Clinical trial NCT01716806
Conditions: Hodgkin Disease Peripheral T Cell Lymphoma
Keywords: Antibody-Drug Conjugate Antibodies, Monoclonal Hematologic Diseases Hodgkin Disease Antigens, CD30 Lymphoma monomethylauristatin E Drug Therapy CD30-expression PTCL Seattle Genetics
Sponsor: Seagen Inc.
Start date: 2012-10-31; Completion date: 2023-09-12
Enrollment: 131 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial will study brentuximab vedotin to find out whether it is an effective treatment for Hodgkin lymphoma (HL) and peripheral T-cell lymphoma (PTCL). Participants in this study will be older or will have other conditions that make them unable to have standard chemotherapy treatment. The study will look at brentuximab vedotin alone and combined with other drugs.

Detailed description:
This study is designed to evaluate the efficacy and tolerability of brentuximab vedotin as monotherapy and in combination with other agents as frontline therapy. There are 6 parts of the study. The population to be studied includes treatment-naïve patients with classical Hodgkin lymphoma (HL) or treatment-naïve patients with CD30-expressing peripheral T-cell lymphoma (PTCL).

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None
Interventions: intervention 1: brentuximab vedotin intervention 2: bendamustine intervention 3: dacarbazine intervention 4: nivolumab
Intervention descriptions: intervention 1: 1.8 mg/kg every 3 weeks by IV infusion intervention 2: 70 mg/m\^2 by IV infusion on Days 1 and 2 of 3-week cycle intervention 3: 375 mg/m\^2 every 3 weeks by IV infusion intervention 4: 3 mg/kg every 3 weeks by IV infusion

Protocol documents:
Prot_000.pdf: 
 
 
 
This document contains information proprietary to Seattle Genetics, Inc. The information is being provided to 
you for the purpose of conducting a clinical trial for Seattle Genetics, Inc. You may disclose the contents of this 
document to study personnel under your supervision and to your Institutional Review Board (IRB) or Ethics 
Committee (EC) for the same purpose. You may not disclose the contents of this document to any other party, 
unless government regulations or laws require such disclosure, without prior written permission from Seattle 
Genetics, Inc. Any supplemental information that may be added to this document is proprietary to Seattle 
Genetics, Inc. and should be handled using the disclosure procedure described above. 
Protocol Number: 
SGN35-015 
Version: 
Amendment 13; 05-May-2020 
Protocol Title: 
A phase 2 open-label study of brentuximab vedotin in front-line 
therapy of Hodgkin lymphoma (HL) and CD30-expressing 
peripheral T-cell lymphoma (PTCL) in older patients or patients 
with significant comorbidities ineligible for standard 
chemotherapy 
Brief Title: 
A study of brentuximab vedotin with Hodgkin lymphoma (HL) 
and CD30-expressing peripheral T-cell lymphoma (PTCL) 
Investigational Drug: 
Brentuximab vedotin  
Indication: 
Hodgkin lymphoma and CD30-expressing peripheral T-cell 
lymphoma 
Phase: 
2 
IND Number: 
71634 
NCT Number 
NCT01716806 
EudraCT Number 
2019-003982-17 
Sponsor: 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
Medical Monitor: 
 
Seattle Genetics, Inc. 
Office: 
 
Cell:  
 
Email: 
 
SAE Email or Fax: 
See email or fax number specified on the SAE report form. 


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PROTOCOL SYNOPSIS 
Protocol Number 
SGN35-015 
Version 
Amendment 13; 05-May-2020 
Phase 
2 
Product Name 
Brentuximab vedotin 
Sponsor 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
Protocol Title 
A phase 2 open-label study of brentuximab vedotin in front-line therapy of Hodgkin lymphoma (HL) and 
CD30-expressing peripheral T-cell lymphoma (PTCL) in older patients or patients with significant 
comorbidities ineligible for standard chemotherapy. 
Study Objectives 
Objectives are applicable to all parts of the study unless otherwise specified. 
Primary 
To assess the objective response rates (ORR) of single-agent brentuximab vedotin and brentuximab vedotin in 
combination with other agents as frontline therapy in patients age ≥60 years and in patient’s ineligible for 
conventional combination chemotherapy due to comorbidities. 
Secondary 
● To evaluate safety and tolerability of single-agent brentuximab vedotin and the safety of brentuximab vedotin 
when given in combination with other agents 
● To assess duration of response 
● To assess complete remission (CR) rate 
● To assess progression-free survival (PFS) 
● To assess resolution of B symptoms 
● To assess pharmacokinetics and immunogenicity of brentuximab vedotin (all parts) and nivolumab (Part D 
only) 
● To assess overall survival (OS) (Parts E and F only) 
 
Additional 
● To assess event-free survival (EFS) 
● To assess OS (Parts A, B, C, and D) 
● To assess biomarkers in serum and tumor biopsies 
● To assess the relationship between pharmacokinetics and disease response 
● To assess immunomodulatory effects of the combination of brentuximab vedotin and nivolumab in peripheral 
blood (Part D only) 
● To assess indeterminate response (IR) rate and subsequent response (Part D only) 
Study Population 
To be eligible, patients in Parts A, B, C, D, and E must have classical HL, excluding nodular 
lymphocyte-predominant HL; patients in Part F must have CD30-expressing PTCL. Patients are to be 
treatment-naive.  
In Parts A, B, C, and D, patients must be ≥60 years of age, and ineligible for or have declined initial 
conventional combination chemotherapy.  
In Parts E and F, patients must be ≥18 years of age and considered unsuitable or unfit for conventional 
combination chemotherapy, due to the presence of comorbidity-related factors, as documented by either a) a 


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Cumulative Illness Rating Scale (CIRS) score ≥10 (according to the criteria specified by Salvi and colleagues 
(Salvi 2008) excluding current active lymphoma) or b) requiring assistance with or dependence on others for 
any Instrumental Activities of Daily Living (IADL). 
Patients must have disease that is fluorodeoxyglucose (FDG)-positron emission tomography (PET)-avid and 
bidimensionally measurable (≥1.5 cm in the longest axis); an Eastern Cooperative Oncology Group (ECOG) 
performance status ≤3 (≤2 Part D only); and adequate organ function. In Part C patients are to have an estimated 
creatinine clearance ≥40 mL/min, in Part D patients are to have an estimated creatinine clearance ≥30 mL/min, 
and in Parts E and F, patients are to have an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m².  
Patients are not eligible for enrollment if they have baseline peripheral neuropathy Grade ≥2 or the 
demyelinating form of Charcot-Marie-Tooth syndrome. Patients are also excluded if they have a history of 
progressive multifocal leukoencephalopathy (PML), kidney disease requiring ongoing dialysis, or any active 
Grade 3 or higher viral, bacterial, or fungal infection within 2 weeks prior to the first dose of brentuximab 
vedotin. Patients requiring concurrent use of other investigational agents are not eligible and patients may not 
receive chemotherapy, radiotherapy (RT), biologics, or immunotherapy that is not completed 4 weeks prior to 
study entry (not applicable to retreatment patients on Part D). 
Number of Planned Patients 
Up to 30 evaluable patients will be enrolled in Part A of the study (single-agent brentuximab vedotin), 
approximately 20 evaluable patients will be enrolled in Part B of the study (brentuximab vedotin+dacarbazine), 
and while initially approximately 30 patients were to be enrolled in Part C 
(brentuximab vedotin+bendamustine), enrollment into Part C of the study ceased as of 7 Oct 2015. 
Approximately 20 evaluable patients will be enrolled in Part D of the study (brentuximab vedotin+nivolumab), 
and approximately 50 evaluable patients each will be enrolled in Parts E and F of the study (single-agent 
brentuximab vedotin). 
Study Design 
This is a phase 2 open-label study designed to evaluate the efficacy and tolerability of brentuximab vedotin as 
monotherapy and in combination with other agents as frontline therapy in patients who are ineligible for or have 
declined initial conventional combination chemotherapy. There are 6 parts of the study.  
● In Part A, treatment with brentuximab vedotin 1.8 mg/kg will be given on Day 1 of each 21-day cycle. 
Patients achieving stable disease (SD) or better will receive up to 16 cycles of single-agent treatment with 
brentuximab vedotin.  
● In Part B, treatment with brentuximab vedotin 1.8 mg/kg in combination with dacarbazine 375 mg/m2 will be 
given on Day 1 of Cycles 1 through 12, followed by single-agent brentuximab vedotin 1.8 mg/kg on Day 1 of 
Cycles 13 through 16 or more.  
● In Part C, treatment with bendamustine 70 mg/m2 will be given in combination with brentuximab vedotin 
1.8 mg/kg on Day 1 and then as a single agent on Day 2 of each cycle for up to 6 cycles, followed by single-
agent brentuximab vedotin 1.8 mg/kg on Day 1 of the remaining cycles for up to 16 cycles.  
● In Part D, treatment with brentuximab vedotin 1.8 mg/kg and nivolumab 3 mg/kg will be given on Day 1 for 
up to 16 total cycles.  
● In Parts E and F, treatment with brentuximab vedotin 1.8 mg/kg will be given on Day 1 of each 21-day cycle. 
Patients achieving a CR, partial remission (PR), or SD will receive up to 16 cycles of single-agent treatment 
with brentuximab vedotin.    
After discussion with the medical monitor, any patient on Parts A, B, or C who complete 16 cycles of treatment 
and experience clinical benefit per the investigator will be eligible to receive continued brentuximab vedotin 
treatment until disease progression, unacceptable toxicity, or study closure. For Part D, patients who experience 
clinical benefit per the investigator will be eligible after discussion with the medical monitor to receive 
continued treatment with the combination of brentuximab vedotin and nivolumab, single-agent brentuximab 
vedotin treatment (if nivolumab discontinued for toxicity), or single-agent nivolumab (if brentuximab vedotin 
discontinued for toxicity) until disease progression, unacceptable toxicity, or study closure. Patients with a 
response of IR will continue on treatment until demonstration of progressive disease (PD) via radiographic 
imaging or biopsy. Retreatment with brentuximab vedotin plus nivolumab is permitted with medical monitor 
approval, for patients who achieve a CR or PR on study and then discontinue treatment. Patients eligible for 


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retreatment must meet all inclusion and exclusion criteria and experience disease progression after 
discontinuing treatment with brentuximab vedotin and nivolumab. The retreatment dose levels will be 
determined by the medical monitor and the site investigator for each patient with consideration of prior study 
treatment dose levels and dose modification criteria if the patient experienced prior treatment-related toxicities. 
Study Treatment in Each 21-day Cycle 
Part A 
Part B 
Part C 
Part D 
Part E 
Part F 
 
Brentuximab vedotin 1.8 mg/kg IV on Day 1 
Xa 
Xa 
X 
X 
X 
X 
 
Dacarbazine 375 mg/m2 IV on Day 1b 
 
X 
 
 
 
 
 
Bendamustine 70 mg/m2 on Day 1b and Day 2c 
 
 
X 
 
 
 
 
Nivolumab 3 mg/kg on Day 1d 
 
 
 
X 
 
 
a 
Patients enrolling on study with estimated creatinine clearance <30 mL/min will receive 1.2 mg/kg brentuximab 
vedotin every 3 weeks either as a single agent in Part A or in combination with a reduced dose of dacarbazine 
(262 mg/m2; ~30% reduced) in Part B. 
b 
Administered within approximately 1 hour of completing treatment with brentuximab vedotin administered via IV on 
Day 1 of each 21-day cycle. 
c 
Bendamustine is administered as a single agent on Day 2 of each 21-day cycle. 
d 
Administered at least 30 minutes after completing treatment with brentuximab vedotin. 
 
Test Product, Dose, and Mode of Administration 
Part A: Brentuximab vedotin, 1.8 mg/kg, will be administered via intravenous (IV) infusion every 3 weeks. 
Part B: Combination treatment with brentuximab vedotin, 1.8 mg/kg IV, and dacarbazine, 375 mg/m2 IV, 
every 3 weeks. 
Part C: Combination treatment with brentuximab vedotin, 1.8 mg/kg IV on Day 1, and bendamustine, 
70 mg/m2 IV on Days 1 and 2, every 3 weeks. 
Part D: Combination treatment with brentuximab vedotin, 1.8 mg/kg IV, and nivolumab, 3 mg/kg IV, every 
3 weeks. 
Part E: Brentuximab vedotin, 1.8 mg/kg IV, every 3 weeks. 
Part F: Brentuximab vedotin, 1.8 mg/kg IV, every 3 weeks. 
Patients enrolling on study with estimated creatinine clearance <30 mL/min will receive 1.2 mg/kg brentuximab 
vedotin every 3 weeks either as a single agent in Part A or in combination with a reduced dose of dacarbazine 
(262 mg/m2; ~30% reduced) in Part B. 
Duration of Treatment 
Patients who achieve at least SD will be eligible to receive single-agent brentuximab vedotin treatment (Parts A, 
E, and F) for up to 16 cycles, brentuximab vedotin and dacarbazine administered in combination for up to 
12 cycles (Part B), brentuximab vedotin and bendamustine administered in combination for up to 6 cycles 
(Part C), or brentuximab vedotin and nivolumab administered in combination for up to 16 cycles (Part D). For 
Parts A, B, and C, patients who complete 16 cycles of treatment and experience clinical benefit per the 
investigator will be eligible to receive continued single-agent brentuximab vedotin treatment until disease 
progression, unacceptable toxicity, or study closure. For Part D, patients who experience clinical benefit per the 
investigator will be eligible to receive continued treatment with the combination of brentuximab vedotin and 
nivolumab, single-agent brentuximab vedotin treatment (if nivolumab discontinued for toxicity), or single-agent 
nivolumab (if brentuximab vedotin discontinued for toxicity) until disease progression, unacceptable toxicity, or 
study closure. Patients with a response of IR will continue on treatment until demonstration of PD via 
radiographic imaging or biopsy. 


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Efficacy Assessments 
Parts A, B, C, and D 
For Parts A, B, and C, disease response and progression will be assessed using the Revised Response Criteria 
for Malignant Lymphoma (Cheson 2007). For Part D of the study, disease response will be assessed using the 
Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas (Lugano 
criteria) (Cheson 2014) and Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) (Cheson 
2016). PD also includes clinical disease progression per investigator.  
Imaging with computed tomography (CT) will be performed at baseline, at Cycles 2, 4, 8, 12, and at end of 
treatment (EOT) approximately 1 month after discontinuation of study treatment. For Parts A, B, and C, 
imaging with PET will be performed at baseline, at Cycles 2 and 8, and at EOT. For Part D, PET scans will be 
performed at baseline, at Cycles 4, 8, and 12, and at EOT. Once a patient achieves a PET CR, PET scan will no 
longer be required. Clinical lymphoma assessments will be performed predose in every treatment cycle. 
In patients eligible for continued treatment with brentuximab vedotin (and/or nivolumab for Part D only) 
beyond 16 cycles, CT (and PET for Part D only) will be performed at Cycle 16. Then for Cycles 17 and beyond, 
CT will be performed per institutional standard of care, or at least every 6 cycles, and PET scans will be 
performed per institutional standard of care.  
For Parts A, B, and C, visual interpretation will be used for evaluation of interim PET scan results with response 
scored with reference to sites of presumed lymphomatous involvement using the 5-Point Scale per the Deauville 
Criteria (Barrington 2010; Meignan 2009). 
For patients on Part D with a response determination of IR, radiographic assessment (CT/PET) of disease must 
be performed 12 weeks following IR or earlier if clinically indicated. If a patient has a second determination of 
IR, then subsequent repeat imaging must be performed between 4 and 8 weeks. Follow-up radiographic 
assessment for patients with IR is not required, if a follow-up biopsy has been performed that confirms 
response.  
After completion of therapy, disease status will be assessed by CT imaging per institutional standard of care or 
intervals of at least every 6 months for the first 2 years, an annual assessment for the third year, then per 
institutional standard of care until progression. 
Parts E and F 
Disease response will be assessed using modified Lugano criteria; the assessment will be per blinded 
independent central review. 
Imaging with CT and PET will be performed at baseline, at Cycles 2, 6, 11, and at EOT approximately 1 month 
after discontinuation of study treatment. Clinical lymphoma assessments will be performed predose in every 
treatment cycle. Once a patient achieves a PET CR, PET scans will no longer be required. Patients 
discontinuing study treatment without progression will be followed until progression or initiation of further 
anti-cancer therapy. Follow-up CT scans will be performed every 4 months for 2 years and then per institutional 
standard of care, and follow-up PET scans will be performed per institutional standard of care.  
Pharmacokinetic/Pharmacodynamic/Immunogenicity Assessments 
For Parts A, B, C, E, and F, serum concentrations of brentuximab vedotin antibody-drug conjugate (ADC) and 
plasma concentrations of monomethyl auristatin E (MMAE) will be measured. Samples will be retained for 
measurement of total antibody, if needed. Antitherapeutic antibodies (ATA) to brentuximab vedotin will also be 
measured. Pharmacodynamic assessments include but are not limited to the measurement of soluble CD30. For 
Part D, serum concentrations of brentuximab vedotin ADC and nivolumab, and plasma concentrations of 
MMAE will also be measured at selected time points. ATA against brentuximab vedotin, ATA against 
nivolumab, and immunomodulatory effects of treatment will also be assessed in Part D. 


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Safety Assessments 
Safety assessments will consist of the surveillance and recording of adverse events (AE) and measurements of 
physical examination findings, vital signs, and laboratory tests. 
A Safety Monitoring Committee (SMC) monitored patient safety in Part C of the trial. The SMC reviewed 
safety data after the first 5 patients in Part C completed 1 cycle of brentuximab vedotin and bendamustine and 
again after the first 5 patients completed 2 cycles of treatment with brentuximab vedotin and bendamustine. It 
was noted in the second safety call that 4 of 7 patients in Part C had experienced serious adverse events (SAEs). 
The starting dose of bendamustine was then reduced from 90 mg/m2 to 70 mg/m2 (Amendment 6). Additional 
key safety observations were reported at a subsequent SMC meeting; 12 of 20 patients enrolled on Part C had 
experienced SAEs and 2 of those patients died within the 30-day safety reporting period. Although no safety 
signal was identified, and neither of the deaths were considered related to study treatment, the sponsor has 
suspended enrollment of patients into Part C and has discontinued bendamustine treatment for all patients 
currently enrolled in Part C as of 7-Oct-2015 (the date of the Dear Investigator Letter). Single-agent 
brentuximab vedotin may be continued for patients who tolerate the therapy and have demonstrated clinical 
benefit. 
Safety review of patients treated with the combination of brentuximab vedotin and nivolumab was conducted by 
the study SMC after the first 5 patients in Part D completed treatment through Cycle 3 Day 1, and will continue 
throughout the study as needed. 
Statistical Methods 
Summaries of patient disposition, demographics, disease characteristics, safety, disease response, and exposure 
to study drug will be provided. All analyses of safety and efficacy endpoints will be descriptive in each study 
part. In addition, the pharmacokinetic parameters of brentuximab vedotin and MMAE, as well as nivolumab 
(Part D only), will be estimated and summarized with descriptive statistics. No formal statistical hypotheses 
have been formulated for primary efficacy, secondary or additional endpoints in any study part. However, the 
secondary and additional endpoints will be analyzed and provided as supporting evidence for the overall clinical 
benefit of brentuximab vedotin. 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ....................................................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................................................... 11 
1 
INTRODUCTION ......................................................................................................................................... 14 
1.1 
Hodgkin Lymphoma ........................................................................................................................... 14 
1.1.1 
Hodgkin Lymphoma in Patients Aged 60 Years and Above ................................................ 15 
1.1.2 
Hodgkin Lymphoma in Patients with Significant Comorbidities ......................................... 16 
1.2 
CD30-Expressing Peripheral T-Cell Lymphoma ................................................................................ 17 
1.3 
Experience With Brentuximab Vedotin .............................................................................................. 18 
1.4 
Experience With Brentuximab Vedotin Combined With Dacarbazine .............................................. 20 
1.5 
Experience With Brentuximab Vedotin Combined with Bendamustine ............................................ 20 
1.6 
Experience With Brentuximab Vedotin Combined with Nivolumab ................................................. 21 
1.7 
Rationale for the Current Study .......................................................................................................... 22 
2 
OBJECTIVES ............................................................................................................................................... 24 
2.1 
Primary Objective ............................................................................................................................... 24 
2.2 
Secondary Objectives ......................................................................................................................... 24 
2.3 
Additional Objectives ......................................................................................................................... 24 
2.4 
Endpoints ............................................................................................................................................ 25 
2.4.1 
Primary Endpoint ................................................................................................................. 25 
2.4.2 
Secondary Endpoints ............................................................................................................ 25 
2.4.3 
Additional Endpoints ............................................................................................................ 25 
3 
INVESTIGATIONAL PLAN ....................................................................................................................... 26 
3.1 
Summary of Study Design .................................................................................................................. 26 
3.2 
Safety Monitoring Committee ............................................................................................................ 30 
3.2.1 
Part C .................................................................................................................................... 30 
3.2.2 
Part D ................................................................................................................................... 30 
3.3 
Retreatment (Part D Only) .................................................................................................................. 31 
3.4 
End of Study ....................................................................................................................................... 31 
3.5 
Discussion and Rationale for Study Design........................................................................................ 31 
3.5.1 
Method of Assigning Patients to Treatment Groups ............................................................ 33 
3.5.2 
Rationale for Selection of Doses .......................................................................................... 33 
3.5.3 
Blinding ................................................................................................................................ 35 
4 
STUDY POPULATION................................................................................................................................ 36 
4.1 
Inclusion Criteria ................................................................................................................................ 36 
4.2 
Exclusion Criteria ............................................................................................................................... 37 
4.3 
Removal of Patients From Therapy or Assessment ............................................................................ 39 
4.3.1 
Discontinuation of Study Drug ............................................................................................. 39 
4.3.2 
Patient Withdrawal From Study ........................................................................................... 40 
5 
TREATMENTS ............................................................................................................................................ 40 
5.1 
Treatments Administered.................................................................................................................... 40 
5.2 
Investigational Study Drug ................................................................................................................. 40 
5.2.1 
Description ........................................................................................................................... 40 
5.2.2 
Dose and Administration ...................................................................................................... 40 
5.2.3 
Required Premedication and Postmedication ....................................................................... 41 
5.2.4 
Dose Modifications .............................................................................................................. 41 
5.2.5 
Storage and Handling ........................................................................................................... 42 
5.2.6 
Packaging and Labeling ....................................................................................................... 42 
5.2.7 
Preparation ........................................................................................................................... 43 
5.3 
Dacarbazine ........................................................................................................................................ 43 
5.3.1 
Description ........................................................................................................................... 43 
5.3.2 
Method of Procurement ........................................................................................................ 43 
5.3.3 
Dose and Administration ...................................................................................................... 43 


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5.3.4 
Required Premedication and Postmedication ....................................................................... 44 
5.3.5 
Dose Modifications .............................................................................................................. 44 
5.3.6 
Storage and Handling ........................................................................................................... 44 
5.3.7 
Packaging and Labeling ....................................................................................................... 44 
5.3.8 
Preparation ........................................................................................................................... 44 
5.4 
Bendamustine (Not Applicable as of 07-Oct-2015) ........................................................................... 44 
5.4.1 
Description ........................................................................................................................... 44 
5.4.2 
Method of Procurement ........................................................................................................ 44 
5.4.3 
Dose and Administration ...................................................................................................... 45 
5.4.4 
Required Premedication and Postmedication ....................................................................... 45 
5.4.5 
Dose Modifications .............................................................................................................. 45 
5.4.6 
Storage and Handling ........................................................................................................... 46 
5.4.7 
Packaging and Labeling ....................................................................................................... 46 
5.4.8 
Preparation ........................................................................................................................... 46 
5.5 
Nivolumab .......................................................................................................................................... 46 
5.5.1 
Description ........................................................................................................................... 46 
5.5.2 
Method of Procurement ........................................................................................................ 46 
5.5.3 
Dose and Administration ...................................................................................................... 46 
5.5.4 
Required Premedication and Postmedication ....................................................................... 47 
5.5.5 
Dose Modifications .............................................................................................................. 47 
5.5.6 
Storage and Handling ........................................................................................................... 50 
5.5.7 
Packaging and Labeling ....................................................................................................... 50 
5.5.8 
Preparation ........................................................................................................................... 50 
5.6 
Concomitant Therapy ......................................................................................................................... 50 
5.6.1 
Required Concomitant Therapy ........................................................................................... 50 
5.6.2 
Allowed Concomitant Therapy ............................................................................................ 50 
5.6.3 
Prohibited Concomitant Therapy ......................................................................................... 52 
5.7 
Management of Adverse Reactions .................................................................................................... 52 
5.7.1 
Management of Infusion Reactions ...................................................................................... 52 
5.7.2 
Management of Suspected PML .......................................................................................... 53 
5.7.3 
Management of Overdose .................................................................................................... 53 
5.8 
Treatment Compliance ....................................................................................................................... 53 
6 
STUDY ACTIVITIES ................................................................................................................................... 54 
6.1 
Schedule of Events ............................................................................................................................. 54 
6.2 
Screening Visit (Days –28 to Day 1) .................................................................................................. 54 
6.2.1 
Baseline Visit (Days –7 to Day 1) ........................................................................................ 55 
6.3 
Treatment Period (Day 1 to Day 21) .................................................................................................. 55 
6.3.1 
Each 21-Day Cycle (Day 1 ±2 days) .................................................................................... 55 
6.3.2 
Cycles 1 to 6 (Day 2 [+1 day]): Part C Only (Not Applicable as of 7-Oct-2015) ................ 56 
6.3.3 
Cycle 1 (Day 8 [±1 day]): Part D Only ................................................................................ 56 
6.3.4 
Cycle 1 (Day 15 [±1 day]): Part D Only .............................................................................. 57 
6.3.5 
Cycle 1 (Days 1, 2, 3, 8, and 15): Parts A, B, and C Only ................................................... 57 
6.3.6 
Cycle 2 (Day 8 [+1 day]): Part D Only ................................................................................ 57 
6.3.7 
Cycles 2, 4, 8, 12, and 16 (Days 15 to 21 [+2 days]): Parts A, B, C, and D only ................. 57 
6.3.8 
Cycles 2, 6, and 11 (Days 15 to 21 [+2 days]): Parts E and F Only ..................................... 57 
6.4 
Cycles 17 and Beyond (Days 15 to 21 [+2 days]): Parts A, B, C, and D Only ................................... 58 
6.5 
At Time of Progression or Relapse (All Parts), or If Residual Disease at Cycle 8 or Suspected Tumor 
Flare/Pseudoprogression (Part D Only) .............................................................................................. 58 
6.6 
End of Treatment Visit (30 to 37 Days After Last Dose of Study Drug) ........................................... 58 
6.7 
Safety Visit (100 days [+2 weeks] After Last Dose of Nivolumab): Part D Only .............................. 59 
6.8 
Follow-up ........................................................................................................................................... 59 
6.9 
End of Study/End of Follow-Up ......................................................................................................... 60 
7 
STUDY ASSESSMENTS ............................................................................................................................. 61 
7.1 
Screening/Baseline Assessments ........................................................................................................ 61 
7.2 
Response Assessments ....................................................................................................................... 62 


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7.2.1 
Parts A, B, and C .................................................................................................................. 62 
7.2.2 
Part D ................................................................................................................................... 63 
7.2.3 
Parts E and F ........................................................................................................................ 64 
7.3 
Lymphoma Assessments .................................................................................................................... 66 
7.4 
Pharmacokinetic and Pharmacodynamic Assessments ....................................................................... 67 
7.5 
Biomarker Studies: Part D Only ......................................................................................................... 71 
7.6 
Other Study Assessments ................................................................................................................... 73 
7.7 
Safety Assessments............................................................................................................................. 74 
7.7.1 
Adverse Events ..................................................................................................................... 74 
7.7.2 
Clinical Laboratory Tests ..................................................................................................... 80 
7.7.3 
Physical Examination ........................................................................................................... 81 
7.8 
Appropriateness of Measurements...................................................................................................... 81 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 82 
8.1 
Site Training and Monitoring Procedures ........................................................................................... 82 
8.2 
Data Management Procedures ............................................................................................................ 83 
8.3 
Access to Source Data ........................................................................................................................ 83 
8.4 
Accuracy and Reliability of Data........................................................................................................ 83 
8.5 
Quality Assurance Procedures ............................................................................................................ 83 
8.6 
Data Handling and Record Keeping ................................................................................................... 84 
8.6.1 
Data Handling ...................................................................................................................... 84 
8.6.2 
Investigator Record Retention .............................................................................................. 84 
9 
DATA ANALYSIS METHODS ................................................................................................................... 85 
9.1 
Determination of Sample Size ............................................................................................................ 85 
9.2 
Study Endpoint Definitions ................................................................................................................ 86 
9.2.1 
Objective Response Rate ...................................................................................................... 86 
9.2.2 
Complete Remission Rate .................................................................................................... 86 
9.2.3 
Disease Control Rate ............................................................................................................ 86 
9.2.4 
Duration of Response ........................................................................................................... 86 
9.2.5 
Duration of Complete Remission ......................................................................................... 86 
9.2.6 
Progression-Free Survival .................................................................................................... 87 
9.2.7 
Indeterminate Response Rate ............................................................................................... 87 
9.2.8 
B Symptom Resolution Rate ................................................................................................ 87 
9.2.9 
Incidence of ATA ................................................................................................................. 87 
9.2.10 
Event-free Survival .............................................................................................................. 87 
9.2.11 
Overall Survival ................................................................................................................... 87 
9.3 
Statistical and Analytical Plans .......................................................................................................... 88 
9.3.1 
General Considerations ........................................................................................................ 88 
9.3.2 
Patient Disposition ............................................................................................................... 90 
9.3.3 
Patient Characteristics .......................................................................................................... 90 
9.3.4 
Treatment Compliance ......................................................................................................... 90 
9.3.5 
Efficacy Analyses ................................................................................................................. 90 
9.3.6 
Pharmacokinetic and Pharmacodynamic Analyses .............................................................. 91 
9.3.7 
Biomarker Analyses ............................................................................................................. 91 
9.3.8 
Health Outcomes Analyses .................................................................................................. 91 
9.3.9 
Safety Analyses .................................................................................................................... 92 
9.3.10 
Interim Analyses .................................................................................................................. 93 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ................. 93 
10.1 Informed Consent ............................................................................................................................... 93 
10.2 Ethical Review .................................................................................................................................... 93 
10.3 Regulatory Considerations.................................................................................................................. 94 
10.3.1 
Investigator Information ....................................................................................................... 94 
10.3.2 
Protocol Amendments and Study Termination .................................................................... 94 
10.4 Study Documentation, Privacy and Records Retention ...................................................................... 94 
10.5 Clinical Trial Agreement .................................................................................................................... 95 


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11 REFERENCES .............................................................................................................................................. 96 
APPENDIX A: 
STUDY SCHEDULE (PARTS A, B, AND C) .................................................................. 103 
APPENDIX B: 
STUDY SCHEDULE (PART D) ....................................................................................... 104 
APPENDIX C: 
STUDY SCHEDULE (PARTS E AND F) ......................................................................... 106 
APPENDIX D: 
NEW YORK HEART ASSOCIATION CLASSIFICATION ............................................ 107 
APPENDIX E: 
GUIDANCE ON CONTRACEPTION .............................................................................. 108 
APPENDIX F: 
PERFORMANCE STATUS SCALES ............................................................................... 109 
APPENDIX G: 
THE CUMULATIVE ILLNESS RATING SCALE .......................................................... 110 
APPENDIX H: 
THE LAWTON INSTRUMENTAL ACTIVITIES OF DAILY LIVING SCALE ........... 123 
APPENDIX I: 
THE 5-POINT VISUAL ASSESSMENT SCALE (DEAUVILLE CRITERIA) ............... 125 
APPENDIX J: 
OVERVIEW OF LYRIC CRITERIA (PART D ONLY) ................................................... 126 
APPENDIX K: 
RESPONSE EVALUATION CRITERIA IN LYMPHOMA ............................................ 128 
APPENDIX L: 
HISTOLOGIC SUBTYPES OF PTCL .............................................................................. 129 
APPENDIX M: 
INTEGRATED PET AND CT RESPONSE ACCORDING TO MODIFIED LUGANO 
CRITERIA PER BICR ................................................................................................................................ 130 
APPENDIX N: 
INVESTIGATOR SIGNATURE PAGE ............................................................................ 131 
APPENDIX O: 
DOCUMENT HISTORY ................................................................................................... 132 
 
 
LIST OF IN-TEXT TABLES 
Table 1: 
Recommended dose modifications for brentuximab vedotin-associated toxicity .......................... 42 
Table 2 
Integrated PET and CT response according to Lugano criteria ..................................................... 66 
Table 3: 
Pharmacokinetic, pharmacodynamic, and immunogenicity sampling time points (Parts A, B, and 
C) ................................................................................................................................................... 68 
Table 4: 
Pharmacokinetic and immunogenicity sampling time points (Part D only) .................................. 69 
Table 5: 
Pharmacokinetic and immunogenicity sampling time points (Parts E and F) ............................... 70 
Table 6: 
Peripheral blood sampling time points for biomarker analyses (Part D only) ............................... 72 
 
 
LIST OF IN-TEXT FIGURES 
Figure 1: Study design .......................................................................................................................................... 29 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
5HT3 
serotonin receptor 
A+ABVD 
brentuximab vedotin combined with ABVD 
A+AVD 
brentuximab vedotin combined with AVD 
A+CHP 
brentuximab vedotin combined with CHP 
ABVD 
doxorubicin, bleomycin, vinblastine, and dacarbazine 
ACE-27 
Adult Comorbidity Evaluation-27 
ADC 
antibody-drug conjugate 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
ASCT 
autologous stem cell transplant 
AST 
aspartate aminotransferase 
ATA 
antitherapeutic antibodies 
AUC 
area under the concentration-time curve 
auto-HSCT 
autologous hematopoietic stem cell transplantation 
AVD 
doxorubicin, vinblastine, and dacarbazine 
β-hCG 
beta human chorionic gonadotropin 
BACOPP 
BEACOPP with etoposide omitted and anthracycline dose increased 
BEACOPP 
bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, 
prednisone 
BICR 
blinded independent central review 
BMI 
body mass index 
BPH 
benign prostate hypertrophy 
Ceoi 
concentration at the end of infusion 
Cmax 
maximum concentration 
Ctrough 
trough concentration 
CBC 
complete blood count 
CCI 
Charlson Comorbidity Index 
CFR 
Code of Federal Regulations 
ChlVPP 
chlorambucil, vinblastine, procarbazine, and prednisone 
ChlVPP/ABV 
ChlVPP plus doxorubicin, bleomycin, and vincristine 
CHOEP 
cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone 
CHOP 
cyclophosphamide, doxorubicin, vincristine, and prednisone 
CHP 
cyclophosphamide, doxorubicin, and prednisone 
CI 
confidence interval 
CIRS 
Cumulative Illness Rating Scale 
CIRS-G 
Cumulative Illness Rating Scale-Geriatric 
CLL 
chronic lymphocytic leukemia 
CMV 
cytomegalovirus 
COPD 
chronic obstructive pulmonary disease 
CR 
complete remission 


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CRF 
case report form 
CT 
computed tomography 
DILI 
drug-induced liver injury 
DLCO 
diffusing capacity of the lung for carbon monoxide 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
DVT 
deep venous thrombosis 
EBV 
Epstein-Barr Virus 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event-free survival 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EOT 
end of treatment 
FDG 
fluorodeoxyglucose 
G-CSF 
granulocyte-colony stimulating factor 
GERD 
gastroesophageal reflux disease 
GHSG 
German Hodgkin Study Group 
GI 
gastrointestinal 
HL 
Hodgkin lymphoma 
HRS 
Hodgkin Reed-Sternberg 
HSR 
hypersensitivity reaction 
IADL 
instrumental activity of daily living 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IR 
indeterminate response 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
Lugano criteria 
Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin 
lymphomas 
LYRIC 
Lymphoma Response to Immunomodulatory Therapy Criteria 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDRD 
Modification of Diet in Renal Disease 
MMAE 
monomethyl auristatin E 
MMSE 
Mini Mental Sate Examination 
MRI 
magnetic resonance imaging 
MUGA 
multigated acquisition 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHL 
non-Hodgkin lymphoma 
NK 
natural killer 


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NSAID 
nonsteroidal anti-inflammatory drugs 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PAD 
peripheral arteries disease 
PBMC 
peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1, PD-L2 
ligands to PD-1 
PET 
positron emission tomography 
PK 
pharmacokinetic 
PFS 
progression-free survival 
PML 
progressive multifocal leukoencephalopathy 
PR 
partial response 
PRN 
pro re nata (as needed) 
PTCL 
peripheral T-cell lymphoma 
PTCL-NOS 
peripheral T-cell lymphoma–not otherwise specified 
PVAG 
prednisone, vinblastine, doxorubicin, and gemcitabine 
RECIL 
Response Evaluation Criteria in Lymphoma 
RNA 
ribonucleic acid 
RT 
radiotherapy 
SAE 
serious adverse event 
sALCL 
systemic anaplastic large cell lymphoma 
SAP 
statistical analysis plan 
sCD30 
soluble CD30 
Scr 
serum creatinine 
SD 
stable disease 
SMC 
Safety Monitoring Committee 
SPD 
sum of the products of the largest diameter 
SUSAR 
suspected unexpected serious adverse reaction 
TCR 
T-cell receptor 
TIA 
transient ischemic attack 
Tmax 
time at which the Cmax occurs 
TSH 
thyroid-stimulating hormone 
TURP 
transurethral resection of the prostate 
ULN 
upper limit of normal 
USAN 
United States adopted name 
UTI 
urinary tract infection 
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. Other nonclinical 
studies suggest additional contributory mechanisms of action, including antibody-dependent 
cellular phagocytosis; bystander effects on nearby cells in the tumor microenvironment due 
to released MMAE; and immunogenic cell death due to endoplasmic reticulum stress which 
drives exposure of immune activating molecules that can promote a T-cell response (Cao 
2016; Gardai 2015; Kim 2015; Li 2014; Muller 2014; Oflazoglu 2007). 
Frontline treatment options are needed for patients who cannot tolerate multi-agent 
chemotherapy regimens. This study will provide data regarding the safety and efficacy of 
brentuximab vedotin used as a single agent in the frontline treatment of patients with newly 
diagnosed classical Hodgkin lymphoma (HL; i.e., excluding nodular lymphocyte 
predominant HL) or CD30-expressing peripheral T-cell lymphoma (PTCL) who cannot 
tolerate or have declined multi-agent chemotherapy. In addition, the efficacy and tolerability 
of brentuximab vedotin combined with dacarbazine, bendamustine, or nivolumab will be 
evaluated in the frontline treatment of classical HL. 
1.1 Hodgkin Lymphoma  
HL is a neoplasm of lymphoid tissue that is histopathologically defined by the presence of 
malignant Hodgkin Reed-Sternberg (HRS) cells in a background of inflammatory cells. The 
characteristic surface antigen expressed on HRS cells is CD30. It is estimated that 
8110 patients will be diagnosed with HL in the US in 2019 and 1000 patients will die of the 
disease (Siegel 2019).  
For most patients, treatment of HL has improved over the past 30 years with combination 
chemotherapy regimens. The current anthracycline-containing regimen of doxorubicin, 
bleomycin, vinblastine, and dacarbazine (ABVD), given with or without consolidative 
radiotherapy (RT), has proved superior to alkylator-based regimens and results in long-term 
cure rates on the order of 70% and higher. However, unlike the majority of younger patients 
with HL who have impressive cure rates with standard frontline therapy, patients 60 and over 
and patients with significant comorbidities experience more severe toxicity and higher rates 
of relapse with this combination regimen. 


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1.1.1 Hodgkin Lymphoma in Patients Aged 60 Years and Above 
Of newly diagnosed HL patients, population-based studies estimate that up to 20% are age 
60 years and above (Stark 2002). Older patients (≥60 years of age) with HL have 
disproportionately inferior outcomes as compared to younger patients with HL (Klimm 
2007). Studies cite 5-year event-free survival (EFS) and freedom from treatment failure rates 
of 30% to 45% in older patients, as compared to rates of 75% to 80% expected in younger 
patients (Evens 2008; Proctor 2009). 
The disease differs in histopathologic presentation, more frequently exhibiting an aggressive 
mixed-cellularity subtype and Epstein-Barr Virus (EBV) positivity. Clinically, older HL 
patients are more likely to present with B symptoms, poorer performance status, elevated 
sedimentation rate, and advanced-stage disease, with a lower incidence of bulky disease. In 
addition to differences in biology and disease-related features, poorer overall outcomes in 
older patients with HL can also be attributed to treatment-related factors which compromise 
cure rates.  
There is a paucity of data concerning outcomes of older patients treated for early stage HL, 
likely due to the preponderance of this patient population presenting with advanced stage 
disease. In 1w review of 67 early stage older HL patients treated with RT alone, 82% 
achieved a complete remission (CR) but 43% went on to relapse, and 11 of the 67 patients 
developed secondary malignancies (Landgren 2006). 
The majority of older patients with HL present with advanced stage disease, for which 
systemic combination chemotherapy is typically administered. Several studies have been 
conducted to examine a variety of chemotherapy regimens in this population. In a recent 
retrospective review of outcomes in older patients with HL, the most common treatment 
given was ABVD-based therapy (Evens 2012). While the CR rate was reasonable at 73%, the 
5-year overall survival (OS) rate for older patients with advanced HL was 46%. In the 
recently reported ECHELON-1 study that compared ABVD to brentuximab vedotin + 
doxorubicin, vinblastine, and dacarbazine (A+AVD) for the frontline treatment of patients 
with advanced classical HL, the brentuximab vedotin + cyclophosphamide, doxorubicin, and 
prednisone (A+CHP) arm showed a significant improvement in modified progression-free 
survival (PFS) (HR=0.77 [0.603, 0.982], p-value=0.035). The A+AVD regimen was 
associated with more myelotoxicity and neurotoxicity, which was managed with growth 
factor support and dose modifications, than ABVD, but less pulmonary toxicity (Connors 
2018). 
Other regimens such as escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, 
vincristine, procarbazine, and prednisone (BEACOPP) have been utilized for younger fit 
patients in some regions including Germany. Variants including standard BEACOPP and 
BACOPP (with etoposide omitted and anthracycline dose increased) have been studied in 
older HL patients and have shown to be too toxic to be recommended in this setting (Ballova 
2005; Halbsguth 2010). 


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Several studies have evaluated the role of anthracycline-based regimens in older patients with 
HL. In a study comparing chlorambucil, vinblastine, procarbazine, and prednisone (ChlVPP) 
with the hybrid ChlVPP/ABV (ChlVPP plus doxorubicin, bleomycin, and vincristine), a 
subset of 56 patients age ≥60 treated with ChlVPP had a poorer outcome than those treated 
with ChlVPP/ABV in terms of 5-year OS (30% versus 67%; p=0.0086) and EFS (24% versus 
52%; p=0.011) (Weekes 2002). A recent small Scandinavian study evaluated the CHOP-21 
regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) ± RT in a 29 patient 
cohort of older patients with early and advanced stage HL, revealing a 3-year OS and PFS of 
79% and 76%, respectively (Kolstad 2007). Other recent non-bleomycin containing strategies 
have included prednisone, vinblastine, doxorubicin, and gemcitabine (PVAG), with 
published OS and PFS rates of 66% and 58% when studied in early unfavorable and 
advanced stage HL patients between 60–75 years of age (Boll 2011). The need to reduce 
drug intensity of PVAG remained a challenge, with relative dose intensity of ≥80% delivered 
in only 45 of the 57 evaluable patients mainly due to frequent omissions of whole cycles of 
therapy. Additionally, although there is little information regarding frontline treatment with 
bendamustine in HL, results from a phase 2 study in the relapsed or refractory setting 
demonstrated that patients treated with bendamustine had an objective response rate (ORR) 
of 53% (CR, 33%; partial response [PR], 19%) (Moskowitz 2013a). Thus far, no agreed upon 
standard treatment approach exists for patients age ≥60 with HL. 
Furthermore, higher rates of treatment-related toxicities have also been reported in older 
patients with HL. In a comprehensive retrospective analysis of older patients with HL by the 
German Hodgkin Study Group (GHSG), severe toxicities (World Health Organization 
[WHO] Grade 4) occurred more often in patients age 60 and older (42% versus 27%; 
P<0.001) including infectious complications and fatal acute treatment-related events (Engert 
2005). Similarly, in a retrospective multicenter analysis of 95 HL patients age ≥60 in the 
Chicago area who most commonly received ABVD for frontline therapy, the incidence of 
bleomycin-associated pulmonary toxicity was 32%, with an associated mortality rate of 25% 
in those affected (Evens 2012). 
Older patients with HL remains a population of unmet need with underrepresentation of 
patients aged ≥60 in HL clinical trials and inferior outcomes as compared to younger 
patients. 
1.1.2 Hodgkin Lymphoma in Patients with Significant Comorbidities 
The presence of significant comorbidities has a major effect on the treatments received, 
treatment toxicity, dose intensity, and prognosis in the HL population, even though the 
impact of comorbidities has not been studied as extensively as the impact of age. 
Significant comorbidities have been reported to be present in 13% of patients with newly 
diagnosed HL aged less than 60 years and 56% of patients aged at least 60 (van Spronsen 
1999). A review of 45,777 patients with HL in the US National Cancer Database found that a 
Charlson Comorbidity Index (CCI) score ≥1 resulted in a significantly lower OS, 
independently of age, disease stage, or use of RT (Parikh 2015). A review of 


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20,600 early-stage HL patients in the US National Cancer Database found that the presence 
of at least 1 CCI comorbidity was significantly associated with treatment choice 
(chemotherapy alone versus combined modality therapy; odds ratio 0.75 [95% confidence 
interval {CI}: 0.67, 0.85], p<0.001) (Olszewski 2015); lymphoma-specific survival was 
significantly lower in patients with morbidities (HR 3.05 [95% CI 2.14, 4.35], p<0.001 for 
CCI ≥2). Retrospective reviews of the effect of age above or below 60 years in patients with 
relapsed or refractory HL or non-Hodgkin lymphomas (NHL) found CCI to be significantly 
and independently associated with treatment toxicity, treatment-related mortality, PFS, and 
OS, while age was not (Martinez 2017) (Wildes 2008). The effect of comorbidities, measured 
using the Cumulative Illness Rating Scale-Geriatric (CIRS-G), on prognosis has also been 
confirmed within the population of older patients (>60 years) with frontline HL (Evens 
2012). In the prospective Study of Hodgkin in the Elderly/Lymphoma Database (SHIELD) 
program, no CR were observed in patients determined to be “frail” according to a modified 
Adult Comorbidity Evaluation-27 (ACE-27) scale, and comorbidity score was significantly 
associated with CR rate and OS (Proctor 2012). National Comprehensive Cancer Network 
(NCCN) Clinical Practice Guidelines recognize that individualized treatment may be 
necessary for patients with comorbidities. There is a need to develop treatments that can be 
used safely and efficaciously in patients with HL who have significant comorbidities, 
irrespective of age. 
1.2 CD30-Expressing Peripheral T-Cell Lymphoma 
T-cell lymphomas are a subset of aggressive NHL that comprise approximately 10% to 15% 
of all newly diagnosed cases of NHL in the US. According to the 2008 WHO Classification 
schema, there are 18 subtypes of mature T- and natural killer (NK)-cell neoplasms 
(Swerdlow 2008). Various subtypes of T- and NK-cell lymphomas are known to express the 
cell surface marker CD30; most notably, systemic anaplastic large cell lymphoma (sALCL), 
in which CD30 expression is a hallmark of the diagnosis (Savage 2008). The median age of 
patients with the most common PTCL subtypes is approximately 60 years, with anaplastic 
lymphoma kinase (ALK)-positive PTCL being the exception, having a median age of 
34 years (Armitage 2015; Vose 2008). 
CD30-expressing PTCL, including ALK-positive and ALK-negative sALCL, peripheral 
T-cell lymphoma–not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell 
lymphoma (AITL) and others, are aggressive lymphoid neoplasms that often present with 
advanced stage, symptomatic disease. These difficult-to-treat lymphomas are often grouped 
together for enrollment in clinical trials based on their universally dismal outcomes. 
Five-year OS in the over 1,300-patient International Peripheral T-Cell and Natural 
Killer/T-Cell Lymphoma Study was poor and ranged from 12% to 49% depending on 
histologic subtype (Vose 2008). Five-year failure-free survival, defined as time from initial 
diagnosis to progression, relapse after response, or death resulting from any cause, ranged 
from 6% to 36%. Other studies have reported CR rates to cyclophosphamide, doxorubicin, 
vincristine, and prednisone (CHOP) therapy between 40% and 50% (Mercadal 2008; Simon 
2010).  


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Although no randomized studies have been conducted to establish the use of CHOP in 
patients with CD30-expressing PTCL, it is the most commonly used regimen in the frontline 
treatment of these patients. The International Peripheral T-Cell and Natural Killer/T-Cell 
Lymphoma Study results indicate that over 85% of patients were treated with an 
anthracycline-based multi-agent chemotherapy regimen (Vose 2008). In published studies 
that have compared new treatment approaches to an established standard of care, CHOP 
administered every 3 weeks (CHOP-21) has been used as the control arm (Simon 2010). A 
post-hoc analysis of pooled data from PTCL patients treated on multiple phase 2 and 3 
studies suggested that the addition of etoposide to CHOP (CHOEP) resulted in improved 
3-year EFS (time to standard PFS or unplanned therapy) but only in patients ≤60 years old 
with a normal lactate dehydrogenase (LDH) (Schmitz 2010). CHOEP proved too toxic for 
patients older than 60 (Lunning 2013; Schmitz 2010). In the recently reported ECHELON-2 
study that compared CHOP to brentuximab vedotin + CHP for the frontline treatment of 
CD30-expressing PTCL, the brentuximab vedotin + CHP arm showed a significant 
improvement in both PFS (hazard ratio 0.71 [95% CI: 0.54, 0.93], p=0.0110) and OS (hazard 
ratio 0.66 [95% CI: 0.46, 0.95], p=0.0244). The safety profile of both treatment arms was 
comparable (Horwitz 2018). 
Even so, in NCCN guidelines, participation in clinical trials is still the suggested frontline 
treatment for patients with PTCL, other than sALCL and ALK-positive subtypes, for which 
multi-agent chemotherapy with or without RT is recommended. The presence of 
comorbidities can lead to the inability to administer multi-agent chemotherapy, higher rates 
of toxicity, and consequent decreases in dose intensity. In a recent retrospective study of 
patients >60 years of age newly diagnosed with PTCL between 2008-2014, a multivariate 
analysis demonstrated that a CCI ≥2 and high International Prognostic Index score (3-5) were 
independent risk factors for worse OS and PFS (Zhao 2016). Similarly, multivariate analysis 
of registry data from Sweden shows that a CCI ≥2 is independently associated with worse OS 
and PFS outcomes (Ellin 2018). 
Frontline treatment regimens for patients with PTCL ineligible for combination 
chemotherapy due to comorbidities have not been defined, necessitating the evaluation of 
alternative strategies.  
1.3 Experience With Brentuximab Vedotin 
A phase 2 pivotal trial of single-agent brentuximab vedotin (1.8 mg/kg, every 3 weeks) 
evaluated 102 patients whose HL had relapsed or was refractory to multiple-agent, high-dose 
chemotherapy and autologous stem cell transplant. A 75% ORR and a 34% CR rate were 
observed and common adverse events (AEs) were primarily mild to moderate in severity and 
generally constitutional in nature with the exception of peripheral sensory neuropathy 
(Younes 2012). 
The safety and efficacy of brentuximab vedotin has been evaluated in more than 
2,700 patients in company-sponsored clinical trials, and approved by multiple regulatory 
agencies. 


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FDA indications: 
● 
Classical HL after failure of autologous hematopoietic stem cell transplantation 
(auto-HSCT) or after failure of at least 2 prior multi-agent chemotherapy regimens in 
patients who are not auto-HSCT candidates.  
● 
Systemic ALCL after failure of at least 1 prior multi-agent chemotherapy regimen. 
● 
Classical HL at high risk of relapse or progression as post auto-HSCT consolidation.  
● 
Previously untreated Stage III or IV classical HL, in combination with doxorubicin, 
vinblastine, and dacarbazine.  
● 
Previously untreated sALCL or other CD30-expressing PTCLs, including 
angioimmunoblastic T-cell lymphoma and PTCL-NOS, in combination with 
cyclophosphamide, doxorubicin, and prednisone.  
● 
Primary cutaneous anaplastic large cell lymphoma or CD30-expressing mycosis 
fungoides who have received prior systemic therapy.  
 
EMA indications: 
● 
Previously untreated CD30+ Stage IV HL in combination with doxorubicin, 
vinblastine and dacarbazine (AVD) 
● 
Treatment of adult patients with CD30+ HL at increased risk of relapse or 
progression following autologous stem cell transplant (ASCT)  
● 
Treatment of adult patients with relapsed or refractory CD30+ HL: 
1. Following ASCT, or 
2. Following at least two prior therapies when ASCT or multi-agent chemotherapy is 
not a treatment option 
● 
Treatment of adult patients with relapsed or refractory sALCL 
● 
Treatment of adult patients with CD30+ cutaneous T-cell lymphoma (CTCL) after at 
least 1 prior systemic therapy 
 
The pivotal clinical trials leading to these approvals included a phase 2 study of brentuximab 
vedotin monotherapy in relapsed or refractory HL after autologous stem cell transplant 
(SG035-0003), a phase 2 study of brentuximab vedotin monotherapy in relapsed or refractory 
sALCL (SG035-0004), a phase 3 study of brentuximab vedotin plus best supportive care 
versus placebo plus best supportive care in the treatment of patients at high risk of residual 
HL following autologous stem cell transplant (SGN35-005), a phase 3 study of A+AVD 
versus ABVD as frontline therapy for newly diagnosed Stage III or IV classical HL patients 
(C25003), a phase 3 study of A+CHP versus CHOP as frontline therapy for newly diagnosed 
CD30-expressing PTCL (SGN35-014), and a phase 3 study of brentuximab vedotin versus 
methotrexate or bexarotene in CD30-expressing cutaneous T-cell lymphoma (C25001). 
A complete summary of the clinical and nonclinical data relevant to the investigational 
product and its study in human patients is provided in the Investigator’s Brochure. 


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1.4 Experience With Brentuximab Vedotin Combined With Dacarbazine 
The combination chemotherapy regimen ABVD (doxorubicin 25 mg/m2, bleomycin 
10 units/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) is a standard regimen for the 
frontline treatment of HL. Because of the efficacy observed with single-agent brentuximab 
vedotin in patients with relapsed or refractory HL, a phase 1 study was conducted in 
51 patients with newly diagnosed HL to evaluate the safety of brentuximab vedotin 
combined with this standard regimen (A+ABVD) or with a modified standard that omitted 
bleomycin (A+AVD). In this study, it was found that concomitant administration of 
brentuximab vedotin with bleomycin was contraindicated due to an unacceptable rate of 
pulmonary toxicity; however, brentuximab vedotin 1.2 mg/kg combined with AVD 
administered every 2 weeks was generally well tolerated by patients and resulted in a CR rate 
of 96% at the end of frontline therapy (Younes 2013). 
Brentuximab vedotin was also tested preclinically in combination with chemotherapy. In the 
L450cy HL tumor model, administration of brentuximab vedotin plus ABVD in 
tumor-bearing mice demonstrated a marked increase in antitumor activity as compared to the 
mice treated with brentuximab vedotin or ABVD alone, suggesting a potential synergistic 
effect. When individual components of ABVD were tested with brentuximab vedotin in the 
tumor model, brentuximab vedotin plus dacarbazine (A+D) was observed to have similarly 
robust combined durable activity as compared to A+ABVD (McEarchern 2010). 
1.5 Experience With Brentuximab Vedotin Combined with Bendamustine 
Bendamustine is a bifunctional mechlorethamine derivative containing a purine-like 
benzimidazole ring, approved in the US for chronic lymphocytic leukemia (CLL) and NHL; 
bendamustine is administered as an intravenous (IV) infusion on Days 1 and 2 for up to six 
28-day cycles in CLL and for up to eight 21-day cycles in NHL. Though the exact 
mechanisms of action of bendamustine are unknown, mechlorethamine derivatives form 
electrophilic alkyl groups, which then form covalent bonds with electron-rich nucleophilic 
moieties and result in interstrand DNA crosslinks that lead to cell death via several pathways. 
The combination chemotherapy regimen brentuximab vedotin and bendamustine is currently 
being studied in a phase 1/2 trial of patients with relapsed or refractory HL (SGN35-016). 
Preliminary results showed that after a median of 2 cycles of combination treatment, the 
ORR was 92% (12/13 patients) and the CR rate was 77% (10/13 patients); 12 of 13 patients 
with a response assessment at the time of interim analysis remained on treatment and all 
13 patients remained free of progressive disease (PD) (LaCasce 2014). Additionally, the 
combination of brentuximab vedotin and bendamustine did not appear to interfere with stem 
cell collection for autologous transplant. AEs seen in ≥20% of patients included nausea, rash, 
fever, fatigue, vomiting, chills, diarrhea, shortness of breath, and lymphopenia. 
Infusion-related reactions (IRRs) and hypersensitivity reactions (HSR) were noted; 6 patients 
had treatment-related and serious events and 3 patients discontinued treatment due to IRRs. 
IRRs were considered related to brentuximab vedotin and bendamustine; most occurred at 
the Cycle 2 infusion. Symptoms included rash, hives, pruritus, shortness of breath, wheezing, 
throat tightness, fever, chills, and hypotension. The study protocol was amended to require 


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premedication with corticosteroids and antihistamines; premedication has reduced the 
severity of IRRs and HSRs. Based on this information, it is recommended that patients in this 
study be premedicated with corticosteroids and antihistamines (see Section 5.4.4). 
Further study of the combination of brentuximab vedotin and bendamustine on the current 
study (Part C of Study SGN35-015) showed additional safety observations as detailed in 
Section 3.1. 
1.6 Experience With Brentuximab Vedotin Combined with Nivolumab 
Nivolumab is a fully-human monoclonal antibody (IgG4) that targets programmed cell death 
protein-1 (PD-1). In vitro, nivolumab binds to PD-1 with high affinity (EC50 0.39–2.62 nM), 
and inhibits the binding of PD-1 to its ligands, PD-L1 and PD-L2 (IC50 ±1 nM). Nivolumab 
binds specifically to PD-1 and not to related members of the CD28 family such as CD28, 
ICOS, CTLA-4, and BTLA. Nivolumab blocks the PD-1 pathway and results in enhancement 
of both proliferation and IFN-γ release in the mixed lymphocyte reaction, augmentation of 
IFN-γ secretion from cytomegalovirus (CMV)-specific memory T-cells in a dose-dependent 
manner in a CMV re-stimulation assay, and enhancement of the antitumor immune response 
and tumor rejection in several immunocompetent mouse tumor models (MC38, SA1/N, and 
PAN02) using a murine analog of nivolumab (Wolchok 2009). 
A recent report from a phase 1 study of nivolumab in patients with advanced hematological 
malignancies demonstrated a high response rate in patients with relapsed or refractory HL, 
with an ORR of 87% (20/23) and a CR rate of 22% (5/23). The responses obtained have been 
durable with the median PFS not yet reached after a median 101 weeks of follow-up. No 
significant difference in the ORR in the subset of 18 patients who had previously failed 
brentuximab vedotin was observed (Ansell 2015). 
A combination therapy regimen of brentuximab vedotin and nivolumab is currently being 
studied (SGN35-025) at Seattle Genetics, Inc. The phase 1/2, open-label, multicenter study is 
designed to evaluate the safety and antitumor activity of brentuximab vedotin treatment 
combined with nivolumab in patients with relapsed or refractory HL after 1 prior treatment. 
Patients are being treated for up to four 3-week cycles with the first dose of brentuximab 
vedotin 1.8 mg/kg being given on Cycle 1 Day 1 and the first dose of nivolumab 3 mg/kg on 
Cycle 1 Day 8. For Cycle 2 and all subsequent cycles, brentuximab vedotin 1.8 mg/kg 
followed by nivolumab 3 mg/kg is being given on Day 1. As of 27 May 2016, 17 patients 
have started treatment and were evaluated for safety on Protocol SGN35-025. Preliminary 
results have demonstrated no dose-limiting toxicities (6 patients in dose-limiting toxicity 
evaluation period of study [Part 1]) and no Grade 4 or 5 AEs have occurred. One patient has 
experienced a treatment-related serious adverse event (SAE) of dehydration, hypercalcemia 
and acute kidney injury after the first dose of brentuximab vedotin. Due to an increased 
incidence of IRRs at Cycle 2 Day 1 during the administration of the first study drug 
brentuximab vedotin (5 of 11 patients [45%], with Grade 1 [2 patients], Grade 2 [2 patients], 
and Grade 3 [1 patient] severity), mandatory premedication was instituted with 
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Cycle 2 infusion and subsequent cycles. Symptoms experienced by patients included rash, 
pruritus, nausea, vomiting, diarrhea, dyspnea, and chest, and throat tightness. Enrollment in 
the second part of this study is ongoing. 
In an ongoing cooperative group trial, brentuximab vedotin and nivolumab are administered 
sequentially on Day 1 of each 3-week cycle using premedication with H1- and H2-antagonists 
alone. Ten patients with relapsed/refractory HL have received this treatment regimen thus far 
on the study, and of those patients, only 1 experienced a Grade 1/2 IRR. The patient was able 
to receive subsequent therapy with additional premedication (Diefenbach 2016). Due to the 
lower incidence of IRRs observed in this cooperative group trial, Part D of the current study 
will mirror the same-day dosing regimen and premedications (see Sections 5.2.2, 5.5.3, and 
5.5.4). 
1.7 Rationale for the Current Study 
The prognosis of patients with HL and CD30-expressing PTCL has improved over the years, 
mainly due to advances in intensified chemotherapy and combined modality regimens. 
However, these improvements have not been reflected in patients with significant 
comorbidities or older patients (for the latter perhaps attributable to the frequency of 
comorbidities) (Martinez 2017). In these patients, chemotherapy-related toxicities, including 
treatment-related mortality, are believed to be more common than previously recognized. 
Anthracycline-based regimens pose problems for those with cardiovascular comorbidities, 
and other chemotherapy-related toxicities such as bleomycin-related pulmonary toxicity are 
often considered prohibitive. The risk associated with the administration of dose-intensive 
combination chemotherapy regimens is exacerbated by concomitant cardiac, renal, or other 
organ dysfunctions. Intensive regimens are typically not well tolerated by these patients, 
while less intensive regimens are not effective; thus, experts agree that challenges remain in 
establishing recommendations for standard treatment of less robust patients.  
Similar to HL, there is no standard treatment regimen for older patients with PTCL, and 
comorbidities, such as depressed cardiac or renal function, limit the ability to use 
combination chemotherapy in many less robust patients. For CD30-expressing PTCL, 
single-agent brentuximab vedotin is an active and well-tolerated treatment for patients with 
relapsed and refractory disease (Horwitz 2014) and the ECHELON-2 study showed that the 
addition of brentuximab vedotin to combination chemotherapy in the frontline treatment 
improves both PFS and OS (Horwitz 2018).  
There is a high unmet need in patients aged >60 years and in patients with significant 
comorbidities with HL and CD30-expressing PTCL for novel therapeutic approaches that are 
well-tolerated and active; brentuximab vedotin has the potential to fill this role. This phase 2 
study will evaluate the efficacy, safety, and tolerability of brentuximab vedotin as frontline 
monotherapy for HL and CD30-expressing PTCL in older patients and patients with 
significant comorbidities. The efficacy, safety, and tolerability of combination treatment with 
brentuximab vedotin and dacarbazine, bendamustine, or nivolumab will also be evaluated. 


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Monotherapy with brentuximab vedotin 
The ADC brentuximab vedotin has an acceptable toxicity profile in clinical studies, with 
robust activity demonstrated as a single agent in HL patients refractory to several lines of 
chemotherapy. The aim of this study is to discover a tolerable regimen with long-term 
clinical benefit for patients with HL and CD30-expressing PTCL ineligible for multi-agent 
chemotherapy.  
Combination with dacarbazine 
Dacarbazine has proven to be a critical component of the ABVD regimen and has not been 
reported to have prohibitive toxicities, unlike bleomycin and doxorubicin. In the 
GHSG HD13 trial, a significant loss of efficacy was observed when dacarbazine was omitted 
from the combination (Borchmann 2010). Therefore, it is reasonable to evaluate the 
combination of brentuximab vedotin with dacarbazine, a highly active alkylator component 
from the ABVD regimen. 
Combination with bendamustine 
Also of note, current studies suggest that single-agent bendamustine produces CR rates as 
high as 38% in relapsed and refractory HL (Anastasia 2014; Moskowitz 2009; Moskowitz 
2013b). As both brentuximab vedotin and bendamustine have demonstrated efficacy in 
lymphoma and act via independent mechanisms, it is rational to expect the combination is 
likely to be effective as treatment in frontline therapy of HL. The combination of 
brentuximab vedotin and bendamustine has demonstrated an ORR of 92% (CR rate 77%) in 
an ongoing study of patients with relapsed or refractory HL (SGN35-016) (LaCasce 2014). 
Combination with nivolumab  
Furthermore, recent results with the PD-1 blocking agent nivolumab have demonstrated 
efficacy for relapsed or refractory HL of the CD28 family of T-cell co-stimulatory receptors 
(Chen 2013b; Pardoll 2003). PD-1 signaling has been shown to inhibit T-cell activation, and 
expansion of previously activated cells. Experimental results suggest that PD-1 blockade has 
the potential to activate anti-self T-cell responses, but these responses are variable and 
dependent upon various host genetic factors (Sharpe 2007). There is evidence that HRS 
cell-mediated PD-1 signaling to tumor infiltrating T-cells contributes to the tumor’s ability to 
avoid clearance by the immune system. The PD-1 ligands, PD-L1 and PD-L2, are both 
expressed by multiple HL cell lines and PD-1 overexpression is found in tumor-infiltrating 
and peripheral blood T-cells of patients with HL (Yamamoto 2008). PD-L1 expression in 
clinical samples, as detected by immunohistochemical staining, is present in more than 80% 
of HL cases, with similar rates of expression in all HL pathological subtypes (Chen 2013a). 
Several mechanisms contribute to upregulated expression of PD-L1 and PD-L2 in HRS cells, 
including amplification of chromosome 9p24.1, which contains the genes PD-L1, PD-L2, 
and JAK2, and results in a direct increase in their copy number. The increase in JAK2 copy 
number also indirectly contributes to PD-ligand overexpression through STAT1 mediated 
transcriptional upregulation of the PD-L1 and PD-L2 genes (Green 2010). Furthermore, EBV 


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infection of malignant HRS cells, which is found in up to 40% of HL cases, contributes to 
overexpression of PD-L1 through direct and indirect effects of the EBV latent membrane 
protein 1 on PD-L1 promoter and enhancer elements (Green 2012). These data provide a firm 
basis for the use of a PD-1 blocking agent to activate an antitumor immune response against 
HRS cells. Furthermore, recent evidence indicates that auristatin-based ADCs like 
brentuximab vedotin may also initiate an antitumor immune response through the induction 
of stress on the endoplasmic reticulum of HRS cells and enhancement of antigen presentation 
(Muller 2014), providing a strong scientific rationale for combining brentuximab vedotin 
with an immune stimulatory agent like nivolumab. Together with clinical data demonstrating 
that brentuximab vedotin and nivolumab both have high single-agent response rates in 
patients with heavily pretreated relapsed or refractory HL, it is hypothesized that the 
combination therapy will be more effective than administration of either agent alone, 
particularly in the frontline setting. Moreover, both agents are well tolerated, have few 
overlapping toxicities, and can be infused in the outpatient setting, making this a potentially 
attractive treatment option for older and medically fragile patients. This study will evaluate 
the safety and antitumor activity of combination therapy with brentuximab vedotin and 
nivolumab in a population of previously untreated older patients with HL. 
2 
OBJECTIVES 
All objectives and endpoints are applicable to all parts of the study unless otherwise 
specified. 
2.1 Primary Objective 
● 
To assess the ORR of single-agent brentuximab vedotin and brentuximab vedotin in 
combination with other agents as frontline therapy in patients age ≥60 years and in 
patients ineligible for conventional combination chemotherapy due to comorbidities  
2.2 Secondary Objectives 
● 
To evaluate safety and tolerability of single-agent brentuximab vedotin and the safety 
of brentuximab vedotin when given in combination with other agents 
● 
To assess duration of response 
● 
To assess CR rate 
● 
To assess PFS 
● 
To assess resolution of B symptoms 
● 
To assess pharmacokinetics (PK) and immunogenicity of brentuximab vedotin (all 
parts) and nivolumab (Part D only) 
● 
To assess OS (Parts E and F only) 
2.3 Additional Objectives 
● 
To assess EFS 
● 
To assess OS (Parts A, B, C, and D) 
● 
To assess biomarkers in serum and tumor biopsies  


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● 
To assess the relationship between PK and disease response 
● 
To assess immunomodulatory effects of the combination of brentuximab vedotin and 
nivolumab in peripheral blood (Part D only) 
● 
To assess indeterminate response (IR) rate and subsequent response (Part D only) 
2.4 Endpoints 
2.4.1 Primary Endpoint 
● 
ORR according to the Revised Response Criteria for Malignant Lymphoma (Cheson 
2007) (Parts A, B, and C) 
● 
ORR according to the Lugano Classification Revised Staging System for nodal 
non-Hodgkin and Hodgkin lymphomas (Lugano criteria) and the Lymphoma 
Response to Immunomodulatory Therapy Criteria (LYRIC) (Cheson 2016; Cheson 
2014) (Part D) 
● 
ORR according to modified Lugano criteria. The assessment will be per blinded 
independent central review (BICR) (Parts E and F)  
2.4.2 Secondary Endpoints 
● 
Type, incidence, severity, seriousness, and relatedness of AEs and laboratory 
abnormalities 
● 
CR rate, disease control rate, duration of ORR, duration of CR, and PFS 
● 
ORR according to Lugano criteria per BICR (Parts E and F) 
● 
B symptom resolution rate 
● 
Estimates of selected PK parameters 
● 
Incidence of antitherapeutic antibodies (ATA) to brentuximab vedotin (all parts) and 
nivolumab (Part D only) 
● 
OS (Parts E and F only) 
2.4.3 Additional Endpoints 
● 
ORR according to the Response Evaluation Criteria in Lymphoma (RECIL) (Younes 
2017) (Appendix J), per BICR (Parts E and F) 
● 
EFS 
● 
OS (Parts A, B, C, and D) 
● 
Co-expression of CD30 and PD-L1/PD-L2 by HRS cells; accompanying T-cell, 
macrophage, and myeloid cell populations in diagnostic tumor specimens; and 
correlation with response rates (Part D only) 
● 
Immune status changes, including immunophenotyping of blood immune cells, in 
response to treatment (Part D only) 
● 
IR rate and subsequent response of CR, PR, or PD (Part D only) 
 


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3 
INVESTIGATIONAL PLAN 
3.1 Summary of Study Design 
Part A of this phase 2 open-label study is designed to evaluate the efficacy and tolerability of 
brentuximab vedotin as frontline monotherapy in adults age 60 and above with HL. 
Brentuximab vedotin, 1.8 mg/kg, will be administered IV every 3 weeks. Patients enrolling 
on study with estimated creatinine clearance <30 mL/min will receive 1.2 mg/kg 
brentuximab vedotin. Patients achieving a CR, PR, or stable disease (SD) will be allowed to 
continue on treatment for up to 16 cycles. After discussion with the medical monitor, patients 
who experience clinical benefit per the investigator will be eligible to receive continued 
brentuximab vedotin treatment until disease progression, unacceptable toxicity, or study 
closure. 
Part B of the study is designed to evaluate the efficacy and tolerability of brentuximab 
vedotin in combination with dacarbazine as frontline therapy in adults age 60 and above with 
HL. Treatment with brentuximab vedotin 1.8 mg/kg in combination with dacarbazine 
375 mg/m2 will be given on Day 1 of Cycles 1 through 12, followed by single-agent 
brentuximab vedotin 1.8 mg/kg on Day 1 of Cycles 13 through 16. Patients enrolling on 
study with estimated creatinine clearance <30 mL/min will receive 1.2 mg/kg brentuximab 
vedotin in combination with a reduced dose of dacarbazine (262 mg/m2; ~30% reduced) 
every 3 weeks. Patients who have unacceptable toxicity to dacarbazine prior to completion of 
12 cycles may continue to receive brentuximab vedotin as a single agent on Day 1 of each 
cycle for a total of 16 cycles or more of treatment. After discussion with the medical monitor, 
patients who complete 16 cycles of treatment and experience clinical benefit per the 
investigator will be eligible to receive continued single-agent brentuximab vedotin treatment 
until disease progression, unacceptable toxicity, or study closure. 
Part C of this study is designed to evaluate the efficacy and tolerability of brentuximab 
vedotin in combination with bendamustine as frontline therapy in adults age 60 and above 
with HL. Treatment with bendamustine 70 mg/m2 will be given in combination with 
brentuximab vedotin 1.8 mg/kg on Day 1 and then as a single agent on Day 2 of each cycle 
for up to 6 cycles, followed by single-agent brentuximab vedotin 1.8 mg/kg on Day 1 of the 
remaining cycles for up to 16 cycles. Patients who have unacceptable toxicity to 
bendamustine, including developing estimated creatinine clearance <40 mL/min, prior to 
completion of up to 6 cycles may continue to receive brentuximab vedotin as a single agent 
on Day 1 of each cycle for a total of 16 cycles or more of treatment. After discussion with the 
medical monitor, patients who complete 16 cycles of treatment and experience clinical 
benefit per the investigator will be eligible to receive continued single-agent brentuximab 
vedotin treatment until disease progression, unacceptable toxicity, or study closure. 
In Parts A, B, and C, disease response and progression will be assessed using the Revised 
Response Criteria for Malignant Lymphoma (Cheson 2007). PD also includes clinical disease 
progression per investigator. 


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Part D of the study is designed to evaluate the tolerability and efficacy of brentuximab 
vedotin in combination with nivolumab as frontline therapy in adults age 60 and above with 
HL. Treatment with brentuximab vedotin 1.8 mg/kg in combination with nivolumab 3 mg/kg 
will be given on Day 1 of each 3-week cycle. Brentuximab vedotin will be administered at 
least 30 minutes prior to nivolumab. Patients with PD or patients with unacceptable toxicity 
at any time will not continue on treatment. Patients with a response of IR will continue on 
treatment until demonstration of PD via radiographic imaging or biopsy. If patients have 
unacceptable toxicity that is attributable to only 1 agent, as determined by the investigator, 
they will be eligible to continue on treatment with the tolerated drug as a single agent. 
Patients may be treated for up to 16 cycles. Additional cycles may be allowed following 
approval from the sponsor medical monitor. Disease response will be assessed using the 
Lugano criteria (Cheson 2014) and LYRIC (Cheson 2016). PD also includes clinical disease 
progression per investigator. 
Parts E and F of the study are designed to evaluate the safety, efficacy, and tolerability of 
brentuximab vedotin as frontline monotherapy in patients with classical HL or 
CD30-expressing PTCL, respectively, who are unsuitable or unfit for combination 
chemotherapy. Unsuitability or unfitness for conventional combination chemotherapy will be 
justified by the presence of comorbidity-related factors, as documented by either a) a 
Cumulative Illness Rating Scale (CIRS) score ≥10 (according to the criteria specified by 
Salvi and colleagues (Salvi 2008) excluding current active lymphoma) or b) requiring 
assistance with or dependence on others for any instrumental Activities of Daily Living 
(IADL). Brentuximab vedotin, 1.8 mg/kg, will be administered IV every 3 weeks. Patients 
achieving a CR, PR, or SD will be allowed to continue on treatment for up to 16 cycles. 
Disease response will be assessed according to modified Lugano criteria, according to the 
original Lugano criteria, and according to RECIL. The assessment will be per BICR. 
Computed tomography (CT) and positron emission tomography (PET) scans are required for all 
patients at baseline. Radiographic imaging for response assessment will be performed as follows: 
● 
Parts A, B, and C: Restage assessments with CT will be performed at Cycles 2, 4, 8, 
12, and at End of Treatment (EOT). Imaging with PET will be performed at Cycles 2, 
8, and at EOT. CT will be performed at Cycle 16 for patients eligible for continued 
brentuximab treatment beyond 16 cycles. Response assessments performed after 
16 cycles of treatment will include CT scans per institutional standard of care or at 
least every 6 cycles and PET scans per institutional standard of care. 
● 
Part D: Restage assessments will be performed with CT at Cycle 2 and with CT and 
PET at Cycles 4, 8, 12, and EOT. CT and PET are required at Cycle 16 for patients 
eligible for continued treatment with brentuximab vedotin and/or nivolumab beyond 
16 cycles. For patients with a response determination of IR, radiographic assessment 
(CT/PET) of disease must be performed 12 weeks following IR or earlier if clinically 
indicated. If a patient has a second determination of IR, then subsequent repeat 
imaging must be performed between 4 and 8 weeks. Follow-up radiographic 


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assessment for patients with IR is not required if a follow-up biopsy has been 
performed that confirms response. 
● 
Parts E and F: Restage assessments with CT and PET will be performed at Cycles 2, 
6, 11, and at EOT approximately 1 month after discontinuation of study treatment. 
Following the EOT visit, patients discontinuing study treatment without progression 
will be followed until progression or initiation of further anti-cancer therapy. 
Follow-up CT scans will be performed every 4 months for 2 years and then per 
institutional standard of care, and follow-up PET scans will be performed per 
institutional standard of care.  
CT/PET of diagnostic quality may be utilized for CT and PET scanning. Once a patient 
achieves a PET CR, PET scans are no longer required. PET scans performed as part of 
institutional standard of care may be collected at any time during the study, as available. 
Patients who receive any amount of brentuximab vedotin will be followed for survival every 
3 months (Parts A to D) or 4 months (Parts E and F) until withdrawal of consent, death, or 
study closure, whichever comes first. Patients who have not progressed will have response 
assessments until disease progression (see Section 6.8). Initiation of alternative treatment for 
lymphoma will also be collected. 
A study schema is provided below in Figure 1. 


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Figure 1: Study design  
 
 


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3.2 Safety Monitoring Committee 
A Safety Monitoring Committee (SMC) consisting of the medical monitor, drug safety and 
risk management representative(s), participating investigators, and study-specific steering 
committee members will be responsible for monitoring patient safety of Parts C and D of the 
trial. The roles and responsibilities of the SMC will be detailed in a separate charter. 
3.2.1 Part C 
The initial starting dose of bendamustine was 90 mg/m2. In order to provide a safety 
assessment of acute toxicities of the combination regimen of brentuximab vedotin with 
bendamustine at the 90 mg/m2 dose, including an assessment of IRRs that were previously 
seen with this combination treatment during Cycle 2 on Study SGN35-016, the SMC 
reviewed safety data after the first 5 patients in Part C completed 1 cycle of brentuximab 
vedotin and bendamustine, and again after the first 5 patients completed 2 cycles of treatment 
with brentuximab vedotin and bendamustine. 
It was noted in the second safety call that 4 out of 7 patients in Part C had experienced SAE. 
Two patients were hospitalized for Grade 3 asthenia, 1 patient was hospitalized for febrile 
neutropenia, and 1 patient was hospitalized for a delayed HSR. The SAEs occurred between 
Cycles 2 and 4. Subsequent to the second safety call, the protocol was amended 
(Amendment 6) to reduce the starting dose of bendamustine to 70 mg/m2 in order to improve 
the safety and tolerability of this combination regimen. 
Additional key safety observations were reported at a subsequent SMC meeting; 12 of the 
20 patients enrolled on Part C had experienced SAEs and 2 of those patients died within the 
30-day safety observation period. Additionally, although the study was not designed to 
compare treatment arms, a higher incidence of specific treatment-emergent AEs (diarrhea, 
asthenia/fatigue, hypokalemia, dehydration, weight decrease, hypotension, neutropenia, 
candidiasis, and pneumonia) and an overall higher incidence of treatment-emergent AEs 
≥ Grade 3 were observed in Part C compared with Parts A and B. Although no specific safety 
signal was identified, and neither of the deaths were considered related to study treatment, 
the sponsor’s interpretation of the safety data is that the combination of brentuximab vedotin 
(at 1.8 mg/kg) and bendamustine at the dose levels evaluated (70 and 90 mg/m2) does not 
represent a low toxicity regimen for this patient population, which is generally considered 
ineligible for conventional combination chemotherapy. Therefore, as of 7-Oct-2015 (the date 
of the Dear Investigator Letter), the sponsor has suspended enrollment of patients into Part C 
and discontinued bendamustine treatment for all patients enrolled in Part C. Single-agent 
brentuximab vedotin may be continued for patients who tolerate the therapy and have 
demonstrated clinical benefit. 
3.2.2 Part D 
Safety review of patients treated with the combination of brentuximab vedotin and 
nivolumab will be conducted by the study SMC after the first 5 patients complete treatment 
through Cycle 3 Day 1, and throughout the study as needed. 


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3.3 Retreatment (Part D Only) 
Retreatment with brentuximab vedotin plus nivolumab is permitted, with medical monitor 
approval, for patients who achieve a CR or PR on study and experience disease progression 
≥6 months after discontinuing study treatment. To be eligible for retreatment, patients must 
meet all inclusion and exclusion criteria specified in Sections 4.1 and 4.2. The retreatment 
regimen will be brentuximab vedotin 1.8 mg/kg in combination with nivolumab 3 mg/kg on 
Day 1 of each 3-week cycle, unless otherwise specified by the medical monitor or the site 
investigator. Patients who previously required a brentuximab vedotin dose reduction due to 
AEs will start brentuximab vedotin at a dose of 1.2 mg/kg and will not escalate to 1.8 mg/kg. 
Retreatment can continue for an unlimited number of cycles. 
3.4 End of Study 
The study will be closed 2 years after the last patient receives their last dose or when the last 
patient completes the last visit, last contact, discontinues from the study, or when no patients 
remain in follow-up, whichever occurs first. In addition, the sponsor may terminate the study 
at any time (see Section 10.3.2). 
3.5 Discussion and Rationale for Study Design 
Part A of this study is designed as an open-label phase 2 study that evaluates the efficacy and 
tolerability of brentuximab vedotin as monotherapy in adults age 60 and above with 
previously untreated HL. As a way to further evaluate efficacy and tolerability of novel 
regimens for older patients and provide additional treatment options, Part B of the study is 
designed to evaluate brentuximab vedotin in combination with dacarbazine, Part C of the 
study is designed to evaluate brentuximab vedotin in combination with bendamustine, and 
Part D of the study is designed to evaluate brentuximab vedotin in combination with 
nivolumab as frontline therapy in these patients. The endpoints of this study are appropriate 
for evaluating efficacy and safety in this population. The frequency of blood draws for 
evaluation of PK and ATA is appropriate based on prior experience with brentuximab 
vedotin.  
Rationale for Eligibility Criteria in Parts E and F 
Parts E and F of the study are designed to evaluate brentuximab vedotin as monotherapy in 
previously untreated patients with HL or CD30-expressing PTCL, respectively, who are 
considered unsuitable or unfit for multiagent chemotherapy treatment of curative intent due 
to coexisting medical conditions. Selection of patients will be based on the following 
comorbidity-related criteria: 
a. CIRS score ≥10 (according to the criteria specified by Salvi and colleagues (Salvi 
2008) and excluding current active lymphoma) (see Appendix G), or  
b. requiring assistance with or dependence on others for any IADLs (Appendix H). 
 
While there is not a standard definition for such patients within the classical HL and PTCL 
populations, the proposed criteria are based upon the recent approval of venetoclax 


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(VENCLEXTA®) in combination with obinutuzumab as a frontline regimen for CLL, 
available data in the literature on comorbidities in patients with classical HL and PTCL 
(Evens 2018), and communication with key opinion leaders.  
Cumulative Illness Rating Scale 
Originally developed in 1968, CIRS is a widely used tool to quickly but comprehensively 
assess physical impairment (Linn 1968). The proposed CIRS criteria, developed by 
Salvi et al., incorporates conditions typically seen in the elderly and comprehensively 
evaluates 14 organ systems, rating each from 0 to 4 based on increasing severity/impairment 
and yielding a score for each organ system and a cumulative score (Salvi 2008). A greater 
CIRS score indicates poorer health status and is widely utilized in trials as an assessment of 
comorbidities (Extermann 2000), and as a measure of the burden of acute and chronic illness 
in adults as measured by mortality over a 24-month period (Mistry 2004). In CLL, a 
cumulative CIRS ≥6 in combination with creatine clearance is used to determine fitness for 
aggressive treatment as part of a “Go-go,” “Slow-go,” or “No-go” algorithm. CLL14, the 
phase 3 trial that led to the approval of venetoclax in frontline CLL in May 2019, used the 
CIRS score both in the inclusion and exclusion criteria to identify patients with coexisting 
medical conditions and determine fitness to receive treatment (VENCLEXTA package insert, 
July 2019). 
CIRS Scoring and IADL in Classical Hodgkin Lymphoma 
In a recent study by Evens et al., a combination regimen of brentuximab vedotin + AVD was 
evaluated in 48 older patients (age ≥60 years) with untreated classical HL (Evens 2018). The 
median CIRS-G score (based on the CIRS by Salvi et al., and with the same scoring criteria) 
at baseline was 7 (range 1 to 20) with 25/48 (52%) patients having at least 1 Grade 3 or 4 
deficit. Fifteen (31%) patients had a CIRS-G score ≥10. Patients with CIRS-G score ≥10 only 
tolerated a median of 5 cycles (range 1 to 12) while patients with CIRS-G <10 received a 
median of 12 cycles (range 6 tp 12) with 68% receiving all 12 intended cycles. The most 
common reason for early discontinuation from the study was toxicity or AE (35%), which 
was more commonly seen in patients with CIRS-G scores ≥10. It has been suggested that the 
primary reason for the poorer outcomes observed in patients with CIRS-G ≥ 0 was the 
presence of significant co-morbidities preventing the patients from tolerating the full regimen 
(personal communication by investigator). Patients with CIRS-G scores of ≥10 (N=14) had a 
2-year PFS rate of 45% (95% CI: 15, 71) vs. 100% (95% CI: 100, 100) in patients with 
CIRS-G scores <10 (N=30). In addition, patients with loss of an IADL at baseline (N=6) had 
2-year PFS rates of 25% (95% CI: 1, 65) vs. 94% (95% CI: 79, 99) in patients without loss of 
an IADL at baseline (N=36) (Evens 2018). Lastly, in patients with a CIRS-G score ≥10, 5/15 
(33%) had loss of IADLs and of patients with loss of IADLs at baseline, 4/6 (67%) had a 
CIRS-G score ≥10. 


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3.5.1 Method of Assigning Patients to Treatment Groups 
Part A is a single-arm evaluation of 1.8 mg/kg brentuximab vedotin administered as a single 
IV infusion on Day 1 of each 3-week treatment cycle, Part B is a single-arm evaluation of 
combination treatment with 1.8 mg/kg brentuximab vedotin and 375 mg/m2 dacarbazine, 
Part C is a single-arm evaluation of combination treatment with 1.8 mg/kg brentuximab 
vedotin on Day 1 and 70 mg/m2 bendamustine on Days 1 and 2, Part D is a single-arm 
evaluation of combination treatment with 1.8 mg/kg brentuximab vedotin and 3 mg/kg 
nivolumab given on Day 1 of each cycle, and Parts E and F are each a single-arm evaluation 
of 1.8 mg/kg brentuximab vedotin administered as a single IV infusion on Day 1 of each 
3-week treatment cycle. Enrollment in Part A will halt once Part B is open for enrollment at a 
site or a total of 30 patients have been enrolled in Part A. Enrollment in Part B will halt once 
approximately 20 patients have been enrolled and Part C is open for enrollment at a site. 
Enrollment on Part C was suspended as of 7-Oct-2015 based on SMC recommendation and 
sponsor decision. Approximately 50 evaluable patients each will be enrolled in Parts E and F. 
In Part F, there will be an enrollment cap of 50% on patients with sALCL (approximately 
25 patients). 
Patients enrolling on study with estimated creatinine clearance <30 mL/min will receive 
1.2 mg/kg brentuximab vedotin either as a single agent in Part A or in combination with a 
reduced dose of dacarbazine (262 mg/m2; ~30% reduced) in Part B. 
3.5.2 Rationale for Selection of Doses 
In a phase 1 dose-escalation study of brentuximab vedotin (SG035-0001), the 
maximum-tolerated dose was defined as 1.8 mg/kg IV 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-expressing hematologic malignancies. Based on historic 
brentuximab vedotin PK data from patients with HL and patients with anaplastic large cell 
lymphoma, including a limited number of older patients, age is not a significant covariate for 
drug exposure. Thus, a dose adjustment specifically for age based on PK is not warranted. 
The dose of dacarbazine to be administered in combination with brentuximab vedotin in 
Part B is the standard dose level (375 mg/m2) that is combined with other therapeutic agents 
for frontline treatment of HL. The standard dosing frequency of dacarbazine is on Days 1 and 
15 of a 28-day cycle, but dacarbazine administration for this study will be on Day 1 of each 
21-day cycle to align with approved brentuximab vedotin dosing. In a phase 1 study of 
brentuximab vedotin + ABVD or + AVD, the maximum-tolerated dose of brentuximab 
vedotin when combined with these chemotherapeutic agents was not exceeded at 1.2 mg/kg 
every 2 weeks (the maximum planned dose). The maximum planned dose of 1.2 mg/kg 
brentuximab vedotin was chosen because this dose administered every 2 weeks was expected 
to achieve the same exposure (area under the curve [AUC]) as the approved single-agent 
dose of 1.8 mg/kg every 3 weeks (Younes 2013). Brentuximab vedotin exposures were 
similar to that obtained with the approved monotherapy regimen when administered in 
combination with AVD every 2 weeks. 


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The starting dose of bendamustine that was initially administered in combination with 
brentuximab vedotin in Part C was 90 mg/m2. Although bendamustine is approved for 
clinical use at a starting dose of 100 mg/m2 for CLL and 120 mg/m2 for NHL, a lower 
starting dose of bendamustine was used because of the overlapping toxicities of the 2 agents, 
in particular myelosuppression. Additionally, interim results from the SGN35-016 study 
supported the administration of a lower dose of bendamustine combined with 1.8 mg/kg 
brentuximab vedotin. The 90 mg/m2 dose is within the effective range of bendamustine; 
however, preliminary safety results observed in Study SGN35-016 suggested that IRRs may 
occur more frequently and at a higher severity with this combination (LaCasce 2014). Thus, 
the safety of the combination at this dose level was to be assessed in 5 patients who 
completed Cycle 1 and again once 5 patients completed Cycle 2 (see Section 3.1). Lower 
dose levels of bendamustine (70 and 50 mg/m2) were to be recommended in the case of 
unacceptable toxicity at the higher dose. Subsequent to Amendment 6, the starting dose of 
bendamustine has been lowered to 70 mg/m2 (see Section 5.4.5). As of 7-Oct-2015, the 
sponsor suspended enrollment of patients into Part C and discontinued bendamustine 
treatment for all patients enrolled in Part C based on SMC recommendation. Single-agent 
brentuximab vedotin may be continued for patients who tolerate the therapy and have 
demonstrated clinical benefit (Section 3.1). 
The dose of nivolumab for this study is 3 mg/kg via IV infusion administered every 3 weeks. 
The approved dose for nivolumab as monotherapy is 3 mg/kg every 2 weeks for the 
treatment of melanoma and metastatic squamous non-small cell lung cancer. However, 
nivolumab has been studied as monotherapy and in combination treatment in several tumor 
types with dosing every 3 weeks. It was recently reported that nivolumab dose levels of 0.3, 
2, and 10 mg/kg every 3 weeks yielded similar ORR, PFS, and OS in a phase 2 trial of 
patients with metastatic renal cell carcinoma (Motzer 2015). Moreover, nivolumab dose 
levels of 0.1, 0.3, 1, 3, and 10 mg/kg every 2 weeks were associated with very similar 
(median 64%–70%) PD-1 receptor occupancy and comparable ORR and PFS in patients with 
advanced melanoma (Topalian 2012). These findings indicate a flat dose-response 
relationship for nivolumab across a wide dose range for both every 2- and 3-week dosing, 
suggesting that dosing nivolumab at 3 mg/kg every 3 weeks is appropriate in the current 
study. Dosing of 3 mg/kg nivolumab in combination with 1.8 mg/kg brentuximab vedotin on 
Day 1 every 3 weeks has also been evaluated in 10 patients with relapsed/refractory HL in an 
ongoing cooperative group trial. Patients on that study are premedicated with H1- and 
H2-antagonists. Only 1 patient experienced a Grade 1/2 IRR thus far and the patient was able 
to receive subsequent therapy with additional premedication (Diefenbach 2016). Due to the 
low incidence of IRRs observed in this cooperative group trial, Part D of the current study 
will mirror the same-day dosing regimen and premedications (see Sections 5.2.2, 5.5.3, and 
5.5.4). There is no recommended maximum number of cycles for brentuximab vedotin 
monotherapy treatment of HL in the relapsed setting (after failure of autologous stem cell 
transplant or after failure of at least 2 prior multi-agent chemotherapy regimens) nor a 
recommended maximum number of cycles for nivolumab treatment in any of the approved 


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indications; therefore, this study will evaluate 16 cycles or more of treatment combined with 
brentuximab vedotin (refer to the package inserts for nivolumab and brentuximab vedotin). 
Renal excretion is a minor route of free MMAE elimination in patients, with the major route 
via feces. The potential impact of renal impairment on the PK of brentuximab vedotin and 
free MMAE was evaluated in a special populations study (SGN35-008B, data on file). No 
meaningful change in brentuximab vedotin PK was observed. An apparent increase in 
MMAE exposure was observed only in the patients with severe renal impairment (estimated 
creatinine clearance <30 mL/min, n=2). In an effort to mitigate risk due to increased MMAE 
exposure, dosing will be reduced to 1.2 mg/kg brentuximab vedotin for patients enrolling on 
Parts A and B of the study with estimated creatinine clearance <30 mL/min. Renal excretion 
is a significant route of dacarbazine elimination; therefore, a dose reduction of ~30% is 
recommended for patients with estimated creatinine clearance <30 mL/min for patients 
enrolled in Part B. Although no formal studies evaluating the impact of renal impairment on 
the PK of bendamustine have been conducted, bendamustine is not recommended for use in 
patients with creatinine clearance <40 mL/min, according to prescribing information. Patients 
in Part C will be excluded from the study if they present with estimated creatinine clearance 
<40 mL/min. Patients in Part D will be excluded from the study if they present with 
estimated creatinine clearance <30 mL/min. Patients enrolling on Parts E and F will be 
excluded from the study if they present with an estimated glomerular filtration rate (eGFR) 
<30 mL/min/1.73m². 
3.5.3 Blinding 
This is an open-label study. No blinding will be performed. 


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4 
STUDY POPULATION 
To be eligible for this study, patients must meet all criteria outlined below in Sections 4.1 and 
4.2. Eligibility criteria are applicable to all parts of the study unless otherwise specified. 
To be eligible for retreatment as described in Section 3.3, patients must meet all inclusion 
and exclusion criteria outlined in Section 4.1 and Section 4.2. 
4.1 Inclusion Criteria 
1. Treatment-naive patients with histopathological diagnosis of classical HL, which 
excludes nodular lymphocyte-predominant HL, (Parts A, B, C, D, and E), or 
treatment-naive patients with CD30-expressing (≥1%) PTCL (Part F) by local testing. 
See PTCL histologic subtypes in Appendix L. Patients eligible for retreatment on Part D 
must have had prior treatment on this study with the combination of brentuximab vedotin 
plus nivolumab.  
2. In Parts A to D: Age ≥60 years; in Parts E and F: age ≥18 years 
3. In Parts A to D: Patients must be ineligible for or have declined initial conventional 
combination chemotherapy for HL (e.g., A+AVD, ABVD, BEACOPP), after being 
informed of the potential benefits and risks of available treatment options  
In Parts E and F: Patients must be unsuitable or unfit for initial conventional combination 
chemotherapy for HL (Part E) or CD30-expressing PTCL (e.g., A+CHP, CHOP, 
CHOEP; Part F) due to the presence of comorbidity-related factors, as documented by:  
a. a CIRS score ≥10 (according to the criteria specified by Salvi and colleagues (Salvi 
2008) and excluding current active lymphoma) (see Appendix G), OR  
b. requiring assistance with or dependence on others for any iIADLs (Appendix H). 
 
4. Patients must have fluorodeoxyglucose (FDG)-PET-avid and bidimensional measurable 
disease of at least 1.5 cm in longest axis as documented by radiographic technique (spiral 
CT preferred). 
5. An Eastern Cooperative Oncology Group (ECOG) Performance Status score of ≤3 
(Parts A, B, C, E, and F) or ≤2 (Part D).  
6. The following baseline laboratory data: 
a. absolute neutrophil count ≥1000/µL. 
b. platelet count ≥50,000/µL (no platelet transfusions for prior 14 days for Part D only). 
c. serum bilirubin ≤2X upper limit of normal (ULN) (Parts A, B, E, and F) or 
≤1.5X ULN (per bendamustine and nivolumab prescribing information) (Parts C or 
D); or ≤3X ULN for patients with Gilbert’s disease or documented hepatic 
involvement with lymphoma (all parts).  
d. alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3X ULN or 
≤5X ULN for patients with documented hepatic involvement with lymphoma; 


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patients enrolled in Parts C or D must have ALT and AST ≤2.5X ULN (per 
bendamustine prescribing information for Part C). 
e. hemoglobin ≥8.5 g/dL (no red blood cell transfusions for prior 7 days) (Part D only). 
f. As determined by Cockroft-Gault formula, estimated creatinine clearance 
≥40 mL/min (Part C only, per bendamustine prescribing information) or ≥30 mL/min 
(Part D only). 
g. As determined by the Modification of Diet in Renal Disease (MDRD) study equation, 
eGFR ≥30 mL/min/1.73m2 (Parts E and F only). The eGFR should be calculated 
using the MDRD equation as applicable, with serum creatinine (Scr) reported in 
mg/dL: 
○ 
eGFR (mL/min/1.73 m2)=175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x 
(1.212 if African American) 
○ 
If Scr is reported in µmol/L, the value should be converted to mg/dL using the 
conversion factor 0.011312 µmol/L to mg/dL. 
7. Patients 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. Patients with false positive results and documented verification 
that the patient is not pregnant are eligible for participation. Patients of non-childbearing 
potential are those who are postmenopausal >1 year or who have had a bilateral 
oophorectomy or hysterectomy. 
8. If sexually active in a way that could result in pregnancy, patients of childbearing 
potential and patients who can father children and have partners of childbearing potential 
must agree to use 2 effective contraception methods (Appendix E) during the study and 
for 6 months following the last dose of study drug (or 8 months following last dose of 
nivolumab in Part D).  
9. The patient or the patient’s legally acceptable representative must provide written 
informed consent.  
10. Diffusing capacity of the lungs for carbon monoxide (DLCO) over 50% (adjusted for 
hemoglobin) (Part D only). 
4.2 Exclusion Criteria 
1. Baseline peripheral neuropathy Grade ≥2 (per NCI CTCAE, Version 4.03) or patients 
with the demyelinating form of Charcot-Marie-Tooth syndrome 
2. History of progressive multifocal leukoencephalopathy (PML) 
3. 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 brentuximab vedotin. Routine 
antimicrobial prophylaxis is permitted. 
4. Chemotherapy, RT, biologics, and/or other treatment with immunotherapy that is not 
completed 4 weeks prior to first dose of study drug 


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5. Concurrent use of other investigational agents 
6. Known hypersensitivity to any excipient contained in the drug formulation of 
brentuximab vedotin (all parts), dacarbazine (Part B only), bendamustine (Part C only) 
(e.g., mannitol), or nivolumab (Part D only). 
7. Kidney disease requiring ongoing dialysis 
The following exclusion criteria are applicable to Part D only: 
8. Received any prior immune-oncology therapy (e.g., therapies targeting the PD-1, 
CTLA4, or CD137 pathways) (not applicable to retreatment patients on Part D). 
9. Previous history of known or suspected autoimmune disease. 
○ 
Patients with type I diabetes mellitus, hypothyroidism only requiring hormone 
replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring 
systemic treatment, or conditions not expected to recur in the absence of an 
external trigger are permitted. 
10. Prior allogeneic stem cell transplant.  
11. History of another primary invasive malignancy that has not been in remission for at least 
1 year. 
12. Documented history of a cerebral vascular event (stroke or transient ischemic attack 
[TIA]), unstable angina, myocardial infarction, or cardiac symptoms consistent with New 
York Heart Association (NYHA) Class III–IV (Appendix D) within 6 months prior to the 
first dose of study drug(s). 
13. Active interstitial lung disease that is symptomatic or may interfere with the detection or 
management of suspected drug-related pulmonary toxicity. 
14. Known history of pancreatitis. 
The following exclusion criteria are applicable to Parts D, E, and F only: 
15. Known cerebral/meningeal disease related to the underlying malignancy. 
16. Systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or 
other immunosuppressive medications within 1 week of enrollment. 
○ 
Inhaled or topical steroids and adrenal replacement steroid doses >10 mg daily 
prednisone equivalent are permitted in the absence of active autoimmune disease. 
17. Known to be positive for hepatitis B by surface antigen expression. Known to be positive 
for hepatitis C infection (positive by polymerase chain reaction [PCR]). Patients who 
have been treated for hepatitis C infection are permitted if they have documented 
sustained virologic response of 12 weeks. 


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18. Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). 
19. Active hepatitis C infection (positive by serology and confirmed by PCR or on antiviral 
therapy for hepatitis C within the last 6 months). 
20. Other serious underlying medical condition that, in the opinion of the investigator, would 
impair the ability to receive or tolerate the planned treatment and follow-up. 
The following exclusion criteria are applicable to Parts E and F only: 
21. History of another malignancy within 1 year before the first dose of study drug or any 
evidence of residual disease from a previously diagnosed malignancy. Exceptions are 
malignancies with a negligible risk of metastasis or death (e.g., 5-year OS ≥90%), such as 
adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, 
localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.  
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). The investigators will make every 
reasonable effort to keep each patient on the study until all planned treatments and 
assessments have been performed. If a patient withdraws from study treatment, every attempt 
should be made to follow the patient until death or administrative study closure. Final 
treatment assessments will be performed before any other therapeutic intervention, if 
possible. Additionally, any planned alternative treatments should be documented on the 
patient’s medical records and 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 
● 
AE 
● 
Investigator decision 
● 
Patient decision, Non-AE 
● 
Study termination by sponsor 
● 
Other, Non-AE 
All patients who receive at least 1 dose of study drug will be followed until withdrawal of 
consent, death, or study closure, whichever comes first (see Section 6.8). 


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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 
● 
Retreatment (Part D only) 
● 
Study termination by sponsor 
● 
Lost to follow-up 
● 
Death 
● 
Other 
 
5 
TREATMENTS 
5.1 Treatments Administered 
All patients enrolled on study will receive brentuximab vedotin, the investigational agent 
under study in this protocol. Brentuximab vedotin 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. 
Patients enrolled in Part B of the study will receive combination treatment with brentuximab 
vedotin and dacarbazine, a commercially-available chemotherapeutic agent. Patients enrolled 
in Part C of the study will receive combination treatment with brentuximab vedotin and 
bendamustine, a commercially-available chemotherapeutic agent. Patients enrolled in Part D 
of the study will receive combination treatment with brentuximab vedotin and nivolumab, a 
commercially-available monoclonal antibody. 
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 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 Instructions for further information. 
5.2.2 Dose and Administration 
In all parts of the study, brentuximab vedotin will be administered on Day 1 of each 3-week 
cycle by IV infusion given over approximately 30 minutes. In the absence of IRRs, the 
infusion rate 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. For Parts B and C, brentuximab vedotin 
should be administered approximately 30 to 60 minutes prior to the start of the infusion of 


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dacarbazine or bendamustine, as applicable. For Part D, brentuximab vedotin should be 
administered approximately 30 minutes prior to the start of the infusion of nivolumab. 
Dosing is based on patient weight according to the institutional standard; however, doses will 
be adjusted for patients who experience a ≥10% change in weight from baseline. An 
exception to weight-based dosing is made for patients weighing >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 
In Parts A, B, E, and F, routine premedication should not be administered for the prevention 
of IRRs prior to the first dose of brentuximab vedotin. However, premedications may be 
administered prior to the first dose of brentuximab vedotin in Parts A, B, E, and F if required 
per institutional standard. Patients who experience a Grade 1 or Grade 2 IRR may receive 
subsequent brentuximab vedotin infusions with premedication as described in Section 5.7.1. 
In Part C, patients are to receive premedication as noted in Section 5.4.4. In Part D, patients 
are to receive premedication as noted in Section 5.5.4. 
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 Dose Modifications 
Table 1 describes the recommended dose modifications for brentuximab vedotin 
treatment-associated toxicity. 
The start of the next cycle may be delayed for up to 3 weeks if additional time is required for 
the patient to recover from study treatment-associated toxicity experienced during the current 
cycle. Delays of greater than 3 weeks are prohibited without approval from the sponsor. 
In addition, doses reduced for treatment-related toxicity should not be re-escalated without 
discussion with the sponsor. 
For patients receiving 1.2 mg/kg brentuximab vedotin due to renal impairment, those patients 
who tolerate multiple doses may be administered 1.8 mg/kg brentuximab vedotin following 
discussion with the sponsor and provision of documentation demonstrating sufficient renal 
function for this dose. Dose reductions below 1.2 mg/kg are not allowed, and toxicities 
should be managed with dose delays. 


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Table 1: 
Recommended dose modifications for brentuximab vedotin-associated toxicity 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Peripheral 
Neuropathy 
Continue at 
same dose 
level 
Reduce dose 
to 1.2 mg/kg 
and resume 
treatment 
Withhold until toxicity 
resolves to ≤ Grade 2 or 
baseline, then resume 
treatment at 1.2 mg/kge 
Discontinue treatment 
Non-
hematologic 
(except 
peripheral 
neuropathy)f 
Continue at 
same dose 
level 
Continue at 
same dose 
level 
Withhold dose until 
toxicity is ≤ Grade 2 or has 
returned to baseline, then 
resume treatment at the 
same dose levela. 
Withhold dose until 
toxicity is ≤ Grade 2 or has 
returned to baseline, then 
reduce dose to 1.2 mg/kg 
and resume treatment, or 
discontinue at the 
discretion of the 
investigatora, d, e. 
Hematologicc 
Continue at 
same dose 
level 
Continue at 
same dose 
level 
Withhold until toxicity resolves to ≤ Grade 2 or baseline, 
then resume treatment at the same dose levelb. Growth 
factor support (G-CSF or granulocyte-macrophage 
colony-stimulating factor [GM-CSF]) should be 
considered for subsequent cycles. If Grade 4 neutropenia 
recurs despite growth factor support, consider 
discontinuation or dose reduction to 1.2 mg/kge. 
a 
Patients who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study treatment without 
interruption. 
b 
Patients who develop Grade 3 or 4 lymphopenia may continue study treatment without interruption. 
c 
Support with blood product transfusions allowed per institutional standard of care. 
d 
Treatment should be discontinued for patients who experience Grade 4 IRRs. 
e 
Dose reductions below 1.2 mg/kg are not allowed, and toxicities should be managed with dose delays. 
f 
For Parts A, B, and C, dose reductions to 1.2 mg/kg should be considered for patients receiving 1.8 mg/kg dosing who 
then develop renal impairment with estimated creatinine clearance consistently below 30 mL/min. For Part D, patients 
who develop renal impairment with estimated creatinine clearance below 30 mL/min should discontinue treatment. For 
Parts E and F, patients who develop renal impairment with eGFR below 30 mL/min/1.73m² should discontinue 
treatment. 
 
5.2.5 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 immediately. If not used immediately, reconstituted vials and solutions must be stored 
no longer than 24 hours from vial reconstitution. 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. 
5.2.6 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. 


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5.2.7 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, US Pharmacopeia. 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 Dacarbazine 
Refer to the dacarbazine package insert for detailed information on the description, 
preparation, administration, and storage of dacarbazine. 
5.3.1 Description 
Dacarbazine is an anticancer agent that is colorless to an ivory colored solid. It is light 
sensitive, and each vial contains 200 mg of dacarbazine (the active ingredient), anhydrous 
citric acid, and mannitol. See the package insert for further information. 
5.3.2 Method of Procurement 
Dacarbazine is commercially available and approved by the US FDA and other regulatory 
agencies for use in treating patients with multiple types of cancer. Dacarbazine 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 B only, dacarbazine should be administered following completion of brentuximab 
vedotin on Day 1 of each 21-day cycle, and patients may receive up to 12 doses of 
dacarbazine while on study. The dose of dacarbazine is 375 mg/m2 administered by 
IV infusion according to the package insert or institutional standard of care. It is 
recommended that the dacarbazine infusion begin within approximately 60 to 90 minutes 
after the end of the brentuximab vedotin infusion. 
Refer to the dacarbazine prescribing information for details on other recommended dose 
adjustments. 


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5.3.4 Required Premedication and Postmedication 
Antiemetics, such as serotonin receptor (5HT3) antagonists, should be considered for the 
prevention of nausea and vomiting within approximately 30 to 60 minutes prior to initiating 
the dacarbazine infusion. Additional premedications for the prevention of nausea and 
vomiting, including steroids, may be given prior to the dacarbazine infusion in accordance 
with institutional standard of care or as clinically indicated. 
5.3.5 Dose Modifications 
Patients enrolling on study with estimated creatinine clearance <30 mL/min will receive 
1.2 mg/kg brentuximab vedotin in combination with a reduced dose of dacarbazine 
(262 mg/m2; ~30% reduced). Dose modifications of dacarbazine are allowed per institutional 
standard of care or per the package insert (e.g., For Grade 3 non-hematologic toxicity or for 
Grade 4 hematologic toxicity, combination treatment may be withheld until toxicity resolves 
to ≤ Grade 2 or baseline). If unacceptable toxicity to dacarbazine develops, dacarbazine must 
be permanently discontinued and brentuximab vedotin monotherapy may continue. If 
unacceptable toxicity to brentuximab vedotin develops, study treatment with single-agent 
dacarbazine may be continued after discussion with the medical monitor. 
5.3.6 Storage and Handling 
Refer to the dacarbazine package insert for dacarbazine storage and handling instructions. 
5.3.7 Packaging and Labeling 
Refer to the dacarbazine package insert for dacarbazine packaging and labeling information. 
5.3.8 Preparation 
Dacarbazine should be prepared according to the package insert or according to institutional 
standards. 
5.4 Bendamustine (Not Applicable as of 07-Oct-2015) 
Refer to the bendamustine package insert for detailed information on the description, 
preparation, administration, and storage of bendamustine. 
5.4.1 Description 
Bendamustine is an anticancer agent containing no antimicrobial preservative and is a clear, 
colorless to yellow solution. Each vial contains either 25 or 100 mg of a lyophilized powder 
formulation of bendamustine HCl, or 45 or 180 mg of a liquid formulation of bendamustine 
HCl. See the package insert for further information. 
5.4.2 Method of Procurement 
Bendamustine is commercially available and approved by the US FDA and other regulatory 
agencies for use in treating patients with CLL and indolent B-cell NHL Bendamustine will be 
supplied by the Canadian study site(s) from their usual suppliers. 


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5.4.3 Dose and Administration 
In Part C only, bendamustine will be administered following completion of brentuximab 
vedotin on Day 1 of each 21-day cycle and again as a single agent on Day 2, approximately 
24 hours after Day 1 study drug dose in the absence of IRRs or HSRs. The bendamustine 
infusion will begin within approximately 30 to 60 minutes after the end of the brentuximab 
vedotin infusion on Day 1 only. 
Patients may receive up to 6 cycles of bendamustine while on study. The dose of 
bendamustine is 70 mg/m2 (with possible reduction to 50 mg/m2) administered by IV 
infusion given over approximately 60 minutes. 
Refer to the bendamustine prescribing information for details on other recommended dose 
adjustments. 
5.4.4 Required Premedication and Postmedication 
Common toxicities with bendamustine include myelosuppression (lymphopenia, anemia, 
leukopenia, thrombocytopenia, and neutropenia, including Grade 3 and higher events) and 
nausea, fatigue, vomiting, diarrhea, fever, constipation, anorexia, cough, headache, decreased 
weight, shortness of breath, rash, and stomatitis. These events should be managed according 
to institutional standards or accepted guidelines (Smith 2006). Prior to treatment with 
bendamustine, prophylactic premedication for prevention of IRRs is to be administered. 
After completion of up to 6 cycles of combination treatment with brentuximab vedotin and 
bendamustine, prophylactic premedications may be discontinued during single-agent 
treatment with brentuximab vedotin for subsequent cycles. 
Methylprednisolone 100 mg IV or equivalent (e.g., dexamethasone 20 mg IV) and 
diphenhydramine 25–50 mg IV or equivalent should be given approximately 30 to 
60 minutes prior to brentuximab vedotin on Day 1 of each 21-day cycle and 30 to 60 minutes 
prior to bendamustine on Day 2. Additional premedication may be administered prior to 
bendamustine on Day 1 at the discretion of the investigator. Acetaminophen may also be 
given at the discretion of the investigator. Ondansetron, or other premedications for the 
prevention of nausea and vomiting, is recommended prior to the bendamustine infusion in 
accordance with institutional standard of care or as clinically indicated. Patients may receive 
myeloid growth factors such as granulocyte-colony stimulating factor (G-CSF) at the 
discretion of the investigator or per institutional standards. Dose modifications of required 
pre- and post-medication are allowed at the discretion of the investigator and only after 
discussion with the medical monitor. 
5.4.5 Dose Modifications 
Dose modifications of bendamustine are allowed per institutional standard of care or per the 
package insert (e.g., treatment with bendamustine may be delayed for Grade 4 hematologic 
toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity). Dose reductions to 
50 mg/m2 are allowed; dose reductions <50 mg/m2 are not allowed without prior discussion 
with the medical monitor. If unacceptable toxicity to bendamustine develops, including 


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developing an estimated creatinine clearance <40 mL/min, bendamustine must be 
permanently discontinued and brentuximab vedotin monotherapy may continue. If 
unacceptable toxicity to brentuximab vedotin develops, study treatment with single-agent 
bendamustine may be continued after discussion with the medical monitor. 
5.4.6 Storage and Handling 
Refer to the bendamustine package insert for bendamustine storage and handling instructions. 
5.4.7 Packaging and Labeling 
Refer to the bendamustine package insert for bendamustine packaging and labeling 
information. 
5.4.8 Preparation 
Bendamustine should be prepared according to the package insert or according to 
institutional standards. 
5.5 Nivolumab 
5.5.1 Description 
Nivolumab is a sterile, preservative-free, clear to opalescent, colorless to pale-yellow 
solution supplied by Seattle Genetics in single-use vials for dilution for IV administration. 
Each single-use vial of the product contains 100 mg/10 mL solution. See the Pharmacy 
Binder for further information. 
5.5.2 Method of Procurement 
Nivolumab will be provided by Bristol-Meyers Squibb and supplied to study sites by Seattle 
Genetics. 
5.5.3 Dose and Administration 
Nivolumab will be administered on Day 1 of each 21-day cycle. Patients will receive 
nivolumab at a dose of 3 mg/kg as a 60-minute infusion (per the nivolumab prescribing 
information). Nivolumab should be administered at least 30 minutes after completing 
brentuximab vedotin infusion. Nivolumab infusions should be administered through an 
IV line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 
0.2 µm to 1.2 µm). Other drugs should not be co-administered through the same IV line 
(e.g., brentuximab vedotin). 
Dosing calculations should be based on the body weight assessed at baseline, then per 
institutional standards. It is not necessary to recalculate subsequent doses if the patient 
weight is within 10% of the weight used to calculate the previous dose. All doses should be 
rounded to the nearest milligram. 
The Pharmacy Binder contains specific instructions for nivolumab dose calculation, dilution, 
preparation of the infusion fluid, and administration. 


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5.5.4 Required Premedication and Postmedication 
Prior to combination treatment on Day 1 of each 21-day cycle, prophylactic premedication 
for prevention of IRRs is to be administered. Antihistamines, including both H1-receptor 
antagonists (e.g., diphenhydramine 25–50 mg IV or equivalent) and H2-receptor antagonists 
(e.g., ranitidine or cimetidine) should be given approximately 30 to 60 minutes prior to 
infusion of brentuximab vedotin. If an increase of IRRs is observed, the SMC may 
recommend additional premedication, including but not limited to hydrocortisone 100 mg IV 
or equivalent. At the discretion of the investigator, further premedications for symptom 
management (e.g., acetaminophen, and/or ondansetron) may also be given. 
If a patient does not experience an IRR with combination treatment during Cycles 1 
through 4, prophylactic premedication may be reduced or stopped at the discretion of the 
investigator for Cycles 5 and beyond. If treatment with nivolumab or brentuximab vedotin is 
discontinued, premedication may be reduced or stopped at the discretion of the investigator 
during single-agent treatment for subsequent cycles. 
5.5.5 Dose Modifications 
Dose modifications of nivolumab, including escalations or reductions, are not allowed. 
Patients who discontinue brentuximab vedotin due to an AE may continue treatment with 
nivolumab monotherapy. If nivolumab is held at the time a cycle of brentuximab vedotin is 
given, once the AE causing the delay of nivolumab has resolved, administration of 
nivolumab should resume on the same schedule with the next cycle of combination therapy. 
See Section 7.7.1.1 for determining causality. 
5.5.5.1 Dose Delays 
Dose delays of both brentuximab vedotin and nivolumab resulting in interruption of all 
therapy for >6 weeks require that a patient discontinue from study treatment, with the 
exception of patients who are receiving protocol-specified consolidative RT (Section 5.6.2) 
or other exceptions noted in Section 5.5.5.2. Patients who experience a dose delay of either 
brentuximab or nivolumab >6 weeks must stop treatment with that component of the 
combination therapy. 
Dose delays for nivolumab-related liver function test (LFT) abnormalities are described in 
Section 5.5.5.3. Otherwise, nivolumab administration should be delayed for the following: 
● 
Any ≥ Grade 2 non-skin, nivolumab-related AEs with the exception of Grade 2 
nivolumab-related fatigue or laboratory abnormalities (excluding LFT abnormalities 
detailed separately) 
● 
Any Grade 3 skin, nivolumab-related AE 
● 
Any Grade 3 nivolumab-related laboratory abnormalities (excluding LFT 
abnormalities detailed separately) with the following exceptions for lymphopenia or 
asymptomatic amylase or lipase: 
○ 
Grade 3 lymphopenia does not require dose delay 


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○ 
Any ≥ Grade 3 nivolumab-related amylase or lipase abnormality that has been 
evaluated clinically and radiographically and is without evidence of pancreatitis 
does not require dose delay. The medical monitor should be consulted for such 
≥ Grade 3 amylase or lipase abnormalities. 
● 
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of nivolumab 
 
Patients who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated. If the dose delay is ≤6 weeks, nivolumab may be resumed at the next 
scheduled treatment cycle if the AE recovers to ≤ Grade 1 or baseline, with the following 
exceptions: 
● 
Patients may resume nivolumab treatment in the presence of Grade 2 fatigue 
● 
Patients who have not experienced a Grade 3 nivolumab-related skin AE may resume 
nivolumab treatment in the presence of Grade 2 skin toxicity 
● 
Nivolumab-related pulmonary toxicity, diarrhea, or colitis must have resolved to 
baseline before nivolumab treatment is resumed. Patients with persistent Grade 1 
pneumonitis after completion of a steroid taper over at least 1 month may be eligible 
for continued nivolumab treatment if discussed with and approved by the medical 
monitor. 
● 
Nivolumab-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume nivolumab treatment after consultation with the 
medical monitor 
5.5.5.2 Dose Discontinuation 
Dose discontinuations for LFT abnormalities are described in Section 5.5.5.3. Otherwise, 
nivolumab treatment should be permanently discontinued for the following: 
● 
Any Grade 2 nivolumab-related uveitis, eye pain or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 severity within 6 weeks 
or requires systemic treatment 
● 
Any Grade 3 non-skin, nivolumab-related AE lasting more than 7 days, with the 
following exceptions for laboratory abnormalities (excluding LFT abnormalities 
detailed separately), nivolumab-related uveitis, pneumonitis, bronchospasm, HSRs, 
infusion reactions, and endocrinopathies: 
○ 
Grade 3 nivolumab-related uveitis, myocarditis, pneumonitis, bronchospasm, 
HSRs, or infusion reaction of any duration requires discontinuation 
○ 
Grade 3 nivolumab-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation 
○ 
Grade 3 nivolumab-related thrombocytopenia lasting more than 7 days or 
associated with bleeding requires discontinuation; other Grade 3 
nivolumab-related laboratory abnormalities (excluding LFT abnormalities 
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● 
Any Grade 4 nivolumab-related AE or laboratory abnormality (excluding LFT 
abnormalities detailed separately), except for the following: 
○ 
Grade 4 neutropenia ≤7 days 
○ 
Grade 4 lymphopenia or leukopenia 
○ 
Isolated Grade 4 amylase or lipase abnormalities not associated with symptoms or 
clinical manifestations of pancreatitis; consult the medical monitor for Grade 4 
amylase or lipase abnormalities 
○ 
Isolated Grade 4 electrolyte imbalances/abnormalities not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset 
○ 
Grade 4 nivolumab-related endocrinopathy AEs, such as adrenal insufficiency, 
Adrenocorticotropic hormone deficiency, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with the medical 
monitor 
● 
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the patient with continued 
nivolumab dosing 
Any event that leads to delay in nivolumab dosing lasting >6 weeks from the previous 
nivolumab dose requires discontinuation of nivolumab treatment unless approved by the 
medical monitor, with the following exceptions: 
● 
Dosing delays to allow for prolonged steroid tapers to manage nivolumab-related AEs 
are allowed. Prior to re-initiating nivolumab treatment in a patient with a nivolumab 
dosing delay lasting >6 weeks from the previous nivolumab dose, the medical 
monitor must be consulted. Tumor assessments should continue as per protocol even 
if nivolumab dosing is delayed. Periodic study visits to assess safety and laboratory 
studies should also continue every 3 weeks or more frequently if clinically indicated 
during such dosing delays. 
● 
Dosing delays lasting >6 weeks from the previous nivolumab dose that occur for 
non-nivolumab-related reasons may be allowed if approved by the medical monitor. 
Prior to re-initiating nivolumab treatment in a patient with a nivolumab dosing delay 
lasting >6 weeks, the medical monitor must be consulted. Tumor assessments should 
continue as per protocol even if nivolumab dosing is delayed. Periodic study visits to 
assess safety and laboratory studies should also continue every 6 weeks or more 
frequently if clinically indicated during such dosing delays. 
 


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5.5.5.3 Dose Modifications for Liver Function Test Abnormalities 
Doses of nivolumab should be delayed in case of AST/ALT >3 and ≤5 times the ULN or 
total bilirubin >1.5 and ≤3 times the ULN. Nivolumab may be resumed if the value improves 
to Grade 0 or 1. 
Doses of nivolumab should be discontinued permanently for the following LFT 
abnormalities: 
● 
AST or ALT >8X ULN (Grade 3) or drug-induced liver injury (DILI) 
● 
Total bilirubin >5X ULN (Grade 3) or DILI 
● 
Concurrent AST or ALT >3X ULN and total bilirubin >2X ULN 
5.5.6 Storage and Handling 
Refer to the nivolumab Pharmacy Binder for nivolumab storage and handling instructions. 
5.5.7 Packaging and Labeling 
Refer to the investigational product label for information regarding packaging and labeling. 
5.5.8 Preparation 
Nivolumab should be prepared according to the package insert or according to institutional 
standards. 
5.6 Concomitant Therapy 
All concomitant medications, blood products, oxygen supplementation, and RT administered 
will be collected from Day 1 (predose) through the safety reporting period. Any concomitant 
medication given for a study protocol-related AE should be recorded from the time of 
informed consent. 
Patients enrolled in Part B of the study should receive premedication as described in 
Section 5.3.4. Patients enrolled in Part C of the study should receive premedication as 
described in Section 5.4.4. For Part D of the study, patients may only receive premedication 
as described in Section 5.5.4. 
5.6.1 Required Concomitant Therapy 
It is recommended that all patients be up-to-date on vaccinations prior to study entry. 
Additional vaccination(s) during each cycle of study treatment may be discussed by the 
medical monitor. 
5.6.2 Allowed Concomitant Therapy 
For patients enrolled in Parts A, B, E, or F, routine premedication for infusion reactions 
should not be administered prior to the first dose of brentuximab vedotin. However, patients 
who experience a Grade 1 or Grade 2 IRR may receive subsequent treatment with 
premedication as described in Section 5.2.3. Patients enrolled in Part B of the study should 
receive premedication as described in Section 5.3.4. Patients enrolled in Part C of the study 


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should receive premedication as described in Section 5.4.4. Patients enrolled in Part D of the 
study should receive premedication as described in Section 5.5.4. 
The use of platelet and/or red blood cell transfusions when applicable is allowed. The use of 
colony stimulating factors for the treatment or prophylaxis of neutropenia per institutional 
practice is permitted during therapy. Prednisone (or equivalent) ≤20 mg/day may be used for 
non-lymphomatous purposes; higher doses of steroids are allowed if indicated for antiemetic 
purposes or prevention of infusion reactions in Parts B, C, or D of the study. 
Routine prophylaxis with vaccines is permitted; it is recommended that vaccines used do not 
contain live micro-organisms. 
At the investigator’s discretion, brentuximab vedotin monotherapy dosing in Part A may be 
interrupted or may be followed after completion of treatment, by consolidative RT. RT may 
be given no sooner than 2 weeks after receiving brentuximab vedotin. If dosing is paused for 
RT, then RT should not be administered starting prior to the Cycle 8 response assessment, 
and brentuximab vedotin may be resumed no sooner than 2 weeks after RT is completed. 
RT-related dosing interruptions longer than 10 weeks must be approved by the sponsor. 
In Part B, combination treatment with brentuximab vedotin and dacarbazine may be followed 
by consolidative RT no sooner than 2 weeks after treatment and only after concluding 
dacarbazine treatment; single-agent brentuximab vedotin may be resumed no sooner than 
2 weeks after RT. 
In Part C, combination treatment with brentuximab vedotin and bendamustine may be 
followed by consolidative RT no less than 3 weeks after treatment and only after concluding 
bendamustine treatment; single-agent brentuximab vedotin may be resumed no less than 
2 weeks after RT. 
In Part D, brentuximab vedotin plus nivolumab dosing may be interrupted or may be 
followed after completion of treatment, by consolidative RT. RT may be given no sooner 
than 2 weeks after receiving treatment and should not be administered prior to the Cycle 8 
response assessment. The combination of brentuximab vedotin plus nivolumab may be 
resumed no sooner than 2 weeks after RT is completed. RT-related dosing interruptions 
longer than 10 weeks must be approved by the sponsor medical monitor. 
Also, in Part D, inhaled or topical steroids and adrenal replacement steroid doses >10 mg 
daily prednisone equivalent are permitted in the absence of active autoimmune disease. In 
addition, a steroid pulse is allowed prior to initiation of therapy for management of 
B symptoms, prophylaxis (e.g., contrast dye allergy), or for treatment of non-autoimmune 
conditions (e.g., delayed-type HSR caused by contact allergen) at the discretion of the 
investigator; the recommended dose is 40 mg of methylprednisolone or equivalent daily, and 
must be completed 1 week prior to initiation of study treatment. 
In Parts E and F, brentuximab vedotin monotherapy may be followed after completion of 
treatment, by consolidative RT, no sooner than 2 weeks after treatment. 


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5.6.3 Prohibited Concomitant Therapy 
Patients may not receive other investigational drugs, immunosuppressive medications 
(excluding steroids as described in Section 5.6.2), or systemic anti-neoplastic therapy during 
the study (with the exception of dacarbazine for patients enrolled on Part B, bendamustine 
for patients enrolled on Part C, and nivolumab for patients enrolled on Part D).  
In Part D, complementary medications (e.g., herbal supplements or traditional Chinese 
medicines) intended to treat the disease under study. Such medications are allowed if they are 
used as supportive care. Any live/attenuated vaccine (e.g., varicella, zoster, yellow fever, 
rotavirus, oral polio and measles, mumps, rubella) are not allowed during treatment and until 
100 days post last dose. 
5.7 Management of Adverse Reactions 
5.7.1 Management of Infusion Reactions 
IRRs may occur during the infusion of study treatment. 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 IRRs. 
Patients who have experienced a Grade 1 or Grade 2 IRR to brentuximab vedotin 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. Patients who experience a Grade 3 IRR to brentuximab 
vedotin may potentially receive additional treatment with brentuximab vedotin at the 
discretion of the investigator after discussion with the sponsor. Treatment with brentuximab 
vedotin should be discontinued for patients who experience Grade 4 IRRs. 
Infusion reactions related to dacarbazine should be managed according to the package insert 
and/or institutional standard of care. 
With the combination of bendamustine and brentuximab vedotin, IRRs and delayed-type 
HSRs have been observed (LaCasce 2014). To reduce the risk of infusion reactions with 
bendamustine, all patients will be premedicated as described in Section 5.4.4. Infusion 
reactions related to bendamustine should be managed according to the package insert and 
institutional standard of care. 
With the combination of nivolumab and brentuximab vedotin (Part D), required 
premedication is described in Section 5.5.4. In case of late-occurring hypersensitivity 
symptoms to nivolumab (e.g., appearance of a localized or generalized pruritus within 
1 week after nivolumab treatment), symptomatic treatment may be given (e.g., oral 
antihistamine). Other premedication may be given based on SMC recommendation 
(e.g., corticosteroids). 


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If anaphylaxis occurs, brentuximab vedotin administration (and dacarbazine or bendamustine 
or nivolumab, if applicable) should be immediately and permanently discontinued. 
5.7.2 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 brentuximab vedotin Investigator’s Brochure for further details. 
If PML is suspected, hold further brentuximab vedotin dosing (and dacarbazine or 
bendamustine dosing, if applicable), and undertake a diagnostic work-up including (but not 
limited to): 
● 
Neurologic examinations, as warranted 
● 
Brain radiologic features by magnetic resonance imaging 
● 
PCR analysis: John Cunningham virus DNA detectable in cerebrospinal fluid 
 
If PML is confirmed, permanently discontinue treatment with brentuximab vedotin (and 
dacarbazine, bendamustine, or nivolumab, if applicable). 
5.7.3 Management of Overdose 
Weight-based dosing for brentuximab vedotin is based on patient actual body weight (see 
Section 5.2.2), with the exception of patients weighing greater than 100 kg; doses will be 
based on 100 kg for these individuals. The maximum dose calculated per cycle in this 
study is 180 mg for patients receiving the 1.8 mg/kg dose level, and 120 mg for patients 
receiving 1.2 mg/kg dose level. 
In the event of an overdose of brentuximab vedotin ≥10%, study personnel should: 
● 
Care for and medically stabilize the patient until there is no immediate risk of 
complications or death, if applicable. There is currently no known antidote for an 
overdose of brentuximab vedotin. 
● 
Notify the Medical Monitor as soon as they become aware of the overdose, to discuss 
details of the overdose (e.g., exact amount of brentuximab vedotin administered, 
patient weight) and AEs, if any. 
For the management of overdoses of dacarbazine, bendamustine, or nivolumab, refer to the 
prescribing information of each drug. 
5.8 Treatment Compliance 
Study drug administration is performed by study site staff and documented in source 
documents and the CRF. 


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6 
STUDY ACTIVITIES 
6.1 Schedule of Events 
AE and concomitant medications will be collected from Day 1 (predose) through the safety 
reporting period (see Section 7.7.1.3). Any study protocol-related AE should be recorded 
from the time of informed consent as well as any concomitant medications given for 
treatment of the AE. A schedule of events for Parts A, B, and C is provided in Appendix A, a 
schedule of events for Part D is provided in Appendix B, and a schedule of events for Parts E 
and F is provided in Appendix C. Study activities are listed by visit in this section and 
descriptions of all study assessments are presented in Section 7. Activities are applicable to 
all parts of the study unless otherwise specified. 
6.2 Screening Visit (Days –28 to Day 1) 
● 
Informed consent 
● 
Study eligibility per inclusion/exclusion criteria (see Sections 4.1 and 4.2) 
● 
Medical history 
● 
Parts E and F: evaluate CIRS score and IADL score  
● 
CT of chest, abdomen, and pelvis (and neck, if clinically indicated) (within prior 
45 days) (see Section 7.2) 
● 
PET (within prior 45 days) (Note: a combined CT/PET may be obtained to satisfy the 
requirements for CT and PET scanning) (see Section 7.2) 
● 
Archived or fresh tumor specimen collection for biomarker analysis, including CD30 
by a central laboratory (see Section 7.6) 
● 
Review pathology report to confirm histopathological diagnosis of HL or PTCL 
● 
Electrocardiogram (ECG) 
● 
Ejection fraction via echocardiogram or multigated acquisition (MUGA) scan (within 
12 months prior to treatment initiation for Parts A, B, C, and D only, and within 
28 days for Parts E and F) 
● 
Part D only 
○ 
Pulmonary function test (see Section 7.1) 
● 
Parts D, E, and F only: 
○ 
Serology for hepatitis B 
○ 
Hepatitis C serology with reflex to hepatitis C virus ribonucleic acid (RNA) by 
PCR (see Section 7.7.2) 
● 
Part F only: Bone marrow biopsy (if bone marrow biopsy was previously performed 
as part of initial diagnostic workup for PTCL and results are available, it is not 
required to be repeated during screening). 


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6.2.1 Baseline Visit (Days –7 to Day 1) 
● 
Height (see Section 7.7.3) and weight 
● 
ECOG performance status, Karnofsky score in Parts A to D (Appendix F) 
● 
Physical examination (see Section 7.7.3) 
● 
Serum chemistry panel (see Section 7.7.2) 
○ 
Including LDH, phosphorus, and uric acid 
○ 
Including lipase (Parts C and D only) 
○ 
Including amylase (Part D only) 
○ 
Including thyroid-stimulating hormone (TSH), free T3, and free T4 (Part D only) 
● 
Complete blood count (CBC) with differential (see Section 7.7.2) 
● 
Estimated creatinine clearance (eGFR for Parts E and F) 
● 
Erythrocyte sedimentation rate 
● 
B symptom assessment 
● 
Measurement of oxygen saturation by pulse oximetry (Part D only) 
● 
In Parts A to D: Geriatric assessment (see Section 7.1) 
● 
In Parts E and F: serum or urine β-hCG pregnancy test for patients of childbearing 
potential 
6.3 Treatment Period (Day 1 to Day 21) 
6.3.1 Each 21-Day Cycle (Day 1 ±2 days) 
● 
Predose (All results, including lab results, should be captured and reviewed prior to 
dosing) 
○ 
Weight (Cycle 2 and all subsequent cycles) 
○ 
ECOG performance status 
○ 
Physical examination (Cycle 2 and all subsequent cycles) 
○ 
Serum chemistry panel 
̵ 
Including LDH, phosphorus, and uric acid 
̵ 
Including lipase (Parts C and D only) 
̵ 
Including amylase (Part D only) 
̵ 
Including TSH, free T3, and free T4 (every other cycle beginning in Cycle 2; 
Part D only) 
○ 
CBC with differential 
○ 
Estimated creatinine clearance (Parts C and D; eGFR for Parts E and F)  
○ 
B symptom assessment 
○ 
Brentuximab vedotin (Parts A, B, C, and D only) and nivolumab (Part D only) PK 
and pharmacodynamic samples (Only Cycles 1, 2, 4, and every 4 cycles 
thereafter; see Sections 7.4 and 7.5) 


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○ 
Brentuximab vedotin (Parts E and F only) PK and samples (Cycles 1, 2, and 3 
only)  
○ 
Brentuximab vedotin (all parts) and nivolumab (Part D only) immunogenicity 
(ATA) (Only Cycles 1, 2, 4, and every 4 cycles thereafter; see Section 7.4 for 
collection time points) 
○ 
Blood samples for biomarker assessments (Only Cycles 1, 2, and 3; Part D only) 
(see Section 7.5) 
● 
Study drug administration 
○ 
Brentuximab vedotin administration 
○ 
Dacarbazine administration (Part B only; Cycles 1 to 12) 
○ 
Bendamustine administration (Part C only; Cycles 1 to 6) (not applicable as of 
7-Oct-2015) 
○ 
Nivolumab administration (Part D only) 
● 
Postdose 
○ 
Brentuximab vedotin (Parts A, B, C, and D only) and nivolumab (Part D only) PK 
samples (Only Cycles 1, 2, 4, and every 4 cycles thereafter; see Section 7.4) 
○ 
Brentuximab vedotin (Parts E and F only), PK and samples (Cycles 1, 2, and 3 
only)  
6.3.2 Cycles 1 to 6 (Day 2 [+1 day]): Part C Only (Not Applicable as of 
7-Oct-2015) 
In the absence of IRRs or HSRs, patients in Part C only will receive bendamustine 
approximately 24 hours after the Day 1 study drug dose for up to 6 cycles. 
6.3.3 Cycle 1 (Day 8 [±1 day]): Part D Only 
● 
Physical examination (see Section 7.7.3) 
● 
Serum chemistry panel (see Section 7.7.2) 
○ 
Including LDH, phosphorus, and uric acid 
○ 
Including amylase and lipase 
● 
CBC with differential (see Section 7.7.2) 
● 
Measurement of oxygen saturation by pulse oximetry 
● 
Brentuximab vedotin and nivolumab PK samples (see Section 7.4) 
● 
Blood samples for biomarker assessments (see Section 7.5) 


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6.3.4 Cycle 1 (Day 15 [±1 day]): Part D Only 
● 
Physical examination (see Section 7.7.3) 
● 
Serum chemistry panel (see Section 7.7.2) 
○ 
Including LDH, phosphorus, and uric acid 
○ 
Including amylase and lipase 
● 
CBC with differential (see Section 7.7.2) 
● 
Measurement of oxygen saturation by pulse oximetry 
● 
Brentuximab vedotin and nivolumab PK samples (see Section 7.4) 
● 
Blood samples for biomarker assessments (see Section 7.5) 
6.3.5 Cycle 1 (Days 1, 2, 3, 8, and 15): Parts A, B, and C Only 
● 
Brentuximab vedotin PK samples (see Section 7.4) 
6.3.6 Cycle 2 (Day 8 [+1 day]): Part D Only 
● 
Blood samples for biomarker assessments (see Section 7.5) 
6.3.7 Cycles 2, 4, 8, 12, and 16 (Days 15 to 21 [+2 days]): Parts A, B, C, and D 
only 
Response assessments will be completed prior to dosing for the subsequent treatment cycle. 
● 
CT: CT of chest, abdomen, and pelvis (and neck, if clinically indicated) (see 
Section 7.2.1 for Parts A, B, and C, and Section 7.2.2 for Part D). CT is required at 
Cycle 16 only for patients eligible for continued treatment with brentuximab vedotin 
(and/or nivolumab for Part D only) beyond 16 cycles. 
● 
PET: For Parts A, B, and C, PET scans at Cycles 2 and 8; for Part D, PET scans at 
Cycles 4, 8, and 12. (Note: a combined CT/PET may be obtained to satisfy the 
requirements for CT and PET scanning). Also, for Part D, PET is required at Cycle 16 
only for patients eligible for continued treatment with brentuximab vedotin and/or 
nivolumab beyond 16 cycles. For all parts, once a PET CR is achieved, PET scans are 
no longer required. PET scans performed as part of institutional standard of care may 
be collected at any time during the study, as available. 
● 
Radiographic imaging for IR response: For patients on Part D with a response 
determination of IR, radiographic assessment (CT/PET) of disease must be performed 
12 weeks following IR or earlier if clinically indicated. If a patient has a second 
determination of IR, then subsequent repeat imaging must be performed between 4 
and 8 weeks. Follow-up radiographic assessment for patients with IR is not required 
if a follow-up biopsy has been performed that confirms response. 
6.3.8 Cycles 2, 6, and 11 (Days 15 to 21 [+2 days]): Parts E and F Only 
● 
CT: CT of chest, abdomen, and pelvis (and neck, if clinically indicated) (see 
Section 7.2.3). 


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● 
PET: (Note: a combined CT/PET may be obtained to satisfy the requirements for CT 
and PET scanning). Once a CR is achieved, PET scans are no longer required. 
● 
Any imaging performed as part of institutional standard of care at any time during the 
study should be collected. 
6.4 Cycles 17 and Beyond (Days 15 to 21 [+2 days]): Parts A, B, C, and D Only 
Response assessments will be completed prior to dosing for the subsequent treatment cycle. 
● 
CT of chest, abdomen, and pelvis (and neck, if clinically indicated) (see Section 7.2) 
per institutional standard of care or at least every 6 cycles after Cycle 16. 
● 
PET scans performed per institutional standard of care. Once a CR is achieved, PET 
scans are no longer required. 
6.5 At Time of Progression or Relapse (All Parts), or If Residual Disease at 
Cycle 8 or Suspected Tumor Flare/Pseudoprogression (Part D Only) 
● 
Biopsy (see Section 7.6); optional at progression of disease for all parts of the study, 
or for Part D, optional if evidence of residual disease is suspected at Cycle 8 to 
distinguish active HL from inflammatory infiltrate or if tumor flare or 
pseudoprogression is suspected to determine if there is viable tumor in new or 
enlarging lesions (Note: It is strongly recommended to confirm that radiological 
evidence of progression is correlated with active HL; when possible, excisional 
biopsies should be performed). 
6.6 End of Treatment Visit (30 to 37 Days After Last Dose of Study Drug) 
If EOT evaluations are completed before 30 days after the last component of study treatment 
(brentuximab vedotin, dacarbazine, bendamustine, or nivolumab), the patient will be 
contacted by phone 30 to 37 days following the last component of study treatment to assess 
for AEs. 
EOT assessments will be performed before any other therapeutic intervention, if possible. 
● 
ECOG performance status 
● 
Physical examination (see Section 7.7.3) 
● 
Parts E and F: evaluate CIRS score and IADL score 
● 
In Parts E and F: serum or urine β-hCG pregnancy test for patients of childbearing 
potential 
● 
B symptom assessment 
● 
Serum chemistry panel (see Section 7.7.2) 
○ 
Including LDH, phosphorus, and uric acid 
○ 
Including amylase and lipase (Part D only) 
○ 
Including TSH, free T3, and free T4 (Part D only) 
● 
CBC with differential (see Section 7.7.2) 


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● 
Brentuximab vedotin (Parts A, B, C, and D only) and nivolumab (Part D only) PK 
and pharmacodynamic samples (see Sections 7.4 and 7.5) 
● 
Brentuximab vedotin (all parts) and nivolumab (Part D only) immunogenicity (ATA) 
(see Section 7.4) 
● 
Blood samples for biomarker assessments (Part D only) (see Section 7.5) 
● 
CT of chest, abdomen, and pelvis (and neck, if clinically indicated). CT not needed if 
done in prior 6 weeks.  
● 
PET (Note: a combined CT/PET may be obtained to satisfy the requirements for CT 
and PET scanning, as long as CT is of diagnostic quality). PET not needed if done in 
prior 6 weeks. Once a CR is achieved, PET scans are not required. 
6.7 Safety Visit (100 days [+2 weeks] After Last Dose of Nivolumab): Part D 
Only 
The final safety visit should occur 100 days after the last dose of nivolumab or 30 to 37 days 
after the last dose of brentuximab vedotin (EOT visit), whichever is later. The following 
assessments will be performed: 
● 
ECOG performance status 
● 
Physical examination, including assessment for potential immune-mediated AEs (see 
Section 7.7.3) 
● 
Serum chemistry panel (see Section 7.7.2) 
○ 
Including LDH, phosphorus, and uric acid 
○ 
Including amylase and lipase 
○ 
Including TSH, free T3, and free T4 
● 
CBC with differential (see Section 7.7.2) 
● 
Nivolumab immunogenicity (ATA) (see Section 7.4) 
● 
Blood samples for biomarker assessments (Part D only) (see Section 7.5) 
6.8 Follow-up 
After the EOT visit and 30-day safety period (or 100-day safety period relative to nivolumab 
dosing on Part D), all patients who receive at least 1 dose of brentuximab vedotin will be 
followed until withdrawal of consent, death, or the study closure. Information regarding 
survival, disease status, and additional or alternative therapies used for treatment of their 
lymphoma will be collected. 


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Prior to Progression 
For Parts A, B, C, and D, patients who have not progressed at EOT will be followed for 
survival status at 3-month intervals (±2 weeks) which may be conducted with a clinic visit or 
a telephone call. Disease status will be assessed by CT imaging per institutional standard of 
care or at least approximately every 6 months following the most recent prior radiographic 
response evaluation for the first 2 years, an annual assessment for the third year, then per 
institutional standard of care until progression.  
For Parts E and F, patients discontinuing study treatment without progression will be 
followed until progression or initiation of further anti-cancer therapy. Follow-up CT scans 
will be performed every 4 months for 2 years and then per institutional standard of care, and 
follow-up PET scans will be performed per institutional standard of care. Lymphoma 
assessments are to be performed at least approximately every 6 months during follow-up. 
Upon progression, data regarding any subsequent anti-cancer therapies administered will be 
summarized and reported. 
After Progression 
Survival status follow-up will be conducted for patients who have progressed or started 
further anti-cancer treatment at 3-month intervals (±2 weeks) in Parts A to D and at 4-month 
intervals (±2 weeks) in Parts E and F. Survival follow-up contact may be conducted with a 
clinic visit or a telephone call. 
6.9 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. 


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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. 
Review of a pathology report from local laboratory will be used to confirm histopathological 
diagnosis of HL when determining eligibility for this study. For PTCL, tissue from the 
diagnostic biopsy must confirm CD30 expression by visual assessment using 
immunohistochemistry. Assessment of CD30 expression to determine eligibility for patients 
with PTCL will be performed by the institutional lab (using the anti-CD30 BerH2 antibody) 
with a requirement that CD30 expression be detected in ≥1% of neoplastic cells. 
Diagnostic tumor tissue will be sent to a central repository designated by the sponsor and will 
subsequently be sent to a central laboratory for a retrospective analysis of disease-related 
biomarkers, including CD30. If archived tissue is not available or of insufficient quantity for 
central analysis, fresh tissue should be collected. 
Performance status will be assessed by the ECOG Performance Status scale and the 
Karnofsky score in Parts A to D (Appendix F). 
In Parts A to D, before initiation of protocol therapy, a baseline geriatric assessment will be 
performed using components from a tool developed and evaluated by Hurria et al. (Hurria 
2011). Assessment variables may include but not be limited to aspects of function, 
comorbidity, cognition, psychological state, social activity/support, and nutritional status. 
Patient medical history includes a thorough review of significant past medical history, 
current conditions, any treatment for prior malignancies and response to prior treatment, and 
any concomitant medications. 
For Part D only, pulmonary function tests evaluating spirometry, such as DLCO (hemoglobin 
adjusted), diffusing capacity of the lungs volume adjusted, diffusing capacity of the lungs 
volume and hemoglobin adjusted, total lung capacity, forced vital capacity, and forced 
expiratory volume in 1 second, are required for all patients at screening. DLCO over 50% 
(adjusted for hemoglobin) must be confirmed by a pulmonary function test of lung diffusion 
capacity prior to study enrollment. 
For Parts E and F, the reason(s) for patients being unsuitable or unfit to receive multi-agent 
chemotherapy determined at screening (the presence of comorbidity-related factors, as 
documented by a CIRS score ≥10 [Appendix G] (according to the criteria specified by Salvi 
and colleagues (Salvi 2008) and excluding current active lymphoma) or requiring assistance 
with or dependence on others for any IADLs [Appendix H]) will documented on the CRF. 


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7.2 Response Assessments 
7.2.1 Parts A, B, and C 
For Parts A, B, and C of the study, treatment response will be assessed by spiral CT scan of 
the chest, abdomen, and pelvis (and neck, if clinically indicated) and PET scans performed at 
protocol-specified time points (see Section 6 and Appendix A), and whenever disease 
progression is suspected. A combined CT/PET of diagnostic quality may be obtained to 
satisfy the requirements for CT and PET scanning. With either CT/PET or diagnostic CT, it 
is preferred that both oral and IV contrast are used, except when contraindicated or not 
feasible. 
The determination of antitumor efficacy will be based on objective response assessments 
made according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007) 
and treatment decisions by the Investigator will be based on these assessments. Clinical 
response of PD, SD, PR, or CR will be determined at each assessment. Progressive disease 
also includes clinical disease progression per investigator. Selection of up to 6 of the largest 
dominant nodes or nodal masses to follow for response assessment must be PET FDG-avid at 
baseline. Investigator evaluation of baseline radiographic assessment will enable study 
enrollment per Inclusion Criterion 4. In addition, per the Revised Response Criteria for 
Malignant Lymphoma, these nodes or masses should be selected according to all of the 
following: they should be clearly measurable in at least 2 perpendicular dimensions; if 
possible, they should be from disparate regions of the body; and they should include 
mediastinal and retroperitoneal areas of disease whenever these sites are involved. The nodes 
or masses should have bidimensional measurements of at least 1.5 cm in the longest axis. 
In addition, visual interpretation will be used for exploratory evaluation of interim PET scans 
with response scored with reference to sites of presumed lymphomatous involvement using 
the 5-Point Scale per the Deauville Criteria in Appendix I (Barrington 2010; Meignan 2009). 
For interim PET scans performed while patients are receiving study therapy, scores of 1, 2, 
and 3 with uptake in sites abnormal on the staging scan equal or less than liver uptake will be 
regarded as “negative” while scores of 4 and 5 with uptake greater than liver will be regarded 
as positive. PET scans performed at the EOT and beyond will be evaluated per the Revised 
Response Criteria for Malignant Lymphoma (Cheson 2007; Juweid 2007). PET scans 
performed per institutional standard of care may be collected at any time during the study, as 
available, for this exploratory evaluation. 
Once a CR is documented, no further PET scans are required during the study. After the 
patient is withdrawn from study drug for any reason, an additional response assessment will 
be performed at the EOT visit if an assessment has not been performed within the prior 
6 weeks. Patients with SD or better may continue on study drug for up to 16 cycles or more. 
After discussion with the medical monitor, patients who complete 16 cycles of treatment and 
experience clinical benefit per the investigator will be eligible to continue receiving 
additional brentuximab vedotin treatment until disease progression, unacceptable toxicity, or 
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Patients’ clinical data must be available for CRF source verification. All imaging studies 
must be copied to CDs and provided to the sponsor. At the end of the study the images may 
either be sent to a central radiology facility for confirmation of disease response or destroyed. 
7.2.2 Part D 
For Part D of the study, the determination of antitumor activity will be based on response 
assessments made according to the Lugano criteria (Cheson 2014) and according to LYRIC 
(Cheson 2016) (Appendix J). Treatment decisions by the investigator will be based on these 
assessments. Staging will be performed by PET/CT of diagnostic quality at 
protocol-specified time points (see Section 6 and Appendix B), with disease involvement 
determined by focal FDG uptake in nodal and extranodal (including spleen, liver, bone 
marrow, and thyroid) sites that is consistent with lymphoma, according to the pattern of 
uptake and/or CT characteristics. Up to 6 of the largest nodes, nodal masses, or other 
involved lesions that are measurable in 2 diameters should be identified as target lesions at 
baseline; if possible, they should be from disparate regions of the body and they should 
include mediastinal and retroperitoneal areas of disease whenever these sites are involved. 
At Cycle 2 (Days 15–21), a CT scan of diagnostic quality will be performed to assess for PD; 
a limited scan that includes sites of disease identified at baseline is acceptable. For all other 
response assessments, a clinical response of PD, SD, PR, or CR will be determined unless 
tumor flare or pseudoprogression is suspected. If tumor flare or pseudoprogression is not 
suspected, PD includes radiological evidence of progression per Lugano criteria. If clinical 
progression is determined by the investigator, radiographic staging should also be performed 
to determine response assessment per Lugano criteria. The PET scan metabolic uptake will 
be graded using the Deauville 5 point scale (Appendix I) (Barrington 2010; Biggi 2013) with 
a score of ≤3 considered to represent a complete metabolic response. Except for the Cycle 2 
response assessment, both PET and CT scanning will be required until disease is PET 
negative; responses will then be followed by CT scan of diagnostic quality only. 
If tumor flare or pseudoprogression is suspected by the Investigator during treatment with the 
combination of brentuximab vedotin and nivolumab, during single-agent nivolumab therapy 
(if brentuximab vedotin discontinued), or during single-agent brentuximab vedotin therapy 
within 12 weeks of discontinuing nivolumab, then a clinical response of IR will be 
determined until subsequent mandatory evaluation of radiographic imaging or biopsy 
confirms or refutes PD. IR is defined below. See Appendix J for further details and criteria 
for follow-up of a response of IR. 
1) An increase in overall tumor burden (as assessed by the sum of the products of the largest 
diameter [SPD]) of ≥50% of up to 6 measurable lesions in the first 12 weeks of therapy, 
without clinical deterioration; 
2) Appearance of new lesions, or growth of 1 or more existing lesion(s) ≥50% at any time 
during treatment, occurring in the context of lack of overall progression (<50% increase) 
of overall tumor burden, as measured by SPD of up to 6 lesions at any time during 
treatment; and  


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3) An increase in FDG uptake (using the 5-Point Scale per the Deauville Criteria 
[Appendix I]) of 1 or more lesion(s) without a concomitant increase in lesion size or 
number. 
Repeat imaging 12 weeks (or earlier if clinically indicated) after a response of IR is 
determined by the Investigator is mandatory and PD must be confirmed or refuted based 
LYRIC follow-up criteria for IR (Cheson 2016). If a patient has a second determination of 
IR, then subsequent repeat imaging must be performed between 4 and 8 weeks. Follow-up 
radiographic assessment for patients with IR is not required if a follow-up biopsy has been 
performed that confirms response. 
Patients’ clinical data must be available for CRF source verification. All imaging studies 
must be copied to CDs and provided to the sponsor. At the end of the study the images may 
either be sent to a central radiology facility for confirmation of disease response or destroyed. 
7.2.3 Parts E and F 
Treatment response will be assessed by spiral CT scan of the chest, abdomen, and pelvis (and 
neck, if clinically indicated) and PET scans performed at protocol-specified time points (see 
Section 6 and Appendix C), and whenever disease progression is suspected. A combined 
CT/PET of diagnostic quality may be obtained to satisfy the requirements for CT and PET 
scanning. With either CT/PET or diagnostic CT, it is preferred that both oral and IV contrast 
are used, except when contraindicated or not feasible. If a patient has an allergy to the IV CT 
contrast agent, magnetic resonance imaging (MRI) with and without gadolinium contrast is 
to be used; if, in addition, the patient cannot tolerate gadolinium, CT without IV contrast 
should be used. Oral contrast should be used whenever possible, even if IV contrast is 
contraindicated. After the patient has discontinued from study drug for any reason, an 
additional response assessment will be performed at the EOT visit if an assessment has not 
been performed within the prior 6 weeks. Patients with SD or better may continue on study 
drug for up to 16 cycles. Clinical data will be submitted. If clinical progression is determined 
by the investigator, radiographic imaging should also be performed to determine response. If 
new lesions are suspected based on the CT/PET assessment, a conformational biopsy may be 
considered. 
All patients’ clinical data and tumor images must be available for CRF source verification. 
Copies of all imaging studies must be made available for review by the sponsor (or its 
designee) and the third party imaging core laboratory. Refer to the Study Manual for details 
(instructions on collecting and submitting tumor imaging studies for third-party imaging core 
laboratory review). 


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7.2.3.1 Modified Lugano Criteria  
Although, treatment decisions and response assessment by the Investigator will be based on 
local disease assessments according to Lugano criteria (Section 7.2.3.2), the primary 
determination of antitumor efficacy will be ORR according to modified Lugano criteria: the 
Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin 
lymphomas (Cheson 2014) modified to take into account CT response in the event of a PET 
PR (Appendix M). Disease response of PD, SD, PR, CR, or not evaluable (NE) will be 
determined at each assessment by BICR. Selection of up to 6 of the largest dominant nodes 
or other tumor lesions to follow for response assessment must be PET FDG-avid at baseline. 
Investigator evaluation of baseline radiographic assessment will enable study enrollment per 
Inclusion Criterion 4. In addition, per Lugano criteria, these nodes or masses should be 
selected according to all of the following: they should be clearly measurable in at least 
2 perpendicular dimensions; if possible, they should be from disparate regions of the body; 
and they should include mediastinal and retroperitoneal areas of disease whenever these sites 
are involved. The nodes or masses should have bidimensional measurements with at least 
1.5 cm in the longest axis. For PET scans, Deauville scores of 1, 2, and 3 will be regarded as 
“negative” while scores of 4 and 5 with uptake greater than background liver uptake will be 
regarded as positive. 
As detailed in the Independent Review Charter, the integrated response at each disease 
assessment will be determined on the basis of PET and CT responses according to modified 
Lugano criteria, as summarized in Appendix M.  
For time points where both PET and CT disease assessments are available, the response 
assessment will in general default to the PET assessment; however, when a PR is determined 
by PET but the CT response in neither CR nor PR, the integrated response will be SD. Once 
a CR has been determined by PET assessment, the integrated response will continue to be CR 
until PD is detected by PET or CT, even if there are no further PET assessments. When the 
CT response is PD and PET was not evaluated the integrated response will be PD.  
7.2.3.2 Lugano Criteria 
Both the Investigator and the BICR will assess response according to the unmodified Lugano 
criteria (Cheson 2014). Assessment of response will be undertaken in the same manner as for 
modified Lugano criteria (Section 7.2.3.1), with the exception that if the PET response is PR 
the integrated response will be PR, irrespective of CT response (Table 2).  


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Table 2 
Integrated PET and CT response according to Lugano criteria 
PET Response 
CT Response 
Integrated Response 
CR 
Any 
CR 
PR 
Any 
PR 
SD 
Any 
SD 
PD 
Any 
PD 
Not done or  
Not evaluable 
Prior PET response a 
CT Response 
 
CR 
Non-PD 
CR b 
non-CR 
Non-PD 
NE 
Any 
PD 
PD 
No FDG-avid disease 
at baseline c 
No disease present (NE) 
NE 
PD 
PD 
NE=not evaluable 
a 
“Prior PET response” refers to the latest prior PET assessment that was evaluable. PET responses may be carried 
forward over multiple CT assessments. 
b 
A CR according to PET will be carried forward irrespective of CT response, until CT shows PD or is assessed as NE. 
c 
Per protocol all patients must have FDG-avid disease at baseline. 
 
7.2.3.3 International Working Group Consensus Response Evaluation Criteria 
in Lymphoma 
ORR according to RECIL per BICR assessment will be evaluated as an additional efficacy 
endpoint. See Appendix K for details concerning RECIL assessment. 
7.3 Lymphoma Assessments 
Lymphoma assessments are to be performed at the time points outlined in Section 6.8, 
Appendix A, Appendix B, and Appendix C. Every effort must be made to perform 
lymphoma assessments according to the schedule of events to prevent the introduction of 
bias based on treatment delays. 
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. 
○ 
Concomitant medications. 
● 
Physical examination, including evaluation of skin, head, eyes, ears, nose, and throat, 
lymph nodes, heart, lungs, abdomen, back, extremities, and neurology. 


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7.4 Pharmacokinetic and Pharmacodynamic Assessments 
For Parts A, B, and C, serum concentrations of brentuximab vedotin ADC and plasma 
concentrations of MMAE will be measured at selected time points in Cycle 1 and at predose 
and end of infusion in subsequent cycles (see Table 3). ATA to brentuximab vedotin will also 
be measured predose on Cycles 1, 2, 4, every 4 cycles thereafter, and EOT. Samples will be 
retained for measurement of total antibody, if needed. 
For Part D, serum concentrations of brentuximab vedotin ADC and nivolumab, and plasma 
concentrations of MMAE will be measured at selected time points (see Table 4). ATA 
against brentuximab vedotin and ATA against nivolumab will also be assessed. 
For Parts E and F, serum concentrations of brentuximab vedotin ADC and plasma 
concentrations of MMAE will be measured at predose and end of infusion in Cycles 1, 2, and 
3 only. ATA to brentuximab vedotin will also be measured predose on Cycles 1, 2, 4, every 
4 cycles thereafter, and EOT. Samples will be retained for measurement of total antibody, if 
needed. 
PK parameters to be estimated include the AUC, maximum concentration for MMAE (Cmax) 
and the time Cmax occurred (Tmax), concentration at the end of infusion (Ceoi) for brentuximab 
vedotin ADC (all parts) and nivolumab (Part D only), and trough concentration (Ctrough). PK, 
demographic, and clinical laboratory data may be incorporated into the brentuximab vedotin 
population PK model for further model refinement and parameter estimation. The incidence 
of ATA to brentuximab vedotin (all parts) and nivolumab (Part D only) will also be assessed. 
For Parts A, B, C, E, and F, blood samples will be collected (predose at each cycle) for 
measurement of pharmacodynamic biomarkers, such as soluble CD30 (sCD30), cytokines, 
chemokines, or other disease-related biomarkers and brentuximab vedotin-related species. 
Table 3 presents the PK, pharmacodynamic, and immunogenicity sample collection time 
points for Parts A, B, and C. Table 4 presents the PK and immunogenicity sample collection 
time points for Part D; see Section 7.5 for pharmacodynamics in Part D. Table 5 presents the 
PK, pharmacodynamic, and immunogenicity sample collection time points for Parts E and F. 
All sampling times are relative to the start of brentuximab vedotin infusion, except for the 
end of infusion concentrations, which are relative to the end of brentuximab vedotin infusion. 
Refer to the Research Specimen Manual for information on collection, processing, storage, 
and shipment of samples. 
 


 
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Table 3: 
Pharmacokinetic, pharmacodynamic, and immunogenicity sampling time points (Parts A, B, and C) 
Cycle 
Study Day 
Time 
Window 
Relative Timea 
PK 
Biomarkersc 
ATAb 
1 
Day 1 
Predose 
Within 24 hours prior to start of infusion 
Start of infusion 
X 
X 
X 
End of infusion 
Within 15 min post end of infusion 
End of infusion 
X 
 
 
Day 2 
24 hours 
±4 hours 
Start of infusion 
X 
 
 
Day 3 
48 hours 
±4 hours 
Start of infusion 
X 
 
 
Day 8 
168 hours 
±24 hours 
Start of infusion 
X 
 
 
Day 15 
336 hours 
±24 hours 
Start of infusion 
X 
 
 
2 and  
subsequent 
cycles  
Day 1 
Predose 
Within 8 hours 
Start of infusion 
X 
X 
X 
End of infusion 
Within 15 min post end of infusion 
End of infusion 
X 
 
 
EOT  
 
X 
X 
X 
a 
The relative time is related to the administration of brentuximab vedotin. 
b 
Samples for immunogenicity will be collected predose on Cycles 1, 2, 4, every 4 cycles thereafter, and EOT. 
c 
Biomarkers include, but are not limited to, pharmacodynamics biomarkers such as sCD30, cytokines, chemokines, or other disease-related biomarkers and brentuximab 
vedotin-related species. 
 
 


 
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Table 4: 
Pharmacokinetic and immunogenicity sampling time points (Part D only) 
Cycle 
Study 
Day 
Time 
Window 
Relative Timea 
Brentuximab 
Vedotin PK 
Nivolumab 
PK 
Brentuximab 
Vedotin 
+ nivolumab ATA 
Baseline 
 
 
 
 
 
 
 
1 
Day 1 
Pre-dose 
Within 24 hours prior to start of 
brentuximab vedotin infusion 
Start of brentuximab 
vedotin infusion 
X 
X 
X 
End of 
infusion 
Within 15 min post end of 
brentuximab vedotin infusion 
End of brentuximab 
vedotin infusion 
X 
 
 
End of 
infusion 
Within 15 min post end of 
nivolumab infusion 
End of nivolumab 
infusion 
 
X 
 
Day 8 
168 hours 
post-dose 
±24 hours 
Start of brentuximab 
vedotin infusion 
X 
X 
 
Day 15 
336 hours 
post-dose 
±24 hours 
Start of brentuximab 
vedotin infusion 
X 
X 
 
2 and 4, 
and every  
4 cycles 
thereafter 
Day 1 
Pre-dose 
Within 24 hours prior to start of 
brentuximab vedotin infusion 
Start of brentuximab 
vedotin infusion 
X 
X 
X 
End of 
infusion 
Within 15 min post end of 
brentuximab vedotin infusion 
End of brentuximab 
vedotin infusion 
X 
 
 
End of 
infusion 
Within 15 min post end of 
nivolumab infusion 
End of nivolumab 
infusion 
 
X 
 
EOT 
30+7 days post last dose of study drug(s) 
X 
X 
X 
Safety 
Follow-up 
100 days post last dose of nivolumab 
 
 
X 
a 
The relative times are related to the administration of brentuximab vedotin or nivolumab as specified. 
 


 
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Table 5: 
Pharmacokinetic and immunogenicity sampling time points (Parts E and F) 
Cycle 
Study Day 
Time 
Window 
Relative Timea 
PK 
ATA 
1  
Day 1 
Predose 
Within 24 hours prior to infusion 
Start of infusion 
X 
X 
End of infusion 
Within 15 min post end of infusion 
End of infusion 
X 
 
2 
Day 1 
Predose 
Within 8 hours 
Start of infusion 
X 
X 
End of infusion 
Within 15 min post end of infusion 
End of infusion 
X 
 
3 
Day 1 
Predose 
Within 8 hours 
Start of infusion 
X 
 
End of infusion 
Within 15 min post end of infusion 
End of infusion 
X 
 
4 then every 4 cycles 
Day 1 
Predose 
Within 8 hours 
Start of infusion 
 
X 
EOT 
 
 
 
 
 
X 
a 
The relative time is related to the administration of brentuximab vedotin. 
 
 


 
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7.5 Biomarker Studies: Part D Only 
Blood and tumor samples will be collected for measurement of other potential 
pharmacodynamic and patient stratification biomarkers. 
For peripheral blood sampling time points for biomarker analyses for Part D, see Table 6. 
Assessments may include, but are not limited to: 
● 
Flow cytometry of peripheral blood leukocytes to assess the expression of CD30, 
CD153, PD-1, PD-L1, and PD-L2 in specific T-cell (Th1, Th2, Th17, native, 
activated, effector and central memory), B-cell (naive, activated, memory, 
plasmablast and plasma cell), and myeloid cell (monocyte, dendritic cell) populations 
● 
Serum and/or plasma sCD30, CD153 (sCD153), and inflammatory 
cytokines/chemokines including, but not limited to, IFN-γ, IL-6, IL-18, CXCL11 
(I-TAC), CXCL9, CXCL10, MIP1 β, and TNF-α 
● 
Peripheral blood T-cell receptor (TCR) repertoire and T-cell responses from 
peripheral blood mononuclear cells (PBMCs) to assess the impact of brentuximab 
vedotin alone and in combination with nivolumab on immune status 
● 
RNA expression profiling 
 


 
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Table 6: 
Peripheral blood sampling time points for biomarker analyses (Part D only) 
Cycle 
Study 
Day 
Time 
Window 
Relative Time 
Flow 
Cytometry 
Plasma and 
Serum 
Cytokines 
Serum  
Bio-
markers 
RNA 
PBMC 
TCR 
1 
Day 1 
Pre-dose 
Within 24 hours 
prior to start of 
brentuximab 
vedotin infusion 
Start of 
brentuximab 
vedotin infusion 
X 
X 
X 
X 
X 
X 
Day 8 
168 hours 
post-dose 
±24 hours 
Start of 
brentuximab 
vedotin infusion 
X 
X 
X 
X 
X 
X 
Day 15 
336 hours 
post-dose 
±24 hours 
Start of 
brentuximab 
vedotin infusion 
X 
X 
X 
X 
X 
X 
2 
Day 1 
Pre-dose 
Within 24 hours 
prior to start of 
brentuximab 
vedotin infusion 
Start of 
brentuximab 
vedotin infusion 
X 
X 
X 
X 
X 
X 
Day 8 
168 hours 
post-dose 
±24 hours 
Start of 
brentuximab 
infusion 
X 
X 
X 
 
 
 
3 
Day 1 
Pre-dose 
Within 24 hours 
prior to start of 
brentuximab 
vedotin infusion 
Start of 
brentuximab 
vedotin infusion 
X 
 
 
 
 
 
EOT 
30+7 days post last dose of study drug(s) 
X 
X 
X 
X 
X 
X 
Safety 
Follow-up 
100 days post last dose of nivolumab 
X 
X 
X 
X 
X 
X 
 


 
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Baseline biomarker levels will be assessed by a central laboratory using tissue blocks or 
unstained slides obtained at screening to evaluate potential sensitivity or resistance to 
brentuximab vedotin and/or nivolumab (e.g., CD30 expression, PD-L1/L2 amplification and 
expression). For biomarker analyses on optional tumor biopsies obtained after disease 
progression or on residual disease at Cycle 8 (see Sections 6.5 and 7.6), samples are to be 
tested for the expression of CD30 and PD-L1/L2 expression and other potential markers to 
understand potential delayed response and/or resistance mechanisms. 
Assessments may include, but are not limited to the following: 
● 
Histopathology and immunohistochemistry of tumor biopsies for: 
○ 
Expression of PD-L1/L2, CD30, immune cell markers and expression of other 
immune checkpoint molecules in malignant Reed-Sternberg cells and tumor 
infiltrating lymphocytes by immunohistochemistry, as well as amplification 
of 9p24.1 
○ 
Tumor infiltrating lymphocytes (CD3, CD4, CD8, Foxp3+ and ratios thereof) 
○ 
Expression of CD30 and PD-1 among T, B, macrophage and myeloid cell 
populations including CD4, CD8, Foxp3, CD68, and CD163 
○ 
Amplification and expression of PD-L1 and PD-L2 by malignant Reed-Sternberg 
cells and tumor infiltrating lymphocytes 
○ 
Expression of other immune checkpoint molecules if an assay becomes available 
○ 
EBV infection status, if not previously known 
7.6 Other Study Assessments 
For Parts A, B, C, E, and F, at the time of study entry, tissue blocks (preferred) or unstained 
slides (if tumor block is unavailable) are required. If archived tissue is not available or of 
insufficient quantity for central analysis, fresh tissue should be collected. Prior to initiation of 
new therapy, additional tissue blocks or unstained slides are required at the time of 
progression or relapse unless re-biopsy would result in unacceptable risk in the setting of 
potential marginal benefit (Parts A, B, and C only). Exploratory assessments are planned for 
disease-related biomarkers. 
For Part D, tissue blocks (preferred) or unstained slides (if tumor block is unavailable) are to 
be collected at screening. If tumor tissue block is not available, a minimum of approximately 
20 unstained charged slides of the tumor tissue will be required. If multiple blocks are 
available, the block with the highest tumor content is preferred. If any tissue remains, the 
tumor pathology block may be returned to the original site by the Sponsor or designee at the 
end of the study upon request. See the Laboratory Manual for details. If tissue is unavailable, 
then discuss with sponsor medical monitor. 
Also for Part D, efforts should be made to take an additional biopsy in patients who 
demonstrate disease progression on study, residual disease at Cycle 8 (biopsy should be taken 
prior to RT if patient is going to have RT administered on study), or if tumor flare or 
pseudoprogression is suspected unless re-biopsy would result in unacceptable risk in the 
setting of potential marginal benefit. 


 
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For patients who provide additional consent on any part of the study, 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 ADCs, the biology of ADC 
sensitivity and resistance mechanisms, and to identify predictive pharmacodynamic 
biomarkers of ADCs. If additional consent is not provided, any remaining biological samples 
will be destroyed after the study has been completed and applicable regulatory obligations 
have been met. 
For Parts E and F, if the etiology of new lesions on CT/PET is uncertain, biopsy or interval 
scanning should be considered. 
7.7 Safety Assessments 
The assessment of safety during the course of this study will consist of the surveillance and 
recording of AE including SAE, recording of concomitant medication and measurements of 
protocol-specified physical examination findings and laboratory tests. For Part D only, pulse 
oximetry tests (O2 saturation) will also be performed. 
Safety will be monitored for patients in Parts C and D by an SMC as described in 
Section 3.2. 
7.7.1 Adverse Events 
7.7.1.1 Definitions 
Adverse Event 
According to the International Council for Harmonisation E2A guideline Definitions and 
Standards for Expedited Reporting, and 21 Code of Federal Regulations (CFR) 312.32, 
Investigational New Drug (IND) Safety Reporting, an AE is any untoward medical 
occurrence in a patient or clinical investigational patient 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 AEs 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. 
● 
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 postdose) through the end of the safety reporting period (see 
Section 7.7.1.3). 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. 


 
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● 
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 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 SAE by this criterion. 
Admission to a palliative unit or hospice care facility is not 
considered to be a hospitalization. Hospitalizations or prolonged 
hospitalizations for scheduled therapy of the underlying 
malignancy 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. Potential DILI also is considered a medically 
significant event (see Section 7.7.1.2 for the definition of potential 
DILI.) 
 
Adverse Event Severity 
AE severity should be graded using the 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 SAEs). 


 
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Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to brentuximab vedotin, dacarbazine, bendamustine, or 
nivolumab 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 
 
For Part D, the Investigator’s Brochures for brentuximab vedotin and nivolumab individually 
describe AEs commonly observed with either agent (i.e., neutropenia or peripheral 
neuropathy with brentuximab vedotin; and immune-mediated AEs with nivolumab), as well 
as less common serious findings. The respective Investigator’s Brochures should be 
referenced when attributing causality. 
7.7.1.2 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. 
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 


 
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Diagnosis versus 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. 
For Parts A, B, C, E, and F, important exceptions are adverse reactions associated with the 
infusion of study drug. For IRRs, do not use the NCI CTCAE terms of ‘cytokine release 
syndrome,’ ‘acute infusion reaction,’ or ‘allergic or HSR.’ Instead, record each sign or 
symptom as an individual AE. 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. 
For Part D, adverse reactions associated with the infusion of study drug must be recorded as 
both the NCI CTCAE term for IRR (i.e., cytokine release syndrome, acute infusion reaction, 
or allergic or HSR) and as each sign or symptom that occurs within a given infusion-related 
event. Level of severity for both the overall IRR term and the individual signs and symptoms 
should also be recorded. 
Recording Serious Adverse Events 
For SAEs, record the primary event on both the CRF and an SAE form; events occurring 
secondary to the primary event should be described on the SAE form in the narrative 
description of the case. 
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 Malignancy 
Since progression of underlying malignancy is being assessed as an efficacy variable, it 
should not be reported as an AE or SAE. The terms “Disease Progression”, “Progression of 
Disease”, or “Malignant disease progression” and other similar terms should not be used to 
describe an AE or SAE. However, clinical symptoms of progression may be reported as AEs 
or SAEs if the symptom cannot be determined as exclusively due to progression of the 
underlying malignancy or does not fit the expected pattern of progression for the disease 
under study. In addition, complications from progression of the underlying malignancy 
should be reported AEs or SAEs. 


 
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Pregnancy 
Complete a Pregnancy Report Form for all pregnancies that occur from the time of first study 
drug dose until 6 months after the last dose of study drug, including brentuximab vedotin, 
dacarbazine, or bendamustine (or 8 months after the last dose of nivolumab), whichever is 
later, including any 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. On the AE and 
Pre-Existing Conditions CRF, record all pregnancies that occur from time of informed 
consent to within 30 days of last study drug dose for Parts A, B, C, E, F or for Part D, from 
the time of informed consent until 6 months after the last dose of brentuximab vedotin or 
8 months after the last dose of nivolumab, whichever is later, (i.e., based on the estimated 
date of conception) including any pregnancies that occur in the partner of a male study 
patient. 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 7.7.1.1) should be reported as SAEs. 
As part of the study, all pregnancies will be monitored for the full duration and all perinatal 
and neonatal outcomes should be reported. Infants should be followed for a minimum of 
8 weeks. 
Potential Drug-Induced Liver Injury 
The observation of the critical importance of altered liver function has been referred to 
informally as Hy’s Law (Reuben 2004). Hy’s Law can be used to estimate severity and the 
likelihood that a study drug may cause an increased incidence of severe hepatotoxicity. 
The absence of hepatotoxicity in clinical trials provides a limited predictive value for 
potential hepatotoxicity in the clinical setting(s) being studied. However, finding 1 Hy’s Law 
case in clinical trials is ominous; finding 2 cases is highly predictive of a potential for severe 
DILI. 
Definition 
Briefly, potential Hy’s Law cases include the following 3 components: 
1. Aminotransferase (ALT and/or AST) elevation >3 x ULN 
AND 
2. Total bilirubin >2 x ULN, without initial findings of cholestasis (i.e., elevated serum 
alkaline phosphatase), 
AND 
3. No other immediately apparent possible causes of aminotransferase elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 


 
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Reporting Requirements 
Any potential Hy’s Law case should be handled as a suspected unexpected serious 
adverse reaction (SUSAR) associated with the use of the drug and reported promptly to 
the Sponsor. 
Reporting should include all available information and should initiate close follow-up until 
complete resolution of the problem and completion of all attempts to obtain supplementary 
data. 
Follow-up for Abnormal Laboratory Results Suggesting Potential DILI 
In general, an increase of serum ALT or AST to >3 x ULN should be followed by repeat 
testing within 48 to 72 hours of serum ALT, AST, alkaline phosphatase, and total bilirubin, 
to confirm the abnormalities and to determine whether they are worsening. 
Appropriate medical assessment should be initiated to investigate potential confounding 
factors and alternative causes of hepatotoxicity. During this investigation, consider 
withholding study drug. 
7.7.1.3 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 [all parts], 
dacarbazine [Part B], or bendamustine [Part C]), or 100 days after the last nivolumab dose 
(Part D), 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 study treatment 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, 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. 
7.7.1.4 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 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. 
7.7.1.5 Sponsor Safety Reporting Requirements in the US 
According to the final rule amending the IND safety reporting requirements under 21 CFR 
312.32 and the FDA final guidance Safety Reporting Requirements for INDs and 
Bioavailability/Bioequivalence Studies (December 2012), endpoints that assess 
disease-related mortality or major morbidity as well 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 FDA as individual IND safety 
reports. 
For Parts A, B, C, and D of this study, the SAEs that do not require individual IND safety 
reports are disease progression. For Parts E and F, disease progression is not reported as an 
AE and will be monitored as an efficacy endpoint. Therefore, disease progression will not be 
reported as an individual IND safety report to the FDA. Other SAEs that are anticipated to 
occur in the study population including Parts A, B, C, D, E, and F will be submitted to the 
FDA as individual IND safety reports per the IND safety reporting final rule.  
These safety reporting requirements apply only to the process by which the sponsor reports 
SAEs to the FDA. Investigators are required to report all SAEs, including anticipated SAEs, 
to the sponsor. In addition, the sponsor will report all SAEs to international authorities as 
required per local regulatory reporting requirements. 
7.7.2 Clinical Laboratory Tests 
The following laboratory assessments will be performed by local laboratories at scheduled 
time points (see Appendix A, Appendix B, and Appendix C) during the course of the study: 
● 
The chemistry panel is to include the following tests: albumin, alkaline phosphatase, 
ALT, AST, blood urea nitrogen, calcium, creatinine, chloride, potassium, sodium, 
total bilirubin, and glucose. 
○ 
LDH, phosphorus, and uric acid will also be obtained as part of the chemistry 
panel. Lipase will be obtained for patients in Parts C and D only. For Part D only, 
amylase will be obtained as well as TSH, free T3, and free T4. 
● 
The CBC with differential is to include the following tests: white blood cell (WBC) 
count with five-part differential (neutrophils, lymphocytes, monocytes, eosinophils, 
and basophils), red blood cell count, platelet count, and hemoglobin/hematocrit. 
● 
Erythrocyte sedimentation rate (at baseline only). 
● 
Hepatitis B and C serologies; if hepatitis C serology is positive, hepatitis C virus 
RNA test by PCR is required to confirm (Parts D, E, and F only). 


 
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● 
For Parts E and F only, the eGFR should be calculated using the MDRD equation as 
applicable, with Scr reported in mg/dL: 
○ 
eGFR (mL/min/1.73 m2)=175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x 
(1.212 if African American) 
○ 
If Scr is reported in µmol/L, the value should be converted to mg/dL using the 
conversion factor 0.011312 µmol/L to mg/dL. 
7.7.3 Physical Examination 
Physical examinations should include assessments of the following body parts/systems: 
abdomen, extremities, head, heart, lungs, neck, and neurological. Height is to be measured; 
measurements obtained within the prior 12 months may be utilized. Vital signs should also 
be recorded at each physical examination (Part D only). 
7.8 Appropriateness of Measurements 
The Revised Response Criteria for Malignant Lymphoma (Cheson 2007) and the Lugano 
Classification Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas 
(Cheson 2014) will be employed to evaluate tumor lesion size in the determination of 
response rate in this study. Tumor imaging at the specified intervals 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. AEs and, when applicable, 
clinical laboratory data will be graded using NCI CTCAE Version 4.03. 
Immunogenicity is commonly assessed for biologics; therefore, standard tests will be 
performed to detect the possible presence of specific antibodies to brentuximab vedotin (all 
parts) and nivolumab (Part D only). PK assessments for drug activity and biomarker 
assessments are also common in clinical studies. 


 
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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 
● 
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, FDA 
representatives, EMA representatives, or representatives of other regulatory agencies. 


 
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8.2 Data Management Procedures 
Seattle Genetics will provide CRF Completion Guidelines for electronic CRF 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 electronic CRF. 
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 information contained in the 
CRFs, such as past history, secondary diagnoses, disease assessment records, AEs, and 
concomitant medications. 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. 
● 
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 Research and Development Quality 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 Research and Development Quality group of Seattle Genetics as part of the written 
record. 


 
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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. 
The investigator should retain records of the changes and corrections, written and/or 
electronic. 
Data handling procedures for this trial have been designed to permit data changes so that they 
are documented by an audit trail. Data changes may only be made by those individuals so 
authorized. 
8.6.2 Investigator Record Retention 
The investigator shall retain study drug disposition records, copies of CRFs (or electronic 
files), 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. 


 
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9 
DATA ANALYSIS METHODS 
9.1 Determination of Sample Size 
Parts A, B, C and D of this study will evaluate whether the ORR (CR + PR) for single-agent 
brentuximab vedotin or brentuximab vedotin in combination with dacarbazine, 
bendamustine, or nivolumab is >25% using a single-arm study design. The objective of 
Parts A to D is to be able to detect an ORR of at least 25%, which is considered to show 
minimal clinical benefit given that the patient population may not have other options for 
initial conventional chemotherapy. 
For Parts A, B, and C of the study, disease response and progression will be assessed using 
the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). For Part D of the 
study, disease response will be assessed using the Lugano criteria (Cheson 2014) and LYRIC 
(Cheson 2016). For Parts A, B, C, and D, PD also includes clinical disease progression per 
investigator. For Parts E and F of the study, disease response will be assessed using the 
Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin 
lymphomas (Cheson 2014). For Parts E and F, the assessment will be per BICR. 
With 30 patients for Part A and an overall significance level of 0.1, observing 13 or more 
objective responses (43% ORR [lower limit of exact 90% CI: 27.87%]) would allow us to 
reject the null hypothesis and claim that the true ORR is >25%. Similarly, with a sample size 
of 20 patients for Part B and an overall significance level of 0.1, observing 9 or more 
objective responses (45% ORR [lower limit of exact 90% CI: 25.87%]) would allow us to 
reject the null hypothesis and claim that the true ORR is >25%. For Part C, approximately 
30 patients will be enrolled, with at least 20 patients treated using the lower starting dose of 
bendamustine (70 mg/m2) combined with 1.8 mg/kg brentuximab vedotin. Using this sample 
size of 20 patients included in the analysis for Part C and an overall significance level of 0.1, 
observing 9 or more objective responses (45% ORR [lower limit of exact 90% CI: 25.87%]) 
in this group would allow us to reject the null hypothesis and claim that the true ORR is 
>25%. An analysis will also be performed for all 30 patients in Part C. With the assumption 
of a true ORR of 75%, Parts A, B, and C of the study will have over 90% power (nQuery). 
For Part D, with a sample size of 20 patients and an overall significance level of 0.1, 
observing 9 or more objective responses (45% ORR [lower limit of exact 90% CI: 25.87%]) 
would allow us to reject the null hypothesis and claim that the true ORR is >25%.  
Part E (the classical HL cohort) is designed to estimate the ORR at a reasonable level of 
precision. Approximately 50 patients will be enrolled to ensure adequate data for safety and 
efficacy evaluation. If 35 responses are observed, the estimated ORR and the associated 
2-sided 95% CI using the Clopper-Pearson method is 70% (95% CI: 55.4%, 82.1%) (Clopper 
1934). 
Part F (the PTCL cohort) is designed to estimate the ORR at a reasonable level of precision. 
Approximately 50 patients will be enrolled to ensure adequate data for safety and efficacy 
evaluation. Enrollment of patients with sALCL will be capped at 50% of the total enrollment 
in Part F (approximately 25 patients out of 50). If 25 responses are observed, the estimated 


 
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ORR and the associated 2-sided 95% CI using the Clopper-Pearson method is 50% (95% CI: 
35.5%, 64.4%) (Clopper 1934). 
9.2 Study Endpoint Definitions 
9.2.1 Objective Response Rate 
The ORR is defined as the proportion of patients with CR or PR, according to the disease 
assessment criteria specified in Section 2.4 for each study part. For Parts E and F, the 
assessment will be per BICR. 
9.2.2 Complete Remission Rate 
The CR rate is defined as the proportion of patients with CR, according to the disease 
assessment criteria specified in Section 2.4 for each study part. For Parts E and F, the 
assessment will be per BICR. 
9.2.3 Disease Control Rate 
Disease control rate is defined as the proportion of patients with CR, PR, or SD, according to 
the disease assessment criteria specified in Section 2.4 for each study part. For Parts E and F, 
the assessment will be per BICR. 
9.2.4 Duration of Response 
Duration of response is defined as the time from start of the first documentation of objective 
tumor response (CR or PR) to the first documentation of tumor progression or to death due to 
any cause, whichever comes first. Duration of response data will be censored on the day 
following the date of the last disease assessment documenting absence of PD for patients 
who do not have tumor progression and are still on study at the time of an analysis, are given 
antitumor treatment (including stem cell transplant) other than the study treatment, or are 
removed from study prior to documentation of tumor progression. Duration of response will 
only be calculated for the subgroup of patients achieving a CR or PR. Responses will be 
assessed according to the disease assessment criteria specified in Section 2.4 for each study 
part. For Parts E and F, the assessment will be per BICR. 
9.2.5 Duration of Complete Remission 
Duration of CR is defined as the time from start of the first documentation of CR to the first 
documentation of tumor progression or to death due to any cause, whichever comes first. 
Duration of CR data will be censored on the day following the date of the last disease 
assessment documenting absence of PD for patients who do not have tumor progression and 
are still on study at the time of an analysis, are given antitumor treatment (including stem cell 
transplant) other than the study treatment, or are removed from study prior to documentation 
of tumor progression. Responses will be assessed according to the disease assessment criteria 
specified in Section 2.4 for each study part. For Parts E and F, the assessment will be per 
BICR. 


 
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9.2.6 Progression-Free Survival 
PFS is defined as the time from start of study treatment to first documentation of tumor 
progression or to death due to any cause, whichever comes first. PFS data will be censored 
on the day following the date of the last disease assessment documenting absence of PD for 
patients who do not have tumor progression and are still on study at the time of an analysis, 
are given antitumor treatment (including stem cell transplant) other than the study treatment, 
or are removed from study prior to documentation of tumor progression. Patients lacking an 
evaluation of tumor response after their first dose will have their event time censored at 
1 day. 
Responses will be assessed according to the disease assessment criteria specified in 
Section 2.4 for each study part. For Parts E and F, the assessment will be per BICR. 
9.2.7 Indeterminate Response Rate 
The IR rate is defined as the proportion of patients with IR according to LYRIC (Cheson 
2016). 
9.2.8 B Symptom Resolution Rate 
B symptom resolution rate is defined as the proportion of patients with lymphoma-related 
B symptoms at baseline who achieve resolution of all B symptoms at any time during the 
treatment period. 
9.2.9 Incidence of ATA 
The ATA incidence rate is defined as the proportion of patients who develop ATA to 
brentuximab vedotin (or nivolumab for Part D) at any time during the study. 
9.2.10 Event-free Survival 
EFS is defined as the time from start of study treatment to any treatment failure including 
disease progression, or discontinuation of treatment for any reason (e.g., disease progression, 
toxicity, patient preference, initiation of new treatment excluding consolidative RT in the 
absence of progression, but including stem cell transplant without documented progression or 
death). EFS will be censored on the last follow-up date if none of the above events occur 
during the study. 
Responses will be assessed according to the disease assessment criteria specified in 
Section 2.4 for each study part. For Parts E and F, the assessment will be per BICR. 
9.2.11 Overall Survival 
OS is defined as the time from start of study treatment to date of death due to any cause. In 
the absence of confirmation of death, survival time will be censored at the last date the 
patient is known to be alive. Patients lacking data beyond the day of first dose will have their 
survival time censored at 1 day. 


 
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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 
This is a phase 2, open-label study where for each part, the primary endpoints will be 
summarized descriptively. The secondary and additional endpoints will be analyzed and 
provided as supporting evidence for the overall clinical benefit of brentuximab vedotin (and 
nivolumab for Part D). 
For each part, descriptive statistics (mean, median, standard deviation, minimum, and 
maximum) will be used to describe continuous variables. Frequencies and percentages will 
be used to describe categorical variables. Summaries will be displayed separately for 
single-agent brentuximab vedotin and combination treatment. 
9.3.1.1 Randomization and Blinding 
Not applicable. 
9.3.1.2 Adjustments for Covariates 
Covariates such as risk factors will be considered for adjustment in the association analyses. 
9.3.1.3 Handling of Dropouts and Missing Data 
With the exception of time-related endpoints, no imputation will be conducted for missing 
data unless otherwise specified in the SAP. 
For time-related endpoints (e.g., duration of response, PFS, and OS, etc), patients who have 
no specified event will be censored at the time of the last valid assessment of the endpoint(s). 
Patients whose disease response cannot be assessed will be counted as non-responders. 
9.3.1.4 Multicenter Studies 
Site-to-site variation will not be adjusted in the analyses. 
9.3.1.5 Multiple Comparisons and Multiplicity 
No multiple comparisons are planned. For retreatment patients, the first treatment experience 
will be used in all analyses. Subsequent treatment experiences will be summarized 
separately. 


 
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9.3.1.6 Data Transformations and Derivations 
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. 
Baseline values used in all analyses will be the most recent measurement prior to the first 
dose of study drug. 
9.3.1.7 Analysis Sets 
Full Analysis Set 
The full analysis set includes all patients who receive any amount of brentuximab vedotin. 
The full analysis set will be used for efficacy analyses and all safety analyses. 
Efficacy Evaluable Analysis Set 
The efficacy evaluable analysis set includes all treated patients with the histology of classical 
HL (Parts A, B, C, D, and E) and CD30-expressing PTCL (Part F), who had both a baseline 
and at least 1 post-baseline disease assessment or who had documented progression of 
disease any time after receiving any amount of brentuximab vedotin. 
Per-protocol Analysis Set 
The per-protocol analysis set includes all patients who receive any amount of brentuximab 
vedotin and who had both a baseline and at least 1 post-baseline disease assessment and no 
major protocol deviations that could potentially affect tumor response. 
The per-protocol analysis set will be used for secondary analyses of all efficacy endpoints. 
9.3.1.8 Examination of Subgroups 
As exploratory analyses, subgroup analyses may be carried out for selected endpoints. The 
subgroups that may be examined include but are not limited to the following: 
● 
Patients who were ineligible/unsuitable/unfit for versus patients who had declined 
initial conventional chemotherapy for HL 
● 
Sex (Male, Female) 
● 
Baseline ECOG performance status 
● 
International Prognostic score at initial disease diagnosis 
● 
Disease staging at initial diagnosis 
 
Additional details and other subgroups will be specified in the SAP. 


 
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9.3.1.9 Timing of Analyses 
The trial is not designed to allow for early stopping for futility or favorable efficacy results 
(see Section 9.3.10 for details) and there is no plan to stop the study for treatment effect. 
The primary analysis for Parts A, B, C, and D will occur when the last patient in each part 
completes Cycle 8 restage. The primary analysis for Parts E and F will be conducted when all 
treated patients have been followed for at least 6 months, discontinued from study, or had 
30 days safety follow-up after PD, whichever comes first. 
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. 
9.3.2 Patient Disposition 
An accounting of study patients by disposition will be tabulated. The number of patients 
enrolled, receiving brentuximab vedotin or brentuximab vedotin in combination with 
dacarbazine, bendamustine, or nivolumab, and completing the study will be summarized. 
Patients who discontinue study treatment and patients who withdraw from the study will be 
summarized by reason for discontinuation or withdrawal and listed. 
9.3.3 Patient Characteristics 
Demographics, other baseline characteristics, and concomitant medications will be 
summarized and listed. 
9.3.4 Treatment Compliance 
The dose (mg/kg) administered at each cycle will be assessed and compliance will be 
summarized. Details will be provided in the SAP. 
9.3.5 Efficacy Analyses 
All efficacy analyses for Parts A to D will be presented using the efficacy evaluable analysis 
set and the full analysis set will be used to present efficacy analyses for Parts E and F. 
Efficacy analyses for all parts may be presented using the per protocol analysis set, as 
applicable. Analyses may also be performed using the subgroups listed in Section 9.3.1.8. 
9.3.5.1 Primary Efficacy Analyses 
The ORR and its 2-sided 95% exact CI will be calculated using the Clopper-Pearson method 
(Clopper 1934).  
For all parts, primary efficacy endpoints will be summarized descriptively and no formal 
statistical hypothesis testing will be performed. 
This endpoint may also be tabulated by covariates such as sex, age, race, categorized weight, 
categorized tumor size at baseline, and ECOG performance status, etc. The maximum 
percent reduction in the SPD of the nodes or nodal masses being followed for response 
assessment will be graphically displayed. 


 
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9.3.5.2 Secondary Efficacy Analyses 
The CR rate will be derived and its two-sided 95% exact CI will be calculated using the 
Clopper-Pearson method (Clopper 1934). Duration of response, duration of CR, and PFS will 
be estimated using Kaplan-Meier survival methodology and Kaplan-Meier survival plots will 
be provided. The median duration of response, duration of CR, and PFS and their two-sided 
95% CI by Brookmeyer and Crowley (Brookmeyer 1982) will be calculated. These endpoints 
may also be summarized by covariates such as sex, age, race, categorized weight, categorized 
tumor size at baseline, prior treatment, and ECOG performance status, etc. 
9.3.5.3 Additional Efficacy Analyses 
EFS and OS will be estimated using Kaplan-Meier survival methodology and Kaplan-Meier 
survival plots will be provided. The median EFS and OS and their two-sided 95% CI by 
Brookmeyer and Crowley (Brookmeyer 1982) will be calculated. Analyses for other efficacy 
endpoints and other additional/exploratory analyses will be specified in the SAP. 
9.3.5.4 Subsequent Therapies  
The data for subsequent therapies will be summarized and listed. 
9.3.6 Pharmacokinetic and Pharmacodynamic Analyses 
Brentuximab vedotin ADC and MMAE concentrations and nivolumab concentrations will be 
listed at each PK sampling time point. All concentrations below the limit of quantification or 
missing data will be labeled as such in the listings. 
Brentuximab vedotin ADC AUC after the first dose, and Ceoi and Ctrough for all cycles will be 
summarized (per collection schedule; Section 7.4). 
Brentuximab vedotin MMAE AUC, Cmax, Tmax after the first dose, and Ctrough for all cycles 
will be summarized. 
The incidence of ATA to brentuximab vedotin and nivolumab will be assessed. 
Pharmacodynamic biomarkers data (such as sCD30) will be reported descriptively. 
Correlative analysis may be conducted to explore the relationships between PK and 
immunogenicity and any of the measured pharmacodynamic biomarkers. 
9.3.7 Biomarker Analyses 
Relationships of biomarkers (e.g., baseline values, absolute and relative changes from 
baseline) to efficacy, safety, and PK parameters may be explored. Relationships and 
associated data that are determined to be of interest will be summarized. Details will be 
described separately. 
9.3.8 Health Outcomes Analyses 
Not applicable. 


 
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9.3.9 Safety Analyses 
9.3.9.1 Extent of Exposure 
Duration of treatment, number of cycles, total dose and dose intensity will be summarized 
and listed by cycle. Dose modifications will also be summarized and listed. Details will be 
provided in the SAP. 
9.3.9.2 Adverse Events 
AEs will be defined as treatment-emergent if they are newly occurring or worsen following 
treatment with brentuximab vedotin or any component of combination therapy. The 
incidence of all AEs, treatment-emergent AEs, and treatment-related AEs will be tabulated 
by treatment group. 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 treatment group, 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 1 patient, the AE will be counted once as the occurrence. The 
incidence of AEs will be tabulated by preferred term. AEs leading to premature 
discontinuation of study drug or withdrawal from the study will be summarized and listed in 
the same manner. 
9.3.9.3 Deaths and Serious Adverse Events 
SAE will be listed and summarized in the same manner as all AEs. Events with a fatal 
outcome will be summarized and listed. 
9.3.9.4 Clinical Laboratory Results 
Summary statistics for actual values and for change from baseline will be tabulated as 
appropriate for laboratory results by scheduled visit. Patients with laboratory values outside 
of the normal reference range at any post-baseline assessment will be listed. Shifts from 
baseline laboratory values will be tabulated as appropriate. 
Laboratory results will also be graded per NCI CTCAE Version 4.03. Patient incidence of 
laboratory values will be summarized by lab test and by maximum grade. Shifts from 
baseline laboratory values in both lab abnormality and NCI CTCAE grade will be tabulated 
as appropriate. 
9.3.9.5 Other Safety Analyses 
ECOG status will be summarized for each visit. Shifts from baseline to the best and worst 
post-baseline score will be tabulated. 
All other assessments that are not described here will be summarized in the SAP. 


 
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9.3.10 Interim Analyses 
An SMC will be responsible for monitoring patient safety in Parts C and D of the study (see 
Section 3.2). 
This study is not designed to allow for early stopping for futility or favorable efficacy results. 
A formal interim efficacy or futility analysis is not considered meaningful or practical for this 
study. An ongoing real-time review of SAEs will be conducted by the Seattle Genetics Drug 
Safety Department. 
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. Interim analyses may also be presented in manuscript form. 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS 
This study will be conducted in accordance with the Note for Guidance on Good Clinical 
Practice (ICH Harmonised Tripartite Guideline E6 [R2]; FDA CFR [21 CFR § 50, 56, 312]), 
Declaration of Helsinki (Brazil, 2015), and all applicable regulatory requirements. 
10.1 Informed Consent 
The investigator is responsible for presenting the risks and benefits of study participation to 
the patient 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 


 
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● 
Required safety and SAE reports 
● 
Any additional submissions required by the site’s IRB/IEC 
 
The investigator must provide the following documentation to the sponsor or its designee: 
● 
The IRB/IEC periodic (e.g., 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. 
All data recorded in the CRF for patients participating in this study will be transcribed from 
medical records or other source documents. 
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 
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the investigator until notified 
by the sponsor in writing that retention is no longer necessary. 
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. 


 
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Records containing patient medical information must be handled in accordance with the 
requirements of the Health Information Portability and Accountability Act (HIPAA) Privacy 
Rule 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. 
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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Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, Ramchandren R, Bartlett NL, Cheson 
BD, de Vos S, Forero-Torres A, Moskowitz CH, Connors JM, Engert A, Larsen EK, Kennedy DA, Sievers EL, 
Chen R (2012). Results of a Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or 
Refractory Hodgkin’s Lymphoma. J Clin Oncol. 
Younes A, Hilden P, Coiffier B, Hagenbeek A, Salles G, Wilson W, Seymour JF, Kelly K, Gribben J, 
Pfreunschuh M, Morschhauser F, Schoder H, Zelenetz AD, Rademaker J, Advani R, Valente N, Fortpied C, 
Witzig TE, Sehn LH, Engert A, Fisher RI, Zinzani PL, Federico M, Hutchings M, Bollard C, Trneny M, 
Elsayed YA, Tobinai K, Abramson JS, Fowler N, Goy A, Smith M, Ansell S, Kuruvilla J, Dreyling M, 
Thieblemont C, Little RF, Aurer I, Van Oers MHJ, Takeshita K, Gopal A, Rule S, de Vos S, Kloos I, Kaminski 
MS, Meignan M, Schwartz LH, Leonard JP, Schuster SJ, Seshan VE (2017). International Working Group 
consensus response evaluation criteria in lymphoma (RECIL 2017). Ann Oncol 28(7): 1436-47. 
Younes A, Radford J, Ansell SM, Gallamini A, Kim WS, Feldman TA, Hamadani M, Chung J, Wang J, 
Huebner D, Connors JM (2013). Phase III study of brentuximab vedotin plus doxorubicin, vinblastine, and 
dacarbazine (A+AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as front-line 
treatment for advanced classical Hodgkin lymphoma (HL). J Clin Oncol 31(15_suppl): TPS8612. 
Zhao H, Wang T, Wang Y, Yu Y, Wang X, Zhao Z, Yang H, Yan B, Wu X, Da W, Zhang Y (2016). 
Comorbidity as an independent prognostic factor in elderly patients with peripheral T-cell lymphoma. Onco 
Targets Ther 9: 1795-9. 






 
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a 
For inclusion criterion No.1, review pathology report to confirm histopathological diagnosis of classical HL; assessment may occur any time prior to study entry. 
b 
See Section 7.6. 
c 
Within prior 12 months prior to treatment initiation. 
d 
See Section 7.7.2. 
e 
See Section 7.1. 
f 
Including LDH, phosphorus, uric acid, lipase, amylase, as well as TSH, free T3, and free T4. 
g 
As determined by Cockroft-Gault formula. 
h 
See Section 7.4. 
i 
See Section 7.5. 
j 
CT scan at Cycle 16 only for patients continuing treatment beyond 16 cycles. CT at EOT not needed if completed within last 6 weeks. After EOT, performed per institutional 
standard of care or at least approximately every 6 months for the first 2 years, an annual assessment for the third year, then per institutional standard of care until progression. 
See Section 6.3.7 for radiographic imaging for patients with IR. 
k 
Required at Cycles 4, 8, and 12. PET scan at Cycle 16 only for patients continuing treatment beyond 16 cycles. Performed per institutional standard of care after Cycle 16. 
PET at EOT not needed if completed within last 6 weeks. PET scans performed as part of institutional standard of care may be collected at any time during the study, as 
available. Once a CR is achieved, PET scans are not required. See Section 6.3.7 for radiographic imaging for patients with IR. 
l 
Within prior 45 days. 
m 
Predose. 
n 
Cycle 2 and all subsequent cycles. 
o 
Cycle 1 Day 8 only. 
p 
See Sections 6.3.7 and 7.2; response assessments will be completed prior to dosing for the subsequent treatment cycle. 
q 
Optional at progression of disease, if evidence of residual disease is suspected to distinguish active HL from inflammatory infiltrate, or if tumor flare or pseudoprogression is 
suspected to determine if there is viable tumor in new or enlarging lesions (Note: It is strongly recommended to confirm that radiological evidence of progression is correlated 
with active HL; when possible, excisional biopsies should be performed). 
r 
If EOT performed prior to 30 days post last dose, a follow-up phone call must be made on or within 7 days after Day 30. 
s 
Response assessments at EOT not needed if done in the prior 6 weeks. 
t 
Including assessment for potential immune-mediated AEs. 
u 
See Section 6.8. 
 




 
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APPENDIX D: NEW YORK HEART ASSOCIATION CLASSIFICATION 
 
A Functional and Therapeutic Classification for Prescription of Physical Activity for 
Cardiac Patients 
Class I: 
patients with no limitation of activities; they suffer no symptoms from ordinary 
activities. 
Class II: patients with slight, mild limitation of activity; they are comfortable with rest or 
with mild exertion. 
Class 
III: 
patients with marked limitation of activity; they are comfortable only at rest. 
Class 
IV: 
patients who should be at complete rest, confined to bed or chair; any physical 
activity brings on discomfort and symptoms occur at rest. 
Online source: http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-
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APPENDIX E: GUIDANCE ON CONTRACEPTION 
For the purposes of this guidance, complete abstinence, if consistent with the patient’s 
preferred lifestyle, is an acceptable form of contraception. Complete abstinence is defined as 
abstinence starting from the time of informed consent and continuing throughout the study 
and until the end of systemic exposure (at least 6 months after the final dose of study drug or 
8 months following last dose of nivolumab in Part D; see Section 4.1). 
Acceptable Methods for Highly Effective Birth Control (preventing conception) 
Patients who are of childbearing potentiala or whose partners are of childbearing potentiala 
and who are sexually active in a way that could lead to pregnancy may choose any TWO of 
the following methods: 
● 
Hormonal methods of contraception (excluding progestin-only pills; method must be 
associated with inhibition of ovulation), unless contraindicated 
● 
Intrauterine device with failure rate <1% 
● 
Tubal ligation 
● 
Vasectomy (at least 90 days from the date of surgery with a semen analysis 
documenting azoospermia) 
● 
Barrier method/s (male or female condom with or without spermicide, cervical cap 
with or without spermicide, diaphragm with or without spermicide) 
 
a 
A person of childbearing potential is defined as anyone born female who has experienced menarche and who has not 
undergone surgical sterilization (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or has not 
completed menopause. Menopause is defined clinically as 12 months of amenorrhea in a person born female over age 45 
in the absence of other biological, physiological, or pharmacological causes. 
 
Acceptable Methods for Preventing Secondary Exposure to Seminal Fluid 
Patients born male and who are sexually active with a pregnant or breastfeeding person, must 
use the contraceptives in Option 1 or 2: 
● 
Option 1: Male condom (with or without spermicide) and cervical cap  
● 
Option 2: Male condom (with or without spermicide) and diaphragm 
 
Unacceptable Methods of Contraception 
● 
Periodic abstinence 
● 
No method 
● 
Withdrawal 
● 
Rhythm 
● 
Spermicide only 
● 
Progestin-only pills 
● 
Concomitant use of female and male condoms 


 
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APPENDIX F: PERFORMANCE STATUS SCALES 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX G: THE CUMULATIVE ILLNESS RATING SCALE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX H: THE LAWTON INSTRUMENTAL ACTIVITIES OF DAILY LIVING 
SCALE 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX I: THE 5-POINT VISUAL ASSESSMENT SCALE (DEAUVILLE 
CRITERIA) 
Negative 
1. No uptake 
2. Uptake ≤ mediastinal blood pool 
3. Uptake > mediastinal blood pool but ≤ liver 
Positive 
1. Uptake > liver 
2. Marked uptake > liver with multiple sites or development, or new uptake consistent with 
PD 
 
From the First International Workshop on Interim-PET Scan in Lymphoma (Barrington 
2010; Meignan 2009) 


 
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APPENDIX J: OVERVIEW OF LYRIC CRITERIA (PART D ONLY) 
If tumor flare or pseudo-progression is suspected, then a clinical response of IR should be 
reported based on LYRIC (Cheson 2016). 
Definition of Indeterminate Response 
• IR1: 
An increase in overall tumor burden (as assessed by SPD) of ≥50% of up to 
6 measurable lesions in the first 12 weeks of therapy, without clinical 
deterioration. 
In general, patients should be experiencing clinical stability or improvement and 
must be able to tolerate continued treatment and not at risk of serious 
complications should tumor growth occur. Symptoms related to tumor growth, 
such as pain at the tumor site or compression of adjacent structure, may not be 
considered as clinical deterioration in this context. 
• IR2: 
Appearance of new lesions, or growth of 1 or more existing lesion(s) ≥50% at any 
time during treatment, occurring in the context of lack of overall progression 
(<50% increase) of overall tumor burden, as measured by SPD of up to 6 lesions 
at any time during treatment; and 
This may occur early or late in the treatment course. A biopsy is strongly 
encouraged when a patient experiences this phenomenon. If the biopsy does not 
confirm the presence of viable tumor in the new or enlarging lesion(s), then the 
lesion(s) are not considered active disease and should not be used in subsequent 
SPD assessments. 
• IR3: 
An increase in FDG uptake (using the 5-Point Scale per the Deauville Criteria 
[Appendix I]) of 1 or more lesion(s) without a concomitant increase in lesion size 
or number. 
Increased immune activity at the site of tumor may manifest as an increase in 
FDG uptake. Therefore, by itself changes in uptake should not trigger an 
assignment of PD. The magnitude of increase in uptake in an immune-mediated 
flare compared to that in true tumor progression is not yet known. It is important 
to investigate this finding, especially in conjunction with a biopsy (if possible) of 
the lesion in question, an increase in FDG avidity of 1 or more lesions suggestive 
of lymphoma, without a concomitant increase in size of those lesions meeting PD 
criteria does not constitute PD. 
It is possible that, at a single time point a patient could fulfill criteria for both IR1 or IR2 
AND IR3. For example, there could be a new FDG-avid lesion in the absence of overall 
progression (IR2), and at the same time, increase in FDG uptake of a separate lesion (IR3). In 
such cases, the designation of IR1 or 2 should take priority (e.g., IR2 in the above example). 


 
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Follow-Up of Indeterminate Response 
At 12 weeks (or earlier if clinically indicated) after a response of IR is determined by the 
Investigator, repeat imaging is mandatory and PD must be confirmed or refuted based 
LYRIC follow-up criteria for IR. PD should be reported if the SPD of the target lesion has 
increased further, with the considerations below: 
• In the case of IR1, the comparison should be between the first IR1 and the current SPD, 
with an increase of >10% constituting PD. In addition, there should be an increase of 
>5 mm (in either dimension) of at least 1 lesion for lesions <2 cm, and 10 mm for lesions 
>2 cm, to be consistent with the Lugano classification (Cheson 2014). If the target SPD 
increase is <10%, the response would still be categorized as IR1, and the patient could 
continue treatment until a subsequent scan shows either PD (>10% increase from first 
IR1 time point and an increase of >5mm in either dimension of at least 1 lesion) or 
response (>50% decrease from baseline). In this situation, it is reasonable to repeat 
imaging in 4–8 weeks to ensure absence of significant further increase. 
• In the case of IR2, the new or growing lesion(s) (unless biopsy proven to be benign) 
should be added to the target lesion(s), up to a total of no more than 6 total lesions. If the 
SPD of the newly defined set of target lesions has increased ≥50% from their nadir value 
(which may precede the IR time point), the patient should be considered to have PD. 
• In the case of IR3, since inflammatory responses may result in an increase in the 
standardized uptake value of a lesion, the patient will not be considered to have PD 
unless there is evidence of PD by an increase in lesion size or the development of new 
lesions, as noted above. 


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APPENDIX K: RESPONSE EVALUATION CRITERIA IN LYMPHOMA 
(See next page)


























 
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APPENDIX L: HISTOLOGIC SUBTYPES OF PTCL 
Patients with any of these histologic subtypes of PTCL from the WHO 2016 classification of 
lymphomas (Swerdlow 2016) may be eligible for Part F of the 35-15 study: 
● 
Peripheral T-cell lymphoma (PTCL), not otherwise specified 
● 
Anaplastic large-cell lymphoma (ALCL), ALK+ 
● 
Anaplastic large-cell lymphoma (ALCL), ALK2 
● 
Adult T-cell leukemia/lymphoma 
● 
Extranodal NK-/T-cell lymphoma, nasal type 
● 
Enteropathy-associated T-cell lymphoma 
● 
Monomorphic epitheliotropic intestinal T-cell lymphoma 
● 
Indolent T-cell lymphoproliferative disorder of the GI tract 
● 
Hepatosplenic T-cell lymphoma 
● 
Angioimmunoblastic T-cell lymphoma 
● 
Follicular T-cell lymphoma 
● 
Nodal PTCL with TFH phenotype 
● 
Breast implant–associated anaplastic large-cell lymphoma 
In addition, cases of T cell leukemias with measurable disease may be eligible on a case by 
case basis. Contact the medical monitor for review of these cases. 
 
Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of 
lymphoid neoplasms. Blood. 2016;127(20):2375-90. 
 


 
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APPENDIX M: INTEGRATED PET AND CT RESPONSE ACCORDING TO 
MODIFIED LUGANO CRITERIA PER BICR 
PET Response 
CT Response 
Integrated Response 
CR 
Any 
CR 
PR 
CR, PR 
PR 
 
Non-CR, Non-PR 
SD 
SD 
Any 
SD 
PD 
Any 
PD 
Not done or  
Not evaluable 
Prior PET responsea 
CT Response 
 
CR 
Non-PD 
CRb 
non-CR 
Non-PD 
NE 
Any 
PD 
PD 
No FDG-avid disease  
at baseline c 
No disease present (NE) 
NE 
PD 
PD 
NE=not evaluable. 
a 
“Prior PET response” refers to the latest prior PET assessment that was evaluable. PET responses may be carried 
forward over multiple CT assessments. 
b 
A CR according to PET will be carried forward irrespective of CT response, until CT shows PD or is assessed as NE. 
c 
Per protocol all patients must have FDG-avid disease at baseline. 


 
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APPENDIX N: INVESTIGATOR SIGNATURE PAGE 
Investigator Statement and Signature 
I have read the attached protocol entitled “A phase 2 open-label study of brentuximab 
vedotin in front-line therapy of Hodgkin lymphoma (HL) and CD30-expressing peripheral T-
cell lymphoma (PTCL) in older patients or patients with significant comorbidities ineligible 
for standard chemotherapy”. 
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 O: DOCUMENT HISTORY 
Version 
Date 
Original 
07-May-2012 
Amendment 1 
19-Nov-2012 
Amendment 2 
08-May-2013 
Amendment 3 
12-Nov-2013 
Amendment 4 
21-Aug-2014 
Amendment 5 
18-Jan-2015 
Amendment 6 
22-Apr-2015 
Amendment 7 
30-Jul-2015 
Amendment 8 
30-Oct-2015 
Amendment 9 
31-Oct-2016 
Amendment 10 
07-Sep-2018 
Amendment 11 
11-Apr-2019 
Amendment 12 
06-Nov-2019 
Amendment 13 
05-May-2020 


 
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Summary of Changes in Amendment 1 
Section(s) 
Change 
Rationale 
Section 1.4 
Added a statement to note a segment of the 
patient population with concomitant organ 
dysfunction including renal impairment.  
Provide background for allowing patients 
with renal impairment to enter the study 
at a reduced dose of 1.2 mg/kg 
brentuximab vedotin. 
Sections 3.1, 
3.2.1, and 
Synopsis 
Added dose of 1.2 mg/kg for patients enrolling 
on study with estimated creatinine clearance 
<30 mL/min. 
Specify dose for patients enrolling with 
estimated creatinine clearance 
<30 mL/min. 
Section 3.1, 
Figure 1, Section 
6.4, Synopsis 
Added restage computed tomography (CT) 
scan at Cycle 16 only for patients eligible for 
continued treatment beyond 16 cycles. 
Specify timing of restage assessments for 
patients continuing on treatment beyond 
16 cycles. 
Section 3.1, 
Figure 1, Section 
6.5, Synopsis 
Added CT and positron emission tomography 
(PET) scanning frequency for patients 
continuing beyond 16 cycles. 
Specify timing of restage assessments for 
patients continuing on treatment beyond 
16 cycles. 
Section 3.1, 
Figure 1, Section 
6.4, 
Section 7.2 
PET scans performed as part of institutional 
standard of care may be collected at any time 
during the study, as available.  
Clarify collection of PET scans 
performed per institutional standard of 
care. 
Section 3.2.2 
Added MMAE PK and safety information from 
the SGN35-008B (special populations) study 
and designation of a 1.2 mg/kg dose for 
patients with estimated creatinine clearance 
<30 mL/min. 
Provide rationale for selection of 
1.2 mg/kg dose for patients with 
estimated creatinine clearance 
<30 mL/min. 
Section 4.1 
Removed inclusion criterion No.6e: 
Estimated creatinine clearance >50 mL/min (as 
determined by the Cockroft-Gault formula) 
Allow enrollment of patients with 
estimated creatinine clearance 
<50 mL/min. 
Section 4.1, 
Synopsis 
Added exclusion criterion No.7: 
Kidney disease requiring ongoing dialysis. 
Patients will not be excluded due to renal 
impairment, with the exception of 
patients who require ongoing dialysis.  
Section 4.2, 
Synopsis 
Exclusion criterion No.1 was clarified as 
follows: 
Symptomatic neurologic disease compromising 
instrumental activities of daily living (IADLs) 
or requiring medications (e.g., ≥ Grade 2 
neuropathy [per the National Cancer Institute 
Common Terminology Criteria for Adverse 
Events, NCI CTCAE], Version 4.03), with the 
exception of patients with mild cognitive 
impairment who are still able to perform age-
appropriate IADLs, even if on medication. 
Clarification 
Section 5.2.6, 
Table 1 
Added dose modification guidance for patients 
dosed at 1.2 mg/kg due to renal impairment. 
To detail conditions for dose increase to 
1.8 mg/kg and to prohibit dose 
reductions below 1.2 mg/kg. 
Section 5.2.6, 
Table 1 
Added recommendation to consider dose 
modification for patients receiving 1.8 mg/kg 
who then develop renal impairment with 
To allow dose reduction to 1.2 mg/kg 
prior to Grade 4 toxicity.  


 
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Section(s) 
Change 
Rationale 
estimated creatinine clearance consistently 
below 30 mL/min. 
Section 5.2.9 
Removed specification of infusion bag types 
with no-known incompatibilities with 
brentuximab vedotin.  
This information is provided in the 
Pharmacy Manual. 
Section 6.3.1 
Added reference to Section 7.4 for ATA 
collection time points. 
Clarification 
Section 7.1,  
Section 7.5 
Added fresh tissue collection. 
Allow the collection of a fresh tissue 
sample for central analysis if archived 
tissue is unavailable or of insufficient 
quantity for central analysis. 
Section 7.2 
Added the following: 
With either CT/PET or diagnostic CT, it is 
preferred that both oral and intravenous 
contrast are used, except when contraindicated 
or not feasible. 
Clarification 
Section 7.4, 
Table 2 
Updated ATA collection frequency as follows: 
Antitherapeutic antibodies (ATA) to 
brentuximab vedotin will also be measured 
predose on Cycles 1, 2, 4, 8, 12, 16, every 4 
cycles thereafter, and EOT.  
Add ATA sampling for patients that may 
continue on study beyond 16 cycles. 
Section 7.6.2 
Corrected the components of the hematology 
panel to be assessed as follows: 
The CBC with differential is to include the 
following tests: white blood cell count with 
five-part differential (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils), bands, 
blasts, red blood cell count, platelet count, and 
hemoglobin/hematocrit. 
Measurement of bands and blasts as part 
of the hematology panel does not pertain 
to HL patients. 
Appendix A 
Updated study schedule to include changes in 
CT and PET scanning frequency. Added study 
activities for those patients continuing on study 
beyond Cycle 16. 
Reflect changes in study schedule 
incorporated in Amendment 1 
 


 
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Summary of Changes in Amendment 2 
Section(s) 
Change 
Rationale 
Synopsis and 
Section 9.1 
Added 10 patients to the number of 
planned patients for a total of 30 evaluable 
patients to be enrolled on this study. 
To further characterize the safety and 
efficacy of brentuximab vedotin in this 
patient population. 
Synopsis and 
Section 7.2 
Added clinical disease progression per 
investigator to the definition of 
progressive disease. 
To specify that disease progression may 
be documented by either radiographic 
(Cheson 2007) or clinical evaluation. 
Sections 6.2, 6.3, 
and Appendix A 
Expanded the window for the baseline CT 
and PET scans. 
To provide operational flexibility for sites 
to perform/collect CT and PET scans. 
Sections 6.2.1, 
6.3.1, 6.7, 7.6.2, 
and Appendix A 
Specified for clarity that the lactate 
dehydrogenase (LDH), phosphorus, and 
uric acid tests are to be included in the 
serum chemistry panel. 
Clarification 
Sections 6.4, 6.5, 
and Appendix A 
Added 2 additional days to the window for 
restage assessments and that restage 
assessments are to be completed prior to 
dosing for the subsequent treatment cycle. 
Since each 21-day cycle has a 2-day 
window for dosing, adding 2 days to the 
window for restage assessments allows 
patients to be assessed in the appropriate 
time period.  
Section 7.6.1.2 
Added reporting period for pregnancies 
occurring in a patient on study or the 
partner of a male patient on study. 
To ensure that all pregnancies occurring 
within 6 months of the last dose of study 
drug are reported. 
Section 9.3.1.2 
Clarified that adjustments for covariates 
will be considered in the association 
analyses. 
Clarification 
Section 9.3.1.3 
Revised definition of patients who will be 
counted as non-responders. 
Since the definition of progressive disease 
now includes clinical disease progression 
per investigator, only patients whose 
disease response cannot be assessed will 
be counted as non-responders instead of 
patients who do not have post-baseline 
response assessments. 
Section 9.3.1.7 
Redefined the per-protocol analysis set 
To ensure that the per-protocol analysis 
set is defined as a subset of the efficacy-
evaluable analysis set since the 
per-protocol analysis set will be used for 
efficacy analyses. 
Section 9.3.1.9 
Changed ‘final’ analysis to ‘primary’ 
analysis occurring when the last patient 
completes Cycle 8 restage. 
Correction 
Throughout 
document 
Minor administrative changes 
For clarity and consistency 
 


 
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Summary of Changes in Amendment 3 
Section(s) 
Change 
Rationale 
Sections 1, 2.1, 
2.3, 2.4, 3.1, 3.2, 
3.2.1, 3.2.2, 5.1, 
5.2.2, 5.2.2, 
6.3.1, 7.6.1.1, 
9.1, 9.3.1, 
9.3.1.9, 9.3.2, 
9.3.8.2, Figure 1, 
Synopsis, and 
Appendix A 
Added Part B to enroll and treat with 
combination treatment of brentuximab vedotin 
and dacarbazine in approximately 20 
efficacy-evaluable patients. 
To describe a new study cohort. 
Sections 1.4, 1.5, 
and 3.2 
Added the background and rationale for 
evaluating brentuximab vedotin in combination 
with dacarbazine for the frontline treatment of 
HL patients aged 60 and above. 
To provide data from prior studies 
showing that preclinical and clinical 
studies have demonstrated efficacy of the 
combination of brentuximab and 
dacarbazine with a manageable safety 
profile. 
Section 3.2.1 
Specified that enrollment in Part A will halt 
once Part B is open for enrollment at a site or a 
total of 30 patients have been enrolled in Part A 
To clarify method of assigning patients 
to treatment groups based on addition of 
Part B. 
Sections 3.1, 
3.2.1, 3.2.2, and 
0, and Synopsis 
Added that renal excretion is a significant route 
of dacarbazine elimination; therefore, a 
dacarbazine dose reduction of ~30% is 
recommended for patients with estimated 
creatinine clearance <30 mL/min. Added other 
dose modifications for dacarbazine, including 
discontinuation of treatment. 
To increase patient safety for those 
enrolling with estimated creatinine 
clearance <30 mL/min and to allow other 
dose modifications of dacarbazine per 
institutional standard of care or per the 
package insert. 
Section 4.1 and 
Synopsis 
Made the following change to inclusion 
criteria: 
3. 
Patients must be ineligible for or have 
declined initial conventional combination 
chemotherapy for Hodgkin lymphoma 
(e.g., ABVD, BEACOPP) after being 
informed of the potential benefits and risks 
of available treatment options. 
To clarify that conventional 
chemotherapy in the inclusion criteria 
means conventional combination therapy 
since the chemotherapeutic agent 
dacarbazine was added to study 
treatment for Part B.  
Section 4.2 and 
Synopsis 
Made the following change to exclusion 
criteria: 
6. 
Known hypersensitivity to any 
excipient contained in the drug formulation 
of brentuximab vedotin (Parts A and B) or 
dacarbazine (e.g., mannitol) (Part B only). 
To exclude patients from Part B if they 
have a known hypersensitivity to any 
component of the dacarbazine 
formulation, specifically mannitol, which 
is common for sensitivities. 
Section 5.2.5 
Added that dacarbazine dosing (if applicable) 
should be held if PML is suspected and 
permanently discontinued if PML is confirmed. 
For safety of patients in whom PML may 
be suspected or confirmed. 


 
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Section(s) 
Change 
Rationale 
Sections 5.3, 
5.3.1, 5.3.2, 
5.3.3, 5.3.4, 
5.3.5, 5.3.5, 
5.3.6, 5.3.7, and 
5.3.8  
Added dacarbazine description, method of 
procurement, dose and administration details, 
required premedication and postmedication, 
management of infusion reactions, dose 
modifications, storage and handling, packaging 
and labeling, and preparation information,  
To provide instructions and details for 
additional study treatment, dacarbazine. 
Section 5.3.2 
Added the drug procurement method for 
dacarbazine. 
To specify that sites will procure the 
commercially-available dacarbazine. 
Sections 5.3.4, 
5.4, 5.5.2, and 
5.5.3 
Specified that for Part B patients, antiemetics 
or other premedications should be considered 
for the prevention of nausea and vomiting prior 
to initiating the dacarbazine infusion. 
To allow investigators to provide 
patients with appropriate premedications 
to minimize patient discomfort following 
treatment with dacarbazine. 
Section 5.5.2 
Added that routine vaccine prophylaxis is 
permitted. 
To allow patients to receive routine 
vaccines (e.g., flu vaccine). 
Section 5.5.2 and 
Figure 1 
Specified that for Part B patients, combination 
treatment with brentuximab vedotin and 
dacarbazine may be followed by consolidative 
RT and that single-agent brentuximab vedotin 
may be resumed 2 weeks after RT. 
To allow consolidated RT as part of the 
frontline combination regimen. 
Section 5.5.3 
Clarified that prohibited systemic anti-
neoplastic therapy does not include dacarbazine 
for patients enrolled on Part B of the study. 
Clarification 
Section 9.2.8 
Added that ATA incidence rate is relevant to 
patients who develop ATA to brentuximab 
vedotin. 
Clarification needed due to addition of 
combination treatment. 
Section 9.3.1.7 
Revised analysis sets to include patients who 
receive any amount of brentuximab vedotin. 
Clarification needed due to addition of 
combination treatment. 
Throughout 
protocol 
Specified Part B where applicable. 
To account for new cohort  
Throughout 
protocol  
Administrative changes and corrections. 
To improve clarity and achieve 
consistency. 
 
 


 
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Summary of Changes in Amendment 4 
Section(s) 
Change 
Rationale 
Sections 1, 2.1, 
2.3, 2.4, 3.1, 3.2, 
3.2.1, 3.2.2, 5.1, 
5.2.2, 6.3.1, 
7.6.1.1, 9.1, 9.3.1, 
9.3.1.9, 9.3.2, 
9.3.8.2, Figure 1, 
Synopsis, and 
Appendix A 
Added Part C to enroll and treat with 
combination treatment of brentuximab vedotin 
and bendamustine in approximately 20 
efficacy-evaluable patients. 
To describe a new study cohort. 
Sections 1.4, 1.5, 
and 3.2 
Added the background and rationale for 
evaluating brentuximab vedotin in combination 
with bendamustine for the frontline treatment 
of HL patients aged 60 and above. 
To provide data from prior studies 
showing that preclinical and clinical 
studies have demonstrated efficacy of 
the combination of brentuximab and 
bendamustine with a manageable safety 
profile. 
Section 3.1 
A new paragraph has been added to describe 
how a Safety Monitoring Committee (SMC) 
will be responsible for monitoring patient 
safety in Part C of the study. 
To provide details regarding how safety 
will be monitored for patients in Part C. 
Section 3.2.1 
Specified that only one part of the study may 
be open at a time and certain parts will take 
priority for enrollment. 
To clarify method of assigning patients 
to treatment groups based on addition of 
Part C. 
Sections 3.1, 
3.2.1, 3.2.2, and 
5.4.5, and 
Synopsis 
Added dose modifications for bendamustine, 
including discontinuation of treatment. 
To allow other dose modifications of 
bendamustine per institutional standard 
of care or per the package insert. 
Section 4.1 
Made the following changes to inclusion 
criterion No.6: 
c. serum bilirubin ≤2X upper limit of normal 
(ULN) or ≤3X ULN for patients with 
Gilbert’s disease or documented hepatic 
involvement with lymphoma; patients 
enrolled in Part C must have serum 
bilirubin ≤1.5X ULN (per bendamustine 
prescribing information) 
d. alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) 
≤3X ULN or ≤5X ULN for patients with 
documented hepatic involvement with 
lymphoma; patients enrolled in Part C 
must have ALT or AST ≤2.5X ULN (per 
bendamustine prescribing information) 
e. creatinine clearance ≥40 mL/min (Part C 
only, per bendamustine prescribing 
information) 
To clarify that baseline laboratory data in 
the inclusion criteria is different for Part 
C, based on prescribing information for 
bendamustine. 
Section 4.2 and 
Synopsis 
Made the following change to exclusion 
criteria: 
6. 
Known hypersensitivity to any 
excipient contained in the drug formulation 
To exclude patients from Part C if they 
have a known hypersensitivity to any 
component of the bendamustine 
formulation, including mannitol. 


 
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Section(s) 
Change 
Rationale 
of brentuximab vedotin, dacarbazine (Part 
B only), or bendamustine (Part C only) 
(e.g., mannitol). 
Section 5.6 
Moved the information regarding the 
management of adverse events (specifically 
infusion reactions and PML) to a new section. 
Added that bendamustine dosing (if 
applicable) should be held if PML is suspected 
and permanently discontinued if PML is 
confirmed. Added information regarding 
infusion reactions related to bendamustine. 
For safety of patients in whom PML may 
be suspected or confirmed and who may 
experience infusion reactions with 
bendamustine. 
Sections 5.3, 
5.3.1, 5.3.2, 5.3.3, 
5.3.4, 5.3.5, 5.3.6, 
5.3.7, and 5.3.8 
Added bendamustine description, method of 
procurement, dose and administration details, 
required premedication and postmedication, 
management of infusion reactions, dose 
modifications, storage and handling, packaging 
and labeling, and preparation information,  
To provide instructions and details for 
additional study treatment, 
bendamustine. 
Section 5.3.2 
Added the drug procurement method for 
bendamustine. 
To specify how sites will procure the 
commercially-available bendamustine. 
Sections 5.3.4, 
5.4, 5.5.2, and 
5.5.3 
Specified that for Part C patients, 
premedications should be considered for the 
prevention of nausea and vomiting, infusion 
reactions, and myeloid growth colony-
stimulating factor prior to initiating the 
bendamustine infusion. 
To allow investigators to provide 
patients with appropriate premedications 
to minimize patient discomfort following 
treatment with bendamustine. 
Section 5.5.2 and 
Figure 1 
Specified that for Part C patients, combination 
treatment with brentuximab vedotin and 
bendamustine may be followed by 
consolidative RT and that single-agent 
brentuximab vedotin may be resumed 2 weeks 
after RT. 
To allow consolidated RT as part of the 
frontline combination regimen. 
Section 9.3.9 
Information has been added regarding interim 
analysis and the SMC. 
To specify that an SMC will be 
responsible for monitoring patient safety 
in Part C of the study. 
Section 5.5.3 
Clarified that prohibited systemic anti-
neoplastic therapy does not include 
bendamustine for patients enrolled on Part C of 
the study. 
Clarification 
Throughout 
protocol 
Specified Part C where applicable. 
To account for new cohort  
Throughout 
protocol  
Administrative changes and corrections. 
To improve clarity and achieve 
consistency. 
 


 
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Summary of Changes in Amendment 5 
Section(s) 
Change 
Rationale 
Section 4.1 
Changed inclusion criterion.6d for Part C to 
require that patients have both ALT and AST 
≤2.5X ULN to enroll.  
Correction. 
Section 5.4.1 
Changed description and vial sizes of 
bendamustine. 
Updated to align with new liquid 
formulation and vial sizes released by 
the manufacturer in November 2014.  
Section 5.4.2 
Deleted that for US sites, bendamustine will be 
provided by the sponsor. 
To provide flexibility for procurement of 
bendamustine for Part C of the study; 
allowing either the sponsor or sites to 
purchase drug if needed. 
Section 5.5.3 
Added that bendamustine is not a prohibited 
anti-neoplastic therapy for patients in Part C. 
Correction. 
Synopsis and  
Section 7.4 
Changed “blood” concentrations to “serum or 
plasma” concentrations of brentuximab 
vedotin ADC and MMAE. 
Correction. 
 
 


 
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Page 141 of 157 
Summary of Changes in Amendment 6 
Section(s) 
Change 
Rationale 
Synopsis, 
Sections 3, 5.4.3, 
and 5.4.5 
Lowered the starting dose of bendamustine in 
Part C from 90 mg/m2 to 70 mg/m2 
Additional safety precaution 
Cover page 
Changed the medical monitor for the study 
Administrative change 
Cover page, 
Sections 7.6.1.2 
and 7.6.1.4 
Indicated SAE forms can be emailed to the 
sponsor 
Administrative change 
 


 
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Summary of Changes in Amendment 7 
Section(s) 
Change 
Rationale 
Synopsis and  
Section 9.1 
Increased the number of patients treated with 
the combination of brentuximab vedotin and 
bendamustine in Part C of the study to 
30 evaluable patients. 
To ensure collection of sufficient safety 
and efficacy data on approximately 20 
patients treated with brentuximab 
vedotin and the reduced dose of 
bendamustine at 70 mg/m2. 
Section 
6.3.1and 
Appendix A 
Specified which study procedures must be 
performed prior to dosing and after dosing. 
Clarification 
Sections 
9.1and 9.3.1.5 
Corrected methods in which statistical 
parameters will be presented. 
Correction 
Section 
9.3.1.7 
Added that patients included in the efficacy 
evaluable analysis set are ones with the 
histology of classical HL. 
Clarification 
Appendix A 
Added to the Study Schedule table that PD 
assessments are to be done at EOT. 
Correction to align with Section 6.7. 
 


 
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Summary of Changes in Amendment 8 
Section(s) 
Change 
Rationale 
Synopsis, Sections 1.6, 
3.1, 3.3, 3.4.2, 5.4, 
6.3.1, and 6.3.2 
Added that enrollment on Part C 
(combination treatment of brentuximab 
vedotin and bendamustine) has been 
suspended, treatment with bendamustine 
has been stopped, and single-agent 
brentuximab vedotin may be continued for 
patients who tolerate the therapy and have 
demonstrated clinical benefit. 
Based on SMC recommendation and 
sponsor decision, combination was not 
deemed to be a low toxicity alternative 
to conventional chemotherapy for HL in 
this fragile patient population. 
 


 
Study SGN35-015 
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Page 144 of 157 
Summary of Changes in Amendment 9 
Section(s) 
Change 
Rationale 
Sections 1, 2.2, 
2.3, 2.4, 3.1, 
3.4.1, 4, 5.1, 
5.2.2, 5.2.3, 5.6.3, 
5.7.2, 6.1, 7.8, 
9.1, 9.3.1, 9.3.1.9, 
9.3.2, Figure 1, 
Synopsis, and 
Appendix B 
Added Part D to enroll and treat with 
combination treatment of brentuximab vedotin 
and nivolumab in approximately 
20 efficacy-evaluable patients. 
To describe a new study cohort. 
Sections 1.6 and 
1.8 
Added the background and rationale for 
evaluating brentuximab vedotin in combination 
with nivolumab for the frontline treatment of 
HL patients aged 60 and above. 
To provide data from prior studies 
showing that preclinical and clinical 
studies have demonstrated efficacy of 
the combination of brentuximab and 
nivolumab with a manageable safety 
profile. 
Sections 2.3, 
2.4.3, 3.1, 6.3.7, 
6.5, 7.2.2, 7.6, 
and 0 
For Part D of the study, disease response will 
be assessed using the Lugano Classification 
Revised Staging System for nodal non-
Hodgkin and Hodgkin lymphomas (Cheson 
2014) and Lymphoma Response to 
Immunomodulatory Therapy Criteria (LYRIC) 
(Cheson 2016). 
To provide consistent criteria for 
determination of response and to align 
response evaluation with the most 
recently available published standards 
for evaluating response in Hodgkin 
lymphoma. 
Sections 3.2.2, 
5.5.4, 5.5.5, 7.7, 
and 9.3.10 
Added descriptions of how a Safety 
Monitoring Committee (SMC) will be 
responsible for monitoring patient safety in 
Part D of the study. 
To provide a description of how safety 
will be monitored for patients in Part 
D. 
Sections 3.3, 4, 
4.1, 4.3.2, and 
9.3.1.5 
Added retreatment option for patients on Part 
D who progress after discontinuing treatment. 
To provide the retreatment option for 
patients who achieve a CR or PR on 
Part D, but later progress. 
Section 3.4.2 
Added rationale for selection of doses for Part 
D. 
To describe approved dose levels of 
nivolumab and results from prior 
studies showing efficacy at the 
3 mg/kg dose level. 
Section 4.1 
Made the following changes to the inclusion 
criterion No.5: 
An Eastern Cooperative Oncology Group 
(ECOG) Performance Status score of ≤3 (Parts 
A, B, and C) or ≤2 (Part D). 
To clarify that patients in Part D must 
have at least an ECOG Performance 
Status of 2 to be eligible. 
Section 4.1 
Made the following changes to the inclusion 
criteria No.6: 
b. platelet count ≥50,000/µL (no platelet 
transfusions for prior 14 days for Part D 
only) 
c. serum bilirubin ≤2X upper limit of normal 
(ULN) (Parts A and B) or ≤1.5X ULN (per 
bendamustine and nivolumab prescribing 
information) (Parts C or D); or ≤3X ULN 
for patients with Gilbert’s disease or 
To clarify that baseline laboratory data 
in the inclusion criteria is different for 
Part D, based on prescribing 
information for nivolumab for some 
parameters or for further safety 
precautions. 


 
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Section(s) 
Change 
Rationale 
documented hepatic involvement with 
lymphoma (all parts); patients enrolled in 
Parts C or D must have serum bilirubin 
≤1.5X ULN (per bendamustine and 
nivolumab prescribing information) 
d. alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) 
≤3X ULN or ≤5X ULN for patients with 
documented hepatic involvement with 
lymphoma; patients enrolled in Parts C or 
D must have ALT and AST ≤2.5X ULN 
(per bendamustine prescribing information 
for Part C) 
e. hemoglobin ≥8.5 g/dL (no red blood cell 
transfusions for prior 7 days) (Part D only) 
f. creatinine clearance ≥40 mL/min (Part C 
only, per bendamustine prescribing 
information) or ≥30 mL/min (Part D only). 
Section 4.1 
Made the following changes to the inclusion 
criteria No.8: 
Males who have partners of childbearing 
potential must agree to use an effective 
contraceptive method during the study and for 
6 months following the last dose of study drug 
(or 8 months following last dose of nivolumab 
in Part D; 2 effective contraceptive methods 
required for Part D). 
The half-life of nivolumab is longer 
than the half-life of brentuximab 
vedotin, so male patients who have 
partners of childbearing potential must 
use contraception for at least 8 months 
following the last dose of nivolumab 
(if later than the 6 months following 
the last dose of brentuximab vedotin). 
Two contraceptive methods required 
for additional safety precaution. 
Section 4.1 
Added inclusion criterion No.10 for Part D: 
Diffusing capacity of the lungs for carbon 
monoxide (DLCO) over 60% (adjusted for 
hemoglobin) (Part D only). 
To ensure patients enrolled on Part D 
have DLCO over 60%. 
Section 4.2 
Made the following change to exclusion 
criterion No.6: 
Known hypersensitivity to any excipient 
contained in the drug formulation of 
brentuximab vedotin (all parts), dacarbazine 
(Part B only), bendamustine (Part C only) 
(e.g., mannitol), or nivolumab (Part D only). 
To exclude patients from Part D if 
they have a known hypersensitivity to 
any component of the nivolumab 
formulation. 
Section 4.2 
The following exclusion criteria have been 
added and are applicable to Part D only: 
8. 
History of another primary invasive 
malignancy that has not been in remission for 
at least 1 year. 
9. Known cerebral/meningeal disease related 
to the underlying malignancy. 
10. Received any prior immune-oncology 
therapy (e.g., therapies targeting the PD-1, 
CTLA4, or CD137 pathways).  
11. Systemic treatment with either 
corticosteroids (>10 mg daily prednisone 
To provide additional parameters for 
the patients who are eligible to enroll 
on Part D of the study. 


 
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Section(s) 
Change 
Rationale 
equivalent) or other immunosuppressive 
medications within 1 week of enrollment. 
○ 
Inhaled or topical steroids and adrenal 
replacement steroid doses >10 mg daily 
prednisone equivalent are permitted in the 
absence of active autoimmune disease. 
12. Positive for hepatitis B by surface antigen 
expression, or any other positive test for 
hepatitis B virus indicating acute or chronic 
infection. 
13. Active hepatitis C infection (positive by 
serology and confirmed by polymerase chain 
reaction [PCR] or on antiviral therapy for 
hepatitis C within the last 6 months). 
14. Known history of testing positive for 
human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome 
(AIDS).  
15. Documented history of a cerebral vascular 
event (stroke or transient ischemic attack), 
unstable angina, myocardial infarction, or 
cardiac symptoms consistent with New York 
Heart Association Class III–IV (Appendix B) 
within 6 months prior to the first dose of study 
drug(s). 
16. Previous history of known or suspected 
autoimmune disease. 
○ 
Patients with type I diabetes mellitus, 
hypothyroidism only requiring hormone 
replacement, skin disorders (such as 
vitiligo, psoriasis, or alopecia) not 
requiring systemic treatment, or conditions 
not expected to recur in the absence of an 
external trigger are permitted. 
17. Active interstitial lung disease that is 
symptomatic or may interfere with the 
detection or management of suspected drug-
related pulmonary toxicity. 
18. Known history of pancreatitis. 
19. Prior allogeneic stem cell transplant  
20. Other serious underlying medical condition 
that, in the opinion of the investigator, would 
impair the ability to receive or tolerate the 
planned treatment and follow-up. 
Sections 5.2.3, 
5.5.4, 5.6, 5.6.2, 
and 5.7.1 
Added required premedications for 
brentuximab vedotin plus nivolumab 
combination. 
To provide prophylactic 
premedications for potential infusion-
related reactions with the combination 
of brentuximab vedotin and 
nivolumab. To allow investigators to 
provide patients with appropriate 
premedications to minimize patient 
discomfort following treatment with 
brentuximab vedotin or nivolumab. 


 
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Section(s) 
Change 
Rationale 
Sections 5.2.3, 
5.2.4, 5.5.5, 
5.5.5.1, 5.5.5.2, 
and 5.5.5.3 
Added dose modifications for brentuximab 
vedotin plus nivolumab combination, including 
discontinuation of treatment. 
To allow other dose modifications of 
the combination of brentuximab 
vedotin and nivolumab. 
Sections 5.5, 
5.5.1, 5.5.2, 5.5.3, 
5.5.4, 5.5.5, 5.5.6, 
5.5.7, and 5.5.8 
Added nivolumab description, method of 
procurement, dose and administration details, 
required pre- and post-medication, dose 
modifications, storage and handling, packaging 
and labeling, and preparation information.  
To provide instructions and details for 
additional study treatment, nivolumab. 
Section 5.6.2 
Specified that for Part D patients, combination 
treatment with brentuximab vedotin and 
nivolumab may be followed by consolidative 
RT and that the combination of brentuximab 
vedotin and nivolumab may be resumed 2 
weeks after RT. 
To allow consolidated RT as part of 
the frontline combination regimen in 
Part D. 
Sections 6.2, 
6.2.1, 6.3.1, 6.3.3, 
6.3.4, 6.3.5, 6.3.6, 
6.3.7, 6.5, 6.6, 
6.7, 6.8, 7.7.2, 
and 7.7.3  
Added study activities for Part D. 
To support additional eligibility 
criteria and provide detailed activities 
required for study conduct of Part D of 
the study. 
Section 6.7 
Added an additional safety visit at 100 days 
(+2 weeks) after the last dose of nivolumab 
Because of the longer half-life of 
nivolumab (~27 days), additional 
safety data should be collected. 
Section 7.1 
Added that for Part D only, pulmonary 
functions tests are to be performed and patients 
must have DLCO over 60% at screening. 
To ensure spirometry is evaluated for 
each patient and that patients enrolled 
on Part D have DLCO over 60%. 
Section 7.2 
Added that nodes or masses should have 
bidimensional measurements of at least 1.5 cm 
in the longest axis. 
Clarification. 
Sections 7.2 and 
7.6 
Added that patients on Part D who experience 
PD should consider optional biopsy. 
Because pseudoprogression and 
delayed responses have been 
experienced by patients treated with 
immunotherapeutic agents. To ensure 
that patients who are determined to 
have disease progression do indeed 
have disease progression and to 
perform additional assessments on 
tumors after disease progression. 
Sections 7.4, 
9.2.9, 9.3.5.4 and 
Table 3 
Added PK and ATA sampling time points and 
parameters to be measured for Part D. 
To specify when sampling should 
occur and what parameters are to be 
measured for Part D. 
Sections 7.5 and 
9.3.7 
Added biomarker studies for Part D. 
To specify when sampling should 
occur for biomarker analyses and what 
biomarkers are to be measured for Part 
D. 
Section 7.6 
Added details for tissue and unstained slides 
required at screening. 
To ensure that patients either have 
tissue block or unstained slides 


 
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Section(s) 
Change 
Rationale 
available for pathology and baseline 
biomarker assessment. 
Section 7.7 
Added safety assessment of pulse oximetry test 
for Part D. 
To evaluate O2 saturation at selected 
time points. 
Sections 7, 
7.7.1.1, 7.7.1.2, 
and 7.7.1.3  
Edited safety definitions and reporting periods 
for Part D. 
To update safety definitions to align 
with the safety reporting for the 
combination of brentuximab vedotin 
and nivolumab. 
Appendix A 
Changed footnote l to read as follows: CT 
performed per institutional standard of care or 
at least approximately every 6 months after 
Cycle 16 while on treatment. PET scans 
performed per institutional standard of care. 
Once a CR is achieved, PET scans are no 
longer required (see Section 6.5). 
Correction. 
Throughout 
protocol 
Specified Part D where applicable. 
To account for new cohort.  
Throughout 
protocol  
Administrative changes and corrections. 
To improve clarity and achieve 
consistency. 
 


 
Study SGN35-015 
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Amendment 13; 05-May-2020 
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Page 149 of 157 
Summary of Changes in Amendment 10 
Section(s) 
Change 
Rationale 
Cover page 
Changed the medical monitor for the study 
Administrative change 
Sections 4.1 and 
7.1 
Changed inclusion criteria to a DLCO over 
50% 
Inclusion criteria broadened 
Appendix B 
Remove footnote ‘n’ from Nivolumab 
treatment on Day 1 in the table. Remove 
‘Note: thyroid hormones not assessed on Days 
8 and 15 of Cycle 1’ from footnote ‘f’. 
Corrections to align with Section 6.3.1 
 


 
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Summary of Changes in Amendment 11 
Section(s) 
Change 
Rationale 
Cover page and 
Synopsis, 1, 1.3, 
1.4, 1.8, 3.1, 3.4, 4, 
4.1, 7.1, and 
Appendix C 
Changed the protocol title and indication to 
include CD30-expressing PTCL. 
Label expansion. 
Cover page 
Changed the medical monitor for the study. 
Administrative change. 
Synopsis, Figure 1, 
Sections 3.1, 3.4, 
4.1, and Appendix 
C 
Added Parts E and F to enroll and treat with 
single-agent treatment of brentuximab vedotin 
in approximately 30 efficacy-evaluable 
patients each with classical HL (Part E) or 
CD30-expressing PTCL (Part F) who are 
ineligible for combination chemotherapy. For 
Parts E and F, the assessment will be per 
BICR. 
To describe new study cohorts. 
Synopsis, Figure 1, 
Sections 3.1, 6.3.8, 
and Appendix C 
For Parts E and F, added restage CT and PET 
scans at baseline, at Cycles 2, 6, 11, and at end 
of treatment (EOT) approximately 1 month 
after completion of therapy.  
Specify timing of restage assessments 
for patients in Parts E and F. 
Synopsis, Sections 
3.1 and 6.8 
For Parts E and F, added follow-up CT 
response assessments every 4 months for 2 
years and then per institutional standards. 
Specify timing of response assessments 
for patients in Parts E and F. 
Section 1.3 
Added the background and rationale for 
evaluating brentuximab vedotin for the 
frontline treatment of CD30-expressing PTCL 
patients 60 years of age and above. 
To provide data from prior studies 
demonstrating efficacy of the treatment 
of brentuximab vedotin in relapsed or 
refractory B- and T-cell lymphomas to 
support an indication of 
CD30-expressing PTCL in patients with 
a manageable safety profile. 
Section 1.4 
Added recent approval language for new 
indications. 
To update experience with brentuximab 
vedotin. 
Section 1.8 
Added rationale for the population of patients 
with classical HL and CD30-expressing PTCL 
who are 75 years of age and above and those 
60 years of age and above who are not 
candidates for combination chemotherapy and 
have a depressed ejection fraction or 
moderately severe renal dysfunction. 
To provide rationale for an unmet need 
in this population. 
Synopsis, Sections 
2.2, 2.3, 2.4.2, and 
2.4.3 
Added secondary objective of OS for Parts E 
and F. Clarified that the additional objective of 
OS is only for Parts A, B, C, and D. 
To characterize the safety and efficacy of 
brentuximab vedotin in the patient 
population of Parts E and F. 
Synopsis, Sections 
2.4.1, 3.1, 9.1, 9.2.1, 
9.2.2, 9.2.3, 9.2.4, 
9.2.5, 9.2.6, and 
9.2.10 
For Part D of the study, disease response will 
be assessed using the Lugano Classification 
Revised Staging System for nodal 
non-Hodgkin and Hodgkin lymphomas 
(Cheson 2014) and LYRIC (Cheson 2016). 
To provide consistent criteria for 
determination of response. 


 
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Section(s) 
Change 
Rationale 
Synopsis, Sections 
2.4.1, 3.1, 9.1, 9.2.1, 
9.2.2, 9.2.3, 9.2.4, 
9.2.5, 9.2.6, and 
9.2.10 
For Parts E and F of the study, disease 
response will be assessed using the Lugano 
Classification Revised Staging System for 
nodal non-Hodgkin and Hodgkin lymphomas 
(Cheson 2014) and the assessment will be per 
BICR. 
To provide consistent criteria for 
determination of response. 
Section 4.1 
Made the following changes to the inclusion 
criterion No.5: 
An Eastern Cooperative Oncology Group 
(ECOG) Performance Status score of ≤3 (Parts 
A, B, C, E, and F) or ≤2 (Part D). 
To clarify that patients in Parts E and F 
must have an ECOG Performance Status 
of at least 3 to be eligible. 
Sections 4.1 and 
7.7.2 
Made the following addition to inclusion 
criterion No. 6 footnote g (eGFR) and Clinical 
Laboratory Tests, as applicable:  
As determined by the Modification of Diet in 
Renal Disease (MDRD) study equation, an 
eGFR ≥30 mL/min/1.73m2 and 
<50 mL/min/1.73m2 (Parts E and F only). The 
eGFR should be calculated using the MDRD 
equation as applicable, with serum creatinine 
(Scr) reported in mg/dL: 
• 
eGFR (mL/min/1.73 m2)=175 x (Scr)-1.154 
x (Age)-0.203 x (0.742 if female) x (1.212 if 
African American) 
• 
If Scr is reported in µmol/L, the value 
should be converted to mg/dL using the 
conversion factor 0.011312 µmol/L to mg/dL. 
To document a change in the calculation 
method of creatinine clearance with the 
Cockroft-Gault formula to eGFR with 
the MDRD study equation, and to update 
inclusion criteria based on eGFR. 
Section 4.1 
The following inclusion criteria are applicable 
to Parts E and F only (meets at least one of the 
following to define ineligible for combination 
therapy): 
11. Age ≥75 years. 
12. Age ≥60 years and 
 
a. a confirmed ejection fraction <45% or 
 
b. an estimated eGFR ≥30 mL/min/1.73m2 
and <50 mL/min/1.73m2, as determined by the 
MDRD study equation as applicable (see 
Section 7.7.2). 
To provide additional parameters for the 
patients who are eligible to enroll on 
Parts E and F of the study (i.e., to define 
the population of ineligible for 
combination therapy). 
Section 4.2 
Updated or reorganized Exclusion Criteria 
Nos. 8-20. Added new No. 21 for Parts E and 
F only: 
History of another malignancy within 1 year 
before the first dose of study drug or any 
evidence of residual disease from a previously 
diagnosed malignancy. Exceptions are 
malignancies with a negligible risk of 
metastasis or death (e.g., 5-year overall 
survival ≥90%), such as adequately treated 
carcinoma in situ of the cervix, non-melanoma 
skin carcinoma, localized prostate cancer, 
To account for new cohorts. 


 
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Section(s) 
Change 
Rationale 
ductal carcinoma in situ, or Stage I uterine 
cancer. 
Section 7.7.1.2 
The following language replaced the current 
language: 
Since progression of underlying malignancy is 
being assessed as an efficacy variable, it 
should not be reported as an AE or SAE. The 
terms “Disease Progression”, “Progression of 
Disease”, or “Malignant disease progression” 
and other similar terms should not be used to 
describe an AE or SAE. However, clinical 
symptoms of progression may be reported as 
AEs or SAEs if the symptom cannot be 
determined as exclusively due to progression 
of the underlying malignancy or does not fit 
the expected pattern of progression for the 
disease under study. In addition, complications 
from progression of the underlying malignancy 
should be reported AEs or SAEs. 
FDA feedback that terms directly related 
to the underlying disease progression 
should be excluded from relevant safety 
analyses. 
Sections 9.1 and 
9.3.5.1 
Added language to distinguish between the 
primary efficacy hypothesis for Parts A, B, C, 
D, and E versus Part F, including the following 
addition: Part F of this study will evaluate 
whether ORR for single-agent brentuximab 
vedotin is >20% using a single-arm study 
design. The hypothesis to be tested is H0: ORR 
≤0.20 versus H1: ORR >0.20. 
To define the primary efficacy 
hypothesis in determination of sample 
size for each part of the study. 
Sections 9.3.1 and 
9.3.5.1 
For Parts A, B, C, and D, no formal statistical 
hypothesis for primary efficacy endpoints will 
be performed. For Parts E and F, formal 
statistical inference will be conducted and 
include CIs and P values. 
To update the formal statistical 
hypotheses to be performed for previous 
and new cohorts. 
Section 9.3.1.7 
Added CD30-expressing PTCL to the efficacy 
evaluable analysis set and updated language to 
clarify all parts related to classical HL. 
To account for new cohorts. 
Section 9.3.1.9 
The primary analysis for Parts E and F will be 
conducted when all treated patients have been 
followed for at least 6 months, discontinued 
from study, or had 30 days safety follow-up 
after PD, whichever comes first. 
To provide timing of analyses for new 
cohorts. 
Section 9.3.5.4 
Added new section to describe the data for 
subsequent therapies. 
Clarification. 
Throughout 
protocol 
Specified Parts E and F where applicable. 
To account for new cohorts. 
Throughout 
protocol 
Minor administrative changes and corrections. 
To improve clarity and achieve 
consistency. 
 


 
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Summary of Changes in Amendment 12 
Section(s) 
Change 
Rationale 
Synopsis, Sections 
2.1, 3.1, 3.4, 4.1, 
6.2, 6.6, 7.1, 
Appendix C, 
Appendix F, and 
Appendix G 
Specified criteria for patients in Parts E and F 
to be considered unsuitable or unfit for 
combination chemotherapy in terms of 
comorbidity scores (Cumulative Illness Rating 
Scale [CIRS] and Instrumental Activities of 
Daily Living [IADL]). 
In order to clearly define in which 
circumstances patients are considered 
ineligible for combination 
chemotherapy. 
Synopsis, Sections 
2.1, 3.1, 3.4, and 
4.1 
Changed the eligibility criteria for Parts E and 
F from patients aged ≥60 years to patients aged 
≥18 years. 
Given that ineligibility for combined 
chemotherapy in Parts E and F is now 
defined in terms of comorbidity (CIRS 
and IADL scores) there is no need to 
limit the population to older patients, as 
all age groups can potentially have 
significant comorbidities. 
Synopsis, Sections 
3.1 and 4.1 
Indicated that patients cannot be eligible for 
Parts E and F if they declined combination 
chemotherapy, as opposed to being unsuitable 
or unfit for chemotherapy.  
Comorbidity now defines unsuitable or 
unfit. 
Synopsis, Sections 
3.1, 3.4, 3.5.2, and 
4.1 
For Parts E and F, removed the eligibility 
criteria requiring that patients have at least 1 of 
the following: impaired cardiac function 
defined as a confirmed ejection fraction <45% 
or moderate renal insufficiency defined as an 
estimated glomerular filtration rate (eGFR) 
≥30 mL/min/1.73m2 and <50 mL/min/1.73m². 
The comorbidity-related factors 
determining ineligibility for combination 
chemotherapy are now CIRS and IADL. 
Synopsis, Sections 
3.5.1 and 9.1 
The number of patients to be enrolled in Parts 
E and F was changed from 30 to 50 in each 
part. 
Sample size was increased to 
accommodate changes in statistical 
hypotheses. 
Synopsis, Sections 
3.1 and 6.8 
Specified that patients will be followed post-
treatment until progression or initiation of 
further anti-cancer treatment, rather than just 
until progression. 
On-study disease assessments are not 
applicable once further anti-cancer 
treatment is initiated. 
Synopsis 
Rearranged “Efficacy Assessments” section. 
To increase clarity regarding disease 
assessments in each study part. 
Synopsis, Sections 
9.3.1 and 9.3.5.1 
Removed specification that formal statistical 
hypothesis testing and statistical inference will 
be performed for the primary endpoint in 
Parts E and F. 
Formal statistical hypothesis testing will 
not be performed, given that each study 
part is single-armed. 
Section 1 
Added text regarding additional contributory 
mechanisms of action for brentuximab vedotin. 
Update to standard description of 
mechanism of action. 
Sections 1.1 and 
1.2 
Modified, rearranged, and added new text 
giving background on HL and PTCL. 
To take into account the fact that the 
study population will no longer all be 
aged >60 years, and to add elements 
concerning the effect of comorbidities on 
treatment choice and outcome. 
Section 1.7 
Updated Study Rationale. 
To take into account the changes to 
eligibility criteria in Parts E and F. 


 
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Section(s) 
Change 
Rationale 
Section 2.4 
For Parts E and F: changed primary endpoint 
to ORR per modified Lugano criteria, added a 
secondary endpoint for ORR per unmodified 
Lugano criteria, and added an additional 
endpoint for ORR per Response Evaluation 
Criteria in Lymphoma (RECIL). 
Regulatory feedback indicated that 
Lugano criteria should be modified in 
the trial context. 
Section 3.1 
Specified that EOT is approximately 1 month 
after discontinuation of study treatment, rather 
than after completion 
Clarification to specify that EOT visit 
does also occur in patients who do not 
complete treatment. 
Sections 3.1, 6.8, 
and Appendix C 
Changed follow-up after progression or further 
anti-cancer treatment from 3 months to 4 months 
in Parts E and F. 
To harmonize with the 4-month follow-
up before progression. 
Section 3.3 
Specified that for retreatment in Part D, patients 
must experience disease progression ≥6 months 
after last study treatment, and specified the 
brentuximab vedotin and nivolumab doses to 
use in retreatment. 
For greater clarity on conditions for 
retreatment. 
Section 3.4 
Added rationale for use of CIRS and IADL scales 
in determination of ineligibility for combination 
chemotherapy. 
To establish that these scales correctly 
identify patients with too high a burden 
of comorbidities for conventional 
treatment. 
Sections 3.5.1 and 
9.1 
Specified an enrollment cap of 50% on patients 
with systemic anaplastic large cell lymphoma 
(sALCL) in Part F. 
In order to ensure that all types of PTCL 
are adequately represented in the Part F 
cohort. 
Section 4.1 
Revised the inclusion criteria concerning 
patients of childbearing potential and use of 
contraception. 
To take into account that potentially 
fertile patients <60 years of age will now 
be enrolled. 
Section 4.1 
Revised the inclusion criteria for informed 
consent. 
Update to Seattle Genetics standard 
language. 
Section 4.2 
Revised the exclusion criteria for hepatitis B. 
Update to Seattle Genetics standard 
language. 
Section 5.5.5.2 
Added Grade 3 myocarditis as a reason for 
permanent discontinuation of nivolumab. 
Update to nivolumab prescribing 
information. 
Section 5.5.5.3 
Revised dose modification criteria for 
nivolumab in the event of liver function test 
abnormalities. 
Update to nivolumab prescribing 
information. 
Section 5.5.5 
Removed specification that SMC could decide 
that patients receive nivolumab 1 mg/kg. 
Update to nivolumab prescribing 
information. 
Section 5.5.7 
Revised packaging and labeling information 
for nivolumab. 
Update to nivolumab prescribing 
information. 
Section 5.6.3 
Added complementary medications and 
live/attenuated vaccines to list of prohibited 
concomitant medications for nivolumab. 
Update to nivolumab prescribing 
information. 
Section 5.7.3 
Added section on management of overdose. 
Update to conform to the Seattle 
Genetics standard language. 


 
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Section(s) 
Change 
Rationale 
Section 6.2 and 
Appendix C 
Specified that ejection fraction needs to be 
evaluated with 28 days of treatment initiation 
for Parts E and F. 
To have an accurate cardiac baseline in 
patients with significant comorbidities. 
Sections 6.2.1, 7.1, 
and Appendix C 
Removed assessment of Karnofsky 
performance status from Parts E and F. 
Simplification of assessments, as all sites 
now use ECOG performance status. 
Sections 6.2.1, 7.1, 
and Appendix C 
Geriatric assessment removed from Parts E and 
F 
No longer applicable as population is no 
longer restricted to patients aged 
>60 years 
Sections 6.2.1, 6.6, 
7.1, and Appendix 
C 
Added serum or urine beta human chorionic 
gonadotropin (β-hCG) pregnancy tests for 
patients of childbearing potential. 
To take into account that potentially 
fertile patients <60 years of age will now 
be enrolled. 
Section 7.2.3 and 
Appendix C 
In Parts E and F, added the use of magnetic 
resonance imaging (MRI) with and without 
gadolinium contrast for patients with allergy to 
CT contrast agents, and use of CT without 
contract for patients with allergy to both. 
To take into account the evaluation of 
patients with allergies to contrast agents. 
Section 7.2.3 and 
Table 2 
Added text and tables to specify how PET and 
CT response assessments are integrated for 
modified Lugano criteria and unmodified 
Lugano criteria. 
For clarity. 
Section 7.4 
Separated the specification of 
pharmacokinetic, pharmacodynamic, and 
immunogenicity sampling time points for Parts 
A to C and Parts E and F into separate tables. 
For clarity. 
Section 7.6 
Added specification that, after completion of 
the study, biological samples will not be 
destroyed until applicable regulatory 
obligations have been met. 
Update to conform to the Seattle 
Genetics standard language. 
Sections 7.7.1.1 
and 7.7.1.2 
Added section and text on drug-induced liver 
damage. 
Update to conform to the Seattle 
Genetics standard language and 
regulatory guidance. 
Section 8.3 
Specified that all source data and study records 
must also be available for inspection by 
Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC). 
Update to conform to the Seattle 
Genetics standard language. 
Section 8.5 
Changed the name for the group responsible 
for audits to Research and Development 
Quality group. 
Update to Seattle Genetics organization 
structure. 
Section 9.1 
Revised the statistical assumptions for the 
sample size calculation in Parts E and F, and 
revised the sample size calculation. 
In light of available information, higher 
assumed true objective response rates 
(ORRs) for study treatment were 
justified.  
Section 9.3.1.5 
Simplified text concerning multiple 
comparisons. 
Clarification. 
Section 9.3.5 
Specified that the full analysis set will be used 
to present efficacy analyses for Parts E and F. 
Alignment with regulatory guidance. 


 
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Section(s) 
Change 
Rationale 
Throughout 
protocol 
In descriptions of the study population, 
removed specifications such as “aged ≥60 
years”. 
To account for the inclusion of patients 
aged <60 years in Parts E and F.  
Throughout 
protocol 
Minor administrative changes, corrections, 
clarifications, and rearrangements of text. 
To improve clarity and achieve 
consistency. 
 


 
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Page 157 of 157 
Summary of Changes in Amendment 13 
Section(s) 
Change 
Rationale 
Title Page 
Addition of NCT Number and EudraCT Number 
Updated to meet EU Regulatory 
requirements  
Section 1.3 
Addition of EMA indications for brentuximab vedotin 
Updated to add EMA indications  
Section 3.4 
Definition of End of Study added 
Updated to meet EU Regulatory 
requirements 
Synopsis, 
Section 4.2 
Exclusion Criteria #1 
Symptomatic neurologic disease compromising IADLs or 
requiring medications (e.g., ≥ Grade 2 neuropathy [per 
the National Cancer Institute Common Terminology 
Criteria for Adverse Events, NCI CTCAE], Version 
4.03), with the exception of patients with mild cognitive 
impairment who are still able to perform age appropriate 
IADLs, even if on medication. Baseline peripheral 
neuropathy Grade ≥2 (per NCI CTCAE, Version 4.03) or 
patients with the demyelinating form of Charcot-Marie-
Tooth syndrome 
Clarification and removal of 
redundant criteria 
Section 4.1 
Inclusion Criteria #1Treatment-naive patients with 
histopathological diagnosis of classical HL, which 
excludes nodular lymphocyte-predominant HL, (Parts A, 
B, C, D, and E), or treatment-naive patients with CD30-
expressing (≥1%) PTCL (Part F) by local testing. See 
PTCL histologic subtypes in Appendix L. Patients 
eligible for retreatment on Part D must have had prior 
treatment on this study with the combination of 
brentuximab vedotin plus nivolumab. 
Clarification 
Section 4.2, 
Appendix E 
Additional information on acceptable contraception 
methods 
Update to meet EU Regulatory 
requirements. Guidance to 
investigators that encompasses 
US and EU contraception 
requirements. 
Section 6.9 
Modified section header 6.9 End of Study/End of Follow-
Up 
Modified section header to 
distinguish it from Section 3.4 
(End of Study) 
Section 10 
Text added: This study will be conducted in accordance 
with the Note for Guidance on Good Clinical Practice 
(ICH Harmonised Tripartite Guideline E6 [R2]; FDA 
CFR [21 CFR § 50, 56, 312]), Declaration of Helsinki 
(Brazil, 2015), and all applicable regulatory 
requirements. 
Updated to meet EU Regulatory 
requirements 
Appendix C 
Addition of days for eGFR testing per Sections 6.2.1 and 
6.3.1. 
Correction 
Appendix L 
Subtypes of PTCL 
Clarification 
Appendix M 
Table ‘Integrated PET and CT responses according to 
modified Lugano criteria per BICR’ moved to Appendix M.  
Clarification 
Throughout 
protocol 
Minor administrative changes, corrections, clarifications, 
and rearrangements of text. 
To improve clarity and achieve 
consistency. 
 

SAP_001.pdf: 
 
 
 
Part or all of the information in this statistical analysis plan may be unpublished material. Accordingly, this 
document is to be treated as confidential and restricted to its intended use. This material is the property of 
Seattle Genetics, Inc. and must not be disclosed or used except as authorized in writing by Seattle Genetics, Inc. 
STATISTICAL ANALYSIS PLAN 
 
Protocol Number: 
SGN35-015 
Version: 
13; 05-May-2020 
Protocol Title: 
A phase 2 open-label study of brentuximab vedotin in front-line 
therapy of Hodgkin lymphoma (HL) and CD30-expressing 
peripheral T-cell lymphoma (PTCL) in older patients or patients 
with significant comorbidities ineligible for standard 
chemotherapy 
Sponsor: 
Seagen, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
 


Study SGN35-015 
Statistical Analysis Plan 
Version 3; 5-May-2023 
Brentuximab vedotin 
Seagen, Inc. - Confidential 
Page 2 of 35 
APPROVAL SIGNATURES 
Product: 
Brentuximab vedotin 
Protocol Number: 
SGN35-015 
SAP Version: 
3 
Version Date: 
5-May-2023 
 
The individuals signing below have reviewed and approve this statistical analysis plan. 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
Date 


Study SGN35-015 
Statistical Analysis Plan 
Version 3; 5-May-2023 
Brentuximab vedotin 
Seagen, Inc. - Confidential 
Page 3 of 35 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................................................ 5 
1 
INTRODUCTION ........................................................................................................................................... 7 
2 
STUDY OBJECTIVES ................................................................................................................................... 7 
2.1 
Primary Objective ................................................................................................................................. 7 
2.2 
Secondary Objectives ............................................................................................................................ 7 
2.3 
Additional Objectives ............................................................................................................................ 7 
3 
STUDY ENDPOINTS .................................................................................................................................... 8 
3.1 
Primary Endpoint .................................................................................................................................. 8 
3.2 
Secondary Endpoints ............................................................................................................................. 8 
3.3 
Additional Endpoints ............................................................................................................................. 8 
4 
STUDY DESIGN ............................................................................................................................................ 9 
5 
ANALYSIS SETS ......................................................................................................................................... 11 
5.1 
Full Analysis Set ................................................................................................................................. 11 
5.2 
Efficacy Evaluable (EE) Analysis Set ................................................................................................. 11 
5.3 
Per-Protocol Analysis Set .................................................................................................................... 11 
6 
STATISTICAL CONSIDERATIONS .......................................................................................................... 12 
6.1 
General Principles ............................................................................................................................... 12 
6.2 
Determination of Sample Size ............................................................................................................. 12 
6.3 
Randomization and Blinding ............................................................................................................... 13 
6.4 
Data Transformations and Derivations ................................................................................................ 13 
6.5 
Handling of Dropouts and Missing Data ............................................................................................. 14 
6.6 
Multicenter Studies ............................................................................................................................. 14 
6.7 
Multiple Comparison/Multiplicity....................................................................................................... 14 
6.8 
Examination of Subgroups .................................................................................................................. 15 
6.9 
Covariates ............................................................................................................................................ 15 
6.10 Timing of Analyses ............................................................................................................................. 15 
7 
PLANNED ANALYSES .............................................................................................................................. 16 
7.1 
Disposition .......................................................................................................................................... 16 
7.2 
Demographic and Baseline Characteristics ......................................................................................... 16 
7.3 
Major Protocol Deviations .................................................................................................................. 16 
7.4 
Treatment Administration ................................................................................................................... 17 
7.5 
Efficacy Analyses ................................................................................................................................ 18 
7.5.1 
Primary Endpoint ................................................................................................................... 19 
7.5.2 
Secondary Endpoints .............................................................................................................. 19 
7.5.3 
Pharmacokinetics, pharmacodynamic, and Immunogenicity Endpoints ................................ 23 
7.5.4 
Additional Endpoints .............................................................................................................. 23 
7.6 
Safety Analyses ................................................................................................................................... 24 
7.6.1 
Adverse Events ....................................................................................................................... 25 
7.6.2 
Clinical Laboratory Parameters .............................................................................................. 26 
7.6.3 
ECOG Performance Status ..................................................................................................... 26 
7.6.4 
Concomitant Medications ....................................................................................................... 26 
7.6.5 
Subsequent therapies .............................................................................................................. 26 
7.6.6 
Deaths ..................................................................................................................................... 26 
8 
INTERIM ANALYSIS.................................................................................................................................. 27 
9 
CHANGES FROM PLANNED ANALYSES .............................................................................................. 27 
9.1 
Changes from the Protocol amendment 13 .......................................................................................... 27 
9.2 
Changes from the Original SAP .......................................................................................................... 27 
10 REFERENCES .............................................................................................................................................. 29 
APPENDIX A: IMPUTATION OF PARTIALLY UNKNOWN ADVERSE EVENT DATES ...................... 30 


Study SGN35-015 
Statistical Analysis Plan 
Version 3; 5-May-2023 
Brentuximab vedotin 
Seagen, Inc. - Confidential 
Page 4 of 35 
APPENDIX B: 
DEFINITION OF THE TERM “TREATMENT-EMERGENT” WITH RESPECT TO AE 
CLASSIFICATION ................................................................................................................. 33 
APPENDIX C: 
INTEGRATED PET AND CT RESPONSE ACCORDING TO MODIFIED LUGANO 
CRITERIA AND ORIGINAL LUGANO CRITERIA ............................................................ 35 
 


Study SGN35-015 
Statistical Analysis Plan 
Version 3; 5-May-2023 
Brentuximab vedotin 
Seagen, Inc. - Confidential 
Page 5 of 35 
LIST OF ABBREVIATIONS 
ABVD 
doxorubicin, bleomycin, vinblastine, and dacarbazine 
ADC 
ADI 
antibody-drug conjugate 
absolute dose intensity 
AE 
adverse event 
ALCL 
anaplastic large cell lymphoma 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATA 
antitherapeutic antibodies 
AUC 
area under the concentration-time curve 
BA/BE 
bioavailability/bioequivalence 
BEACOPP 
BICR 
bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone 
blinded independent central review 
Ceoi 
concentration at the end of infusion 
Cmax 
maximum concentration 
Ctrough 
trough concentration 
CBC 
complete blood count 
ChlVPP 
chlorambucil, vinblastine, procarbazine, and prednisone 
ChlVPP/ABV 
chlorambucil, vinblastine, procarbazine, and prednisone plus doxorubicin, bleomycin, and 
vincristine 
CHOP 
cyclophosphamide, adriamycin, vincristine, and prednisone 
CI 
CIRS 
confidence interval 
Cumulative Illness Rating Scale 
CR 
complete remission 
CRF 
CSR 
case report form 
clinical study report 
CT 
CTCAE 
computed tomography 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DNA 
DOR 
deoxyribonucleic acid 
duration of response 
EBV 
Epstein-Barr Virus 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
EOS 
event-free survival 
end of study 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FFTF 
freedom from treatment failure 
G-CSF 
granulocyte colony stimulating factor 
GHSG 
German Hodgkin Study Group 
GM-CSF 
granulocyte macrophage colony stimulating factor 
HEENT 
head, eyes, ears, nose, and throat 
HIPAA 
Health Information Portability and Accountability Act 
HL 
Hodgkin lymphoma 
HRS 
iADL 
Hodgkin Reed-Sternberg 
instrumental activity of daily living 


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ICH 
IDI 
International Conference on Harmonization  
Intended dose intensity 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INN 
International Nonproprietary Name 
IPS 
International Prognostic score 
IR 
IRB 
indeterminate response 
Institutional Review Board 
IV 
intravenous 
JCV 
John Cunningham virus 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAE 
monomethyl auristatin E 
MRI 
magnetic resonance imaging 
MTD 
maximum-tolerated dose 
MUGA 
multigated acquisition 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NLPHL 
nodular lymphocyte-predominant Hodgkin lymphoma 
ORR 
objective response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission tomography 
PK 
pharmacokinetic 
PFS 
progression-free survival 
PML 
progressive multifocal leukoencephalopathy 
PR 
PTCL 
partial remission 
peripheral T-cell lymphoma 
PVAG 
RDI 
prednisone, vinblastine, doxorubicin, and gemcitabine 
relative dose intensity 
RT 
radiotherapy 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
SLD 
SMQ 
SOC 
stable disease 
sum of the longest diameters 
standardized MedDRA query 
system organ class 
SPD 
sum of the products of the largest diameter 
TAb 
TEAE 
total antibody 
treatment-emergent adverse event 
Tmax 
time at which the maximum concentration occurs 
ULN 
upper limit of normal 
USAN 
United States adopted name 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 
 


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1 
INTRODUCTION 
This document outlines the statistical methods to be implemented within the scope of 
Protocol SGN35-015 amendment 13, entitled “A phase 2 open-label study of brentuximab 
vedotin in front-line therapy of Hodgkin lymphoma (HL) and CD30-expressing peripheral 
T-cell lymphoma (PTCL) in older patients or patients with significant comorbidities 
ineligible for standard chemotherapy”. Results of the proposed analyses will become the 
basis of the clinical study report (CSR) for this protocol. 
The purpose of this plan is to provide specific guidelines from which the analysis will 
proceed.  All planned analyses specified in this document will be performed.  Any changes to 
this plan in the form of “post hoc” or “data driven” analyses will be identified as such in the 
final clinical study report.  Any changes will either be reflected in amendments to this plan 
before the database lock or specifically documented in the clinical study report. 
2 
STUDY OBJECTIVES 
All objectives and endpoints are applicable to all parts of the study unless otherwise 
specified. 
2.1 Primary Objective 
● 
To assess the objective response rate (ORR) of single-agent brentuximab vedotin and 
brentuximab vedotin in combination with other agents as frontline therapy in subjects 
age ≥60 years and in subjects ineligible for conventional combination chemotherapy 
due to comorbidities 
2.2 Secondary Objectives 
● 
To evaluate safety and tolerability of single-agent brentuximab vedotin and the safety 
of brentuximab vedotin when given in combination with other agents 
● 
To assess duration of response 
● 
To assess complete remission (CR) rate 
● 
To assess progression-free survival (PFS) 
● 
To assess resolution of B symptoms 
● 
To assess pharmacokinetics (PK) and immunogenicity of brentuximab vedotin (all 
parts) and nivolumab (Part D only) 
● 
To assess overall survival (OS) (Parts E and F only) 
2.3 Additional Objectives 
● 
To assess event-free survival (EFS) 
● 
To assess OS (Parts A, B, C and D) 
● 
To assess biomarkers in serum and tumor biopsies  
● 
To assess the relationship between PK and disease response 
● 
To assess immunomodulatory effects of the combination of brentuximab vedotin and 
nivolumab in peripheral blood (Part D only) 
● 
To assess indeterminate response (IR) rate and subsequent response (Part D only) 


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3 
STUDY ENDPOINTS 
3.1 Primary Endpoint 
● 
ORR according to the Revised Response Criteria for Malignant Lymphoma 
(Cheson 2007) (Parts A, B, and C) 
● 
ORR according to the Lugano Classification Revised Staging System for nodal 
non-Hodgkin and Hodgkin lymphomas (Lugano criteria) and the Lymphoma 
Response to Immunomodulatory Therapy Criteria (LYRIC) (Cheson 2014; 
Cheson 2016) (Part D) 
● 
ORR according to modified Lugano criteria. The assessment will be per blinded 
independent central review (BICR) (Parts E and F) 
3.2 Secondary Endpoints 
● 
Type, incidence, severity, seriousness, and relatedness of adverse events (AE) and 
laboratory abnormalities 
● 
CR rate, disease control rate, duration of ORR, duration of CR, and PFS 
● 
ORR according to Lugano criteria per BICR (Parts E and F) 
● 
B symptom resolution rate 
● 
Estimates of selected PK parameters  
● 
Incidence of antitherapeutic antibodies (ATA) to brentuximab vedotin (all parts) and 
nivolumab (Part D only) 
● 
OS (Parts E and F only) 
3.3 Additional Endpoints 
● 
ORR according to the Response Evaluation Criteria in Lymphoma (RECIL) 
(Younes 2017), per BICR (Parts E and F) 
● 
EFS 
● 
OS (Parts A, B, C and D) 
● 
Co-expression of CD30 and PD-L1/PD-L2 by HRS cells; accompanying T-cell, 
macrophage, and myeloid cell populations in diagnostic tumor specimens; and 
correlation with response rates (Part D only) 
● 
Immune status changes, including immunophenotyping of blood immune cells, in 
response to treatment (Part D only) 
● 
IR rate and subsequent response of CR, PR, or PD (Part D only) 
 


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4 
STUDY DESIGN 
Part A of this phase 2 open-label study is designed to evaluate the efficacy and tolerability of 
brentuximab vedotin as front-line monotherapy in adults age 60 and above with HL.  
Brentuximab vedotin, 1.8 mg/kg, will be administered intravenously (IV) every 3 weeks.  
Subjects enrolling on study with estimated creatinine clearance <30 mL/min will receive 
1.2 mg/kg brentuximab vedotin.  Subjects achieving a CR, partial remission (PR), or stable 
disease (SD) will be allowed to continue on treatment for up to 16 cycles.  After discussion 
with the medical monitor, subjects who experience clinical benefit per the investigator will 
be eligible to receive continued brentuximab vedotin treatment until disease progression, 
unacceptable toxicity, or study closure. 
Part B of the study is designed to evaluate the efficacy and tolerability of brentuximab 
vedotin in combination with dacarbazine as frontline therapy in adults age 60 and above with 
HL. Treatment with brentuximab vedotin 1.8 mg/kg in combination with dacarbazine 
375 mg/m2 will be given on Day 1 of Cycles 1 through 12, followed by single-agent 
brentuximab vedotin 1.8 mg/kg on Day 1 of Cycles 13 through 16.  Subjects enrolling on 
study with estimated creatinine clearance <30 mL/min will receive 1.2 mg/kg brentuximab 
vedotin in combination with a reduced dose of dacarbazine (262 mg/m2; ~30% reduced) 
every 3 weeks. Subjects who have progressive disease must discontinue treatment with both 
investigational agents. Subjects who have unacceptable toxicity to dacarbazine prior to 
completion of 12 cycles may continue to receive brentuximab vedotin as a single agent on 
Day 1 of each cycle for a total of 16 cycles or more of treatment.  After discussion with the 
medical monitor, subjects who complete 16 cycles of treatment and experience clinical 
benefit per the investigator will be eligible to continue to receive single-agent brentuximab 
vedotin treatment until disease progression, unacceptable toxicity, or study closure. 
Part C of this study is designed to evaluate the efficacy and tolerability of brentuximab 
vedotin in combination with bendamustine as frontline therapy in adults age 60 and above 
with HL.  Treatment with bendamustine 70 mg/m2 will be given in combination with 
brentuximab vedotin 1.8 mg/kg on Day 1 and then as a single agent on Day 2 of each cycle 
for up to 6 cycles, followed by single-agent brentuximab vedotin 1.8 mg/kg on Day 1 of the 
remaining cycles for up to 16 cycles.  Subjects who have unacceptable toxicity to 
bendamustine, including developing estimated creatinine clearance <40 mL/min, prior to 
completion of up to 6 cycles may continue to receive brentuximab vedotin as a single agent 
on Day 1 of each cycle for a total of 16 cycles or more of treatment.  After discussion with 
the medical monitor, subjects who complete 16 cycles of treatment and experience clinical 
benefit per the investigator will be eligible to receive continued single-agent brentuximab 
vedotin treatment until disease progression, unacceptable toxicity, or study closure. 
In Parts A, B, and C, disease response and progression will be assessed using the Revised 
Response Criteria for Malignant Lymphoma (Cheson 2007).  
Part D of the study is designed to evaluate the tolerability and efficacy of brentuximab 
vedotin in combination with nivolumab as frontline therapy in adults age 60 and above with 


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HL.  Treatment with brentuximab vedotin 1.8 mg/kg in combination with nivolumab 3 mg/kg 
will be given on Day 1 of each 3-week cycle.  Brentuximab vedotin will be administered at 
least 30 minutes prior to nivolumab.  Subjects with PD or subjects with unacceptable toxicity 
at any time will not continue on treatment.  Subjects with a response of IR will continue on 
treatment until demonstration of PD via radiographic imaging or biopsy.  If subjects have 
unacceptable toxicity that is attributable to only one agent, as determined by the investigator, 
they will be eligible to continue on treatment with the tolerated drug as a single agent.  
Subjects may be treated for up to 16 cycles.  Additional cycles may be allowed following 
approval from the sponsor medical monitor. Disease response will be assessed using the 
Lugano criteria (Cheson 2014) and LYRIC (Cheson 2016).  
Part E and F of the study are designed to evaluate the safety, efficacy, and tolerability of 
brentuximab vedotin as frontline monotherapy in subjects with classical HL or 
CD30-expressing PTCL, respectively, who are unsuitable or unfit for combination 
chemotherapy. Unsuitability or unfitness for conventional combination chemotherapy will be 
justified by the presence of comorbidity-related factors, as documented by either a) a 
Cumulative Illness Rating Scale (CIRS) score ≥10 (according to the criteria specified by 
Salvi and colleagues (Salvi 2008) excluding current active lymphoma) or b) requiring 
assistance with or dependence on others for any instrumental Activities of Daily Living 
(IADL). Brentuximab vedotin, 1.8mg/kg, will be administered IV every 3 weeks. Subjects 
achieving a CR, PR, or SD will be allowed to continue treatment for up to 16 cycles. Disease 
response will be assessed according to modified Lugano criteria, according to the original 
Lugano criteria, and according to RECIL. The assessment will be per BICR. 
Computed tomography (CT) and positron emission tomography (PET) scans are required for 
all subjects at baseline.  Radiographic imaging for response assessment will be performed as 
follows: 
● 
Parts A, B, and C:  Response assessments with CT will be performed at Cycles 2, 4, 
8, 12, and at End of Treatment (EOT).  Imaging with PET will be performed at 
Cycles 2, 8, and at EOT.  CT will be performed at Cycle 16 for subjects eligible for 
continued brentuximab treatment beyond 16 cycles.  Response assessments 
performed after 16 cycles of treatment will include CT scans per institutional standard 
of care or at least every 6 cycles and PET scans per institutional standard of care. 
● 
Part D:  Response assessments will be performed with CT at Cycle 2 and with CT and 
PET at Cycles 4, 8, 12, and EOT.  CT and PET are required at Cycle 16 for subjects 
eligible for continued treatment with brentuximab vedotin and/or nivolumab beyond 
16 cycles. For subjects with a response determination of IR, radiographic assessment 
(CT/PET) of disease must be performed 12 weeks following IR or earlier if clinically 
indicated.  If a subject has a second determination of IR, then subsequent repeat 
imaging must be performed between 4 and 8 weeks.  Follow-up radiographic 
assessment for subjects with IR is not required if a follow-up biopsy has been 
performed that confirms response.  


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● 
Parts E and F: Response assessments with CT and PET will be performed at Cycles 2, 6, 
11, and at EOT approximately 1 month after completion of therapy. Following the EOT 
visit, subjects discontinuing study treatment without progression will be followed 
until progression or initiation of further anti-cancer therapy. Follow-up CT scans will 
be performed every 4 months for 2 years and then per institutional standard of care, 
and follow-up PET scans will be performed per institutional standard of care. 
 
CT/PET of diagnostic quality may be utilized for CT and PET scanning.  Once a subject 
achieves a CR, PET scans are no longer required. PET scans performed as part of 
institutional standard of care may be collected at any time during the study, as available. 
Subjects who receive any amount of brentuximab vedotin will be followed for survival every 
3 months (Parts A to D) or 4 months (Parts E and F) until withdrawal of consent, death, or 
study closure, whichever comes first.  Subjects who have not progressed will have response 
assessments until disease progression. Initiation of alternative treatment for lymphoma will 
also be collected. 
Safety assessments will include the subject incidence and severity of adverse events and 
changes in clinical laboratory values, and physical examination findings.  Serum 
concentrations of ATA to brentuximab vedotin and ATA against nivolumab will also be 
measured. 
A detailed study assessment schedule can be found in the protocol. 
5 
ANALYSIS SETS 
This section defines each of the analysis sets that will be utilized. The use of each analysis set 
will be discussed in Section 7. 
5.1 Full Analysis Set 
The full analysis set includes all subjects who receive any amount of brentuximab vedotin.  
The full analysis set will be used for efficacy analyses and all safety analyses.  
5.2 Efficacy Evaluable (EE) Analysis Set 
The efficacy evaluable analysis set includes all subjects with the histology of classical HL 
(Parts, A, B, C, D and E) and CD30-expressing PTCL (Part F) who receive any amount of 
brentuximab vedotin and who had both a baseline and at least one post-baseline disease 
assessment any time after receiving any amount of brentuximab vedotin. 
5.3 Per-Protocol Analysis Set 
The per-protocol analysis set includes all subjects who receive any amount of brentuximab 
vedotin and who had both a baseline and at least one post-baseline disease assessment and no 
important protocol deviations that could potentially affect tumor response. 
The per-protocol analysis set may be used for secondary analyses of selected efficacy 
endpoints. 


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6 
STATISTICAL CONSIDERATIONS 
6.1 General Principles 
This is a phase 2 open-label study to evaluate the overall clinical benefit of brentuximab 
vedotin as a monotherapy (in Part A, E, and F) and in combinations (with dacarbazine in 
Part B, with bendamustine in Part C, and with nivolumab for Part D).  
Unless otherwise specified, analyses and summaries will be provided by part.  For each part, 
descriptive statistics (mean, median, standard deviation, minimum and maximum) will be 
used to summarize continuous variables.  Frequencies and percentages will be used to 
summarize categorical variables.  
All confidence intervals will be calculated at two-sided 95% level. Any analysis not 
described in this plan will be considered exploratory, and will be documented in the clinical 
study report as a post hoc analysis or a change to the planned analysis. 
To comply with regulatory electronic submission guidelines, listings of all clinical data will 
be submitted as electronic data sets.  To facilitate data review for the study report, only 
pertinent data listings will be created and attached to the appendix of the CSR. 
All statistical Tables, Listings and Figures will be produced using SAS®, version 9.2 or 
higher.  Other statistical software used will be described in the CSR. 
6.2 Determination of Sample Size 
Parts A, B, C, and D will evaluate whether the ORR (CR + PR) for single-agent brentuximab 
vedotin or brentuximab vedotin in combination with dacarbazine, bendamustine, or 
nivolumab is greater than 25% using a single-arm study design.  The objective of this study 
is to be able to detect an ORR of at least 25%, which is considered to show minimal clinical 
benefit given that the subject population may not have other options for initial conventional 
chemotherapy.   
With a sample size of 30 subjects for Part A and an overall significance level of 0.1, 
observing 13 or more objective responses (43% ORR [lower limit of exact 90% CI, 27.87%]) 
would allow us to reject the null hypothesis and claim that the true ORR is greater than 25%.  
Similarly, with a sample size of 20 subjects for Part B and an overall significance level of 
0.1, observing 9 or more objective responses (45% ORR [lower limit of exact 90% CI, 
25.87%]) would allow us to reject the null hypothesis and claim that the true ORR is greater 
than 25%.  For Part C, approximately 30 subjects will be enrolled, with at least 20 subjects 
treated using the lower starting dose of bendamustine (70 mg/m2) combined with 1.8 mg/kg 
brentuximab vedotin.  Using this sample size of 20 subjects included in the analysis for 
Part C and an overall significance level of 0.1, observing 9 or more objective responses 
(45% ORR [lower limit of exact 90% CI, 25.87%]) in this group would allow us to reject the 
null hypothesis and claim that the true ORR is greater than 25%.  An analysis will also be 
performed for all 30 subjects in Part C.  With the assumption of a true ORR of 75%, Parts A, 
B, and C of the study will have over 90% power (nQuery).  For Part D, with a sample size of 


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20 subjects and an overall significance level of 0.1, observing 9 or more objective responses 
(45% ORR [lower limit of exact 90% CI, 25.87%]) would allow us to reject the null 
hypothesis and claim that the true ORR is greater than 25%. 
Part E (the classical HL cohort) is designed to estimate the ORR at a reasonable level of 
precision. Approximately 50 subjects will be enrolled to ensure adequate data for safety and 
efficacy evaluation. If 35 responses are observed, the estimated ORR and the associated 
2-sided 95% CI using the Clopper-Pearson method is 70% (95% CI: 55.4%, 82.1%) 
(Clopper 1934). 
Part F (the PTCL cohort) is designed to estimate the ORR at a reasonable level of precision. 
Approximately 50 subjects will be enrolled to ensure adequate data for safety and efficacy 
evaluation. Enrollment of subjects with sALCL will be capped at 50% of the total enrollment 
in Part F (approximately 25 subjects out of 50). If 25 responses are observed, the estimated 
ORR and the associated 2-sided 95% CI using the Clopper-Pearson method is 50% (95% 
CI: 35.5%, 64.4%) (Clopper 1934). 
6.3 Randomization and Blinding 
This is a phase 2, open-label study.  No randomization or blinding will be utilized. 
6.4 Data Transformations and Derivations 
Age in years will be calculated with SAS INTCK function using first dose date and birth 
date. 
Study Day will be calculated as Date – First Dose Date + 1 for dates on or after the first dose 
date.  For dates prior to the first dose date, Study Day will be calculated as Date – First Dose 
Date.  For all calculations of Study Day, the First Dose Date will be the earliest date of 
treatment administration of any study drug. 
Other time variables based on two 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. 
The following unit conversion will be implemented unless otherwise specified: 
Months = Days / 30.4375 
Years =Days / 365.25 
Baseline values used in all analyses will be the most recent measurement prior to the first 
dose of study drug. 
The end-of-treatment (EOT) date will be the date the EOT visit is performed; if an EOT visit 
is not performed, the EOT date will be either the EOS date or 30 days after the last dose of 
any study drug, whichever is earlier.  
The change from baseline is the post-baseline value minus the baseline value: 
(Post-baseline Value – Baseline Value) 


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If the baseline or post-baseline is missing, then the change from baseline is set to missing. 
The percent change from baseline is the change from baseline divided by baseline and 
multiplied by 100: 
(Post-baseline – Baseline)/Baseline*100 
If the baseline value is 0 and the postbaseline value is also 0, then the percentage change 
from baseline is set to 0. If the baseline value is 0 and the post-baseline value is non-zero, 
then the percent change from baseline is set to missing. 
For efficacy assessments for all parts, the date of response will be the latest of all radiologic 
scan dates for the given response assessment.  The date of progression will be the earliest of 
all radiologic scan dates for the given response assessment.  
The investigator claim of clinical progression is also collected in Part D, E and F. A 
sensitivity analysis to incorporate investigator claim of clinical progression, in addition to the 
radiologic scan information will be provided for Part D, E and F. In the sensitivity analysis, 
subjects in Part D-F who have a response of stable disease or better per response assessment 
at the same visit as investigator claim of clinical progression will be counted as disease 
progression. The date of progression will be the earliest of all radiologic scan dates for the 
given response assessment, or date of investigator claim of clinical progression.  
6.5 Handling of Dropouts and Missing Data 
Missing data will not be imputed with the exception of AE start dates while calculating 
duration of events (see Appendix A for AE partial date imputation details) and treatment-
emergent status (see Appendix B for treatment-emergent definition).  Subjects with missing 
values of a variable other than the time-to-event endpoints (e.g. duration of response, 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 (Section 7.5). Subjects 
whose disease response cannot be assessed will be scored as non-responders for calculating 
the CR rate and ORR. 
6.6 Multicenter Studies 
There are multiple centers in this study, however it is not anticipated that any center will 
accrue enough subjects to warrant an analysis by center. 
6.7 Multiple Comparison/Multiplicity 
No multiple comparisons are planned. For retreatment subjects, the first treatment experience 
will be used in all analyses. Subsequent treatment experience/s will be summarized 
separately. 


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6.8 Examination of Subgroups 
As exploratory analyses, subgroup analyses may be carried out for primary efficacy endpoint 
and selected secondary efficacy endpoints.  The subgroups that may be examined include but 
are not limited to the following: 
● 
Subjects who were ineligible versus subjects who had declined initial conventional 
chemotherapy for HL (Parts A-D only) 
● 
Age at baseline (< median age, ≥ median age) 
● 
Sex (Male, Female) 
● 
Weight at baseline (<median, ≥ median weight) 
● 
Baseline Eastern Cooperative Oncology Group (ECOG) performance status (grade 0, 
1, and ≥2) 
● 
Disease staging at initial diagnosis (stage I-II, stage III-IV) 
● 
Instrumental Activities of Daily Living (IADL) score at baseline for Parts E and F 
only (<median, ≥ median) 
● 
Cumulative Illness Rating Scale (CIRS) at baseline for Parts E and F only (<median, 
≥ median) 
6.9 Covariates 
Covariates are not considered for adjustment in the analyses. 
6.10 Timing of Analyses 
The trial is not designed to allow for early stopping for futility or favorable efficacy results 
(see Section 8 for details). 
The primary analysis for Parts A, B, C, and D will occur when the last subject in each part 
completes Cycle 8 restage. The primary analysis for Parts E and F will be conducted when all 
treated subjects have been followed for at least 6 months, discontinued from study, or had 
30 days safety follow-up after PD, or study terminates, whichever comes first. 
Preceding and subsequent cutoff dates may be defined and corresponding database 
snapshots/locks may occur to allow for more precise estimates of time-to-event endpoints. 
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. 


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7 
PLANNED ANALYSES 
All analyses will be presented by Part A, B, C, D, E and F separately. Analyses may be 
presented on further pooling (e.g. pooling of subjects in Parts A and E as BV monotherapy 
on cHL) as exploratory analyses where applicable. Analyses on selected efficacy endpoints 
may also be performed using the subgroups listed in Section 6.8. 
7.1 Disposition 
Subject enrollment and disposition will be summarized by part using the full analysis set.  
The table will present the number and percentage of subjects who were enrolled, received at 
least one dose of study drug, completed 16 and more than 16 treatment cycles, and 
participated in follow-up visits.  The number and percentage of subjects who discontinued 
treatment will be summarized by the primary reason for treatment discontinuation.  The 
number and percentage of subjects who discontinued the study will be summarized by the 
primary reason for study discontinuation. A listing of disposition data will be provided for 
the full analysis set. 
Number of subjects who signed informed consent, the number of screen failures, and number 
of subjects in each analysis set will be summarized for all enrolled subjects. Screen failures 
will also be summarized by primary reason for screen failure. 
A data listing will also be generated to include the primary end of treatment and end of study 
reasons for each subject. 
7.2 Demographic and Baseline Characteristics 
Demographics and baseline characteristics, including age, gender, ethnicity, race, baseline 
height, weight, BMI, electrocardiogram (ECG), and ECOG score will be summarized using 
the full analysis set.  Disease specific characteristics, including time from disease diagnosis, 
disease staging at baseline, international prognostic index (IPI) score (for part F only), 
B symptom at baseline, geriatric assessment score (parts E and F only) will be summarized 
using the full analysis set. 
Listings of demographics, and disease characteristics will be provided for the full analysis 
set. 
7.3 Major Protocol Deviations 
Major protocol deviations/violations, defined as a violation that is a divergence from the 
protocol that has a significant effect on subject’s rights, safety, or welfare, or on the integrity 
of the resultant data, will be summarized by violation category (see Clinical SOP AA-000506 
Handling Clinical Study Protocol Deviations).  A list of subjects with major protocol 
deviations/violations will be presented.  Protocol deviations that may affect the study results 
will be reviewed prior to the database lock. 


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7.4 Treatment Administration 
Treatment administration will be summarized using the full analysis set and presented for 
each study drug. Summary statistics for duration of therapy (weeks) and the number of cycles 
per subject will be presented, as well as a frequency count for number of cycles received.  
Cumulative dose (mg), absolute dose intensity (ADI) and relative dose intensity (RDI) will 
be described.  The number and percentage of subjects whose dose was ever modified will be 
summarized by modification type, cycle and overall (i.e., over all drug administrations for a 
subject). The number and percentage of doses that were modified may also be summarized 
by modification type, cycle and overall. Study drug administration and exposure information 
will be presented in a data listing by subject and visit. 
The duration of treatment is defined as time from the first study dose to 21 days after the last 
study dose [(last dose date + 21) – first dose date].  If death occurs less than 21 days after the 
last study dose, duration of treatment is defined as [date of death – first dose date +1]. 
Intended Dose Intensity (IDI) is defined as is the intended dose of drug (e.g. mg/kg) per unit 
of time.  
Absolute Dose Intensity (ADI) is defined as the actual dose (e.g. mg/kg) per unit of time that 
the subject received over the entire treatment period. 
Relative Dose Intensity (RDI) is defined as the absolute dose intensity over the intended dose 
intensity. 
RDI = ADI/IDI * 100. 
Example 1: 
For brentuximab vedotin, consider a subject treated for four cycles.  The first intended dose 
was 1.2 mg/kg due to renal insufficiency and the later doses were increased to 1.8 mg/kg. 
The third dose was delayed for one week, and for the fourth cycle the infusion was not 
completed and the subject received less than the full dose, as represented in the following 
table: 
Visit 
Intended Dose 
Regimen (mg/kg) 
Intended Dose 
(mg) 
Actual Dose 
(mg) 
Cycle Length 
C1D1 
1.2 
60 
60 
3 weeks  
C2D1 
1.8 
90 
90 
3 weeks + 1 week delay 
C3D1 
1.8 
90 
90 
3 weeks 
C4D1 
1.8 
90 
45 
3 weeks 
 
ADI (per week): 
= (1.2+1.8 + 1.8 + (1.8*[45/90])) / (3 wks +3 wks + 1 wk delay + 3 wks + 3 wks) 
mg/kg per week 
= 0.44 mg/kg per week 


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IDI (per week) 
= (1.2+1.8+1.8+1.8) / (3 weeks * 4) mg/kg per week 
= 0.55 mg/kg per week 
 RDI: 
=0.44/0.55 * 100 
=80% 
Example 2: 
For dacarbazine, consider a subject treated for four cycles. The first intended dose was 
262 mg/m2. The third dose was delayed for one week, and for the fourth cycle the infusion 
was not completed and the subject received less than the full dose, as represented in the 
following table: 
Visit 
Intended Dose 
Regimen (mg/m2) 
Intended Dose 
(mg) 
Actual Dose 
(mg) 
Cycle Length 
C1D1 
262 
420 
420 
3 weeks  
C2D1 
375 
600 
600 
3 weeks + 1 week delay 
C3D1 
375 
600 
600 
3 weeks 
C4D1 
375 
600 
300 
3 weeks 
 
ADI (per week): 
= (262 + 375 + 375 + (375*[300/600])) / (3 wks + 3 wks + 1 wk delay + 3 wks + 3 
wks) mg/m2 per week 
= 92.3 mg/m2 per week 
IDI (per week) 
= (262 + 375 + 375 + 375) / (3 wks*4) mg/m2 per week 
= 115.6 mg/m2 per week 
RDI: 
  = 92.3/115.6 * 100 
  = 80% 
7.5 Efficacy Analyses 
All efficacy analyses may be presented using the EE analysis set, the full analysis set and the 
per-protocol (PP) analysis set.  The EE analysis set and full analysis set will be used for the 
primary analysis of the efficacy endpoints. Additional analyses of efficacy endpoints using 
the PP set will be presented only when the analysis based on the EE analysis results in a 
different interpretation to that based on the PP set.  Analyses may also be performed using 
the subgroups listed in Section 6.8. 


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7.5.1 Primary Endpoint 
7.5.1.1 Objective Response Rate (ORR) 
Objective response rate (ORR) is defined as the proportion of subjects with CR or PR 
through the end of study or prior to the start of new anti-cancer treatment (including stem cell 
transplant, and excluding consolidative radiotherapy) other than the study treatment. The 
response will be assessed according to the Revised Response Criteria for Malignant 
Lymphoma (Cheson 2007) for Parts A, B and C, according to the Lugano Classification 
Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas (Lugano criteria) 
and the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) (Cheson 
2014; Cheson 2016) for Part D, and the modified Lugano Classification Revised Staging 
System for nodal non-Hodgkin and Hodgkin lymphomas (Cheson 2014) for Parts E and F.  
Details on response assessment according to the Modified Lugano criteria are provided in 
Appendix C. For part E and F, the assessment will be per BICR. Subjects whose disease 
response cannot be assessed will be scored as non-responders for calculating the ORR. 
The ORR and its two-sided 95% exact confidence interval (Clopper 1934) will be calculated.  
This endpoint may also be tabulated by the subgroups defined in Section 6.8. 
Best clinical response will be presented and may also be tabulated by the subgroups defined 
in Section 6.8.  
Sensitivity analysis of ORR will be performed to include investigator claim of clinical 
disease progression for Parts D, E and F. Subjects in Parts D-F who have a response of stable 
disease or better per response assessment at the same visit as investigator claim of clinical 
progression will be counted as disease progression in the sensitivity analysis. 
Up to 6 of the largest dominant nodes or nodal masses will be quantitatively identified at 
baseline based on the product of diameters (Cheson 2007).  The nodes or nodal masses being 
followed for response assessment will also be quantitatively assessed at each pre-specified 
time point. SPD of these nodes or nodal masses is defined as the sum of the products of 
diameters from those nodes or nodal masses being followed for response assessment. The 
maximum SPD percent reduction (or minimum percent increase if there is no reduction) from 
baseline will be derived for each subject and will be graphically displayed (e.g. using a 
waterfall plot). 
7.5.2 Secondary Endpoints 
7.5.2.1 Complete Remission (CR) Rate 
The CR rate is defined as the proportion of subjects with CR, according to the disease 
assessment criteria specified in Section 7.5.1.1 for each part. Subjects whose disease 
response cannot be evaluated will be scored as non-evaluable for calculating the CR. 
CR rate will be summarized using descriptive statistics and an exact two-sided 95% 
confidence interval F distribution method given in (Collett 1991) will be calculated. 


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7.5.2.2 Disease Control Rate (DCR) 
Disease control rate (DCR) is defined as the proportion of subjects with CR, PR or stable 
disease (SD), according to the disease assessment criteria specified in Section 7.5.1.1 for 
each part. Subjects whose disease response cannot be evaluated will be scored as non-
evaluable for calculating the DCR. 
DCR will be summarized using descriptive statistics and an exact two-sided 95% confidence 
interval F distribution method given in (Collett 1991) will be calculated. 
7.5.2.3 Duration of Response 
Duration of response is defined as the time from start of the first documentation of objective 
tumor response (CR or PR) to the first documentation of tumor progression (progressive 
disease, PD) based on radiographic evidence of progression or to death due to any cause, 
whichever comes first. 
Duration of response data will be censored as described below: 
● 
Subjects who do not have tumor progression and are still on study at the time of an 
analysis will be censored at the date of the last disease assessment documenting absence 
of progressive disease 
● 
Subjects who have started an antitumor treatment (including stem cell transplant, and 
excluding consolidative radiotherapy) other than the study treatment prior to documented 
PD or death will be censored at the date of the last disease assessment prior to start of 
new therapy 
● 
Subjects who are removed from study prior to documentation of tumor progression will 
be censored at the date of the last disease assessment documenting absence of progressive 
disease 
● 
Subjects who have disease progression or death after missing two or more consecutive 
radiologic tumor assessments will be censored at the date of last visit with adequate 
tumor assessment prior to missed scans. 
Duration of response will only be calculated for the subgroup of subjects achieving a CR or 
PR. Responses will be assessed according to the assessment criteria specified in 
Section 7.5.1.1 for each study part.  
Duration of response will be analyzed using Kaplan-Meier methodology and Kaplan-Meier 
plots will be provided.  The median duration of response and its two-sided 95% CI using the 
complementary log-log transformation method (Collett 1994) will be calculated. 
7.5.2.4  Duration of Complete Remission 
Duration of complete remission is defined as the time from start of the first documentation of 
complete remission (CR) to the first documentation of tumor progression (PD) based on 
radiographic evidence of progression, or to death due to any cause, whichever comes first.  


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Duration of complete remission data will be censored as described in the section of duration 
of response. 
Responses will be assessed according to the disease assessment criteria specified in 
Section 7.5.1.1.  
Duration of complete remission will only be calculated for the subgroup of subjects 
achieving a CR. Duration of complete remission will be analyzed using Kaplan-Meier 
methodology and Kaplan-Meier plots will be provided.  The median duration of complete 
remission and its two-sided 95% CI using the complementary log-log transformation method 
(Collett 1994) will be calculated. 
7.5.2.5 Progression-Free Survival (PFS) 
Progression-free survival (PFS) is defined as the time from start of study treatment to first 
documentation of tumor progression based on radiographic evidence of progression, or to 
death due to any cause, whichever comes first.   
Specifically, 
PFS = Date of first documented PD or death – Date of first dose of study treatment + 1. 
PFS will be censored as described in Table 1. 
Table 1: 
Primary PFS censoring 
Situation 
Date of Progression or Censoring 
Outcome 
No adequate baseline tumor assessments 
Date of first dose of study treatment 
Censored 
Progression documented at scheduled 
visit 
Date of documented progression 
Progressed 
Progression documented between 
scheduled visits 
Date of documented progression 
Progressed 
No progression through end of study or 
subject withdrawal 
Date of the last disease assessment documenting 
absence of progressive disease.  
Censored 
No post-baseline tumor assessments 
Date of first dose of study treatment 
Censored 
New anti-cancer treatment (including 
stem cell transplant, and excluding 
consolidative radiotherapy) other than 
the study treatment started before 
documented PD or death  
Date of last visit with adequate assessment prior 
to start of anti-cancer treatment 
Censored 
Death before first tumor assessment 
Date of death 
Progressed 
Death without prior progression 
Date of death 
Progressed 
Death or progression documented after 
missing two or more consecutive 
radiologic tumor assessments 
Date of last visit with adequate assessment prior 
to missed visits 
Censored 
 


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Responses will be assessed according to the assessment criteria specified in Section 7.5.1.1 
for each study part.   
PFS will be analyzed using Kaplan-Meier methodology and Kaplan-Meier plots will be 
provided.  The median PFS and its two-sided 95% CI using the complementary log-log 
transformation method (Collett 1994) will be calculated.   
Sensitivity analyses of CR, DCR, DOR, duration of CR, and PFS to incorporate investigator 
claim of clinical progression, in addition to the radiologic scan information will be provided 
for Part D, E and F. Sensitivity analysis of PFS and DOR by treating progression or death 
after missing two or more consecutive visits as an PFS event will also be provided for each 
part. 
7.5.2.6 ORR per Lugano per BICR (Parts E and F only) 
The ORR will be evaluated by BICR, according to the original Lugano criteria (Cheson 
2014) as a secondary endpoint for parts E and F. The ORR will be summarized by parts and 
its two-sided 95% exact confidence interval (Clopper 1934) will be calculated. 
7.5.2.7 B Symptom Resolution Rate 
B symptom resolution rate is defined as the proportion of subjects with lymphoma-related 
B symptoms at baseline who achieve resolution of all B symptoms at any time during the 
treatment period. 
For those subjects with any B symptom(s) at baseline, the B symptom resolution rate and its 
two-sided 95% exact confidence interval will be derived using the F distribution method 
given in (Collett 1991). 
Additionally, a cross-tabulation of best clinical responses (CR, PR, SD, PD , and SD or 
better) versus B-symptom resolution (dichotomized, “yes” or “no”) will be presented for 
those subjects with any B symptom(s) at baseline. 
7.5.2.8 Overall Survival (OS) 
Overall survival is defined as the time from start of study treatment to date of death due to 
any cause. Specifically, 
OS=Date of death – Date of first dose of study treatment + 1. 
In the absence of confirmation of death, overall survival time will be censored at the last date 
the subject is known to be alive (i.e., date of last contact). The last contact date will be 
derived based on data points including, but not limited to, start/end dates from subsequent 
cancer-related therapy, last date subject known to be alive from long-term follow-up 
assessment, and end of study date.  Subjects lacking data beyond the date of first dose will 
have their overall survival time censored to 1 day. 
OS will be analyzed using Kaplan-Meier methodology and Kaplan-Meier plots will be 
provided by each part. The median OS and its two-sided 95% CI using the log-log 


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transformation method (Collett 1994) will be calculated if median is reached. OS will be 
analyzed as secondary efficacy endpoints for Parts E and F, and as additional endpoints for 
Parts A-D. 
7.5.3 Pharmacokinetics, pharmacodynamic, and Immunogenicity Endpoints 
All pharmacokinetics and pharmacodynamics parameters, and immunogenicity endpoints 
will be presented using the full analysis set who have at least one sample tested for these 
parameters post the first dose of study drug. 
7.5.3.1 Pharmacokinetics and Pharmacodynamic Analyses 
PK parameters including area under the concentration-time curve (AUC),  concentration at 
the end of infusion (Ceoi) and trough concentration (Ctrough), maximum concentration (Cmax) 
and time Cmax occurred (Tmax) will be summarized as appropriate by cycle for brentuximab 
vedotin and unconjugated  MMAE (Details are provided in protocol amendment 13 
Section 7.4). 
Brentuximab vedotin and unconjugated MMAE concentrations and nivolumab 
concentrations (Part D only) will be listed at each PK sampling time point. All concentrations 
below the limit of quantification or missing data will be labeled as such in listing.  
Pharmacodynamic biomarkers data will be reported descriptively. 
Correlative analysis may be conducted to explore the relationships between PK and 
immunogenicity and any of the measured pharmacodynamic biomarkers. 
7.5.3.2 Anti-therapeutic Antibody (ATA) Incidence Rate 
The ATA incidence rate is defined as the proportion of subjects that develop ATA at any 
time during the study. The incidence of ATA to brentuximab vedotin (all parts) and 
nivolumab (Part D only) will be assessed. 
7.5.4 Additional Endpoints 
7.5.4.1 ORR per RECIL (Parts E and F only) 
For Parts E and F, ORR will be assessed per BICR, according to the Response Evaluation 
Criteria in Lymphoma (RECIL) (Younes 2017) as additional endpoint. ORR will be 
summarized by part and its two-sided 95% exact confidence interval (Collett 1991) will be 
calculated. 
Up to 3 target lesions will be quantitatively identified at baseline based on the longest 
diameters (Younes 2017). The maximum percent reduction (or minimum percent increase if 
there is no reduction) in the sum of the longest diameters (SLD) of these nodes or nodal 
masses will be summarized and graphically displaced (e.g. using a waterfall plot). 


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7.5.4.2 ORR per Lugano per investigator (Parts E and F only) 
The ORR will be evaluated by investigator, according to the original Lugano criteria (Cheson 
2014) as additional endpoint for parts E and F. The ORR will be summarized by part and its 
two-sided 95% exact confidence interval (Clopper 1934) will be calculated. 
7.5.4.3 Event Free Survival (EFS) 
EFS is defined as the time from start of study treatment until any cause of treatment failure: 
PD, discontinuation of treatment for any reason, or death due to any cause, whichever occurs 
first. Subjects who withdraw consent or start new anti-cancer treatment (including stem cell 
transplant, and excluding consolidative radiotherapy) other than the study treatment will be 
treated as an EFS event. Subjects without post baseline data for disease assessment and no 
treatment discontinuation or death recorded will be censored at the date of first dose of study 
treatment. 
EFS will be analyzed similarly as the PFS as described in Section 7.5.2.5. 
7.5.4.4 Exploratory Correlation Analysis of Biomarkers and Pharmacokinetics 
parameters with Tumor Response (part D only) 
Pharmacodynamic biomarkers and exploratory correlative analyses will be defined in a 
separate analysis plan and presented in a separate report. 
7.5.4.5 IR Rate and Subsequent Response (part D only) 
The IR rate is defined as the proportion of subjects with IR according to the LYRIC (Cheson 
2016). 
For subjects in Part D with an indeterminate response, a listing of response assessments by 
cycle will be provided. The indeterminate response rate and its two-sided 95% exact 
confidence interval will be derived using the F distribution method given in (Collett 1991). 
Their subsequent response of CR, PR, or PD will also be summarized. 
7.6 Safety Analyses 
The full analysis set will be used to summarize all safety endpoints. 
Adverse events (AEs) will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA, Version 23.0 or higher). 
Laboratory values will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE version 4.03). 
Concomitant medications will be coded using WHODrug (version: WHODrug Global B3 
March 1, 2020 or more recent). 


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7.6.1 Adverse Events 
Adverse events will be summarized by descending order of frequency and then of MedDRA 
preferred term unless otherwise specified.  For incidence reporting, if a subject reports more 
than one AE that was coded to the same system organ class or preferred term, the subject will 
be counted only once for that specific system organ class or preferred term. 
A treatment-emergent AE (TEAE) is defined as a newly occurring or worsening AE after the 
first dose of any study drug component. Unless documented as a pre-existing condition, 
adverse events with unknown start date will be counted as treatment-emergent (see 
Appendix B for treatment-emergent definition). 
Treatment-related AEs are defined as treatment-emergent AEs that are determined by the 
investigator to be related to the treatment on study.   
Summary of subject incidence of AEs by each part will be provided for the following: 
● 
Pre-existing AEs 
● 
All treatment-emergent AEs 
● 
TEAEs related to brentuximab vedotin/dacarbazine/bendamustine/ nivolumab 
● 
Treatment-emergent serious adverse events (SAEs) 
● 
Treatment-emergent SAEs related to brentuximab vedotin/ 
dacarbazine/bendamustine/ nivolumab 
● 
TEAEs leading to dose delay of brentuximab vedotin/dacarbazine/bendamustine/ 
nivolumab 
● 
TEAEs leading to dose reduction of brentuximab vedotin/dacarbazine/bendamustine/ 
nivolumab 
● 
TEAEs leading to dose interruption (full dose received) of brentuximab 
vedotin/dacarbazine/bendamustine/ nivolumab 
● 
TEAEs leading to the dose being stopped early (full dose not received) of 
brentuximab vedotin/dacarbazine/bendamustine/ nivolumab 
● 
TEAEs leading to dose discontinuation of brentuximab vedotin/dacarbazine/ 
bendamustine/nivolumab 
● 
TEAEs leading to treatment discontinuation of brentuximab 
vedotin/dacarbazine/bendamustine/nivolumab 
● 
Treatment-emergent AEs by system organ class (SOC), preferred term (PT) and 
maximum severity.  At each system organ class or preferred term, multiple 
occurrences of events within a subject are counted only once at the highest severity 
● 
Grade 3 – 5 treatment-emergent AEs 
● 
Treatment-emergent AEs by system organ class and preferred term 
● 
Treatment-emergent peripheral neuropathy (PN) SMQ (defined by the peripheral 
neuropathy SMQ broad search) by preferred term 
● 
Grade 3 –5 treatment-emergent peripheral neuropathy (PN) SMQ by preferred term 


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● 
Infusion reactions related to brentuximab vedotin/dacarbazine/bendamustine/ 
nivolumab by preferred term and severity grade 
● 
Infusion reactions related to brentuximab vedotin/ dacarbazine/ 
bendamustine/nivolumab by cycle and severity grade 
● 
Treatment-emergent immune-mediated AEs for Part D 
7.6.2 Clinical Laboratory Parameters 
Clinical laboratory data (CBC with differential and serum chemistry) will be summarized as 
appropriate using the full analysis set. 
A summary of the worst post baseline NCI CTCAE (Version 4.03) grade will be presented 
for each parameter. 
Laboratory results and NCI CTCAE grades for hematology, serum chemistry and 
pregnancies tests results will be presented as appropriate in data listings.   
7.6.3 ECOG Performance Status 
Shifts from baseline to the best and worst post-baseline score will be tabulated. 
7.6.4 Concomitant Medications 
Concomitant medications will be summarized by the WHO Drug substance name and listed 
by subject. Transfusions, colony-stimulating factors, and erythropoietin stimulating agents 
will also be summarized by the WHO Drug substance name. 
7.6.5 Subsequent therapies  
The data for subsequent anti-cancer therapies will be summarized and listed. For all parts, 
subsequent anti-cancer therapies will be summarized by the WHO Drug substance name. 
7.6.6 Deaths 
The number of total deaths, deaths that occur within 30 days of last study treatment, deaths 
that occur more than 30 days after last study treatment and relationship to disease will be 
summarized for each part (except for part D) and by total. For part D, number of total deaths, 
deaths that occur within 30 days of last brentuximab vedotin or 100 days of last nivolumab, 
whichever is later, deaths that occur more than 30 days after last brentuximab vedotin dose or 
100 days of last nivolumab and relationship to disease will be summarized. In addition, cause 
of death will be identified by descending MedDRA preferred term (unless otherwise 
specified) and summarized for each part and by total. Death information will be listed by 
subject. 


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8 
INTERIM ANALYSIS 
This study is not designed to allow for early stopping for futility or favorable efficacy results.  A 
formal interim efficacy or futility analysis is not considered meaningful or practical for this study. 
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. 
Cumulative safety reviews by the Medical Monitor will occur approximately monthly.  An 
ongoing real-time review of SAEs will be conducted by the Seattle Genetics Drug Safety 
Department. 
9 
CHANGES FROM PLANNED ANALYSES 
9.1 Changes from the Protocol amendment 13 
● 
Analyses of efficacy endpoints using the PP set may be performed for a subset of 
efficacy endpoints. Results for PP set will be presented only when the analysis based 
on the EE analysis results in a different interpretation to that based on the PP set.   
● 
Subgroup by International prognostic score (IPS) at initial disease diagnosis for Parts 
A – E is not to be performed because some components of IPS data were not 
collected on the study case report form. 
9.2 Changes from the Original SAP 
Study design, determination of sample size, study objectives and endpoints, and analysis 
were updated to incorporate the newly added cohorts based on protocol amendments. 
Changes from the original SAP include the followings: 
● 
Parts B, C, D, E and F were added. 
● 
Languages about formal statistical hypothesis for primary efficacy endpoints in part 
A were removed.  
● 
Full analysis set was added in Section 5.1. 
● 
Safety analysis set was replaced by full analysis set in Section 5.1. 
● 
Updated confidence intervals (CIs) to 95% CI throughout the SAP for consistency. 
● 
Section 6.8 and Section 7.5.1 removed the statement about the timing of primary 
analysis occurring when the last patient completes Cycle 8 restage for Part A. 
● 
Timing of analysis was added for all parts in Section 6.10. 
● 
Summary of subsequent anti-cancer therapies was added in Section 7.6.5. 
● 
Minor editorial changes were made to improve consistency and clarification 
throughout the document. 
9.3 Changes from the SAP Amendment 1 
● 
Updated the start date for survival time calculation to first dose date in Section 7.5.2.8 
and clarified censoring rule for unknown survival status. 


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• Timing of analysis was updated to take into consideration of possible study closed out 
in Section 6.10. 
 


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10  REFERENCES 
 
Cheson BD, Ansell S, Schwartz L, et al. Refinement of the Lugano Classification lymphoma response criteria in 
the era of immunomodulatory therapy. Blood. 2016;128(21):2489-96. 
 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response 
assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 
2014;32(27):3059-68. 
 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 
2007;25(5):579-86. 
 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. 
Biometrika. 1934;26(4):404-13. 
 
Collett D. Statistical inference for binary data. Modelling Binary Data. London, Chapman and Hall. 1991:23-6. 
 
Collett D. Interval-censored survival data. Modelling survival data in medical research. London, Chapman & 
Hall. 1994:237-51. 
 
Salvi F, Miller MD, Grilli A, et al. A manual of guidelines to score the modified cumulative illness rating scale 
and its validation in acute hospitalized elderly patients. J Am Geriatr Soc. 2008;56(10):1926-31. 
 
Younes A, Hilden P, Coiffier B, et al. International Working Group consensus response evaluation criteria in 
lymphoma (RECIL 2017). Ann Oncol. 2017;28(7):1436-47. 
 
 


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APPENDIX A: IMPUTATION OF PARTIALLY UNKNOWN ADVERSE EVENT 
DATES 
The algorithm below should be used to impute pre-existing condition and adverse event (AE) 
start dates for which only partial information is known.  For ease of reading, both pre-existing 
conditions and AEs will be referred to as AE for the remainder of this document. The algorithm 
should be applied to every AE record on a record by record basis. AE start dates should be 
imputed before imputation of AE condition end date in all cases. The AE condition end date 
should only be used in the imputation of the AE start date if it a full known date. 
AE day and month are missing 
If the year is the same as the year of first dose of investigational agent and the onset period 
and/or onset time indicate that the start of the AE was pre-dose: 
● 
AE start date will be imputed as the minimum of (AE condition end date*, day prior 
to first dose of investigational agent) 
If the year is the same as the year of first dose of investigational agent and the onset period 
and/or onset time indicate that the start of the AE was post-dose: 
● 
AE start date will be imputed as the minimum of (AE condition end date*, first dose 
date of investigational agent) 
If the year is before the year of first dose of investigational agent: 
● 
AE start date will be imputed as the minimum of (AE condition end date*, December 
31st see example 2 below) 
If the year is after the year of first dose of investigational agent: 
● 
AE start date will be imputed as the minimum of (AE condition end date*, January 
31st see example 2 below) 
AE month only is missing 
Treat day as missing and replace both month and day according to the above procedure 
AE day only is missing 
If the month/year is the same as the month/year of first dose of investigational agent and the 
onset period and/or onset time indicate that the start of the AE was pre-dose: 
● 
AE start date will be imputed as the minimum of (AE condition end date*, day prior 
to first dose of investigational agent) 
If the month/year is the same as the month/year of first dose of investigational agent and the 
onset period and/or onset time indicate that the start of the AE was post-dose: 
● 
AE start date will be imputed as the minimum of (AE condition end date*, first dose 
date of investigational agent) 
If the month/year is before the month/year of first dose of investigational agent: 


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● 
AE start date will be imputed as the minimum of (AE condition end date*, last day of 
the month) 
If the month/year is after the month/year of first dose of investigational agent: 
● 
AE start date will be imputed as the minimum of (AE condition end date*, last day of 
the month) 
* only use condition end date if known and full end date is available. 
 
The following algorithm should be used to impute AE condition end dates. The AE records 
for a condition/event should be sorted by the imputed start dates then record position (order 
of entry into the eCRF). After sorting the AE records, apply the following rules to partial or 
missing AE condition end dates: 
For all records excluding the last chronological record for a condition/event 
AE condition end date will be imputed as the start date of the subsequent record 
For the last chronological record for a condition/event 
If outcome is “recovered/resolved”, “recovered/resolved with sequelae”, or “fatal”: 
● 
AE condition end date will be imputed as the minimum of (last dose date + 30, death 
date, data extraction date) 
If outcome is “recovering/resolving”, “not recovered/resolved”, “unknown”, or blank: 
● 
AE condition end date will not be imputed 
Example 1 
AESPID 1: 
Condition/Event HEADACHE  
First dose date 01JAN2012 
Prior to imputation: 
Start date 
Condition end date 
Severity 
Outcome 
Onset 
UNUNK2011 
15APR2012 
1 
not recovered/resolved 
pre-ICF 
15APR2012 
UNMAY2012 
2 
recovering/resolving 
post 1st dose 
UNMAY2012 
UNJUN2012 
1 
not recovered/resolved 
post 1st dose 
UNJUN2012 
UNJUN2012 
3 
recovering/resolving 
post 1st dose 
UNJUN2012 
10JUL2012 
2 
recovering/resolving 
post 1st dose 
10JUL2012 
-- 
1 
not recovered/resolved 
post 1st dose 
 


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Seagen, Inc. - Confidential 
Page 32 of 35 
Post imputation: 
Start date 
Condition end date 
Severity 
Outcome 
31DEC2011 
15APR2012 
1 
not recovered/resolved 
15APR2012 
31MAY2012 
2 
recovering/resolving 
31MAY2012 
30JUN2012 
1 
not recovered/resolved 
30JUN2012 
30JUN2012 
3 
recovering/resolving 
30JUN2012 
10JUL2012 
2 
recovering/resolving 
10JUL2012 
-- 
1 
not recovered/resolved 
 
Example 2 (highlights choice of last day of the month as opposed to the 1st or the 15th) 
AESPID 4: 
Condition/Event NAUSEA 
First dose date 01APR2012 
Prior to imputation: 
Start date 
Condition end date 
Severity 
Outcome 
Onset 
UNUNK2011 
25APR2012 
1 
not recovered/resolved 
pre-ICF 
25APR2012 
UNAPR2012 
2 
recovering/resolving 
post 1st dose 
UNAPR2012 
04MAY2012 
1 
recovered/resolved 
post 1st dose 
 
Post imputation: 
Start date 
Condition end date 
Severity 
Outcome 
31DEC2011 
25APR2012 
1 
not recovered/resolved 
25APR2012 
31APR2012 
2 
recovering/resolving 
31APR2012 
04MAY2012 
1 
recovered/resolved 
 
 


Study SGN35-015 
Statistical Analysis Plan 
Version 3; 5-May-2023 
Brentuximab vedotin 
Seagen, Inc. - Confidential 
Page 33 of 35 
APPENDIX B: DEFINITION OF THE TERM “TREATMENT-EMERGENT” WITH 
RESPECT TO AE CLASSIFICATION  
The algorithm below should be used to determine whether an adverse event (AE) is classified 
as a treatment-emergent adverse event (TEAE). A TEAE is defined as any AE which 
worsens in severity during the safety reporting period or is newly occurring at any time, 
where newly occurring means that the AE was not present at baseline. For ease of reading, 
both pre-existing conditions and AEs will be referred to as AEs for the remainder of this 
document. AE dates should be imputed in accordance with the algorithm detailed in 
Appendix A prior to determination of TEAE classification. Details of the TEAE 
classification are as follows: 
1. For each subject, determine the first dose date, which is the earliest date the subject 
receives any amount of study drug. 
2. Baseline AEs: classify an AE record as baseline AE if it satisfies both criteria a and b 
below: 
a. AE onset satisfies either of i, ii or iii below: 
● Onset date is prior to the first dose date 
● Onset date is the same as the first dose date, and Onset Period is “started after 
consent but before the first dose of any study treatment” or Onset Time Relative to 
Study Treatment is “started before first infusion or before infusion on any dosing 
day” 
● Onset Period is “started before the signing of consent” or “started after consent but 
before the first dose of any study treatment” 
b. AE end date satisfies either of i or ii below: 
● End date is the same as or after the first dose date  
● End date is missing with outcome equal to  
− 
recovering/resolving, or 
− 
not recovered/not resolved, or  
− 
unknown or missing 
3. Post-baseline AEs: classify an AE record as post-baseline AE if it meets either of criteria 
a, b or c below: 
a. Onset date is after the first dose date 
b. Onset date is the same as the first dose date, and Onset Period is “started after the first 
dose of any study treatment” or Onset Time Relative to Study Treatment is not 
“started before first infusion or before infusion on any dosing day” 
c. Onset Period is “started after the first dose of any study treatment”  


Study SGN35-015 
Statistical Analysis Plan 
Version 3; 5-May-2023 
Brentuximab vedotin 
Seagen, Inc. - Confidential 
Page 34 of 35 
4. TEAE flag will be derived as follows: 
a. For all AE records that have an end date prior to the first dose date, assign TEAE flag 
to ‘N’ 
b. For all baseline AEs, assign TEAE flag to ‘N’ 
c. For post-baseline AEs: 
• If the post-baseline AE is a continuing event of a baseline AE (i.e., events with 
the same AE identifier, where AE identifier is the number before the colon in 
SDTM AE.AESPID), then compare the post-baseline AE to the most recent 
baseline AE with the same AE identifier (to be referred to as “baseline AE” 
below). Assign TEAE flag to ‘Y’ for the applicable post-baseline AE records if a 
post-baseline AE record meets any of the following worsening criteria based on 
relatedness, seriousness or CTCAE grade: 
− If the post-baseline AE is related to treatment, or 
− If the post-baseline AE meets the criteria for an SAE and the most recent 
baseline AE was not an SAE, or 
− If the post-baseline AE has a higher CTCAE grade 
All subsequent episodes of the same AE should have TEAE flag = ‘Y’. 
• Otherwise, assign TEAE flag to ‘N’ 
• If the post-baseline AE is not a continuing event of a baseline AE, then assign 
TEAE flag to ‘Y’ 
 
NOTE: 
For summaries which include only treatment emergent AEs, include all AEs 
which have at least one record classified as a TEAE as well as those AEs for 
which TEAE status could not be determined (e.g., the value of the TEAE 
variable may be missing if the event cannot be identified as baseline or 
post-baseline – missing information on the AE CRF should be queried). Only 
exclude those AEs which were determined to not be treatment emergent for 
all records. 


Study SGN35-015 
Statistical Analysis Plan 
Version 3; 5-May-2023 
Brentuximab vedotin 
Seagen, Inc. - Confidential 
Page 35 of 35 
APPENDIX C: INTEGRATED PET AND CT RESPONSE ACCORDING TO 
MODIFIED LUGANO CRITERIA AND ORIGINAL LUGANO 
CRITERIA 
The primary determination of antitumor efficacy will be ORR according to the Lugano 
Classification Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas 
modified to take into account CT response in the event of a PET partial response (PR) 
(modified Lugano criteria). The disease assessment on the basis of PET and CT response 
according to modified Lugano criteria is summarized in the table below: 
PET Response 
CT Response 
Integrated Response 
CR 
Any 
CR 
PR 
CR, PR 
PR 
Non-CR, Non-PR 
SD 
SD 
Any 
SD 
PD 
Any 
PD 
 
Prior PET responsea 
CT Response 
 
Not done or  
CR 
Non-PD 
CRb 
Not evaluable 
non-CR 
Non-PD 
NE 
 
Any 
PD 
PD 
No FDG-avid disease  
at baselinec 
No disease present (NE) 
NE 
PD 
PD 
NE=not evaluable. 
a 
"Prior PET response" refers to the latest prior PET assessment that was evaluable. PET responses may be carried 
forward over multiple CT assessments. 
b 
A CR according to PET will be carried forward irrespective of CT response, until CT shows PD or is assessed as NE. 
c 
Per protocol all subjects must have FDG-avid disease at baseline. 
 
Assessment of response, according to the original (unmodified) Lugano criteria 
(Cheson 2014), will be undertaken in the same manner as for modified Lugano, with the 
exception that if the PET response is PR the integrated response will be PR, irrespective of 
CT response.