Clinical trial NCT01925612
Conditions: Lymphoma, B-cell Lymphoma, Large B-cell, Diffuse
Keywords: Antibodies, Monoclonal Antibody-Drug Conjugate Antigens, CD30 Drug Therapy Hematologic Diseases Lymphoma, B-cell Lymphoma, Large B-cell, Diffuse Monomethyl auristatin E
Sponsor: Seagen Inc.
Start date: 2013-08-01; Completion date: 2017-05-01
Enrollment: 87 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study has 3 parts. The purpose of Part 1 of this study is to assess the safety and efficacy of brentuximab vedotin in combination with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) (known as BV+RCHOP) in patients with DLBCL who have never been treated. Patients will be randomly assigned in a 1:1 ratio to receive RCHOP together with 1 of 2 doses of brentuximab vedotin. Patients will be tested to see if there is a difference in side effects between the 2 groups.

The purpose of Part 2 of this study is to assess the safety and efficacy of brentuximab vedotin in combination with RCHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) (known as BV+RCHP) in patients with CD30-positive DLBCL who have never been treated. Patients will be enrolled to receive RCHP together with 1.8mg/kg of brentuximab vedotin.

The purpose of Part 3 of this study is to assess the safety and efficacy of BV+RCHP compared to standard RCHOP in patients with CD30-positive DLBCL that have never been treated. Patients will be randomly assigned in a 1:1 ratio to receive either BV+RCHP or RCHOP. Patients will be tested to see if there is a difference in side effects between the 2 groups.

Detailed description:
In the first part of this study, patients in the 2 groups were tested to see if there was a difference in the response to treatment and whether there were differences in the side effects (unwanted effects).

The second and third parts of the study are being done to see if there are any side effects (unwanted effects) of the higher dose of brentuximab vedotin when combined with a modified version of RCHOP that omits vincristine. The third part of the study is being done to see if there is a difference between BV+RCHP and RCHOP in the response to treatment.

Arms: arm 1: Brentuximab vedotin 1.2 mg/kg plus rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone

Part 1 of the study is a phase 2, randomized, open-label, multicenter study designed to evaluate the antitumor activity and safety of brentuximab vedotin when administered in combination with standard RCHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Patients in this arm were randomized into the 1.2 mg/kg brentuximab vedotin dosing cohort, to be administered in combination with RCHOP. arm 2: Brentuximab vedotin 1.8 mg/kg plus rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone

Part 1 of the study is a phase 2, randomized, open-label, multicenter study designed to evaluate the antitumor activity and safety of brentuximab vedotin when administered in combination with standard RCHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Patients in this arm were randomized into the 1.8 mg/kg brentuximab vedotin dosing cohort, to be administered in combination with RCHOP. arm 3: Brentuximab vedotin 1.8 mg/kg plus rituximab, cyclophosphamide, doxorubicin, prednisone

Part 2 of the study is a phase 2, non-randomized, open-label, multicenter study designed to evaluate the antitumor activity and safety of brentuximab vedotin 1.8 mg/kg when administered in combination with RCHP chemotherapy (rituximab, cyclophosphamide, doxorubicin, and prednisone). Patients in this treatment arm were enrolled into a dosing cohort with 1.8 mg/kg brentuximab vedotin administered in combination with RCHP. arm 4: Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone

Part 3 of the study is a phase 2, randomized, open-label, multicenter study designed to evaluate the antitumor activity and safety of brentuximab vedotin 1.8 mg/kg when administered in combination with RCHP chemotherapy compared to RCHOP chemotherapy alone. Patients in this treatment arm were randomized to receive RCHOP treatment alone. arm 5: Brentuximab vedotin 1.8 mg/kg plus rituximab, cyclophosphamide, doxorubicin, prednisone

Part 3 of the study is a phase 2, randomized, open-label, multicenter study designed to evaluate the antitumor activity and safety of brentuximab vedotin 1.8 mg/kg when administered in combination with RCHP chemotherapy compared to RCHOP chemotherapy alone. Patients in this treatment arm were randomized to receive RCHOP treatment alone. Randomization in this part of the study is for the purpose of evaluating the safety of 1.8 mg/kg brentuximab vedotin in combination with RCHP versus standard RCHOP chemotherapy.

Part 3 of the study is a phase 2, randomized, open-label, multicenter study designed to evaluate the antitumor activity and safety of brentuximab vedotin 1.8 mg/kg when administered in combination with RCHP chemotherapy compared to RCHOP chemotherapy alone. Patients in this treatment arm were randomized to receive 1.8 mg/kg brentuximab vedotin administered in combination with RCHP.
Interventions: intervention 1: brentuximab vedotin intervention 2: brentuximab vedotin intervention 3: rituximab intervention 4: vincristine intervention 5: cyclophosphamide intervention 6: prednisone intervention 7: doxorubicin
Intervention descriptions: intervention 1: 1.2 mg/kg by IV infusion every 3 weeks for up to 6 cycles intervention 2: 1.8 mg/kg by IV infusion every 3 weeks for up to 6 cycles intervention 3: 375 mg/m2 every 3 weeks by IV infusion for up to 6 cycles intervention 4: 1.4 mg/m2 every 3 weeks by IV infusion for up to 6 cycles (dose capped at 2 mg total) intervention 5: 750 mg/m2 every 3 weeks by IV infusion for up to 6 cycles intervention 6: 100 mg on Days 1 to 5 of each 3-week cycle, orally for up to 6 cycles intervention 7: 50 mg/m2 every 3 weeks by IV infusion for up to 6 cycles

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
Protocol Number: 
SGN35-017 
Version: 
Amendment 5; 10-August-2015 
Protocol Title: 
A phase 2 study of brentuximab vedotin in combination with 
standard of care treatment (rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone [RCHOP]) or RCHP 
(rituximab, cyclophosphamide, doxorubicin, and prednisone) as 
front-line therapy in patients with diffuse large B-cell lymphoma 
(DLBCL) 
Brief Title: 
A phase 2 study of brentuximab vedotin given with RCHOP or 
RCHP for front-line treatment of patients with diffuse large  
B-cell lymphoma 
Investigational Drug: 
Brentuximab vedotin  
Indication: 
Diffuse large B-cell lymphoma 
Phase: 
2 
IND Number: 
71634  
Sponsor: 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
Medical Monitor: 
 
Seattle Genetics, Inc. 
 
E-mail: 
 
SAE Email or Fax: 
See email or fax number specified on the sponsor’s SAE report 
form 


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PROTOCOL SYNOPSIS 
Protocol Number 
SGN35-017 
Version 
Amendment 5; 10-August-2015 
Phase 
2 
Product Name 
Brentuximab vedotin 
Sponsor 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
Protocol Title 
A phase 2 study of brentuximab vedotin in combination with standard of care treatment (rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone [RCHOP]) or RCHP (rituximab, 
cyclophosphamide, doxorubicin, and prednisone) as front-line therapy in patients with diffuse large B-cell 
lymphoma (DLBCL) 
Study Objectives 
Primary: 
● To assess the antitumor activity of brentuximab vedotin administered in combination with RCHOP or 
RCHP, and in combination with RCHP versus RCHOP alone, as measured by the complete remission (CR) 
rate at the end of treatment per investigator assessment in treatment-naive patients with high-intermediate 
or high risk systemic DLBCL 
● To assess the safety profile of brentuximab vedotin administered at dose levels of 1.2 mg/kg versus 
1.8 mg/kg in combination with RCHOP or brentuximab vedotin 1.8 mg/kg in combination with RCHP in 
treatment-naive patients with high-intermediate or high risk systemic DLBCL 
Secondary: 
● To assess the antitumor activity of brentuximab vedotin administered in combination with RCHOP or 
RCHP, and in combination with RCHP versus RCHOP alone,  as measured by the objective response rate 
(ORR) at the end of treatment per investigator assessment 
● To assess the progression-free survival (PFS) associated with brentuximab vedotin administered in 
combination with RCHOP or RCHP, and in combination with RCHP versus RCHOP alone 
● To assess survival associated with brentuximab vedotin administered in combination with RCHOP or 
RCHP, and in combination with RCHP versus RCHOP alone 
Additional: 
● To assess CD30 expression on tumor specimens 
● To assess the pharmacokinetics (PK) of brentuximab vedotin administered in combination with RCHOP or 
RCHP 
Study Population 
The population to be studied includes treatment-naive patients with systemic de novo or transformed DLBCL or 
follicular non-Hodgkin lymphoma (NHL) grade 3b.  Patients must have high-intermediate or high risk disease 
based on standard IPI (score ≥3 for patients >60 years of age) or age-adjusted IPI (score 2 or 3 for patients 
≤60 years of age), and stage IAX (bulk defined as single lymph node mass >10 cm in diameter), IB–IV disease.  
Eligible patients must be age ≥18 years, have fluorodeoxyglucose (FDG)-avid disease by positron emission 
tomography (PET), measurable disease of at least 1.5 cm by computed tomography (CT), an Eastern 
Cooperative Oncology Group (ECOG) performance status ≤2, and adequate organ function.  In addition, 
patients enrolled in Parts 2 and 3 must have CD30-positive disease; CD30 expression will be determined by 
visual assessment using immunohistochemistry (IHC). 


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Patients are not eligible for enrollment if they have a previous history of treated indolent lymphoma; however, 
newly diagnosed patients with DLBCL who are found to have small cell infiltration of the bone marrow or other 
diagnostic material (representing a discordant lymphoma) are eligible.  Patients are also excluded if they have a 
history of another primary invasive cancer, hematologic malignancy, or myelodysplastic syndrome that has not 
been in remission for at least 3 years, a history of progressive multifocal leukoencephalopathy (PML), 
cerebral/meningeal disease related to the underlying malignancy, baseline peripheral neuropathy ≥ Grade 2 (per 
the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], Version 4.03), 
or the demyelinating form of Charcot-Marie-Tooth syndrome.  Patients must not have left ventricular ejection 
fraction less than 45% or symptomatic cardiac disease (including symptomatic ventricular dysfunction, 
symptomatic coronary artery disease, and symptomatic arrhythmias), myocardial infarction within the past 
6 months, or previous treatment with complete cumulative doses of doxorubicin or other anthracyclines.  In 
addition, patients must not have any active Grade 3 or higher (per the NCI CTCAE, Version 4.03) viral, 
bacterial, or fungal infection within 2 weeks prior to the first dose of study treatment, known urinary outflow 
obstruction, or known human immunodeficiency virus (HIV) infection, be positive for hepatitis B surface 
antigen or anti-hepatitis B core antibody, or have known or suspected active hepatitis C infection.  Patients must 
not be receiving current therapy with other systemic anti-neoplastic or investigational agents, have a known 
hypersensitivity to any excipient contained in any of the drug formulations of study treatments, or be a female 
who is breastfeeding. 
Number of Planned Patients 
There are 3 parts to this study.  Approximately 50 patients (no less than 25 patients in each cohort) will be 
randomized in Part 1 of this study.  Up to 25 patients will be enrolled (non-randomized) in Part 2 of this study.  
Approximately 50 patients (no less than approximately 25 patients in each arm) will be randomized in Part 3 of 
this study. 
Study Design 
This study has three parts.  Part 1 of the study is a phase 2, randomized, open-label, multicenter study designed 
to evaluate the antitumor activity and safety of brentuximab vedotin 1.2 and 1.8 mg/kg when administered in 
combination with standard RCHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone); this regimen is abbreviated as A+RCHOP.  Part 2 of the study is a phase 2, non-randomized, open-
label, multicenter study designed to evaluate the antitumor activity and safety of brentuximab vedotin 1.8 mg/kg 
when administered in combination with RCHP chemotherapy (rituximab, cyclophosphamide, doxorubicin, and 
prednisone); this regimen is abbreviated as A+RCHP.  Part 3 of the study is a phase 2, randomized, open-label, 
multicenter study designed to evaluate the antitumor activity and safety of brentuximab vedotin 1.8 mg/kg when 
administered in combination with RCHP chemotherapy compared to RCHOP chemotherapy alone. 
In Part 1, a total of approximately 50 patients will be randomized 1:1 into 2 dosing cohorts of 1.2 or 1.8 mg/kg 
brentuximab vedotin administered in combination with RCHOP.  Randomization in this part of the study is for 
the purpose of evaluating the safety of 1.2 and 1.8 mg/kg brentuximab vedotin in combination with RCHOP.  
Randomization will be stratified by high-intermediate or high risk disease.  The safety of the combination of 
brentuximab vedotin and RCHOP will be assessed by a Safety Monitoring Committee (SMC). 
In Part 2, up to 25 patients will be enrolled into a dosing cohort with 1.8 mg/kg brentuximab vedotin 
administered in combination with RCHP.  The safety of the combination of brentuximab vedotin and RCHP 
will also be assessed by the SMC. 
In Part 3, a total of approximately 50 patients will be randomized 1:1 into either 1.8 mg/kg brentuximab vedotin 
administered in combination with RCHP or RCHOP alone.  Randomization in this part of the study is for the 
purpose of evaluating the safety of 1.8 mg/kg brentuximab vedotin in combination with RCHP versus standard 
RCHOP chemotherapy.  Randomization will be stratified by high-intermediate or high risk disease.  The safety 
of the combination of brentuximab vedotin and RCHP will also be assessed by the SMC. 
Each site may only enroll patients into one part of the study at a time.  For example, if Part 2 and Part 3 have 
been approved by the site’s IRB and are open at a site, enrollment in Part 2 will close prior to enrolling in Part . 


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Test Product, Dose, and Mode of Administration 
In Part 1, brentuximab vedotin 1.2 or 1.8 mg/kg will be administered every 3 weeks via outpatient 
intravenous (IV) infusion combined with rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 
50 mg/m2, and vincristine 1.4 mg/m2 (dose capped at 2 mg total) administered IV on Day 1 of every 21-day 
cycle together with prednisone 100 mg administered orally on Days 1–5 of every 21-day cycle. 
In Part 2, brentuximab vedotin 1.8 mg/kg will be administered every 3 weeks via outpatient IV infusion 
combined with rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2 administered 
IV on Day 1 of every 21-day cycle together with prednisone 100 mg administered orally on Days 1–5 of every 
21-day cycle. 
In Part 3, patients will be randomized to receive either: 
● Brentuximab vedotin 1.8 mg/kg administered every 3 weeks combined with rituximab 375 mg/m2, 
cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2 administered IV on Day 1 of every 21-day cycle 
together with prednisone 100 mg administered orally on Days 1–5 of every 21-day cycle or 
● Rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 
(dose capped at 2 mg total) administered IV on Day 1 of every 21-day cycle together with prednisone 
100 mg administered orally on Days 1–5 of every 21-day cycle. 
Duration of Treatment 
Study treatment consists of a maximum of 6 cycles (approximately 18 weeks). 
Efficacy Assessments 
Disease response will be assessed by the investigator, based on the Revised Response Criteria for Malignant 
Lymphoma (Cheson 2007).  Radiographic assessments, including CT scans of chest, neck, abdomen, and pelvis, 
will be performed at baseline, 5 weeks post last dose of study treatment, every 4 months after the last scan for 
the first 2 years, and every 6 months thereafter until progression, death, or study closure, whichever comes first. 
Pharmacokinetic Assessments 
Serum or plasma concentrations of brentuximab vedotin antibody-drug conjugate (ADC) and related analytes 
will be measured. 
Biomarker Assessments 
Biomarker assessments include the measurement of soluble CD30 (sCD30) pre-dose prior to each cycle, cell of 
origin (COO) and molecular characterization of tumor biopsies, and evaluation of minimal residual disease 
(MRD). 
Safety Assessments 
Safety assessments will include the surveillance and recording of adverse events (AEs), physical examination 
findings, and laboratory tests. 
Statistical Methods 
The CR rate and ORR at the end of treatment will be summarized and exact 95% confidence intervals (CI) will 
be calculated.  PFS and overall survival (OS) will be estimated using Kaplan-Meier methodology.  Descriptive 
summaries of patient disposition, demographics, disease characteristics, safety, and exposure to study drug will 
be provided.  Serum or plasma levels of brentuximab vedotin and related analytes will be summarized with 
descriptive statistics at each PK sampling time point. 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ....................................................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................................................... 8 
1 
INTRODUCTION ......................................................................................................................................... 10 
1.1 
Diffuse Large B-cell Lymphoma......................................................................................................... 10 
1.2 
Front-line Treatment of Diffuse Large B-cell Lymphoma .................................................................. 11 
1.3 
Clinical Experience with Brentuximab Vedotin .................................................................................. 12 
1.4 
Rationale for Brentuximab Vedotin in Combination with RCHOP .................................................... 12 
1.5 
Rationale for Brentuximab Vedotin in Combination with RCHP in CD30-Positive DLBCL Patients13 
2 
OBJECTIVES ............................................................................................................................................... 14 
2.1 
Primary Objectives .............................................................................................................................. 14 
2.2 
Secondary Objectives .......................................................................................................................... 14 
2.3 
Additional Objectives .......................................................................................................................... 15 
2.4 
Endpoints ............................................................................................................................................. 15 
2.4.1 
Primary Endpoints .................................................................................................................. 15 
2.4.2 
Secondary Endpoints .............................................................................................................. 15 
2.4.3 
Additional Endpoints .............................................................................................................. 15 
3 
INVESTIGATIONAL PLAN ....................................................................................................................... 15 
3.1 
Summary of Study Design .................................................................................................................. 15 
3.2 
Discussion and Rationale for Study Design ........................................................................................ 17 
3.2.1 
Method of Assigning Patients to Treatment Groups .............................................................. 18 
3.2.2 
Rationale for Selection of Doses ............................................................................................ 18 
3.2.3 
Blinding .................................................................................................................................. 19 
4 
STUDY POPULATION................................................................................................................................ 19 
4.1 
Inclusion Criteria ................................................................................................................................. 19 
4.2 
Exclusion Criteria ................................................................................................................................ 20 
4.3 
Removal of Patients From Therapy or Assessment ............................................................................. 21 
4.3.1 
Discontinuation of Study Drug ............................................................................................... 21 
4.3.2 
Patient Withdrawal From Study ............................................................................................. 21 
5 
TREATMENTS ............................................................................................................................................ 21 
5.1 
Treatments Administered .................................................................................................................... 21 
5.2 
Investigational Study Drug .................................................................................................................. 22 
5.2.1 
Description ............................................................................................................................. 22 
5.2.2 
Dose and Administration ........................................................................................................ 22 
5.2.3 
Required Premedication and Postmedication ......................................................................... 23 
5.2.4 
Management of Infusion Reactions ........................................................................................ 23 
5.2.5 
Management of Suspected PML ............................................................................................. 23 
5.2.6 
Dose Modifications ................................................................................................................ 24 
5.2.7 
Storage and Handling ............................................................................................................. 24 
5.2.8 
Packaging and Labeling ......................................................................................................... 25 
5.2.9 
Preparation.............................................................................................................................. 25 
5.3 
Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone ....................................... 25 
5.3.1 
Description ............................................................................................................................. 25 
5.3.2 
Method of Procurement .......................................................................................................... 25 
5.3.3 
Dose and Administration ........................................................................................................ 25 
5.3.4 
Required Premedication and Postmedication ......................................................................... 26 
5.3.5 
Management of Infusion Reactions ........................................................................................ 26 
5.3.6 
Dose Modifications ................................................................................................................ 26 
5.3.7 
Storage and Handling ............................................................................................................. 27 
5.3.8 
Packaging and Labeling ......................................................................................................... 27 
5.3.9 
Preparation.............................................................................................................................. 27 
5.4 
Concomitant Therapy .......................................................................................................................... 27 


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5.4.1 
Required Concomitant Therapy.............................................................................................. 27 
5.4.2 
Allowed Concomitant Therapy .............................................................................................. 27 
5.4.3 
Prohibited Concomitant Therapy ............................................................................................ 28 
5.5 
Treatment Compliance ........................................................................................................................ 28 
6 
STUDY ACTIVITIES ................................................................................................................................... 28 
6.1 
Schedule of Events .............................................................................................................................. 28 
6.2 
Screening Visit (Days -28 to 1) ........................................................................................................... 28 
6.2.1 
Baseline Visit (Days -7 to Day 1) ........................................................................................... 29 
6.3 
Treatment Period (Day 1 to Day 21) ................................................................................................... 29 
6.3.1 
Cycle 1 Day 1 (-1 day) ........................................................................................................... 29 
6.3.2 
Cycle 1 Day 2 ......................................................................................................................... 29 
6.3.3 
Cycle 1 Day 3 (± 1 day) ......................................................................................................... 29 
6.3.4 
Cycles 2–6 Day 1 (± 1 day) .................................................................................................... 30 
6.3.5 
Cycle 3 Day 2 ......................................................................................................................... 30 
6.4 
End of Treatment Visit (30 to 37 days after last dose of study treatment) .......................................... 30 
6.5 
End of Treatment Response Assessment (5 weeks [± 1 week] after last dose of study treatment) ..... 30 
6.6 
Long-Term Follow-Up Visit (every 4 months [± 1 week] after last scan for the first 2 years, and 
every 6 months thereafter) ................................................................................................................... 31 
6.7 
End of Study/End of Follow-up .......................................................................................................... 31 
7 
STUDY ASSESSMENTS ............................................................................................................................. 31 
7.1 
Screening/Baseline Assessments ......................................................................................................... 31 
7.1.1 
CD30 Expression and Histologic Subtype ............................................................................. 32 
7.2 
Response/Efficacy Assessments .......................................................................................................... 32 
7.3 
Pharmacokinetic Assessments ............................................................................................................. 33 
7.4 
Biomarker Analysis ............................................................................................................................. 33 
7.4.1 
Pharmacodynamic Biomarkers ............................................................................................... 33 
7.4.2 
Exploratory Correlative Studies ............................................................................................. 33 
7.5 
Biospecimen Repository...................................................................................................................... 34 
7.6 
Safety Assessments ............................................................................................................................. 34 
7.6.1 
Adverse Events ....................................................................................................................... 35 
7.6.2 
Clinical Laboratory Assessments ........................................................................................... 39 
7.6.3 
Physical Examination ............................................................................................................. 40 
7.7 
Appropriateness of Measurements ...................................................................................................... 40 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 40 
8.1 
Site Training and Monitoring Procedures ........................................................................................... 40 
8.2 
Data Management Procedures ............................................................................................................. 41 
8.3 
Access to Source Data ......................................................................................................................... 41 
8.4 
Accuracy and Reliability of Data ........................................................................................................ 41 
8.5 
Quality Assurance Procedures ............................................................................................................. 42 
8.6 
Data Handling and Record Keeping .................................................................................................... 42 
8.6.1 
Data Handling ......................................................................................................................... 42 
8.6.2 
Investigator Record Retention ................................................................................................ 42 
9 
DATA ANALYSIS METHODS ................................................................................................................... 42 
9.1 
Determination of Sample Size ............................................................................................................. 42 
9.1.1 
Part 1 ...................................................................................................................................... 42 
9.1.2 
Part 2 ...................................................................................................................................... 43 
9.1.3 
Part 3 ...................................................................................................................................... 43 
9.2 
Study Endpoint Definitions ................................................................................................................. 43 
9.2.1 
Primary Efficacy Endpoint ..................................................................................................... 43 
9.2.2 
Secondary Efficacy Endpoints................................................................................................ 43 
9.3 
Statistical and Analytical Plans ........................................................................................................... 44 
9.3.1 
General Considerations .......................................................................................................... 44 
9.3.2 
Patient Disposition ................................................................................................................. 46 
9.3.3 
Patient Characteristics ............................................................................................................ 47 


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9.3.4 
Treatment Compliance ........................................................................................................... 47 
9.3.5 
Efficacy Analyses ................................................................................................................... 47 
9.3.6 
Pharmacokinetic and Pharmacodynamic Analyses ................................................................ 47 
9.3.7 
Safety Analyses ...................................................................................................................... 47 
9.3.8 
Interim Analyses ..................................................................................................................... 48 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ................. 49 
10.1 Informed Consent ................................................................................................................................ 49 
10.2 Ethical Review .................................................................................................................................... 49 
10.3 Regulatory Considerations .................................................................................................................. 50 
10.3.1 Investigator Information ......................................................................................................... 50 
10.3.2 Protocol Amendments and Study Termination ....................................................................... 50 
10.4 Study Documentation, Privacy and Records Retention ....................................................................... 50 
10.5 Clinical Trial Agreement ..................................................................................................................... 51 
11 REFERENCES .............................................................................................................................................. 52 
APPENDIX A:  SCHEDULE OF EVENTS ........................................................................................................ 54 
APPENDIX B:  INDEX SCALES ....................................................................................................................... 55 
APPENDIX C:  ECOG PERFORMANCE STATUS .......................................................................................... 56 
APPENDIX D:  INVESTIGATOR SIGNATURE PAGE ................................................................................... 57 
APPENDIX E:  DOCUMENT HISTORY ........................................................................................................... 58 
 
List of In-Text Tables 
Table 1: 
Recommended brentuximab vedotin and vincristine dose modifications for treatment- 
associated neuropathy .................................................................................................................... 24 
Table 2: 
Pharmacokinetic sampling timepoints ........................................................................................... 33 
 
List of In-Text Figures 
Figure 1:  Study design ......................................................................................................................................... 17 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
aaIPI 
age-adjusted International Prognostic Index 
A+RCHOP 
brentuximab vedotin (ADCETRIS®), rituximab, cyclophosphamide, doxorubicin, 
vincristine, and prednisone 
ABVD 
doxorubicin, bleomycin, vinblastine, and dacarbazine 
ABC 
activated B-cell 
ADC 
antibody-drug conjugate 
AE 
adverse event 
ALCL 
anaplastic large cell lymphoma 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AVD 
doxorubicin, vinblastine, and dacarbazine 
β-hCG 
beta human chorionic gonadotrophin 
BM 
bone marrow 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CHOP 
cyclophosphamide, doxorubicin, vincristine, and prednisone 
CHP 
cyclophosphamide, doxorubicin, and prednisone 
CI 
confidence interval 
Cmax 
maximum concentration 
COO 
cell of origin 
CR 
complete remission 
CRF 
case report form 
CT 
computed tomography 
Ctrough 
trough concentration 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
GCB 
germinal center B-cell 
GCP 
good clinical practice 
HEENT 
head, eyes, ears, nose, and throat 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation  
IEC 
independent ethics committee 
IHC 
immunohistochemistry 
IND 
Investigational New Drug 
INN 
International Nonproprietary Name 
IPI 
International Prognostic Index  
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous 


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JCV 
John Cunningham virus 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAE 
monomethyl auristatin E 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHL 
non-Hodgkin lymphoma 
NK 
natural killer 
NOS 
not otherwise specified 
ORR 
objective response rate 
OS 
overall survival 
PCP 
Pneumocystis jiroveci pneumonia 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PML 
progressive multifocal leukoencephalopathy 
PN 
peripheral neuropathy 
PR 
partial remission 
RBC 
red blood cell 
RCHOP 
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone 
RCHP 
rituximab, cyclophosphamide, doxorubicin, and prednisone 
SAE 
serious adverse event 
sALCL 
systemic anaplastic large cell lymphoma 
SAP 
statistical analysis plan 
sCD30 
soluble CD30 
SCT 
stem cell transplant 
SMC 
safety monitoring committee 
ULN  
upper limit of normal 
USAN 
United States adopted name 
USP 
United States Pharmacopeia 
USPI 
United States Prescribing Information 
WBC 
white blood cell 
WHO 
World Health Organization 
 


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1 
INTRODUCTION 
Brentuximab vedotin is a CD30-directed antibody-drug conjugate (ADC) consisting of 
3 components:  1) the chimeric IgG1 antibody cAC10, specific for human CD30; 2) the 
microtubule-disrupting agent monomethyl auristatin E (MMAE); and 3) a protease-cleavable 
linker that covalently attaches MMAE to cAC10.  The anticancer activity of brentuximab 
vedotin is due to the binding of the ADC to CD30-expressing cells, followed by 
internalization of the ADC-CD30 complex, and the release of MMAE via proteolytic 
cleavage.  Binding of MMAE to tubulin disrupts the microtubule network within the cell, 
subsequently inducing cell cycle arrest and apoptotic death of the cell.  Mechanisms of action 
in addition to the CD30-targeted hypothesis described above are possible. 
A complete summary of the clinical and nonclinical data relevant to the investigational 
product and its study in human subjects is provided in the Investigator’s Brochure. 
This study has 3 parts.  Part 1 of the study is a randomized, open-label, multicenter, phase 2 
clinical trial designed to evaluate the efficacy and safety of including brentuximab vedotin in 
the treatment of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL).  
The standard of care in this patient population consists of 6 cycles of RCHOP chemotherapy 
(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) delivered in 21-day 
cycles.  Patients will be randomized in a 1:1 manner to receive 6 cycles of RCHOP with 
brentuximab vedotin 1.2 mg/kg or brentuximab vedotin 1.8 mg/kg.  Brentuximab vedotin 
administered in combination with RCHOP is abbreviated as A+RCHOP. 
Part 2 of the study is a non-randomized, open-label, multicenter, phase 2 clinical trial 
designed to evaluate the efficacy and safety of including brentuximab vedotin in the 
treatment of patients with newly diagnosed, CD30-positive DLBCL.  Patients will receive 6 
cycles of RCHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) with 
brentuximab vedotin 1.8 mg/kg delivered in 21-day cycles.  Brentuximab vedotin 
administered in combination with RCHP is abbreviated as A+RCHP. 
Part 3 of the study is a phase 2, randomized, open-label, multicenter study designed to 
evaluate the antitumor activity and safety of brentuximab vedotin 1.8 mg/kg when 
administered in combination with RCHP chemotherapy compared to RCHOP alone.  Patients 
will be randomized in a 1:1 manner to receive 6 cycles of with brentuximab vedotin 1.8 
mg/kg or RCHOP alone delivered in 21-day cycles. 
1.1 Diffuse Large B-cell Lymphoma 
DLBCL is a subset of non-Hodgkin lymphomas (NHL) that comprises approximately 30% of 
all newly diagnosed cases of NHL in the United States, representing the most common 
lymphoid neoplasm in adults (Swerdlow 2008).  According to the 2008 World Health 
Organization (WHO) classification schema, DLBCL not otherwise specified (NOS) is a 
heterogeneous grouping of lymphomas comprising neoplasms of large B-lymphoid cells that 
do not belong to other specific subtypes or disease entities (Swerdlow 2008).  DLBCL NOS 


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cases can be further subclassified based on morphological, molecular, and 
immunophenotypical features. 
Outcomes for patients with DLBCL have improved over the past decade, with the addition of 
rituximab to standard anthracycline-based multi-agent chemotherapy.  The addition of 
rituximab to CHOP or CHOP-like multi-agent chemotherapy regimens improved the overall 
survival (OS) of patients by 10–16% compared to multi-agent chemotherapy alone (Coiffier 
2010; Pfreundschuh 2010).  Long-term outcomes from the LNH-98.5 trial conducted in older 
patients have recently been reported, with a 10-year progression-free survival (PFS) and OS 
rate of 36.5% and 43.5% in the RCHOP arm vs. 20.1% and 27.6% in the CHOP arm, 
respectively (Coiffier 2010).  A total of 204 of 399 patients in the study experienced disease 
progression and 87% of the progression events occurred during the first 3 years of follow up. 
In addition, long-term outcomes from the Mabthera International Trial (MInT) in younger 
patients have recently been reported, with 6-year PFS and OS rates of 79.9% and 89.8% 
when rituximab was combined with multi-agent chemotherapy, compared with 63.8% and 
80%, respectively, with multi-agent chemotherapy alone (Pfreundschuh 2010).  Amidst these 
excellent results, less favorable patient subgroups were identified with inferior outcomes, 
namely those patients with an age-adjusted International Prognostic Index (IPI) score of 1 or 
higher and/or bulky disease. 
Taken together, these results highlight the long-term benefit of combining rituximab with 
multi-agent chemotherapy, while underscoring the need for new agents in subgroups of 
patients with inferior outcomes.  Patients with high-intermediate and high risk disease, as 
identified by an IPI score of 3 or higher (for patients >60 years of age) or an age-adjusted IPI 
(aaIPI) of 2 or 3 (for patients who are ≤60 years of age) and those with bulky disease, appear 
to be underserved by the current standard of care and new agents that can be combined with 
RCHOP are needed. 
1.2 Front-line Treatment of Diffuse Large B-cell Lymphoma 
The standard of care for newly diagnosed, treatment-naive patients with DLBCL consists of 
6 cycles of RCHOP delivered in 21-day cycles (NCCN 2013).  In large randomized trials, the 
benefit of RCHOP has been demonstrated by a 3-year PFS rate of approximately 70% and a 
3-year OS rate of approximately 75% (Pfreundschuh 2008; Cunningham 2011).  Complete 
remission (CR) rates of 75%–78% have been reported in analyses that included both high and 
low risk patients (Coiffier 2002; Pfreundschuh 2008). 
Despite the good outcomes achieved with RCHOP in newly diagnosed patients with DLBCL, 
high risk patient populations still remain.  The IPI identifies patients with a score of 3–5 as 
having inferior outcomes compared to those with a score of 0–2.  Higher risk patients with an 
IPI score of 3–5 have a 3-year PFS rate of approximately 55%.  Patients with an IPI score of 
3 or higher comprise approximately 40% of the frontline DLBCL population (25% IPI 3, 
15% IPI 4–5) (Pfreundschuh 2008).  Younger patients (≤60 years of age) with aaIPI scores of 
2–3 have similarly inferior outcomes as the traditional higher risk patients with IPI scores 3-5 
(Shipp 1993; Ziepert 2010). 


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1.3 Clinical Experience with Brentuximab Vedotin 
The clinical safety data observed in the phase 1 dose-escalation study (Study SG035-0001) of 
brentuximab vedotin administered once every 3 weeks support the 1.8 mg/kg dose level as 
the maximum tolerated dose (MTD) and this dose and schedule was selected for pivotal 
phase 2 studies.  In this phase 1 study, the most frequent adverse events (AEs) were nervous 
system (peripheral neuropathy), constitutional (fatigue and pyrexia), gastrointestinal 
(diarrhea, nausea), and hematologic (neutropenia) (Younes 2010). 
The clinical safety and activity of brentuximab vedotin administered sequentially and 
concurrently with multi-agent chemotherapy were evaluated in a phase 1 study in patients 
with newly diagnosed CD30-positive mature T- and natural killer (NK)-cell neoplasms, 
including systemic anaplastic large cell lymphoma (sALCL; Study SGN35-011).  This 
phase 1 study was implemented to determine the safety and activity of sequential and 
combination frontline treatment approaches of brentuximab vedotin with CHOP or CHP 
chemotherapy.  At an interim analysis of 26 patients in this study (Fanale 2012), the MTD of 
brentuximab vedotin in combination with CHP was not exceeded at 1.8 mg/kg, based on 
1 dose-limiting toxicity (DLT) (Grade 3 rash) among 6 patients.  Treatment-emergent AEs 
occurring in >30% of patients included nausea, fatigue, diarrhea, peripheral sensory 
neuropathy, and alopecia.  Adverse events with a severity of Grade 3 or higher occurring in 
>5% of patients included febrile neutropenia, nausea, neutropenia, and pulmonary embolism.  
The dose of brentuximab vedotin was reduced to 1.2 mg/kg in 4 of 26 patients (15%).  At the 
time of analysis, all 26 patients had been assessed for clinical response at the end of 6 cycles 
of combination therapy or at the latest assessment for 3 patients who had discontinued 
treatment prior to Cycle 6.  All 26 patients achieved an objective response, with 23 patients 
(88%) achieving a CR.  All 7 non-sALCL patients achieved a CR with combination therapy.  
This experience demonstrates the combinability of brentuximab vedotin with CHP 
chemotherapy and the associated high level of clinical activity. 
Brentuximab vedotin has shown activity as a monotherapy treatment in patients with relapsed 
or refractory DLBCL.  In an ongoing Phase 2 study (Study SGN35-012), an objective 
response rate (ORR) of 44% (11/25) was observed in patients with DLBCL, with 20% of 
patients achieving a CR.  In this study, CD30 expression by immunohistochemistry (IHC) 
per local pathology assessment was required for enrollment; however, antitumor activity, 
including CRs, was observed in patients who had no evidence of or very low levels of CD30 
expression by central pathology review (Jacobsen 2012). 
1.4 Rationale for Brentuximab Vedotin in Combination with RCHOP 
Given the activity observed with brentuximab vedotin in the relapsed DLBCL setting, 
including activity in patients with low or absent CD30 expression, there is rationale to 
support the hypothesis that brentuximab vedotin may benefit patients with newly diagnosed 
DLBCL, irrespective of CD30 expression as assessed by IHC.  DLBCL patients with adverse 
risk factors (IPI score of 3 or higher for patients >60 years of age or an aaIPI score of 2 or 3 
for patients who are ≤60 years of age), have poor outcomes with RCHOP therapy and new 
agents are needed.  It is hypothesized that a treatment approach combining brentuximab 


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vedotin with RCHOP may yield an improved CR rate, with the potential to prolong PFS 
and OS. 
The current study aims to evaluate the clinical activity of this ADC when combined with 
RCHOP in newly diagnosed high-risk DLBCL patients and to identify the optimal dose of 
brentuximab vedotin to safely administer in combination with RCHOP.  Peripheral 
neuropathy (PN) is the most clinically meaningful AE associated with both brentuximab 
vedotin and vincristine, a microtubule inhibitor that is part of the RCHOP regimen 
(ADCETRIS® Prescribing Information, Seattle Genetics, Inc., January 2012; Vincristine 
[Marquibo®] Prescribing Information, Pfizer, October 2012; and (Coiffier 2002; 
Pfreundschuh 2008). 
Brentuximab vedotin has previously demonstrated combinability with CHP multi-agent 
chemotherapy in the Phase 1 study SGN35-011 (Fanale 2012).  The rate of PN during the 
first 6 cycles of combination chemotherapy was 50%; the majority of events were Grade 1 
and sensory in nature (Seattle Genetics, data on file).  The rate of PN during the first 6 cycles 
of brentuximab vedotin when given as monotherapy was 39% (62/160 patients) in a 
combined analysis of patients with relapsed or refractory HL and sALCL.  Again, the 
majority of events were Grade 1 or 2 and sensory in nature; Grade 3 events occurred in 2% of 
patients (3/160) (Seattle Genetics, data on file). 
The expected incidence of PN with vincristine, delivered as part of RCHOP, is 
approximately 50%; similar to brentuximab vedotin, the majority of neuropathy events are 
sensory in nature and low grade (Grade 1 or 2).  Grade 3 peripheral sensory neuropathy is 
observed in approximately 10% of patients; Grade 3 peripheral motor neuropathy events 
have been infrequently reported in the literature and are typically rare in clinical practice 
(Coiffier 2002; Pfreundschuh 2008). 
The co-primary objective of this study is to assess the safety and tolerability of combining 
2 different doses of brentuximab vedotin with RCHOP.  Patients will be randomized to 
facilitate a comparison of the safety, including peripheral neuropathy, between these 2 dose 
levels.  This study of brentuximab vedotin in combination with RCHOP chemotherapy will 
provide a better understanding of the efficacy, safety, and tolerability in patients with newly 
diagnosed DLBCL, who are unselected for CD30 expression. 
1.5 Rationale for Brentuximab Vedotin in Combination with RCHP in CD30-
Positive DLBCL Patients 
After 10 patients in each cohort in Part 1 completed treatment (N=20), a Safety Monitoring 
Committee (SMC) assessed the safety of the combination of brentuximab vedotin and 
RCHOP (see Section 9.3.8).  In the 1.8 mg/kg brentuximab vedotin cohort, 30% of patients 
(3/10) had Grade 3 neuropathy; thus, per the stopping rules, no further patients were treated 
at that dose level and enrollment continued in the 1.2 mg/kg brentuximab vedotin cohort 
(Yasenchak 2014). 


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Vincristine is an anti-tubulin vinca alkaloid and a component of multi-agent RCHOP 
chemotherapy.  Neurotoxicity is the dose-limiting toxicity of vincristine and appears to be 
cumulative.  Neurologic manifestations that have been associated with vincristine include 
paresthesia, tingling of the hands and feet, numbness, sensory loss, neuropathic pain, 
pharyngeal and parotid gland pain, loss of deep tendon reflexes, and difficulty in walking 
(gait disturbances), including slapping gait.  Infrequently, hoarseness of voice, ocular palsies, 
atony of the urinary bladder, and autonomic neuropathy presenting as postural hypotension 
have occurred (Oncovin®) (Tangun 1977; Legha 1986; Tobias 1991).  As a result of toxic 
neuropathy, vincristine is often dose-reduced or eliminated after several cycles of RCHOP.  
The rationale to administer brentuximab vedotin as a substitution in place of vincristine in 
RCHOP as front-line multi-agent chemotherapy is due to the potential concern for additive 
neurotoxicity in combination with brentuximab vedotin. 
In a previous study (SGN35-011), brentuximab vedotin and CHP exhibited manageable 
toxicity with substantial and durable antitumor activity observed in both sALCL and non-
ALCL patients (ORR 100%, CR rate 88%) with CD30-positive disease (Fanale 2014).  The 
estimated 2-year PFS and OS rates were 54% and 80%, respectively.  Therefore, it is 
reasonable to expect the safety profile would be acceptable and manageable. 
This amendment also restricts the patient population to CD30-positive DLBCL patients.  
Preliminary data from the current study suggest that the CR rate in CD30-positive patients 
was higher (>90%, 10/11) than in CD30-negative patients (Yasenchak 2014).  Interim results 
from another study (SGN35-012) appeared to show higher response in DLBCL patients who 
are confirmed CD30-positive (Bartlett 2014).  In addition, brentuximab vedotin is 
recommended as treatment for CD30-positive relapsed/refractory DLBCL patients (NCCN 
2015).  Based on the known brentuximab vedotin mechanism of action and recent 
recommendations from the NCCN guidelines, it is reasonable to assume CD30-positive 
patients will benefit more from treatment than CD30-negative patients. 
2 
OBJECTIVES 
2.1 Primary Objectives 
● 
To assess the antitumor activity of brentuximab vedotin administered in combination 
with RCHOP or RCHP, and in combination with RCHP versus RCHOP alone, as 
measured by the CR rate at the end of treatment per investigator assessment in 
treatment-naive patients with high-intermediate or high risk systemic DLBCL 
● 
To assess the safety profile of brentuximab vedotin administered at dose levels of 
1.2 mg/kg versus 1.8 mg/kg in combination with RCHOP or brentuximab vedotin 
1.8 mg/kg in combination with RCHP in treatment-naive patients with high-
intermediate or high risk systemic DLBCL 
2.2 Secondary Objectives 
● 
To assess the antitumor activity of brentuximab vedotin administered in combination 
with RCHOP or RCHP, and in combination with RCHP versus RCHOP alone,  as 


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measured by the objective response rate (ORR) at the end of treatment per 
investigator assessment 
● 
To assess the progression-free survival (PFS) associated with brentuximab vedotin 
administered in combination with RCHOP or RCHP, and in combination with RCHP 
versus RCHOP alone 
● 
To assess survival associated with brentuximab vedotin administered in combination 
with RCHOP or RCHP, and in combination with RCHP versus RCHOP alone 
2.3 Additional Objectives 
● 
To assess CD30 expression on tumor specimens 
● 
To assess the pharmacokinetics (PK) of brentuximab vedotin administered in 
combination with RCHOP or RCHP 
2.4 Endpoints 
2.4.1 Primary Endpoints 
● 
Complete remission (CR) rate per investigator assessment following the completion 
of study treatment 
● 
Type, incidence, severity, seriousness, and relatedness of adverse events and 
laboratory abnormalities 
2.4.2 Secondary Endpoints 
● 
Objective response rate (ORR) per investigator 
● 
Progression-free survival (PFS) per investigator 
● 
Overall Survival (OS) 
2.4.3 Additional Endpoints 
● 
CD30 expression on tumor specimens 
● 
Estimates of selected PK parameters 
3 
INVESTIGATIONAL PLAN 
3.1 Summary of Study Design 
This study has 3 parts.  Part 1 of the study is a phase 2, randomized, open-label, multicenter 
study designed to evaluate the antitumor activity and safety of brentuximab vedotin when 
administered in combination with standard RCHOP chemotherapy (A+RCHOP) in newly 
diagnosed DLBCL patients with high-intermediate or high risk disease (IPI score of 3 or 
higher for patients >60 years of age or aaIPI score of 2 or 3 for patients ≤60 years of age). 


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Part 1 of this study will evaluate brentuximab vedotin 1.2 or 1.8 mg/kg administered 
intravenously (IV) every 21 days in combination with standard RCHOP chemotherapy 
(rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 
1.4 mg/m2 [dose capped at 2 mg total] administered IV on Day 1 of every 21-day cycle 
together with prednisone 100 mg administered orally on Days 1–5 of every 21-day cycle) for 
6 cycles.  A total of approximately 50 patients will be randomized 1:1 into 2 dosing cohorts 
of 1.2 or 1.8 mg/kg brentuximab vedotin administered in combination with RCHOP.  The 
safety of the combination of brentuximab vedotin and RCHOP will be assessed by a Safety 
Monitoring Committee (SMC) as detailed in Section 9.3.8.  The SMC will review 
accumulating safety data after 10 patients in each cohort (N=20) have completed treatment 
and after all patients in both dose cohorts have completed treatment (N=50).  If Grade 3 
neuropathy (sensory or motor) is observed in >20% of patients in either dosing cohort, that 
dose level will have exceeded the stopping criteria.  If the 1.8 mg/kg brentuximab vedotin 
cohort exceeds the stopping criteria, but acceptable safety is observed at 1.2 mg/kg during the 
first SMC review, patients receiving treatment at 1.8 mg/kg will be dose reduced to 
1.2 mg/kg, randomization will cease, and all remaining patients will be enrolled and treated 
at 1.2 mg/kg brentuximab vedotin.  If the SMC determines that the risks outweigh the 
benefits of study treatment at both dose levels, no further patients will be enrolled. 
Part 2 of the study is designed as an open-label, multicenter study designed to evaluate the 
antitumor activity and safety of brentuximab vedotin when administered in combination with 
RCHP chemotherapy (A+RCHP) in CD30-positive, newly diagnosed DLBCL patients with 
high-intermediate or high risk disease (IPI score of 3 or higher for patients >60 years of age 
or aaIPI score of 2 or 3 for patients ≤60 years of age). 
Part 2 of this study will evaluate brentuximab vedotin 1.8 mg/kg administered IV every 21 
days in combination with RCHP chemotherapy (rituximab 375 mg/m2, cyclophosphamide 
750 mg/m2, and doxorubicin 50 mg/m2 administered IV on Day 1 of every 21-day cycle 
together with prednisone 100 mg administered orally on Days 1–5 of every 21-day cycle) for 
6 cycles.  A total of approximately 25 patients will be enrolled into Part 2 of the study.  An 
SMC will also assess the safety of the combination of brentuximab vedotin and RCHP as 
detailed in Section 9.3.8.  The SMC will review accumulating safety data after 10 patients 
have completed treatment and after all patients have completed treatment. 
Part 3 of the study is a phase 2, randomized, open-label, multicenter study designed to 
evaluate the antitumor activity and safety of brentuximab vedotin 1.8 mg/kg when 
administered in combination with RCHP chemotherapy compared to RCHOP alone. 
Part 3 of the study will evaluate brentuximab vedotin 1.8 mg/kg administered IV every 21 
days in combination with RCHP chemotherapy compared to standard RCHOP chemotherapy 
for 6 cycles.  A total of approximately 50 patients will be randomized 1:1 into either 1.8 
mg/kg brentuximab vedotin administered in combination with RCHP or RCHOP alone.  The 
safety of the combination of brentuximab vedotin and RCHP will also be assessed by the 
SMC. 


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A study schema is provided in Figure 1.  See Appendix A for a schedule of evaluations. 
Figure 1:  Study design 
 
3.2 Discussion and Rationale for Study Design 
The activity observed with brentuximab vedotin in the relapsed DLBCL setting, including 
activity in patients with low or absent CD30 expression (Jacobsen 2012) suggests that 
brentuximab vedotin may benefit patients with newly diagnosed DLBCL, irrespective of 
CD30 expression as assessed by IHC.  Additionally, the activity observed with brentuximab 
vedotin in patients with CD30-positive mature T-cell and NK-cell neoplasms (including 
systemic ALCL) suggests that CD30-positive patients, regardless of disease diagnosis, may 
benefit from combination therapy with brentuximab vedotin 1.8 mg/kg plus RCHP (Bartlett 
2014).  Patients with DLBCL who are >60 years of age and have an IPI score of 3 or higher 
or patients who are ≤60 years of age with an aaIPI score of 2 or 3 have poor outcomes with 
RCHOP therapy.  Combining brentuximab vedotin with components of RCHOP may 
improve response rates with the potential to prolong PFS and OS.  Additionally, further 
development in this indication would be supported by understanding response rates to each 
regimen (A+RCHP versus RCHOP alone) in a randomized part of the study. 
The endpoints of this study are appropriate for evaluating efficacy and safety in this patient 
population.  The frequency of blood draws for evaluation of pharmacokinetics is appropriate 
based on prior experience with brentuximab vedotin. 


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3.2.1 Method of Assigning Patients to Treatment Groups 
Following informed consent and screening assessments, patients in Part 1 will be randomly 
assigned to 1 of 2 dosing cohorts in a 1:1 ratio.  Randomization in this part of the study is for 
the purpose of evaluating the safety of 1.2 and 1.8 mg/kg brentuximab vedotin in 
combination with RCHOP.  Randomization will be centrally performed using a system that 
will assign a unique patient randomization number and specify the actual treatment 
assignment.  Randomization procedures are detailed in the Study Manual.  Randomization 
will be stratified by high-intermediate versus high risk disease based on standard IPI for 
patients >60 years of age or aaIPI for patients ≤60 years of age (i.e., standard IPI score ≥3 
and aaIPI score of 2 versus IPI score of 4 or 5 and aaIPI score of 3). 
Following informed consent and screening assessments, patients in Part 2 who meet 
eligibility criteria and have detectable CD30 expression by visual assessment using IHC will 
receive combination treatment with A+RCHP. 
Following informed consent and screening assessments, patients in Part 3 will be randomly 
assigned to 1 of 2 arms in a 1:1 ratio.  Randomization in this part of the study is for the 
purpose of evaluating the safety of 1.8 mg/kg brentuximab vedotin in combination with 
RCHP versus RCHOP alone.  Randomization will be centrally performed using a system that 
will assign a unique patient randomization number and specify the actual treatment 
assignment.  Randomization will be stratified by high-intermediate versus high risk disease 
based on standard IPI for patients >60 years of age or aaIPI for patients ≤60 years of age (i.e., 
standard IPI score ≥3 and aaIPI score of 2 versus IPI score of 4 or 5 and aaIPI score of 3). 
Each site may only enroll patients into one part of the study at a time.  For example, if Part 2 
and Part 3 have been approved by the site’s IRB and are open at a site, enrollment in Part 2 
will close prior to enrolling in Part 3. 
3.2.2 Rationale for Selection of Doses 
In a phase 1 dose-escalation study of brentuximab vedotin (SG035-0001), the MTD was 
defined as 1.8 mg/kg via IV infusion administered every 3 weeks.  This dose and schedule 
was further evaluated in 2 pivotal phase 2 studies (SG035-0003 and SG035-0004) in patients 
with CD30-positive hematologic malignancies.  When brentuximab vedotin is administered 
as a single agent, the recommended dose modification in the setting of Grade 2 or higher 
peripheral neuropathy is a reduction to 1.2 mg/kg IV every 3 weeks. 
In a previous Phase 1 experience (Study SGN35-009), when brentuximab vedotin was 
combined with another anti-microtubule agent with the potential for additive peripheral 
neuropathy (vinblastine, as part of ABVD [doxorubicin, bleomycin, vinblastine, and 
dacarbazine]/AVD), an equivalent dose of 1.8 mg/kg every 3 weeks was achieved with 
manageable toxicity.  In addition, the combinability of 1.8 mg/kg brentuximab vedotin with 
CHP chemotherapy was previously demonstrated in a Phase 1 study in CD30-positive 
lymphomas (Study SGN35-011).  In the current study, there will be a randomized 
comparison of the safety and tolerability of 2 dose levels of brentuximab vedotin when 
combined with RCHOP: 1.8 mg/kg IV every 21 days, which is the FDA-approved dose of 


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brentuximab vedotin monotherapy and 1.2 mg/kg IV every 21 days, which is the reduced 
dose in the setting of neuropathy.  There will be a non-randomized dose cohort of 1.8 mg/kg 
brentuximab vedotin combined with RCHP chemotherapy to assess the safety and tolerability 
in a regimen that omits vincristine.  There will also be a randomized part to assess the safety 
and tolerability of 1.8 mg/kg brentuximab vedotin combined with RCHP chemotherapy 
compared to standard RCHOP chemotherapy. 
3.2.3 Blinding 
This study will not be blinded. 
4 
STUDY POPULATION 
The population to be studied includes treatment-naive patients with high-intermediate or high 
risk systemic DLBCL. 
Patients must meet all of the enrollment criteria to be eligible for this study.  Eligibility 
criteria may not be waived by the investigator and are subject to review in the event of Good 
Clinical Practice (GCP) or health regulatory authority inspection. 
4.1 Inclusion Criteria 
1. Treatment-naive patients with systemic de novo or transformed DLBCL, or follicular 
NHL grade 3b; patients must have high-intermediate or high risk disease based on 
standard IPI (score ≥3 for patients >60 years of age) or aaIPI (score 2 or 3 for patients 
≤60 years of age), and stage IAX (bulk defined as single lymph node mass >10 cm in 
diameter), IB–IV disease 
2. Fluorodeoxyglucose (FDG)-avid disease by positron emission tomography (PET) and 
measurable disease of at least 1.5 cm by computed tomography (CT), as assessed by the 
site radiologist 
3. An Eastern Cooperative Oncology Group (ECOG) performance status ≤2 
4. Age 18 years or older 
5. Patients must have the following baseline laboratory data: 
● 
bilirubin ≤1.5X upper limit of normal (ULN) or ≤3X ULN for patients with Gilbert's 
disease or documented hepatic involvement with lymphoma 
● 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3X ULN or 
≤5X ULN for patients with documented hepatic involvement with lymphoma 
● 
serum creatinine ≤2X ULN 
● 
absolute neutrophil count (ANC) ≥1000/µL (unless documented bone marrow 
involvement with lymphoma) 
● 
platelet count ≥50,000/µL (unless documented bone marrow involvement with 
lymphoma) 


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6. Females of childbearing potential must have a negative serum or urine beta human 
chorionic gonadotropin (β-hCG) pregnancy test result within 7 days prior to the first dose 
of brentuximab vedotin.  Females of non-childbearing potential are those who are 
post-menopausal for more than 1 year or who have had a bilateral tubal ligation or 
hysterectomy. 
7. Females of childbearing potential and males who have partners of childbearing potential 
must agree to use 2 effective contraception methods during the study and for 12 months 
following the last dose of study drug 
8. Patients or their legally authorized representative must provide written informed consent 
9. Patients in Parts 2 and 3 must have histologically confirmed diagnosis of CD30-positive 
DLBCL (see Section 7.1.1) 
4.2 Exclusion Criteria 
1. Previous history of treated indolent lymphoma.  Newly diagnosed patients with DLBCL 
who are found to have small cell infiltration of the bone marrow or other diagnostic 
material (representing a discordant lymphoma) are eligible. 
2. History of another primary invasive cancer, hematologic malignancy, or myelodysplastic 
syndrome that has not been in remission for at least 3 years 
3. History of progressive multifocal leukoencephalopathy (PML) 
4. Cerebral/meningeal disease related to the underlying malignancy 
5. Baseline peripheral neuropathy ≥ Grade 2 (per the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events [NCI CTCAE], Version 4.03) or patients with 
the demyelinating form of Charcot-Marie-Tooth syndrome 
6. Left ventricular ejection fraction less than 45% or symptomatic cardiac disease (including 
symptomatic ventricular dysfunction, symptomatic coronary artery disease, and 
symptomatic arrhythmias), or myocardial infarction within the past 6 months or previous 
treatment with complete cumulative doses of doxorubicin or other anthracyclines 
7. Any active Grade 3 or higher (per the NCI CTCAE, Version 4.03) viral, bacterial, or 
fungal infection within 2 weeks prior to the first dose of study treatment 
8. Current therapy with other systemic anti-neoplastic or investigational agents 
9. Females who are breastfeeding 
10. Known hypersensitivity to any excipient contained in any of the drug formulations of 
study treatments 
11. Patients with known urinary outflow obstruction 


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12. Known human immunodeficiency virus (HIV) infection or known or suspected active 
hepatitis C infection. Patients with a positive hepatitis B polymerase chain reaction 
(PCR) assay who have also tested positive for hepatitis B surface antigen and/or anti-
hepatitis B core antibody; patients with a negative PCR assay are permitted with effective 
anti-viral prophylaxis. 
4.3 Removal of Patients From Therapy or Assessment 
Seattle Genetics or their designee must be notified if a patient is withdrawn from study 
treatment or from the study.  The reason(s) for withdrawal must be documented in the 
patient’s medical records and case report form (CRF). 
4.3.1 Discontinuation of Study Drug 
A patient’s treatment with study drug may be discontinued for any of the following reasons: 
● 
Completed treatment 
● 
Progressive disease 
● 
Adverse event (AE) 
● 
Investigator decision 
● 
Patient decision, non-AE 
● 
Study termination by sponsor 
● 
Other, non-AE 
 
Patients who discontinue from study treatment will remain on study for follow-up unless they 
withdraw consent. 
4.3.2 Patient Withdrawal From Study 
Any patient may be discontinued from the study for any of the following reasons: 
● 
Patient withdrawal of consent 
● 
Study termination by sponsor 
● 
Lost to follow-up 
● 
Death 
● 
Other 
5 
TREATMENTS 
5.1 Treatments Administered 
Brentuximab vedotin, the investigational agent under study in this protocol, is an ADC 
consisting of the antibody cAC10, specific for human CD30; the microtubule-disrupting 
agent MMAE; and a protease-cleavable linker that covalently attaches MMAE to cAC10. 
In Part 1 of the study, RCHOP, a standard chemotherapy regimen consisting of rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone, is administered in combination 


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with brentuximab vedotin in this protocol (A+RCHOP).  In Part 2 of the study, an RCHOP 
regimen omitting vincristine will be administered in combination with brentuximab vedotin 
in this protocol (A+RCHP).  In Part 3 of the study, an RCHOP regimen omitting vincristine 
will be administered in combination with brentuximab vedotin (A+RCHP) or standard 
RCHOP chemotherapy (a standard chemotherapy regimen consisting of rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone) will be administered.  See 
Section 5.3 for information on the description, preparation, administration, and storage of 
agents contained in the RCHOP and RCHP regimens. 
Study Treatment in Each 21-Day Cycle 
Part 1 
Part 2 
Part 3 
Brentuximab vedotin 1.2 mg/kg IV on Day 1 
Xa 
 
 
Brentuximab vedotin 1.8 mg/kg IV on Day 1 
Xa 
X 
Xd 
Rituximab 375 mg/m2 IV on Day 1b 
X 
X 
X 
Cyclophosphamide 750 mg/m2 IV on Day 1b 
X 
X 
X 
Doxorubicin 50 mg/m2 on Day 1b 
X 
X 
X 
Vincristine 1.4 mg/m2 on Day 1b,c 
X 
 
Xd 
Prednisone 100 mg orally 70 mg/m2 on Days 1-5 
X 
X 
X 
a 
Patients will be randomized to receive treatment with either 1.2 or 1.8 mg/kg brentuximab vedotin in Part 1 
b 
Administered within approximately 1 hour of completing treatment with brentuximab vedotin administered via IV on 
Day 1 of each 21-day cycle, as applicable 
c 
Dose capped at 2 mg total 
d 
Patients will be randomized to receive treatment with either 1.8 mg/kg brentuximab vedotin combined with RCHP or 
standard RCHOP in Part 3 
5.2 Investigational Study Drug 
Detailed information describing the preparation, administration, and storage of brentuximab 
vedotin is located in the Pharmacy Instructions. 
5.2.1 Description 
Brentuximab vedotin is a sterile, preservative free, white to off-white lyophilized cake or 
powder supplied by Seattle Genetics, Inc. in single-use vials for reconstitution for IV 
administration.  Each vial of the product contains brentuximab vedotin, trehalose, sodium 
citrate, and polysorbate 80.  See the Pharmacy Manual for further information. 
5.2.2 Dose and Administration 
Brentuximab vedotin (1.2 mg/kg or 1.8 mg/kg) will be administered on Day 1 of each 21-day 
cycle by IV infusion given over approximately 30 minutes.  Brentuximab vedotin should be 
administered within approximately 1 hour of completing treatment with RCHOP or RCHP 
(see Section 5.3.3).  In the absence of infusion-related reactions, the infusion rate for 
brentuximab vedotin for all patients should be calculated in order to achieve a 30-minute 
infusion period.  Brentuximab vedotin must not be administered as an IV push or bolus.  
Brentuximab vedotin should not be mixed with other medications. 
Dosing is based on patient actual body weight.  Doses must be adjusted for patients who 
experience a ≥10% change in weight from baseline.  Other dose adjustments for changes in 
body weight are permitted per institutional standard.  An exception to weight-based dosing is 


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made for patients weighing greater than 100 kg; doses will be based on 100 kg for these 
individuals.  Rounding is permissible within 5% of the nominal dose. 
5.2.3 Required Premedication and Postmedication 
Premedication for rituximab will be given as specified in Section 5.3.4.  Routine 
premedication should not be administered for the prevention of infusion-related reactions 
prior to the first dose of brentuximab vedotin (after RCHOP or RCHP administration is 
completed).  However, patients who experience a Grade 1 or Grade 2 infusion reaction 
related to brentuximab vedotin may receive subsequent infusions with premedication as 
described in Section 5.2.4.  Patients who experience a Grade 3 or Grade 4 infusion-related 
reaction may potentially receive additional treatment with brentuximab vedotin at the 
discretion of the investigator after discussion with the sponsor. 
Patients should be individually evaluated to assess the need for tumor lysis prophylaxis prior 
to the first dose of brentuximab vedotin.  Patients should receive prophylaxis as appropriate 
per the institutional standards. 
5.2.4 Management of Infusion Reactions 
Infusion-related reactions may occur during the infusion of brentuximab vedotin.  The 
infusion should be administered at a site properly equipped and staffed to manage 
anaphylaxis should it occur.  All supportive measures consistent with optimal patient care 
should be given throughout the study according to institutional standards.  Supportive 
measures may include extending the infusion time and/or administering medications for 
infusion-related reactions. 
Patients who have experienced an infusion-related reaction should be premedicated for 
subsequent infusions.  Premedication may include acetaminophen, an antihistamine, and a 
corticosteroid administered 30–60 minutes prior to each infusion or according to institutional 
standards. 
If anaphylaxis occurs, brentuximab vedotin administration should be immediately and 
permanently discontinued. 
5.2.5 Management of Suspected PML 
Signs and symptoms of PML may include altered mental status, motor deficits such as 
hemiparesis or ataxia, visual disturbances, or higher cortical dysfunction such as dysphasia or 
agnosia.  See the Investigator’s Brochure for further details. 
If PML is suspected, hold further brentuximab vedotin dosing and undertake a diagnostic 
work-up including (but not limited to): 
● 
Neurologic examinations, as warranted 
● 
Brain radiologic features by magnetic resonance imaging (MRI) 
● 
PCR analysis: John Cunningham virus (JCV) DNA detectable in cerebrospinal fluid 
 


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If PML is confirmed, permanently discontinue treatment with brentuximab vedotin and 
rituximab. 
5.2.6 Dose Modifications 
Table 1 describes the recommended brentuximab vedotin and vincristine dose modifications 
for study treatment-associated neuropathy.  Doses reduced for treatment-related neuropathy 
should not be re-escalated without discussion with the sponsor. 
Table 1: 
Recommended brentuximab vedotin and vincristine dose modifications for 
treatment-associated neuropathy 
Grade of 
Treatment-
Associated 
Neuropathy 
Recommended Dose Modification 
Sensory Neuropathy 
Motor Neuropathy 
1 
Continue study treatment at same dose level 
Continue study treatment at same dose level 
 
 
 
2 
Reduce dose of brentuximab vedotina 
Reduce dose levels of brentuximab vedotin 
or vincristinea 
 
 
 
3 
Hold brentuximab vedotin and vincristine; 
restart after recovery to Grade 1 with 
reduced dose levels of brentuximab vedotin 
and vincristinea 
Discontinue treatment with brentuximab 
vedotin or vincristine 
 
 
 
4 
Discontinue treatment with brentuximab 
vedotin and vincristine 
Discontinue treatment with brentuximab 
vedotin or vincristine 
a 
For patients assigned to 1.8 mg/kg brentuximab vedotin, the reduced dose is 1.2 mg/kg.  For patients in Part 1 assigned 
to 1.2 mg/kg brentuximab vedotin, the reduced dose is 0.8 mg/kg.  The reduced dose of vincristine in Part 1 is 1 mg; 
vincristine dose modifications are not applicable for patients in Part 2. 
 
Brentuximab vedotin dose reductions are also recommended for patients who experience 
Grade 4 neutropenia despite growth factor support.  Patients assigned to 1.8 mg/kg 
brentuximab vedotin should be dose reduced to 1.2 mg/kg and patients in Part 1 assigned to 
1.2 mg/kg brentuximab vedotin should be dose reduced to 0.8 mg/kg. 
5.2.7 Storage and Handling 
Refrigeration should be set at 2–8°C for storage of vials and solutions containing 
brentuximab vedotin.  The controlled location must be accessible only to the pharmacist, the 
investigator, or a duly designated person.  Brentuximab vedotin does not contain 
preservatives; therefore, opened and reconstituted vials of brentuximab vedotin should be 
used as soon as possible.  If not used immediately, the in-use storage should not be longer 
than 24 hours.  It is recommended that brentuximab vedotin vials and solutions be protected 
from direct sunlight until the time of use.  Reconstituted vials and solutions must not be 
shaken. 
Drug accountability instructions are provided in the Pharmacy Manual. 


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5.2.8 Packaging and Labeling 
Drug product vials may be labeled as brentuximab vedotin, the United States adopted name 
(USAN) and the International Nonproprietary Name (INN), or as SGN-35, the compound 
code; the 2 names can be used interchangeably. 
5.2.9 Preparation 
Brentuximab vedotin vials are provided via single-use containers.  Any partially used vials or 
diluted dosing solutions should be discarded using appropriate institutional drug disposal 
procedures. 
Brentuximab vedotin should be reconstituted with the appropriate amount of Sterile Water 
for Injection, United States Pharmacopeia (USP) or equivalent (see Pharmacy Instructions for 
details).  The vial should be gently swirled until the contents are completely dissolved.  The 
vial must not be shaken.  The reconstituted drug product should be inspected visually for any 
particulate matter and discoloration. 
The required volume of reconstituted drug product should be diluted into an infusion bag.  
The bag should be gently inverted to mix the solution.  The bag must not be shaken.  Prior to 
administration, the reconstituted and diluted drug product should be inspected visually for 
any particulate matter and discoloration. 
Detailed drug preparation instructions are provided in the Pharmacy Instructions. 
5.3 Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone 
5.3.1 Description 
RCHOP is a standard chemotherapy regimen consisting of rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone; RCHP is a modified version that omits vincristine.  
Rituximab is a CD20-directed cytolytic antibody. Cyclophosphamide is a nitrogen mustard 
alkylating agent.  Doxorubicin is a cytotoxic anthracycline antibiotic.  Vincristine is a vinca 
alkaloid with a mechanism of action related to the inhibition of microtubule formation in the 
mitotic spindle.  Prednisone is a corticosteroid. 
5.3.2 Method of Procurement 
Agents contained in the RCHOP regimen are commercially available and approved by the 
United States FDA and other regulatory agencies for use in treating patients with multiple 
types of cancer. 
Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone will be supplied by 
the study site and billed to patients and/or their third-party payer (insurance, a healthcare 
provider, or applicable government program). 
5.3.3 Dose and Administration 
In Part 1 of the study, rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 
50 mg/m2, and vincristine 1.4 mg/m2 (dose capped at 2 mg total) will be administered IV on 


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Day 1 of every 21-day cycle together with prednisone 100 mg administered orally on Days 
1–5 of every 21-day cycle.  In Part 2 of the study, rituximab 375 mg/m2, cyclophosphamide 
750 mg/m2, and doxorubicin 50 mg/m2, will be administered IV on Day 1 of every 21-day 
cycle together with prednisone 100 mg administered orally on Days 1–5 of every 21-day 
cycle. 
In Part 3, patients will be randomized to receive either: 
● 
Rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and 
vincristine 1.4 mg/m2 (dose capped at 2 mg total) administered IV on Day 1 of every 
21-day cycle together with prednisone 100 mg administered orally on Days 1–5 of 
every 21-day cycle or 
● 
Rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2 
administered IV on Day 1 of every 21-day cycle together with prednisone 100 mg 
administered orally on Days 1–5 of every 21-day cycle. 
The order of RCHOP or RCHP administration should be according to the institutional 
standard.  If part of the combination treatment, brentuximab vedotin should be administered 
within approximately 1 hour of completing treatment with the other agents. 
Dosing should be based on the patient’s baseline (predose, Cycle 1 Day 1) height and weight 
or per institutional standards at the site. 
5.3.4 Required Premedication and Postmedication 
Acetaminophen and an antihistamine should be given within 30 to 60 minutes prior to 
initiating the rituximab infusion.  Additional premedications, including steroids, may be 
given prior to the rituximab infusion in accordance with the rituximab package insert, 
institutional standard of care, or as clinically indicated. 
There are no protocol-required pre- or post-medications for cyclophosphamide, doxorubicin, 
vincristine or prednisone.  Routine anti-emetic prophylaxis should be administered per 
institutional standard. 
5.3.5 Management of Infusion Reactions 
Infusion reactions related to rituximab should be managed according to the package insert 
and/or institutional standard of care. 
5.3.6 Dose Modifications 
See Table 1 for vincristine dose modifications related to neuropathy.  Dose modifications of 
rituximab, cyclophosphamide, doxorubicin, vincristine (if applicable) or prednisone due to 
hematologic and non-hematologic toxicity are allowed per institutional standards and 
according to the product specific United States Prescribing Information (USPI) at the 
discretion of the investigator.  Permitted dose modifications include discontinuation of a 
treatment component. 


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5.3.7 Storage and Handling 
Rituximab, cyclophosphamide, doxorubicin, vincristine (if applicable), and prednisone 
should be stored and handled per institutional guidelines. 
5.3.8 Packaging and Labeling 
Supplies of rituximab, cyclophosphamide, doxorubicin, vincristine (if applicable), and 
prednisone are commercially available. 
5.3.9 Preparation 
Rituximab, cyclophosphamide, doxorubicin, vincristine (if applicable), and prednisone 
should be prepared per institutional guidelines. 
5.4 Concomitant Therapy 
All concomitant medications, blood products, and radiotherapy administered will be 
collected from Day 1 (predose) through the safety reporting period.  Any concomitant 
medication given for a study protocol-related adverse event should be recorded from the time 
of informed consent. 
5.4.1 Required Concomitant Therapy 
Patients with a negative hepatitis PCR assay who also tested positive for hepatitis B surface 
antigen and/or hepatitis B core antibody must begin antiviral prophylaxis prior to receiving 
study treatment and for at least 6 months following the completion of study treatment, per 
institutional standard.  Patients receiving antiviral prophylaxis should be regularly monitored 
for viral reactivation by PCR per institutional standard. 
See Section 5.3.4 for required rituximab premedications. 
5.4.2 Allowed Concomitant Therapy 
Routine premedication for infusion reactions should not be administered prior to the first 
dose of brentuximab vedotin.  However, patients who experience an infusion-related reaction 
may receive subsequent treatment with premedication as described in Section 5.2.3. 
The use of corticosteroids to treat conditions other than DLBCL is permitted per institutional 
standard.  Systemic corticosteroids may be used to keep DLBCL symptoms under control 
prior to Cycle 1 Day 1 as long as the duration of steroid use is no longer than 14 days. 
Routine infectious prophylaxis for Pneumocystis jiroveci pneumonia (PCP) should be 
considered for all patients.  In addition, the NCCN 2012 guideline for the prevention and 
treatment of cancer-related infections is recommended (NCCN 2012). 
Routine prophylaxis with vaccines that do not contain live micro-organisms is permitted. 
The use of transfusions, platelet and/or colony-stimulating factors per the American Society 
of Clinical Oncology (ASCO) guideline for the use of white blood cell growth factors is 
recommended for the management of neutropenia and febrile neutropenia (Smith 2006).  


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Intrathecal prophylactic treatment for cerebral/meningeal disease is permitted at the 
discretion of the investigator. 
The use of colony-stimulating factors and/or chemotherapy for stem-cell collection to enable 
a future autologous stem cell transplant (SCT) is permitted per institutional standard.  
Chemo-mobilization of stem cells is only permitted after end of treatment (EOT) procedures 
are completed. 
Consolidative radiotherapy or SCT may be given at the investigator’s discretion after EOT 
procedures are completed.  At least 6 cycles of study treatment should be given prior to 
initiating post-treatment consolidative radiotherapy or SCT. 
Patients who are receiving strong CYP3A4 inhibitors concomitantly with brentuximab 
vedotin should be closely monitored for adverse reactions. 
5.4.3 Prohibited Concomitant Therapy 
Patients may not receive other investigational drugs, immunosuppressive medications, 
radiotherapy, or systemic anti-neoplastic therapy from Day 1 through EOT.  Exceptions are 
noted in Section 5.4.2. 
5.5 Treatment Compliance 
Study drug administration will be performed by study site staff and documented in source 
documents and the CRF. 
6 
STUDY ACTIVITIES 
6.1 Schedule of Events 
Adverse events and concomitant medications will be collected from Day 1 (predose) through 
the safety reporting period (see Section 7.6.1.3).  Any study protocol-related adverse event 
should be recorded from the time of informed consent as well as any concomitant 
medications given for treatment of the adverse event.  A schedule of events is provided in 
Appendix A.  Study activities are listed by visit in this section and descriptions of all study 
assessments are presented in Section 7. 
6.2 Screening Visit (Days -28 to 1) 
● 
Informed consent 
● 
Study eligibility per inclusion/exclusion criteria (see Section 4) 
● 
Medical history 
● 
Collection/acquisition of tumor specimen for central pathology review (see Section 
7.1.1) 
● 
Patient International Prognostic Index (IPI) score (see Appendix B) 
● 
Echocardiogram or multigated acquisition (MUGA) scan 
● 
Serology for hepatitis B surface antigen and anti-hepatitis B core antibody; if 
positive, PCR for hepatitis B viremia must also be performed (see Section 5.4.1) 


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● 
CT of diagnostic quality of neck, chest, abdomen, and pelvis 
● 
PET (Note:  a combined CT/PET may be obtained to satisfy the requirements for CT 
and PET scanning) 
● 
Bone marrow biopsy (Note: must be collected within 60 days of the first dose of 
brentuximab vedotin).  Results of the bone marrow biopsy must be available prior to 
enrollment. 
● 
B symptom assessment 
● 
IHC staining for CD30 expression on tumor tissue will be performed in Parts 2 and 3 
of the study, using a local pathology laboratory; a tumor specimen will be collected 
for an additional central pathology review to confirm CD30 expression 
6.2.1 Baseline Visit (Days -7 to Day 1) 
● 
Physical exam including focused lymphoma assessment (see Section 7.2) 
● 
Height and weight 
● 
Electrocardiogram (ECG) 
● 
Pregnancy test for females of childbearing potential 
● 
ECOG Performance Status (see Appendix C) 
● 
Serum chemistry panel (see Section 7.6.2) 
● 
Complete blood count (CBC) with differential (see Section 7.6.2) 
6.3 Treatment Period (Day 1 to Day 21) 
6.3.1 Cycle 1 Day 1 (-1 day) 
● 
B symptom assessment 
● 
Serum chemistry panel (see Section 7.6.2) 
● 
CBC with differential (see Section 7.6.2) 
● 
Blood samples for PK and biomarkers (see Sections 7.3 and 7.4) 
● 
RCHOP (Parts 1 and 3) or RCHP (Parts 2 and 3) administration (prednisone on 
Days 1–5) 
● 
Brentuximab vedotin administration (if applicable for patients in Part 3) 
 
If Baseline Visit activities occur within 1 day prior to Cycle 1, Day 1, the following 
assessments do not need to be repeated at Visit 1: serum chemistry panel and CBC with 
differential. 
6.3.2 Cycle 1 Day 2 
● 
Blood samples for PK (first 10 enrolled patients in Part 1 only; see Section 7.3) 
6.3.3 Cycle 1 Day 3 (± 1 day) 
● 
Optional malignant lymphoma biopsy (for patients who consent to the procedure) 


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6.3.4 Cycles 2–6 Day 1 (± 1 day) 
● 
Physical exam including focused lymphoma assessment (see Section 7.2) 
● 
ECOG Performance Status (see Appendix C) 
● 
B symptom assessment 
● 
Serum chemistry panel (see Section 7.6.2) 
● 
CBC with differential (see Section 7.6.2) 
● 
Blood samples for PK and biomarkers (see Sections 7.3 and 7.4) 
● 
RCHOP (Parts 1 and 3) or RCHP (Parts 2 and 3) administration (prednisone on 
Days 1–5) 
● 
Brentuximab vedotin administration (if applicable for patients in Part 3) 
6.3.5 Cycle 3 Day 2 
● 
Blood samples for PK (first 10 enrolled patients in Part 1 only; see Section 7.3) 
6.4 End of Treatment Visit (30 to 37 days after last dose of study treatment) 
End of Treatment (EOT) visits should occur 30 to 37 days after the last dose of study drug.  
However, EOT evaluations must be performed before initiation of a new therapy.  If EOT 
evaluations are completed before 30 days after the last study treatment, the patient will be 
contacted 30 to 37 days following the last treatment to assess for adverse events. 
● 
Physical examination including focused lymphoma assessment (see Section 7.2) 
● 
ECOG Performance Status (see Appendix C) 
● 
Serum chemistry panel (see Section 7.6.2) 
● 
CBC with differential (see Section 7.6.2) 
● 
Pregnancy test for females of childbearing potential 
● 
Blood samples for PK and biomarkers (see Sections 7.3 and 7.4) 
● 
B symptom assessment 
6.5 End of Treatment Response Assessment (5 weeks [± 1 week] after last 
dose of study treatment) 
● 
CT of diagnostic quality of neck, chest, abdomen, and pelvis 
● 
PET (Note: a combined CT/PET may be obtained to satisfy the requirements for CT 
and PET scanning) 
● 
Physical examination including focused lymphoma assessment (see Section 7.2) 
● 
Optional malignant lymphoma biopsy (Note: only for patients who experience 
progressive disease and who consent to the procedure) 
● 
Bone marrow (BM) biopsy (required to confirm CR if BM positive at baseline; 
should be obtained within 4 weeks after documentation of CR) 


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6.6 Long-Term Follow-Up Visit (every 4 months [± 1 week] after last scan for 
the first 2 years, and every 6 months thereafter) 
Patients who discontinue from study treatment will remain on the study for follow-up until 
they withdraw from the study (see Section 4.3.2). 
● 
All patients who receive at least one dose of study drug will be followed for survival 
and disease status at 4-month intervals after their last scan for the first 2 years, and at 
6 month intervals thereafter until death or study closure, whichever comes first. 
● 
Patients who discontinue study treatment for any reason other than disease 
progression or initiation of a non-protocol therapy for treatment of lymphoma will 
have CT and PET scans of the neck, chest, abdomen, and pelvis every 4 months after 
the last scan for the first 2 years and every 6 months thereafter until disease 
progression, death, or study closure, whichever comes first.  If PET scan negativity 
was previously achieved during the course of the study, PET scans are not required 
during long-term follow-up and/or can be discontinued once PET scan negativity is 
achieved during long-term follow-up. 
● 
Information will also be collected regarding subsequent anticancer therapies received 
● 
Optional malignant lymphoma biopsy (Note: only for patients who experience 
progressive disease and who consent to the procedure) 
6.7 End of Study/End of Follow-up 
The date the patient met criteria for study discontinuation and the reason for study 
discontinuation will be collected. 
7 
STUDY ASSESSMENTS 
7.1 Screening/Baseline Assessments 
Only patients who meet all inclusion and exclusion criteria specified in Section 4 will be 
enrolled in this study. 
Patient IPI scores should be calculated based on the International Non-Hodgkin Lymphoma 
Prognostic Factors Project (Shipp 1993) to determine eligibility (see Appendix B), and used 
for randomization into study arms.  The IPI is calculated by scoring 5 prognostic factors:  
age, stage of disease, lactate dehydrogenase (LDH) level, ECOG score, and number of 
extranodal sites.  Patient aaIPI scores should be calculated based on the method initially 
published by Shipp et al to be used for randomization.  The aaIPI is calculated by scoring 
3 prognostic factors: stage of disease, lactate dehydrogenase (LDH) level, and ECOG score.  
Refer to the Study Manual for details and scoring sheets. 
Patient disease stage is to be calculated to determine eligibility, per the Cotswolds 
Modification of Ann Arbor Staging System (Lister 1989). 
Cardiac function will be determined by performing either an echocardiogram or MUGA scan 
and an ECG. 


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Patient medical history includes a thorough review of significant past medical history, and 
current conditions, any treatment for prior malignancies, and any concomitant medications. 
7.1.1 CD30 Expression and Histologic Subtype 
Histologically confirmed DLBCL must be determined by local pathology assessment. 
Submission of the tumor block or approximately 14 unstained slides is required for central 
pathology evaluation. 
In Part 2 of the study, assessment of CD30 expression to determine eligibility will be 
performed by the institutional or central lab.  Tissue samples will be sent to the central 
pathology lab (selected by the sponsor) for further evaluation of CD30 expression. 
Details and shipping instructions are provided in the Research Specimen Laboratory Manual. 
7.2 Response/Efficacy Assessments 
Lymphoma assessments are to be performed at the timepoints outlined in Section 6 and 
Appendix A.  An adequate focused lymphoma assessment consists of: 
● 
Patient medical history, including a thorough review of: 
○ 
The patient’s current signs and symptoms, including B symptoms (fever, night 
sweats, or weight loss >10%) 
○ 
Concomitant medications 
● 
Physical examination, including evaluation of skin, HEENT (head, eyes, ears, nose, 
and throat), lymph nodes, heart, lungs, abdomen, back, extremities, and neurology 
Radiographic assessments (CT of chest, neck, abdomen, and pelvis) will be performed at 
protocol-specified time points or if disease progression is suspected.  After the patient is 
withdrawn from study treatment for any reason, an additional response assessment will be 
performed if an assessment has not been performed within the prior 6 weeks.  Assessment of 
lymphoma progression will be made according to the Revised Response Criteria for 
Malignant Lymphoma (Cheson 2007).  Treatment decisions by the investigator will be based 
on these assessments.  CT and PET scans are required per protocol as directed in Section 6 
and Appendix A.  A combined CT/PET may be obtained to satisfy the requirements for CT 
and PET scanning when both are required per protocol, as long as the CT scan is of 
diagnostic quality.  CT and/or PET scans may also be obtained throughout the study if 
clinically indicated. 
A bone marrow biopsy is required at baseline.  Information from an assessment performed 
within 60 days of the first dose of study treatment, as part of clinical care, may be used to 
satisfy the baseline bone marrow biopsy requirement.  Postbaseline biopsies are required to 
confirm CR if bone marrow is positive at baseline; this confirmation is to be obtained within 
4 weeks of documentation of CR by radiographic assessment. 


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If cutaneous lesions are the sole site of progressive disease, a biopsy must be obtained to 
histologically confirm progression. 
Patients’ clinical data must be available for CRF source verification. Copies of tumor images 
must be made available for review by the sponsor (or its designee), upon request. 
7.3 Pharmacokinetic Assessments 
Serum or plasma concentrations of brentuximab vedotin ADC and MMAE will be measured 
at the timepoints shown in Table 2 and at the end of treatment.  If brentuximab vedotin is 
discontinued, PK assessments are not required at subsequent visits.  If patients in Part 3 are 
randomized to standard RCHOP chemotherapy, PK assessments are not required. 
Trough serum ADC and plasma MMAE concentrations (Ctrough), as well as 24-hour post-dose 
plasma MMAE concentrations in a subset of patients, will be determined.  The relationship 
between these concentrations and safety or efficacy of brentuximab vedotin will be explored. 
Refer to the Research Specimen Manual for information on collection, processing, storage, 
and shipment of samples. 
Table 2: 
Pharmacokinetic sampling timepoints 
Cycle 
Study Day 
Time 
Window 
Relative Time 
1 and 3 only 
Day 1 
Predose 
Within 24 h prior to 
start of infusion 
Start of infusion 
Day 2a 
24 h 
± 4 h 
Start of infusion 
2 and subsequent 
cycles 
Day 1 
Predose 
Within 8 h 
Start of infusion 
a 
Samples collected in the first 10 patients in Part 1 of the study for measurement of MMAE only 
 
7.4 Biomarker Analysis 
7.4.1 Pharmacodynamic Biomarkers 
Protein Markers in Blood 
Blood samples will be collected predose prior to each cycle for measurement of 
pharmacodynamic biomarkers, which may include markers such as sCD30 and other 
disease-related biomarkers and brentuximab vedotin-related species. 
7.4.2 Exploratory Correlative Studies 
Characterization of Tumor Tissue 
CD30 expression will be evaluated on baseline tumor specimens by multiple modalities 
which may include both protein and mRNA-based assays. 
On Cycle 1 Day 3 (±1 day), an optional malignant lymphoma biopsy will be obtained for 
patients with accessible sites of disease and in instances where obtaining a fresh biopsy 


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would not pose an unnecessary risk to the patient.  An optional malignant lymphoma biopsy 
will also be requested from patients who experience PD. 
All samples will be used to evaluate disease-related biomarkers, including but not limited to 
characterization of the tumor microenvironment as well as determination of the presence of 
brentuximab vedotin-related species.  This evaluation may include both protein and mRNA-
based assays. 
Cell of origin (COO) and molecular characterization of tumor biopsies 
By gene expression profiling DLBCL can be classified based on COO into germinal center 
B-cell (GCB) and activated B-cell (ABC) subtypes which have different prognoses.  In 
addition, a number of somatic mutations such as Myc, Bcl-6, and EZH2 have been identified 
in DLBCL in both GCB and ABC subtypes and represents different oncogenic pathways.  
Patients with Myc and Bcl-2 translocation have particularly poor outcome.  If samples are 
available, correlation of response to brentuximab vedotin with rates of these known 
mutations, as well as immune cell infiltrates, may be evaluated. 
Minimal Residual Disease (MRD) 
MRD evaluation may also be carried out to understand the depth of response to therapy and 
to correlate the depth of response with ORR and other patient outcomes.  Molecular MRD 
status may be analyzed using the Adaptive ClonoSEQ assay. 
7.5 Biospecimen Repository 
In the US only, for patients who provide additional consent, remaining de-identified unused 
blood and/or tissue will be retained by Seattle Genetics and used for future research, 
including but not limited to the evaluation of targets for novel therapeutic agents, the biology 
of ADC sensitivity and resistance mechanisms, and to identify predictive pharmacodynamic 
biomarkers of ADCs.  Blood and tissue samples donated for future research will be retained 
for a period of up to 25 years.  If additional consent is not provided, any remaining biological 
samples will be destroyed following study completion. 
7.6 Safety Assessments 
The assessment of safety during the course of this study will consist of the surveillance and 
recording of adverse events (AEs) including serious adverse events (SAEs), recording of 
concomitant medication and measurements of protocol-specified physical examination 
findings and laboratory tests. 
Safety will be monitored over the course of the study by an SMC as described in Section 
9.3.8. 


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7.6.1 Adverse Events 
7.6.1.1 Definitions 
Adverse Event 
According to the International Conference on Harmonisation (ICH) E2A guideline 
Definitions and Standards for Expedited Reporting, and 21 CFR 312.32, Investigational New 
Drug (IND) Safety Reporting, an AE is any untoward medical occurrence in a patient or 
clinical investigational subject administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment. 
The following information should be considered when determining whether or not to record a 
test result, medical condition, or other incident on the Adverse Events and Pre-existing 
Conditions CRF: 
● 
From the time of informed consent through the day prior to study Day 1, only study 
protocol-related AEs should be recorded.  A protocol-related AE is defined as an 
untoward medical event occurring as a result of a protocol mandated procedure. 
● 
All medical conditions present or ongoing predose on study Day 1 should be recorded. 
● 
All AEs (regardless of relationship to study drug) should be recorded from study Day 
1 (during and post-dose) through the end of the safety reporting period (see Section 
7.6.1.3).  Complications that occur in association with any procedure (e.g., biopsy) 
should be recorded as AEs whether or not the procedure was protocol mandated. 
● 
Changes in medical conditions and AEs, including changes in severity, frequency, or 
character, during the safety reporting period should be recorded. 
● 
In general, an abnormal laboratory value should not be recorded as an AE unless it is 
associated with clinical signs or symptoms, requires an intervention, results in a 
serious adverse event (SAE), or results in study termination or interruption/ 
discontinuation of study treatment.  When recording an AE resulting from a 
laboratory abnormality, the resulting medical condition rather than the abnormality 
itself should be recorded (e.g., record “anemia” rather than “low hemoglobin”). 
Serious Adverse Events 
An AE should be classified as an SAE if it meets one of the following criteria: 
Fatal: 
AE resulted in death 
 
Life threatening: 
The AEs placed the patient at immediate risk of death. This classification does not 
apply to an AE that hypothetically might cause death if it were more severe. 
 
Hospitalization: 
The AE required or prolonged an existing inpatient hospitalization. Hospitalizations 
for elective medical or surgical procedures or treatments planned before the signing 
of informed consent in the study or routine check-ups are not SAEs by this criterion. 
Admission to a palliative unit or hospice care facility is not considered to be a 


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hospitalization.  Hospitalizations or prolonged hospitalizations for scheduled therapy 
of the underlying cancer or study target disease need not be captured as SAEs. 
 
Disabling/ 
incapacitating: 
Resulted in a persistent or significant incapacity or substantial disruption of the 
patient’s ability to conduct normal life functions. 
 
Congenital anomaly or 
birth defect: 
An adverse outcome in a child or fetus of a patient exposed to the molecule or study 
treatment regimen before conception or during pregnancy. 
 
Medically significant: 
The AE did not meet any of the above criteria, but could have jeopardized the patient 
and might have required medical or surgical intervention to prevent one of the 
outcomes listed above or involves suspected transmission via a medicinal product of 
an infectious agent. 
Adverse Event Severity 
AE severity should be graded using the National Cancer Institute’s Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 4.03.  These criteria are provided in the 
study manual. 
AE severity and seriousness are assessed independently.  ‘Severity’ characterizes the 
intensity of an AE.  ‘Serious’ is a regulatory definition and serves as a guide to the sponsor 
for defining regulatory reporting obligations (see definition for Serious Adverse Events). 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to each study treatment (brentuximab vedotin, RCHOP) should 
be evaluated by the investigator using the following criteria: 
Related: 
There is evidence to suggest a causal relationship between the drug and the AE, such 
as: 
● an event that is uncommon and known to be strongly associated with drug 
exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) 
● an event that is not commonly associated with drug exposure, but is otherwise 
uncommon in the population exposed to the drug (e.g., tendon rupture) 
Unrelated: 
Another cause of the AE is more plausible (e.g., due to underlying disease or occurs 
commonly in the study population), or a temporal sequence cannot be established 
with the onset of the AE and administration of the study treatment, or a causal 
relationship is considered biologically implausible 
 
7.6.1.2 Procedures for Eliciting and Recording Adverse Events 
Investigator and study personnel will report all AEs and SAEs whether elicited during patient 
questioning, discovered during physical examination, laboratory testing and/or other means 
by recording them on the CRF and/or SAE form, as appropriate. 
Eliciting Adverse Events 
An open-ended or non-directed method of questioning should be used at each study visit to 
elicit the reporting of AEs. 


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Recording Adverse Events 
The following information should be recorded on the Adverse Events and Pre-existing 
Conditions CRF: 
● 
Description including onset and resolution dates 
● 
Whether it met serious criteria 
● 
Severity 
● 
Relationship to study treatment or other causality 
● 
Outcome 
Diagnosis vs. Signs or Symptoms 
In general, the use of a unifying diagnosis is preferred to the listing out of individual 
symptoms.  Grouping of symptoms into a diagnosis should only be done if each component 
sign and/or symptom is a medically confirmed component of a diagnosis as evidenced by 
standard medical textbooks.  If any aspect of a sign or symptom does not fit into a classic 
pattern of the diagnosis, report the individual symptom as a separate AE. 
Important exceptions for this study are adverse reactions associated with the infusion of 
study drug.  For infusion-related reactions, do not use the NCI CTCAE terms of ‘cytokine 
release syndrome,’ ‘acute infusion reaction,’ or ‘allergic or hypersensitivity reaction.’  
Instead, record each sign or symptom as an individual adverse event.  If multiple signs or 
symptoms occur with a given infusion-related event, each sign or symptom should be 
recorded separately with its level of severity. 
Recording Serious Adverse Events 
For SAEs, record the event(s) on both the CRF and the SAE form. 
The following should be considered when recording SAEs: 
● 
Death is an outcome of an event.  The event that resulted in the death should be 
recorded and reported on both an SAE form and CRF. 
● 
For hospitalizations, surgical, or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself.  The procedure should be captured in the narrative as part of the action taken in 
response to the illness. 
Progression of the Underlying Cancer 
Do not use the term ‘disease progression’ when reporting an AE because it is too general.  
Instead, report the specific disease (clinical) manifestation of the progression (e.g., 
‘malignant pleural effusion’, ‘spinal bone metastases’, ‘lymphadenopathy from underlying 
non-Hodgkin lymphoma’, ‘brain metastases’). 


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Pregnancy 
Notification to Drug Safety:  Complete a Pregnancy Report Form for all pregnancies that 
occur from the time of first study drug dose until 12 months after the last dose of study 
drug(s), including any pregnancies that occur in the partner of a male study patient.  Only 
report pregnancies that occur in a male patient’s partner if the estimated date of conception is 
after the male patient’s first study drug dose.  Email or fax to the sponsor’s Drug Safety 
Department within 48 hours of becoming aware of a pregnancy.  All pregnancies will be 
monitored for the full duration; all perinatal and neonatal outcomes should be reported.  
Infants should be followed for a minimum of 8 weeks. 
Collection of data on the CRF:  All pregnancies (as described above) that occur within 
30 days of the last dose of study drug(s) will also be recorded on the Adverse Events and Pre-
Existing Conditions CRF. 
Abortion, whether accidental, therapeutic, or spontaneous, should be reported as an SAE.  
Congenital anomalies or birth defects, as defined by the ‘serious’ criterion above (see 
definitions Section 7.6.1.1) should be reported as SAEs. 
7.6.1.3 Reporting Periods for Adverse Events and Serious Adverse Events 
The safety reporting period for all AEs and SAEs is from study Day 1 (predose) through the 
EOT visit or 30 days after the last study treatment (brentuximab vedotin or combination 
therapy), whichever is later.  However, all study protocol-related AEs are to be collected 
from the time of informed consent.  All SAEs that occur after the safety reporting period and 
are considered related to any component of RCHOP or brentuximab vedotin in the opinion of 
the investigator should also be reported to the sponsor. 
SAEs will be followed until significant changes return to baseline, the event stabilizes 
(recovering/resolving) or is no longer considered clinically significant by the investigator, or 
the patient dies or withdraws consent, or study closure.  All non-serious AEs will be followed 
through the safety reporting period.  Certain AEs of interest may be followed until resolution, 
return to baseline, or study closure. 
7.6.1.4 Serious Adverse Events Require Immediate Reporting 
Within 24 hours of observing or learning of an SAE, investigators are to report the event to 
the sponsor, regardless of the relationship of the event to the study treatment regimen. 
For initial SAE reports, available case details are to be recorded on an SAE form. At a 
minimum, the following should be included: 
● 
Patient number 
● 
Date of event onset 
● 
Description of the event 
● 
Study treatment, if known 
 


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The completed SAE form and SAE Fax Cover Sheet are to be emailed or faxed to the 
sponsor’s or contract research organization’s Drug Safety Department (see email address or 
fax number included on the SAE report form) within 24 hours. 
Relevant follow-up information is to be submitted to the sponsor as soon as it becomes 
available. 
7.6.1.5 Sponsor Safety Reporting to Regulatory Authorities 
Investigators are required to report all SAEs, including anticipated SAEs, to the sponsor (see 
Section 7.6.1.4). 
The sponsor will report all SAEs to regulatory authorities as required per local regulatory 
reporting requirements.  In the United States, endpoints that assess disease-related mortality 
or major morbidity as well as other SAEs that are not study endpoints, but are known 
consequences of the underlying disease or condition that are anticipated to occur in the study 
population should not be reported to the Food and Drug Administration (FDA) as individual 
IND safety reports per the final rule amending the IND safety reporting requirements under  
21 CFR 312.32 and the FDA’s final guidance Safety Reporting Requirements for INDs and 
Bioavailability (BA) and Bioequivalence (BE) Studies (December 2012). 
In this study, the SAE that does not require individual IND safety reports to the FDA is 
progression of the underlying cancer.  This anticipated SAE will be reviewed periodically by 
the Seattle Genetics Drug Safety Department.  If, upon review, an SAE is occurring at a 
higher rate than that which would be expected for the study population, then an IND safety 
report for the SAE will be submitted to the FDA. 
7.6.2 Clinical Laboratory Assessments 
Samples will be drawn for central and local labs.  Local laboratory testing will include 
institutional standard tests for evaluating safety and making clinical decisions.  The following 
assessments will be performed by the central lab to evaluate safety at scheduled timepoints 
(see Appendix A) during the course of the study: 
● 
Chemistry panel:  albumin, alkaline phosphatase, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), blood urea nitrogen (BUN), calcium, creatinine, 
chloride, glucose, lactate dehydrogenase (LDH), potassium, sodium, total bilirubin, 
and uric acid 
● 
Hematology panel:  white blood cell (WBC) count with five-part differential 
(neutrophils, lymphocytes, monocytes, eosinophils, and basophils), red blood cell 
(RBC) count, platelet count, hematocrit, and hemoglobin. 
The following laboratory assessment will be performed by local laboratories at scheduled 
timepoints (see Appendix A) during the course of the study: 
● 
A serum or urine β-hCG pregnancy test for females of childbearing potential 
● 
Hepatitis B surface antigen or anti-hepatitis B core antibody testing 


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7.6.3 Physical Examination 
Physical examinations should include assessments of the following body parts/systems:  
abdomen, extremities, head, heart, lungs, neck, and neurological.  Measurements of height 
obtained within the prior 12 months may be utilized. 
7.7 Appropriateness of Measurements 
Internationally accepted criteria for the evaluation of lymphoma will be employed to assess 
tumor lesion size and extent of disease in the determination of response rate and PFS in this 
study (Cheson 2007).  The schedule for tumor imaging is consistent with general oncological 
practice and appropriately balances measurement of tumor control with the expense and 
patient inconvenience associated with CT and PET scanning. 
The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications. 
Pharmacokinetic and pharmacodynamic assessments for drug activity are also common in 
clinical studies. 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE 
8.1 Site Training and Monitoring Procedures 
A study manual with instructions for study compliance and CRF completion will be 
provided.  Prior to the enrollment of patients at the site, Seattle Genetics or its designated 
clinical and medical personnel will review the following items with the investigator and 
clinic staff: 
● 
The protocol, study objectives, eligibility requirements, study procedures, registration 
and withdrawal processes 
● 
Current Investigator’s Brochure/ package insert 
● 
Recording and reporting AE and SAE 
● 
Enrollment goals and study timelines 
● 
The CRF completion process and source documentation requirements 
● 
Monitoring requirements 
● 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) review and 
approval process 
● 
Informed consent process 
● 
Good Clinical Practice guidelines and related regulatory documentation requirements 
● 
Key study team roles and responsibilities 


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● 
Investigational product storage, accountability, labeling, dispensing and record 
keeping 
● 
Patient coding and randomization (if applicable) 
● 
Study samples/specimen collection, handling and shipping 
● 
Protocol compliance 
● 
Clinical study record keeping, document retention, and administrative requirements 
Monitoring visits will occur periodically, with frequency dependent on the rate of enrollment 
and workload at each site.  During monitoring visits, the Seattle Genetics representative will 
review regulatory documentation, CRFs, source documentation, and investigational product 
storage, preparation, and accountability.  The CRFs will be reviewed for completeness, 
adherence to the provided guidelines, and accuracy compared to the source documents.  The 
investigators must ensure that the monitor is allowed to inspect all source documents 
pertinent to study patients, and must cooperate with the monitor to ensure that any problems 
noted in the course of the trial are resolved.  The investigator must maintain a comprehensive 
and centralized filing system of all study-related documentation that is suitable for inspection 
by Seattle Genetics or its designated monitors and by quality assurance auditors, or 
representatives of regulatory authorities. 
8.2 Data Management Procedures 
Seattle Genetics will provide CRF Completion Guidelines for electronic CRF (eCRF) data 
entry.  Study specific data management procedures will be maintained in the data 
management plan.  Queries resulting from edit checks and/or data verification procedures 
will be posted electronically in the eCRF. 
8.3 Access to Source Data 
The investigator will permit the sponsor’s representatives to monitor the study as frequently 
as the sponsor deems necessary to determine that protocol adherence and data recording are 
satisfactory.  Appropriate measures to protect patient confidentiality are to be employed 
during monitoring.  The CRFs and related source documents will be reviewed in detail by the 
monitor at each site visit.  Original source documents or certified copies are needed for 
review.  This review includes inspection of data acquired as a requirement for participation in 
this study and other medical records as required to confirm that the information contained in 
the CRFs, such as disease assessments, AEs, and concomitant medications, is complete and 
correct.  Other study records, such as correspondence with the sponsor and the IRB/IEC and 
screening and drug accountability logs will also be inspected.  All source data and study 
records must also be available for inspection by representatives of regulatory authorities. 
8.4 Accuracy and Reliability of Data 
Steps to be taken to assure the accuracy and reliability of data include: 
● 
The selection of qualified investigators and appropriate study centers. 


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● 
Review of protocol procedures with the investigators and associated personnel prior 
to the study. 
● 
Periodic monitoring visits by the designated monitor(s). 
● 
CRFs will be reviewed for accuracy and completeness by the designated monitor(s) 
during monitoring visits to the study centers.  Any discrepancies will be resolved with 
the investigator or designees as appropriate. 
8.5 Quality Assurance Procedures 
The Clinical Quality Assurance group or its designee may conduct audits at the clinical site 
or other study-related facilities and organizations.  Audit reports will be retained by the 
Clinical Quality Assurance group of Seattle Genetics as part of the written record. 
8.6 Data Handling and Record Keeping 
8.6.1 Data Handling 
It is the investigator’s responsibility to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported to the sponsor in the CRFs and in all required reports.  Data 
reported on the CRF that is derived from source documents should be consistent with the 
source documents or the discrepancies should be explained. 
Any change or correction to a CRF will be maintained in an audit trail within the electronic 
data capture system.  Data changes may only be made by those individuals so authorized.  
The investigator should retain records of the changes and corrections, written and/or 
electronic. 
8.6.2 Investigator Record Retention 
The investigator shall retain study drug disposition records and all source documentation 
(such as original ECG tracings, laboratory reports, inpatient or office patient records) for the 
maximum period required by the country and Institution in which the study will be 
conducted, or for the period specified by Seattle Genetics, whichever is longer.  The 
investigator must contact Seattle Genetics prior to destroying any records associated with the 
study.  If the investigator withdraws from the study (due to relocation, retirement, etc.), the 
records shall be transferred to a mutually agreed upon designee, such as another investigator 
or IRB/IEC.  Notice of such transfer will be provided in writing to Seattle Genetics. 
9 
DATA ANALYSIS METHODS 
9.1 Determination of Sample Size 
9.1.1 Part 1 
In order to guarantee enrollment of no less than 25 patients per cohort, approximately 
50 patients will be randomized in Part 1 of this study.  The null hypothesis is assumed to be a 
70% CR rate in both cohorts combined.  The alternative hypothesis is that the CR rate is 


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≥84%.  A sample size of 50 patients provides the study with 73% power to reject the null 
hypothesis when the true CR rate is 84%. 
For safety evaluations, with a sample size of 50 patients, the study would provide an 88% 
chance of observing at least 3 occurrences (6%) of a clinically relevant AE with a true event 
rate of 10%.  Within each cohort, at least 25 patients would provide a 93% chance of 
observing at least 1 occurrence (5%) of a clinically relevant AE with a true event rate of 
10%. 
9.1.2 Part 2 
In order to guarantee enrollment of no fewer than 25 evaluable patients, approximately 25 
patients will be enrolled in Part 2 of this study.  Although there is no formal statistical 
hypothesis, a sample size of 25 patients is considered adequate to detect antitumor activity of 
A+RCHP within this group of CD30-positive DLBCL patients.  For safety evaluations within 
Part 2, a sample size of 25 would provide a 93% probability of observing at least 1 (5%) 
occurrence of a clinically relevant AE with a true event rate of 10%. 
9.1.3 Part 3 
In order to guarantee enrollment of no fewer than 50 evaluable patients, approximately 25 
patients will be randomized to each arm in Part 3 of this study.  The null hypothesis is 
assumed to be a 70% CR rate in the RCHOP arm.  The alternative hypothesis is that the CR 
rate is ≥90% in the A+RCHP arm.  A sample size of 50 patients provides the study with 70% 
power to reject the null hypothesis when the true CR rate is 90%. 
For safety evaluations, with a sample size of 50 patients, the study would provide an 88% 
chance of observing at least 3 occurrences (6%) of a clinically relevant AE with a true event 
rate of 10%.  Within each cohort, at least 25 patients would provide a 93% chance of 
observing at least 1 occurrence (5%) of a clinically relevant AE with a true event rate of 
10%. 
9.2 Study Endpoint Definitions 
9.2.1 Primary Efficacy Endpoint 
CR rate is defined as the proportion of patients with CR at the end of treatment according to 
the Revised Response Criteria for Malignant Lymphoma (Cheson 2007), as assessed by the 
investigator.  Patients whose disease response cannot be assessed will be scored as 
nonresponders for calculating the CR. 
9.2.2 Secondary Efficacy Endpoints 
9.2.2.1 Objective Response Rate (ORR) per Investigator 
ORR is defined as the proportion of patients with CR or partial remission (PR) at the end of 
treatment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 
2007), as assessed by the investigator.  Patients whose disease response cannot be assessed 
will be scored as non-responders for calculating the ORR. 


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9.2.2.2 Progression-Free Survival (PFS) 
PFS is defined as the time from randomization or enrollment (for those patients who are not 
randomized) to first documentation of disease progression (PD), death due to any cause, or 
receipt of subsequent lymphoma chemotherapy other than the components of the study 
treatment regimen (excludes post-treatment consolidative radiotherapy, post-treatment 
chemotherapy for the purpose of mobilizing peripheral blood stem cells, and consolidative 
autologous or allogeneic SCT), whichever comes first. 
PFS data will be censored as described below: 
● 
Patients who do not have disease progression and are still on study at the time of an 
analysis will be censored on the date of the last disease assessment documenting 
absence of PD 
● 
Patients who do not have disease progression and are given post-treatment  consolidative 
radiotherapy, post-treatment chemotherapy for the purpose of mobilizing peripheral 
blood stem cells, or consolidative autologous or allogeneic SCT will be censored on the 
date of the last disease assessment documenting absence of PD 
● 
Patients who are removed from study prior to documentation of disease progression will 
be censored on the date of the last disease assessment documenting absence of PD 
Patients lacking an evaluation of tumor response after their first dose will have their event 
time censored at one day. 
9.2.2.3 Overall Survival (OS) 
OS is defined as the time from randomization or enrollment to death due to any cause.  
Specifically, 
OS = Date of death – Date of randomization or enrollment + 1. 
For a patient who is not known to have died by the end of study follow-up, observation of OS 
is censored on the date the patient was last known to be alive (i.e., date of last contact). 
Patients lacking data beyond the day of randomization or enrollment will have their survival 
time censored on the date of randomization or enrollment (i.e., OS duration of 1 day). 
9.3 Statistical and Analytical Plans 
The statistical and analytical plans presented below summarize the more complete plans to be 
detailed in the statistical analysis plan (SAP).  A change to the data analysis methods 
described in the protocol will require a protocol amendment only if it alters a principal 
feature of the protocol.  The SAP will be finalized prior to database lock.  Any changes to the 
methods described in the final SAP will be described and justified in the clinical study report. 
9.3.1 General Considerations 
Parts 1 and 3 of this study are phase 2, randomized, open-label studies with formal statistical 
hypotheses for the primary efficacy endpoint.  Part 2 of this study is a phase 2, non-


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randomized, open-label study with no formal statistical hypothesis for the primary efficacy 
endpoint.  For all parts of the study, there are no formal pre-specified statistical hypotheses 
for the primary safety objective. 
Descriptive statistics (mean, median, standard deviation, minimum, maximum) will be used 
to describe continuous variables.  Frequencies and percentages will be used to describe 
categorical variables. 
All analyses will be evaluated separately for each part of this study; Part 1 will be evaluated 
by dosing cohort, Part 2 will be evaluated as a single dose cohort, and Part 3 will be 
evaluated by treatment arm. 
9.3.1.1 Randomization and Blinding 
In Part 1, approximately 50 patients will be randomized in a 1:1 manner to receive either 1.2 
mg/kg or 1.8 mg/kg of brentuximab vedotin plus RCHOP. 
In Part 3, approximately 50 patients will be randomized in a 1:1 manner to receive either 1.8 
mg/kg brentuximab vedotin combined with RCHP or RCHOP alone. 
Randomization for Parts 1 and 3 will be stratified by high-intermediate versus high risk 
group. 
● 
High-intermediate risk includes patients with either: 
○ 
IPI Score: 3 
○ 
Age-adjusted IPI Score:  2 
● 
High risk  includes patients with either: 
○ 
IPI Score: 4–5 
○ 
Age-adjusted IPI Score:  3 
Randomization will be centrally performed using a system that will assign a unique patient 
randomization number and specify the actual treatment assignment. 
Part 2 is a non-randomized study that will enroll approximately 25 patients who will receive 
1.8 mg/kg brentuximab vedotin plus RCHP. 
9.3.1.2 Adjustments for Covariates 
Stratified analyses will include adjustment for the stratification factor as recorded at 
randomization (described in Section 9.3.1.1).  Covariates may be considered for adjustment 
in exploratory analyses. 
9.3.1.3 Handling of Dropouts and Missing Data 
Missing data will not be imputed, with the exception of AE start dates while calculating 
duration of events.  Patients with missing values of a variable other than the time-to-event 
endpoints (PFS and OS) will be excluded from the analysis of that endpoint.  Censoring rules 
will be applied to the estimation of the distribution of the time-to-event endpoints. 


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9.3.1.4 Multicenter Studies 
Site-to-site variation will not be adjusted for in the analyses. 
9.3.1.5 Multiple Comparisons and Multiplicity 
No multiple comparisons are planned and no alpha adjustment is needed because only 1 
primary endpoint will be summarized in this study. 
9.3.1.6 Data Transformations and Derivations 
No data transformations are planned for the primary endpoints. 
Age in years will be calculated using informed consent date and birth date as (informed 
consent date - birth date)/365.25 truncated to the whole number. 
Other time variables based on 2 dates, e.g., start date and end date, will be calculated as (End 
Date – Start Date + 1) (in days) unless otherwise specified in the planned analysis section. 
9.3.1.7 Analysis Sets 
Modified Intent-to-Treat (mITT) Analysis Set:  The mITT analysis set will include all 
patients who receive any amount of brentuximab vedotin or any component of RCHOP.  
Randomized patients will be included in the treatment group assigned at randomization 
regardless of the actual treatment received. 
Safety Analysis Set:  The safety analysis set will include all patients who receive any amount 
of brentuximab vedotin or any component of RCHOP.  For randomized patients, the 
treatment group will be determined using the actual treatment received, regardless of the 
randomization treatment assignment. 
CD30-positive Analysis Set:  The CD30-positive analysis set will include all patients in 
Part 1 who receive any amount of brentuximab vedotin or any component of RCHOP and 
who are CD30-positive (≥1% CD30-expression) per the central laboratory. 
9.3.1.8 Examination of Subgroups 
As exploratory analyses, subgroup analyses may be conducted for selected endpoints.  
Detailed methodology will be provided in the SAP. 
9.3.1.9 Timing of Analyses 
There are no formal interim analyses planned for this study. 
The final primary analysis of CR per investigator will occur after all patients have completed 
treatment on each part of the study.  The database cutoff date for this analysis will be 
determined once all study patients have completed treatment. 
9.3.2 Patient Disposition 
An accounting of study patients by disposition will be tabulated by study part.  The number 
of patients in each analysis set will be summarized by study part.  Patients who discontinue 


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study treatment and patients who withdraw from the study will be summarized by study part 
and reason for discontinuation or withdrawal and listed. 
9.3.3 Patient Characteristics 
Demographics, other baseline characteristics, and concomitant medications will be 
summarized by study part and listed. 
9.3.4 Treatment Compliance 
The dose administered at each cycle for each study part and cohort or arm will be assessed 
and dose intensity will be summarized.  Details will be provided in the SAP. 
9.3.5 Efficacy Analyses 
9.3.5.1 Primary Efficacy Analyses 
CR rate at the end of treatment will be summarized by study part and cohort or arm using the 
mITT analysis set. An exact two-sided 95% CI using the Clopper-Pearson method (Clopper 
1934) will be calculated. 
9.3.5.2 Secondary Efficacy Analyses 
ORR at the end of treatment will be summarized by study part and cohort or arm using the 
mITT analysis set.  An exact two-sided 95% CI using the Clopper-Pearson method (Clopper 
1934) will be calculated. 
PFS and OS will be estimated using Kaplan-Meier methodology and Kaplan-Meier plots will 
be provided.  The median survival time and its two-sided 95% CI using the log-log 
transformation method (Collett 1994) will be calculated. 
9.3.6 Pharmacokinetic and Pharmacodynamic Analyses 
Antibody drug-conjugate (brentuximab vedotin) and unconjugated drug (MMAE) PK in 
serum or plasma will be summarized with descriptive statistics. 
Relationships of biomarker and pharmacodynamic parameters (e.g. baseline values, absolute 
and relative changes from baseline) to efficacy, safety and pharmacokinetic parameters will 
be explored.  Relationships and associated data that are determined to be of interest will be 
summarized.  Details of this analysis will be described separately. 
9.3.7 Safety Analyses 
9.3.7.1 Extent of Exposure 
Exposure of each treatment agent, including duration of treatment, number of cycles, total 
dose, and dose intensity will be summarized by study part and cohort or arm using the safety 
analysis set.  Dose modifications will also be summarized. 
Details will be provided in the SAP. 


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9.3.7.2 Adverse Events 
Adverse events will be defined as treatment emergent if they are newly occurring or worsen 
following study treatment.  The incidence of all AEs, treatment-emergent AEs, and 
treatment-related AEs will be tabulated by study part and cohort or arm.  AEs will be 
classified by system organ class and preferred term using the Medical Dictionary for 
Regulatory Activities (MedDRA). 
AEs will be listed and summarized by study part and cohort or arm, MedDRA preferred 
term, severity, and relationship to study drug.  In the event of multiple occurrences of the 
same AE with the same preferred term in one patient, the AE will be counted once as the 
occurrence.  The incidence of AEs will be tabulated by preferred term and cohort or arm.  
AEs leading to premature discontinuation of study drug will be summarized and listed in the 
same manner. 
9.3.7.3 Deaths and Serious Adverse Events 
Serious adverse events will be listed and summarized in the same manner as all AEs.  Events 
with a fatal outcome will be listed. 
9.3.7.4 Clinical Laboratory Results 
Summary statistics for actual values and for change from baseline will be tabulated as 
appropriate for laboratory results by study part and cohort or arm and scheduled visit.  Patients 
with laboratory values outside of the normal reference range at any postbaseline assessment 
will be listed by study part. 
9.3.8 Interim Analyses 
In Part 1 of the study, an SMC will monitor the trial for safety and efficacy and will convene 
periodically during the study.  The SMC will review accumulating safety data after 10 patients 
in each cohort (N=20) have completed treatment and after all patients in both dose cohorts 
have completed treatment (N=50).  If Grade 3 neuropathy (sensory or motor) is observed in 
>20% of patients in either dosing cohort, that dose level will have exceeded the stopping 
criteria.  If the 1.8 mg/kg brentuximab vedotin cohort exceeds the stopping criteria, but 
acceptable safety is observed at 1.2 mg/kg during the first SMC review, patients receiving 
treatment at 1.8 mg/kg will be dose reduced to 1.2 mg/kg, randomization will cease, and all 
remaining patients will be enrolled and treated at 1.2 mg/kg brentuximab vedotin.  If the SMC 
determines that the risks outweigh the benefits of study treatment at both dose levels, no further 
patients will be enrolled. 
In Part 2 of the study, the SMC will review accumulating safety data after 10 patients have 
completed treatment and after all patients have completed treatment.  If the SMC determines 
that the risks outweigh the benefits of study treatment with 1.8 mg/kg A+RCHP, no further 
patients will be enrolled in Part 2 and the study will be halted.  For those patients still receiving 
therapy, treatment with standard of care or appropriate treatment will continue outside of the 
study at the discretion of the investigator. 


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In Part 3 of the study, the SMC will review accumulating safety and efficacy data after 
12 patients (approximately equal numbers of patients in each arm) have completed treatment.  
If the SMC determines that the risks outweigh the benefits of study treatment with 1.8 mg/kg 
A+RCHP, no further patients will be enrolled in Part 3 and the study will be halted.  For those 
patients still receiving therapy, treatment with standard of care or appropriate treatment will 
continue outside of the study at the discretion of the investigator. 
An ongoing real-time review of serious AEs (SAEs) in both parts of the study and all cohorts 
or arms will also be conducted by the Seattle Genetics Program Safety Monitoring Team. 
Additionally, interim data from the study may be presented at scientific meetings such as the 
annual meetings of the American Society of Clinical Oncology and the American Society of 
Hematology. 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS 
10.1 Informed Consent 
The investigator is responsible for presenting the risks and benefits of study participation to 
the subject in simple terms using the IRB/IEC approved informed consent document and for 
ensuring patients are re-consented when the informed consent document is updated during 
the study, if required.  The investigator will ensure that written informed consent is obtained 
from each patient, or legally authorized representative, if applicable, by obtaining the 
signature and date on the informed consent document prior to the performance of protocol 
evaluations or procedures. 
If informed consent is obtained from a legally authorized representative for a patient who is 
unable to provide informed consent at study entry, but the patient is later able to provide 
informed consent, the investigator must obtain written informed consent from the patient. 
10.2 Ethical Review 
The investigator will provide the sponsor or its designee with documentation of the IRB/IEC 
approval of the protocol and the informed consent document before the study may begin at 
the investigative site(s).  The name and address of the reviewing ethics committee are 
provided in the investigator file. 
The investigator will supply the following to the investigative site’s IRB/IEC: 
● 
Protocol and amendments 
● 
Informed consent document and updates 
● 
Clinical Investigator’s Brochure and updates 
● 
Relevant curricula vitae, if required 
● 
Required safety and SAE reports 
● 
Any additional submissions required by the site’s IRB/IEC 
 


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The investigator must provide the following documentation to the sponsor or its designee: 
● 
The IRB/IEC periodic (eg quarterly, annual) re-approval of the protocol. 
● 
The IRB/IEC approvals of any amendments to the protocol or revisions to the 
informed consent document. 
● 
The IRB/IEC receipt of safety and SAE reports, as appropriate. 
10.3 Regulatory Considerations 
This study will be conducted in accordance with the protocol and ethical principles stated in 
the applicable guidelines on good clinical practice, and all applicable local and/or regional 
laws, rules, and regulations. 
10.3.1 Investigator Information 
The contact information and qualifications of the principal investigator and subinvestigators 
and name and address of the research facilities are included in the investigator file. 
10.3.2 Protocol Amendments and Study Termination 
Any investigator-initiated changes to the protocol (with the exception of changes to eliminate 
an immediate hazard to a study patient) must be approved by the sponsor prior to seeking 
approval from the IRB/IEC, and prior to implementing.  The investigator is responsible for 
enrolling patients who have met protocol eligibility criteria.  Protocol deviations must be 
reported to the sponsor and the local IRB/IEC in accordance with IRB/IEC policies. 
The sponsor may terminate the study at any time.  The IRB/IEC must be advised in writing 
of study completion or early termination. 
10.4 Study Documentation, Privacy and Records Retention 
To protect the safety of participants in the study and to ensure accurate, complete, and 
reliable data, the investigator will keep records of laboratory tests, clinical notes, and patient 
medical records in the patient files as original source documents for the study.  If requested, 
the investigator will provide the sponsor, its licensees and collaborators, applicable 
regulatory agencies, and applicable IRB/IEC with direct access to original source documents 
or certified copies. 
Records containing patient medical information must be handled in accordance with local 
and national laws, rules, and regulations and consistent with the terms of the patient 
authorization contained in the informed consent document for the study (the Authorization).  
Care should be taken to ensure that such records are not shared with any person or for any 
purpose not contemplated by the Authorization.  Furthermore, CRFs and other documents to 
be transferred to the sponsor should be completed in strict accordance with the instructions 
provided by the sponsor, including the instructions regarding the coding of patient identities. 
In compliance with local and/or regional regulations, this trial may be registered and trial 
results may be posted on public registries, such as ClinicalTrials.gov. 


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10.5 Clinical Trial Agreement 
Payments by the sponsor to investigators and institutions conducting the trial, requirements 
for investigators’ insurance, the publication policy for clinical trial data, and other 
requirements are specified in the clinical trial agreement. 


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Sebban C, Belhadj K, Bordessoule D, Ferme C and Tilly H (2010). Long-term outcome of patients in the LNH-
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Cunningham D, Smith P, Mouncey P, Qian W, Jack AS, Pocock C, Ardeshna K, Radford JA, Davies AJ, 
McMillan A and Linch MD (2011). R-CHOP14 versus R-CHOP21: Result of a randomized phase III trial for 
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Huebner D, Kennedy DA and Shustov AR (2014). Brentuximab vedotin in combination with CHP in patients 
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Fanale MA, Shustov AR, Forero-Torres A, Bartlett NL, Advani RH, Pro B, Chen RW, Davies A, Illidge T, 
Kennedy DA and Horwitz SM (2012). Brentuximab Vedotin Administered Concurrently with Multi-Agent 
Chemotherapy As Frontline Treatment of ALCL and Other CD30-Positive Mature T-Cell and NK-Cell 
Lymphomas. Blood 120: Abstract 60. 
Hamlin PA, Zelenetz AD, Kewalramani T, Qin J, Satagopan JM, Verbel D, Noy A, Portlock CS, Straus DJ, 
Yahalom J, Nimer SD and Moskowitz CH (2003). Age-adjusted International Prognostic Index predicts 
autologous stem cell transplantation outcome for patients with relapsed or primary refractory diffuse large B-
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Jacobsen ED, Advani RH, Oki Y, Sharman J, Horwitz SM, Forero-Torres A, O'Connor OA, Shustov AR, 
Siddiqi T, Grove LE and Bartlett NL (2012). A Phase 2 Study of Brentuximab Vedotin in Patients with 
Relapsed or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results. Blood 120: Abstract 2746. 
Legha SS (1986). Vincristine neurotoxicity. Pathophysiology and management. Med Toxicol 1: 421-7. 
Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, Rosenberg SA, Coltman CA and 
Tubiana M (1989). Report of a committee convened to discuss the evaluation and staging of patients with 
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Moskowitz CH, Nimer SD, Glassman JR, Portlock CS, Yahalom J, Straus DJ, O'Brien JP, Elkin N, Bertino JR 
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National Comprehensive Cancer Network (2012). NCCN Guidelines Version 1.2012: Prevention and Treatment 
of Cancer-Related Infections. http://www.nccn.org Accessed: March 25, 2013. 
National Comprehensive Cancer Network (2013). NCCN Guidelines Version 1.2013: Non-Hodgkin's 
Lymphomas. http://www.nccn.org  Accessed: February 21, 2013. 
National Comprehensive Cancer Network (2015). NCCN Guidelines: Non-Hodgkin's Lymphomas. 
http://www.nccn.org/ Accessed: 1/9/2015. 
Pfreundschuh M, Kuhnt E, Trumper L, Osterborg A, Trneny M, Shepherd L, Gill DS, Walewski J, Pettengell R, 
Jager U, Zinzani PL, Shpilberg O, Kvaloy S, Hansen M, Stahel R, Milpied N, Lopez-Guillermo A, Grass S, 
Murawski N, Poschel V and Loffler M (2010). Randomised Intergroup Trial of First line Treatment for young 
Low-Risk Patients (<61 years) with Diffuse Large B-Cell Non-Hodgkin's Lymphoma (DLBCL) with a CHOP-
like Regimen with or without the Anti-CD20 Antibody Rituximab - 6-Year Follow-up of the Mint Study of the 
Mabthera International Trial (MInT) Group. ASH Annual Meeting Abstracts 116: 111. 
Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens 
M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trumper L, Balleisen L, 
Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M and 
German High-Grade Non-Hodgkin Lymphoma Study G (2008). Six versus eight cycles of bi-weekly CHOP-14 
with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised 
controlled trial (RICOVER-60). Lancet Oncol 9: 105-16. 
Shipp MA (1993). A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-
Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329: 987-94. 
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, Bennett CL, Cantor SB, Crawford J, 
Cross SJ, Demetri G, Desch CE, Pizzo PA, Schiffer CA, Schwartzberg L, Somerfield MR, Somlo G, Wade JC, 
Wade JL, Winn RJ, Wozniak AJ and Wolff AC (2006). 2006 update of recommendations for the use of white 
blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 24: 3187-205. 
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J and Vardiman JW (2008). Chapter 
11: Mature T- and NK-cell Neoplasms. WHO classification of tumours of haematopoietic and lymphoid tissues. 
Lyon, France, International Agency for Research on Cancer: 269-319. 
Tangun Y and Atamer T (1977). More on vincristine in treatment of ITP. N Engl J Med 297: 894-5. 
Tobias JD and Bozeman PM (1991). Vincristine-induced recurrent laryngeal nerve paralysis in children. 
Intensive Care Med 17: 304-5. 
Yasenchak CA, Farber CM, Budde LE, Ansell S, Advani R, Holkova B, Halwani A, Knapp M, Fayad L, 
Kolibaba KS, Patel-Donnelly D, Seetharam M, Manley TJ and Bartlett NL (2014). Brentuximab Vedotin in 
Combination with RCHOP As Front-Line Therapy in Patients with DLBCL: Interim Results from a Phase 2 
Study. Blood 124: Abstract 1745. 
Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL and Forero-Torres A (2010). 
Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363: 1812-21. 
Ziepert M, Hasenclever D, Kuhnt E, Glass B, Schmitz N, Pfreundschuh M and Loeffler M (2010). Standard 
International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell 
lymphoma in the rituximab era. J Clin Oncol 28: 2373-80. 


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APPENDIX A:  SCHEDULE OF EVENTS 
SCHEDULE OF EVENTS 
Screening 
Baseline 
Enrollment 
C1 
C2 
C3 
C4 
C5 
C6 
EOTH 
EOT 
Response 
Assessment 
Long-term 
follow-up 
Visit Window 
D –28 to 1 
D –7 to 1 
D –7 to 1 
D1 (–1 day) 
D2 
D3 (±1 day) 
D1 (±1 day) 
D1 (±1 day) 
D2 
D1 (±1 day) 
D1 (±1 day) 
D1 (±1 day) 
30±7 days  
post last 
dose 
5 wks  
(±1 wk)  
post last 
dose 
Q4 mos 
after last 
scan for  
1st 2 yrs 
then  
Q6 mos 
Screening/ 
Baseline 
Assessments 
Informed consent 
X 
 
Eligibility documentation submitted to Sponsor  
prior to study start 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Specimen Submission 
XK 
 
 
 
 
 
 
 
 
 
 
 
 
 
IPI or age-adjusted IPI score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height & weight 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Echo or MUGA scan 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology for hepatitis BM 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
TreatmentR 
Brentuximab vedotin  
 
 
X 
 
 
X 
X 
 
X 
X 
X 
 
 
 
RCHOP or RCHP 
 
 
X 
 
 
X 
X 
 
X 
X 
X 
 
 
 
Research 
SamplesA 
ADC PK sample 
 
 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
 
MMAE PK sample 
 
 
X 
XD,L 
 
X 
X 
XD,L 
X 
X 
X 
X 
 
 
CD30 statusN 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Soluble CD30 
 
 
X 
 
 
X 
X 
 
X 
X 
X 
 
 
 
MRDQ 
 
 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
 
Malignant lymphoma biopsy 
 
 
 
 
XI,L 
 
 
 
 
 
 
 
XJ 
XJ 
Response 
Assessments 
CTB 
X 
 
 
 
 
 
 
 
 
 
 
 
XG 
X 
PETC 
X 
 
 
 
 
 
 
 
 
 
 
 
XF, G 
XO 
BM biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
XE 
 
B symptoms 
X 
 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
 
Survival status  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Safety 
Assessments 
Phys exam/focused lymph assess 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
XP 
 
ECOG 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
 
 
Serum chemistry 
 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
 
CBC with differential 
 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
 
Con meds & AEs 
Collect any related to 
study procedures 
Collect from Day 1 (predose) thru 30 days post last dose or EOT visit, whichever is later 
 
 
 
A 
Refer to Sections 7.3 and 7.4 for detailed schema; PK is not required for Part 3 patients randomized to standard RCHOP chemotherapy 
B 
CT of chest, neck, abdomen, and pelvis 
C 
A combined CT/PET may be obtained to satisfy the requirements for CT and PET scanning 
D 
First 10 enrolled patients in Part 1 only 
E 
Bone marrow (BM) biopsy required to confirm CR if BM positive at baseline; should be obtained within 4 weeks after documentation 
of CR 
F 
Once negative PET or CT/PET is documented, no further PET or CT/PET is required;CT scans only are acceptable 
G 
Should be repeated if not done within the previous 6 weeks 
H 
EOT evaluations should be done before initiation of non-protocol therapy. If done <30 days post last study treatment, conduct a phone 
screen 30-37 days post last treatment to ensure no change in AE profile has occurred. 
I 
Optional malignant lymphoma biopsy for accessible nodes, and in instances where obtaining a fresh biopsy would not pose an 
unnecessary risk to the patient 
J 
Optional malignant lymphoma biopsy (for patients who experience PD) 
K 
Archived tumor specimen must be submitted for central pathology review 
L 
Relative to timing of brentuximab vedotin administration 
M Hepatitis B surface antigen and anti-hepatitis B core antibody; if positive, PCR for hepatitis B viremia must also be performed 
N 
For patients enrolled in Parts 2 and 3 only; determined using IHC staining. 
O 
If PET scan negativity was previously achieved during the course of the study, PET scans are not required during long-term follow-up 
and/or can be discontinued once PET scan negativity is achieved during long-term follow-up. 
P 
The EOT physical exam and the EOT response assessment physical exam may be combined. 
Q 
Minimal residual disease (MRD) predose all cycles and at EOT. 
R 
In Part 3, patients will be randomized to receive either brentuximab vedotin and RCHP or RCHOP alone. 


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APPENDIX B:  INDEX SCALES 
International Prognostic Index (IPI, for patients >60 years of age) 
1 point for any of the following: 
● 
Age >60 
● 
Serum LDH >1 x ULN 
● 
ECOG Performance Status ≥2 
● 
Stage III or IV 
● 
Extranodal involvement ≥2 sites 
 
Risk Category: 
● 
Low:  
 
 
0–1 
● 
Low-intermediate: 
 
2 
● 
High-intermediate: 
 
3 
● 
High:  
 
 
4–5 
 
From the International Non-Hodgkin’s Lymphoma Prognostic Factors Project (Shipp 1993). 
Age-adjusted International Prognostic Index (aaIPI, for patients ≤60 years of age) 
1 point for any of the following: 
● 
Serum LDH >1 x ULN 
● 
ECOG Performance Status ≥2 
● 
Stage III or IV 
 
Risk Category: 
● 
Low:  
 
 
0 
● 
Low-intermediate: 
 
1 
● 
High-intermediate: 
 
2 
● 
High:  
 
 
3 
 
Based on (Shipp 1993; Moskowitz 1999; Hamlin 2003). 
 


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APPENDIX C:  ECOG PERFORMANCE STATUS 
Score 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair. 
5 
Dead. 
 


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APPENDIX D:  INVESTIGATOR SIGNATURE PAGE 
 
Investigator Statement and Signature 
 
I have read the attached protocol entitled “A Phase 2 Study of Brentuximab Vedotin in 
Combination with Standard of Care Treatment (Rituximab, Cyclophosphamide, Doxorubicin, 
Vincristine, and Prednisone [RCHOP]) or RCHP (Ritiximab, Cyclophosphamide, 
Doxorubicin, and Prednisone) as Front-line Therapy in Patients with Diffuse Large B-cell 
Lymphoma (DLBCL)” 
I understand and agree to the provisions of the protocol, and I accept the responsibilities 
listed above in my role as principal investigator for the study. 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Investigator Name, Printed 
 
 
 


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APPENDIX E:  DOCUMENT HISTORY 
Version 
Date 
Original 
27-Mar-2013 
Amendment 1 
19-June-2013 
Amendment 2 
04-Nov-2013 
Amendment 3 
26-Feb-2014 
Amendment 4 
14-Jan-2015 
Amendment 5 
10-Aug-2015 


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Summary of Changes in Amendment 1 
Section(s) 
Change 
Rationale 
Synopsis, 3.2.1, 
6.2, 7.1.1, 
9.3.1.1, 9.3.1.2, 
Appendix A 
Removed CD30 expression by local pathology laboratory as a screening 
assessment.  In addition, patients will no longer be stratified by CD30 
expression. 
For operational ease because CD30 staining is not part 
of the routine immunostaining panel for DLBCL 
patients at local pathology laboratories.  Central 
pathology evaluation will still be performed.  
 
Randomization will no longer be stratified by CD30 
expression because it is unlikely that significant 
imbalances will be observed between treatment arms. 
6.5, 6.6, 7.4.2, 
Appendix A 
Clarified that the optional malignant lymphoma biopsy may be requested for 
patients who progress at any time during their participation on the study. 
Clarification. 
9.2.2.2 
Clarified the definition of PFS and associated censoring rules. 
Clarification. 
 


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Summary of Changes in Amendment 2 
Section(s) 
Change 
Rationale 
Protocol cover 
page 
The sponsor’s medical monitor has been changed. 
Administrative change. 
Synopsis, 4.2 
12. Known human immunodeficiency virus (HIV) infection, positive for 
hepatitis B surface antigen positive status or anti-hepatitis B core antibody, or 
known or suspected active hepatitis C infection. 
 
To exclude patients who are positive for either hepatitis B 
surface antigen or anti-hepatitis B core antibody because 
of the risk of hepatitis B reactivation in patients treated 
with rituximab. 
5.4.2 
The use of corticosteroids to treat conditions other than DLBCL is permitted per 
institutional standard.  Systemic corticosteroids may be used to keep DLBCL 
symptoms under control prior to Cycle 1 Day 1 as long as the duration of 
steroid use is no longer than 14 days. 
Routine infectious prophylaxis for Pneumocystis jiroveci pneumonia (PCP) 
should be considered for all patients.  In addition, the NCCN 2012 guideline for 
the prevention and treatment of cancer-related infections is recommended 
(NCCN 2012). 
Routine prophylaxis with vaccines that do not contain live micro-organisms is 
permitted. 
To clarify permissible use of corticosteroids prior to first 
dose and to clarify that routine vaccination is permitted as 
long as the vaccine does not contain live micro-
organisms. 
6.2 and 
Appendix A 
Removed the requirement for tumor specimen slides to be submitted between 
Day -28 and Day 14. 
For operational ease. 
6.2 and 
Appendix A 
Added serology for hepatitis B surface antigen and anti-hepatitis B core 
antibody to the screening assessments 
To ensure exclusion of patients who are positive for 
either hepatitis B surface antigen or anti-hepatitis B core 
antibody because of the risk of hepatitis B reactivation in 
patients treated with rituximab. 
7.1.1 
Increased the number of tumor specimen slides required for central pathology 
evaluation from approximately 12 to approximately 14. 
To ensure adequate tissue is available for exploratory 
correlative studies. 
7.6.1.3 
The safety reporting period for all AEs and SAEs is from study Day 1 (predose) 
through the EOT visit or 30 days after the last study treatment (brentuximab 
vedotin or combination therapy), whichever is later.  However, all study 
protocol-related AEs are to be collected from the time of informed consent.  All 
SAEs that occur after the safety reporting period and are considered study 
treatment-related to any component of RCHOP or brentuximab vedotin in the 
opinion of the investigator should also be reported to the sponsor. 
To clarify the definition of study treatment-related and to 
clarify that certain AEs of interest may be followed until 
resolution, return to baseline, or study closure. 


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Section(s) 
Change 
Rationale 
SAEs will be followed until significant changes return to baseline, the event 
stabilizes (recovering/resolving) or is no longer considered clinically significant 
by the investigator, or the patient dies or withdraws consent, or study closure.  
All non-serious AEs will be followed through the safety reporting period.  
Certain non-serious AEs of interest may be followed until resolution, return to 
baseline, or study closure. 
Synopsis, 9.1 
In order to guarantee enrollment of no less than 25 patients per cohort, 
Aapproximately 50 patients (approximately 25 patients in each cohort) will be 
randomized in this study.  The null hypothesis is assumed to be a 70% CR rate 
in both cohorts combined.  The alternative hypothesis is that the CR rate is 
≥84%.  A sample size of 50 patients provides the study with 73% power to 
reject the null hypothesis when the true CR rate is 84%. With a sample size of 
50, observing 42 complete remissions (CR; 84%) at the end of treatment across 
both cohorts would allow us to state with 95% confidence (lower limit 
one-sided exact 95% confidence interval [CI], 73.0%) and 73% power that the 
true CR is greater than 70%. 
For safety evaluations, with a sample size of 50 patients, the study would 
provide an 88% chance of observing at least 3 occurrences (6%) of a clinically 
relevant AE with a true event rate of 10%.  Within each arm, at least 1225 
patients would provide a 72 93% chance of observing at least 1 occurrence (5%) 
of a clinically relevant AE with a true event rate of 10%. 
To clarify the sample size, state the null and alternative 
hypotheses, and clarify the power calculation for safety 
based on each 25-patient cohort.  
Appendix A 
Footnotes added: 
L 
Relative to timing of brentuximab vedotin administration 
M Hepatitis B surface antigen and anti-hepatitis B core antibody 
Clarification. 
 


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Summary of Changes in Amendment 3 
Section(s) 
Change 
Rationale 
Synopsis, 1.1, 
1.2, 1.4, 2.1, 3.1, 
3.2, 3.2.1, 4, 4.1, 
7.1, 9.3.1.1, 
Appendix A, 
Appendix B 
Text throughout the protocol has been revised to define high-intermediate and 
high risk patients based on standard IPI (score ≥3 for patients >60 years of age) 
or age-adjusted IPI (score 2 or 3 for patients ≤60 years of age). 
It is standard for younger patients to be evaluated using an 
age-adjusted IPI scoring system rather than the traditional 
IPI scoring system; including younger patients with high-
intermediate or high risk disease better represents this 
patient population. 
Abbreviations 
Added aaIPI and sCD30 
For consistency with abbreviations in the document. 
Title page, 7.6.1.4 
Added new information for the SAE fax number. 
A new fax number for SAEs is provided on the SAE form. 
7.4.2 
Text revised for exploratory correlative studies as follows:  These All samples 
will be used to evaluate disease-related biomarkers on treatment, including but 
not limited to characterization for the tumor microenvironment as well as 
determination of the presence and/or binding properties of brentuximab 
vedotin-related species.  
Clarification to show that all samples provided by patients 
may be used to evaluate disease-related biomarkers, 
including baseline tumor specimens and not just those 
specimens taken on treatment. 
7.6.1.5 
Included the final date of guidance.  
To update the referenced guidance as final. 
11 
New references added. 
To update the references for age-adjusted IPI scores. 
 


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Summary of Changes in Amendment 4 
Section(s) 
Change 
Rationale 
Synopsis and 
Section 2  
Updated the objectives: 
● To assess the antitumor activity of brentuximab vedotin administered in 
combination with RCHOP or RCHP as measured by the complete 
remission (CR) rate at the end of treatment per investigator assessment in 
treatment-naive patients with high-intermediate or high risk systemic 
DLBCL 
● To assess the safety profile of brentuximab vedotin administered at dose 
levels of 1.2 mg/kg versus 1.8 mg/kg in combination with RCHOP or 
brentuximab vedotin 1.8 mg/kg in combination with RCHP in treatment-
naive patients with high-intermediate or high risk systemic DLBCL 
● To assess the antitumor activity of brentuximab vedotin administered in 
combination with RCHOP or RCHP as measured by the objective 
response rate (ORR) at the end of treatment per investigator assessment 
● To assess the progression-free survival (PFS) associated with brentuximab 
vedotin administered in combination with RCHOP or RCHP 
● To assess survival associated with brentuximab vedotin administered in 
combination with RCHOP or RCHP 
● To assess the pharmacokinetics (PK) of brentuximab vedotin administered 
in combination with RCHOP or RCHP 
To reflect the addition of a modified RCHOP regimen to 
be studied in combination with brentuximab vedotin. 
Synopsis and 
Section 3.1 
The overall study design was updated to reflect the addition of Part 2 
(1.8 mg/kg A+RCHP). 
To reflect the revised study design and objectives. 
Section 1.5 
Added background and rationale for treatment of CD30-positive DLBCL 
patients with 1.8 mg/kg A+RCHP.  Rationale includes an overview of the 
safety and efficacy of current treatment, as well as a discussion of known 
vincristine toxicities. 
Phase 1 studies of brentuximab vedotin included treatment 
with CHP; it is reasonable to add this dose cohort. 
Synopsis and 
Section 4.1 
A new inclusion criterion was added for Part 2, requiring patients to have 
confirmed CD30-positive disease. 
To restrict the added patient population to CD30-positive 
patients, which are expected to benefit more from 
treatment with brentuximab vedotin. 
Section 6.2 and 
7.1.1 
Procedures for determining CD30 status were added for patients in Part 2. 
To address the new requirement for patients enrolled in 
Part 2 of the study. 
Section 6.6 and 
Appendix A 
The following sentence was added to long-term follow-up visits: 
To clarify that PET is required during follow-up until 
confirmed to be negative. 


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PET is required during long-term follow-up if PET-negativity is not previously 
documented and the patient has achieved at least SD, and has not received 
additional treatment (excluding consolidative treatment). 
Section 7.3 
The following sentence was added to the sampling timepoints: 
If brentuximab vedotin is eliminated, PK is not required at subsequent visits. 
To clarify that once brentuximab vedotin has been 
discontinued, PK sampling is no longer required. 
Section 9.1 
Sample size was updated to include Part 2. 
To provide rationale for adding 25 patients to Part 2 of the 
study. 
Sections 9.2.2.2 
and 9.2.2.3 
Revised definitions for PFS and OS. 
PFS and OS now include Part 2 patients who were not 
randomized; the definition has been updated to include 
these patients in the censoring. 
Section 9.3 
Section has been revised to include patients in Part 2. 
To reflect the change in sample size and differentiate 
between randomization procedures for Part 1 and Part 2. 
Section 9.3.8 
Section has been updated to include an SMC for Part 2. 
To clarify that an SMC will review data for patients in 
Part 2. 
Appendix A 
Footnotes have been added. 
To clarify timing of and need for assessments. 
Throughout 
protocol 
References to RCHOP chemotherapy and components of RCHOP 
chemotherapy were revised as needed to distinguish between Part 1 and Part 2 
of the study.  Editorial changes have also been made for clarity and 
consistency. 
To reflect the change to the combination therapy from 
brentuximab vedotin and RCHOP to brentuximab vedotin 
and RCHP. 


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Summary of Changes in Amendment 5 
Section(s) 
Change 
Rationale 
Synopsis and 
Section 2  
Added objectives for Part 3: 
● To assess the antitumor activity of brentuximab vedotin administered in 
combination with RCHP versus RCHOP alone as measured by the CR rate 
at the end of treatment per investigator assessment in treatment-naive 
patients with high-intermediate or high risk systemic DLBCL 
● To assess the safety profile of brentuximab vedotin administered at 
1.8 mg/kg in combination with RCHP in treatment-naive patients with 
high-intermediate or high risk systemic DLBCL 
● To assess the antitumor activity of brentuximab vedotin administered in 
combination with RCHP versus RCHOP alone as measured by the 
objective response rate (ORR) at the end of treatment per investigator 
assessment 
● To assess the progression-free survival (PFS) associated with brentuximab 
vedotin administered in combination with RCHP versus RCHOP alone 
● To assess survival associated with brentuximab vedotin administered in 
combination with RCHP versus RCHOP alone 
To reflect the addition of a randomized part of the trial 
that will study brentuximab vedotin in combination with a 
modified RCHOP regimen versus standard RCHOP 
chemotherapy. 
Synopsis and 
Section 3.1 
The overall study design was updated to reflect the addition of Part 3. 
To describe a new study part. 
Section 3.2 
Added language explaining how patients will be randomized into Part 3 and 
how sites will be expected to enroll patients. 
To reflect the revised study design. 
Section 4.1 
Revised Inclusion criterion #7 to clarify patients must use 2 effective 
contraception methods during the study. 
To reflect additional concerns of pregnancy during a 
clinical trial. 
Section 4.2 
Revised Exclusion criterion #12 to allow patients with negative PCR assay. 
To allow patients on study if they have a negative PCR 
assay and receive effective anti-viral prophylaxis. 
Sections 5.4.1, 
6.2, and 7.6.2 
Added language regarding patients with a negative hepatitis B PCR assay. 
To include additional instructions regarding testing for 
hepatitis B PCR assay and concomitant therapy with 
antiviral prophylaxis. 
Section 7.3 
The following sentence was added to the sampling timepoints: 
If patients in Part 3 are randomized to standard RCHOP chemotherapy, PK 
assessments are not required. 
To clarify patients who are not receiving brentuximab 
vedotin in Part 3 do not require PK sampling. 


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Section 7.4 
Added text regarding the testing of cell of origin and molecular 
characterization of tumor biopsies and minimal residual disease.  Also clarified 
that the biospecimen repository will be utilized for US patients only. 
To include additional biomarker testing and clarification 
for retaining samples. 
Section 9.1 
Sample size was updated to include Part 3. 
To provide rationale for adding 50 patients to Part 3 of the 
study. 
Section 9.3 
Section has been revised to include patients in Part 3. 
To reflect the change in sample size and differentiate 
between randomization procedures for all parts of the 
study. 
Section 9.3.6 
Section has been revised to include a summary of the biomarker analyses to be 
performed. 
To provide a summary of the biomarker and 
pharmacodynamic parameters to be explored. 
Section 9.3.8 
Section has been updated to include an SMC for Part 3 and to describe what 
will happen to patients if the study is stopped due to safety concerns. 
To clarify that an SMC will review data for patients in 
Part 3 and what will happen to patients in treatment if the 
study is halted. 
Appendix A 
Footnotes have been added and revised. 
To clarify timing of and need for assessments. 
Throughout 
protocol 
References to combination (A+RCHP) and standard RCHOP chemotherapy 
were revised as needed to distinguish between all parts of the study. 
Editorial and administrative changes have also been made for clarity and 
consistency. 
To reflect the addition of Part 3. 
 

SAP_001.pdf: