A Phase 2 Study of Nivolumab and Brentuximab Vedotin Consolidation After Autologous Stem Cell Transplantation in Patients With High-Risk Classical Hodgkin Lymphoma
Phase: PHASE2
Conditions: Classic Hodgkin Lymphoma, Recurrent Hodgkin Lymphoma, Refractory Hodgkin Lymphoma
Sponsor: City of Hope Medical Center

 
IRB 16378 
 
05/16/2022 
Packet: 12 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF HEMATOLOGY 
 
TITLE:  
A Phase 2 Study of Nivolumab and Brentuximab Vedotin Consolidation After Autologous Stem 
Cell Transplantation in Patients with High-Risk Classical Hodgkin Lymphoma 
 
CITY OF HOPE PROTOCOL NUMBER: 
IRB # 16378  
 
Protocol Date: 05/16/22  
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
 
COH Initial Approval 
Protocol Dated 03/03/17v00 
 Title Page Version: 00 
Amendment 01  
Protocol Dated 04/11/17v01 
Title Page Version: 01 
Amendment 02  
Protocol Dated 05/03/17v02 
Title Page Version: 02 
Amendment 03  
Protocol Dated 09/22/17v03 
Title Page Version: 03 
Amendment 04  
Protocol Dated 11/21/17v04 
Title Page Version: 04 
Amendment 05 
Title Page Dated 06/21/2018 
Title Page Version: 05 
Amendment 06 
Title Page Dated 10/08/2018 
Title Page Version: 06 
Amendment 07 
Protocol Dated 02/25/19v05 
Title Page Version: 07 
Amendment 08 
Protocol Dated 04/24/19v06 
Title Page Version: 08 
Amendment 09 
Protocol Dated 05/01/19v07 
Title Page Version: 09 
Amendment 10 
Protocol Dated 03/01/21v08 
Packet: 10 
COH Amendment 11 at Continuation 
Protocol Dated 03/01/21 (TP) 
 
 
      Packet: 11  
Amendment 12 
Protocol Dated 05/16/22 
Packet: 12 
 
SITE:  
 
 
 
 
Hodgkin Lymphoma 
STAGE (If applicable): 
 
 
N/A 
MODALITY:  
 
 
 
Immunotherapy and Drug-Antibody Conjugate 
TYPE:  
 
 
 
 
Phase 2 
 
PRINCIPAL INVESTIGATOR: 
 
Alex Herrera, M.D. 
 
COLLABORATING INVESTIGATOR(S): 
Stephen Forman M.D. 
 
PARTICIPATING CLINICIANS: 
Matthew Mei MD, Monzr Al Malki, MD., Elizabeth Budde, MD., 
Leslie Popplewell, MD., Tanya Siddiqi, MD., Leonardo Farol, MD., 
Firoozeh Sahebi, MD., Ricardo Spielberger, MD., Ji-Lian Cai, MD., 
Thai Cao, MD., Jasmine Zain, MD., Eileen Smith MD., Liana 
Nikolaenko MD., Saro Armenian MD., Nicole Karras MD., 
Karamjeet Sandhu MD, William Boswell, MD., Arnold Rotter., MD. 
Haris Ali, MD, Shukaib Arslan M.D. 
 
BIO-STATISTICIAN: 
Lu Chen, PhD 
 
NURSE PRACTITIONER: 
Yi-Ping Wen, NP (M.S.) 
 
PARTICIPATING SITES: 
City of Hope, Duarte, CA 
 
Kaiser Permanente, 
 
Fred Hutchinson Cancer Center, WA, 
 
Mayo Clinic, MN, 
 
MD Anderson, Tx, 
 
Hackensack University, NJ, 
 
Memorial Sloan Kettering Cancer Center, NY 

 
IRB 16378 
 
05/16/2022 
Packet: 12 
 
Dana Farber Cancer Institute, MA 

This document is confidential and for research purposes only. Do not copy, redistribute, 
disclose or use except as authorized 
 
 
 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Clinical Trial Protocol 
A Phase 2 Study of Nivolumab and Brentuximab Vedotin Consolidation After 
Autologous Stem Cell Transplantation in Patients with High-Risk Classical 
Hodgkin Lymphoma 
 
Version Date: May 16 2022 
Protocol Version: 09 
 
City of Hope #: 16378 
Agents: Nivolumab, Brentuximab Vedotin 
IND Number: 134189 
Sponsor/ IND Holder: City of Hope 
Industry Partner/ Funding Support: Bristol Myers Squibb Company   
NCT Number: NCT03057795 
 
 
 
 
 
 
Principal Investigator 
Alex F. Herrera, M.D. 
City of Hope National Medical Center 
Dept. of  Hematology 
T: 626-256-4673 x 62405 
F: 626-301-8256 
Email: aherrera@coh.org 
 
Coordinating Center 
Data Coordinating Center 
City of Hope National Medical Center 
Phone: (626)-218-7904 
E-mail: DCC@coh.org  
 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
City of Hope #: 16378  
Protocol Version:  09- May 16 2022 
 
CONFIDENTIAL 
Page 2  
PROTOCOL TEAM 
Biostatistician 
Lu Chen, PhD. 
Dept. Information Sciences 
City of Hope National Medical 
Center 
T: 626-256-4673 x 86626 
Email: lchen@coh.org 
Co-Investigator 
Stephen Forman, MD 
Dept. Hematology/HCT 
City of Hope National Medical 
Center 
T: 626-256-4673 x 82405 
Email: sforman@coh.org 
 
 
Participating non-COH sites  
Site Lead Investigator 
Leona Holmberg, MD 
Fred Hutchinson Cancer Center 
Seattle Cancer Care Alliance 
825 Eastlake Ave. East 
G3-200 
Seattle, Washington 98109  
T: (206) 288-2035 
Email: lholmber@fredhutch.org 
Site Lead Investigator 
Yago Nieto, MD., PhD 
The University of Texas MD 
Anderson Cancer Center 
1515 Holcombe Blvd., Unit 423 
Houston, TX 77030 
T: (713) 792-8750 
Email: ynieto@mdanderson.org 
Site Lead Investigator 
Gunjan Shah, MD 
Memorial Sloan Kettering Cancer 
Center 
1275 York Avenue 
New York, NY 10065 
Email: shahg@mskcc.org 
Site Lead Investigator 
Patrick Johnston, MD. PhD. 
Mayo Clinic College of Medicine 
and Mayo Foundation,  
Rochester, MN, 55905 
Email: johnston.patrick@mayo.edu 
 
 
Site Lead Investigator 
Tatyana Feldman, MD 
Hackensack University 
John Theurer Cancer Center 
92 2nd Street 
Hackensack, NJ, 07601 
T: 551-996-4469 
Email:  
Tatyana.Feldman@hackensackmeri
dian.org 
 
 
Translational Investigator 
Margaret A. Shipp, MD 
Dana-Farber Cancer Institute 
Division of Hematologic Neoplasia 
450 Brookline Avenue 
Boston, MA 02215 
O: 617-632-3874 
F: 617-632-4734 
Email: 
margaret_shipp@dfci.harvard.edu 
 
Translational Investigator 
Scott J. Rodig, MD, PhD 
Dana-Farber Cancer Institute 
Department of Pathology 
450 Brookline Avenue 
Boston, MA 02215 
O: 617-732-7510 
Email: srodig@partners.org 
 
 
 
 
 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
City of Hope #: 16378  
Protocol Version:  09- May 16 2022 
 
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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
City of Hope #: 16378  
Protocol Version:  09- May 16 2022 
 
CONFIDENTIAL 
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PROTOCOL SYNOPSIS 
Protocol Title: 
A Phase 2 Study of Nivolumab and Brentuximab Vedotin Consolidation After Autologous Stem Cell 
Transplantation in Patients with High-Risk Classical Hodgkin Lymphoma 
Study Detail 
Indication(s) 
Relapsed/ refractory Hodgkin lymphoma post-ASCT 
Phase: 
2 
Number of participants: 
59 evaluable; anticipated maximum: 65 
Estimated Accrual Duration: 
24 months 
Estimated Study Duration 
42 months 
Participant Duration: 
Minimum 18 months from start of treatment 
Participating Sites: 
 
City of Hope, Duarte, CA 
 
Fred Hutchinson Cancer Center 
 
MD Anderson Cancer Center 
 
Memorial Sloan Kettering Cancer Center  
 
Hackensack Medical Center 
 
Mayo Clinic 
Study Agents: 
Nivolumab, Brentuximab Vedotin 
Brief Protocol Title for the Lay 
Public: 
Nivolumab and brentuximab vedotin therapy for relapsed/ refractory 
Hodgkin lymphoma patients after autologous stem cell transplantation. 
Sponsor: 
City of Hope 
Industry Partner: 
Bristol Myers Squibb Company 
Industry Partner Protocol ID: 
CA209-878 
Rationale for this Study: 
Classical HL is a lymphoma of B-cell origin that is defined by the presence of Hodgkin-Reed-Sternberg cells in a 
background of inflammatory cells. Although the majority of patients with Hodgkin Lymphoma (HL) are cured 
with upfront therapy, as many as 20-40% of patients will have relapsed or refractory (rel/ref) disease. Standard 
of care treatment for patients with relapsed/refractory HL is salvage chemotherapy followed by autologous 
stem cell transplantation (ASCT) in chemosensitive patients, but about half of HL patients who undergo ASCT 
will relapse. HL patients who are refractory to second-line therapy or relapse after ASCT have poor outcomes. 
Therefore, improved therapies for patients with relapsed/refractory HL are urgently needed. 
 
Brentuximab vedotin (BV) – an antibody-drug conjugate (ADC) of an anti-CD30 monoclonal antibody with the 
anti-tubulin agent monomethyl auristatin E – is effective in treating relapsed/refractory HL, with an overall 
response rate (ORR) of 75% and complete response (CR) rate of 34%. Recently, the AETHERA trial 
demonstrated that BV consolidation treatment following ASCT prolongs PFS in patients with high risk relapsed 
or refractory classical HL compared to placebo. 
 
The programmed death receptor-1 (PD-1) pathway is an immune checkpoint that normally serves to dampen 
immune responses in tissues. PD-1 is expressed on activated T-cells and binds its ligands, PD-L1 and PD-L2, on 
tissue cells or antigen presenting cells to decrease T-cell activation, proliferation, and survival. Tumor cells can 
co-opt this pathway to evade attack by the host immune system. A wide range of hematologic malignancies 
express PD-1 or PD-L1, including Hodgkin’s lymphoma (HL). In addition, molecular analyses have demonstrated 
that genetic alterations involving PD-L1 and its overexpression are critical in the pathogenesis of HL. PD-1 
inhibitors, including nivolumab, have produced dramatic responses in early-phase studies of patients with 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
City of Hope #: 16378  
Protocol Version:  09- May 16 2022 
 
CONFIDENTIAL 
Page 5  
relapsed/refractory HL. An 87% ORR and 100% clinical benefit rate were observed in a phase I study of single-
agent nivolumab in patients with relapsed/refractory HL. 
 
Despite the incremental benefit of the addition of post-ASCT BV consolidation, the 2-year PFS in BV-
consolidated patients in the AETHERA trial was only 63%. Clearly, there is room for improvement. In addition, 
with a planned 16 cycles of BV therapy in the AETHERA trial, 23% of patients discontinued BV consolidation 
therapy and 31% had modification of the BV dose due to peripheral neuropathy. We propose to add 
nivolumab to the backbone of post-ASCT BV consolidation to improve upon the efficacy of BV post-ASCT 
consolidation, and to shorten the total duration of consolidation therapy from 16 to 8 cycles to improve 
tolerability of the combination regimen. Based on the preliminary findings of an ongoing phase 1/2 study, 
which is evaluating the combination of BV and nivolumab as initial salvage treatment after the failure of 
frontline therapy, the combination of BV and nivolumab appears safe and well-tolerated. We propose a single-
arm phase 2 study to evaluate the efficacy of BV plus nivolumab consolidation therapy in patients with 
relapsed/refractory HL who have undergone ASCT. 
Study Design: 
This is a single-arm, open-label Phase 2 study of nivolumab plus BV consolidation for patients with relapsed/ 
refractory HL who have undergone ASCT. Participant screening can initiate 21 days post-ASCT. Participants 
must initiate protocol therapy within 30 to 60 days post-ASCT. Study PI can grant exception for a patient to 
start as late as 75 days post-ASCT with a reasonable justification for delay (e.g. recovery from post-ASCT 
toxicity) and this will not be a protocol deviation, nor require an exception to be filed. Nivolumab and 
brentuximab vedotin will be administered in 21-day cycles. BV and nivolumab will be administered on Day 1 of 
each cycle. Participants will receive up to 8 cycles of protocol therapy, or until unacceptable toxicity or disease 
progression. Response assessments will occur during screening, Cycle 4 Day 15, 30 days post-last dose, and at 
12 and 18 months from start of treatment visits. The primary endpoint is 18-month progression-free survival. 
Secondary endpoints include overall survival, cumulative incidence of relapse/progression, cumulative 
incidence of non-relapse mortality, overall response rate, and toxicity. 
 
Objectives: 
Primary Objective 
 
Assess the efficacy of nivolumab plus brentuximab vedotin consolidation after autologous stem cell 
transplantation (ASCT) in participants with relapsed/refractory classical Hodgkin Lymphoma (HL), as 
assessed by 18-month progression-free survival (PFS). 
Secondary Objective 
 
Estimate the overall survival (OS), the cumulative incidence of relapse/progression, the cumulative 
incidence of non-relapse mortality (TRM) in participants with relapsed/ refractory HL who receive 
nivolumab plus brentuximab vedotin consolidation after ASCT.  
 
Estimate the overall response rate to nivolumab plus brentuximab vedotin therapy in participants 
with measurable disease after ASCT. 
 
Establish the safety and tolerability of nivolumab plus brentuximab vedotin when used as 
consolidation after ASCT in participants with relapsed/ refractory HL. 
Exploratory Objective 
 
Evaluate the Lymphoma Response to Immunomodulatory therapy Criteria (LYRIC) definition of 
indeterminate response to guide the management of patients regarding treatment past progressive 
disease. 
 
Explore the impact of nivolumab plus brentuximab vedotin therapy on immune reconstitution after 
ASCT. 
 
Explore the prognostic impact of and temporal dynamics of minimal residual disease (MRD) in the 
peripheral blood as assessed by the next-generation sequencing-based ClonoSEQ platform. 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
City of Hope #: 16378  
Protocol Version:  09- May 16 2022 
 
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 
Explore the prognostic impact of 9p24.1 abnormalities in tumor tissue assessed by FISH on outcomes 
after ASCT and nivolumab plus brentuximab vedotin post-ASCT consolidation therapy. 
 
Explore the relationship between immune cells and HRS in tumor samples by 6-color quantitative 
spatial image analysis using the Vectra system, and correlate with outcome after ASCT and nivolumab 
plus brentuximab vedotin post-ASCT consolidation therapy. 
 
Explore whether genetic alterations (e.g. gene expression profiles or genetic mutations) in HL tumor 
samples are associated with outcome after ASCT and nivolumab plus brentuximab vedotin post-ASCT 
consolidation therapy. 
 
Evaluation Criteria and Endpoints:  
 
Response will be assessed per 2014 Lugano Classification. 
 
Clinical endpoints are as follows: 
Endpoint 
Patients 
Definition 
Progression-Free Survival 
(PFS) 
Evaluable patients 
Defined as the time from the first dose of study 
treatment to the first observation of disease 
relapse/progression or death from any cause, whichever 
occurs first. 
Overall Survival (OS) 
Evaluable patients 
Defined as the time from the first dose of study 
treatment to death from any cause. 
Cumulative Incidence of Non-
Relapse Mortality (NRM) 
Evaluable patients 
Defined as the time from the first dose of study 
treatment to non-disease related death. 
Cumulative Incidence of 
Relapse/Progression 
Evaluable patients 
Defined as the time from the first dose of study 
treatment to disease relapse/progression. 
Overall response rate (ORR) 
Evaluable patients with 
measureable disease 
post-ASCT 
Proportion of patients achieving CR or PR 
 
Evaluable patients are defined as eligible participants who received at least one dose of the protocol 
treatment. Eligible participants who did not receive any protocol treatment will be considered in-
evaluable, replaced, and excluded from all analyses. 
 
For patients who meet PD per Lugano Classification and also meet IR per LYRIC criteria (Appendix H) 
[1]: In the analysis, patients with PD per Lugano classification and IR per LYRIC criteria who continue 
study treatment beyond progression per Lugano classification and have confirmation of subsequent 
PD per LYRIC criteria will be counted as PD at the initial time point of progression per Lugano 
classification; patients with PD per Luagno classifcation and IR per LYRIC criteria who continue study 
treatment beyond progression per Lugano classification and do not have confirmation of subsequent 
PD per LYRIC criteria, with subsequent SD, PR, or CR per Lugano classification, will NOT be counted as 
PD at the initial time point of progression per Lugano classifcation. Patients with PD per Lugano 
classification and IR per LYRIC criteria who did NOT continue study treatment beyond progression per 
Lugano classification will be considered PD at the initial timepoint of progression per Lugano 
classification. 
 
Toxicity and adverse events will be recorded using the NCI CTCAE v 4.0. All toxicities/AEs will be 
recorded from the initiation of protocol therapy through the follow-up period. 
 
Statistical Considerations:  
Based on the AETHERA trial, the 18-month PFS rate in patients with relapsed/refractory HL who undergo ASCT 
followed by BV consolidation is approximately 65% (from the independent assessment data).  We hypothesize 
that adding nivolumab to BV consolidation after ASCT will improve the 18-month PFS rate to 80%. A sample 
size of 59 evaluable patients will provide approximately 81% power for detecting the increase in 18-month PFS 
from the baseline of 65% to 80% in this study at 1-sided type I error of 0.05. The power estimation is based on 
the exact binomial test. Operationally, the study treatment will be considered promising if at least 45 of the 59 
evaluable participants are alive and progression-free at 18 months after the first dose of study treatment. The 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
City of Hope #: 16378  
Protocol Version:  09- May 16 2022 
 
CONFIDENTIAL 
Page 7  
probability of observing at least 45 surviving and progression-free participants out of a total 59 participants, 
assuming different PFS rates, is shown in below: 
 
True 18-month PFS rate 
65% 
70% 
75% 
80% 
The probability of observing at least 45 
participants (out of 59 total) being alive and 
progression-free at 18-months 
0.044 
0.18 
0.48 
0.81 
 
To achieve 59 evaluable participants, the maximum study accrual is set to be 65, accounting for up to 10% 
inevaluable enrollments. 
Toxicity Monitoring 
Close and continuous monitoring for toxicity will occur throughout the study duration per institutional 
standards. The COH DSMC will review the AE data quarterly. In the AETHERA trial, 56% of patients who 
received brentuximab vedotin experienced at least one grade 3-4 adverse event, including 29% with grade 3-4 
neutropenia, 10% with grade 3-4 peripheral sensory neuropathy, and 6% with grade 3-4 peripheral motor 
neuropathy.  In this study, the total treatment number of cycles is reduced to 8 but the addition of nivolumab 
may introduce additional toxicities.  
Given the prior toxicity experiences in AETHERA trial and the differences in treatment, in this study we will 
specifically monitor the occurrence of any “unacceptable AE”. Unacceptable AE is defined as any of the 
following AEs that is at least possibly attributed to protocol therapy during treatment and safety follow-up: 
Any ≥ Grade 3 immune-related AE; Grade 3 fatigue or non-irAE skin toxicity that does not resolve within 7 days 
to ≤ Grade 1/baseline; Any other ≥ Grade 3 non-hematologic non-irAE that does not improve within 3 days to  
≤ Grade 1/baseline as applicable with supportive care (with the following exception: ≥ Grade 3 laboratory 
abnormality that is not clinically significant); Grade 4 neutropenia that does not resolve to ≤ Grade 2 within 3 
days with supportive care (e.g. GCSF); Grade 3 or 4 thrombocytopenia with bleeding, and Any Grade 5 AE.  
 
This specific monitoring will be performed according to the rule below, which is based on the 50% quartile of 
the binomial distribution with an unacceptable toxicity rate of 33%.   
 
3 or more patients with unacceptable toxicities when ≤ 9 patients have been treated. 
 
5 or more patients with unacceptable toxicities when ≤16 patients have been treated. 
 
8 or more patients with unacceptable toxicities when ≤23 patients have been treated. 
 
11 or more patients with unacceptable toxicities when ≤33 patients have been treated. 
 
15 or more patients with unacceptable toxicities when ≤46 patients have been treated. 
 
19 or more patients with unacceptable toxicities when ≤ 59 patients have been treated. 
If the monitoring rule is met, the study PMT will review and assess the safety of the trial and submit a report 
outlining the findings and proposed action plans if any to the COH DSMC. The COH DSMC will review and make 
the decision to continue, modify, or permanently suspend accrual to the trial. At the end of the study with 59 
evaluable participants, the 95% exact binomial confidence interval for the rate of such unacceptable AE will have 
a width of no more than 27%.  
Eligibility Criteria 
Inclusion Criteria 
 
Age: ≥ 18 years 
 
ECOG performance status ≤ 2  
 
Histologically confirmed diagnosis of classical Hodgkin lymphoma (excluding nodular lymphocyte 
predominant Hodgkin lymphoma) according to the WHO classification, with hematopathology review 
at the participating institution. 
 
Have high-risk relapsed or refractory Hodgkin lymphoma (HL), defined as at least one of the following: 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
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Protocol Version:  09- May 16 2022 
 
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− 
Primary refractory disease to front-line therapy. 
− 
Relapse within 1 year of completing front-line therapy. 
− 
Extranodal involvement at the time of pre-ASCT relapse. 
− 
B symptoms at pre-ASCT relapse. 
− 
More than one type of pre-ASCT salvage therapy required. 
 
Planning to receive or have received autologous stem cell transplantation (ACST) per institutional 
standards as part of standard of care.   
− 
Pre-ASCT participants may consent but will not be eligible to begin treatment until after ASCT, 
and will have to fulfill all inclusion and exclusion criteria before starting protocol therapy.   
− 
All participants must initiate Day 1 of protocol therapy within 30-60 days post stem cell 
reinfusion. Study PI can grant exception for a patient to start as late as 75 days post stem cell 
reinfusion with a reasonable justification for delay (e.g. recovery from post-ASCT toxicity) and this 
will not be a protocol deviation, nor require an exception to be filed. 
 
Recovery from ASCT toxicity as defined as outpatient status , able to drink, eat normally, and do not 
need intravenous hydration prior to Day 1 of therapy 
 
Achieved at least stable disease to salvage treatment determined by PET/CT using 2014  Lugano 
classification prior to ASCT. 
 
Brentuximab vedotin naïve OR had at least stable disease by Lugano classification to prior 
brentuximab vedotin treatment 
 
ANC ≥ 1000/mm3  
 
Platelets ≥ 50,000/mm3  
 
Hemoglobin ≥ 8 g/dL  
 
Total bilirubin ≤ 1.5 x ULN OR 3 x ULN for Gilbert’s disease 
 
AST and ALT ≤ 2.5 x ULN  
 
Creatinine clearance ≥ 40 mL/min per 24 hour urine collection or the Cockcroft-Gault formula  
 
Forced expiratory volume in one second (FEV1) and  carbon monoxide diffusion capacity (DLCO) 
(adjusted for Hb) ≥ 50% adjusted 
 
WOCBP only: Negative urine or serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units 
o f HCG  ) 
 
Woman of childbearing potential (WOCBP): use two effective methods of contraception (hormonal or 
barrier method) or be surgically sterile, or abstain from heterosexual activity for the course of the 
study through 7 months post last dose of nivolumab. Male: use two effective methods of 
contraception (barrier method) or abstain from heterosexual activity with the first dose of study 
therapy through 7 months post last dose of nivolumab. 
Exclusion Criteria 
 
Post-ASCT anti-lymphoma or investigational therapy. Immediate post-ASCT consolidative radiation 
therapy is allowed as long as it occurs prior to initiation of study therapy. Baseline imaging and PFTs 
must be performed after completion of radiation. 
 
Previous allogeneic transplant 
 
Total BCNU dose of > 600 mg/m2 with prior treatments including transplant conditioning regimen 
 
Live vaccine within 30 days prior to Day 1 of protocol therapy (e.g. measles, mumps, rubella, varicella, 
yellow fever, rabies, BCG, oral polio vaccine, and oral typhoid) 
 
Refractory to prior brentuximab vedotin (i.e. progression while on treatment) 
 
Refractory to prior anti-PD-1/PD-L agent  
 
History of prior ≥ Grade 3 hypersensitivity to either brentuximab vedotin or nivolumab 
 
History of another primary malignancy that has not been in remission for at least 3 years. Exceptions 
include:  
− 
Basal cell carcinoma of the skin or  
− 
Squamous cell carcinoma of the skin that has undergone potentially curative therapy or  
− 
In situ cervical cancer. 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
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Protocol Version:  09- May 16 2022 
 
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 
Known active central nervous system (CNS) involvement by lymphoma, including parenchymal and/or 
lymphomatous meningitis.   
 
History of progressive multifocal leukoencephalopathy (PML) 
 
≥ Grade 2 peripheral neuropathy  
 
Prior diagnosis of inherited or acquired immunodeficiency 
 
Condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or 
equivalent) or other immunosuppressive medications within 14 days of study drug administration. 
Exceptions are: 
− 
Inhaled or topical steroids and  
− 
Adrenal replacement doses > 10 mg daily prednisone equivalents in the absence of active 
autoimmune disease. 
− 
Uncontrolled illness including ongoing or active infection 
 
History of active pneumonitis or interstitial lung disease with the following exception: 
− 
For history of pneumonitis to be an exclusion, patient had to have required supplemental oxygen 
or corticosteroid treatment.  Radiographic changes alone are not an exclusion  
 
An active, known or suspected autoimmune disease. The following are exceptions:  
− 
Vitiligo,  
− 
Type I diabetes mellitus,  
− 
Residual hypothyroidism due to autoimmune condition only requiring hormone replacement, 
− 
Psoriasis not requiring systemic treatment, or  
− 
Conditions not expected to recur in the absence of an external trigger 
 
Active or known history (standard pre-ASCT assessments) of: 
− 
Hepatitis B or C infection  
− 
Human immunodeficiency virus (HIV) 
− 
Acquired immunodeficiency syndrome (AIDS) 
 
Pregnant or breastfeeding 
 
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 within 6 
months prior to Day 1 of protocol therapy 
 
History or current evidence of any condition, therapy, or laboratory abnormality that might confound 
the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is 
not in the best interest of the subject to participate, in the opinion of the treating investigator  
 
Investigational Product Dosage and Administration 
 
Agent 
Dose 
Route 
Schedule  
Max. 
Cycles 
Brentuximab  
Vedotin 
1.8 mg/kg 
IV over 30 minutes 
Day 1 of each 21-day cycle 
8 
Nivolumab 
3 mg/kg 
IV over 60 minutes 
Day 1 of each 21-day cycle* 
* Nivolumab is administered at least 30 minutes after the brentuximab vedotin infusion has ended. 
Clinical Observations and Tests to be Performed 
 
Medical history and physical exam 
 
Safety assessments (CBCs with differential, comprehensive chemistry panel, and thyroid function) 
 
PET-CT/ CT scans  
 
Correlative tumor tissue and blood samples 
 
 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
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TABLE OF CONTENTS 
Protocol Team ............................................................................................................................................... 2 
Experimental Design Schema ........................................................................................................................ 3 
Protocol Synopsis .......................................................................................................................................... 4 
Table of Contents ........................................................................................................................................ 10 
List of Tables and Figures ............................................................................................................................ 12 
Abbreviations .............................................................................................................................................. 13 
1.0 
Objectives ....................................................................................................................................... 14 
1.1 
Primary Objectives ........................................................................................................... 14 
1.2 
Secondary Objectives ....................................................................................................... 14 
1.3 
Exploratory Objectives ..................................................................................................... 14 
2.0 
Background..................................................................................................................................... 15 
2.1 
Introduction/Rationale for Development ........................................................................ 15 
2.2 
Nivolumab ........................................................................................................................ 16 
2.3 
Brentuximab Vedotin ....................................................................................................... 17 
2.4 
Overview and Rationale of Study Design ......................................................................... 21 
3.0 
Eligibility Criteria ............................................................................................................................ 25 
3.1 
Inclusion Criteria .............................................................................................................. 25 
3.2 
Exclusion Criteria .............................................................................................................. 27 
4.0 
Participant Enrollment ................................................................................................................... 29 
4.1 
Pre-Enrollment Informed Consent and Screening Procedures ........................................ 29 
4.2 
Participant Enrollment ..................................................................................................... 29 
4.3 
Screen Failures and Registered Participants Who Do Not begin Study Treatment ......... 30 
5.0 
Treatment Program ........................................................................................................................ 30 
5.1 
Treatment Program Overview ......................................................................................... 30 
5.2 
Treatment Cycle Definition .............................................................................................. 30 
5.3 
Treatment Plan ................................................................................................................ 30 
5.4 
Agent Administration ....................................................................................................... 31 
5.5 
Assessments and Special Monitoring ............................................................................... 32 
5.6 
Duration of Therapy and Criteria for Removal from Study Treatment ............................ 32 
5.7 
Follow-Up ......................................................................................................................... 33 
5.8 
Duration of Participation and Criteria for End of Participation ....................................... 34 
5.9 
Supportive care, Prohibited and Concomitant Medications/ Therapies ......................... 34 
6.0 
Anticipated Toxicities and Dose Delay/Modifications .................................................................... 42 
6.1 
Anticipated Toxicities ....................................................................................................... 42 
6.2 
Dose Modification/Delays ................................................................................................ 45 
7.0 
Adverse Event and Unanticipated Problem Reporting ................................................................... 55 
7.1 
Definitions ........................................................................................................................ 55 
7.2 
Definition of Secondary Malignancy ................................................................................ 56 
7.3 
Overdose .......................................................................................................................... 56 
7.4 
Pregnancy ......................................................................................................................... 57 
7.5 
Laboratory Test Abnormalities......................................................................................... 57 
7.6 
Other Safety Considerations ............................................................................................ 57 
7.7 
Routine AE Reporting Guidelines ..................................................................................... 57 
7.8 
Expedited AE Reporting Guidelines ................................................................................. 58 
7.9 
Reporting of AE/UP by the Study PI ................................................................................. 59 
8.0 
Agent Information .......................................................................................................................... 62 
8.1 
Nivolumab ........................................................................................................................ 62 
8.2 
Brentuximab vedotin ....................................................................................................... 64 

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9.0 
Correlative & Special Studies ......................................................................................................... 67 
9.1 
Correlative Study Plan ...................................................................................................... 67 
9.2 
Tumor Tissue Studies ....................................................................................................... 67 
9.3 
Blood samples .................................................................................................................. 70 
10.0 
Study Calendar ............................................................................................................................... 74 
11.0 
Endpoint Evaluation Criteria/Measurement of Effect .................................................................... 77 
11.1 
Response, Clinical Endpoints and Toxicity ....................................................................... 77 
12.0 
Statistical Considerations ............................................................................................................... 82 
12.1 
Study Design..................................................................................................................... 82 
12.2 
Sample Size Accrual Rate ................................................................................................. 82 
12.3 
Statistical Analysis Plan .................................................................................................... 82 
13.0 
Data Handling, Data Management, Record Keeping ...................................................................... 85 
13.1 
Source Documents ........................................................................................................... 85 
13.2 
Data Capture Methods and Management ....................................................................... 85 
13.3 
Case Report Forms/ Data Submission Schedule .............................................................. 85 
13.4 
Regulatory Records .......................................................................................................... 86 
14.0 
Adherence to the Protocol ............................................................................................................. 86 
14.1 
Emergency Modifications ................................................................................................ 86 
14.2 
Planned Non-Emergency Deviations ................................................................................ 86 
14.3 
Unplanned Deviations – Deviations Discovered After They Have Occurred. ................... 86 
14.4 
Single Subject Exceptions ................................................................................................. 87 
15.0 
Study Oversight, Quality Assurance, and Data & Safety Monitoring ............................................. 88 
15.1 
Site Lead Investigator Responsibilities ............................................................................. 88 
15.2 
All Investigator Responsibilities ....................................................................................... 88 
15.3 
Study PI Responsibilities .................................................................................................. 89 
15.4 
Protocol Management Team (PMT) ................................................................................. 89 
15.5 
Monitoring/ Auditing ....................................................................................................... 89 
15.6 
Quality Assurance ............................................................................................................ 89 
15.7 
City of Hope Data and Safety Monitoring Committee (DSMC) ........................................ 90 
16.0 
Ethical and Regulatory Considerations ........................................................................................... 90 
16.1 
Ethical Standard ............................................................................................................... 90 
16.2 
Regulatory Compliance .................................................................................................... 90 
16.3 
Institutional Review Board ............................................................................................... 91 
16.4 
Informed Consent ............................................................................................................ 91 
16.5 
Participant Withdrawal .................................................................................................... 92 
16.6 
Special and Vulnerable Populations ................................................................................. 92 
16.7 
Participant Confidentiality ............................................................................................... 93 
16.8 
Future Use of Stored Specimens and Other Identifiable Data ......................................... 93 
16.9 
Conflict of Interest ........................................................................................................... 94 
16.10 
Financial Obligations, Compensation, and Reimbursement of Participants .................... 94 
16.11 
Publication/Data Sharing ................................................................................................. 94 
17.0 
References ...................................................................................................................................... 95 
Appendix A: ECOG Performance Status....................................................................................................... 98 
Appendix B: Registration Coversheet .......................................................................................................... 99 
Appendix C: Tissue Shipping Guidelines for External Non-COH Sites ........................................................ 100 
Appendix D: Correlative Blood Collection Form (Non-COH Sites Only) ..................................................... 101 
Appendix E: Blood Shipping Guidelines for External Non-COH Sites......................................................... 102 
Appendix G: Expedited Reporting CoverSheet .......................................................................................... 103 
Appendix H: Lyric Criteria .......................................................................................................................... 104 
Appendix I: Correlative Tissue Form (For All Sites) .................................................................................... 105 
 

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LIST OF TABLES AND FIGURES 
Table 5.3 Dosing regimen and schedule ......................................................................................... 31 
Table 6.2.1 Dose management guidelines for Nivolumab ............................................................. 47 
Table 6.2.2 Dose modifications for brentuximab vedotin associated toxicity ............................... 53 
Table 7.8.2 Expedited Reporting Guidelines .................................................................................. 58 
Table 9.1 Correlative Study Plan .................................................................................................... 67 
Table 9.3 Overview of correlative blood studies ............................................................................ 70 
Table 11.1 2014 Lugano Classification Response Criteria .............................................................. 77 
Table 12.2 City of Hope Patient Availability ................................................................................... 82 
Table 12.3.1 The probability of declaring the trial a success assuming different PFS rates ........... 83 
Table 13.3 Data Submission Schedule ............................................................................................ 85 
 
 
 
 

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ABBREVIATIONS 
Abbrevation 
 
 
Meaning 
ASCT 
AE 
ALT 
ANC 
AST 
BMS 
BV 
C 
CFR 
COH 
CR 
CRA 
CRF 
CTCAE 
CTEP 
CTMS 
DSMC 
ECOG 
EOT 
FDA 
GCP 
HL 
IB 
ICF 
IND 
IR 
ir 
IRB 
IV 
LYRIC 
PD 
PFS 
PI 
PMT 
PR 
SAE 
SD 
WHO 
Autologous Stem Cell Transplant 
Adverse Event 
Alanine Aminotransferase 
Absolute Neutrophil Count 
Aspartate Aminotransferase 
Bristol Myers-Squibb Company 
Brentuximab vedotin 
Cycle 
Code of Federal Regulations 
City of Hope 
Complete Response 
Clinical Research Associate 
Case Report Form 
Common Terminology Criteria for Adverse Events 
Cancer Therapy Evaluation Program 
Clinical Trial Management System 
Data Safety Monitoring Committee 
Eastern Cooperative Oncology Group 
End of Treatment 
Food and Drug Administration 
Good Clinical Practice 
Hodgkin Lymphoma 
Investigator Brochure 
Informed Consent Form 
Investigational New Drug  
Indeterminate Response 
Immune Related 
Institutional Review Board 
Intravenous 
LYmphoma Response to Immunomodulatory Therapy Criteria 
Progressive Disease 
Progression-Free Survival 
Principal Investigator 
Protocol Monitoring Team 
Partial Response 
Serious Adverse Event 
Stable Disease 
World Health Organization 
 
 
 

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1.0 OBJECTIVES  
1.1 Primary Objectives 
o Assess the efficacy of nivolumab plus brentuximab vedotin consolidation after autologous stem 
cell transplantation (ASCT) in participants with relapsed/refractory Hodgkin Lymphoma (HL), as 
assessed by 18-month progression-free survival (PFS). 
1.2 Secondary Objectives 
o Estimate the overall survival (OS), the cumulative incidence of relapse/progression, the 
cumulative incidence of non-relapse mortality (TRM) in participants with relapsed/ refractory HL 
who receive nivolumab plus brentuximab vedotin consolidation after ASCT.  
o Estimate the overall response rate to nivolumab plus brentuximab vedotin therapy in 
participants with measurable disease after ASCT. 
o Establish the safety and tolerability of nivolumab plus brentuximab vedotin when used as 
consolidation after ASCT in participants with relapsed/ refractory HL. 
1.3 Exploratory Objectives 
o Evaluate the Lymphoma Response to Immunomodulatory therapy Criteria (LYRIC) definition of 
indeterminate response to guide the management of patients regarding treatment past 
progressive disease. 
o Explore the impact of nivolumab plus brentuximab vedotin therapy on immune reconstitution 
after ASCT. 
o Explore the prognostic impact of and temporal dynamics of minimal residual disease (MRD) in 
the peripheral blood as assessed by the next-generation sequencing-based ClonoSEQ platform. 
o Explore the prognostic impact of 9p24.1 abnormalities in tumor tissue assessed by FISH on 
outcomes after ASCT and nivolumab plus brentuximab vedotin post-ASCT consolidation therapy. 
o Explore the relationship between immune cells and HRS in tumor samples by 6-color 
quantitative spatial image analysis using the Vectra system, and correlate with outcome after 
ASCT and nivolumab plus brentuximab vedotin post-ASCT consolidation therapy. 
o Explore whether genetic alterations (e.g. gene expression profiles or genetic mutations) in HL 
tumor samples are associated with outcome after ASCT and nivolumab plus brentuximab 
vedotin post-ASCT consolidation therapy. 

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2.0 BACKGROUND 
2.1 Introduction/Rationale for Development 
2.1.1 
Classical Hodgkin Lymphoma 
Classical Hodgkin Lymphoma (HL) is a lymphoma of B-cell origin that is defined by the presence of 
Hodgkin-Reed-Sternberg cells in a background of inflammatory cells. Although the majority of patients 
with HL are cured with upfront therapy, as many as 20-40% of patients will have relapsed or refractory 
disease [2, 3]. Standard of care treatment for patients with relapsed/ refractory HL is salvage 
chemotherapy followed by autologous stem cell transplantation (ASCT) in chemosensitive patients, but 
about half of HL patients who undergo ASCT will relapse [4, 5]. HL patients who are refractory to second-
line therapy or relapse after ASCT have poor outcomes [6]. Therefore, improved therapies to prevent post-
ASCT relapse in patients with relapsed/ refractory HL are urgently needed. 
2.1.2 
PD-1 in Hodgkin Lymphoma 
The programmed death receptor-1 (PD-1) pathway is an immune checkpoint that normally serves to 
dampen immune responses in tissues. PD-1 is expressed on activated T-cells and binds its ligands, PD-L1 
and PD-L2, on tissue cells or antigen presenting cells to decrease T-cell activation, proliferation, and 
survival [7]. Tumor cells can co-opt this pathway to evade attack by the host immune system [7]. A wide 
range of hematologic malignancies express PD-1 or PD-L1, including HL [8, 9], diffuse large B-cell 
lymphoma (DLBCL) [9], primary mediastinal B-cell lymphoma (PMBCL),[8, 10] follicular lymphoma (FL) 
[11], chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) [12], peripheral T-cell 
lymphomas (PTCL) [13-17], multiple myeloma (MM),[18] acute myelogenous leukemia (AML) [19, 20], and 
myelodysplastic syndrome (MDS) [21, 22].  
More specifically, the PD-1/PD-L1 pathway appears to play a critical role in the pathogenesis of HL. HL is 
histologically defined by a small proportion of neoplastic HRS in a polymorphous inflammatory infiltrate, 
however, it is not clear that the inflammation represents an effective host anti-tumor immune response. 
In fact, frequent genetic alterations of the 9p24.1 region, which includes the PD-L1/PD-L2 loci, have been 
identified in HL cell lines and primary HL tissue samples, supporting the concept that the PD-1/PD-L1 
pathway plays a key role in host immune evasion that is central to HL pathogenesis [8]. PD-L1 gene 
amplification has been linked with increased expression of PD-L1 in HL tumor samples [8]. In addition, the 
JAK2 locus is contained within the 9p24.1 region, and JAK2 activation upregulates PD-L1 transcription and 
expression [8]. Furthermore, Epstein-Barr virus infection, which is frequently observed in HL, has also 
been identified as a mechanism of PD-L1 upregulation and expression in HL [23]. Based on these findings, 
it appears that the PD-1/PD-L1 pathway plays a critical role in immune evasion in HL, and supports the 
use of PD-1 inhibitors for the treatment of HL. 
Indeed, inhibitors of PD-1 have produced impressive clinical responses in early-phase studies of these 
agents in patients with relapsed/ refractory HL. A Phase 1 study of nivolumab demonstrated an 87% ORR 
and 100% clinical benefit rate in 23 patients with relapsed or refractory HL.[24] A subsequent Phase 2 
study of 80 patients who failed ASCT as well as prior brentuximab vedotin confirmed a high ORR of 66% 
(72% by investigator assessment), with 9% (28% by investigator assessment) of patients having a complete 
response. Notably, many responders remain in remission (62% of responders at time of censoring), thus 
a significant proportion of remissions appear to be durable [25]. A Phase 1b study of pembrolizumab in 
31 patients with relapsed/ refractory HL who failed prior brentuximab vedotin demonstrated a 65% ORR 
with 16% of patients achieving CR [26]. A Phase II study of pembrolizumab in patients with relapsed/ 

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refractory HL is ongoing, but interim reports have demonstrated an ORR of 70% in heavily treated patients 
with advanced HL [27]. 
2.2 Nivolumab 
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal antibody (HuMAb; 
immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 (PD-1) cluster of differentiation 
279 (CD279) cell surface membrane receptor. PD-1 is a negative regulatory molecule expressed by 
activated T and B lymphocytes [28]. Binding of PD-1 to its ligands, programmed death–ligands 1 (PD-L1) 
and 2 (PD-L2), results in the down-regulation of lymphocyte activation. Inhibition of the interaction 
between PD-1 and its ligands promotes immune responses and antigen-specific T-cell responses to both 
foreign antigens as well as self-antigens. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and 
is produced using standard mammalian cell cultivation and chromatographic purification technologies. 
The clinical study product is a sterile solution for parenteral administration. OPDIVOTM (nivolumab) is 
approved for use in multiple countries including the United States (US, Dec-2014), the European Union 
(EU, Jun-2015), and Japan (Jul-2014) [29]. 
2.2.1 
Effects in Humans 
The PK, clinical activity, and safety of nivolumab have been assessed in subjects with non-small cell lung 
cancer (NSCLC), melanoma, clear-cell renal cell carcinoma (RCC), and classical Hodgkin Lymphoma (cHL) 
in addition to other tumor types. This updated Investigator Brochure (IB) references the most recent US 
Prescribing Information (USPI) and EU Summary of Product Characteristics (SmPC) as the basis for the 
current state of knowledge on nivolumab for use in humans [29]. See Appendix 1 for USPI and Appendix 
2 for SmPC. Nivolumab monotherapy is approved in multiple countries, including the US and EU, for 
unresectable or metastatic melanoma, previously treated metastatic NSCLC, and previously treated 
advanced RCC; it is also approved for the treatment of cHL in the US. In addition, nivolumab has been 
approved for use in combination with ipilimumab for unresectable melanoma in multiple countries, 
including the US and EU [29]. 
Nivolumab is being investigated both as monotherapy and in combination with chemotherapy, targeted 
therapies, and other immunotherapies. Additional clinical activity and safety information presented in this 
IB focus primarily on data from clinical studies that are relevant to ongoing clinical investigations not in 
the approved USPI and SmPC (squamous cell carcinoma of the head and neck [SCCHN], small cell lung 
cancer [SCLC], gastric cancer, urothelial cancer, hepatocellular carcinoma [HCC], colorectal cancer [CRC], 
and glioblastoma [nivolumab monotherapy]; SCLC, gastric cancer, NSCLC, RCC, and CRC [nivolumab 
combination therapy]; and Ono Pharmaceutical Co., Ltd. [ONO] studies in Japanese or Korean 
subjects)[29]. 
2.2.2 
Clinical Efficacy 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy and in combination 
with ipilimumab in several tumor types, including NSCLC, melanoma, RCC, cHL, SCLC, gastric cancer, 
urothelial cancer, HCC, and CRC. In confirmatory trials, nivolumab as monotherapy demonstrated a 
statistically significant improvement in OS as compared with the current standard of care in subjects with 
advanced or metastatic NSCLC, unresectable or metastatic melanoma, advanced RCC, or SCCHN. 
Nivolumab in combination with ipilimumab improved PFS and ORR over ipilimumab alone in subjects with 
unresectable or metastatic melanoma. Recently, a Phase 1 trial in relapsed/refractory HL was performed 

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which showed an ORR of 87% [24]. A Phase 2 trial confirmed the response rate (66%) [25], and this led to 
accelerated FDA approval of nivolumab in patients who progressed after ASCT and brentuximab vedotin. 
2.2.3 
Clinical Safety 
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 12,300 subjects treated to date. 
For monotherapy, the safety profile is similar across tumor types. There is no pattern in the incidence, 
severity, or causality of AEs to nivolumab dose level. In Phase 3 controlled studies, the safety profile of 
nivolumab monotherapy is acceptable in the context of the observed clinical efficacy, and manageable 
using established safety guidelines. Clinically relevant AEs typical of stimulation of the immune system 
were infrequent and manageable by delaying or stopping nivolumab treatment and timely 
immunosuppressive therapy or other supportive care. 
In several ongoing clinical trials, the safety of nivolumab in combination with other therapeutics such as 
ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted therapies is being explored. Most 
studies are ongoing and, as such, the safety profile of nivolumab combinations continues to evolve.  
The most advanced combination under development is nivolumab with ipilimumab, which is approved in 
subjects with unresectable or metastatic melanoma, and being studied in multiple tumor types. Results 
to date suggest that the safety profile of nivolumab in combination with ipilimumab is consistent with the 
mechanisms of action of nivolumab and ipilimumab. The nature of the AEs is similar to that observed with 
either agent when used as monotherapy; however, both frequency and severity of most AEs are increased 
with the combination. 
2.3 Brentuximab Vedotin 
Brentuximab vedotin, previously known as SGN-35, is an ADC consisting of the chimeric antibody SGN-30 
(cAC10) chemically conjugated to a synthetic analog (monomethylauristatin E [MMAE]) of the naturally 
occurring antitubulin agent, dolastatin10. Brentuximab vedotin is proposed to have a multi-step 
mechanism of action that is initiated by binding to CD30 on the cell surface and internalization of the ADC. 
Upon trafficking to lysosomes, MMAE is released from the conjugate through proteolytic degradation of 
the drug linker [30]. Binding of released MMAE to tubulin disrupts the microtubule network, leading to 
G2/M phase cell cycle arrest and apoptosis [31]. 
2.3.1 
Phase 2 Pivotal Study (SG035-0003) in Patients with HL 
SG035-0003 was a Phase 2, single-arm, open-label, multicenter, pivotal study of brentuximab vedotin (1.8 
mg/kg IV, every 3 weeks) as a single agent in patients with relapsed or refractory HL. The primary objective 
was to assess efficacy based on ORR by an IRF. Secondary objectives were to assess duration of tumor 
control (duration of response and PFS), survival, safety and tolerability, and PK. Patients could remain on 
treatment for up to 16 cycles (approximately 1 year), or until disease progression, whichever occurred 
earlier. 
There were 102 patients enrolled in the study. The study population was generally balanced with regard 
to gender (female, 53%) and was primarily white (87%). The median age was 31 years (range 15 to 77); 3 
patients were older than 65 years of age and 1 patient was younger than 18 years. Patients entering the 
study were generally ambulatory and able to perform normal activities without assistance as indicated by 
an ECOG performance status of 0 (41%) or 1 (59%). 

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Approximately half of patients (46%) had Stage II disease at initial diagnosis; 26% had Stage III, 20% had 
Stage IV, 4% had Stage I, and 4% had unknown disease stage. Relative to most recent therapy 58% of 
patients were relapsed and 42% were refractory. Notably, 71% of patients had primary refractory disease, 
defined as not achieving a best response of CR with frontline therapy or relapsing within 3 months of 
completing front-line therapy. All patients had previously received autologous SCT (1 transplant, 89%; 2 
transplants, 11%) and all had received at least one prior regimen of systemic chemotherapy (median 3.5 
[range, 1 to 13]). 
The median time from autologous SCT to relapse was 6.7 months and 71% of patients had experienced 
relapse within 1 year of autologous SCT. In the intent-to-treat (ITT) analysis set of 102 patients, ORR per 
IRF was 75% (95% CI [64.9, 82.6]): 33% CR (34 patients) and 41% partial remission (PR) (42 patients). The 
remaining patients had SD (22 patients), progressive disease (PD) (3 patients), or were not evaluable for 
response (1 patient). Tumor size reductions were observed in 94% of all patients. 
The B symptom resolution rate was 77% (27 of 35 patients with B symptoms at baseline). Median time to 
resolution of B symptoms was 3.1 weeks (range, 0.4 to 11.9). After a median follow-up period of 
approximately 3 years for all enrolled patients, the median PFS was 9.3 months (95% CI: 7.1, 12.2 months) 
and the median OS was 40.5 months (95% CI: 28.7, – months). The estimated 4-year survival rate was 46% 
(95% CI: 36%, 56%). At the time of study closure, the estimated 5-year overall survival rate was 41% (95% 
CI: 31 %, 51%) and the median OS was 40.5 months (95% CI: 28.7, 61.9 [range, 1.8 to 72.9+]). The median 
PFS was 9.3 months overall. Of the 102 enrolled patients, 15 remained in follow-up and in remission at 
study closure. Among these 15 patients, 6 received consolidative allo-SCT and 9 have received no further 
therapy since completing brentuximab vedotin. 
2.3.2 
Phase 3 Randomized, Placebo-Controlled (SGN35-005) Trial of Post-ASCT Maintenance in 
Patients with HL 
Study SGN35-005 was a randomized, double-blind, two-arm, placebo-controlled, multicenter, Phase 3 
clinical trial designed to evaluate the efficacy and safety of brentuximab vedotin and best standard of care 
(BSC) compared with placebo and BSC in the treatment of patients at risk of disease progression following 
ASCT. Patients who had received an ASCT in the previous 30-45 days were randomized in a 1:1 manner to 
receive study treatment (brentuximab vedotin or placebo), administered as an outpatient IV infusion on 
Day 1 of each 21 day cycle. Patients were allowed to continue on study treatment for a maximum of 16 
cycles, representing approximately 1 year of treatment. The primary objective was to compare the PFS of 
brentuximab vedotin and BSC versus placebo and BSC. Secondary objectives were to compare overall 
survival (OS) between the 2 treatment arms, to evaluate the safety and tolerability of brentuximab vedotin 
compared with placebo, and to characterize the incidence of anti-therapeutic antibodies (ATA). A total of 
329 patients were randomized (165 patients to brentuximab vedotin and 164 to placebo). Out of 329 
randomized patients, 327 patients received study treatment (167 patients received at least 1 dose of 
brentuximab vedotin and 160 patients received placebo; 2 patients in the placebo arm withdrew consent 
before receiving study treatment and 2 additional patients who were randomized to receive placebo each 
received 1 dose of brentuximab vedotin in error). The overall median age of study patients was 32 years 
(range, 18 to 76) and the majority of patients (321/329 [98%]) were <65 years of age. The study population 
was generally balanced with regard to gender (male = 53%) and was primarily white (94%). Patients 
entering the study were generally ambulatory and able to perform normal activities without assistance as 
indicated by an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (56%) or 1 (44%). 
Forty-one percent of patients had Stage II HL at initial diagnosis; 2% had Stage I, 28% had Stage III, 29% 
had Stage IV, and 1% had unknown disease stage. Patients were considered to be at high risk of residual 

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HL post ASCT and risk factors at baseline included refractory to frontline therapy (60%), relapsed < 12 
months (33%), and extranodal disease at time of pre- ASCT relapse (33%). The median PFS per IRF for 
patients randomized to receive brentuximab vedotin was 42.9 months [95% CI (30.4, 42.9)] (range, 0.03+ 
to 42.94) compared with 24.1 months [95% CI (11.5, -)] (range, 0.03+ to 42.35+) for patients who received 
placebo. The difference between the 2 arms was statistically significant by stratified log-rank test 
(P=0.001). As assessed by Cox regression analysis, the stratified HR was 0.57 [95% CI (0.40, 0.81)].The 
estimated 24-month PFS rate was 63% [95% CI (55%, 70%)] for patients in the brentuximab vedotin arm 
versus 51% [95% CI (43%, 59%)] for patients in the placebo arm. 
An additional prespecified analysis per investigator assessment was performed that included clinical 
lymphoma assessments for defining events and censoring of patients who had not yet progressed. At 24 
months (the time of the last protocol-mandated CT scan), there remained a substantial separation 
between the PFS rate for brentuximab vedotin compared with placebo. 
By this analysis, the median PFS for patients who received brentuximab vedotin was not reached (95% CI 
[-, -]) (range, 0.03+ to 49.05+) compared with 15.8 months (95% CI [8.5,-]) (range, 0.03+ to 48.36+) for 
patients who received placebo. As assessed by Cox regression analysis, the stratified HR was 0.50 (95% CI 
[0.36, 0.70]). 
By Kaplan-Meier analysis, the estimated 24-month PFS rate was 65% (95% CI [57%, 72%]) for patients in 
the brentuximab vedotin arm versus 45% (95% CI [37%, 52%]) for patients in the placebo arm. 
At the time of the interim OS analysis (a median OS observation time of 30 months [range, 0 to 50]), 53 
patients (16%) had died; 28/165 patients (17%) in the brentuximab vedotin arm versus 25/164 patients 
(15%) in the placebo arm. The OS data are immature and the interpretation of these data is limited by the 
small number of events observed within a relatively short follow-up period. Interim OS is also confounded 
by the high rate of crossover to brentuximab vedotin. On the placebo arm, 72 of the 85 (85%) patients 
who received subsequent therapies received brentuximab vedotin, versus 9 of the 51 (18%) patients on 
the brentuximab vedotin arm. In part, this was due to a separate companion study that offered 
brentuximab vedotin only to placebo patients who had progressed. Patients are still on study and being 
followed for survival. 
The median OS was not reached for patients in either treatment arm. There was no significant difference 
in OS between the treatment arms; the stratified log-rank test P value was 0.62 and the stratified HR was 
1.15 [95% CI (0.67, 1.97)]. 
The estimated 24-month OS rate was 88% [95% CI (82%, 92%)] for brentuximab vedotin and 89% [95% CI 
(82%, 93%)] for placebo. 
2.3.3 Phase 2 Retreatment and Extension Treatment (SGN35-006) 
Study SGN35-006 was a Phase 2, open-label study that evaluated the safety and efficacy of brentuximab 
vedotin as retreatment or extension treatment. 
Retreatment 
Patients with CD30-positive hematologic malignancies who had experienced CR or PR with brentuximab 
vedotin on a prior study but who then experienced disease progression or relapse after treatment 
discontinuation were eligible for brentuximab vedotin retreatment in this study. 
There were 32 unique patients enrolled and retreated; these patients had a potential for 35 patient 
retreatment experiences, as 3 patients re-enrolled and were retreated more than once in the retreatment 

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arm. Of note, 1 patient did not have any post-baseline efficacy assessments captured and is not included 
in the efficacy evaluable set; thus, 34 retreatment experiences are summarized for analyses of efficacy. 
Retreatment arm patients had a median age of 37 years (range, 16 to 72 years). Seventeen patients (53%) 
were female and 47% were male. 
Twenty-seven patients (84%) were white. At retreatment baseline, 38% of patients had an ECOG 
performance status of 0 and 56% of patients had an ECOG performance status of 1. 
The remaining 6% of patients had an ECOG performance status of 2 at retreatment baseline. Of the 32 
unique retreatment patients, 21 patients were diagnosed with HL, 8 patients were diagnosed with 
systemic ALCL (63% were ALK negative), and 3 patients were diagnosed with another disease (2 patients 
with diffuse large B-cell lymphoma and 1 patient with angioimmunoblastic T-cell lymphoma). 
The primary efficacy analysis for this study was performed using the efficacy-evaluable patient set, which 
includes all retreatment experiences for patients who were retreated at least once on this study and had 
at least 1 post-baseline restage assessment (N=34). 
The ORR was 68% (95% CI, 49.5, 82.6; 60% for HL patients (95% CI, 36.1, 80.9), 91% for systemic ALCL 
patients (95% CI, 58.7, 99.8), and 33% for patients with other disease diagnoses (95% CI, 0.8, 90.6). 
Notably, the patient with an “other” disease diagnosis of diffuse large B-cell lymphoma achieved a CR with 
retreatment.  
Of the 23 patients with an objective response, 14 patients had subsequent disease progression or died. 
The estimated median duration of objective response by Kaplan-Meier analysis was 9.2 months [95% CI 
(6.6, 12.9 months)]; the range of response duration was 0+ to 28+ months. Of the 13 patients with CR, 9 
patients have had subsequent disease progression or died. The estimated median duration of response 
for patients with CR by Kaplan-Meier analysis was 12.3 months [95% CI (6.2, 14.2 months)]; the range of 
response duration was 1.7 to 28+ months. 
2.3.4 
Summary of Clinical Safety of Post-ASCT BV Therapy 
Exposure was balanced between treatment groups on the AETHERA study (Study SGN35-005, the 
randomized, double-blind, placebo-controlled Phase 3 study in HL patients who are at risk of disease 
progression following ASCT) [32]. The median number of cycles was 15 (range, 1 to 16) and the median 
duration of treatment was approximately 48 weeks, which was higher than the median exposure on the 
pivotal studies. For the pivotal Phase 2 studies (Studies SG035-0003 and SG035-0004) in HL or systemic 
ALCL patients, the median number of cycles of treatment with brentuximab vedotin was 7 (range, 1 to 
16), a median duration of approximately 24 weeks (range, 3 to 56).  
AEs that had a higher relative risk of occurring in patients in the brentuximab vedotin arm compared with 
patients in the placebo arm (as indicated by a relative risk >1 and CIs that do not include 1) were peripheral 
motor neuropathy, paresthesia, abdominal pain, constipation, peripheral sensory neuropathy, weight 
decreased, neutropenia, nausea, myalgia, vomiting, diarrhea, and arthralgia. The most frequently 
reported Grade 3 or higher AEs included neutropenia, peripheral sensory neuropathy, and peripheral 
motor neuropathy and the majority of these were considered to be related to treatment with 
brentuximab vedotin. The most common Grade 4 event across the pivotal studies and StudySGN35-005 
was neutropenia. The only other Grade 4 AE reported in more than 1 patient in these studies was 
thrombocytopenia. 

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2.4 Overview and Rationale of Study Design 
Both brentuximab vedotin and nivolumab have produced high response rates as single-agents in patients 
with relapsed/ refractory HL. In addition, the AETHERA trial demonstrated that brentuximab vedotin 
consolidation treatment following ASCT prolongs PFS in patients with high risk relapsed or refractory 
classical Hodgkin lymphoma (HL) compared to placebo [32]. Despite the incremental benefit of the 
addition of post-ASCT brentuximab vedotin consolidation, the 2-year PFS in brentuximab vedotin-
consolidated patients in the AETHERA trial was only 63%. Clearly, there is room for improvement. 
In addition, with a planned 16 cycles of brentuximab vedotin therapy in the AETHERA trial, 23% of patients 
discontinued brentuximab vedotin consolidation therapy and 31% had modification of the brentuximab 
vedotin dose due to peripheral neuropathy. We propose to add nivolumab to the backbone of post-ASCT 
brentuximab vedotin consolidation to improve upon the efficacy of brentuximab vedotin post-ASCT 
consolidation, and to shorten the total duration of consolidation therapy from 16 to 8 cycles to improve 
tolerability of the combination regimen. 
Based on the preliminary findings of an ongoing Phase 1/2 study, which is evaluating the combination of 
brentuximab vedotin and nivolumab as initial salvage treatment after the failure of frontline therapy, the 
combination of brentuximab vedotin and nivolumab appears safe and well-tolerated (Herrera AF et al., 
ASH 2016, Oral Presentation). 
We propose a single-arm Phase 2 study to evaluate the efficacy of brentuximab vedotin plus nivolumab 
consolidation therapy in patients with brentuximab vedotin-naïve or brentuximab vedotin-responsive (at 
least SD to prior BV therapy,  to prior brentuximab vedotin therapy, no progression while on brentuximab 
vedotin therapy) relapsed/ refractory HL who have undergone ASCT. 
2.4.1 
Rationale for dose and schedule selection 
The recommended dose for brentuximab vedotin per its prescribing information is 1.8 mg/kg via 
intravenous (IV) infusion administered every 3 weeks. This dose and schedule was evaluated in two pivotal 
Phase 2 studies (SG035-0003 and SG035-0004) in patients with CD30-positive hematologic malignancies.  
The dose for 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 every 3 week dosing. 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 [33]. 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 [34]. 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.  
By delivering brentuximab vedotin, a directly cytotoxic agent, together with nivolumab in Cycle 1 it is 
anticipated that tumor-associated antigens will be released and available for presentation to resident 
cytotoxic T-cells at the same time that these cells become activated through PD-1 blockade.  
Participants will be treated at the doses and schedule deemed safe in the currently ongoing Phase 1/2 
study of nivolumab plus brentuximab vedotin as initial treatment of participants with relapsed/ refractory 
HL after failure of front-line therapy (NCT02572167), except that the drugs will both be given on day 1 of 

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cycle 1. This change is supported by the safety demonstrated in an ongoing clinical trial (NCT01896999) 
evaluating the same combination in patients with relapsed or refractory HL in second-line or beyond. In 
that trial, the rate of infusion reactions was < 10% in that trial, as compared to the 38% infusion-related 
reaction rate observed in NCT02572167 (both studies presented at ASH 2016). NCT02572167 is being 
amended to enroll additional patients dosing both medications on Day 1 of Cycle 1. 
For this study, we will decrease the number of cycles of post-ASCT consolidation to 8 cycles as compared 
to 16 cycles in the AETHERA trial [32]. If BV is moved to first line therapy based on the ECHELON-1 trial 
(NCT01712490), patients will be receiving the equivalent of 6 cycles as a part of induction. Additionally, 
BV (alone or in combination) as first salvage therapy is being investigated, and patients who receive the 
agent prior to ASCT typically receive 4 cycles. Most importantly, in the AETHERA trial, the median number 
of cycles BV completed for patients who completed fewer than 16 cycles was 10.5 cycles [32]. Therefore, 
since 16 cycles is the maximum number of cycles to be administered in a single patient, many patients will 
have received 4-6 cycles of BV as part of prior therapy and 10 cycles appeared to be the inflection point 
for discontinuation of BV for toxicity on the AETHERA trial [32], we chose 8 cycles to stay short of the 
toxicity inflection point and keep patients from receiving more than 16 total cycles. In addition, other 
ongoing studies of single-agent PD-1 inhibition as post-ASCT consolidation in HL are employing 8 cycles, 
therefore, the 8 cycles utilized here will be consistent with the prior experience of anti-PD1 post-ASCT 
consolidation. 
2.4.2 
Rationale for correlative studies 
The correlative analyses that will be performed as part of this clinical trial are exploratory and intended 
to generate hypotheses that can be validated in a larger study. The rationale for specific proposed 
correlative studies is included below, though the list of possible correlative studies is not necessarily 
exhaust, as it is anticipated that the exact nature and type of correlative studies may change as new 
scientific data emerges during the course of the study. 
2.4.2.1 Minimal Residual Disease Assessment 
Circulating tumor DNA detection has been examined in lymphoma. Next-generation sequencing (NGS)-
based ctDNA detection performed by NGS of the immunoglobulin (Ig) or T-cell receptor genes (Ig-NGS) 
can identify ctDNA in the peripheral blood mononuclear cells (PBMC) and plasma (cell-free ctDNA) at 
diagnosis in patients with a range of lymphomas, including classical Hodgkin lymphoma and DLBCL.[35-
38] In addition, ctDNA levels (measured by Ig-NGS) track with treatment response in DLBCL, and the 
persistence or recurrence of ctDNA during and after upfront therapy is associated with subsequent DLBCL 
relapse.[37, 38] Following allogeneic hematopoietic stem cell transplantation in patients with lymphoma 
or chronic lymphocytic leukemia (CLL), the presence of ctDNA (Ig-NGS) is associated with a higher risk of 
subsequent relapse and poorer progression-free survival (PFS).[39-41] Moreover, we have demonstrated 
that ctDNA assessment is a biomarker of outcome in patients with DLBCL who undergo autologous 
hematopoietic stem cell transplantation.[42] 
2.4.2.2 9p24.1 Abnormalities in HL 
Frequent genetic alterations in the 9p24.1 region, which includes the PD-L1 and PD-L2 loci, have been 
observed in HL [8]. PD-L1 gene amplification has been linked with increased expression of PD-L1 in HL 
tumor samples [8]. In addition, the JAK2 locus is contained within the 9p24.1 region, and JAK2 activation 
upregulates PD-L1 transcription and expression [8]. Furthermore, Epstein-Barr virus infection, which is 
frequently observed in HL, has also been identified as a mechanism of PD-L1 upregulation and expression 

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in HL.[23] These findings support the concept that the PD-1/PD-L1 pathway plays a key role in host 
immune evasion that is central to HL pathogenesis,[8] and provides a strong rationale for the use of PD-
1/PD-L1 pathway inhibitors in HL. 
Although genetic alterations in the 9p24.1 region are nearly universal in HL patients, inferior outcomes 
after standard initial treatment are observed in patients with amplification (3 or more copies, 36% of 
patients at diagnosis) of 9p24.1.[43] While genetic alterations in the 9p24.1 region are commonly 
observed in patients with HL treated with PD-1 inhibitors [24], the specific types of 9p24.1 alterations 
have not been examined for association with outcome after PD-1 inhibition. 
2.4.2.3 Gene Expression Profiles 
In HL patients treated with standard induction chemotherapy, gene expression profiles (GEP) of HL tissue 
samples, which includes GEP of both the tumor microenvironment (TME) and tumor cells, are associated 
with outcomes[44-46]. Studies have shown that GEP of genes associated with macrophage activation, the 
cell cycle, and apoptosis can identify high-risk subsets of patients with poorer survival.[44-46]  
Gene expression profiles are associated with outcome after immune checkpoint inhibitor therapy in 
patients with advanced melanoma. Increased expression of genes that encode for immune-related 
targets, such as T-cell surface markers, immune receptors, and cytokines/chemokines, in pre-treatment 
melanoma tumor samples are associated with response to the CTLA4 inhibitor, ipilimumab.[47] In 
addition, a set of gene expression signatures (upregulation of genes associated with mesenchymal and 
inflammatory tumor phenotypes, angiogenesis, and wound healing) were enriched in melanoma patients 
who failed to respond to PD-1 inhibitors (nivolumab and pembrolizumab).[48] 
Given the key role of the TME in response to anti-PD-1 therapy as well as in the pathogenesis of HL, we 
hypothesize that GEP will highlight features of the HL TME in pre-treatment tumor tissue that will be 
associated with outcome in patients with relapsed or refractory HL treated with PD-1/PD-L1 pathway 
inhibitors.  
2.4.2.4 Multiplexed Immunohistochemistry 
The composition and spatial orientation of immune cells and immune checkpoints in and around a tumor 
is associated with outcome after checkpoint inhibitor therapy. Specifically, the pre-treatment density of 
CD8+ T-cells, PD-1+ cells, and PD-L1+ cells in melanoma tumors and at the invasive margin is associated 
with response to pembrolizumab therapy. In addition, the proximity between CD8+ T-cells and PD-L1+ 
cells in and around melanoma tumors is associated with response to therapy.[49] On treatment biopsies 
revealed that patients responding to anti-PD-1 therapy had an increase in intratumoral CD8+ T-cells when 
compared to non-responders. These findings suggest that the melanoma patients who are most likely to 
respond to PD-1/PD-L1 pathway inhibitors had adaptive immune resistance, an underlying immune 
response that was shut down by the PD-1/PD-L1 pathway and released by anti-PD-1 therapy. 
HL is histologically defined by few Hodgkin Reed-Sternberg (RS) cells surrounded by an ineffective, mixed 
immune infiltrate. The nearly universal genetic alterations in the PD-L1 and PD-L2 loci observed in RS cells, 
which results in increased expression of PD-L1 on RS cells, suggests that exploitation of the PD-1/PD-L1 
pathway to evade the host immune response is fundamental to the pathogenesis of HL.[8] In addition, 
multispectral imaging-based multiplexed immunohistochemistry has demonstrated that the majority of 
PD-L1 expressing cells in the HL TME are tumor-associated macrophages, which appear to have PD-L1 
expression induced by RS cells (Carey et al., ASH 2015). Despite this underlying dependence on the PD-
1/PD-L1 pathway, not all patients respond to PD-1/PD-L1 pathway inhibitors, and some responding 

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patients have a short duration of response. We hypothesize that there are differences in the TME, 
specifically the phenotype and spatial orientation of the immune cells in the TME and their proximity to 
PD-L1 expressing cells and RS cells, which predict response to nivolumab and/or NICE therapy. 
2.4.2.5 Impact of Study Treatment on Immune Reconstitution after ASCT  
Anti-PD-1 therapy increases the number of cytotoxic T lymphocytes in the peripheral blood, and results 
in increased IFN-gamma levels and upregulation of IFN-gamma gene target expression. [26, 50] 
Checkpoint inhibitor therapy, including anti-CTLA4 and anti-PD-1 therapy, also impacts peripheral blood 
T-cell receptor repertoire (TCR) diversity.[51, 52] Immune reconstitution after autologous stem cell 
transplantation (ASCT) is well studied, but no there are no data describing immune reconstitution in the 
setting of ongoing anti-PD-1 therapy. We hypothesize that patients treated with brentuximab vedotin and 
nivolumab will have earlier and enhanced reconstitution of effector T-cell subsets, and earlier recovery of 
and broader TCR diversity. 

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3.0 ELIGIBILITY CRITERIA 
Participant MRN (COH Only):  
Participant Initials (F, M, L): 
Institution: 
Participants must meet the following criteria on screening examination to be eligible to participate in the study: 
3.1 Inclusion Criteria 
Informed Consent and Willingness to Participate 
__1. Documented informed consent 
__2. Agreement to allow the use of archival tissue from pre-ASCT tumor biopsies (See Section 9.2 for 
details) 
 If unavailable, exceptions may be granted with Study PI approval. 
Age Criteria and Performance Status  
__3. Age: ≥ 18 years 
__4. ECOG performance status ≤ 2 (See Appendix A) 
Nature of Illness and Treatment History 
__5. Histologically confirmed diagnosis of classical Hodgkin lymphoma (excluding nodular lymphocyte 
predominant Hodgkin lymphoma) according to the WHO classification, with hematopathology review at 
the participating institution. 
__6. Have high-risk relapsed or refractory Hodgkin lymphoma (HL), defined as at least one of the 
following: 
 Primary refractory disease to front-line therapy. 
 Relapse within 1 year of completing front-line therapy. 
 Extranodal involvement at the time of pre-ASCT relapse. 
 B symptoms at pre-ASCT relapse. 
 More than one type of pre-ASCT salvage therapy required. 
__7. Planning to receive or have received autologous stem cell transplantation (ACST) per institutional 
standards as part of standard of care.   
 Pre-ASCT participants may consent but will not be eligible to begin treatment until after 
ASCT, and will have to fulfill all inclusion and exclusion criteria before starting protocol 
therapy.   
 All participants must initiate Day 1 of protocol therapy within 30-60 days post stem cell 
reinfusion. Study PI can grant exception for a patient to start as late as 75 days post stem 
cell reinfusion with a reasonable justification for delay (e.g. recovery from post-ASCT 
toxicity) and this will not be a protocol deviation, nor require an exception to be filed. 
__8. Recovery from ASCT toxicity as defined as outpatient status , able to drink, eat normally, and do 
not need intravenous hydration prior to Day 1 of therapy 
__9. Achieved at least stable disease to salvage treatment determined by PET/CT using 2014 Lugano 
Classification [2] prior to ASCT. 
__10. Brentuximab vedotin naïve OR had at least stable disease by Lugano Classification to prior 
brentuximab vedotin treatment 

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Organ Function Criteria and Pregnancy  
__11. ANC ≥ 1000/mm3  
ANC: 
Date: 
__12. Platelets ≥ 50,000/mm3  
Plts: 
Date: 
__13. Hemoglobin ≥ 8 g/dL  
Hgb: 
Date: 
__14. Total bilirubin ≤ 1.5 x ULN OR 3 x ULN for Gilbert’s disease 
ULN: 
Bil: 
Date: 
__15. AST and ALT ≤ 2.5 x ULN  
ULN:           ALT: 
ULN:           AST: 
Date: 
Date: 
__16. Creatinine clearance* ≥ 40 mL/min per 24 hour urine collection 
or the Cockcroft-Gault formula  
* Calculated per institutional standard 
ULN: 
Serum Cr: 
Cr Cl: 
Date: 
__17. Forced expiratory volume in one second (FEV1) and  carbon 
monoxide diffusion capacity (DLCO) (adjusted for Hb) ≥ 50% 
adjusted  
FEV1: 
DLCO: 
Date: 
__18. WOCBP only: Negative urine or serum pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) 
 If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required 
Urine test: 
 
Serum test: 
 
Date: 
Contraception 
 
__19. Woman of childbearing potential (WOCBP): use two effective methods of contraception 
(hormonal or barrier method) or be surgically sterile, or abstain from heterosexual activity for the 
course of the study through 7 months post last dose of nivolumab. 
 WOCBP defined as not being surgically sterilized or have not been free from menses for > 1 
year. 
Male: use two effective methods of contraception (barrier method) or abstain from heterosexual 
activity with the first dose of study therapy through 7 months post last dose of nivolumab. 
 
Participant MRN (COH Only):  
Participant Initials (F, M, L): 
Institution: 

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3.2 Exclusion Criteria 
Prospective participants who meet any of the following criteria will not be eligible to participate in the study: 
Prior Therapy/ Procedures  
__1.  Post-ASCT anti-lymphoma or investigational therapy. Immediate post-ASCT 
consolidative radiation therapy is allowed as long as it occurs prior to initiation of study 
therapy. Baseline imaging and PFTs must be performed after completion of radiation. 
__2.  Previous allogeneic transplant 
__3.  Total BCNU dose of > 600 mg/m2 with prior treatments including transplant conditioning 
regimen 
__4.  Live vaccine within 30 days prior to Day 1 of protocol therapy (e.g. measles, mumps, 
rubella, varicella, yellow fever, rabies, BCG, oral polio vaccine, and oral typhoid) 
Other Illnesses and Conditions 
__5.  Refractory to prior brentuximab vedotin (i.e. progression while on treatment) 
__6.  Refractory to prior anti-PD-1/PD-L1 agent  
__7.  History of prior ≥ Grade 3 hypersensitivity to either brentuximab vedotin or nivolumab 
__8.  History of another primary malignancy that has not been in remission for at least 3 
years. Exceptions include:  
 Basal cell carcinoma of the skin or  
 Squamous cell carcinoma of the skin that has undergone potentially curative therapy or  
 In situ cervical cancer. 
__9.  Known active central nervous system (CNS) involvement by lymphoma, including 
parenchymal and/or lymphomatous meningitis.   
__10.  History of progressive multifocal leukoencephalopathy (PML) 
__11.  Grade ≥ 2 peripheral neuropathy at the present time 
__12.  Prior diagnosis of inherited or acquired immunodeficiency 
__13.  Condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone or equivalent) or other immunosuppressive medications within 14 days of study 
drug administration. Exceptions are: 
 Inhaled or topical steroids and  
 Adrenal replacement doses > 10 mg daily prednisone equivalents in the absence of active 
autoimmune disease. 
Participant MRN (COH Only):  
Participant Initials (F, M, L): 
Institution: 

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__14.  Uncontrolled illness including ongoing or active infection 
__15.  History of or active pneumonitis or interstitial lung disease: 
 For history of pneumonitis to be an exclusion, patient had to have required supplemental 
oxygen or corticosteroid treatment.  Radiographic changes alone are not an exclusion. 
__16.  An active, known or suspected autoimmune disease. The following are exceptions:  
 Vitiligo,  
 Hemolytic anemia associated with the lymphoma (history of or at the present time) 
 Type I diabetes mellitus,  
 Residual hypothyroidism due to autoimmune condition only requiring hormone 
replacement, 
 Psoriasis not requiring systemic treatment, or  
 Conditions not expected to recur in the absence of an external trigger 
__17.  Active or known history (standard pre-ASCT assessments) of: 
 Hepatitis B or C infection  
 Human immunodeficiency virus (HIV) 
 Acquired immunodeficiency syndrome (AIDS) 
__18.  Women who are pregnant or lactating 
__19.  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 within 6 months prior to Day 1 of protocol therapy 
__20.  History or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion 
of the treating investigator  
Noncompliance 
__21.  Prospective participants who, in the opinion of the investigator, may not be able to 
comply with all study procedures (including compliance issues related to feasibility/logistics). 
Eligibility Confirmed* by 
(Choose as applicable): 
Print Name 
Signature 
Date 
 Site PI 
 
 
 
 Authorized study MD 
 
 
 
 Study Nurse 
 
 
 
 Study CRA/ CRC 
 
 
 
Other:______________ 
 
 
 
*Eligibility should be confirmed per institutional policies. 
Participant MRN (COH Only):  
Participant Initials (F, M, L): 
Institution: 

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4.0 PARTICIPANT ENROLLMENT  
NOTE: Sites must meet activation requirements prior to enrolling participants. 
4.1 
Pre-Enrollment Informed Consent and Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility will be done only after 
obtaining written informed consent.  Studies or procedures that are performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values and/or to determine pre-
eligibility, even if the studies were done before informed consent was obtained. The informed consent 
process is to be fully documented (see Section 16.4), and the prospective participant must receive a copy 
of the signed informed consent document.   
Screening can initiate 21 days after ASCT and screening assessments are listed in Section 10.0. 
Participants who signed informed consent prior to ASCT must have completed ASCT and have recovered 
from ASCT toxicities to be eligible per Section 3.0 to receive protocol therapy.  
4.2 
Participant Enrollment 
4.2.1 
COH DCC Availability and Contact Information 
Eligible participants will be registered on the study centrally by the DCC at City of Hope.  DCC staff are 
available between the hours of 8:00 a.m. and 5:00 p.m. PST, Monday through Friday (except holidays).   
DCC contact information is as follows: 
 
phone: (626)-218-7904 
 
e-mail: DCC@coh.org 
4.2.2 
Slot verification and reservation 
Designated study staff should call the DCC to verify current slot availability, and to reserve a slot for a 
specific prospective subject.  
The DCC should be notified of cancellations of prospective participants holding slots as soon as possible. 
4.2.3 
Registration Process 
To register a participant, the subsequent procedure is to be followed. 
1. The participating site’s data manager/coordinator/research nurse should contact the DCC via 
telephone or email to provide notification regarding the pending registration and communicate 
desired timeline of the registration, especially if it must be completed promptly to meet the 
registration window. 
2. The data manager/coordinator/research nurse should then e-mail copies to DCC@coh.org  of 
the following documents to the DCC:  
 
Registration Cover Sheet (Appendix B) 
 
Completed Eligibility Criteria List (printed from Section 3.0 of the protocol) 
 
Source documentation to support eligibility criteria**  
 
Signed informed consent document 
 
Signed HIPAA authorization form (if separate from the informed consent document) 
 
Signed subject’s Bill of Rights (COH only)  

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**For COH participants, provide copies of source documentation only if not readily available 
as a finalized record in the COH Electronic Medical Record (EMR).  
3. After having received all transferred documentation, the DCC will complete the review the 
documents to verify eligibility, working with the participating site as needed to resolve any 
missing required source elements. A participant failing to meet all protocol eligibility 
requirements will not be registered.  
4. Once eligibility has been confirmed, DCC staff will register the participant by: assigning a subject 
accession number, register the subject on study centrally into a COH clinical trials management 
system for non-COH participants, and enter the subject into the eCRF system, Medidata RAVE. 
5. Once registration has been completed, DCC staff will send a Confirmation of Registration Form, 
including the participant study number to:  
 
the site study team: Site Lead Investigator, treating physician, protocol nurse, CRC and 
pharmacy 
 
the COH sponsor team designees 
4.3 
Screen Failures and Registered Participants Who Do Not begin Study Treatment 
The DCC is to be notified of all participants who sign consent but do not meet eligibility criteria or do not 
initiate protocol therapy.  For non-COH sites, the reason for screen failure will be documented in 
registration coversheet (see Appendix B) and submitted to the DCC. 
5.0 TREATMENT PROGRAM 
5.1 Treatment Program Overview 
This is a multi-center, open-label, Phase 2 clinical trial for participants with relapsed or refractory Hodgkin 
lymphoma who have undergone autologous stem cell transplant (ASCT). Participants will initiate protocol 
therapy within 30 to 60 days post stem cell reinfusion. Study PI can grant exception for a patient to start 
as late as 75 days post stem cell reinfusion with a reasonable justification for delay (e.g. recovery from 
post-ASCT toxicity) and this will not be a protocol deviation, nor require an exception to be filed. 
Nivolumab and brentuximab vedotin will be administered in an outpatient setting in each 21-day cycle.  
Participants will receive up to 8 cycles of protocol therapy. If one agent is discontinued due to toxicity, 
then the participant may continue to receive single agent monotherapy. 
Participants who complete protocol therapy (Section 5.6) will undergo follow-up (Section 5.7). Windows 
for all assessments and treatments are detailed in Section 10.0. 
5.2 Treatment Cycle Definition 
In the absence of treatment-related delay, a cycle of therapy is defined as 21 days with a ± 3 day window.  
Day 1 of a cycle is defined as the administration of brentuximab vedotin (Section 5.3); the only exception 
to this will be if brentuximab vedotin is held or discontinued in which case Day 1 of a cycle will be defined 
as the adminitration of nivolumab. 
5.3 Treatment Plan  
Table 5.3 describes the combination regimen. The starting dose for brentuximab vedotin will be 1.8 
mg/kg. Protocol therapy must be initiated within 30 to 60 days post stem cell reinfusion. Study PI can 

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grant exception for a patient to start as late as 75 days post stem cell reinfusion with a reasonable 
justification for delay (e.g. recovery from post-ASCT toxicity) and this will not be a protocol deviation, nor 
require an exception to be filed. 
Table 5.3 Dosing regimen and schedule 
Agent 
Dose 
Route 
Schedule  
Max. 
Cycles 
Brentuximab  
Vedotin 
1.8 mg/kg 
IV over 30 minutes 
Day 1 of each 21-day cycle 
8 
Nivolumab 
3 mg/kg 
IV over 60 minutes 
Day 1 of each 21-day cycle 
5.4 Agent Administration 
Mandatory prophylaxis for infusion related reaction must be initiated at least 30 minutes prior to agent 
administration.  
o For participants without history of infusion reaction to brentuximab vedotin or nivolumab. 
Recommended pre-medication to include, per institutional standard: 
 Acetaminophen/paracetamol 
 Anti-histamine (e.g. diphenhydramine) 
o For participants who have experienced an infusion related reaction to brentuximab vedotin or 
nivolumab (prior to this study, or on this study while not taking corticosteroid prophylaxis). 
Recommended pre-medication to include (and modifiable per institutional standard): 
 Acetaminophen/paracetamol 325 to 1000 mg  
 Anti-histamine: Diphenhydramine 25–50 mg (or equivalent)  
 Corticosteroid: Hydrocortisone IV no more than 100 mg (or equivalent) 
 Ranitidine may be considered 
o For participants who experience infusion related reaction to study agents while taking 
prophylactic corticosteroids.    
 Premedication to follow above, but increase corticosteroids: 
− 
Methylprednisolone 40 mg IV (or equivalent e.g. hydrocortisone IV 200 mg).  
For supportive care during infusion reaction, see Section 5.9.2. 
5.4.1 
Brentuximab Vedotin 
Brentuximab vedotin will be administered as a 30 minute IV infusion on Day 1.  
When both agents are administered sequentially, brentuximab vedotin will be administered first. The 
infusion must have ended at least 30 minutes prior to the nivolumab infusion.  
Dosing is based on participant actual body weight. It is not necessary to re-calculate subsequent doses if 
the participant weight is within 10% of the weight from baseline. Other dose adjustments for changes in 
body weight are permitted per institutional standard. An exception to weight-based dosing is made for 
participants weighing > 100 kg; doses will be based on 100 kg for these individuals. Rounding is permissible 
within 5% of the nominal dose. 
Management and dose reductions associated with brentuximab vedotin AEs are outlined in Section 6.2. 

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5.4.2 
Nivolumab 
Nivolumab will be administered as a 60 minute (± 5 minute) IV infusion on Day 1.  
Nivolumab should be administered at least 30 minutes after completing treatment with brentuximab 
vedotin on Day 1. 
The nivolumab dose is fixed at 3 mg/kg. Doses of nivolumab may be interrupted, delayed, or 
discontinued depending on how well the participant tolerates the treatment.  Refer to Section 8.1.9 for 
additional administration information.  
The dosing calculations for nivolumab should be based on the actual body weight at baseline. If the 
subject’s weight on the day of dosing differs by > 10% from the weight used to calculate the original 
dose, the dose must be recalculated. All doses should be rounded to the nearest milligram. There will be 
no dose modifications allowed. 
Management and dose delays associated with nivolumab AEs are outlined in Section 6.2. 
5.5 Assessments and Special Monitoring 
Refer to Section 10.0 for schedule of assessments. Note: on days when agent(s) is/are administered, 
assessments are to be completed (and results reviewed if a safety or response assessment) prior to 
administration of agent(s).  
5.5.1 
Special Monitoring 
o Infusion reactions 
 
Infusion or hypersensitivity reactions may occur to either brentuximab vedotin or 
nivolumab.  
 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. 
 
If such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, 
pruritus, arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like 
reactions. 
 
Refer to Section 5.9.2 for management guidelines. 
o Immune-related Adverse Events (AEs) 
 
Nivolumab is associated with AEs that can differ in severity and duration than AEs caused by 
other therapeutic classes.  
 
Early recognition and management of AEs associated with nivolumab may mitigate severe 
toxicity.  
 
Refer to Section 5.9.2 for management guidelines. 
5.6 Duration of Therapy and Criteria for Removal from Study Treatment 
Participants will receive protocol therapy until one of the below criteria are met: 
o Disease progression 
 
Note: Following consultation with the Study PI, participants who meet progression per 2014 
Lugano classification [53] but who meet the criteria of “indeterminate response” (IR) 
according to the provisional modification to the 2014 Lugano Classification, the LYRIC 

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criteria [1] (Appendix H), and are deriving clinical benefit may continue to receive protocol 
therapy beyond progression as long as they meet the following criteria: 
− 
Continue to meet treatment criteria 
− 
Investigator-assessed clinical benefit and subject is tolerating study drug. 
− 
Tolerance of study drug 
− 
Stable performance status 
− 
Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (e.g., CNS metastases) 
 
If the patient has IR per LYRIC criteria and is receiving therapy beyond progression:  
− 
A confirmatory PET-CT should be performed within 12 weeks after initial 
progression to determine whether the patient meets PD criteria according to the 
LYRIC criteria [1]. 
− 
Further progression is defined according to the LYRIC criteria  
− 
Protocol therapy should be discontinued permanently upon documentation of PD 
per the LYRIC criteria 
o Participant receives 8 cycles (~ 6 months) of protocol therapy 
o Unacceptable toxicity related to protocol therapy despite dose delay/ modification  
 
Note: If one agent is delayed due to toxicity, then participants many continue with 
monotherapy for the other agent. 
o General or specific changes in the participant's condition (including intercurrent illness)  which 
render the participant unacceptable for further treatment in the judgment of the investigator 
o Withdrawal of consent for further protocol therapy by the participant (See Section 16.5) 
Once participants meet criteria for removal from protocol therapy, the participant should then proceed 
to Follow-up. 
Documentation of the reason for discontinuing protocol therapy and the date effective should be made 
in the medical record and appropriate eCRF. The COH DCC and the Study PI should be promptly notified 
of the change in participant status. 
5.7 Follow-Up  
Following completion of protocol therapy, participant will enter follow-up. Note, the safety follow-up 
visits may occur concurrently with other follow-up visits: 
o Safety Follow-up - All participants will undergo safety follow-up visits, typically at 30 days and 
100 days following the end of treatment.   
o Active Response Follow-Up – for participants who have yet to progress/relapse. These visits 
also involves the collection of research samples.  This period has a maximum of 18 months from 
start of treatment.  
o Long Term Follow-Up – for all participants who have progressed/relapsed OR completed Active 
Response Follow-Up. This follow-up will be performed typically via medical record review.  It will 
entail (a) Disease status (for those who have yet to relapse/progress) (b) Vital status (all 
participants). The long-term follow-up period will have a maximum duration of 5 years (from start 
of treatment). 
See Section 10.0 for details and windows. 

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5.8 Duration of Participation and Criteria for End of Participation 
Study participation may conclude when any of the following occur:  
o Completion of study activities (treatment and follow-up) 
o Participant withdrawal (see Section 16.5). 
o Participant is lost to follow-up. All attempts to contact the participant must be documented. 
o At the discretion of the investigator for reasons including but not limited to study termination, 
behavioral or administrative reasons 
Documentation of the reason for discontinuing study participation and the date effective should be made 
in the medical record and appropriate eCRF. The COH DCC should be promptly notified of the change in 
participant status.   
5.9 Supportive care, Prohibited and Concomitant Medications/ Therapies 
Participants must be instructed not to take any additional medications (including over-the-counter 
products) during the trial without prior consultation with the investigator.  
5.9.1 
Prohibited medications/ therapies 
The following medications/ therapies are prohibited from Day 1 of protocol therapy until end of 
protocol therapy (last day of study agent or decision to end study agent(s) whichever occurs later): 
o Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than 
corticosteroids used for treatment of an IrAE are prohibited during the treatment period, unless 
discussed with the Study PI and felt to be of low clinical risk to the participant.  
o Live attenuated vaccines 
o Herbal and natural remedies 
The following medications/therapies are prohibited any time after ASCT, active protocol treatment, or 
follow-up. If the patient receives one of these therapies in the absence of disease progression, the 
patient will be censored at the time of initiation. 
o Other investigational therapy  
o Concurrent anti-cancer therapy: chemotherapy, biological response modifiers, hormone 
therapy, surgery, palliative radiation therapy, or immunotherapy). 
5.9.2 
Supportive care and permitted medications/ therapies  
With the exception of prohibited therapies (see Section 5.9.1), participants should receive prophylactic or 
supportive care as clinically indicated per institutional policies and suspected immune-related AEs (irAE) 
guidelines stated below. 
Blood products 
 
Platelet and/or red blood cell supportive growth factors or transfusions 
- 
Permitted when applicable 
 
Colony stimulating factors (CSFs) 
- 
Permitted for treatment of neutropenia per institutional practice.  
Corticosteroids 

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 Topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal 
systemic absorption) 
- 
Permitted 
 
Systemic corticosteroids 
- 
Physiologic replacement doses permitted even if > 10 mg/day prednisone or 
equivalent. 
 
Brief course of corticosteroids (< 3 weeks)  
- 
Permitted for prophylaxis (e.g. contrast dye allergy)  
- 
Permitted for treatment of non-autoimmune conditions (e.g, delayed-type 
hypersensitivity reaction caused by contact allergen)  
Strong CYP3A4/5 inhibitors 
Closely monitor for AEs when administered concomitantly with brentuximab vedotin. 
Required prophylaxis 
Standard international guidelines for infection prophylaxis for herpes simplex virus (HSV), 
varicella-zoster virus (VZV), and Pneumocystis jiroveci (PCP) after ASCT must be followed. 
Per international guidelines, Herpes virus prophylaxis with acyclovir or similar agent and 
pneumocystis jiroveci (PCP) prophylaxis is required for all patients on this study. Administer 
prophylaxis from the time of engraftment (or the time of first study treatment dosing) for at 
least 9 months after ASCT. If herpes virus or PCP prophylaxis is held, the reasoning (e.g. 
renal dysfunction) must be documented. 
 
First Choice 
− 
Trimethoprim-sulfamethoxazole: 1 double-strength (DS) tablet (160/800 mg) orally 
3 times/week; 1 DS tablet orally daily; 1 single-strength (80/400 mg) tablet orally 
daily; or 1 DS tablet two times a day 2 days a week. 
 
 
First Alternative 
− 
Atovaquone: 750 mg twice daily or 1500 mg once daily, orally 
 
 
Other Alternatives 
− 
Dapsone: 50 mg orally 2 times/day; or 100 mg orally daily 
− 
Pentamidine: 300 mg every 3-4 weeks by Respirgard II™ nebulizer 
Management of infusion reactions 
Treatment recommendations are provided below may be modified based on local treatment standards 
and guidelines as appropriate. 
Grade 2 infusion reactions 
 If the onset of a reaction occurs during an infusion,  
− 
The infusion may be interrupted for treatment of the infusion-related reaction, 
and/or 
− 
The infusion time may be extended. 
− 
Recommended treatments include: antihistamines, corticosteroids, and/or 
bronchodilator therapy, as appropriate. 

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Grade 3 or 4 infusion reactions 
 If the onset of a reaction occurs during infusion, the infusion must be interrupted. 
 Begin an IV infusion of normal saline 
 Recommend treatments include: 
− 
bronchodilators,  
− 
epinephrine 0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 
0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV administration, and/or 
− 
Diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as 
needed.  
 Monitor until the investigator is comfortable that the symptoms will not recur.  
 Follow institutional guidelines for anaphylaxis. 
 For late-occurring hypersensitivity symptoms (e.g. appearance of a localized or 
generalized pruritus within 7 days post-treatment): 
− 
Symptomatic treatment may be given (e.g., oral antihistamine, or corticosteroids) 
Management of immune-related AEs 
The following immune-related AEs (irAEs) related to nivolumab should be managed as outlined below.  
5.9.2.1 Hepatic  
 Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy. Consider imaging for obstruction. 
 Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed. Lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 
For patients with baseline LFT that are within normal limits: 
Grade 1: AST or ALT > ULN – 3.0 x ULN and/or Total bilirubin > ULN -1.5X ULN 
 Continue liver function tests (LFT) monitoring per protocol 
 If worsens treat as Grade 2 or 3-4 
Grade 2: AST or ALT > 3.0 to ≤ 5 x ULN and/or Total bilirubin >1.5 to ≤ 3 x ULN 
 Increase frequency of monitoring to every 3 days 
 If returns to baseline: Resume routine monitoring, resume therapy per protocol 
 If elevations persist > 5-7 days or worsen : 
− 
0.5-1 mg/kg/day methylprednisolone or oral equivalent and when LFT returns to 
grade 1 or baseline, taper steroids over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections and resume nivolumab per protocol 
Grade 3-4: AST or ALT > 5 x ULN and /or Total bilirubin >3 x ULN 
 Increase frequency of monitoring to every 1-2 days 
 Administer 1.0 to 2.0 mg/kg/day methylprednisolone IV or IV equivalent. The 
recommended starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV. 

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 Add prophylactic antibiotics for opportunistic infections 
 Consult gastroenterologist 
 If returns to grade 2: 
− 
Taper steroids over at least 1 month 
 If does not improve in >3-5 days, worsens or rebounds: 
− 
Add mycophenolate mofetil 1 gram (g) twice daily (BID) 
− 
If no response within an additional 3-5 days, consider other immunosuppressants 
 
For patients with baseline LFTs (transaminases or bilirubin) in the Grade 1 range (AST or 
ALT > ULN to 3.0 x ULN and/or total bilirubin > ULN to 1.5 x ULN) should be managed 
according to the hepatic algorithm as applied to the absolute increase in AE grade 
level above baseline. Therefore, for these patients, management of a Grade 3 LFT 
abnormality would be per the Grade 2 algorithm, and management of a Grade 4 LFT 
abnormality would be per the Grade 3 algorithm. 
5.9.2.2 Renal  
Grade 1: Creatinine > ULN and > than baseline but ≤ 1.5x baseline 
 Monitor creatinine weekly 
 If returns to baseline: 
− 
Resume routine creatinine monitoring per protocol 
 If worsens: 
− 
Treat as Grade 2 or 3/4 
Grade 2-3: Creatinine > 1.5x baseline to ≤ 6x ULN 
 Monitor creatinine every 2-3 days 
 Administer 0.5 to 1.0 mg/kg/day methylprednisolone IV or oral equivalent 
 Consider renal biopsy 
 If returns to Grade 1: 
− 
Taper steroids over at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume nivolumab and routine creatinine monitoring 
per protocol 
 If elevations persist > 7 days or worsen: 
− 
Treat as Grade 4 
Grade 4: Creatinine > 6x ULN 
 Monitor creatinine daily 
 Administer 1.0-2.0 mg/kg/day methylprednisolone IV or IV equivalent 
 Consult nephrologist 
 Consider renal biopsy 
 If returns to Grade 1 :  
− 
Taper steroids over at least 1 month and add prophylactic antibiotics for 
opportunistic infections 
 Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed. Lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids 

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5.9.2.3 Diarrhea/Colitis 
 Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat 
accordingly and continue I-O therapy.  
 Opiates/narcotics may mask symptoms of perforation.  
 Infliximab should not be used in cases of perforation or sepsis 
Grade 1 Diarrhea/ Colitis 
 Symptomatic treatment 
 Close monitoring for worsening symptoms. 
 Educate patient to report worsening immediately 
 If worsens: 
− 
Treat as Grade (G) 2 or 3/4 
Grade 2 Diarrhea/ Colitis 
 Symptomatic treatment 
 If persists > 5-7 days or recur: 
− 
Administer 0.5-1.0 mg/kg/day methylprednisolone or oral equivalent 
− 
When symptoms improve to grade 1, taper steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic infections 
 If worsens or persists > 3-5 days with oral steroids: 
− 
Treat as grade 3/4 
Grade 3-4 Diarrhea/ Colitis 
 Administer 1.0 to 2.0 mg/kg/day methylprednisolone IV or IV equivalent 
 Add prophylactic antibiotics for opportunistic infections 
 Consider lower endoscopy 
 If improves: 
− 
Continue steroids until grade 1, then taper over at least 1 month 
 If persists > 3-5 days, or recurs after improvement: 
− 
Add infliximab 5 mg/kg (if no contraindication). 
− 
Note: Infliximab should not be used in cases of perforation or sepsis 
 Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed. Lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
5.9.2.4 Endocrinopathy 
 Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy.  
 Consider visual field testing, endocrinology consultation, and imaging. 
 Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed. 
 Lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids 

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Asymptomatic thyroid stimulating hormone (TSH) elevation 
 If TSH < 0.5 x lower limit of normal (LLN), or TSH > 2 x ULN, or consistently out of range 
in 2 subsequent measurements: include free thyroxine (fT4) at subsequent cycles as 
clinically indicated; consider endocrinology consult 
Symptomatic endocrinopathy 
 Evaluate endocrine function 
 Consider pituitary scan 
 Symptomatic with abnormal lab/pituitary scan: 
− 
1-2 mg/kg/day methylprednisolone IV or by mouth (PO) equivalent 
− 
Initiate appropriate hormone therapy 
 No abnormal lab/pituitary MRI scan but symptoms persist: 
− 
Repeat labs in 1-3 weeks /MRI in 1 month 
 If improves (with or without hormone replacement): 
− 
Taper steroids over at least 1 month and consider prophylactic antibiotics for 
opportunistic infections 
− 
Patients with adrenal insufficiency may need to continue steroids with 
mineralocorticoid component. 
Suspicion of adrenal crisis (e.g. severe dehydration, hypotension, shock out of proportion to 
current illness) 
 Rule out sepsis 
 Stress dose of IV steroids with mineralocorticoid activity 
 IV fluids 
 Consult endocrinologist 
5.9.2.5 Neurological 
 Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed. 
 Lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 
Grade 1: Asymptomatic or mild symptoms; Intervention not indicated 
 Continue to monitor the patient 
Grade 2: Moderate symptoms; instrumental ADL 
 Treat symptoms per local guidelines 
 Consider 0.5 to 1.0 mg/kg/day methylprednisolone IV or PO equivalent 
 If worsens: 
− 
Treat as Grade 3-4 
Grade 3-4: Severe symptoms; Limiting self-care ADL; Life-threatening 
 Obtain neurology consult 
 Treat symptoms per local guidelines 
 1.0-2.0 mg/kg/day IV methylprednisolone IV or IV equivalent 

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 Add prophylactic antibiotics for opportunistic infections 
 If improves to Grade 2: 
− 
Taper steroids over at least 1 month 
 If worsens or atypical presentation: 
− 
Consider IVIG or other immunosuppressive therapies per local guidelines 
5.9.2.6 Pulmonary 
 Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy.  
 Evaluate with imaging and pulmonary consultation. 
 Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed. 
 Lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 
Grade 1: Radiographic changes only 
 Monitor for symptoms every 2-3 days 
 Consider Pulmonary and Infectious Disease (ID) consults 
Grade 2: Mild to moderate new symptoms 
 Pulmonary and ID consults 
 Monitor symptoms daily, consider hospitalization 
 1.0 mg/kg/day methylprednisolone IV or oral equivalent 
 Consider bronchoscopy , lung biopsy 
 Re-image every 1-3 days 
 If improves: 
− 
When symptoms return to near baseline, taper steroids over at least 1 month and 
consider prophylactic antibiotics 
 If not improving after 2 weeks or worsening: 
− 
Treat as Grade 3-4 
Grade 3-4: Severe new symptoms; New/worsening hypoxia; Life-threatening 
 Hospitalize 
 Pulmonary and ID consults 
 2-4 mg/kg/day methylprednisolone IV or IV equivalent 
 Add prophylactic antibiotics for opportunistic infections 
 Consider bronchoscopy, lung biopsy 
5.9.2.7 Skin 
Grade 1-2 Covering ≤ 30% body surface area (BSA) 
 Symptomatic therapy (e.g. antihistamines, topical steroids) 
 If persists > 1-2 weeks or recurs: 
− 
Consider skin biopsy 

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− 
Consider 0.5-1.0 mg/kg/day methylprednisolone IV or oral equivalent. Once 
improving , taper steroids over at least 1 month, consider prophylactic antibiotics 
for opportunistic infections 
 If worsens: 
− 
Treat as Grade 3-4 
Grade 3-4: Covering >30% BSA; Life threatening consequences 
 Consider skin biopsy 
 Dermatology consult 
 1.0-2.0 mg/kg/day IV methylprednisolone IV or IV equivalent 
 If improves to Grade 1: 
− 
Taper steroids over at least 1 month and add prophylactic antibiotics for 
opportunistic infection 

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6.0 ANTICIPATED TOXICITIES AND DOSE DELAY/MODIFICATIONS 
6.1 Anticipated Toxicities 
6.1.1 
Brentuximab vedotin 
Per the IB the expected toxicities for brentuximab vedotin are as follows: 
System Organ Class 
Adverse Reactions 
Infections and infestations  
 
Very common 
Infectiona, upper respiratory tract infection 
 
Common 
Herpes zoster, pneumonia, herpes simplex, oral candidiasis 
 
Uncommon 
Pneumocystis jiroveci pneumonia, staphylococcal 
bacteremia, cytomegalovirus infection or reactivation, 
sepsis/septic shock 
 
Frequency not known 
Progressive multifocal leukoencephalopathy 
Blood and lymphatic system disorders 
 
Very common 
Neutropenia 
 
Common 
Anamia, thrombocytopenia 
 
Uncommon 
Febrile neutropenia 
Immune system disorders 
 
Uncommon 
Anaphylactic reaction 
Metabolism and nutrition disorders 
 
Common 
Hyperglycemia 
 
Uncommon 
Tumor lysis syndrome 
Nervous system disorders 
 
Very common 
Peripheral sensory neuropathy, peripheral motor neuropathy 
 
Common 
Dizziness 
 
Uncommon 
Demyelinating polyneuropathy 
Respiratory, thoracic and mediastinal disorders 
 
Very common 
Cough, dyspnea 
Gastro-intestinal disorders 
 
Very common 
Nausea, diarrhea, vomiting, constipation, abdominal pain 
 
Uncommon 
Pancreatitis acute 
Hepatobiliary disorders 
 
Common 
Alanine aminotransferase/aspartate aminotransferase 
increased 
Skin and subcutaneous tissue disorders 
 
Very common 
Rasha, pruritus 
 
Common 
Alopecia 
 
Uncommon 
Stevens-Johnson syndrome/toxic epidermal necrolysis 
Musculoskeletal and connective tissue disorders 
 
Very common 
Arthralgia, myalgia 
 
Common 
Back pain 
General disorders and administration site conditions 

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System Organ Class 
Adverse Reactions 
 
Very common 
Fatigue, pyrexia, infusion-related reactionsa 
 
Common 
Chills 
Investigations 
 
Very common 
Weight decreased 
a Represents pooling of preferred terms 
Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to 
<1/1,000); Very rare (<1/10,000); not known (cannot be estimated from the available data). 
6.1.2 
Nivolumab 
Per the IB (version 17, June 2018) the expected toxicities for nivolumab are as follows: 
System Organ Class 
Adverse Reactions 
Infections and infestations  
 
Common 
Upper respiratory tract infection 
 
Uncommon 
Pneumoniaa, bronchitis 
Neoplasms benign, malignant and unspecified (including cysts and polyps) 
 
Rare 
Histiocytic necrotising lymphadenitis (Kikuchi lymphadenitis) 
Blood and lymphatic system disorders 
 
Very common 
Neutropeniaa,b, lymphopenia, leucopenia, thrombocytopenia, 
anemia 
 
Uncommon 
Eosinophilia 
Immune system disorders 
 
Common 
Infusion related reactionc, hypersensitivityc 
 
Rare 
Anaphylactic reactionc 
 
Not known 
Solid organ transplant rejection 
Endocrine disorders 
 
Common 
Hypothyroidism, hyperthyroidism 
 
Uncommon 
Adrenal insufficiency, hypopituitarism, hypophysitis, 
thyroiditis, diabetes mellitus 
 
Rare 
Diabetic ketoacidosis 
Metabolism and nutrition disorders 
 
Common 
Decreased appetite 
 
Uncommon 
Dehydration, metabolic acidosis 
Hepatobiliary disorders 
 
Uncommon 
Hepatitisc 
 
Rare 
Cholestasis 
Nervous system disorders 
 
Common 
Peripheral neuropathy, headache, dizziness 
 
Uncommon 
Polyneuropathy, autoimmune neuropathy (including facial and 
abducens nerve paresis) 
 
Rare 
Guillain-Barré syndrome, demyelination, myasthenic 
syndrome, encephalitisa,c 

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System Organ Class 
Adverse Reactions 
Eye disorders 
 
Uncommon 
Uveitis, blurred vision, dry eye 
 
Not known 
Vogt-Koyanagi-Harada syndromeg 
Cardiac disorders 
 
Uncommon 
Tachycardia 
 
Rare 
Arrhythmia (including ventricular arrhythmia), atrial 
fibrillation, myocarditisa,e 
Vascular disorders 
 
Common 
Hypertension 
 
Rare 
Vasculitis 
Respiratory, thoracic and mediastinal disorders 
 
Common 
Pneumonitisa,c, dyspneaa, cough 
 
Uncommon 
Pleural effusion 
 
Rare 
Lung infiltration 
Gastro-intestinal disorders 
 
Very common 
Diarrhea, nausea 
 
Common 
Colitisa, stomatitis, vomiting, abdominal pain, constipation, dry 
mouth 
 
Uncommon 
Pancreatitis, gastritis 
 
Rare 
Duodenal ulcer 
Skin and subcutaneous tissue disorders 
 
Very common 
Rashd, pruritus 
 
Common 
Vitiligo, dry skin, erythema, alopecia 
 
Uncommon 
Erythema multiforme, psoriasis, rosacea, urticaria 
 
Rare 
Toxic epidermal necrolysisa,e, Stevens-Johnson syndromea,e 
Musculoskeletal and connective tissue disorders 
 
Common 
Musculoskeletal painf, arthralgia 
 
Uncommon 
Polymyalgia rheumatica, arthritis 
 
Rare 
Sjogrengia rheumatica, arthritis myositis (including 
polymyositis)a,e, rhabdomyolysisa,e 
Renal and urinary disorders 
 
Uncommon 
Tubulointerstitial nephritis, renal failure (including acute 
kidney injury)a,c 
General disorders and administration site conditions 
 
Very common 
Fatigue 
 
Common 
Pyrexia, oedema (including peripheral oedema) 
 
Uncommon 
Pain, chest pain 
Investigations 
 
Very common 
Increased AST, increased ALT, increased alkaline phosphatase, 
increased lipase, increased amylase, hypocalcemia, increased 
creatinine, hyperglycemiac, hypercalcemia, hyperkalemia, 
hypokalemia, hypomagnesemia, hyponatremia 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
City of Hope #: 16378  
Protocol Version:  09- May 16 2022 
 
CONFIDENTIAL 
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System Organ Class 
Adverse Reactions 
 
Common 
Increased total bilirubin, hypoglycemia, hypermagnesemia, 
hypernatremia, weight decreased 
a Fatal cases have been reported in completed or ongoing clinical studies 
b Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from baseline in 
laboratory measurements. 
c Life-threatening cases have been reported in completed or ongoing clinical studies. 
d Rash is a composite term which includes maculopapular rash, rash erythematous, rash pruritic, rash follicular, rash 
macular, rash morbilliform, rash papular, rash pustular, rash papulosquamous, rash vesicular, rash generalised, 
exfoliative rash, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, 
dermatitis exfoliative, dermatitis psoriasiform, drug eruption and pemphigoid. 
e Reported also in studies outside the pooled dataset.  
f Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, 
musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain. 
g Post-marketing event 
Adverse reactions reported in the pooled dataset for patients treated with nivolumab monotherapy (n = 
2578). These reactions are presented by system organ class and by frequency. 
Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 
to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from 
available post-marketing data). Within each frequency grouping, adverse reactions are presented in the 
order of decreasing seriousness. 
6.2 Dose Modification/Delays 
o Toxicities will be graded using the NCI CTCAE v 4.0. 
o Baseline values are from the last values obtained prior to treatment. 
o If one agent is held due to toxicity for a given cycle, administration of the delayed agent should 
resume once the toxicity is resolved on the same schedule with the next cycle of combination 
therapy.   
o If one agent is permanently discontinued, then the participant may continue monotherapy with 
the other agent.  
o If both agents are held together and the toxicity lasts > 6 weeks, then protocol therapy will be 
discontinued.  
o Nivolumab dose management guidelines are described in Table 6.2.1. 
 
Management algorithms for nivolumab have been developed to assist investigators in 
assessing and managing the following groups of AEs: Gastrointestinal, Renal, Pulmonary, 
Hepatic, Endocrinopathies, Skin, and Neurological. The algorithms have been incorporated 
into Table 6.2.1 and can also be found in the Nivolumab IB. The guidance provided in these 
algorithms should not replace the Investigator’s medical judgment but should complement 
it. 
 
Dose reductions or dose escalations are not permitted for nivolumab. 
 
Asterisk (*) in Table 6.2.1: Following consultation with the Study PI, treatment delay > 6 
weeks due to prolonged steroid taper is permissible. 
 
Dosing interruptions or delays lasting > 6 weeks that occur for non-nivolumab-related 
reasons may be allowed if approved by the Study PI. Prior to re-initiating treatment in a 
participant with a dosing interruption lasting > 6 weeks, the Study PI must be consulted. 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
City of Hope #: 16378  
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Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
City of Hope #: 16378  
Protocol Version:  09- May 16 2022 
 
CONFIDENTIAL 
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o Brentuximab vedotin dose modification/ delay are described in Table 6.2.2.  
 
Doses reduced for brentuximab vedotin-related toxicity should not be re-escalated without 
discussion with the Study PI. 
Table 6.2.1 Dose management guidelines for Nivolumab  
Toxicity 
Nivolumab Dose Management Guidelines 
Hematological Toxicity 
Anemia or thrombocytopenia 
Grade 3 
Platelets: < 50,000 - 25,000/mm3 
Continue nivolumab  
Anemia or thrombocytopenia 
Grade 4 
Platelets <25,000/mm3 
 
Hold nivolumab  
 
Once toxicity resolves ≤ Grade 2 resume nivolumab per protocol 
 
Permanently discontinue if there is a treatment delay > 6 weeks. 
Neutropenia Grade 3 
ANC <1000 - 500/mm3 
Continue nivolumab 
 
Consider growth factor (G-CSF) support 
Neutropenia Grade 4 
ANC < 500/mm3 
 
Hold the nivolumab dose  
 
Once toxicity resolves to ≤ Grade 2 or baseline, resume treatment with 
nivolumab per protocol  
 
Growth factor support should be instituted. 
 
A repeat blood draw to evaluate the grade of neutropenia should be 
performed within 3 days. 
 
Consider growth factor support (G-CSF or GMCSF) for subsequent 
cycles.  
 
If toxicity recurs despite growth factor support, consider nivolumab 
discontinuation. 
 
Permanently discontinue if there is a treatment delay > 6 weeks. 
 
Eye (Blurred Vision, Eye Pain, Uveitis) 
Eye pain, blurred vision  
Grade 2 
Discontinue nivolumab if toxicity does not respond to topical therapy and 
does not improve to Grade 1 within 6 weeks or requires systemic 
treatment. 
 
Uveitis Grade 2  
Discontinue nivolumab if toxicity does not respond to topical therapy and 
does not improve to Grade 1 within 6 weeks or requires systemic 
treatment. 
 
Uveitis Grade 3  
Discontinue nivolumab 

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Toxicity 
Nivolumab Dose Management Guidelines 
Hepatic (AST, ALT, Total bilirubin) – when baseline LFTs are within normal limits 
Note: for participants with Grade 1 baseline LFTs, hepatic dose management guidelines below should be 
followed. 
Grade 1 
AST or ALT > ULN- 3.0 xULN and/or 
Total bilirubin > ULN -1.5 x ULN 
 
Continue nivolumab per protocol 
 
See Section 5.9.2.1 for supportive care. 
 
Grade 2 
AST or ALT > 3.0 to ≤ 5 x ULN OR  
T. bili > 1.5 to ≤ 3 x ULN 
 
 
 
 
Hold the dose of nivolumab 
 
See Section 5.9.2.1 for supportive care. 
 
If toxicity resolves within 5 days to baseline resume nivolumab per 
protocol 
 
If elevations persist > 5-7 days or worsen  
− 
Resume therapy per protocol when LFT returns to Grade ≤ 1 or 
baseline and when steroid taper (≥ 1 month*) is complete. (* See 
exception in Section 6.2.) 
 
Discontinue treatment if toxicity lasts for > 6 weeks or unable to 
initiate steroid taper within a 6 week period.  
 
Low Grade 3 
AST or ALT > 5-≤ 8 x ULN x ULN OR 
total bilirubin >3-≤ 5 x ULN  
 
Per investigator discretion the nivolumab dose may be delayed rather 
than discontinued. 
High Grade 3 and Grade 4 
AST or ALT > 8 x ULN OR  
total bilirubin >5 x ULN 
 
Discontinue nivolumab therapy 
 
See Section 5.9.2.1 for supportive care. 
 
Concurrent ≥ Grade 2 AST or ALT 
(> 3 x ULN) AND 
total bilirubin > 2 x ULN 
 
Discontinue nivolumab therapy 
 
See Section 5.9.2.1 for supportive care. 
 
Hepatic (AST, ALT, Total bilirubin) – when baseline LFTs are Grade 1 
Note: for participants with baseline LFTs that are within normal limits, hepatic dose management guidelines 
above should be followed. 
Grade 1 and 2 
G1: AST or ALT > ULN- 3.0 xULN 
and/or Total bilirubin > ULN -1.5 x 
ULN 
 
G2: AST or ALT > 3.0 to ≤ 5 x ULN OR  
T. bili > 1.5 to ≤ 3 x ULN 
 
Continue nivolumab per protocol 
 
See Section 5.9.2.1 for supportive care. 
 
Low Grade 3 
AST or ALT > 5-≤ 8 x ULN x ULN OR 
total bilirubin >3-≤ 5 x ULN 
 
Hold the dose of nivolumab 
 
See Section 5.9.2.1 for supportive care. 
 
If toxicity resolves within 5 days to baseline resume nivolumab per 
protocol 
 
If elevations persist > 5-7 days or worsen  
− 
Resume therapy per protocol when LFT returns to Grade ≤ 2 or 
baseline and when steroid taper (≥ 1 month*) is complete. (* See 
exception in Section 6.2.) 
 
Discontinue treatment if toxicity lasts for > 6 weeks or unable to 
initiate steroid taper within a 6 week period.  
 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
City of Hope #: 16378  
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CONFIDENTIAL 
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Toxicity 
Nivolumab Dose Management Guidelines 
High Grade 3 and Grade 4 
AST or ALT > 8 x ULN OR  
total bilirubin >5 x ULN 
 
Discontinue nivolumab therapy 
 
See Section 5.9.2.1 for supportive care. 
 
Concurrent ≥ Grade 2 AST or ALT 
(> 3 x ULN) AND 
total bilirubin > 2 x ULN 
 
Discontinue nivolumab therapy 
 
See Section 5.9.2.1 for supportive care. 
 
Renal  (Creatinine) 
Grade 1 
Creatinine > ULN and > than baseline 
but ≤ 1.5x baseline 
 
Continue nivolumab per protocol 
 
See Section 5.9.2.2 for supportive care. 
 
If worsens: 
− 
Treat as Grade 2 or 3/4 
Grade 2-3 
Creatinine > 1.5x baseline to ≤ 6x 
ULN 
 
Hold the dose of nivolumab 
 
See Section 5.9.2.2 for supportive care. 
 
Resume therapy per protocol once the toxicity returns to Grade ≤ 1  
and when steroid taper (≥ 1 month*) is complete. (* See exception in 
Section 6.2.) 
 
Discontinue treatment if toxicity lasts for > 6 weeks or unable to 
initiate steroid taper within a 6 week period.  
 
If elevations persist > 7 days or worsen: 
− 
Treat as Grade 4 
 
Grade 4 
Creatinine > 6x ULN 
 
Discontinue nivolumab 
 
See Section 5.9.2.2 for supportive care. 
Gastrointestinal (Diarrhea/ Colitis) Toxicity 
Diarrhea/Colitis Grade 1 
Diarrhea:< 4 stools/day over 
baseline; 
 
Colitis: asymptomatic 
 
Continue nivolumab. 
− 
See Section 5.9.2.3 for supportive care. 
 
If worsens: 
− 
Treat as Grade (G) 2 or 3/4 
Diarrhea/Colitis Grade 2 
 
Diarrhea: 4-6 stools per day over 
baseline; IV fluids indicated <24 
hours (hrs); not interfering with ADL 
 
Colitis: abdominal pain; blood in 
stool 
 
Hold the dose of nivolumab 
 
See Section 5.9.2.3 for supportive care. 
 
If toxicity resolves to Grade ≤ 1 within 5 days resume therapy with 
study regimen 
 
If persists > 5-7 days or recur: 
− 
Resume study regimen per protocol once the toxicity returns to 
Grade ≤ 1 and when steroid taper (≥ 1 month*) is complete. (* See 
exception in Section 6.2.) 
 
Discontinue treatment if toxicity lasts for > 6 weeks or unable to 
initiate steroid taper within a 6 week period.  
 
If worsens or persists > 3-5 days with oral steroids: 
− 
Treat as Grade 3-4 
 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
City of Hope #: 16378  
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Toxicity 
Nivolumab Dose Management Guidelines 
Diarrhea/Colitis  Grade 3-4 
Diarrhea (G3): ≥7 stools per day over 
baseline; incontinence; IV fluids ≥24 
hrs; interfering with activities of 
daily living (ADL) 
 
Colitis (G3): severe abdominal pain, 
medical intervention indicated, 
peritoneal signs 
 
G4: life-threatening, perforation 
 
Discontinue study regimen 
 
See Section 5.9.2.3 for supportive care. 
 
 
Endocrinopathy 
Asymptomatic thyroid 
stimulating hormone (TSH) 
elevation 
 
Continue nivolumab per protocol 
 
See Section 5.9.2.4 for supportive care. 
Symptomatic 
endocrinopathy 
Symptomatic with abnormal lab/pituitary scan: 
 
Hold the dose of nivolumab  
 
See Section 5.9.2.4 for supportive care. 
 
If toxicity improves (with or without hormone replacement): 
− 
Resume therapy per protocol when steroid taper (≥ 1 month*) is 
complete. (* See exception in Section 6.2.) 
 
Discontinue treatment if toxicity lasts for > 6 weeks or unable to 
initiate steroid taper within a 6 week period.  
− 
Note: Grade 3 endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation 
 
Suspicion of adrenal 
crisis (e.g. severe dehydration, 
hypotension, shock out of 
proportion to current illness) 
 
Hold or discontinue nivolumab per investigator discretion  
− 
Note: Grade 4 endocrinopathy AEs, such as adrenal insufficiency, 
ACTH 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 and approval from the Study 
PI. 
 
See Section 5.9.2.4 for supportive care. 
 
If adrenal crisis was ruled out, then treat as above for Symptomatic 
Endocrinopathy. 
 
Neurological 
Grade 1  
Asymptomatic or mild symptoms; 
Intervention not indicated 
 
Continue nivolumab per protocol 
 
See Section 5.9.2.5 for supportive care. 
 
If worsens: 
− 
Treat as Grade 2 or 3-4 

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Toxicity 
Nivolumab Dose Management Guidelines 
Grade 2  
Moderate symptoms; Limiting 
instrumental ADL 
 
Hold the nivolumab dose 
 
See Section 5.9.2.5 for supportive care. 
 
Resume therapy per protocol once the toxicity returns to Grade ≤ 1 
and when steroid taper (≥ 1 month*) is complete. (* See exception in 
Section 6.2.) 
 
Discontinue treatment if toxicity lasts for > 6 weeks or unable to 
initiate steroid taper within a 6 week period.  
 
If worsens: 
− 
Treat as Grade 3-4 
 
Grade 3-4  
G3:Severe symptoms; Limiting self-
care ADL 
  
G4:Life-threatening consequences; 
urgent intervention indicated 
 
Discontinue nivolumab 
 
See Section 5.9.2.5 for supportive care. 
 
Pulmonary 
Pulmonary Grade 1 
Radiographic changes only 
 
Consider holding nivolumab 
 
See Section 5.9.2.6 for supportive care. 
Pulmonary Grade 2 
Mild to moderate new 
symptoms 
 
Hold nivolumab  
 
See Section 5.9.2.6 for supportive care. 
 
Resume therapy per protocol once the toxicity returns to Grade ≤ 1 
and when steroid taper (≥ 1 month*) is complete. (* See exception in 
Section 6.2.) 
 
 
Discontinue treatment if toxicity lasts for > 6 weeks or unable to 
initiate steroid taper within a 6 week period.  
 
If not improving after 2 weeks or worsening: 
− 
Treat as Grade 3-4 
 
Pulmonary Grade 3-4 
Severe new symptoms; New or 
worsening hypoxia; Life-threatening 
 
Discontinue nivolumab  
 
See Section 5.9.2.6 for supportive care. 
Skin 
Skin Grade 1-2 
Covering ≤ 30% body surface area 
(BSA) (refer to CTCAE v4.0 for term 
specific criteria) 
 
Continue nivolumab per protocol 
− 
Note: Subjects who have not experienced a Grade 3 drug-related 
skin AE may resume treatment in the presence of Grade 2 skin 
toxicity. 
 
See Section 5.9.2.7 for supportive care. 
 
If persists > 1-2 weeks or recurs: 
− 
Hold nivolumab 
− 
Once improving , taper steroids over at least 1 month*, and 
resume study regimen per protocol. (* See exception in Section 
6.2.) 
 
If worsens: 
− 
Treat as Grade 3-4 
 
 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
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Toxicity 
Nivolumab Dose Management Guidelines 
Skin Grade 3 
Covering >30% BSA; Life threatening 
consequences (refer to CTCAE v4.0 
for term specific criteria) 
 
Hold nivolumab  
 
See Section 5.9.2.7 for supportive care. 
 
Resume study regimen per protocol once toxicity returns to Grade ≤ 1 
and when steroid taper (≥ 1 month*) is complete. (* See exception in 
Section 6.2.) 
 
Discontinue treatment if toxicity lasts for > 6 weeks or unable to 
initiate steroid taper within a 6 week period.  
 
Skin: Grade 4 
(refer to CTCAE v4.0 for term specific 
criteria) 
 
Discontinue nivolumab 
 
See Section 5.9.2.7 for supportive care. 
Fatigue 
Grade 2  
Continue nivolumab per protocol 
Grade 3 
 
Hold study agents  
 
Resume study regimen per protocol once toxicity returns to Grade ≤ 2 
 
Discontinue treatment if toxicity lasts for > 6 weeks  
 
Grade 4 
Discontinue nivolumab 
Amylase or Lipase elevation 
Grade 2 
Continue nivolumab per protocol 
 
Lipase or amylase Grade 3  
Asymptomatic or not associated 
with clinical manifestations of 
pancreatitis 
 
Continue nivolumab per protocol 
 
Consult the Study PI  
Isolated Grade 4 amylase or lipase 
Asymptomatic or not associated 
with clinical manifestations of 
pancreatitis 
 
Delay the dose of nivolumab until resolution to < Grade 2 
 
Consult the Study PI 
 
If toxicity > 7 days from onset, discontinue therapy. 
 
Lipase or amylase Grade 4 
Symptomatic or associated with 
clinical manifestations of 
pancreatitis 
 
 
Discontinue nivolumab 
Laboratory abnormalities  
NOTE: Follow guidelines above for hematologic, hepatic (ALT, AST, total bilirubin), creatinine or amylase/lipase. 
Grade 2  
Continue nivolumab per protocol 
Grade 3 
 
Delay the dose of nivolumab until resolution to ≤ Grade 1 
 
Discontinue treatment if toxicity lasts for > 6 weeks 
Grade 4 
Discontinue nivolumab if not an isolated Grade 4 event and is associated 
with clinical sequelae and are not corrected with 
supplementation/appropriate management within 72 hours of their onset. 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
City of Hope #: 16378  
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Toxicity 
Nivolumab Dose Management Guidelines 
Immune-related (ir) AEs related to Nivolumab (Other than irAEs specified above) 
Note: See above sections for specific orientation regarding the following ir-related toxicities: eye related 
toxicities, ALT/AST/total bilirubin, creatinine, diarrhea/colitis, endocrinopathies, neurological, pulmonary, and 
skin.  
Grade 2  
 
Hold nivolumab dose 
 
Resume study regimen per protocol once toxicity returns to Grade ≤ 1 
or baseline and if applicable, when steroid taper (≥ 1 month*) is 
complete. (* See exception in Section 6.2.) 
 
Discontinue treatment if toxicity lasts for > 6 weeks or unable to 
initiate steroid taper within a 6 week period.  
 
Grade 3 or 4 
Discontinue nivolumab 
 
Non-hematologic non-immune related toxicities related to Nivolumab (except fatigue and laboratory 
abnormalities) 
Grade 2  
If persistent > 3 days despite supportive measures, delay the dose of 
nivolumab until resolution to ≤ Grade 1 or baseline 
Grade 3  
 
Delay the dose of nivolumab until resolution to ≤ Grade 1 or baseline 
 
Discontinue if toxicity lasts > 7 days. 
 
Grade 4 
Discontinue nivolumab 
Table 6.2.2 Dose modifications for brentuximab vedotin associated toxicity 
Toxicity 
Brentixumab vedotin Dose Management Guidelines 
Peripheral Neuropathy 
Grade 1 
Continue at same dose level 
Grade 2  
Reduce dose to 1.2 mg/kg and resume treatment 
Grade 3 
Withhold until toxicity resolves to ≤ Grade 2 or baseline, then resume treatment at 1.2 
mg/kg^ 
^ Dose reductions below 1.2 mg/kg are not allowed, and toxicities should be managed with dose 
delays. 
Grade 4 
Discontinue brentuximab vedotin 
Non-hematologic (except peripheral neuropathy) 
Grade 1 
Continue at same dose level 
Grade 2  
Continue at same dose level 
Grade 3  
Withhold dose until toxicity is ≤ Grade 2 or has returned to baseline, then resume treatment 
at the same dose level.  
− 
Note: Patients who develop Grade 3 or 4 electrolyte laboratory abnormalities may 
continue study treatment without interruption. 
Grade 4 
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 investigator a,b,c 
a. 
Dose reductions below 1.2 mg/kg are not allowed, and toxicities should be managed with 
dose delays. 
b. 
Patients who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study 
treatment without interruption. 
c. 
Treatment should be discontinued for patients who experience Grade 4 infusion-related 
reactions. See Section 5.9.2 for supportive care. 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
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Toxicity 
Brentixumab vedotin Dose Management Guidelines 
Hematologic 
Grades 1-3  
Continue at same dose level 
Grade 4 
 
Withhold until toxicity resolves to ≤ Grade 2 or baseline, then resume treatment at the 
same dose level. 
− 
 NOTE: Patients who develop Grade 3 or 4 lymphopenia may continue study 
treatment without interruption 
 
In case of grade 4 neutropenia, growth factor support should be instituted and a repeat 
blood draw to evaluate the grade of neutropenia should be performed within 3 days. 
 
Growth factor support (G-CSF or GMCSF) should be considered for subsequent cycles. If 
Grade 4 neutropenia recurs despite growth factor support, consider discontinuation or 
dose reduction to 1.2 mg/kg. 
 

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7.0 ADVERSE EVENT AND UNANTICIPATED PROBLEM REPORTING 
The authorized investigator will be responsible for determining the event name, assessing the severity 
(i.e., grade), expectedness, and attribution of all adverse events. 
7.1 Definitions 
o Adverse Event (AE) - [Modified from the definition of adverse event in 21 CFR 312.32] An adverse 
event is any untoward medical experience or change of an existing condition that occurs during 
or after protocol intervention, whether or not it is considered to be related to the protocol 
intervention.  
o Serious Adverse Event (SAE) [per 21 CFR 312.32] - defined as any expected or unexpected adverse 
events that result in any of the following outcomes: 
 
Death 
 
Is life-threatening experience (places the subject at immediate risk of death from the event 
as it occurred) 
 
Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of existing 
hospitalization 
 
A persistent or significant disability/incapacity 
 
A congenital anomaly/birth defect 
 
Secondary malignancy* 
 
Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the 
outcomes listed above (examples of such events include allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood dyscrasias of convulsions that 
do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse). 
*Modified from 21 CFR 312.32 
o Adverse Event Description and Grade 
 
The description and grading scales found in the most recent version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized to characterize AEs. AEs not 
covered by specific terminology listed should be reported with common medical terminology, 
and documented according to the grading scales provided in the CTCAE v 4.0. All appropriate 
treatment areas should have access to a copy of the CTCAE v. 4.0.  A copy can be downloaded 
from the NCI/ CTEP web site.  
o Unexpected Adverse Event – An adverse event is unexpected if it is not listed in the investigator’s 
brochure and/or package insert; is not listed at the specificity or severity that has been observed; 
is not consistent with the risk information described in the protocol and/or consent; is not an 
expected natural progression of any underlying disease, disorder, condition, or predisposed risk 
factor of the research participant experiencing the adverse event. Modified from 21 CFR 312.32 
(a) 
o Expected Adverse Event – An adverse event is expected if it does not meet the criteria for an 
unexpected event, OR is an expected natural progression of any underlying disease, disorder, 
condition, or predisposed risk factor of the research participant experiencing the adverse event. 
o Adverse Event Attribution- The following definitions will be used to determine the causality 
(attribution) of the event to the study agent(s) or study procedure. 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
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• 
Unrelated – The event is clearly related to other factors such as the participant’s clinical 
state, other therapeutic interventions, or concomitant medications administered to the 
participant. 
• 
Unlikely – The event is doubtfully related to the investigational agent(s). The event was 
most likely related to other factors such as the participant’s clinical state, other 
therapeutic interventions, or concomitant drugs. 
• 
Possible – The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the participant’s 
clinical state, other therapeutic interventions, or concomitant drugs. 
• 
Probable – The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event 
cannot be reasonably explained by other factors such as the participant’s clinical state, 
therapeutic interventions, or concomitant drugs. 
• 
Definite – The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be 
reasonably explained by other factors such as the participant’s condition, therapeutic 
interventions, or concomitant drugs, AND occurs immediately following study drug 
administration, improves upon stopping the drug, or reappears on re-exposure. 
 
o Unanticipated Problem (UP) – Any incident, experience, or outcome that meets all three of the 
following criteria: 
 
Unexpected (in terms of nature, severity, or frequency) given the following: a) the research 
procedures described in the protocol-related documents such as the IRB approved research 
protocol, informed consent document or Investigator Brochure (IB); and b) the characteristics 
of the subject population being studied; AND 
 
Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcomes may have been caused by 
the drugs, devices or procedures involved in the research); AND 
 
Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm) than previously known or recognized. 
7.2 Definition of Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with 
investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered 
a metastasis of the initial neoplasm.  
The investigator must immediately notify the Study PI/ DCC via an expedited report (see Section 7.8). 
7.3 Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product that is 
considered both excessive and medically important. All occurrences of overdose must be reported as an 
SAE to the Study PI/ DCC (see Section 7.8). 

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7.4 Pregnancy 
If, following initiation of protocol therapy, it is subsequently discovered that a participant is pregnant or 
may have been pregnant at the time of investigational product exposure, including during at least 6 half-
lives after product administration, the protocol therapy will be permanently discontinued in an 
appropriate manner (eg, dose tapering if necessary for subject safety). The investigator must immediately 
notify the Study PI/ DCC via an expedited report; the Study PI or designee will subsequently inform BMS 
(see Section 7.8). 
The Investigator should make every effort to follow the female participant until completion of the 
pregnancy per institutional policies, and should notify the Study PI/ DCC.  
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome 
and, where applicable, offspring information must be reported via an expedited report. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to the Study 
PI/DCC expeditiously; the Study PI or designee will subsequently inform BMS (see Section 7.8).  
7.5 Laboratory Test Abnormalities 
The following laboratory abnormalities should be documented and reported appropriately: 
o any laboratory test result that is clinically significant or meets the definition of an SAE 
o any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted 
o any laboratory abnormality that required the subject to receive specific corrective therapy. 
Potential drug induced liver injury requires an expedited report and should be reported as an Important 
medical event (see Section 7.8).  
7.6 Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, x rays, 
and any other potential safety assessments, whether or not these procedures are required by the 
protocol, should also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
requires an expedited report (see Section 7.8). 
7.7 Routine AE Reporting Guidelines 
Routine AE reporting will occur via data entry into the study eCRF.   
AEs reported through expedited processes (e.g., reported to the IRB, FDA, etc.) must also be reported in 
routine study data submissions. 
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or evaluation 
of a participant. (In order to prevent reporting bias, participants should not be questioned regarding the 
specific occurrence of one or more AEs.) 
All AEs will be recorded from the initiation of protocol therapy through the follow-up period. The highest 
grade for any toxicity plus Grade 3 or 4 event for the same toxicity (if not the highest grade) will be 
reported during each cycle and during the safety follow-up period. 

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AE information recorded in the CRF include: Attribution to protocol therapy, grade and seriousness. 
The collection of nonserious AE information should begin at initiation of protocol therapy up to a 
minimum of 100 days following the last dose of protocol therapy. Nonserious AEs should be followed to 
resolution or stabilization, or reported as SAEs if they become serious. Follow-up is also required for 
nonserious AEs that cause interruption or discontinuation of study drug and for those present at the end 
of study treatment as appropriate. 
7.8 Expedited AE Reporting Guidelines 
Each AE will be assessed to determine if it meets the criteria for expedited reporting. Adverse event 
reporting is to occur according to the site’s specific IRB guidelines, and as outlined in this Section.  
7.8.1 
Expedited Adverse Event Reporting to Local IRB 
Sites are to report to their local IRB per their site’s specific institutional and IRB guidelines.  As soon as 
possible, non-COH sites will provide to the DCC copies of the IRB submission and corresponding IRB 
response.   
7.8.2 
Expedited Adverse Event Reporting to DCC/ Study PI 
o Adverse events that meet the specified guidelines below are to be reported to the DCC and 
Study PI within the timelines and per the procedures in the sections that follow.  
o Report the following per Table 7.8.2 to the DCC /Study PI within 24 hours of being aware that 
the event met reporting criteria: 
Table 7.8.2 Expedited Reporting Guidelines 
Time point 
What to report expeditiously 
From the signing of the consent to 
study completion 
All unanticipated problems 
 
From time of signing of the consent 
to Day 1 of protocol therapy 
All SAEs related to protocol procedures  
From Day 1 of protocol therapy 
through (i) 30 days post-last dose 
visit AND (ii) 100 days post last dose 
visit or until initiation of a new 
anticancer therapy. 
  
 
All SAEs regardless of relationship to protocol therapy, study 
procedure, underlying disease or concomitant treatment. 
 
AEs that meet the definition of an unanticipated problem 
 
Potential drug induced liver injury  
 
Suspected transmission of an infectious agent (eg, pathogenic or 
nonpathogenic) via the study drug  
 
Secondary malignancy 
 
Pregnancy and lactation 
 
Overdose 
 
Grade 3/4 infusion reactions 
 
Discontinuation of protocol therapy due to unusual or unusually 
severe AE considered related to study agents. 
After the 100 days post last dose visit 
(i.e. follow-up) 
 
All SAEs that are considered possibly, probably, or definitely related 
to therapy. 
 
Pregnancy and lactation  (up to 7 months post last dose of 
nivolumab) 
Note: All reportable events will require follow up until stabilization or resolution per the agreement of the 
Study PI. 

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o Reportable adverse events must be followed until the event is resolved, stabilized, or determined 
to be irreversible by the investigator; for ongoing reportable AEs that are unrelated to protocol 
therapy, the follow-up period may end at the 100 days post-last dose of protocol therapy 
assessment. The DCC and Study PI should be consulted prior to ending the follow-up of events 
that have stabilized. 
7.8.3 
Expedited reporting to the DCC/Study PI – Non COH Sites 
1. Document/describe AE/UP on each of the following: 
a. MedWatch 3500A  or local IRB submission document* 
i. 
MedWatch 
3500A 
is 
downloadable 
form 
at  
http://www.fda.gov/medwatch/getforms.htm 
 
ii. 
*The local IRB submission document may be used if the document template is 
approved by the DCC 
b. Expedited Reporting Coversheet 
i. 
The Expedited Reporting Coversheet is found in Appendix G.  A modifiable Microsoft 
Word document is also available from the DCC.  An electronic signature on the 
document will be accepted. 
2. Scan and email above documents to DCC@coh.org with the subject title as “Herrera Nivolumab 
SAE”.   
a. All expedited reports received at this account are forwarded immediately to the Study PI, and 
to DCC personnel.  
b. While not required, if available and applicable, please also include the local IRB submission 
for this event in the submission.  
3. If an email receipt from DCC personnel is not received within one working day, please call (626)-
218-7904 and/or email DCC@coh.org. 
7.8.4 
Expedited reporting to the DCC/Study PI –COH Only 
1. Email the following information to DCC@coh.org and the Study PI. 
a. Participant ID, date the event met criteria for reporting, whether the event meets the 
definition of serious, whether the event is an unanticipated problem, grade of event, 
attribution of event, whether the event is a known expected toxicity to study agent. 
2. Complete the iRIS AE/UP reporting form per COH reporting timeline. 
7.9 Reporting of AE/UP by the Study PI 
The Study PI (or designee) will: 
o Report to COH IRB and DSMC all reportable AEs that meet COH IRB and DSMC reporting criteria 
and occur at non-COH sites according to City of Hope’s Institutional policy on reporting AE/UP and 
indicate whether or not a protocol and/or consent form change is required. 
o Report all expedited reportable AEs to participating investigators as an IND Safety Report 
occurring within 15 calendar days of receipt of sponsor (lead site) notification, and indicate 

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whether or not a protocol and/or consent form change is required.  A cover letter will indicate 
the protocol title, the IND#, whether the FDA was informed, and, for non-COH sites, a statement 
that the report should be submitted to their local IRB for review as an IND safety report if 
applicable per local IRB policy. 
o For IND Sponsor reporting purposes only: using a MedWatch 3500A form, report to the FDA, (via 
COH Office of IND Development and Regulatory Affairs (OIDRA)) regardless of the site of 
occurrence, any SAE that meets the FDA’s criteria for expedited reporting following the reporting 
requirements and timelines set by the FDA: 
Serious Adverse Events meeting the requirements for expedited reporting to the Food and Drug 
Administration (FDA), as defined in 21 CFR 312.32, will be reported as an IND safety report using 
the MedWatch Form FDA 3500A for Mandatory Reporting. 
The criteria that require reporting using the MedWatch 3500A are: 
- Any unexpected fatal or life threatening adverse experience associated with use of the 
drug must be reported to the FDA no later than 7 calendar days after initial receipt of the 
information [21 CFR 312.32(c)(2)] 
- Any adverse experience associated with use of the drug that is both serious and 
unexpected must be submitted no later than 15 calendar days after initial receipt of the 
information [21 CFR 312.32(c)(1)] 
- Any follow-up information to a study report shall be reported as soon as the relevant 
information becomes available. [21 CFR 312.32(d)(3)] 
The PI or designee will be responsible for contacting the Office of IND Development and 
Regulatory Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the FDA.  OIDRA 
will assist the PI with the preparation of the report and submit the report to the FDA in accordance 
with the approved City of Hope’s Institutional policy.  
o Report to Global Pharmacovigilance & Epidemiology at Bristol-Myers Squibb Company (BMS), 
regardless of the site of occurrence, any expedited AEs within 24 hours of being aware of the 
event via email or facsimile. On all correspondence to BMS also include the BMS protocol ID: 
CA209-878. 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  609-818-3804 
 
The initial report will be as complete as possible and include an assessment of the causal 
relationship between the event and the study agent(s).  Information not available at the time 
of the initial report will be documented on a follow-up report. 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report. 
 
All pregnancy related events, including pregnancy that occurs in a female partner of a male 
study participant perinatal and neonatal outcome and, where applicable, offspring 
information will be submitted on the BMS Pregnancy Surveillance Form [provided upon 
request from BMS] 
o Submit annually within 60 days (via COH OIDRA) of the anniversary date of when the IND went 
into effect, an annual report to the FDA which is to include a narrative summary and analysis of 
the information of all FDA reports within the reporting interval, a summary report adverse drug 
experiences, history of actions taken since the last report because of adverse drug experiences. 

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o Report every 3 months to the COH DSMC a Protocol Management Team (PMT) report, to include 
aggregate analysis of safety information, accrual and participant status. 
o Circulate to all participating sites for submission to their IRBs the COH DSMC report and DSMC 
recommendation, in accordance with NIH guidance. 
o Report to BMS aggregate safety information (including nonserious events) at time of COH PMT 
report. 
o Report all reportable serious adverse events to participating investigators as an IND Safety Report 
occurring within 30 calendar days of receipt of sponsor (lead site) notification, and indicate 
whether or not a protocol and/or consent form change is required.  A cover letter will indicate 
the protocol title, the IND#, whether the FDA was informed, and, for non-COH sites, a statement 
that the report should be submitted to their local IRB for review as an IND safety report if 
applicable per local IRB policy. 
o Forward to participating sites all safety reports received from BMS for nivolumab, that have not 
occurred directly on this protocol, indicating whether a consent form or protocol change is 
required within 30 calendar days of notification to Study PI. 

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8.0 AGENT INFORMATION 
8.1 Nivolumab 
Nivolumab has been FDA approved for the treatment of patients with classical HL that has relapsed or 
progressed after ASCT and post-transplantation brentuximab vedotin.  
Additionally nivolumab is approved for: 
o Patients with unresectable or metastatic melanoma and disease progression following 
ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor 
o Patients with advanced (metastatic) squamous non-small cell lung cancer (NSCLC) with 
progression on or after platinum-based chemotherapy 
For additional information refer to the IB.  
8.1.1 
Other Names 
BMS-936558-01, MDX1106, ONO-4538, anti-PD-1, OPDIVOTM. 
8.1.2 
Description  
Type 
IgG4 monoclonal 
Source: 
Human 
Target: 
PD-1 
Molecular weight:  146 kDa 
8.1.3 
Mechanism of Action 
Nivolumab blocks the interaction between human PD-1 receptor and its ligands (PD-L1 and PD-L2). This 
promotes immune responses and antigen specific T-cell responses to both foreign and self-antigens.  
8.1.4 
Pharmacokinetics 
Half-life: 
~26 days 
Steady state clearance (CLss): 
8.2 mL/h 
Volume of distribution (Vss): 
6.8 L 
Steady-state concentration: 
~ 12 weeks when 3 mg/kg is administered every 14 days 
8.1.5 
Human Toxicity 
See Section 6.1.2. 

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8.1.6 
Formulation  
8.1.7 
Storage  
o Injection 100 mg/10 mL: Vials for nivolumab injection must be stored at 2-8oC and protected 
from light and freezing. If stored in a glass front refrigerator, vials should be stored in the carton. 
Recommended safety measures for preparation and handling of nivolumab include laboratory 
coats and gloves. 
o Undiluted and Diluted Injection in the IV Container: The administration of nivolumab infusion 
must be completed within 24 hours of preparation. If not used immediately, the infusion 
solution may be stored under refrigeration conditions (2-8 oC) for up to 24 hours, and a 
maximum of 4 hours of the total 24 hours can be at room temperature (20-25 oC) and room 
light. The maximum 4-hour period under room temperature and room light conditions includes 
the product administration period. 
For additional details on prepared drug storage and use time of nivolumab under room 
temperature/light and refrigeration, please refer to the BMS-936558 (nivolumab) Investigator 
Brochure section for “Recommended Storage and Use Conditions” 
8.1.8 
Handling and Dispensing 
The investigator should ensure that the study drug is stored in accordance with the environmental 
conditions (temperature, light, and humidity) as per product information and the Investigator Brochure 
and per local regulations. It is the responsibility of the investigator to ensure that investigational product 
is only dispensed to study subjects.  
The investigational product must be dispensed only from official study sites by authorized personnel 
according to local regulations.  
If concerns regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately. 
8.1.9 
Preparation and Administration 
Please refer to the most recent investigator’s brochure for nivolumab. 
Do not administer nivolumab as an IV push or bolus injection. 
For additional administration details refer to Section 5.4.2. 
8.1.10 Supplier 
The investigational agent will be supplied free of charge by Bristol-Myers Squibb Company. 
Product Description and Dosage 
Form 
Potency 
Primary 
Packaging 
(Volume)/ 
Label Type 
Appearance 
Nivolumab (BMS-936558-01)* 
Injection drug product is a sterile, 
non-pyrogenic, single-use, isotonic 
aqueous solution formulated at 10 
mg/mL   
100 
mg/Vial 
(10 
mg/mL). 
Carton of 5 
or 10 vials 
 
Clear to opalescent, colorless to pale 
yellow liquid.  May contain particles 
* Nivolumab may be  labeled as BMS-936558-01 Solution for Injection 

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8.1.11 Ordering 
o Initial Orders  
Following submission and approval of the required regulatory documents, a supply of nivolumab 
may be ordered from by completing a Drug Request Form provided by BMS for this specific trial. 
The first request may take place upon screening of the first patient  
The initial order should be limited to 20 vials. Allow 5 business days for shipment of drug from 
BMS receipt of the Drug Request Form. Drug is protocol specific, but not patient specific. All drug 
product will be shipped by courier in a temperature-controlled container. It is possible that sites 
may have more than one nivolumab clinical study ongoing at the same time.  
It is imperative that only drug product designated for this protocol number be used for this 
study. 
Pharmacy supplies not provided by BMS:  Empty IV bags/containers, approved diluents, In-line 
filters and infusion tubing 
o Re-Supply 
 
Drug re-supply request form should be submitted electronically business days before 
the expected delivery date.  Deliveries will be made Tuesday through Friday. 
 
When assessing need for resupply, institutions should keep in mind the number of vials 
used per treatment dose, and that shipments may take 14 business days from receipt of 
request. Drug is not patient-specific. Be sure to check with your pharmacy regarding 
existing investigational stock to assure optimal use of drug on hand. 
8.1.12 Drug Excursions 
Drug excursions should be reported immediately to BMS on the form provided with the study-specific 
drug order form. 
8.1.13 Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the inventory and disposition of the agent (investigational or free of charge) using a drug accountability 
log. 
8.1.14 Destruction and Return 
The investigator is responsible for keeping accurate records of the clinical supplies received from Bristol-
Myers Squibb Company or designee, the amount dispensed to participants, and the amount remaining at 
the conclusion of the trial.  
Any unused agent at the end of the study, expired agent, and damaged agent will be destroyed according 
to applicable federal, state, local and institutional guidelines and procedures.  
Prior to the destruction of nivolumab, the DCC should be notified and an acknowledgement to proceed 
from the DCC should be received.  
Destruction will be documented in a drug accountability log. 
8.2 Brentuximab vedotin 
Please refer to the package insert for a detailed description. Brentuximab vedotin has been FDA approved 
for the treatment of patients with classical HL after failure of autologous hematopoietic stem cell 

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transplantation (auto-HSCT), after failure of at least 2 prior multi-agent chemotherapy regimens in 
patients who are not auto-HSCT candidates, and treatment of patients with classical HL at high risk of 
relapse or progression as post-auto-HSCT consolidation. 
8.2.1 
Other Names 
ADCETRIS® 
8.2.2 
Description  
Structural Formula: 
Empirical Formula: 
C6476H9930N1690O2030S40 (C68H105N11O15)3–5 

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Type: 
Antibody-drug conjugate (ADC).  
The chimeric monoclonal IgG1 antibody cAC10 is covalently linked to the 
monomethyl auristatin E (MMAE) via a protease-cleavable linker.  
About 4 molecules of MMAE are attached to each antibody molecule. 
Source: 
Mouse-human chimera 
Target: 
CD30 
Molecular weight:  153 kDa 
8.2.3 
Mechanism of Action 
Brentuximab vedotin targets the cell surface receptor CD30 which is expressed in Hodgkin’s lymphoma 
(HL). Nonclinical data suggest that the binding of the ADC to CD30-expressing cells leads to the 
internalization of the ADC-CD30 complex. Proteolytic cleavage of ADC within the cell results in the release 
of the MMAE. Free MMAE binds to the microtubule network and subsequently leads to cell cycle arrest 
and apoptosis. 
8.2.4 
Pharmacokinetics 
MMAE Tmax: 
1 to 3 days 
MMAE Steady-State  21 days with every 3-week dosing  
ADC Vd: 
6 to 10 L 
MMAE protein binding: 
68-82% 
MMAE Metabolism: 
Metabolized via CYP3A4/5; inhibits CYP3A4/5 
MMAE Excretion: 
renal excretion up to 24% and in feces 72% 
ADC Elimination half-life: 
4-6 days 
8.2.5 
Human Toxicity 
See Section 6.1.1. 
8.2.6 
Formulation 
For injection: 50 mg of brentuximab vedotin will be supplied as sterile, white to off-white lyophilized, 
preservative-free cake or powder in a single-use vial for reconstitution. 
8.2.7 
Storage 
Store at 2-8°C in the original carton to protect from light. DO NOT FREEZE. 
8.2.8 
Handling  
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the 
environment, should undertake the preparation, handling, and safe disposal of the agent. 
8.2.9 
Preparation  
Follow package label instructions for reconstituting the lyophilized powder and diluting into 0.9% Sodium 
Chloride Injection, 5% Dextrose Injection or Lactated Ringer’s Injection for infusion. 
8.2.10 Dose and Administration 
Administer brentuximab vedotin as an intravenous infusion only over 30 minutes. 
Do not mix brentuximab vedotin with, or administer as an infusion with, other medicinal products.  

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See Section 5.4.1 for dosing and additional administration guidelines. 
8.2.11 Supplier 
Brentuximab vedotin is available commercially. 
9.0  CORRELATIVE & SPECIAL STUDIES 
9.1 Correlative Study Plan 
The correlative analyses that will be performed as part of this clinical trial are exploratory and intended 
to generate hypotheses that can be validated in a larger study. The list of correlative studies below is not 
meant to be exhaustive, as it is anticipated that the exact nature and type of correlative studies may 
change as new scientific data emerges during the course of the study. 
Table 9.1 Correlative Study Plan 
Tissue type 
Planned correlative anlysis 
Tumor tissue 
 
FISH of the 9p24.1 region will be performed by the COH Cytogenetics Core Laboratory 
in HL tumor samples to assess the relationship between 9p24.1 abnormalities and 
outcome after study therapy. 
 
Gene expression profiling of HL tumor specimens to determine whether there are 
profiles associated with outcome after study therapy. 
 
Quantitative spatial image analysis of immune and tumor cells in tumor samples via 8-
color histology using the Vectra system to assess the presence of and spatial 
relationships between tumor infiltrating lymphocytes/immune cell populations (e.g., 
CD8+ T-cells, tumor-associated macrophages) and immune checkpoint 
ligands/receptors (e.g., PD-L1). 
Blood 
 
Peripheral blood flow cytometry of immune cell subsets (including PD-L1 and PD-L2 
bearing lymphocytes) at baseline, during treatment, and at 12 and 18 months after 
ASCT to determine the impact of study therapy on post-ASCT immune reconstitution 
 
Next-generation sequencing-based minimal residual disease (MRD) assessment using 
the Adaptive Biotechnologies ClonoSEQ assay (previously Sequenta, Inc LymphoSIGHT 
assay), which is able to detect MRD in the peripheral blood of patients with HL[36]. 
We will assess MRD at baseline, during treatment, and at 12 and 18 months after 
ASCT. These sequential samples will allow us to track the temporal dynamics of MRD 
after brentuximab vedotin plus nivolumab consolidation therapy, and to determine 
whether study therapy can eradicate MRD in patients who are MRD+ after ASCT 
 
9.2 Tumor Tissue Studies 
9.2.1 
Timepoints of Collection 
1. Baseline tissue: Archival tissue from pre-ASCT tumor biopsies will be retrieved and 
submitted post-enrollment. Preferred time point: Post-relapse biopsy or biopsy performed 
to confirm refractory disease after first-line therapy but if this is not available the diagnostic 
biopsy will be used instead.   

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 NOTE: If unavailable, exceptions may be granted with Study PI approval. 
 
2. From participants who progress/ relapse during study (strongly encouraged, but not 
mandatory): If safe and feasible, submission of a tumor lesion core or excisional.  
9.2.2 
Guidelines for archival specimens  
Using the formalin-fixed paraffin embedded (FFPE) tissue block, the following samples will be processed 
for correlative studies:  
o If tissue block is available submit: 
 
6 paraffin scrolls measuring 10 µm thick placed into a Nunc tube and frozen at -80° C 
AND 
 
10 x 5 micron unstained slides 
o If tissue block is unavailable submit 20 x 5 µm unstained slides 
9.2.3 
Guidelines for fresh tumor tissue processing  
9.2.3.1 Non-COH sites 
Tumor lesion core or excisional biopsies should be flash frozen and kept at -80 oC until batch shipment. 
9.2.3.2 COH only 
Three core biopsies OR excisional biopsies should be submitted. If fewer than 3 core biopsies are available 
because of safety, then 1 or 2 cores may be submitted. 
Core biopsies:  
o Three core biopsies will be obtained for diagnostic purposes and 3 similar additional cores will 
be obtained for research.  
1. One core biopsy will snap frozen in OCT fixative, and an additional half of a core will be snap 
frozen without OCT fixative.  
2. Half of a core will be finely minced in a 10cm petri dish and frozen at -80° C in a Nunc tube in 
1 ml of RPMI-1640 medium containing 20% fetal calf serum and 10% DMSO, then will be 
transferred to liquid nitrogen.  
3. Half of a core will be processed for DNA and RNA extraction according to the manufacturer’s 
recommendation.  
4. The final half of a core biopsy will be processed to dissociate the cells, with the cell 
suspension cryopreserved in liquid nitrogen. 
For excisional biopsies:   
o An approximately 1cm x 1cm tumor sample will be divided into 5 equal portions and processed 
as described for core biopsies. 
The diagnostic portion of the specimen:  
o Process in a routine fashion by hematopathology. Using the formalin-fixed paraffin embedded 
(FFPE) tissue block, 15 x 5 micron unstained slides will be obtained 

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9.2.4 
Labeling of samples 
Samples will labeled with the study number, institution (for non-COH sites), subject ID (issued by COH), 
date, timepoint of collection (i.e. baseline or progression) and if applicable patient initials.  
9.2.5 
Sample shipment and receiving lab 
Tissue specimens collected at the above indicated timepoints will either be taken to (COH only) or batch-
shipped (non-COH sites) to COH Pathology Core. For all sites, please include the Correlative Tissue form 
(Appendix I) with your shipment. 
Please note that samples should be batch shipped from non-COH sites on Monday to Wednesday in time 
for receipt Tuesday to Friday. Refer to Appendix C for shipping details.  

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9.3 Blood samples 
Table 9.3 provides an overview of correlative blood studies. 
Table 9.3 Overview of correlative blood studies 
Timepoint of collection 
Total 
volume 
per 
timepoint  
Tube Type 
Processing/ 
Receiving 
Laboratory 
Type of Laboratory 
Analysis 
Timepoints for all blood studies except where noted: 
 Cycle 1 Day 1 (baseline) 
 Green-top ONLY: Cycle 2 Day 1  
 Cycle 5 Day 1 (OR 3 months^ if off treatment but yet to 
progress), 
 30 days post last dose visit   
 6 months^ if off treatment but yet to progress  
 12 month from start of treatment follow up visit (if yet to 
progress)  
 18 month from start of treatment follow up visit (if yet to 
progress) 
 
~20 mL 
Green-top 
(sodium or lithium 
heparin) 
 
Analytical 
Pharmacology 
Core Facility 
(APCF) at COH 
Dr. Peter Lee/ Dr. 
Tim Synold (COH) 
 
PBMC isolation 
to assess 
immune 
reconstitution 
 
Plasma for 
cytokine 
analysis 
~20 mL 
COH only:  
Purple-top 
(K+EDTA) 
APCF at COH 
Minimal residual 
disease (MRD) 
assessment using 
next-generation 
sequencing (NGS)  
~20 mL 
 
Non-COH:  
Cell-free BCT® DNA 
tubes 
 
 
^ Collect during Active Follow-up assessment visit(s) if received < 8 cycles of therapy 
 
 
 
Whole blood will be separated into peripheral blood mononuclear cells (PBMCs) and plasma and subjected to NGS for 
ctDNA assessment. ctDNA will be measured in the plasma fraction and PBMCs will provide germline sequences. Samples 
will be shipped to and NGS/ctDNA assessment performed in collaboration with Dr. Margaret Shipp at the Dana-Farber 
Cancer Institute. 

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9.3.1 
Notification to APCF, Blood sample collection and Labeling 
Notification to COH 
APCF of Pending 
Collection 
Site 
Tube 
Type 
Labeling and Collection Details 
Post-collection 
Instructions 
 Notify at least one 
day in advance) 
 Send calendar 
invite via e-mail: 
Leslie Smith-Powell 
(LSmith-
Powell@coh.org) or 
Stephanie Lee 
(stlee@coh.org) 
COH  
 Green-
top  
 Purple-
top 
1. 
Label tubes with COH protocol #, subject ID (issued by DCC), 
institution (for non-COH sites), date and timepoint of collection (e.g. 
D1C1 for Day1 of Cycle 1), and if applicable patient initials. 
2. 
Timepoints of collection are stated in Table 9.3. 
3. 
Blood samples will be collected from an indwelling venous catheter 
or by venipuncture  
4. 
Invert tubes eight times after collection.  
5. 
Immediately place the tubes on ice. 
 
Promptly deliver the 
blood samples on ice to 
the APCF, Shapiro room 
1042 for processing 
within 4 hours. 
Non-
COH 
Green- 
top 
 Peripheral blood 
samples will be 
shipped overnight at 
~+4oC to APCF 
laboratory. 
 Include with 
shipment: 
- Blood sample 
collection form 
(Appendix D) 
- Copy of the latest 
CBC results (with 
differential) and 
the date of the test 
Non-
COH 
Cell free 
DNA 
BCT® 
tubes 
1. 
Label tubes with COH protocol #, subject ID, institution (for non-
COH sites), date and timepoint of collection (e.g. D1C1 for Day1 of 
Cycle 1), and if applicable patient initials. 
2. 
Timepoints of collection are stated in Table 9.3. 
3. 
Fill in sample collection form in Appendix D. 
4. 
If applicable, follow recommendations for order of draw outlined in 
Clinical and Laboratory Standards Institute (CLSI) H3-A6. 
a. 
BCT® tubes may not be drawn immediately following a 
heparin tube; if necessary collect a non-additive or EDTA tube 
as “waste tube” prior to collection in the BCT® tube. 
5. 
Blood samples will be collected from an indwelling venous catheter 
or by venipuncture.  
6. 
Below guidelines to avoid possible backflow from the tube should 
be followed since BCT® tubes contain a formaldehyde-free 
preservative: 
a. 
Keep patient’s arm in the downward position during collection. 
b. 
Hold the tube with the stopper in the uppermost position so 
that the tube contents do not touch the stopper or the end of 
the needle during sample collection. 
c. 
Release tourniquet once blood starts to flow in the tube, or 
within 2 minutes of aapplication. 
7. 
Completely fill the tube. 
8. 
Remove tube from adapter and immediately invert the tubes 8 to 
10 times.  
9. 
DO NOT FREEZE samples. Store samples at 18-25 oC until shipment. 
See Appendix E for 
shipment details. 

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9.3.2 
Sample Processing by APCF 
 
COH samples only: Blood samples will be kept on a rocker set at low speed to mimic circulation and avoid 
clot formation until processing.  
Tube Type 
and 
Volume 
Processing Details 
Downstream 
assay 
Green-top  
(~20 mL) 
Plasma 
1. Centrifuge for 10 minutes at 1800 x g at 4 oC.  
2. The resulting upper plasma layer from each tube will be drawn 
up sequentially into a sterile 5 mL syringe and pushed through a 
sterile 0.2/0.8 micron disposable filter.  
a. Save the plasma-depleted portion for isolation of PBMC. 
3. The filtered plasma will then be transferred in 500 µL aliquots 
into multiple appropriately-labeled Starstedt microfuge tubes.  
4. To one aliquot, add 0.5 mL glycerol/0.02% sodium azide solution 
to dilute the plasma 50/50 v/v. Keep the diluted plasma sample 
at -20˚C and do not freeze.  
5. All the remaining plasma aliquots will be stored frozen at -80˚C 
until use. 
Cytokine 
analysis 
Peripheral 
blood 
mononuclear 
cells (PBMC) 
6. Any blood remaining in the two green-top tubes used to prepare 
plasma above will be diluted 1:1 with Hank’s Balanced Salt 
Solution (HBSS)  in a sterile 50 mL  conical centrifuge tube. 
7. PBMC will then be isolated from the combined whole blood 
sample by Ficoll-gradient per COH APCF procedures. 
8. Isolated PBMC will be stored in liquid nitrogen until use.   
FACS 

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Tube Type 
and 
Volume 
Processing Details 
Downstream 
assay 
Purple-top 
(~10 mL) 
Plasma and 
Plasma 
depleted 
whole blood 
cells (PDWB) 
1. Centrifuge for 10 minutes at 1800 x g at 4 oC.  
2. Remove the tubes from the centrifuge. Do not disturb the 
cellular layer.  
3. Extract plasma carefully. 
a. Do not disturb the buffy coat while pipetting plasma; leave 
~3-4mm of plasma behind to ensure the buffy coat is 
undisturbed.  
4. Freeze plasma at -80°C in 1-2mL aliquots.  Do not fill tubes 
beyond 70% capacity.   
Sequencing-
cell free 
circulating 
tumor DNA 
and germline 
DNA 
5. Mix the remaining PDWB.  
6. Freeze PDWB at -80°C in 1-2mL aliquots.  
Purple-top 
(~10 mL) 
PBMC 
1. Dilute whole blood with 1:1 with Hank’s Balanced Salt Solution 
(HBSS)  in a sterile 50 mL conical centrifuge tube. 
2. PBMC will then be isolated from the combined whole blood 
sample by Ficoll-gradient per COH APCF procedures. 
3. Isolated PBMC will be stored at -80°C until use.   
 
Sequencing 
Cell free 
DNA BCT®  
(~10 mL) 
Plasma and 
Plasma 
depleted 
whole blood 
cells (PDWB) 
1. Centrifuge for 10 minutes at 1600 x g at room temperature. 
2. Remove the upper plasma layer and transfer to a new conical 
tube.  
a. Save the PDWB portion (see below). 
3. Centrifuge the plasma at 16000 x g for 10 minutes.  
4. Collect the plasma. 
5. Freeze plasma at -80°C in 1-2mL aliquots.  Do not fill tubes 
beyond 70% capacity.  
Sequencing-
cell free 
circulating 
tumor DNA 
and germline 
DNA 
6. Mix the remaining PDWB.  
7. Freeze at -80°C in 1-2mL aliquots. 
Cell free 
DNA BCT®  
(~10 mL) 
PBMC 
1. Dilute whole blood with 1:1 with Hank’s Balanced Salt Solution 
(HBSS)  in a sterile 50 mL conical centrifuge tube. 
2. PBMC will then be isolated from the combined whole blood 
sample by Ficoll-gradient per COH APCF procedures. 
3. Isolated PBMC will be stored at -80°C until use.   
 
Sequencing 
   

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10.0 STUDY CALENDAR 
All procedures may increase in frequency if clinically indicated. 
Table 10.0 Study Activity Calendar  
 
 
 
Safety visits may be combined with Active Follow-
up visits if the windows for the two visits overlap  
 
Protocol Activity 
Screeninga 
Protocol Therapy b,c 
Safety Visitsi 
 
 
Time from last 
dose 
 Active Follow-up  h,i 
Long-term Follow-upl 
Cycle 
1 
Cycle  
2 
Cycle 
3 
Cycles  
4-7 
Cycle 
8  
 
 
Time from start of 
treatment 
D1 d,e 
D1e 
D1e 
D1e 
D1e 
30 days f 
100 days g 
3 months j 
6 monthsk 
12 months 
18 months 
Informed consent m 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility n 
X 
 
 
 
 
 
 
 
 
 
 
Registration o 
X 
 
 
 
 
 
 
 
 
 
 
Medical history p 
X 
 
 
 
 
 
 
 
 
 
 
Physical exam q 
X 
X 
X 
X 
X 
X  
X 
 
 
 
Vital signs r 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECOG status (Appx. A) 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Con-meds s 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse Events t 
X t 
---------------------------------------X u----------------------------------------- 
 
 
 
Pregnancyv 
Xw 
Xd 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
Pulmonary x 
X 
 
 
 
 
 
 
 
 
 
Thyroid y 
Xw 
 
 
X 
C6 only 
 
X 
 
 
 
 
CBC w/diff, plts 
Xw 
X 
X 
X 
X 
X 
X 
 
 
 
Serum chemistry z 
Xw 
X 
X 
X 
X 
X 
X 
 
 
 
Amylase, lipase 
Xw 
X 
X 
X 
X 
X 
X 
 
 
 
Immunoprofiling blood aa 
 
X 
X 
 
C5 only 
 
X 
 
X 
X 
 
MRD blood aa 
 
X 
 
 
C5 only 
 
X 
 
X 
X 
 
Tumor tissue 
Xbb 
 
 
 
 
 
---------------------------Xcc---------------------------- 
CT dd  
X dd 
 
 
 
C4 D15 ee,gg 
 
X ee,hh 
 
Xee 
X ee 
Xee,ii 
 
PET-CT dd 
X dd 
 
 
 
C4 D15 ee,gg 
 
X ee,hh 
 
Xee 
X ee 
Xee,ii 
 
Response ff 
 
 
 
 
C4 D15 gg 
 
X 
 
X 
X 
 
Nivolumab jj 
 
X 
D1 of  each cycle 
 
 
 
 
Brentuximab vedotinjj 
 
X 
D1 of  each cycle 
 
 
 
 
Long-terml 
 
 
 
 
 
 
 
 
 
X 
 

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a. Screening can initiate 21 days post-ASCT. Screening evaluations will be performed within 28 days from Day 1 of protocol 
therapy (including cardiac and pulmonary function tests), except laboratory assessments to be performed within 14 days 
prior to Day 1 of protocol therapy. 
b. Protocol therapy must initiate within 30-60 days post-ASCT. Study PI can grant exception for a patient to start as late as 
75 days post-ASCT with a reasonable justification for delay (e.g. recovery from post-ASCT toxicity) and this will not be a 
protocol deviation, nor require an exception to be filed. Protocol therapy may last up to 8 cycles (~ 6 months), until 
unacceptable toxicity or disease progression (see Section 5.6 for more comprehensive list).  
c. 
In the absence of treatment delay, each treatment cycle lasts 21 days ± 3 days.  
d. Day 1 of Cycle 1 is defined as the day of first administration of brentuximab vedotin. Screening evaluations performed 
within 14 days prior to start of protocol therapy may serve as Day 1 baseline evaluations, except for pregnancy test which 
must be performed within 24 hours prior to Day 1 of protocol therapy. 
e. Activities (except imaging and response assessment) and safety assessment review to be performed within 72 hours prior 
to initiation of the new cycle.  
f. 
The 30 days post-last dose assessments to occur 30 (-2/+7) days post-last dose or, if > 30 days elapsed since last dose, 
within 7 days after decision to end treatment. Expedited reporting will occur during this period (see Section 7.8). 
g. The 100 days post-last dose assessments to occur 100 (-7/+28) days post-last dose or at initiation of a new anticancer 
therapy. Expedited reporting will occur during this period (see Section 7.8). Safety follow-up may be extended until 
resolution/ stabilization of reportable AEs.  
h. For participants who ended protocol therapy and have yet to progress/relapse, Active follow-up visit to occur at 3 months 
(± 14 days), 6 months (± 14 days), 12 months (± 28 days) and 18 months (± 28 days) from start of treatment until 
progression or initiation of new anticancer therapy.  
i. 
The Safety assessments/activities may be joint with Active Follow-up assessments/activities if the windows for the two 
visits overlap. 
j. 
The 3 month Active Follow-up activities to occur if the participant ended protocol therapy prior to the Cycle 4 Day 15 
scan. 
k. 
The 6 month Active Follow-up activities to occur if the participant ended protocol therapy prior to Cycle 8. 
l. 
Long-term follow-up for those for all participants who have progressed/relapsed OR completed Active Response Follow-
Up. Assessment to occur biannually or as requested by the Study PI via medical record review, review of social security 
registry/ public records, and/or telephone call. 
m. Informed consent process to be fully documented (see Section 16.4). Informed consent must occur prior to any research 
only (non-SOC) screening procedures.  
n. Eligibility criteria are detailed in Section 3.0.  
 
o. Registration in a COH clinical trial management system (CTMS). 
p. Medical history to include a review of treatment history, any ongoing medical conditions and medical history pertaining 
to eligibility on study and involvement during study.  
q. Standard physical exam with skin analysis.  
r. 
Vital signs:  Weight, heart rate, temperature, respiratory rate, blood pressure and oxygen saturation.  Height will be 
measured at screening only. 
s. 
Concomitant medications: All medications taken within 28 days of start of protocol therapy should be recorded in source 
documents. All concomitant medications and blood products administered or changed during the patient’s participation 
in the study until the Safety follow up visit and the reason for administration must be recorded in the source documents 
and in eCRFs. See Section 5.9 for restrictions and guidelines.  
t. 
Adverse events (AE) will be assessed using CTCAE v.4.0. SAEs related to study procedures will be recorded and reported 
from time of informed consent until Day 1 of protocol therapy.  
u. AE recording and reporting will continue until the completion of the Safety follow-up or until resolution or stabilization of 
any reportable AEs during Safety follow-up. 
v. 
Serum or urine pregnancy test for WOCBP. 

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w. Laboratory assessments (pregnancy, thyroid, blood counts, serum chemistry and amylase/lipase) to be performed within 
14 days prior to start of protocol therapy. 
x. 
Pulmonary function tests to include spirometry, lung volume measurements and diffusion capacity measurement. 
y. 
Thyroid stimulating hormone (TSH) and free T4 at baseline, and Day 1 of Cycles 3 and 6.  
z. 
Chemistry panel to include: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, LDH, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, uric acid, and phosphorus. 
aa. Correlative blood will be collected as follows. See Section 9.3 for details for notifying APCF, processing and non-COH site 
shipment. 
 
All sites for immunoprofiling studies: 20 mL into green-top tubes per timepoint 
 
COH only for MRD studies: 20 mL into purple-top tubes per timepoint, and 
 
Non-COH only for MRD studies: 20 mL into cell free DNA BCT tubes per timepoint 
bb. Archival tumor tissue to be submitted post-enrollment. Note: If unavailable, exceptions may be granted by the Study PI. 
Refer to Section 9.2.1. 
cc. If safe and feasible, submission of a research tumor biopsy (fresh core or excisional biopsy) from participants who 
progress/relapse during study is encouraged. Refer to Section 9.2.1. 
dd. PET-CT or CT of neck, chest, abdomen and pelvis can be performed at screening. If there is evidence of neck involvement 
by lymphoma at baseline, neck CT should be continued at subsequent tumor evaluation.  
ee. If prior response was CR perform CT for subsequent timepoints; if prior response was PR perform CT or PET-CT. NOTE: 
Conversions from PR to CR should be confirmed with a PET-CT scan. 
ff. Response assessments per 2014 Lugano Classification (See Section 11.1) [53]. Note: Participants who meet progression 
per 2014  Lugano Classification but meet “indeterminate response” per LYRIC criteria [1] may continue to receive protocol 
therapy beyond progression (Refer to Section 5.6 and Appendix H for details). 
gg. Imaging and response assessment to occur at Cycle 4 Day 15 (+7 days). NOTE: If receiving therapy beyond progression per 
IR LYRIC criteria: A confirmatory PET-CT should be performed within 12 weeks after initial progression per Lugano criteria 
(Refer to Section 5.6).  
hh. For participants who progressed or completed 8 cycles of planned therapy. 
ii. 
Every effort should be made to perform PET-CT at ‘18-months from start of treatment’ visit (especially if the participant 
never achieved CR after ASCT). However, if a PET-CT is not possible, a diagnostic quality CT will be acceptable. 
jj. The dosing plan for the agents is described in Section 5.3; recommended supportive care is described in Section 5.9. Refer 
to Section 6.2 for dose delay/ modification guidelines. 
 
 
 

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11.0 ENDPOINT EVALUATION CRITERIA/MEASUREMENT OF EFFECT 
11.1 Response, Clinical Endpoints and Toxicity 
11.1.1 Response/Progression 
HL response/progression will be evaluated using 2014 Lugano Classification (see Table 11.1) [53, 54]. 
Participants who meet the definition of progressive disease per Lugano Classification should be evaluated 
using the LYRIC criteria (see Appendix H).   
PET-CT or diagnostic quality CT of the neck, chest, abdomen, and pelvis (N/C/A/P) with IV contrast will be 
performed at baseline and the pre-specified time points in the study calendar. PET and CT may be co-
acquired or acquired separately.  Additional necessary restaging studies including dedicated CT scans, 
MRI, or bone marrow biopsies, are permitted at the investigator’s discretion.  Although diagnostic quality 
CT is acceptable, PET-CT is the preferred disease assessment method throughout the study, particularly 
for patients not in CR. Since 18-month PFS is the primary endpoint, every effort should be made to 
perform PET-CT at the “18-month from start of treatment” time point (particularly if the patient never 
achieved CR after ASCT), but if not possible, diagnostic quality CT will be acceptable. PET-CT and CT results 
will be read by a radiologist at each study site and investigator response based on radiology reading will 
be performed.  
For patients with progression of disease on imaging, it is strongly recommended that a confirmatory 
biopsy be obtained whenever possible. Note that an FDG-negative PET scan will only be considered 
complete remission in patients whose tumor was FDG-avid at baseline. 
A disc copy of the study-required images, including post-salvage/pre-ASCT PET scan should be sent to the 
Study PI upon request. Per institutional practices, the images should be de-identified (coded) and the disc 
should be labeled with Subject ID, COH Protocol # and institution name. 
Table 11.1 2014 Lugano Classification Response Criteria 
Response 
Site 
CT-Based Response 
PET-CT Based Response 
Complete 
Response 
 
Complete radiologic response (all 
of the following) 
Complete metabolic response (even 
with a persistent mass) 
Lymph nodes and 
extralymphatic sites 
 
Target nodes/nodal masses 
must regress to ≤1.5 cm in 
longest diameter (LDi).  
 
 
No extralymphatic sites of 
disease. 
 
Score ≤ 3* with or without a 
residual mass on 5-point scale†. 
 
 
It is recognized that in Waldeyer’s 
ring or extranodal sites with high 
physiologic uptake or with 
activation within spleen or 
marrow (e.g., with chemotherapy 
or myeloid colony-stimulating 
factors), uptake may be greater 
than normal mediastinum and/or 
liver. In this circumstance, 
complete metabolic response may 
be inferred if uptake at sites of 
initial involvement is no greater 
than surrounding normal tissue 

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Response 
Site 
CT-Based Response 
PET-CT Based Response 
even if the tissue has high 
physiologic uptake. 
Nonmeasured 
lesion 
Absent 
Not applicable 
Organ enlargement 
Regress to normal 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Normal by morphology; if 
indeterminate, IHC negative 
No evidence of FDG-avid disease in 
marrow 
Partial 
Response 
 
Partial remission (all of the 
following) 
Partial metabolic response 
Lymph nodes and 
extralymphatic sites 
 
≥ 50% decrease in SPD of up 
to 6 target measurable nodes 
and extranodal sites 
 
When a lesion is too small to 
measure on CT, assign 5 mm 
X 5 mm as the default value 
 
When no longer visible, 0 X 0 
mm 
 
For a node > 5 mm X 5 mm, 
but smaller than normal, use 
actual measurement for 
calculation 
 
Score 4 or 5† with reduced uptake 
compared with baseline and 
residual mass(es) of any size 
 
At interim, these findings suggest 
responding disease 
 
At end of treatment, these 
findings indicate residual disease 
Nonmeasured 
lesion 
Absent/normal, regressed, but 
no increase 
Not applicable 
Organ enlargement 
Spleen must have regressed by 
> 50% in length beyond normal 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Not applicable 
Residual uptake higher than uptake 
in normal marrow but reduced 
compared with baseline (diffuse 
uptake compatible with reactive 
changes from chemotherapy 
allowed). If there are persistent focal 
changes in the marrow in the context 
of a nodal response, consideration 
should be given to further evaluation 
with MRI or biopsy or an interval 
scan 
No response or 
stable disease 
 
Stable disease 
No metabolic response 
Target nodes/nodal 
masses, extranodal 
lesions 
< 50% decrease from baseline 
in SPD of up to 6 dominant, 
measurable nodes and 
extranodal sites; no criteria for 
progressive disease are met 
Score 4 or 5† with no significant 
change in FDG uptake from baseline 
at interim or end of treatment 
Nonmeasured 
lesion 
No increase consistent with 
progression 
Not applicable 

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Response 
Site 
CT-Based Response 
PET-CT Based Response 
Organ enlargement 
No increase consistent with 
progression 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Not applicable 
No change from baseline 
Progressive 
disease 
 
Progressive disease requires at 
least 1 of the following 
Progressive metabolic disease 
Individual 
target 
nodes/nodal masses 
PPD progression: 
Score 4 or 5† with an increase in 
intensity of uptake from baseline 
and/or 
Extranodal lesions 
An individual node/lesion must be 
abnormal with: 
 
Longest diameter (LDi) > 1.5 
cm and 
 
Increase by ≥ 50% from PPD 
nadir and 
 
An increase in LDi or shortest 
diameter (SDi) from nadir 
 
0.5 cm for lesions ≤ 2 cm 
 
1.0 cm for lesions > 2 cm 
 
In the setting of 
splenomegaly, the splenic 
length must increase by > 
50% of the extent of its prior 
increase beyond baseline 
(e.g., a 15-cm spleen must 
increase to >16 cm). If no 
prior splenomegaly, must 
increase by at least 2 cm 
from baseline 
 
New or recurrent 
splenomegaly 
 
New FDG-avid foci consistent with 
lymphoma at interim OR 
 
end-of-treatment assessment 
Nonmeasured 
lesion 
New or clear progression of 
preexisting nonmeasured 
lesions 
None 
New lesions 
 
Regrowth of previously 
resolved lesions 
 
A new node > 1.5 cm in any 
axis 
 
A new extranodal site > 1.0 
cm in any axis; if < 1.0 cm in 
any axis, its presence must 
be unequivocal and must be 
attributable to lymphoma 
 
Assessable disease of any 
size unequivocally 
attributable to lymphoma 
 
New FDG-avid foci consistent with 
lymphoma rather than another 
etiology (eg, infection, 
inflammation).  
 
If uncertain regarding etiology of 
new lesions, biopsy or interval 
scan may be considered. 
Bone marrow 
New or recurrent involvement 
New or recurrent FDG-avid foci 

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Measured dominant lesions:  
Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly 
measurable in two diameters. Nodes should preferably be from disparate regions of the body and should 
include, where applicable, mediastinal and retroperitoneal areas.  
 
Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous 
lesions, or those noted on palpation.  
 
Nonmeasured lesions:  
Any disease not selected as measured, dominant disease and truly assessable disease should be considered 
not measured. These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or 
measurable or that do not meet the requirements for measurability but are still considered abnormal, as well 
as truly assessable disease, which is any site of suspected disease that would be difficult to follow 
quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, 
abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or 
in extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum 
with complete metabolic response, but should be no higher than surrounding normal physiologic uptake (eg, 
with marrow activation as a result of chemotherapy or myeloid growth factors). 
 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of 
an interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to 
consider a score of 3 as inadequate response (to avoid undertreatment).  
 
†PET 5-point scale:  
1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake 
moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to 
be related to lymphoma. 
 
Abbreviations:   
CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; LDi, longest transverse 
diameter of a lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, cross 
product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the 
product of the perpendicular diameters for multiple lesions. 
 
 
11.1.2 Clinical Endpoints  
Evaluable patients are defined as eligible participants who received at least one dose of the protocol 
treatment. Eligible participants who did not receive any protocol treatment will be considered in-
evaluable, replaced, and excluded from all analyses.  
Endpoint 
Patients 
Definition 
Progression-Free 
Survival (PFS)* 
Evaluable 
patients 
Defined as the time from the first dose of study treatment to the first 
observation of disease relapse/progression or death from any cause, 
whichever occurs first.  
For patients who are alive and have not had disease relapse/progression 
at the last follow-up, it is censored at the time of last follow-up. If a 
patient receives non-protocol anti-HL treatment prior to disease 
relapse/progression, the patient will be censored at the time of non-
protocol anti-HL treatment. 

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Endpoint 
Patients 
Definition 
Overall Survival (OS) 
Evaluable 
patients 
Defined as the time from the first dose of study treatment to death from 
any cause.   
For patients alive at the last follow-up, it is censored at the time of last 
follow-up. 
Cumulative Incidence 
of Non-Relapse 
Mortality (NRM)* 
Evaluable 
patients 
Defined as the time from the first dose of study treatment to non-disease 
related death.  
Disease relapse or progression is considered a competing risk. For 
surviving patients without disease relapse/progression at the last follow-
up, it is censored at the time of last follow-up. If a patient receives non-
protocol anti-HL treatment prior to disease relapse/progression, the 
patient will be censored at the time of non-protocol anti-HL treatment. 
Cumulative Incidence 
of 
Relapse/Progression* 
Evaluable 
patients 
Defined as the time from the first dose of study treatment to disease 
relapse/progression. 
Death without relapse/progression is considered a competing risk. For 
surviving patients without relapse/progression at the last follow-up, it is 
censored at the time of last follow-up. If a patient receives non-protocol 
anti-HL treatment prior to disease relapse/progression, the patient will 
be censored at the time of non-protocol anti-HL treatment. 
Overall response rate 
(ORR) 
Evaluable 
patients 
with 
measureable 
disease 
post-ASCT 
Proportion of patients achieving CR or PR [53]  
 
*   For patients who meet PD per Lugano Classification and also meet IR per LYRIC criteria (Appendix H) [1]: In 
the analysis, patients with PD per Lugano classification and IR per LYRIC criteria who continue study treatment 
beyond progression per Lugano classification and have confirmation of subsequent PD per LYRIC criteria will 
be counted as PD at the initial time point of progression per Lugano classification; patients with PD per 
Luagno classifcation and IR per LYRIC criteria who continue study treatment beyond progression per Lugano 
classification and do not have confirmation of subsequent PD per LYRIC criteria, with subsequent SD, PR, or CR 
per Lugano classification, will NOT be counted as PD at the initial time point of progression per Lugano 
classifcation. Patients with PD per Lugano classification and IR per LYRIC criteria who did NOT continue study 
treatment beyond progression per Lugano classification will be considered PD at the initial timepoint of 
progression per Lugano classification. 
11.1.3 Toxicity 
Toxicity and adverse events will be recorded using the NCI CTCAE v 4.0. All toxicities/AEs will be recorded 
from the initiation of protocol therapy through the follow-up period. The highest grade for any toxicity 
plus Grade 3 or 4 event for the same toxicity (if not the highest grade) will be reported during each cycle 
and during the safety follow-up period.  
Eligible participants who did not receive any protocol treatment will be considered in-evaluable, replaced, 
and excluded from all analyses on toxicity.  

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12.0 STATISTICAL CONSIDERATIONS 
12.1 Study Design 
This is a single-arm, open-label Phase 2 study of nivolumab plus BV consolidation following ASCT in 
patients with relapsed/ refractory HL who have undergone ASCT. Participants will receive protocol 
treatment consisting of 21-day cycles, for up to 8 cycles. The primary endpoint is 18-month progression-
free survival. Secondary endpoints include overall survival, cumulative incidence of relapse/progression, 
cumulative incidence of non-relapse mortality, overall response rate, and toxicity. The target sample size 
is 59 eligible participants who received at least one dose of the protocol treatment. Eligible participants 
who did not receive any protocol treatment will be considered in-evaluable and replaced. The total study 
accrual may be increased slightly beyond 59 patients in order to achieve 59 evaluable participants with at 
least one dose. To account for up to 10% inevaluable enrollments, the maximum study accrual is set to be 
65 participants. The projected study accrual duration is 24 months at the estimated accrual rate of 2-3 
patients per month. With a planned follow-up until 18 months from the first dose of study treatment for 
the last accrued patient, the projected total study duration for accrual and follow-up is approximately 42 
months. 
12.2 Sample Size Accrual Rate 
The target sample size is 59 participants with at least one dose of the protocol treatment, with the study 
total accrual potentially slightly larger to accommodate some eligible participants who did not receive any 
protocol treatment due to various reasons. City of Hope performs approximately 20-30 ASCT in patients 
with HL each year. Table 12.2 below describes the number of patients with HL evaluated at COH each 
year, as well as the number of ASCT for HL performed between 2011 and 2015. Based on this estimate, 
we expect to accrue 15-20 patients per year at COH. This will be a multicenter study with 6 total sites. We 
expect a total accrual of 2-3 patients per month across all sites. Therefore, accrual is expected to be 
completed in 24 months. With a planned follow-up until 18 months from the first dose of study treatment 
for the last accrued patient, the total anticipated study duration will be approximately 42 months. 
Table 12.2 City of Hope Patient Availability 
Disease Site 
2011 
2012 
2013 
2014 
2015 
Hodgkin Lymphoma (HL) 
388 
392 
361 
425 
394 
HL patients undergoing ASCT 
21 
33 
22 
33 
30 
12.3 Statistical Analysis Plan 
12.3.1 Power Estimation 
The primary endpoint is 18-month PFS, as defined in Section 11.0. Eligible participants who received at 
least one dose of the protocol treatment will be evaluable for the primary endpoint; eligible participants 
who did not receive any protocol treatment will be considered in-evaluable and excluded from all 
analyses.  
Based on the AETHERA trial, the 18-month PFS rate in patients with relapsed/refractory HL who undergo 
ASCT followed by BV consolidation is approximately 65% (from the independent assessment data) [32].  
We hypothesize that adding nivolumab to BV consolidation after ASCT will improve the 18-month PFS rate 
to 80%. A sample size of 59 evaluable patients will provide approximately 81% power for detecting the 

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increase in 18-month PFS from the baseline of 65% to 80% in this study at 1-sided type I error of 0.05. The 
power estimation is based on the exact binomial test. Operationally, the study treatment will be 
considered promising if at least 45 of the 59 evaluable participants are alive and progression-free at 18 
months after the first dose of study treatment. The probability of observing at least 45 surviving and 
progression-free participants out of a total 59 participants, assuming different PFS rates, is shown in Table 
12.3.1.  
Table 12.3.1 The probability of declaring the trial a success assuming different PFS rates  
 
True 18-month PFS rate 
65% 
70% 
75% 
80% 
The probability of observing at least 45 
participants (out of 59 total) being alive and 
progression-free at 18-month 
0.044 
0.18 
0.48 
0.81 
12.3.2 Analysis Plans 
Patient demographics and baseline disease characteristics, including age, gender, medical history, and 
prior therapy, will be summarized using descriptive statistics. For continuous variables, descriptive 
statistics such as number, mean, standard deviation, standard error, median (range) etc. will be provided. 
For categorical variables, patient counts and percentages will be provided. 
For all analyses, only eligible participants who received at least one dose of protocol treatment will be 
considered evaluable and included in the analyses. Eligible participants who did not receive any protocol 
treatment will be considered in-evaluable and excluded from all analyses.  
PFS will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood 
estimator of standard error. When there is no censoring in PFS prior to 18 months after the first dose of 
study treatment, the observed 18-month PFS will be compared to the baseline of 65% by one-sided exact 
test of binomial proportion. In case of censoring in PFS prior to 18 months after the first dose  of study 
treatment (which are expected to be rare), the Kaplan-Meier estimate for 18-month PFS along with the 
Greenwood standard error estimator will be used for the testing of null hypothesis at 65%. 
OS will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood 
estimator of standard error. Cumulative incidence of relapse/progression and cumulative incidence of 
non-relapse mortality, as well as their confidence intervals will be estimated using competing risk 
methodology, treating the other event as a competing risk. Overall response rate will be estimated by the 
proportion of patients achieving either CR or PR among participants with measurable disease after ASCT, 
along with the exact binomial confidence interval.   
Observed toxicities will be summarized by type (organ affected or laboratory determination such as 
absolute neutrophil count), severity (by NCI CTCAE v4.0 and nadir or maximum values for lab measures), 
date of onset, duration, reversibility, and attribution.  
For the exploratory objects, descriptive statistics will be used to summarize the responses and outcomes 
for patients who receive protocol treatment past disease progression and the correlative study measures. 
For continuous variables, number, mean, standard deviation, standard error, median (range) etc., will be 
provided. For categorical variables, patient counts and percentages will be provided. Changes in these 
measures before, during, and after treatment (when measured) will also be summarized by descriptive 
statistics and tables/plots. Various statistical analyses will be used to explore the association between 

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these correlative endpoint measures (at different time points and the associated changes over time, when 
measured) with clinical outcomes such as PFS/OS and response.  For the exploratory correlation of these 
endpoints with survival outcomes, survival analysis techniques such as Log rank test and Cox proportional 
hazard models will be considered. For the exploratory correlation of these endpoints with response, 
analyses comparing groups of participants defined by response  may be conducted by various two sample 
tests such as two-sample t-test or Wilcoxon rank sum test for the continuous correlative endpoints, or 
Chi-square test/Fisher’s exact test for the categorical correlative endpoints. Appropriate regression 
models will also be considered, such as logistic regression for analyses on response and Cox proportional 
hazards models for survival outcomes.   All these analyses are exploratory in nature and no multiple 
comparison adjustments will be made in these exploratory analyses  
12.3.3 Toxicity Monitoring 
Close and continuous monitoring for toxicity will occur throughout the study duration per institutional 
standards. The COH DSMC will review the AE data quarterly. In the AETHERA trial [32], 56% of patients 
who received brentuximab vedotin experienced at least one Grade 3-4 adverse event, including 29% with 
Grade 3-4 neutropenia, 10% with Grade 3-4 peripheral sensory neuropathy, and 6% with Grade 3-4 
peripheral motor neuropathy.  
In this study, the total treatment number of cycles is reduced to 8 but the addition of nivolumab may 
introduce additional toxicities.  
Given the prior toxicity experiences in AETHERA trial and the differences in treatment [32], in this study 
we will specifically monitor the occurrence of any “unacceptable AE”. Unacceptable AE is defined as any 
of the following AEs that is at least possibly attributed to protocol therapy during treatment and safety 
follow-up:  
o Any ≥ Grade 3 immune-related AE 
o Grade 3 fatigue or non-irAE skin toxicity that does not resolve within 7 days to ≤ Grade 
1/baseline 
o Any other ≥ Grade 3 non-hematologic non-irAE that does not improve within 3 days to  ≤ Grade 
1/baseline as applicable with supportive care with the following exception: 
− 
≥ Grade 3 laboratory abnormality that is not clinically significant 
o Grade 4 neutropenia that does not resolve to ≤ Grade 2 within 3 days with supportive care (e.g. 
GCSF) 
o Grade 3 or 4 thrombocytopenia with bleeding  
o Any Grade 5 AE 
 
This specific monitoring will be performed according to the rule below, which is based on the 50% 
quartile of the binomial distribution with an unacceptable toxicity rate of 33%.   
o 3 or more patients with unacceptable toxicities when ≤ 9 patients have been treated. 
o 5 or more patients with unacceptable toxicities when ≤ 16 patients have been treated. 
o 8 or more patients with unacceptable toxicities when ≤ 23 patients have been treated. 
o 11 or more patients with unacceptable toxicities when ≤ 33 patients have been treated. 
o 15 or more patients with unacceptable toxicities when ≤ 46 patients have been treated. 

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o 19 or more patients with unacceptable toxicities when ≤ 59 patients have been treated. 
If the monitoring rule is met, the study PMT will review and assess the safety of the trial and submit a 
report outlining the findings and proposed action plans if any to the COH DSMC. The COH DSMC will review 
and make the decision to continue, modify, or permanently suspend accrual to the trial. At the end of the 
study with 59 evaluable participants, the 95% exact binomial confidence interval for the rate of such 
unacceptable AE will have a width of no more than 27%.  
13.0 DATA HANDLING, DATA MANAGEMENT, RECORD KEEPING 
13.1 Source Documents 
Source documents are original documents, data, and records (e.g., medical records, pharmacy 
dispensing records, recorded data from automated instruments, laboratory data) that are relevant to 
the clinical trial.  The Site Investigator or their designee will prepare and maintain adequate and 
accurate source documents.  These documents are designed to record all observations and other 
pertinent data for each patient enrolled in this clinical trial.  Source documents must be adequate to 
reconstruct all data transcribed onto the case report forms. 
13.2 Data Capture Methods and Management 
Data for this trial will be collected using Medidata RAVE, City of Hope’s electronic capture system. 
Medidata RAVE is a web based, password protected system that is fully compliant with global regulatory 
requirements, including 21CRF Part 11 compliant.  
13.3 Case Report Forms/ Data Submission Schedule 
Study personnel at each site will enter data from source documents corresponding to a participant’s visit 
into the protocol-specific electronic Case Report Form (eCRF) when the information corresponding to 
that visit is available.  
The investigator is responsible for all information collected on participants enrolled in this study.  All 
data collected during the course of this study must be reviewed and verified for completeness and 
accuracy by the investigator. All case report forms must be completed by designated study personnel.  
The completed case report forms must be reviewed, signed and dated by the Site Investigator or 
designee in a timely fashion. 
All data will be collected using electronic data collection system described in Section 13.2, and will be 
submitted according to the timelines indicated in Table 13.3. 
Table 13.3 Data Submission Schedule 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration  
On Study Forms 
Within 14 calendar days of registration 
Baseline Assessment Forms 
Within 14 calendar days of registration 
Treatment Forms 
Within 14 calendar days of treatment administration 
Adverse Event Report Forms 
Within 10 calendar days of the assessment/notification 
Response Assessment Forms 
Within 10 calendar days of the response assessment 
Other Assessment Forms  
Within 10 calendar days of the assessment 
Off 
Treatment/Off 
Study 
Forms 
Within 10 calendar days of completing treatment or being taken off study for 
any reason 
Follow up/ Survival Forms 
Within 14 calendar days of the protocol defined follow up visit date or call 

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13.4 Regulatory Records 
The investigator will maintain regulatory records, including updating records in accordance with Good 
Clinical Practice guidelines and FDA regulations. 
14.0 ADHERENCE TO THE PROTOCOL 
A deviation is a divergence from a specific element of a protocol that occurred without prior IRB approval. 
It is understood that deviations from the protocol should be avoided, except when necessary to eliminate 
an immediate hazard to a research participant. Protocol deviations may be on the part of the participant, 
the investigator, or study staff.   
All deviations from the protocol must be documented in study participant source documents and 
promptly reported to the Study PI and to the local IRB according to its policies requirements.  The Study 
PI will report the deviation according to City of Hope’s deviation policy for reporting deviations.  
14.1 Emergency Modifications 
Investigators may implement a deviation from the protocol to eliminate an immediate hazard(s) for the 
protection, safety, and well-being of the study patient to trial participants without prior IRB or Sponsor 
approval.  
For any such emergency modification implemented:  
o The local IRB and/or DSMC must be notified according to local institutional policies.  
o The Study PI must be notified as soon as practicable (within 24 hours) via email to the Study 
PI and dcc@coh.org.  This email should provide input on the following: 
 Description of the event 
 Impact on participant safety or the safety to others 
 Impact on the study design 
14.2 Planned Non-Emergency Deviations 
All non-emergency planned deviations from the protocol must have prior approval by the Study PI, the 
Site Lead Investigator and the local IRB, and if applicable the COH IRB.  
14.3 Unplanned Deviations – Deviations Discovered After They Have Occurred. 
For deviations to the protocol discovered after they have occurred:  
o The local IRB and/or DSMC must be notified according to local institutional policies.  
o The Study PI must be notified as soon as practicable (within 24 hours of awareness of event) 
via email to the Study PI and dcc@coh.org.  This email should provide input on the following: 
 Description of the event 
 Impact on participant safety or the safety to others 
 Impact on the study design 
 A corrective and preventative action plan 
A list of deviations from all participating sites will be submitted along with the Protocol Management 
Team (PMT) progress report to the COH DSMC. 

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14.4 Single Subject Exceptions 
An SSE is a planned deviation, meaning that it involves circumstances in which the specific procedures 
called for in a protocol are not in the best interests of a specific patient. It is a deviation that is anticipated 
and receives prior approval by the PI and the IRB.  
COH only: Reporting SSEs: the SSE must be submitted as a “Single Subject Exception Amendment Request” 
via iRIS in accordance with IRB guidelines and the Clinical Research Protocol Deviation policy. An IRB 
approved SSE does not need to be submitted as a deviation to the DSMC. 

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15.0 STUDY OVERSIGHT, QUALITY ASSURANCE, AND DATA & SAFETY MONITORING 
15.1 Site Lead Investigator Responsibilities 
The Site Lead Investigator is responsible for the conduct of the clinical trial at the site in accordance with 
Title 21 of the Code of Federal Regulations (CFR). The Site Lead Investigator must assure that all study site 
personnel, including sub-investigators and other study staff members, adhere to the study protocol and 
all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study 
completion. 
It is the responsibility of the Site Lead Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events, deviations, 
and unanticipated problems.  
The Site Lead Investigator will be responsible for assuring that all the required data will be collected and 
entered onto the Case Report Forms at his/her site. For remote or onsite monitoring and auditing, the 
Site Lead Investigator will provide access to his/her original records to permit verification of proper entry 
of data. At the completion of the study, all case report forms will be reviewed by the Site Lead Investigator 
and will require his/her final signature to verify the accuracy of the data. 
An investigator is responsible for ensuring that an investigation is conducted according to the signed 
investigator statement, the investigational plan, and applicable regulations; for protecting the rights, 
safety, and welfare of participants under the investigator's care; and for the control of drugs under 
investigation.  
15.2 All Investigator Responsibilities 
All investigators agrees to: 
o Conduct the study in accordance with the protocol and only make changes after notifying the 
Sponsor (or designee), except when necessary to protect the safety, rights or welfare of 
subjects.  
o Personally conduct or supervise the study (or investigation).  
o Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.  
o Report to the Sponsor or designee any AEs that occur in the course of the study, in accordance 
with §21 CFR 312.64.  
o Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments.  
o Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make those 
records available for inspection with the Sponsor (or designee).  
o Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be responsible 
for initial and continuing review and approval of the clinical study.  
o Promptly report to the IRB and the Sponsor all changes in the research activity and all 
unanticipated problems involving risks to subjects or others (to include amendments and IND 
safety reports).  
o Seek IRB and Sponsor approval before any changes are made in the research study, except 
when necessary to eliminate hazards to the patients/subjects.  

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o Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312. 
15.3 Study PI Responsibilities 
The Study PI is responsible for the conduct of the clinical trial, including overseeing that sponsor 
responsibilities as defined in § 21 CFR 312. 
15.4 Protocol Management Team (PMT) 
The PMT minimally consisting of the Study Principal Investigator, Site Lead Investigator(s), collaborating 
investigators, the research nurse, the clinical research associate/coordinator, and the study biostatistician 
is responsible for ongoing monitoring of the data and safety of this study. 
The PMT will meet (in person or via teleconference) at least monthly, and will meet at least quarterly with 
the study biostatistician, to review study status. This review will include, but not be limited to, reportable 
AEs and UPs, and an update of the ongoing study summary that describes study progress in terms of the 
study schema. The meeting will be a forum to discuss study related issues including accrual, SAE/AEs 
experienced, study response, deviations/violations and study management issues. The appropriateness 
of further subject enrollment and the specific intervention for subsequent subject enrollment are 
addressed, including the implementation of stopping rules. 
15.5 Monitoring/ Auditing 
Clinical site auditing/ monitoring is conducted to ensure that the rights of human subjects are protected, 
that the study is implemented in accordance with the protocol and regulatory requirements, and that the 
quality and integrity of study data and data collection methods are maintained. Monitoring for this study 
will be performed by the City of Hope Office of Clinical Trials Auditing and Monitoring (OCTAM). 
  
The site Investigator/Institution will permit the study monitors and appropriate regulatory authorities 
direct access to the study data and to the corresponding source data and documents to verify the accuracy 
of this data. The Investigator will allocate adequate time for such monitoring activities.  The Investigator 
will also ensure that the monitor or other compliance or quality assurance reviewer is given access to all 
the above noted study-related documents and study related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.), and has adequate space to conduct the monitoring visit. 
  
Details of clinical site monitoring are documented in the OCTAM SOP that is provided as a supplement to 
this document. This document specifies the frequency of monitoring, monitoring procedures, the level of 
clinical site monitoring activities (e.g., the percentage of subject data to be reviewed), and the distribution 
of monitoring reports.  Staff from OCTAM will conduct monitoring activities and provide reports of the 
findings and associated action items in accordance with the details described in the SOP.  Documentation 
of monitoring activities and findings will be provided to the site study team, the site PI, study PI, and the 
COH DSMC. 
15.6 Quality Assurance 
The City of Hope Clinical Research Information Support will provide quality assurance.  
An additional level of quality assurance of the study-required images will be performed by the Study PI 
(see Section 11.1.1 for details). 

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15.7 City of Hope Data and Safety Monitoring Committee (DSMC) 
This is a Risk Level 4 study, as defined in the City of Hope Data and Safety Monitoring Plan because the 
trial involves a COH IND. 
The DSMC is a multidisciplinary committee charged with overseeing the monitoring of safety of 
participants in clinical trials, and the conduct, progress, validity, and integrity of the data for all clinical 
trials that are sponsored by City of Hope. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. The committee reviews the 
progress and safety of all active research protocols that are not monitored by another safety and data 
monitoring committee or board. 
The COH DSMC will review and monitor toxicity and accrual data from this trial. Information that raises 
any questions about participant safety will be addressed with the Principal Investigator, statistician and 
study team. The COH DSMC Charter is a supplement to this protocol. 
The DSMC will review the study’s status every 3 months and/or more frequently if necessary. The DSMC 
will review up-to-date participant accrual; summary of all adverse events captured via routine and 
expedited reporting; a summary of deviations; any response information; monitoring reports, and 
summary comments provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. A review of outcome results (response, toxicity and adverse events) and factors 
external to the study (such as scientific or therapeutic developments) is discussed, and the Committee 
votes on the status of each study.  
Data and safety will be reported to the COH DSMC using the PMT report and submitted every 3 months 
from the date of activation. 
16.0 ETHICAL AND REGULATORY CONSIDERATIONS 
16.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research (US National Commission for 
the Protection of Human Subjects of Biomedical and Behavioral Research, April 18, 1979) and the 
Declaration of Helsinki. 
16.2 Regulatory Compliance 
This study is to be conducted in compliance with the IRB approved protocol and according to the following 
considerations: 
o US Code of Federal Regulations (CFR) governing clinical study conduct 
 
Title 21 Part 11 – Electronic Records; Electronic Signatures  
 
Title 21 Part 50 – Protection of Human Subjects  
 
Title 21 Part 54 – Financial Disclosure by Clinical Investigators  
 
Title 21 Part 56 – Institutional Review Boards  
 
Title 21 Part 58 – Good Laboratory Practice for Nonclinical Laboratory Studies  
 
Title 21 Part 312 – Investigational New Drug Application  
 
Title 45 Part 46 – Protection of Human Subjects  

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o US Federal legislation, including but not limited to 
 
Health Insurance Portability and Accountability Act of 1996  
 
Section 801 of the Food and Drug Administration Amendments Act   
o Applicable state and local laws. For research occurring in California, this includes but is not 
limited to State of California Health and Safety Code, Title 17 
o Applicable institutional research policies and procedures 
16.3 Institutional Review Board 
Each participating institution must provide for the review and approval of this protocol and the associated 
informed consent documents by an appropriate IRB holding a current US Federal wide Assurance issued 
by and registered with the Office for Human Research Protections (OHRP). Any documents that the IRB 
may need to fulfill its responsibilities (such as protocol, protocol amendments, Investigator’s Brochure, 
consent forms, information concerning patient recruitment, payment or compensation procedures, or 
other pertinent information) will be submitted to the IRB.  The IRB’s written unconditional approval of the 
study protocol and the informed consent document will be in the possession of the Investigator, and, for 
sites external to COH, the possession of the coordinating center, before the study is initiated. The 
Investigator will obtain assurance of IRB/IEC compliance with regulations. 
The IRB will be informed of revisions to other documents originally submitted for review; serious 
unexpected or unanticipated adverse experiences occurring during the study, and any additional adverse 
experiences in accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; an annual 
update and/or request for re-approval; and when the study has been completed. 
Any amendment to the protocol document and accompanying informed consent document/template, as 
developed and provided by the Study PI, will require review and approval by the IRB before the changes 
are implemented in the study.  The protocol and consent will be reviewed and approved by the COH IRB 
before submission to a participating site IRB. 
16.4 Informed Consent  
For a multi-site study, each participating institution will be provided with a model informed consent form. 
Each institution may revise or add information to comply with local and/or institutional requirements, but 
may not remove procedural or risk content from the model consent form. Furthermore, prior to 
submission to the IRB (initial submission and amendments), the consent and accompanying HIPAA form, 
if separate to the consent, must be reviewed and approved by the DCC. 
After the study has been fully explained, written informed consent will be obtained from either the patient 
or his/her guardian or legal representative before study participation.  The method of obtaining and 
documenting the informed consent and the contents of the consent must comply with the ICH-GCP and 
all applicable regulatory requirements. 
Before implementing any study procedure, informed consent shall be documented by the use of a written 
consent form approved by the IRB/IEC and signed and dated by the patient or the patient’s legally 
authorized representative at the time of consent.  A copy of the signed informed consent will be given to 
the patient or patient’s legally authorized representative.  The original signed consent must be maintained 
by the Site Investigator and available for inspection sponsor designated representatives, or regulatory 
authority at any time. 

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Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout study participation. 
16.5 Participant Withdrawal 
Participants may withdraw from the study at any time and for any reason without prejudice. The 
withdrawal must be documented per institutional policies.   
Participant withdrawal may consist of any of the following with regard to study procedures and data 
collection: 
o Withdrawal from study treatment, but agreement to continue with active study procedures 
and chart review and follow-up procedures. 
o Withdrawal from study treatment and all active procedures, but agreement for chart review 
and follow-up procedures. 
o Withdrawal from study treatment, all active procedures, and any future data collection. 
Participants who agreed to the collection of research blood samples may withdraw consent to use their 
specimens, if they are not yet processed as detailed in the consent form.  Once the PI and site PI is notified 
of this withdrawal of informed consent, the research specimens will not be used in any research. At that 
time, any of the existing specimens will be destroyed. 
16.6 Special and Vulnerable Populations  
16.6.1 Inclusion of Women and Minorities 
The study is open anyone regardless of gender or ethnicity. If differences in outcome that correlate to 
gender, racial, or ethnic identity are noted, accrual may be expanded or additional studies may be 
performed to investigate those differences more fully. 
Pregnant women are excluded because non-clinical safety findings of adverse pregnancy outcomes and 
infant losses in the absence of maternal toxicity have been reported. Findings in monkeys suggest a 
potential risk to human pregnancy if there is continued treatment with nivolumab during pregnancy [29]. 
The effects of brentuximab vedotin on embryogenesis, reproduction, and spermatogenesis in humans are 
unknown. 
16.6.2 Exclusion of Children 
Children/ adolescents (< 18 years old of age) are excluded from this study because the historical 
comparator trials were conducted in adults. Future studies may be planned to include children/ 
adolescents. 
16.6.3 Inclusion of HIV Positive Individuals 
Participants with a history of HIV are excluded due to concerns about inadvertent augmentation of 
infectious and/or inflammatory activity. 
16.6.4 Vulnerable Populations 
45 CFR §46.111 (a)(3) and 45 CFR §46, Subparts B-D identifies children, prisoners, pregnant women, 
mentally incapacitated persons, or economically or educationally disadvantaged persons as vulnerable 
populations.  

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Adults lacking capacity to consent are not excluded from participation. This study does not pose additional 
risks for adults lacking capacity than for the general population.  In such instances, informed consent will 
be sought and documented from the prospective participant’s legally authorized representative in 
agreement with institutional policies and COH IRB approval. 
16.7 Participant Confidentiality  
Participant confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) and 
their agents. This confidentiality is extended to cover testing of biological samples in addition to any study 
information relating to participants. 
This research will be conducted in compliance with federal and state requirements relating to protected 
health information (PHI), including the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA).  HIPAA regulations require a signed participant authorization 
informing the participant of the nature of the PHI to be collected, who will have access to that information 
and why, who will use or disclose that information, ant the rights of a research participant to revoke their 
authorization for use of their PHI. In the event that a participant revokes authorization to collect or use 
PHI, the investigator, by regulation, retains the ability to use all information collected prior to the 
revocation of participant authorization.  For participants that have revoked authorization to collect or use 
PHI, attempts should be made to obtain permission to collect at least vital status (i.e. that the participant 
is alive) at the end of their scheduled study period. 
Release of research results should preserve the privacy of medical information and must be carried out in 
accordance with Department of Health and Human Services Standards for Privacy of Individually 
Identifiable Health Information, 45 CFR 164.508. When results of this study are reported in medical 
journals or at meetings, identification of those taking part will not be disclosed and no identifiers will be 
used. 
Medical records of participants will be securely maintained in the strictest confidence, according to 
current legal requirements.  Data will be entered, analyzed and stored in encrypted, password protected, 
secure computers that meet all HIPAA requirements.   All data capture records, drug accountability 
records, study reports and communications will identify the patient by initials and the assigned patient 
number. Source documents provided to coordinating center for the purpose of auditing or monitoring will 
be de-identified and labeled with the study number, subject ID, and if applicable patient initials. 
The investigator/institution will permit direct access to source data and documents by sponsor 
representatives, the FDA, and other applicable regulatory authorities.  The access may consist of trial-
related monitoring/ auditing, IRB reviews, and FDA/regulatory authority inspections. The participant’s 
confidentiality will be maintained and will not be made publicly available to the extent permitted by the 
applicable laws and regulations. 
Participant specimens will be de-identified (coded) prior to submission to research laboratories. The 
specimens will be labeled with the study number, subject ID, institution and timepoint of collection. The 
key to the code will be maintained in the COH clinical trials management system which is a secure 
environment. 
16.8 Future Use of Stored Specimens and Other Identifiable Data 
Samples will be stored for up to 10 years following the end of the study.  The Study PI will be the 
administrator. Identifiable data analysis will cease following analysis of samples and the results have been 
published. 

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16.9 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a 
properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study Sponsor (City of Hope) prior to participation in 
this study.  All City of Hope investigators will follow the City of Hope conflict of interest policy. 
16.10 Financial Obligations, Compensation, and Reimbursement of Participants 
Nivolumab will be provided by the manufacturer free of charge to study participants.  
The research participant nor the insurance carrier will be responsible for the research procedures related 
to this study.  
The research participant will be responsible for the cost of purchasing brentuximab vedotin, all 
copayments, deductibles, and other costs of treatment and diagnostic procedures as set forth by the 
insurance carrier.  The research participant and/or the insurance carrier will be billed for the costs of 
treatment and diagnostic procedures in the same way as if the research participant were not in a research 
study.   
In the event of physical injury to a research participant, resulting from research procedures, appropriate 
medical treatment will be available at the City of Hope or at the non-COH site to the injured research 
participant, however, financial compensation will not be available. There are no plans for City of Hope to 
provide financial compensation in the event of physical injury to a participant. 
The research participant will not receive reimbursement or payment for taking part in this study. 
16.11 Publication/Data Sharing  
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of 
the information provided by City of Hope for the purposes of performing the study, will be published or 
passed on to any third party without the written approval of the Study PI. Any investigator involved with 
this study is obligated to provide City of Hope with complete test results and all data derived from the 
study. 
The preparation and submittal for publication of manuscripts containing the study results shall be in 
accordance with a process determined by mutual written agreement among City of Hope and BMS. The 
publication or presentation of any study results shall comply with all applicable privacy laws, including, 
but not limited to, the Health Insurance Portability and Accountability Act of 1996.  
In accordance with the U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 
or FDAAA), Title VIII, Section 801, this trial will be registered onto ClinicalTrials.gov and results will be 
reported on ClinicalTrials.gov within 12 months of the estimated or actual completion date of the trial, 
whichever date is earlier. 

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17.0 REFERENCES 
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3. Oza, A.M., et al., Patterns of survival in patients with Hodgkin's disease: long follow up in a single centre. Ann Oncol, 1993. 
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4. Smith, S.D., et al., Autologous stem cell transplant for early relapsed/refractory Hodgkin lymphoma: results from two 
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5. Schmitz, N., et al., Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous 
haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet, 2002. 
359(9323): p. 2065-71. 
6. Kharfan-Dabaja, M.A., et al., Managing Hodgkin lymphoma relapsing after autologous hematopoietic cell transplantation: a 
not-so-good cancer after all! Bone Marrow Transplant, 2014. 49(5): p. 599-606. 
7. Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 2012. 12(4): p. 252-64. 
8. Green, M.R., et al., Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further 
induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood, 2010. 
116(17): p. 3268-77. 
9. Chen, B.J., et al., PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated 
malignancies. Clin Cancer Res, 2013. 19(13): p. 3462-73. 
10. Shi, M., et al., Expression of Programmed Cell Death 1 Ligand 2 (PD-L2) Is a Distinguishing Feature of Primary Mediastinal 
(Thymic) Large B-cell Lymphoma and Associated With PDCD1LG2 Copy Gain. Am J Surg Pathol, 2014. 38(12): p. 1715-23. 
11. Carreras, J., et al., High numbers of tumor-infiltrating programmed cell death 1-positive regulatory lymphocytes are associated 
with improved overall survival in follicular lymphoma. J Clin Oncol, 2009. 27(9): p. 1470-6. 
12. Xerri, L., et al., Programmed death 1 is a marker of angioimmunoblastic T-cell lymphoma and B-cell small lymphocytic 
lymphoma/chronic lymphocytic leukemia. Hum Pathol, 2008. 39(7): p. 1050-8. 
13. Dorfman, D.M., et al., Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic 
T-cell lymphoma. Am J Surg Pathol, 2006. 30(7): p. 802-10. 
14. Krishnan, C., et al., PD-1 expression in T-cell lymphomas and reactive lymphoid entities: potential overlap in staining patterns 
between lymphoma and viral lymphadenitis. Am J Surg Pathol, 2010. 34(2): p. 178-89. 
15. Zhan, H.Q., et al., Expression of follicular helper T cell markers in nodal peripheral T cell lymphomas: a tissue microarray 
analysis of 162 cases. J Clin Pathol, 2011. 64(4): p. 319-24. 
16. Han, L., et al., Role of programmed death ligands in effective T-cell interactions in extranodal natural killer/T-cell lymphoma. 
Oncol Lett, 2014. 8(4): p. 1461-1469. 
17. Shimauchi, T., et al., Augmented expression of programmed death-1 in both neoplastic and non-neoplastic CD4+ T-cells in 
adult T-cell leukemia/lymphoma. Int J Cancer, 2007. 121(12): p. 2585-90. 
18. Liu, J., et al., Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation 
with IFN-gamma and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood, 2007. 110(1): p. 296-304. 
19. Kronig, H., et al., Interferon-induced programmed death-ligand 1 (PD-L1/B7-H1) expression increases on human acute myeloid 
leukemia blast cells during treatment. Eur J Haematol, 2014. 92(3): p. 195-203. 
20. Tamura, H., et al., Expression of functional B7-H2 and B7.2 costimulatory molecules and their prognostic implications in de 
novo acute myeloid leukemia. Clin Cancer Res, 2005. 11(16): p. 5708-17. 
21. Kondo, A., et al., Interferon-gamma and tumor necrosis factor-alpha induce an immunoinhibitory molecule, B7-H1, via nuclear 
factor-kappaB activation in blasts in myelodysplastic syndromes. Blood, 2010. 116(7): p. 1124-31. 

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22. Yang, H., et al., Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with 
hypomethylating agents. Leukemia, 2014. 28(6): p. 1280-8. 
23. Green, M.R., et al., Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant 
lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res, 2012. 18(6): p. 1611-8. 
24. Ansell, S.M., et al., PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med, 2015. 372(4): 
p. 311-9. 
25. Younes, A., et al., Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and 
brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol, 2016. 
26. Armand, P., et al., Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After 
Brentuximab Vedotin Failure. J Clin Oncol, 2016. 
27. Chen, R.W., et al., Pembrolizumab for relapsed/refractory classical Hodgkin lymphoma (R/R cHL): phase 2 KEYNOTE-087 study. 
J Clin Oncol 34, 2016 (suppl; abstr 7555), 2016. 
28. Sharpe, A.H., et al., The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat 
Immunol, 2007. 8(3): p. 239-45. 
29. Bristol-Myers Squibb: Investigator Brochure for Nivolumab. 2016. 
30. Sutherland, M.S., et al., Lysosomal trafficking and cysteine protease metabolism confer target-specific cytotoxicity by peptide-
linked anti-CD30-auristatin conjugates. J Biol Chem, 2006. 281(15): p. 10540-7. 
31. Francisco, J.A., et al., cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor 
activity. Blood, 2003. 102(4): p. 1458-65. 
32. Moskowitz, C.H., et al., Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients 
with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 
3 trial. Lancet, 2015. 
33. Motzer, R.J., et al., Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. New England Journal of Medicine, 2015. 
373(19): p. 1803-1813. 
34. Topalian , S.L., et al., Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer. New England Journal of 
Medicine, 2012. 366(26): p. 2443-2454. 
35. Armand, P., et al., Detection of circulating tumour DNA in patients with aggressive B-cell non-Hodgkin lymphoma. Br J 
Haematol, 2013. 163(1): p. 123-6. 
36. Oki, Y., et al., Detection of classical Hodgkin lymphoma specific sequence in peripheral blood using a next-generation 
sequencing approach. Br J Haematol, 2015. 169(5): p. 689-93. 
37. Roschewski, M., et al., Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a 
correlative biomarker study. Lancet Oncol, 2015. 16(5): p. 541-9. 
38. Kurtz, D.M., et al., Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing. 
Blood, 2015. 125(24): p. 3679-87. 
39. Logan, A.C., et al., Immunoglobulin and T cell receptor gene high-throughput sequencing quantifies minimal residual disease 
in acute lymphoblastic leukemia and predicts post-transplantation relapse and survival. Biol Blood Marrow Transplant, 2014. 
20(9): p. 1307-13. 
40. Logan, A.C., et al., Minimal residual disease quantification using consensus primers and high-throughput IGH sequencing 
predicts post-transplant relapse in chronic lymphocytic leukemia. Leukemia, 2013. 27(8): p. 1659-65. 
41. Herrera, A.F., et al., Next-generation sequencing-based detection of circulating tumour DNA After allogeneic stem cell 
transplantation for lymphoma. Br J Haematol, 2016. 
42. Herrera, A.F., et al. Sequencing-Based Detection of Circulating Tumor DNA in the Autologous Stem Cell Grafts of Patients with 
Diffuse Large B-Cell Lymphoma Undergoing Hematopoietic Stem Cell Transplantation. . in ASH Annual Meeting Abstracts 
2015;126:3156. 
43. Roemer, M.G., et al., PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. J Clin 
Oncol, 2016. 34(23): p. 2690-7. 

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44. Scott, D.W., et al., Gene expression-based model using formalin-fixed paraffin-embedded biopsies predicts overall survival in 
advanced-stage classical Hodgkin lymphoma. J Clin Oncol, 2013. 31(6): p. 692-700. 
45. Steidl, C., et al., Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with 
correlations to treatment outcome. Blood, 2010. 116(3): p. 418-27. 
46. Sanchez-Espiridion, B., et al., A molecular risk score based on 4 functional pathways for advanced classical Hodgkin lymphoma. 
Blood, 2010. 116(8): p. e12-7. 
47. Ji, R.R., et al., An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol 
Immunother, 2012. 61(7): p. 1019-31. 
48. Hugo, W., et al., Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma. Cell, 2016. 
165(1): p. 35-44. 
49. Tumeh, P.C., et al., PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature, 2014. 515(7528): p. 
568-71. 
50. Herbst, R.S., et al., Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature, 2014. 
515(7528): p. 563-7. 
51. Robert, L., et al., Distinct immunological mechanisms of CTLA-4 and PD-1 blockade revealed by analyzing TCR usage in blood 
lymphocytes. Oncoimmunology, 2014. 3: p. e29244. 
52. Robert, L., et al., CTLA4 blockade broadens the peripheral T-cell receptor repertoire. Clin Cancer Res, 2014. 20(9): p. 2424-32. 
53. Cheson, B.D., et al., Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin 
Lymphoma: The Lugano Classification. Journal of Clinical Oncology, 2014. 
54. Barrington, S.F., et al., Role of imaging in the staging and response assessment of lymphoma: consensus of the International 
Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol, 2014. 32(27): p. 3048-58. 
55. Oken, M.M., et al., Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol, 1982. 5(6): p. 
649-55. 
 
 
 
 

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APPENDIX A: ECOG PERFORMANCE STATUS  
ECOG Performance Status Scale [55] 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-
care, but unable to carry out any work activities.  Up and about 
more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any 
self-care.  Totally confined to bed or chair. 
5 
Dead. 
 
 
 

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APPENDIX B: REGISTRATION COVERSHEET  
COH IRB# 16378: A Phase 2 Study of Nivolumab and Brentuximab Vedotin Consolidation After Autologous 
Stem Cell Transplantation in Patients with High-Risk Classical Hodgkin Lymphoma 
Data Coordinating Center:   
City of Hope 
1500 Duarte Road 
Duarte, CA 91010  
Tel:  (626)-218-7904 
Email:  DCC@coh.org (use #secure# in subject line) 
Site Principal Investigator  
Name: 
Address: 
 
 
Phone:  
Fax:  
e-mail: 
CRA/Study Coordinator:     
Contact Number:   
Patient’s Initials: (F M L): 
Institution: 
Medical Record No: 
Investigator/Treating Physician: 
Patient’s DOB: 
IRB approval valid until (date): 
Sex: 
______Male 
______Female 
Date Informed Consent Signed: 
Projected start date of treatment: 
Race 
Ethnicity 
Method of 
Payment:_______________________ 
 
Black 
 Hispanic 
Codes: 
 
Caucasian 
 Non-Hispanic 
01 Private 
06 Military or Veterans 
Adm. sponsored 
 
Asian 
 Other_________________ 
02 Medicare 
07 Self-pay (no 
insurance) 
 
American Indian 
 
03 Medicare & 
private ins. 
08 No means of 
payment  (no insurance) 
 
Native Hawaiian/Pacific 
Islander 
04 Medicaid 
09 Unknown 
 
Other_______________
____________________ 
05 Medicaid & Medicare 
Reason for Screen Failure:  
 
Reason for Failing to Initiate Protocol Therapy: 
 
 
 
 

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APPENDIX C: TISSUE SHIPPING GUIDELINES FOR EXTERNAL NON-COH SITES  
These guidelines apply to non-COH sites only. 
All biological material must be shipped according to applicable government and International Air 
Transport Association (IATA) regulations.  
Shipping guidelines can also be found on the FedEx website. 
 
1. Aim to ship samples on a Monday through Wednesday. If this is not feasible, advance 
arrangements should be made with City of Hope Pathology Core (DL-PATHCORE-
BiospecimenSupport@COH.org).   
2. Notify City of Hope Pathology Core (DL-PATHCORE-BiospecimenSupport@COH.org) of impending 
shipment. To request a FedEx shipping label, email DCC@coh.org and indicate the planned 
shipment date. 
3. Slides/ Blocks: Batch ship at room temperature via FedEx. During extreme heat, include 
refrigerated (not frozen) gel packs or gel insulators. 
It is recommended to ship samples via FedEx overnight (for a delivery by 3 pm or earlier the next 
day) or FedEx 2-day (with a morning delivery). During extreme heat, ship via FedEx overnight (for 
a delivery ideally by 10.30 am, or 3 pm the next day). 
4. Frozen samples should be batch shipped on dry ice via FedEx overnight (for a delivery by 10.30 
am the next day). The shipment should contain enough dry ice to last at least 72 hours. 
5. On the day of shipment, email the sample shipment information to City of Hope Pathology Core 
(DL-PATHCORE-BiospecimenSupport@COH.org). 
6. Ship samples with a copy of the correlative tissue form (Appendix I) and a copy of the pathology 
report to: 
 
Karen Miller 
COH Pathology Core 
City of Hope National Medical Center 
1500 E. Duarte Road 
Familian Science (Building 084), Room 1207 
Duarte, CA 91010 
Telephone: 626-218-8408 
Email: DL-PATHCORE-BiospecimenSupport@COH.org 
 

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APPENDIX D: CORRELATIVE BLOOD COLLECTION FORM (NON-COH SITES ONLY) 
Subject ID (issued by DCC):   
Participant Initials (F, M, L) (if applicable): 
Institution: 
 
Blood samples will be collected from an indwelling venous catheter or by venipuncture.  Refer to Section 9.3 for 
collection details. 
 
Before scheduled blood collection (at least one day in advance) send calendar invite via email to Leslie Smith-
Powell (LSmith-Powell@coh.org) and Stephanie Lee (stlee@coh.org) or their designee at the Analytical 
Pharmacology Core Facility (APCF) to inform them of a pending collection. 
 
Sample 
# 
Timepoint of Collection 
Expected 
Volume 
Tube Type 
Used 
(Select One) 
Collected 
Volume 
Time of Collection 
Date of Collection 
1. 
 
Cycle 1 Day 1 
(C1D1)-Baseline 
20 mL 
Green-top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
20 mL 
BCT tube 
_____ mL 
____:____ AM/ PM 
____/____/____ 
2. 
 
Cycle 2 Day 1 
(C2D1)  
20 mL 
Green-top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
3. 
 
Cycle 5 Day 1 
(C5D1)  
(OR 3 months *^) 
20 mL 
Green-top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
20 mL 
BCT tube 
_____ mL 
____:____ AM/ PM 
____/____/____ 
4. 
 
30 days post-last dose  
20 mL 
Green-top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
20 mL 
BCT tube 
_____ mL 
____:____ AM/ PM 
____/____/____ 
5. 
 
6 months *^ 
20 mL 
Green-top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
20 mL 
BCT tube 
_____ mL 
____:____ AM/ PM 
____/____/____ 
6. 
 
12 months from start of 
treatment (if yet to progress) 
20 mL 
Green-top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
20 mL 
BCT tube 
_____ mL 
____:____ AM/ PM 
____/____/____ 
7. 
 
18 months from start of 
treatment (if yet to progress) 
20 mL 
Green-top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
20 mL 
BCT tube 
_____ mL 
____:____ AM/ PM 
____/____/____ 
* If off treatment (i.e. < 8 cycles of treatment) but yet to progress  
^ Collect during Active Follow-up assessment per Section 10.0. 
 
A copy of this form should accompany the sample shipments to COH APCF. Refer to Appendix E for 
shipping instructions COH APCF. 
 
CRA/Study Coordinator/ Nurse:   
Contact Number: 
CRA/Study Coordinator/ Nurse Signature:   
Date: 

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APPENDIX E: BLOOD SHIPPING GUIDELINES FOR EXTERNAL NON-COH SITES  
Follow the requirements for the proper packaging and shipping of biomedical material found in 42 CFR 
Part 72 - Interstate Shipment of Etiologic Agents Centers for Disease Control and Prevention, Office of 
Health and Safety Biosafety Branch. 
When to ship and 
temperature of shipment: 
BCT tubes: Via overnight courier at ambient temperature. 
 
Green-tops: On the day of collection overnight at around +4 oC with a refrigerated 
cool pack in an appropriate container via FedEx 
 
Days to ship: 
Monday-Wednesday for receipt Tuesday-Friday by the laboratory.  
If this is not feasible, advance arrangements should be made with Leslie Smith-
Powell (LSmith-Powell@coh.org) or Stephanie Lee (stlee@coh.org) or their 
representative. 
Notification on the day of 
shipment 
Email the FedEx shipment # with a copy of Appendix D. 
 
Leslie Smith-Powell (LSmith-Powell@coh.org) or  
 
Stephanie Lee (stlee@coh.org) or their representative  
 
What to include with the 
shipment 
 
Copy of Appendix D  
 
Copy of the latest CBC results (with differential) and the date of the test  
Shipment address 
Dr. Tim Synold 
Analytical Pharmacology Core Facility  
Shapiro 1042 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
 
 
 
 
 
 
 
 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
City of Hope #: 16378  
Protocol Version:  09- May 16 2022 
 
CONFIDENTIAL 
Page 103  
APPENDIX G: EXPEDITED REPORTING COVERSHEET 
NOTIFICATION OF UNANTICIPATED PROBLEM/SERIOUS ADVERSE EVENT 
For Use by Participating Institutions Only 
THIS FORM ALONG WITH A COPY OF THE MEDWATCH 3500 OR IRB REPORTING FORM MUST BE EMAILED TO DCC@COH.ORG 
WITHIN 24 HOURS OF KNOWLEDGE OF ONSET OF SERIOUS ADVERSE EVENT OR UNANCTICIPATED PROBLEM  
COH IRB #16378- Participating Site IRB # ___________ 
From: 
Date: 
Phone No.: 
Email: 
Reporting Investigator: 
Event:  
Participant ID: 
Institution: 
Date Event Met Reporting Criteria (as defined in protocol):   
 
Type of Report: 
 Initial    Follow-up 
CTCAE Grade:   
 G1/mild    G2/moderate     G3/severe    G4/life threatening   
 G5 
Attribution to nivolumab: 
 Unrelated   Unlikely   Possible    Probable   Definite 
Attribution to brentuximab 
vedotin: 
 Unrelated   Unlikely   Possible    Probable   Definite 
Historical/Known Correlation to 
nivolumab: 
 Expected    Unexpected 
Historical/Known Correlation to 
brentuximab vedotin: 
 Expected    Unexpected   
Meets Definition of Serious AE:      Serious      Non-serious 
Meets Definition of 
Unanticipated Problem: 
   UP      Not a UP 
Has the event been reported to 
the following institution’s IRB? 
   No      Yes; Date:_____/____/_____ 
 
Authorized Investigator Signature:   
Date:____/____/____ 
 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
City of Hope #: 16378  
Protocol Version:  09- May 16 2022 
 
CONFIDENTIAL 
Page 104  
APPENDIX H: LYRIC CRITERIA 
Lugano Classification was developed based on treatment with cytotoxic agents [53]. Immunotherapeutic 
drugs, may produce antitumor effects by potentiating endogenous cancer-specific immune responses. 
The response patterns seen with such an approach may extend beyond the typical time course of 
responses seen with cytotoxic agents, and can manifest as clinical responses after initial increases in 
tumor burden or even the appearance of new lesions. Thus, the 2014 Lugano Classification may not 
provide an accurate assessment of response to immunotherapeutic agents. Provisional modification of 
the Lugano criteria (LYRIC Criteria) may be used to assess participants who meet progressive disease per 
Lugano Classification [1, 53]. 
Complete Response 
Partial Response 
Progressive Disease 
Same as Lugano  
Same as Lugano  
As with Lugano with the following exceptions: 
 
Indeterminate response (IR) 
 
IR1: ≥50% increase in SPD of up to 6 measurable lesions 
in first 12 weeks of therapy without clinical deterioration 
 
IR2: <50% increase in the overall SPD with 
a. Appearance of a new lesion(s), or 
b. ≥50% increase in PPD of a lesion or set of lesions at 
any time during treatment 
 
IR(3): Increase in FDG uptake without a concomitant 
increase in lesion size or number  
 
Patients with IR should continue on therapy and have repeat 
imaging after an additional 12 weeks (or sooner if clinically 
indicated). 
Progressive disease criteria in these patients will be met if:  
 
IR1: An additional increase in the target SPD of ≥ 10% 
between the first IR1 timepoint and the SPD being 
assessed; or an increase in ≥ 5mm in either dimension of 
at least one lesion for lesions ≤ 2cm and 10mm for 
lesions > 2cm. 
 
IR2: the new or growing lesion(s) should be added to the 
target lesions (total of no more than 6) and there is PD if 
the SPD if the newly defined set of target lesions has 
increased ≥50% from their nadir value (which may 
precede the IR time point). 
 
IR3: There is evidence of PD by an increase in lesion size 
or the development of new lesions. 
Abbreviations: SPD, sum of the product of the diameters; PPD, product of the perpendicular diameters. 
 
 
 

Nivolumab and Brentuximab vedotin Consolidation for HL post-ASCT  
City of Hope #: 16378  
Protocol Version:  09- May 16 2022 
 
CONFIDENTIAL 
Page 105  
APPENDIX I: CORRELATIVE TISSUE FORM (FOR ALL SITES) 
 
A copy of this form should accompany the sample shipments to COH Pathology Core. 
Non-COH sites: refer to Appendix C for shipping instructions to COH Pathology Core. 
 
COH IRB number: 16378 
Shipping date (MM-DD-YYYY):   ________/________/________ 
Subject ID (issued by DCC):   
Participant Initials (F, M, L) (if applicable): 
Institution: 
Date of collection/ biopsy (MM-DD-YYYY):    ________/________/________ 
Time point:     
  Baseline       
  Progression 
Diagnosis: 
Tissue type (FFPE scrolls, slides, biopsies): 
Number of scrolls: 
Number of slides: 
 
 
 
 
 
 
CRA/Study Coordinator/Nurse Printed Name:   
CRA/Study Coordinator/Nurse Signature:   
Contact Number: