleeping 
• Mood swings 
• Skin changes, acne 
 
5.1.4. Management of Specific Adverse Events 
Guidelines for management of specific adverse events are outlined in Table 7. 

 
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Additional guidelines are provided in the subsections below. 
5.1.4.1. 
Dose Delays and Dose Modifications 
Patients should be assessed clinically for toxicity before each dose using NCI CTCAE 
v5.0 unless otherwise stated. These guidelines pertain to dose delays and 
modifications based on physical examination findings, observed toxicities, and 
laboratory results obtained within 72 hours before study treatment administration. 
Dosing will occur only if a patient’s clinical assessment and laboratory test values are 
acceptable. The determination of all dose and schedule modifications will be made on 
the basis of the investigator’s assessment of ongoing clinical benefit with continuing 
study treatment in consultation with the Medical Monitor and with the approval of the 
Medical Monitor. 
 
These guidelines pertain to dose delays and modifications based on physical 
examination findings, observed toxicities, and laboratory results obtained within 72 
hours before study treatment administration. Guidelines for dose delays and 
modifications of polatuzumab vedotin, cyclophosphamide and doxorubicin are shown in 
Table 3, Table 4, and Table 5. The determination of all dose and schedule modifications 
will be made on the basis of the investigator’s assessment of ongoing clinical benefit 
with continuing study treatment in consultation with and with the approval of the Medical 
Monitor. 
 
Cyclophosphamide and Doxorubicin doses may be reduced as outlined in Table 4 and 
Table 5, respectively. Cyclophosphamide or doxorubicin may be reduced separately; 
that is, one or both agents may be reduced in 25%-50% increments per investigator 
preference. Cyclophosphamide and doxorubicin doses may be re-escalated (even to 
the full dose) with the approval of the Medical Monitor. 
 
The dose of polatuzumab vedotin and chemotherapy (cyclophosphamide or 
doxorubicin) can be reduced stepwise to a maximum of two levels for management of 
drug-related toxicities. If further dose reduction is indicated after two dose reductions, 
the patient must discontinue the specific study drug but may continue treatment with the 
remaining study drugs at the investigator’s discretion in consultation with the Medical 
Monitor. 
The administration of polatuzumab vedotin and R-CHP should be delayed for the same 
time frame; that is, all study drugs should be delayed for the same time frame so that 
they are all given together beginning on Day 1 of the same cycle. 
 
Table 3 Recommended steps of Dose Reduction for Polatuzumab Vedotin 
 
Dose level 
Polatuzumab Vedotin 
Starting dose 
1.8 mg/kg per cycle 
First dose reduction 
1.4 mg/kg per cycle 
Second dose reduction 
1.0 mg/kg per cycle 
Third dose reduction 
Discontinue drug 
 

 
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Table 4  Recommended steps of Dose reduction for Cyclophosphamide 
 
Dose level 
Cyclophosphamide 
Starting dose 
100% of starting dose per cycle 
First dose reduction 
75%-50% of starting dose per cycle 
Maximum dose reduction 
50% of starting dose per cycle or 
discontinue drug 
Subsequent dose reduction 
Discontinue drug 
 
Table 5 Recommended steps of Dose reduction for Doxorubicin 
 
Dose level 
Doxorubicin 
Starting dose 
100% of starting dose per cycle 
First dose reduction 
75%-50% of starting dose per cycle 
Maximum dose reduction 
50% of starting dose per cycle or 
discontinue drug 
Subsequent dose reduction 
Discontinue drug 
 
 
5.1.4.2.Treatment interruptions and Schedule Modifications 
Patients with DLBCL who have received Cycle 1 treatment may have the dosing 
schedule changed to a 28-day cycle if it is considered by the investigator that changing 
a patient’s dosing regimen from 21-day to 28-day cycles would provide sufficient time 
for recovery from a transient and reversible toxicity (e.g., cytopenia without requiring 
repeated treatment delays).  Modifications of this type to the dosing schedule must be 
made in consultation with the Medical Monitor and have the approval of the Medical 
Monitor. 
 
Study treatment may be temporarily suspended in patients who experience toxicity 
considered to be related to study drug (see Table 7). Aside from the withholding of 
polatuzumab vedotin for neuropathy per Table 7, study drugs withheld for >14 days 
because of toxicity should be discontinued, unless resumption of treatment is approved 
following investigator discussion with the Medical Monitor. In this previously untreated 
curative setting, study treatments can continue with the remaining study drugs in the 
event one or more of the study drugs are discontinued. 
Study treatment may be suspended for reasons other than toxicity (e.g., surgical 
procedures) with Medical Monitor approval. The investigator and the Medical Monitor  
will determine the acceptable length of treatment interruption. If scheduled dosing 
coincides with a holiday that precludes dosing, dosing should commence on the nearest 
following date, with subsequent dosing continuing on a 21-day schedule as applicable. 
 
Specific guidelines around dosage modifications for Cycles 2-6 are detailed below. 
Patients who are receiving study treatment and experience toxicities should undergo 
dose interruptions and reductions, per instructions in Table 7. All considerations of dose 
and schedule modifications should be discussed with and approved by the Medical 

 
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Monitor. 
 
5.1.4.3. 
Non-Hematologic Toxicities 
5.1.4.3.1. Infusion-Related Reactions and Anaphylaxis 
Medications including epinephrine for SC injections, corticosteroids, diphenhydramine 
hydrochloride for IV injection, and resuscitation equipment should be available for 
immediate use during the first cycle of treatment.  Management of infusion-related 
symptoms for rituximab are summarized in Table 6 according to the administration 
rates in Section 4.2.3.2. In the event of a life-threatening IRR (which may include 
pulmonary or cardiac events) or IgE- mediated anaphylactic reaction, rituximab should 
be discontinued, and no additional drug should be administered.  Patients who 
experience any of these reactions should receive aggressive symptomatic treatment 
and will be discontinued from study treatment.  See Appendix 4 for recommended 
management of anaphylaxis. 
 
Patients who experience rituximab-associated infusion-related temperature elevations 
of > 38.5°C or other minor infusion-related symptoms may be treated symptomatically 
with acetaminophen/paracetamol (500−1000 mg) and/or H1- and H2- histamine 
receptor antagonists (e.g., diphenhydramine hydrochloride) and ranitidine.  Serious 
infusion-related events, manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress, should 
be managed with additional supportive therapies (e.g., supplemental oxygen, β2 
agonists, epinephrine, and/or corticosteroids) as clinically indicated according to 
standard clinical practice.  See Appendix 4 for recommended management of 
anaphylaxis. 
 
Guidelines for the management of IRRs and anaphylaxis are detailed in Table 6. 

 
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Table 6 
Management of Infusion-Related Symptoms: Rituximab and PoV 
 
Infusion-Related 
Symptoms 
Guidance 
Grade 1-2 
• 
Slow or hold infusion. 
• 
Give supportive treatment. A 
• 
Upon symptom resolution, may resume infusion-rate 
escalation at the investigator’s discretion. 
• 
Note: For Grade 2 wheezing or urticaria, patient must be 
premedicated for any subsequent doses. If symptoms recur, 
the infusion must be stopped immediately, and study drug 
permanently discontinued. 
Grade 3 
• 
Discontinue infusion. 
• 
Give supportive treatment. A 
• 
Upon symptom resolution, may resume infusion-rate 
escalation, at investigator discretion. B 
• 
Note: If the same adverse event recurs with same severity, 
treatment must be permanently discontinued. 
• 
Note: For Grade 3 hypotension or fever, patient must be 
premedicated before re-treatment. If symptoms recur, then 
study drug must be permanently discontinued. 
• 
Note: If patient has Grade 3 wheezing, bronchospasm, or 
generalized urticaria at first occurrence, study drug must be 
permanently discontinued. 
Grade 4 
• 
Discontinue infusion immediately, treat symptoms 
aggressively, and permanently discontinue study drug. 
IV = intravenous; NCI CTCAE v5.0 = National Cancer Institute Common Terminology Criteria for 
Adverse Events, version 5.0 
Refer to the NCI-CTCAE v5.0 scale for the grading of symptoms. Management of IgE-mediated 
allergic reactions should be as directed in the text following this table. 
A   Supportive treatment: Patients should be treated with acetaminophen/paracetamol and an 
antihistamine such as diphenhydramine if they have not been received in the previous 4 
hours. IV saline may be indicated. For bronchospasm, urticaria, or dyspnea, patients may 
require antihistamines, oxygen, corticosteroids (e.g., 100 mg IV prednisolone or equivalent), 
and/or bronchodilators. Patients with hypotension who require vasopressor support must be 
permanently discontinued from study drug. 
B   Infusion rate escalation after re-initiation: Upon complete resolution of symptoms, 
the infusion may be resumed at 50% of the rate achieved prior to interruption. In the absence 
of infusion-related symptoms, the rate of infusion may be escalated in increments of 
50 mg/hour every 30 minutes. 

 
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Table 7 
Guidelines for Dose Delay or Modification of Polatuzumab Vedotin and R-CHP 
 
 
Event(s) 
Dose Delay or Modification 
Grade 3 or 4 neutropenia on 
Day 1 of any Cycle with or 
without infection or fever a 
First delay 
• 
Delay all study treatment. Treatment cannot be delayed for more than 2 weeks. 
• 
Administer growth factors as appropriate; (e.g., G-CSF for neutropenia as indicated and for all subsequent 
cycles). 
• 
If ANC recovers to > 1000/µL by Day 7 of the scheduled date for the next cycle, administer full dose of 
polatuzumab vedotin, and rituximab. 
• 
If ANC recovers to > 1000/µL after Day 7 of the scheduled date for the next cycle, Polatuzumab dose will be 
reduced to 1.4mg/m2 if growth factor support was administered per protocol. If a second occurrence is noted 
of >7 days, steps will be followed per section 5.1.4.1. 
• 
If the primary cause of neutropenia is thought to be lymphoma infiltration into the bone marrow, the 
investigator may elect not to reduce the dose. Decisions must be made in consultation with and with 
approval of the Medical Monitor. 
Recurrent Grade 3 or 4 
neutropenia on Day 1 of any 
Cycle 
• 
Delay doses of all study treatment. Treatment cannot be delayed for more than 2 weeks. 
• 
If ANC recovers to > 1000/µL by Day 14 of the scheduled date for the next cycle, administer full dose of 
study treatment. 
Grade 3 or 4 
thrombocytopenia on Day 1 of 
any Cycle, first episode 
• 
Delay doses of all study treatment. 
• 
If platelet count recovers to 75,000/µL by Day 14 of the scheduled date of the next cycle, administer full dose 
of study treatment. 
• 
If the patient had baseline thrombocytopenia and the primary cause of thrombocytopenia is thought to be 
lymphoma infiltration into the bone marrow, the investigator may elect not to reduce the dose of medications. 
Recurrent Grade 3 or 4 
thrombocytopenia 
• 
Delay doses of all study treatment. 
• 
If platelet count recovers to 75,000/µL by Day 14 of the scheduled date of the next cycle, administer full dose 
of study treatment. 
Grade 1 or 2 neutropenia 
and/or thrombocytopenia 
• No dose reduction or delay 
Grade 4 peripheral 
neuropathy (including its signs 
and symptoms) 
• 
Discontinue polatuzumab vedotin permanently 
 
 
 
 
 

 
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Event(s) 
Dose Delay or Modification 
Grade 2 or 3 peripheral 
neuropathy (including its signs 
and symptoms) 
• 
Delay all study treatment 
• 
If recovered to Grade ≤ 1 within ≤ 14 days of the scheduled date of the next cycle: 
• 
If the dose of polatuzumab vedotin is 1.8 mg/kg, then reduce polatuzumab vedotin to 1.4 mg/kg 
(permanent dose reduction). RCHP may be administered at their full doses. 
• 
If there was a prior dose reduction of polatuzumab vedotin to 1.4 mg/kg for Grade 2 or 3 
neurotoxicity: all study treatment must be permanently discontinued. 
• 
If not recovered to Grade ≤ 1 until 14 days or after the scheduled date for the next cycle, Polatuzumab 
Vedotin must be permanently discontinued. Resumption of PV for future cycles may be considered upon 
discussion with the medical monitor. 
Total Bilirubin > 3.0 mg/dL 
• 
Delay treatment until resolution to ≤ 1.5 mg/dL within ≤ 14 days. Evaluate for causality. 
• 
Any case involving an increase in hepatic transaminase >3 × baseline AND an increase in direct bilirubin 
> 2 × ULN, WITHOUT any findings of cholestasis or jaundice or signs of hepatic dysfunction AND in the 
absence of other contributory factors (e.g., worsening of metastatic disease or concomitant exposure to 
known hepatotoxic agent or of a documented infectious etiology) is suggestive of potential treatment toxicity, 
and 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. 
• 
Begin appropriate TLS measures (IVF, rasburicase if needed, allopurinol, hospitalization) per institutional 
guidelines 
• 
Following complete resolution TLS, study treatment may be re-administered at the full dose during next 
scheduled infusion, in conjunction with prophylactic therapy. 
Grade 3 or 4 non-hematologic 
toxicity not specifically 
described above (excluding 
alopecia, nausea, and 
vomiting) 
• 
Delay study treatment for a maximum of 14 days 
• 
If improvement to Grade ≤ 1 or baseline, continue study therapy at full dose, or dose reduce at the discretion 
of the investigator per site’s standard after discussion with the Medical Monitor. 
Grade 2 
non-hematologic toxicity 
• 
Delay study treatment for a maximum of 14 days. 
• 
If improvement to Grade ≤ 1 or baseline, administer previous doses of study treatment. 
Grade 1 
non-hematologic toxicity 
• 
No dose reduction or delay 
 
 
 
 
 
 
 
 

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

 
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5.1.4.4. 
Hematologic Toxicity 
Note that lymphopenia is not considered to be a hematologic toxicity because it is an 
expected outcome of therapy.  See Table 2 for specific guidance. 
 
5.1.4.4.1. Dose Discontinuation 
Dosing delay exceeding 14 days in the initiation of the next planned cycle polatuzumab 
vedotin plus R-CHP will require study treatment discontinuation unless Medical Monitor 
approval is obtained to continue on study treatment. 
 
If scheduled dosing coincides with a holiday that precludes dosing, commence dosing 
on the nearest following date, with subsequent dosing continuing on a 21- or 28-day 
schedule as applicable. 
 
Patients who discontinue all study treatment for adverse events should remain in the 
study and continue to have disease assessments until progression and standard follow 
up per Section 4.4. 
5.1.4.5. 
Treatment Discontinuation Criteria 
5.1.4.5.1. Polatuzumab Vedotin 
A patient should permanently discontinue polatuzumab vedotin if any of the following 
occur: 
• 
Grade 4 peripheral neuropathy 
• 
Grade 3 peripheral neuropathy that leads to a treatment delay of 14 days or more 
and does not improve to Grade ≤ 1 within 14 days 
• 
Recurrence of a Grade ≥ 2 peripheral neuropathy at the reduced dose 
 
5.1.4.5.2. Rituximab 
A patient should permanently discontinue rituximab if any of the following occur: 
• 
Grade 4 infusion-related symptom or anaphylaxis.  The patient should be 
withdrawn from study treatment immediately and supportive treatment given. 
• 
Recurrence of Grade 3 infusion-related symptoms at re-challenge, regardless of 
timing (e.g., within same session or at the next session) 
• 
If patient has Grade 3 wheezing, bronchospasm, or generalized urticaria at first 
occurrence. 
5.1.4.5.3. Polatuzumab Vedotin plus R-CHP 
A patient should permanently discontinue polatuzumab vedotin + R-CHP if any of the 
following occur: 
• 
Grade 3 or 4 hematologic toxicity that does not resolve to Grade ≤ 2 and delays 
treatment by > 14 days despite administration of growth factors and transfusion 
support 
• 
Grade ≥ 2 non-hematologic toxicity that does not resolve to Grade ≤ 1 or baseline 
value and delays treatment by > 14 days 

 
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• 
Hepatitis B reactivation despite initiation of the appropriate anti-viral therapy 
 
• 
Disease progression 
 
 
5.2. 
ADVERSE EVENT REPORTING 
 
Specification of Safety Variables 
 
Safety assessments will consist of monitoring and reporting adverse events (Aes) 
and serious adverse events (SAEs) per protocol. This includes all events of death, 
and any study specific issue of concern. 
 
Adverse Events 
 
An AE is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an investigational 
medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. 
 
This includes the following: 
• Aes not previously observed in the subject that emerge during the protocol- 
specified AE reporting period, including signs or symptoms associated with 
Untreated Double and Triple Hit Lymphoma that were not present prior to the AE 
reporting period. 
• Complications that occur as a result of protocol-mandated interventions (e.g., 
invasive procedures such as cardiac catheterizations) 
• If applicable, Aes that occur prior to assignment of study treatment associated 
with medication washout, no treatment run-in, or other protocol-mandated 
intervention. 
• Preexisting medical conditions (other than the condition being studied) judged by 
the investigator to have worsened in severity or frequency or changed in 
character during the protocol-specified AE reporting period. 
 
Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
• 
It results in death (i.e., the AE actually causes or leads to death). 
• 
It is life threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more 
severe form, might have caused death). 
• 
It requires or prolongs inpatient hospitalization. 
• 
It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP. 

 
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• 
It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical 
intervention to prevent one of the outcomes listed above). 
 
 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY 
VARIABLES 
The investigator is responsible for ensuring that all Aes and SAEs that are observed or 
reported during the study are collected and reported to the FDA, appropriate IRB(s), and 
Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports). 
 
Adverse Event Reporting Period 
The reporting period begins after informed consent is obtained and initiation of study 
treatment and ends 30 days following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. After this period, investigators should 
only report SAEs that are attributed to prior study treatment. 
 
Assessment of Adverse Events 
All Aes and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately. Each reported AE or SAE will be described by its 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, 
suspected relationship to study drugs (see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should 
assess the attribution of the event to study drugs by the following general guideline: 
 
Yes 
There is a plausible temporal relationship between the onset of the AE and 
administration of study drugs, and the AE cannot be readily explained by the 
subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the AE 
follows a known pattern of response to study drugs; and/or the AE abates or 
resolves upon discontinuation of study drugs or dose reduction and, if applicable, 
reappears upon re- challenge. 
 
No 
Evidence exists that the AE has an etiology other than the study drugs (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship to 
study drugs administration (e.g., cancer diagnosed 2 days after first dose of study 
drug). 
 
Expected adverse events are those adverse events that are listed or characterized in the 

 
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Package Insert (P.I) or current Investigator Brochure (I.B). 
 
Unexpected adverse events are those not listed in the P.I or current I.B or not identified. 
This includes adverse events for which the specificity or severity is not consistent with 
the description in the P.I. or I.B. For example, under this definition, hepatic necrosis 
would be unexpected if the P.I. or I.B. only referred to elevated hepatic enzymes or 
hepatitis. 
 
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy.  
 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE 
EVENTS 
 
Eliciting Adverse Events 
A consistent methodology for eliciting Aes at all subject evaluation time points should be 
adopted. Examples of non-directive questions include: 
• 
“How have you felt since your last clinical visit?” 
• 
“Have you had any new or changed health problems since you were last here?” 
 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting Aes or 
SAEs. Avoid colloquialisms and abbreviations. 
 
a. Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported 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, it is acceptable to report the information that is currently available. If a 
diagnosis is subsequently established, it should be reported as follow-up information. 
 
b. Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 5.2), 
regardless of attribution, will be reported to the appropriate parties. When recording a 
death, the event or condition that caused or contributed to the fatal outcome should be 
reported as the single medical concept. If the cause of death is unknown and cannot be 
ascertained at the time of reporting, report “Unexplained Death”. 
 
c. Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be reported as medical and surgical history. A preexisting medical 

 
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condition should be re-assessed throughout the trial and reported as an AE or SAE only 
if the frequency, severity, or character of the condition worsens during the study. When 
reporting such events, it is important to convey the concept that the preexisting condition 
has changed by including applicable descriptors (e.g., “more frequent headaches”). 
 
d. Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE. If a subject is hospitalized to undergo a medical or surgical 
procedure as a result of an AE, the event responsible for the procedure, not the 
procedure itself, should be reported as the SAE. For example, if a subject is hospitalized 
to undergo coronary bypass surgery, record the heart condition that necessitated the 
bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
• 
Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study 
e. Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0 Update current 
versions) will be used for assessing adverse event severity. Below Table should be used 
for assessing severity for adverse events that are not specifically listed in the NCI 
CTCAE. 
 
f. 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.

 
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Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI 
CTCAE 
 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: Based on the most recent version of NCI CTCAE (v5.0), which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a. Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b. Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who 
are not bedridden. 
c. If an event is assessed as a “significant medical event,” it must be reported as a serious 
adverse event 
d. Grade 4 and 5 events must be reported as serious adverse events 
 
g. Pregnancy 
If a female subject becomes pregnant while receiving polatuzumab or within 3 months 
after the last dose of polatuzumab, or if the female partner of a male study subject 
becomes pregnant while the study subject is receiving polatuzumab or within 5 months 
after the last dose of study drug, a report should be completed and expeditiously 
submitted to Genentech, Inc. Additionally, if a female subject becomes pregnant while 
receiving rituximab or within 12 months after the last dose of rituximab, or if the female 
partner of a male study subject becomes pregnant while the study subject is receiving 
rituximab or within 160 days after the last dose of study drug, a report should be 
completed and expeditiously submitted to Genentech, Inc. Follow-up to obtain the 
outcome of the pregnancy should also occur. Abortion, whether accidental, therapeutic, 
or spontaneous, should always be classified as serious, and expeditiously reported as 
an SAE. Similarly, any congenital anomaly/birth defect in a child born to a female 
subject exposed to the study drug should be reported as an SAE. 
 
h. Post-Study Adverse Events 
 
For studies involving collection of follow up until progression free period the investigator after 
the end of the adverse event reporting period (defined as 30 days after the last dose of study 
drug) should report all deaths, (regardless of cause), and any serious adverse event including 
development of cancer or a congenital anomaly in a subsequently conceived offspring of a 

 
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female subject (including pregnancy occurring in the partner of a male study subject) who 
participated in the study that is believed to be related to prior exposure to study drug. 
 
Case Transmission Verification will be performed by both parties during this period to ensure 
successful transmission of Single case reports  
 
 
i. 
Product Complaints 
 
A Product Complaint is defined as any written or oral information received from a 
complainant that alleges deficiencies related to identity, quality, safety, strength, purity, 
reliability, durability, effectiveness, or performance of a product after it has been released 
and distributed to the commercial market or clinical trial. 
 
j. 
Other Special Situation Reports 
 
The following other Special Situations Reports should be collected even in the absence of 
an Adverse Event and transmitted to Genentech: 
• Data related to the Product usage during breastfeeding 
• Data related to overdose, abuse, misuse or medication error (including potentially 
exposed or intercepted medication errors) 
• In addition, reasonable attempts should be made to obtain and submit the age or 
age group of the patient, in order to be able to identify potential safety signals 
specific to a particular population 
 
 

 
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k. AEs of Special Interest (AESIs) 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern 
specific to the product, for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor is required. Such an event might require further 
investigation in order to characterize and understand it. Depending on the nature of the 
event, rapid communication by the trial Sponsor to other parties (e.g., Regulatory 
Authorities) may also be warranted. 
 
Adverse events of special interest for this study include the following: 
• 
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: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical 
jaundice 
• 
Data related to a suspected transmission of an infectious agent by the study 
drug (STIAMP), 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 
 
The Polatuzumab Events of Special Interest Are: 
• 
Tumor lysis syndrome of any grade (irrespective of causality) 
• 
Second malignancies 
 
The Rituximab Events of Special Interest Are: N/A 
 

 
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5.3. 
EXPEDITED REPORTING REQUIREMENTS FOR SERIOUS ADVERSE 
EVENTS 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures and address potential new risks in a clinical trial. The investigator must 
report such events to Karmanos within 24 hours of awareness of the event.  These 
events must also be reported to Genentech per the timelines described below. 
These events will be reported on FDA Medwatch Form 3500A 
(https://www.fda.gov/downloads/aboutfda/reportsmanualsforms/forms/ucm048334.pdf).  
Please see page 99 for instructions on completing the Medwatch Form. 
The following is a list of events that the investigator must report within 24 hours after 
learning of the event, regardless of relationship to study drug: 
• 
Serious adverse events 
• 
Any death not due to progression of lymphoma, regardless of relationship to study 
drug 
• 
Non-serious adverse events of special interest 
• 
Pregnancies 
• 
Accidental overdoses or medication errors 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local IRB/EC. 
 
Each site is responsible for reporting these events to both Karmanos and Genentech 
via email or fax: 
 
 
Report to Karmanos within 24 hours: 
 
delucan@karmanos.org 
modid@karmanos.org 
Fax:  313-576-8368 
Report to Genentech per the timelines in the table below: 
 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
 
 
 
Emergency Medical Contacts 
Medical Monitor Contact Information 
 

 
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Medical Monitor:  
Dipenkumar Modi M.D. 
 
 
 
Mobile Telephone No.: 313-576-8739 
OR 
313-676-0320 
 
 
All serious adverse events that have not resolved by the end of the study, or that have 
not resolved upon discontinuation of the subject’s participation in the study, must be 
followed until any of the following occurs: 
• The event resolves 
 
• The event stabilizes 
 
 
• The event returns to baseline, if a baseline value/status is available 
 
 
• The event can be attributed to agents other than the study drug or to factors unrelated 
to study conduct 
 
 
• It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow up after 
demonstration of due diligence with follow-up efforts) 
 
 
 
Exchange OF SINGLE CASE REPORTS 
 
The investigator will be responsible for collecting all protocol-defined Adverse Events 
(Aes)/Serious Adverse Events (SAEs), pregnancy reports (including pregnancy occurring in 
the partner of a male study subject), other Special Situation reports, AESIs and Product 
Complaints with an AE where the patient has been exposed to the Product. The completed 
MedWatch form should be sent to the Genentech contact specified below. Transmission of 
these reports (initial and follow-up) will be either electronically via email or by fax and within 
the timelines specified below: 
 
 
Fax: 650-238-6067 
Email: usds_aereporting-
d@gene.com 

 
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All Product Complaints without an 
AE should call via: 
PC Hotline Number: (800) 334-
0290 (M-F: 5 am to 5 pm PST) 
 
 
 
 
Serious Adverse Drug Reactions 
(SADRs) 
15 calendar days of the awareness date 
Other SAEs 
30 calendar days of the awareness date. 
Special Situation Reports (Pregnancy)  
 
Special Situation Reports (Other)  
30 calendar days of the awareness date. 
30 calendar days of the awareness date. 
Product Complaints  
15 calendar days of the awareness date. 
AESIs 
15 calendar days of the awareness date. 
 
 
• 
SADRs 
Serious AE reports that  are  related  to  the  Product  shall  be  transmitted  to 
Genentech within fifteen (15) calendar days of the awareness date. 
 
• 
Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to 
Genentech within thirty (30) calendar days of the awareness date. 
 
• AESIs 
AESIs requiring expedited reporting (related or possibly related to Genentech 
product or where the causality is assessed as unknown or not provided) shall be 
forwarded to Roche within fifteen (15) calendar days of the awareness date. 
Others (non-related to Roche product) shall be sent within thirty (30) calendar 
days. 
 
 
• 
Special Situation Reports   
Pregnancy reports  
While such reports are not serious Aes or Adverse Drug Reactions (ADRs) per 
se, as defined herein, any reports of pregnancy (including pregnancy occurring 
in the partner of a male study subject), where the fetus may have been exposed 
to the Product, shall be transmitted to Genentech within thirty (30) calendar days 
of the awareness date. Pregnancies will be followed up until the outcome of the 
pregnancy is known, whenever possible, based upon due diligence taken to obtain 
the follow-up information. 
 

 
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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 (see section 5.2.f for pregnancy reporting timelines).  A Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to Genentech 
within thirty (30) calendar days of the awareness date. 
• 
Other Special Situation Reports, as defined above, shall be transmitted to 
Genentech within thirty (30) calendar days of the awareness date. 
• 
Product Complaints 
All Product Complaints (with or without an AE) shall be forwarded to Genentech 
within fifteen (15) calendar days of the awareness date. 
 
 
 
 
Case Transmission Verification of Single Case Reports 
The Sponsor agrees to conduct the Case Transmission verification to ensure that all 
single case reports have been adequately received by Genentech via the 
investigator emailing Genentech a Quarterly line-listing documenting single case 
reports sent by the investigator to Genentech in the preceding time period. 
The periodic line-listing will be exchanged within seven (7) calendar days of the end 
of the agreed time period. Confirmation of receipt should be received within the time 
period mutually agreed upon. 
 
If discrepancies are identified, the Sponsor and Genentech will cooperate in 
resolving the discrepancies. The responsible individuals for each party shall handle 
the matter on a case-by-case basis until satisfactory resolution. The sponsor shall 
receive reconciliation guidance documents within the ‘Activation Package’. 
 
Following Case Transmission Verification, single case reports which have not been 
received by Genentech shall be forwarded by the investigator to Genentech within 
five (5) calendar days from request by Genentech. 
 
At the end of the study, a final cumulative Case Transmission Verification report will 
be sent to Genentech. 
 
 
 
MEDWATCH 3500A REPORTING GUIDELINES 
 

 
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In addition to completing appropriate patient demographic (Section A) and suspect 
medication information (Section C & D), the report should include the following 
information within the Event Description (Section B.5) of the MedWatch 3500A form: 
 
• Protocol number and title description  
• Description of event, severity, treatment, and outcome if known 
• Supportive laboratory results and diagnostics (Section B.6) 
• Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
 
Follow-Up Information 
 
• Additional information may be added to a previously submitted report by any of 
the following methods: 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with 
the original MedWatch 3500A form 
• Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B. initial, patient number), protocol description and number, 
if assigned, brief adverse event description, and notation that additional or 
follow-up information is being submitted (The patient identifiers are important 
so that the new information is added to the correct initial report) 
 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
https://www.fda.gov/media/69876/download 
 
 
Reporting to Regulatory Authorities, Ethics Committees and Investigators 
 
The investigator, as the Sponsor of the Study, will be responsible for the expedited 
reporting of safety reports originating from the Study to the Regulatory Authorities 
(FDA) where it has filed a clinical trial approval, in compliance with local regulations. 
 
The investigator, as the Sponsor of the Study, will be responsible for the expedited 
reporting of safety reports originating from the study to the EMA through 
Eudravigilance Clinical Trial Module (EVCTM), where applicable.  
 
The investigator, will be responsible for the expedited reporting of safety reports 
originating from the Study to the Ethics Committees and Institutional Review Boards 
(IRB), where applicable. 
 
The investigator, will be responsible for the distribution of safety information to its own 
investigators, where relevant, in accordance with local regulations. Safety information 
that occurs on other clinical studies utilizing polatuzumab vedotin will be distributed by 
Karmanos Cancer Institute directly to sites participating on this clinical study. Each 
site is responsible for reviewing and processing the safety reports per their policies. 

 
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AGGREGATE REPORTS 
IND ANNUAL REPORTS 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech 
 
Copies of such reports should be emailed to Genentech at: Genentech Drug Safety CTV 
mail box: ctvist_drugsafety@gene.com 
 
STUDY CLOSE-OUT 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final study 
report). Additionally, any literature articles that are a result of the study should be sent to 
Genentech.  
Copies of such reports should be mailed to the assigned Clinical Operations contact for the 
study at: polatuzumab-gsur@gene.com 
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com 
 
QUERIES 
Queries related to the Study will be answered by the investigator. However, responses 
to all safety queries from regulatory authorities or for publications will be discussed and 
coordinated between all involved parties including sponsor and treating site. The Parties 
agree that Genentech shall have the final say and control over safety queries relating to 
the Product. The investigator agrees that it shall not answer such queries from 
regulatory authorities and other sources relating to the Polatuzumab Vedotin (PoV) 
independently but shall redirect such queries to Genentech. 
 
Both Parties will use all reasonable effort to ensure that deadlines for responses to 
urgent requests for information or review of data are met. The Parties will clearly 
indicate on the request the reason for urgency and the date by which a response is 
required. 
 
SAFETY CRISIS MANAGEMENT 
In case of a safety crisis, e.g., where safety issues have a potential impact on the 
indication(s), on the conduct of the Study, may lead to labeling changes or regulatory 
actions that limit or restrict the way in which the Product is used, or where there is 
media involvement, the Party where the crisis originates will contact the other Party as 
soon as possible. 
 
The Parties agree that Genentech shall have the final say and control over safety crisis 

 
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management issues relating to the Product. The investigator agrees that it shall not 
answer such queries from media and other sources relating to the Product but shall 
redirect such queries to Genentech. 
 
COMPLIANCE WITH PHARMACOVIGILANCE AGREEMENT / AUDIT 
 
The Parties shall follow their own procedures for adherence to AE reporting timelines.  
Each Party shall monitor and, as applicable, request feedback from the other Party 
regarding AE report timeliness in accordance with its own procedures. The Parties 
agree to provide written responses in a timely manner to inquiries from the other Party 
regarding AE reports received outside the agreed upon Agreement timelines. If there is 
any detection of trends of increasing or persistent non-compliance to transmission 
timelines stipulated in this Agreement, both Parties agree to conduct ad hoc or institute 
a regular joint meeting to address the issue. 
In case of concerns related to non-compliance of processes, other than exchange 
timelines, with this Agreement, the Parties will jointly discuss and collaborate on 
clarifying and resolving the issues causing non-compliance. Every effort will be made by 
the non-compliant Party to solve the non-compliance issues and inform the other Party 
of the corrective and preventative actions taken. 
Upon justified request, given sufficient notice of no less than sixty (60) calendar days, an 
audit under the provisions of this Agreement can be requested by either Party. The 
Parties will then discuss and agree in good faith upon the audit scope, agenda and 
execution of the audit. The requesting Party will bear the cost of the audit. 
 
5.4. 
EXPEDITED REPORTING TO REGULATORY AGENCIES 
Serious adverse events that are unexpected and at least possibly related to the study 
drug will be reported to the FDA in an expedited manner by the IND holder (Karmanos 
Cancer Institute) according to 21 CFR 312.32. 
 
It is the responsibility of the Investigator and the research team to ensure that serious 
adverse events are reported according to the Code of Federal Regulations, Good 
Clinical Practices (GCP), the protocol guidelines, the sponsor’s guidelines, and the 
Institutional Review Board policy. 
 
6. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
 
The Phase II study is designed to assess the safety and tolerability of the combination 
of polatuzumab vedotin with R-CHP in Double or triple hit lymphoma subtypes of 
DLBCL. 
6.1. DETERMINATION OF SAMPLE SIZE 
The sample size is justified using Simon’s two-stage optimal design. The null hypothesis 
that the true complete remission (CR) rate is 20% will be tested against the alternative 
CR rate of 35%. In the first stage, 13 patients will be accrued. If there are 2 or fewer 

 
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responses in these 13 patients, the study will be stopped. Otherwise, 33 additional 
patients will be accrued for a total of 46. The null hypothesis will be rejected if 13 or 
more responses are observed in 46 patients. This design yields a 1-sided type I error 
rate of 10% and power of 80% when the true response rate is 35%. Considering the 
drop-out rate (including nonevaluable patients) of 5%, the required sample size would 
be 49 patients. We allowed a high false positive rate because the DLBCL (diffuse large 
B-cell lymphoma), which is an inclusion criterion, is a rare disease and there is an 
urgent need for novel therapeutic strategies in this high-risk study population. 
 
The expected accrual rate is 2 patients per month on the basis of a total of four 
institutions. The first stage patients (i.e., 13 patients) will be accrued at KCI and another 
institution (i.e., two institutions) and 33 additional patients will be accrued at all four 
institutions. Thus, it will take about 31 months (= 13 months + 18 months) to enroll 49 
patients. Taking into account additional 6 months to be approved by all four institutional 
IRBs, it will take about 37 months to enroll a total of 49 patients at all four institutions. 
6.2. SUMMARY OF CONDUCT OF STUDY 
The analysis populations are as follows: 
• 
All treated subjects: patients who receive at least one study treatment 
• 
All response evaluable subjects: all treated subjects who have evaluable tumor 
measurement 
• 
Biomarker subjects: all treated subjects with available biomarker data.   
Patient baseline and clinical characteristics will be descriptively summarized for all 
treated subjects. The efficacy and safety analyses will be performed based on all 
treated subjects. The exploratory analysis will be carried out based on the biomarker 
subjects. The primary efficacy analysis will be also performed based on all response 
evaluable subjects as a sensitivity analysis. 
6.3. EFFICACY ANALYSES 
The efficacy analysis will be performed based on all treated subjects. 
 
6.3.1. Primary Efficacy Endpoint and Analysis 
The complete remission (CR) rate is the primary efficacy endpoint. The CR will be 
determined using the Lugano Response Criteria (Cheson et al. 2014), specified in 
Appendix 3, at the time of primary response assessment (6−8 weeks after Cycle 6 Day 
1 or last dose of study medication). The CR rate will be summarized by a bionomial 
response rate and its associated 2-sided 80% confidence interval (CI) using Pearson- 
Klopper method. The primary efficacy analysis will be also performed based on all 
response evaluable subjects as a sensitivity analysis. 
 
6.3.2. Secondary Efficacy Endpoints and Analyses 
The progression-free survival (PFS) will be defined as the duration from the start date of 
the treatment until the date of progression or death from any cause, whichever occurs 
first and the overall survival (OS) will be defined as the duration from the start date of 

 
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the treatment until the date of death from any cause. The distributions of PFS and OS 
will be graphically summarized using the Kaplan-Meier (KM) curve and the median 
PFS/OS and  their associated 2-sided Cis will be estimated using the KM estimator. 
The median follow-up times and their 2-sided Cis will be estimated using the reverse 
KM estimator. 
 
The overall response rate (ORR) is defined as the proportion of patients who have CR 
or partial response (PR) at primary response assessment based on the Lugano 
Response Criteria specified in Appendix 3 among all treated subjects. CR and PR will 
be summarized using frequency and percentage. The ORR will be summarized by a 
bionomial response rate and its associated 2-sided confidence interval (CI) using 
Pearson-Klopper method. 
 
The duration of response (DOR) will be measured from the date of CR or PR 
(whichever is first recorded) until the first date that recurrent or progressive disease is 
documented among all treated subjects who had a confirmed CR or PR. The 
distribution of DOR will be graphically summarized using the Kaplan-Meier (KM) curve 
and the median PFS and its associated 2-sided CI will be estimated using the KM 
estimator. 
6.4. SAFETY ANALYSES 
Safety will be assessed through summaries of adverse events, summaries of changes 
from screening assessments in laboratory test results, ECGs, and changes in vital 
signs. 
 
All adverse events occurring on or after first study treatment will be summarized by 
mapped term, appropriate thesaurus levels, and NCI CTC Adverse Event v5.0 toxicity 
grade.  All serious adverse events will be listed separately and summarized. 
 
Deaths reported during the study treatment period and those reported during follow-up 
after treatment discontinuation will be listed. 
 
Relevant laboratory and vital sign (temperature, heart rate, respiratory rate,  and blood 
pressure) data will be displayed by time, with NCI CTCAE v5.0. Grade 3 and 4 values 
identified where appropriate. 
 
6.5. EXPLORATORY ANALYSES 
Exploratory analyses of biomarkers (see Section 3.5.3.) 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 
separately for each histological subtype and both investigator and IRC assessed 
outcomes.  Specifically, the association between candidate biomarkers and PET-CT CR 
rate and OR rate and potentially other measures of efficacy and safety, independent of 
treatment, will be explored to assess potential prognostic value.  In addition, the 
potential effect modification of treatment effect on PET-CT CR rate and OR rate and 

 
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potentially other measures of efficacy and safety, by biomarker status, will be explored 
to assess potential predictive value. 
 
6.6 INTERIM AND FINAL ANALYSES 
One interim analysis of CR rate will be performed when the first 13 patients have been 
treated. If there are 2 or fewer CRs in these 13 patients, the study will be stopped. 
Otherwise, 33 additional subjects will be accrued for the second stage, resulting in a 
total of 46 treated subjects. The null hypothesis will be rejected if 13 or more CRs are 
observed in these 46 patients. 
 
 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1. DATA AND SAFETY MONITORING 
1. Scheduled meetings will be held monthly or more frequently depending on the activity 
of the protocol. These meetings will include the protocol investigators and research staff 
involved with the conduct of the protocol. 
 
2. During these meetings the investigators will discuss: 
 
 
• 
Safety of protocol participants (adverse events and reporting) 
 
• 
Validity and integrity of the data (data completeness on case report forms and 
complete source documentation) 
 
• 
Enrollment rate relative to expectation of target accrual, (eligible and ineligible 
 
• 
participants) 
 
• 
Retention of participants, adherence to the protocol and protocol deviations 
 
• 
Protocol amendments 
 
 
3. Completed Data and Safety Monitoring Reports of these regular investigator 
meetings will be kept on file in the Clinical Trials Office (see form in appendix 7). The 
study coordinator assigned to the clinical trial at each site will be responsible for 
completing the report form. The completed reports will be reviewed and signed off by 
the site Principal Investigator (PI) or by one of the Co-investigators in the absence of 
the PI. The study coordinator will submit the completed forms to the Data and Safety 
Monitoring Committee. 
 
4. The Barbara Ann Karmanos Cancer Institute, Data and Safety Monitoring Committee 
(DSMC) provide the primary oversight of data and safety monitoring for KCI 

 
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Investigator-initiated trials. The DSMC will meet on a regular basis to review the 
prior Serious Adverse Event forms and Data and Safety Monitoring study specific 
reports that have been filed. 
 
7.2. DATA QUALITY ASSURANCE 
Clinical trial data will be captured in OnCore’s (Clinical Trial Management System) 
electronic data capture system. Site personnel will be trained on the eCRF system by 
the Karmanos OnCore administrator. Trial data entered in Oncore will be verified by 
source documentation. 
CRFs should be completed within 10 business days of the availability of clinical 
documentation of a study visit. Data clarification and queries should be completed 
within 7 working days of notification. 
Each participating site will submit source documents to KCI’s clinical trials office. A KCI 
CTO monitor specialist will remotely monitor essential clinical trial data. Frequency of 
monitoring will be based on accrual at a site but will occur at least once every 1 month if 
a patient has been enrolled. 
If deemed necessary by the primary site or sponsor an audit team may review 
contracted site data and materials in an on-site review. 
 
7.3. SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel 
are accurate, complete, and verifiable from source documents. 
 
Source documents 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 until 
otherwise instructed by the sponsor. 
 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, DSMC audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4. RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ICFs, laboratory test results, and medication inventory records, 
must be retained by the site 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 

 
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another party or moving them to another location. 
 
8. 
ETHICAL CONSIDERATIONS 
8.1. COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki, or the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the 
individual.  The study will comply with the requirements of the ICH E2A guideline 
(Clinical Safety Data Management:  Definitions and Standards for Expedited Reporting). 
Studies conducted in the United States or under a U.S. Investigational New Drug (IND) 
application will comply with 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). 
8.2. INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the ICFs, any information to be given to the patient, and relevant 
supporting information must be submitted to the IRB/EC 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 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 9.5). 
 
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. 
8.3. CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. This means that 
patient names are not included in data sets that are transmitted to any Sponsor 
location. 
 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the ICF (or separate authorization for use and 
disclosure of personal health information) signed by the patient, unless permitted or 
required by law. 

 
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Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
 
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
8.4. 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 (i.e., last patient last visit 
[LPLV]). 
 
9. 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION 
9.1. STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, ICF, and documentation of IRB/EC and governmental approval. 
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. 
9.3. ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed the Karmanos Cancer Institute. Clinical trial 
data will be captured in OnCore’s (Clinical Trial Management System) electronic data 
capture system. 
 
9.4. Publication of Data and Protection of Trade Secrets 
 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results 
9.5. PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by Karmanos and submitted to Roche for 

 
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review and approval prior to local IRB submission. Protocol amendments will be 
submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. Protocol amendments will be distributed to participating 
institutions for submission to their local IRB only after it is approved by the IRB at 
Karmanos. 
 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 

 
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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
 
Study visits 
Screening 
phase 
Treatment phase (1 cycle = 21 days) 
Suspected 
progression 
End of 
treatment 
Follow up 
visit up to 
5 years 
after last 
treatmentm 
Cycle 1 
Cycle 2 
Cycles 3-6n 
Day 
1(±2 
days) 
Day 3 
Day 
1(±2 
days) 
Day 3 
Day 1(± 
2 days) 
Day 3 
Study visit windows 
-28 days 
Any time 
Within 30 
days (± 5 
days) of 
last 
treatment 
Every 3 
or 6 
months 
(± 14 
days) 
Procedures 
Informed consent 
X 
Medical history 
X 
X 
X 
X 
X 
X 
X 
Confirmation of 
eligibility 
X 
 
Tumor biopsy 
Xd 
Xi 
Concomitant 
medications 
X 
X 
X 
X 
X 
 
Adverse eventsa 
X 
X 
X 
X 
X 
Height 
X 
Physical exam, vital 
signs, weight, ECOG 
X 
X 
X 
X 
X 
X 
X 
Disease assessment: 
PET/CT Scane 
Xe 
Xe 
X 
Xe 
CT/MRI Scanf 
Xf 
Xe 
Xf 
Xe 
Xf 
Bone marrow biopsy 
and aspirateg 
Xg 
 
Xg 
Disease-related 
symptomsh 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 

 
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Study visits 
Screening 
phase 
Treatment phase (1 cycle = 21 days) 
Suspected 
progression 
End of 
treatment 
Follow up 
visit up to 
5 years 
after last 
treatmentm 
Cycle 1 
Cycle 2 
Cycles 3-6n 
Day 
1(±2 
days) 
Day 3 
Day 
1(±2 
days) 
Day 3 
Day 1(± 
2 days) 
Day 3 
Study visit 
windows 
-28 days 
 
Any time 
Within 30 
days (± 5 
days) of 
last 
treatment 
Every 3 or 
6 months 
(± 14 
days) 
Procedures 
Overall response 
assessment –tumor 
grid completion 
X 
X 
X 
X 
IPI 
X 
CBC with differential 
X 
X 
X 
X 
X 
Comprehensive 
metabolic panelb 
X 
X 
X 
X 
X 
pregnancy testo 
X 
X 
X 
X 
Creatinine clearance 
(Cockcroft-Gault) 
X 
X 
X 
X 
X 
Hepatitis serologies 
Xc 
Xj 
Xj 
HIV 
X 
B2-microglobulin 
X 
Hemoglobin A1C 
Xk 
Xk 
PT, PTT, INR 
X 
LDH 
X 
12-lead EKG 
X 
Echocardiogram or 
MUGA 
X 
Polatuzumab plus R- 
CHP 
X 
X 
X 
Intrathecal 
Methotrexate 12 mgl 
X 
X 
X 
Neupogen/Neulasta/ 
Udenyca 
X 
X 
X 

 
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a: AEs are reported from the time the patient receives study drug until 30 days following last treatment of the study drug. In addition to all routine AE reporting, all 
new malignant tumors including solid tumors, skin malignancies and hematologic malignancies are to be reported as adverse events for the duration of the study 
treatment and during any protocol specified follow-up periods including post-progression follow-up for overall survival. Peripheral neuropathy should be assessed 
at screening, on day 1 of each treatment cycles, and at the treatment completion visit. 
 
b: Comprehensive metabolic panel includes sodium, potassium, chloride, bicarbonate, BUN/urea, calcium, albumin, glucose, creatinine, AST, ALT, alkaline 
phosphatase, total bilirubin, total protein, magnesium, phosphorus, and Uric Acid.  Amylase should be performed at screening only.  NOTE: participants with 
diabetes must have weekly chemistries including glucose during cycles 1-3 
 
c: Hepatitis serologies to be performed at screening include Hepatitis B surface antibody (HBsAb), HBsAg (surface antigen) and HBcAb (core antibody). If HBcAb 
(core antibody) is positive the patient will need negative HBV-DNA by PCR to be eligible for study. Hepatitis C serology includes Hepatitis C antibody (HCV 
antibody).. 
d: Archival tissue is preferred if sample quantity is sufficient. If insufficient, fresh tissue biopsy can be performed. 
 
e: PET/CT performed at screening, interim analysis between cycle 3 D15 to cycle 4 D15 then 6-8 weeks after cycle 6 D1 or last dose of study treatment, whichever 
is applicable. 
 
f: Diagnostic quality CT of thorax, abdomen and pelvis (and neck if clinically indicated) with contrast performed during screening, interim analysis between cycle 
3 day 15 to cycle 4 day 15, at EOT and/or progression and every 6 months after completion of treatment for up to one year.  
g: Bone marrow biopsy and/or aspirate is optional per investigator’s decision at screening however if positive must be performed at CR. 
h: Disease-related symptoms include weight loss, fatigue, fever, night sweats, pruritus abdominal pain/discomfort due to splenomegaly including early satiety, and 
anorexia. 
 
i: Tumor and/or bone marrow biopsy will be performed per investigator’s discretion  at the time of disease progression. The tissue sample will be processed per 
local pathology only. No additional testing is required per study. 
 
j: HBV DNA PCR should be performed on Day 1 of each cycle ONLY for patients with occult or prior HBV infection (defined as negative HBsAb and positive 
hepatitis B core antibody (HBcAb). HCV RNA by PCR should be performed on Day 1 of each cycle if HCV antibody is positive at screening. 
 
k: Hemoglobin A1C (HBA1C) should be performed at screening and on Day 1 cycle 4. 
 
l: Intrathecal methotrexate 12 mg will be given on either day 1, 2 or 3 of each cycle as CNS prophylaxis. 
 
m. Follow up will occur at every 3 months during first 2 years, and then every 6 months during the next 3 years 

 
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   n. Patients who received a cycle of R-CHOP prior to study enrollment will still receive 6 cycles of R-CHP plus Polatuzumab 
 
o. For women of child bearing potential, a pregnancy test will be obtained up to 7 days prior to cycle 1 day 1 of treatment .   On day 1 of each subsequent cycle a 
serum OR urine pregnancy test will be performed. See section 4.4.7.1 for guidance in the event of any positive pregnancy test.

 
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Appendix 2 
Revised Criteria for Response Assessment: Lugano Classification 
Response should be determined on the basis of radiographic and clinical evidence of disease.  For the Primary Response 
Assessment, an FDG-PET (18F fluorodeoxyglucose positron emission tomography)/CT (computed tomography) scan will be 
performed 6−8 weeks after Cycle 6 Day 1 as assessed by IRC and by investigator.  Assessment of the PET-CT scan should follow 
the criteria described by Cheson BD 2014 presented below. 
 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin 
and Non-Hodgkin lymphoma: The Lugano Classification. J Clin Oncol. 2014 
 
Selection of measured dominant (indicator) lesions: 
• 
Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two 
diameters 
A measurable node must have an LDi greater than 1.5 cm. 
A measurable extranodal lesion should have an LDi greater than 1.0 cm. 
• 
Nodes should preferably be from disparate regions of the body and should include, where applicable, mediastinal and 
retroperitoneal areas. 
• 
Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, and lungs), GI involvement, cutaneous lesions, or 
those noted on palpation. 
• 
If possible, they should be from disparate regions of the body. 
• 
Should include mediastinal and retroperitoneal areas of disease whenever these sites are involved 

 
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Appendix 2 
Revised Criteria for Response Assessment: Lugano Classification (cont.) 
 
Selection of non-measured (non-indicator) lesions: 
• 
Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured. 
These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet 
the requirements for measurability but are still considered abnormal, as well as truly assessable disease, which is any site of 
suspected disease that would be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone 
lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging. 
 
In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, and bone marrow), FDG uptake may be greater than in the mediastinum 
with complete metabolic response but should be no higher than surrounding normal physiologic uptake (e.g., with marrow activation 
as a result of chemotherapy or myeloid growth factors). 

 
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Appendix 2 
Revised Criteria for Response Assessment: Lugano Classification (cont.) 
 
 
 
Response 
Site 
PET-CT-based Response 
CT-based Response 
Complete 
Complete metabolic response 
Complete radiologic response (all of the 
following) 
Lymph nodes and 
extralymphatic 
sites 
Score 1, 2, or 3a with or without a residual mass on 5PSb 
It is recognized that in Waldeyer’s ring or extranodal  
sites with high physiologic uptake or with activation  
within spleen or marrow (e.g., with chemotherapy or 
myeloid colony-stimulating factors), uptake may be 
greater than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response may be 
inferred if uptake at sites of initial involvement is no 
greater than surrounding normal tissue even if the tissue 
has high physiologic uptake 
Target nodes/nodal masses must regress to ≤ 1.5 cm 
in LDi 
No extralymphatic sites of disease 
Nonmeasured 
lesion 
Not applicable 
Absent 
Organ 
enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if indeterminate, IHC negative 
Normal by morphology; if indeterminate, IHC negative 

 
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Appendix 2 
Revised Criteria for Response Assessment: Lugano Classification (cont.) 
 
Response 
Site 
PET-CT-based Response 
CT-based Response 
Partial 
Partial metabolic response 
Partial remission (all of the following) 
Lymph nodes and 
extralymphatic 
sites 
Score of 4 or 5b with reduced uptake compared with 
baseline and residual mass(es) of any size 
at interim, these findings suggest responding disease 
at end of treatment, these findings indicate residual 
disease 
≥ 50% decrease in SPD of up to 6 target measureable 
nodes and extranodal sites 
When a lesion is too small to measure on CT, assign 
5 mm × 5 mm as the default value 
When no longer visible, 0 × 0 mm 
For a node >5 mm × 5 mm, but smaller than normal, 
use actual measurement for calculation 

 
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Appendix 2 
Revised Criteria for Response Assessment: Lugano Classification (cont.) 
 
Response 
Site 
PET-CT-based Response 
CT-based Response 
Partial 
(cont.) 
Nonmeasured 
lesions 
Not applicable 
Absent/normal, regressed, but no increase 
Organ 
enlargement 
Not applicable 
Spleen must have regressed by > 50% in length 
beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake 
compatible with reactive changes from chemotherapy 
allowed). If there are persistent focal changes in the 
marrow in the context of a nodal response, consideration 
should be given to further evaluation with MRI or biopsy 
or an interval scan 
Not applicable 
None or 
Stable 
Disease 
No metabolic response 
Stable disease 
Target 
nodes/nodal 
masses, 
extranodal lesions 
Score 4 or 5 b with no significant change in FDG uptake 
from baseline at interim or end of treatment 
< 50% decrease from baseline in SPD for up to 
6 dominant, measurable nodes and extranodal sites; 
no criteria for progressive disease are met 
Nonmeasured 
lesions 
Not applicable 
No increase consistent with progression 
Organ 
enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 

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

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Appendix 2 
Revised Criteria for Response Assessment: Lugano Classification (cont.) 
 
5-PS = 5-point scale; CT = computed tomography; FDG = fluorodeoxyglucose; IHC = immunohistochemistry; LDi = longest transverse diameter of a lesion; 
MRI = magnetic resonance imaging; PET = positron emission tomography; PPD = cross product of the LDi and perpendicular diameter; SDi = shortest axis 
perpendicular to the LDi; SPD = sum of the product of the perpendicular diameters for multiple lesions. 
a   A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving 
PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment). 
b   PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake mediastinum but liver; 4, uptake moderately liver; 5, uptake markedly 
higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma. 

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Appendix 3 
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-C SF 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/µL) neutropenia, age > 65 years, uncontrolled primary disease, pneumonia, hypotension and multi-organ dysfunction 
(sepsis), invasive fungal infection, being hospitalized at the time of fever development 
 
Source:  Smith et al. 2006 Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical 
practice guideline. J Clin Oncol 2006;24:3187−205. 

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Appendix 4 
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 5 
Commonly Used CYP1A2 Inhibitors and Inducers (Drugs, Foods, Over the Counter Medications, 
and Supplements) (cont.) 
 
CYP1A2 Inhibitors 
Amiodarone 
Imipramine 
Amitriptyline 
Isoniazid 
Amlodipine 
Ketoconazole 
Anastrozole 
Lidocaine 
Caffeine 
Losartan 
Cimetidine (Tagamet) 
Erythromycin 
Ciprofloxacin (Cipro) 
Estrogens 
Citalopram 
Mexiletine 
Clarithromycin 
Mexiletine 
Clotrimazole 
Modafenil 
Clozapine 
Nifedipine 
Diclofenac 
Olanzapine 
Diltiazem 
Omeprazole 
Echinacea 
Ondansetron 
Ethinyl Estradiol 
Paroxetinee 
Fluoroquinolones 
Propafenone 
Fluconazole 
Propanolol 
Fluvoxamine 
Ranitidine 
Gemfibrozil 
Rofecoxib 
Ginseng 
Sertraline 
 
 
 
 

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Cruciferous vegetables (broccoli, 
cauliflower, arugula, brussel sprouts, 
cabbage, kale, chard, turnips, radishes, 
wasabi, bok choy, watercress, collard 
)
Smoking 
Char-grilled meat 
Triamterene (Dyrenium) 
Carbamazepine (e.g., Tegretol) 
Zolmitriptan (Zomig) 
Primidone 
Adapted from ctep.cancer.gov/protocolDevelopment/docs/cyp1a2.doc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CYP1A2 Inducers 
Barbiturates (e.g., Phenobarbital) 
Rifampin (e.g., Rifadin) 

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Appendix 6 
International Prognostic Index (IPI) for DLBCL 
 
Age >60 
Serum lactate dehydrogenase concentration above normal 
ECOG PS ≥ 2 
Ann Arbor Stage III or IV 
Number of extranodal disease sites >1 
One point is given for each of the above characteristics present in the patient, for a total score ranging from zero to five. When applied to the 
initial group of 2031 patients with aggressive NHL treated with anthracycline-based regimens that did NOT include rituximab, five-year overall 
survival (OS) and complete response (CR) rates according to score were as follows: 
Score 
Risk group 
5-year OS, percent 
CR rate, percent 
0 to 1 
Low risk 
73 
87 
2 
Low intermediate 
51 
67 
3 
High intermediate 
43 
55 
4 to 5 
High 
26 
44 
 
 
 
 
 
 
 
 

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Appendix 7 
Barbara Ann Karmanos Cancer Institute 
Data and Safety Monitoring (DSM) Report 
 
 
 
 
PROTOCOL TITLE 
ATTENDANCE 
PROTOCOL ACTIVITY SINCE LAST REPORT 
Accrual Goal: 
Eligible: 
Total number of AE’s to date: 
Accrual to Date: 
Ineligible 
(provide reason): 
Accrual Since 
Last Monthly 
Report: 
SPECIFICALLY FOR PHASE I TRIAL &/OR DOSE ESCALATING TRIALS: 
DOSE LEVEL 
ACCRUAL 
  1 
  2 
  3 
RECORD ALL GRADE 3, 4, AND 5 AE’S AND GROUP BY CTCAE CATEGORIES. RECORD THE DATE OF 
THE OCCURRENCE, ATTRIBUTION AND IF REPORTABLE TO THE IRB.  SHADE THE ROWS OF THE 
AE’S THAT HAVE OCCURRED FOR THIS REPORT. ATTACH THE IRB REPORT FORM FOR THE 
REPORTABLE EVENTS THAT OCCURRED ON THIS REPORT. 
Pt. ID# 
Category and  type of adverse reaction 
Date of 
Occurrenc 
e 
Grade1 
Attribution2 
Reportable to IRB 
(Y/N) 
Yes with date 
1. Grade: 1-Mild, 2-Moderate, 3- Severe, 4-Life-threatening, or 5- Death. 
2. Attribution: 1-unrelated, 2 - unlikely, 3 - possibly, 4 - probably, or 5 - definitely 
 
OFF TREATMENT: Provide reason [progression, death, toxicity, completed therapy, etc]. 
PROTOCOL DEVIATIONS: Accidental or unintentional change from the protocol. 
PROTOCOL AMENDMENTS:Include date submitted and approved by the IRB. 
 
PROTOCOL #: 
REPORT DATE: 

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DSM Report 
Protocol # 
Report Date: 
 
OTHER COMMENTS 
Investigator Signature/Date: 
Study Coordinator Signature/Date: 
Revised: 5/29/14