Clinical trial NCT02581631
Conditions: Non-Hodgkin's Disease
Sponsor: Bristol-Myers Squibb
Start date: 2016-02-11; Completion date: 2022-02-07
Enrollment: 145 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine whether Nivolumab, in combination with brentuximab vedotin, is safe and effective in patients with certain subtypes of non-Hodgkin's lymphomas with CD30 expression that have not responded to treatment or have come back. The subtypes we are studying are Diffuse Large B-Cell Lymphoma (DLBCL), Peripheral T-Cell Lymphoma (PTCL), Cutaneous T-Cell Lymphoma (CTCL), Primary Mediastinal Large B-Cell Lymphoma (PMBL) and Mediastinal Gray Zone Lymphoma (MGZL).

Detailed description:

Arms: arm 1: Nivolumab+Brentuximab Vedotin dose as specified
Interventions: intervention 1: Nivolumab intervention 2: Brentuximab Vedotin
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Protocol for 
 
Official Title of Study 
A Phase I/ II Study to Evaluate the Safety and Preliminary Efficacy of Nivolumab in 
Combination with Brentuximab Vedotin in Subjects with Relapsed Refractory Non Hodgkin 
Lymphomas with CD30 Expression CheckMate 436: CHECKpoint pathway and nivolumab 
clinical Trial Evaluation 
 
NCT02581631 
 
September 14, 2016 


Page:
1
Protocol Number:
CA209436
IND Number:
119,380
Ex-US
Non-IND
EUDRACT Number
2015-003286-28
Date:
05-Aug-2015
Revised Date:
14-Sep-2016
Clinical Protocol CA209436
A Phase I/ II Study to Evaluate the Safety and Preliminary Efficacy of Nivolumab in 
Combination with Brentuximab Vedotin in Subjects with Relapsed Refractory Non Hodgkin 
Lymphomas with CD30 Expression CheckMate 436: CHECKpoint pathway and nivolumab
clinical Trial Evaluation
Revised Protocol Number: 01
Incorporates Amendment: 04
Route 206 & Province Line Road
Lawrenceville, NJ - 08543 - USA
Telephone (office): 
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USA:
International: 
Bristol-Myers Squibb Research and Development
Route 206 & Province Line Road
Lawrenceville, NJ 08543
Avenue de Finlande 8, Building F - 1st Floor
B-1420 Braine-L’Alleud, Belgium
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
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BMS-936558
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Revised Protocol No.: 01
Date:  14-Sep-2016
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expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Revised Protocol No.: 01
Date:  14-Sep-2016
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 01
14-Sep-2016
Incorporates Amendment 04
Amendment 04
14-Sep-2016
This amendment will allow additional cohorts in subjects with relapsed 
PMBL & MGZL to participate in the expansion cohort. Additionally, the 
amendment will also provide defined Indeterminate response (IR) criteria 
along with changes in the biomarker section. Minor clarification in the 
inclusion, exclusion criteria and clarification of dose adjustment for 
brentuximab vedotin for grade 3 neurological toxicity has also been 
updated
Original 
Protocol
05-Aug-2015
Not applicable
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SYNOPSIS
Clinical Protocol CA209436
Protocol Title: A Phase I/ II Study to Evaluate the Safety and Preliminary Efficacy of Nivolumab in Combination 
with Brentuximab Vedotin in Subjects with Relapsed Refractory Non Hodgkin Lymphomas with CD30 Expression 
CheckMate 436: CHECKpoint pathway and nivolumab clinical Trial Evaluation
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Brentuximab vedotin 1.8 mg/kg is to be administered as a 30-minute intravenous infusion on day 1 of 
every 3-week cycle during the Dose Evaluation Phase (Cohort A). The brentuximab vedotin dose for the Expansion 
Phase (Cohort B) will be determined once the Dose Limiting Toxicity (DLT) period in Cohort A is complete.
Nivolumab dose will be 240 mg flat administered intravenously over a 30-minute infusion throughout Cohort A and 
Cohort B. Nivolumab is to be administered on Cycle 1, day 8. Subsequent to cycle 1, both drugs will be 
administered on the Day 1 of every 3-week cycle. 
Study Phase:  Phase I/II
Research Hypothesis: The study will investigate the hypothesis that brentuximab vedotin can be safely combined 
with nivolumab. Additionally, the study will investigate that the combination can result in a clinical meaningful 
ORR in subjects with relapsed/refractory Diffuse Large B Cell Lymphoma (DLBCL), relapsed/refractory Peripheral 
T Cell Lymphoma (PTCL) (all subtypes excluding Anaplastic Large Cell Lymphoma), relapsed/refractory Primary 
Mediastinal B Lymphoma (PMBL), relapsed/refractory Mediastinal Gray Zone Lymphoma (MGZL) and 
relapsed/refractory Cutaneous T Cell Lymphoma (CTCL) Mycosis Fungoides/Sezary Syndrome (MF/SS).
Objectives: 
Primary Objectives: 
•
To evaluate the safety and tolerability of the combination of nivolumab and brentuximab in subjects with the 
diagnosis of relapsed, refractory DLBCL, PTCL (all subtypes excluding ALCL), CTCL (MF/SS), PMBL and 
MGZL.
•
To assess the clinical benefit of nivolumab and brentuximab vedotin combination regimen in subjects with the 
diagnosis of relapsed/refractory DLBCL, relapsed/refractory PTCL (excluding ALCL), relapsed refractory 
CTCL, relapsed/refractory PMBL, and relapsed/refractory MGZL (MF/SS) (CD30 expression t 1% by 
immunohistochemistry (IHC) is a prerequisite for all subjects participating in this study), as measured by ORR, 
defined as the proportion of subjects achieving either a PR or CR. In subjects with relapsed/refractory DLBCL,
relapsed/refractory PTCL, relapsed/refractory PMBL, and relapsed/refractory MGZL, the response will be 
assessed according to Lugano Classification 2014. For subjects with relapsed/refractory CTCL, response will be 
assessed according to consensus Global Response Score as per the consensus statement of the International 
Society for Cutaneous Lymphoma.
Secondary Objectives:
•
To assess overall duration of response (DOR) of the brentuximab vedotin and nivolumab combination regimen 
based on investigators assessments
•
To assess the complete response rate (CRR) with the combination regimen and the duration of CR based on 
investigators assessments. 
•
To assess progression free survival (PFS) based on investigators assessments and overall survival (OS) of the
brentuximab vedotin and nivolumab combination regimen.
Exploratory Objectives:
•
To assess the Indeterminate response (IR) per Lymphoma Response to Immunomodulatory therapy Criteria 
(LYRIC) in subjects with DLBCL, PTCL, PMBL, MGZL and CTCL (if applicable)
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•
To assess CD30 expression and correlate with response, and to assess PD-L1/L2 status and correlate it with 
response
•
To characterize the molecular effects of the brentuximab vedotin and nivolumab combination regimen on tumor 
cells and the immune response; and identify biomarkers of response or resistance to the combination
•
To assess tumor microenvironment and peripheral immune status
•
To characterize pharmacokinetics of nivolumab and brentuximab and explore exposure response relationships
•
To characterize the immunogenicity of nivolumab and brentuximab following combination therapy
•
To evaluate changes in general health status assessed by the EQ-5D 3L (Cohort B only)
Study Design:  
This is an open-label, multicenter phase I/II study of nivolumab in combination with brentuximab vedotin designed 
to evaluate the safety and efficacy in subjects with the diagnosis relapsed/refractory of DLBCL, PTCL (excluding 
ALCL) , CTCL (MF/SS), PMBL and MGZL. 
The study will consist of three phases: Screening, Treatment and Follow-up. The treatment phase is divided in two 
parts: Cohort A consists of the Dose Evaluation Phase and Cohort B is the Expansion Phase.
It is anticipated that 170 subjects will be enrolled in the United States, Canada and Europe for the entire study 
(Cohort A and Cohort B combined). All subjects will undergo a screening period to determine eligibility within 28 
days prior to initial dosing. 
Dose Evaluation Phase (Cohort A)
The Dose Evaluation Phase (Cohort A) will include a dose limiting toxicity (DLT) evaluation for the dose level of 
brentuximab vedotin 1.8 mg/kg intravenously in combination with nivolumab 240 mg flat dose intravenously in a q 
3 week cycle. Refer to section 4.5.1 for further details. 
In cycle 1, brentuximab vedotin 1.8mg/kg will be administered on day 1 nivolumab 240 mg flat dose will be 
administered on day 8. Subsequent to cycle 1, both drugs will be administered on the first day of the new cycle. 
Brentuximab vedotin will be administered first as a 30-minute infusion followed by a minimum 30-minute rest. 
Nivolumab will then be administered also as a 30-minute infusion.  
The DLT evaluation period, which consists of the first dose of study drug through the first 6 weeks of treatment, will 
be conducted in the first 6 treated subjects (all comers). Decisions to enroll up to 6 additional subjects onto the same 
dose of brentuximab vedotin 1.8 mg/kg in combination with nivolumab 240 mg flat dose intravenously every 3 
weeks or at a reduced dose of brentuximab vedotin at 1.2 mg/kg will be based on the safety data reviewed 
throughout the DLT evaluation period. 
If any of the first 6 treated subjects discontinue treatment for reasons other than a DLT but prior to completing the 
DLT evaluation period, then they will be replaced. Subjects enrolled to Cohort A will be monitored for DLT 
throughout the DLT evaluation period. Refer to section 4.5.1 for DLT definition. 
After 6 DLT-evaluable subjects have been followed through the first 6 weeks of treatment, or at the point that 2 or 
more subjects experience a DLT, whichever comes first, the study team will review the available data and provide 
any of the following recommendations, but not limited to:
1.
If one or none (d 1) of the 6 subjects experience a DLT, the expansion cohort will begin with brentuximab 
vedotin 1.8 mg/kg Cycle 1 Day 1 and nivolumab 240 mg flat dose on Cycle 1 Day 8. 
2.
If two or more (t 2) of the 6 subjects are determined to have had a DLT based on the protocol definition (refer 
to section 4.5.1) , the following options will be considered
a.
To repeat Cohort A of the study and treat up to 6 additional subjects at the same drug doses and schedule 
previously tested 
b.
To repeat Cohort A of the study and treat up to 6 additional subjects at a reduced dose of brentuximab 
vedotin 1.2 mg/kg
c.
Administration of the combination treatment on Day 1 of every cycle, including cycle 1
d.
To close the study to additional enrollment
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NOTE: Doses may not be increased to above 1.8 mg/kg brentuximab vedotin or nivolumab 240 mg flat dose.
On review of all available data, the study team may determine that the classification of DLT was not appropriate for 
one or more of the subjects, in which case enrollment may resume if the target of 6 DLT-evaluable subjects has not 
yet been reached. However, if 2 or more subjects were determined to have experienced DLTs, then expansion will 
not occur as the next step. Based on the study team’s recommendations, up to 6 additional subjects may be enrolled 
in Cohort A at the same drug dose levels and schedule or at a modified treatment (described above in this section). 
These additional subjects will then be assessed for DLT in the same manner described above to determine if it is 
appropriate to move to the Expansion Phase (Cohort B). If it is determined by the study team that due to safety
concerns no additional dose levels or schedules should be enrolled, then the study will be closed to enrollment.
There is no planned interim analysis (IA). However, all available efficacy and safety data will be used to select the 
recommended brentuximab vedotin dose and treatment schedule that will be further evaluated in the Expansion 
Phase (Cohort B). 
Expansion Phase (Cohort B)
The Expansion Phase will assess the combination of nivolumab and brentuximab vedotin and will consist of a 
single-arm phase II study which will expand enrollment at the recommended dose level and treatment schedule as 
deemed safe by the study team in Cohort A.  An additional 40 subjects in DLBCL (cohort B1), 30 subjects in PTCL 
(cohort B2), 20 subjects in CTCL (cohort B3), 30 subjects in PMBL (cohort B4) and 10 subjects MGZL (cohort B5)
will be enrolled to complete this evaluation. 
If one or none (d 1) of the 6 subjects experience a DLT, the expansion cohort will begin with brentuximab vedotin 
1.8 mg/kg Cycle 1 Day 1 and nivolumab 240 mg flat dose on Cycle 1 Day 8. Subsequent to cycle 1, both drugs will 
be administered on the first day of the new cycle. Brentuximab vedotin will be administered first as a 30-minute 
infusion followed by a minimum 30-minute rest. Nivolumab will be then be administered as a 30-minute infusion. If 
two or more (t 2) of the 6 subjects are determined to have had a DLT based on the protocol definition (refer to 
section 4.5.1) treatment modification or enrollment closure will be considered, as described above.
All subjects in Cohort A and Cohort B will be allowed to be treated until disease progression or unacceptable 
toxicity as described in Section 4.5.3 and Section 4.5.5. If during therapy it appears that a subject is benefiting from 
the combination but experiencing toxicities related to one agent that would require permanent treatment 
discontinuation, then they have the option to continue therapy with the single agent not attributing to toxicities.
Subjects that present progressive disease during treatment may be allowed to be treated beyond progression until 
further progression is observed. Refer to Section 4.5.9 for further details.
Once subjects discontinue from study treatment for any reason, subjects will enter the follow-up phase of the study. 
During follow-up, long-term safety, survival status, disease progression, subsequent anticancer therapy and 
occurrence of other primary malignancy data will be collected. Follow-up visit 1 (X01) and follow-up visit 2 (X02) 
will be in person visits and all subsequent follow-up visits may be done in person or by phone. All treated subjects 
will be followed for survival at least every 3 months until death or lost to follow-up. Subjects with residual toxicity 
G t 2 at the time of discontinuation must follow these until resolved to at least G1, end of study or deemed 
irreversible, whichever occurs first. Subjects who discontinue for reasons different than progressive disease must 
continue to perform tumor assessments as described in Section 5.4 until disease progression is documented. 
The primary endpoint for Cohort B will be investigator-assessed ORR for all five tumor types. This analysis will 
occur 8 months after the last patient receives their first treatment (LPFT). Depending on the enrollment for each 
disease cohort, the analysis may be done at different times for each cohort or at the same time for the five cohorts.
The study design schematic is presented below.
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Study Population: Subjects with pathologically confirmed non-hodgkin lymphoid malignancies. The types of 
lymphoma for key eligibility criteria include; Diffuse Large B cell Lymphoma (DLBCL), Peripheral T cell 
Lymphoma (PTCL, all subtypes excluding Anaplastic Large Cell Lymphoma), Primary Mediastinal B Lymphoma
(PMBL), Mediastinal Gray Zone Lymphoma (MGZL) and Cutaneous T cell Lymphoma (Mycosis Fungoides and 
Sezary Syndrome) that have failed at least one prior line of chemotherapy, along with measurable disease and 
confirmed CD30 expression t 1%. Subjects must have an eastern cooperative oncology group (ECOG) score of 0-1, 
along with laboratory criteria as outlined in Section 3.3.
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Study Drug include both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug for CA209436
Medication 
Potency 
IP/Non-IP 
Nivolumab
100mg (10mg/dL)
IP
Brentuximab Vedotin
50mg
IP
Study Assessments: 
Safety Evaluation: Adverse events will be assessed continuously during the study and for 100 days post last 
treatment. Adverse events will be coded using the most current version of MedDRA and reviewed for potential 
significance and importance. Adverse events will be evaluated according to the NCI CTCAE Version 4.03. Subjects 
should be followed until all treatment-related adverse events have recovered to baseline or are deemed irreversible 
by the investigator.
Efficacy Assessments: Primary efficacy endpoint in this study is Objective Response Rate. Subjects will perform 
tumor assessments at week 6 and week 12 continuing every 9 weeks (+/- 1 week) for the subsequent 4 tumor 
assessment timepoints, regardless of dosing schedule. After the first year, tumor assessments are to occur every 
12 weeks (+/- 2 weeks) until disease progression is documented. Subjects with DLBCL, PTCL, PMBL, and MGZL
will follow the Lugano Classification 2014 and perform FDG PET-CT at the tumor assessment time points. Subjects 
with CTCL will follow the mSWAT and Global Response Score and will perform CT/MRI along with whole blood 
and medical photography (as appropriate) at the tumor assessment time points described in Section 5.4.
Statistical Considerations:
Sample Size: In the Dose Evaluation Phase (Cohort A), 6 -12 subjects will be treated. The number of subjects is not 
based on statistical power considerations. If less than 1/3 of 6 subjects experience a DLT, the upper limit of the 80% 
1-sided exact confidence interval for the true DLT rate will not be greater than 42%. If less than 1/3 of 12 subjects 
experience a DLT, the upper limit of the 1-sided 80% exact confidence interval (CI) for the true DLT rate will not 
be greater than 41.2%. 
In the Expansion Phase (Cohort B), a total of 130 subjects will be treated, with 40 subjects in cohort B1 (DLBCL), 
30 subjects in cohort B2 (PTCL), 20 subjects in B3 (CTCL), 30 subjects in cohort B4 (PMBL) and 10 subjects in 
cohort B5 (MGZL). 

Given 40 subjects in DLBCL, the one-sided 90% confidence interval (ie, two-sided 80% confidence 
interval) for the ORR is 48.6% - 70.6% if we assume an observed ORR rate of 60%. The lower bound of 
the 90% CI excludes 40%, which is the null hypothesis ORR rate for PTCL.

Given 30 subjects in PTCL, the one-sided 90% confidence interval (ie, two-sided 80% confidence interval) 
for the ORR is 46.7% - 72.3% if we assume an observed ORR rate of 60%. The lower bound of the 90% CI 
excludes 40%, which is the null hypothesis ORR rate for PTCL. 

Given 20 subjects in CTCL, the one-sided 90% confidence interval (ie, two-sided 80% confidence interval) 
for ORR is 63.9% - 91.0% if we assume an observed ORR rate of 80%. The lower bound of the 90% CI 
excludes 60%, which is the null hypothesis ORR rate for CTCL. 

Given 30 subjects in PMBL, the one-sided 90 % confidence interval (ie, two-sided 80% confidence 
interval) for the ORR is 37.0% - 63.0% if we assume an observed ORR rate of 50%. The lower bound of 
the 90% CI excludes 30%, which is the null hypothesis ORR rate for PMBL. 

Given 10 subjects in MGZL, the one-sided 90 % confidence interval (ie, two-sided 80% confidence 
interval) for the ORR is 11.6% - 55.2% if we assume an observed ORR rate of 50%. The lower bound of 
the 90% CI excludes 10%, which is the null hypothesis ORR rate for MGZL.
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Table below summarizes the 90% exact CI for different targeted ORRs and sample sizes. The targeted ORR of 60% 
in DLBCL and PTCL and 80% in CTCL, and null hypothesis ORR rate of 40% in DLBCL and PTCL and 60% in 
CTCL are based on the historical data and the activity of brentuximab vedotin and nivolumab as single agents from 
phase I and phase II studies.
One-sided 90% Exact CI for different number of subjects in each cohort
If the observed ORR rate is 60% in Cohort B1 and B2
Power
N=30
[46.7% - 72.3%] 
82%
N=40
[48.6% - 70.6%]
87%
If the observed ORR rate is 80% in Cohort B3
N=20
[63.9% - 91.0%]
62 % 
If the observed ORR rate is 50% in Cohort B4
N=30
[37.0% - 63.0%]
81 %
If the observed ORR rate is 30% in Cohort B5
N=10
[11.6% - 55.2%]
61%
Also, If we have 20 subjects in Cohort B3, assuming true ORR is 80%, there will be approximately 62% power to 
reject null hypothesis that the true ORR is <=60%, considering a one-sided alpha of 10%. Given a very low 
prevalence of CTCL, 20 subjects in cohort B3 is considered as feasible and adequate for a phase II signal detecting 
trial. Sample size of 30 subjects in Cohort B2 and 40 subjects in Cohort B1 are corresponding to power of 82% and 
87% respectively to reject null hypothesis that the true ORR is <=40% assuming true ORR is 60% and considering a 
one-sided alpha of 10%. If we have 30 subjects in Cohort B4, assuming true ORR is 50%, there will be 
approximately 81% power to reject null hypothesis that the true ORR is <= 30%, considering a one-sided alpha of 
10%. Finally if we have 10 subjects in Cohort B5, assuming true ORR is 30%, there will be approximately 61% 
power to reject null hypothesis that the true ORR is <= 10%, considering a one-sided alpha of 10%.
Endpoints:
The safety endpoints include incidence of deaths, adverse events, serious adverse events, adverse 
events leading to discontinuation, adverse events leading to dose delay, select adverse events and specific laboratory 
abnormalities (worst grade). Toxicities will be graded using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03.
The primary efficacy endpoint is ORR. It is defined as the number of subjects with a best overall response (BOR) of 
confirmed CR or PR divided by the number of treated subjects. The BOR is defined as the best response designation 
recorded between the date of first dose and the date of initial objectively documented progression or the date of 
subsequent therapy, whichever occurs first. In subjects with relapsed/refractory DLBCL, relapsed/refractory PTCL, 
relapsed refractory PMBL and relapsed refractory MGZL the response (CR, PR, PD, and progression) will be 
assessed according to Lugano Classification 2014. For subjects with relapsed/refractory CTCL, response will be 
assessed according to consensus Global Response Score as per the consensus statement of the International Society 
for Cutaneous Lymphoma. The secondary endpoints are DOR, CR rate, duration of CR, PFS and OS.
Analyses:  All analyses will be performed separately for each cohort and also for all treated subjects.
Descriptive statistics of safety will be presented using National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03. All on study AEs, drug-related, AEs, SAEs and drug-related 
SAEs will be tabulated using worst grade per NCI CTCAE v4.03 criteria by system organ class and MedDRA 
preferred term. On-study lab parameters including hematology, chemistry, liver function, thyroid function, and renal 
function will be summarized using worst grade per NCI CTCAE v4.0 criteria. 
The ORR will be summarized by binomial response rates and their corresponding one-sided 90% exact CIs using the 
Clopper-Pearson method. The same analysis will be performed for CR rate.
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The DOR will be summarized by cohort for subjects who achieve confirmed PR or CR using the Kaplan Meier 
(KM) product-limit method. Median values of DOR, along with one-sided 90% CI using log-log transformation 
method and range, will also be calculated. The same analysis will be performed for duration of CR, PFS and OS at 
1 year.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Unmet medical need in DLBCL ............................................................... 
1.1.2 Rationale for nivolumab and brentuximab vedotin in relapsed DLBCL . 
1.1.3 Unmet medical need in Peripheral T Cell NHL (PTCL) ......................... 
1.1.4 Rationale for nivolumab combination with brentuximab vedotin in PTCL
.....................................................................................................................
1.1.5 Unmet medical need in CTCL Mycosis Fungoides (MF) and Sezary 
Syndrome (SS) ............................................................................................. 
1.1.6 Rationale for nivolumab and brentuximab vedotin in CTCL (MF/SS) .... 
1.1.7 Unmet Need in Primary Mediastinal B Lymphoma (PMBL) ................... 
1.1.8 Rationale for nivolumab combination with brentuximab vedotin in PMBL
.....................................................................................................................
1.1.9 Unmet Medical Need in Mediastinal Gray Zone Lymphoma (MGZL) .... 
1.1.10 Rationale for nivolumab combination with brentuximab vedotin in 
MGZL .......................................................................................................... 
1.1.11 Rationale for permitting continued treatment in select cases of PD ..... 
1.1.12 Rationale and Aims for Biomarker Assessments ................................... 
1.1.13 Rationale for Study Design .................................................................... 
1.1.13.1 Rationale for Dose Selection ........................................................ 
1.1.13.2 Flat Dose Rationale ...................................................................... 
1.1.13.3 Every 3 Week Dosing Interval Rationale ...................................... 
1.1.13.4 Thirty Minute Infusion Time Rationale ......................................... 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
1.3.3 Exploratory Objectives ............................................................................ 
1.4 Product Development Background ................................................................... 
1.4.1 Clinical Pharmacology Summary (Nivolumab) ....................................... 
1.4.2 Clinical Pharmacology Summary (Brentuximab Vedotin) ...................... 
1.4.3 Safety Summary (Nivolumab) .................................................................. 
1.4.4 Safety Summary (Brentuximab Vedotin) .................................................. 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
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CA209436
nivolumab
Revised Protocol No.: 01
Date: 14-Sep-2016
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3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.4.2.1 Permitted Therapy .......................................................................... 
3.5 Discontinuation of subjects following any treatment with study drug ............. 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.3.1 Brentuximab Vedotin ............................................................................... 
4.3.2 Nivolumab ................................................................................................ 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Dose Evaluation Phase: (Cohort A) ........................................................ 
4.5.2 Premedication .......................................................................................... 
4.5.3 Dose Modifications for Brentuximab Vedotin ......................................... 
4.5.4 Dose Modifications for Nivolumab .......................................................... 
4.5.4.1 Nivolumab Dose Delays .................................................................. 
4.5.4.2 Criteria to Resume Nivolumab Dosing ........................................... 
4.5.4.3 Nivolumab Dose Reductions and Escalations ................................ 
4.5.5 Nivolumab Treatment Discontinuation .................................................... 
4.5.5.1 Management Algorithms for Immuno-Oncology Agents ................ 
4.5.6 Treatment of Infusion Related Reactions (nivolumab/brentuximab 
vedotin) ....................................................................................................... 
4.5.7 Management of Suspected PML............................................................... 
4.5.8 Guidelines for Assessment and Initial Management of Tumor Lysis 
Syndrome.....................................................................................................
4.5.9 Treatment Beyond Disease Progression .................................................. 
4.5.9.1 Circumstances in which post-progression treatment is permitted .. 
4.5.9.2 Assessment Schedule for the Subjects with Post-progression 
Treatment .............................................................................................. 
4.5.9.3 Discontinuation due to “Further Progression” ............................. 
4.5.9.4 Efficacy Assessment for Subjects who Discontinue Study Drug 
during Post-Progression Treatment ..................................................... 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
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4.10 Retained Samples for Bioavailability / Bioequivalence ................................. 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Imaging Assessment for the Study............................................................ 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Radiographic Assessments ....................................................................... 
5.4.2 Assessment of Overall Tumor Burden and Measurable Disease ............. 
5.4.2.1 Measurable Lesions ........................................................................ 
5.4.2.2 Non-Measurable Lesions ................................................................ 
5.4.3 Specifications by Method of Assessment .................................................. 
5.4.3.1 Measurement of Lesions ................................................................. 
5.4.3.2 Method of Assessment ..................................................................... 
5.4.3.3 FDG PET-CT, CT Scan and MRI ................................................... 
5.4.3.4 Clinical Lesions .............................................................................. 
5.4.3.5 Medical Photography (Skin lesions only) ....................................... 
5.4.3.6 Whole Blood (SS-CTCL only) ......................................................... 
5.4.3.7 Target Lesions ................................................................................. 
5.4.3.8 Non-Target Lesions ......................................................................... 
5.4.4 Bone Marrow Assessments ...................................................................... 
5.4.5 Disease Response Evaluation .................................................................. 
5.5 Pharmacokinetic and Immunogenicity Assessments ........................................ 
5.5.1 Pharmacokinetics: Collection and Processing ........................................ 
5.6 Biomarker Assessments .................................................................................... 
5.6.1 Biomarker Sampling ................................................................................ 
5.6.2 Detailed Biomarkers ................................................................................ 
5.7 Outcomes Research Assessments ..................................................................... 
5.8 Other Assessments ............................................................................................ 
5.8.1 Immunogenicity Assessments ................................................................... 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
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8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.3.3 Exploratory Endpoint(s) .......................................................................... 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.5 Biomarker Analyses ................................................................................. 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses ......................................................................................... 
8.4.7.1 Immunogenicity Analyses ................................................................ 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 ECOG PERFORMANCE STATUS ..................................................... 
APPENDIX 2 2014 LUGANO CLASSIFICATION: STAGING AND RESPONSE 
EVALUATION (DIFFUSE LARGE B CELL LYMPHOMA, PERIPHERAL T 
CELL LYMPHOMA, PRIMARY MEDIASTINAL B LYMPHOMA & 
MEDIASTINAL GRAY ZONE LYMPHOMA). ................................................... 
APPENDIX 3 CUTANEOUS T CELL LYMPHOMA ISCL/EORTC STAGING 
CRITERIA .............................................................................................................. 
APPENDIX 4 MODIFIED SEVERITY WEIGHTED ASSESSMENT TOOL / 
GLOBAL RESPONSE SCORE ............................................................................. 
APPENDIX 5 ACUTE GVHD GRADING AND STAGING ..................................... 
APPENDIX 6 MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS ................................................................................................................. 
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1
INTRODUCTION AND STUDY RATIONALE
Treatment with conventional cytotoxic chemotherapy results in promising responses by 
eliminating tumor cells, however a great majority of subjects relapse with need for therapies that 
can result in durable responses. The therapeutic efficacy of standard conventional 
chemotherapeutic treatments is often limited by the emergence of molecular resistance resulting 
in relapse. Evasion of the host immune responses is an important mechanism for inducing 
resistance to cancer therapy.1,2 Over the last several decades drug development in oncology has 
seen the emergence of immune therapies.3 The armamentarium includes 1) vaccine approaches to 
cause strong specific immune responses to tumor antigens 2) adoptive transfer of ex vivo expanded 
engineered or innate tumor specific lymphocytes 3) therapeutic administration of monoclonal 
antibodies such as rituximab against CD20 on lymphoid malignant cells, Herceptin® 
(trastuzumab) directed against HER2 on breast cancer cells and 4) strategies to block molecular 
and cellular mediators of cancer induced immunosuppression such as Cytotoxic T-Lymphocyte 
Antigen 4 (CTLA4, CD152), Programmed Death -1 receptor (PD-1, CD279) or T regulatory cells 
(T reg).1
Tumor cells up regulate expression of the immune check point receptors (ICR) such as CTLA4, 
PD-1 and the ligands (PD-L1, B7-H1/CD274) ICR which effectively attenuates the T-cell 
proliferation and anti tumor effects.4 The success of anti-Cytotoxic T-Lymphocyte Antigen 4
(CTLA4) (ipilimumab) in cancer therapy has highlighted the potential role for other check point 
inhibitors.4 Analogous to anti-CTLA4, a second immune check point inhibitor, directed against 
PD-1 has gained interest due to the potential to circumvent multiple immunosuppressive 
mechanisms emanating in the tumor microenvironment.5 PD-1 is an immune inhibitory receptor 
of the CD28/CTLA-4 family which regulates the homeostasis of T cells activation, tolerance and 
immunopathology.6 The PD-1/PD-L1 interaction inhibits T lymphocyte proliferation, survival and 
effector function (cytotoxicity, cytokine release). PD-1 immune check point inhibition has been 
shown to result in up regulation of genes associated with effector, NK cell function and cytolytic 
effects.6 The cardinal biological effects of PD-1immune check point inhibition are manifested by 
reversal of exhaustive CD8+T cells, averting depletion of memory B cells, depleting Foxp3+iTreg 
cells and restoring robust Th1 immunity.6 Targeting PD-1immune check points has the potential 
to play a major role in cancer therapy by reversing tumor immune escape. Nivolumab is a fully 
human, IgG4(ദ) isotype mAb that binds PD-1 on activated immune cells and disrupts engagement 
of the receptor with its ligands PD-L1(B7-H1/CD274) and PD-L2 (B7-DC/CD273), abrogating 
the inhibitory signals and augmenting host antitumor immune response.6 Nivolumab has 
demonstrated efficacy in solid and hematological malignancies.7,8 Clinical studies are ongoing to 
further elucidate the efficacy of PD-1 immune check-point inhibition in hematologic 
malignancies.9,10
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Nivolumab
Nivolumab is a fully-human monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]) that 
targets PD-1. In vitro, nivolumab binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and 
inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 ± 1 nM). Nivolumab binds 
specifically to PD-1 and not to related members of the CD28 family such as CD28, ICOS, CTLA-4 
and BTLA. Nivolumab blocks the PD 1 pathway and results in a reproducible enhancement of 
both proliferation and IFN-Ȗ release in the mixed lymphocyte reaction (MLR). Using a 
cytomegalovirus (CMV) re-stimulation assay with human PBMC, the effect of nivolumab on 
antigen specific recall response indicates that nivolumab augments IFN- J secretion from 
CMV-specific memory T cells in a dose-dependent manner versus isotype-matched control. In 
vivo blockade of PD-1 by a murine analog of nivolumab enhances the anti-tumor immune response 
and results in tumor rejection in several immunocompetent mouse tumor models (MC38, SA1/N, 
and PAN02).11 Nivolumab is indicated for the treatment of subjects with unresectable or metastatic 
melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a 
BRAF inhibitor.12 Nivolumab is indicated for the treatment of metastatic Squamous Non-Small 
Cell Lung Cancer (NSCLC) with progression on or after platinum-based chemotherapy.13
Nivolumab is approved in US, Europe and Japan for the treatment of subjects with unresectable 
or metastatic melanoma following progression on ipilimumab. Nivolumab is approved in US and 
Europe for the treatment of metastatic Squamous Non-Small Cell Lung cancer (NSCLC).
Nivolumab has demonstrated efficacy in lymphoid malignancies. Results from a phase I trial with 
heavily pre treated group of lymphoid malignancies demonstrated anti tumor effects of Nivolumab 
in subjects with relapsed B, T Non Hodgkin Lymphoma (NHL) and Hodgkin Lymphoma (HL). 
The Overall Response Rate (ORR) in 29 subjects with B NHL was 28% and in 23 subjects with T 
NHL was 17% respectively.9 Nivolumab has demonstrated remarkable efficacy in subjects with 
relapsed refractory HL. In a heavily pre treated group of 23 subjects, therapy with nivolumab 
demonstrated promising clinical activity. The ORR reported in this study was 87%, Complete 
Response Rate (CRR) of 17% Partial Response Rate (PRR) of 70% and (13%) of subjects achieved 
Stable Disease (SD). The Progression Free Survival (PFS) at 24 weeks was reported as 86% 
Nivolumab has been designated breakthrough therapy for the treatment of relapsed HL after failure 
of autologous stem cell transplantation and brentuximab vedotin.8,9 Nivolumab is currently being 
developed by Bristol Myers Squibb for the treatment of solid tumors and hematological 
malignancies. 
Brentuximab Vedotin
Brentuximab vedotin is a CD30-directed antibody-drug conjugate (ADC) consisting of 
3 components:1) the chimeric IgG1 antibody cAC10, specific for human CD30; 2) the 
microtubule-disrupting agent monomethyl auristatin E (MMAE); and 3) a protease-cleavable 
linker that covalently attaches MMAE to cAC10. The primary mechanism of anticancer activity 
of brentuximab vedotin is binding of the ADC to CD30-expressing cells, followed by 
internalization of the ADC-CD30 complex, and the release of MMAE via proteolytic cleavage. 
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Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently 
inducing cell cycle arrest and apoptotic death of the cell.14
Additionally brentuximab vedotin has shown to induce Immunogenic Cell Death (ICD).15 ICD is 
a distinct cell killing mechanism mediated through toll like receptor ligands which can abrogate 
the inhibitory effect of tumor immunosuppressive microenvironment and reinitiate the immune 
responses. Brentuximab vedotin possible immune modulatory properties were demonstrated in a 
report analyzing brentuximab vedotin’s effects in CD30+ Hodgkin Lymphoma cell lines. 
Brentuximab vedotin was evaluated for its ability to induce Endoplasmic Reticulum Stress (ER). 
It was shown that brentuximab vedotin in a dose dependent manner up regulated the apoptotic 
endoplasmic reticulum ER sensor C/EBP homologous protein which resulted in cleavage and 
activation of ATF6, a transcription factor required for induction of the ER stress. The net results 
were induction of ER stress and ICD markers. Induction of ICD was associated with activation of 
immune reaction. It was concluded that exposure of dendritic cells to brentuximab vedotin- killed 
tumor cells evoked an inflammatory phenotype including an increase in co-stimulatory markers 
CD86 and Major Histocompatibility Complex (MHC) Class II antigens, and activation of Nuclear 
Factor ദB (NFദB) an intermediate of inflammatory signaling pathway. This suggests additional 
brentuximab vedotin anti tumor effects by activating the innate immune response, although this
effect remains to be validated, as the observations are early and ex vivo.
In a pivotal phase 2 study of 102 subjects with relapsed or refractory Hodgkin lymphoma (HL) 
following autologous stem cell transplant (SCT), treatment with brentuximab vedotin resulted in 
an ORR of 75% (95% CI, 64.9%–82.6%). The CRR was 34% (95% CI, 25.2%–44.4%) and the 
median PFS for all subjects on study was 5.6 months (95% CI, 5.0–9.0 months).14 Brentuximab 
vedotin is approved for the therapy of relapsed HL after failure of autologous transplant or after 
failure of at least two multi agent systemic chemotherapy for subjects who are not candidates for 
autologous transplant. 
Brentuximab vedotin has also demonstrated activity in systemic Anaplastic Large Cell Lymphoma 
(ALCL). In a trial of 58 subjects with relapsed CD30+ ALCL who had received prior systemic 
chemotherapy, brentuximab vedotin demonstrated an ORR of 86%, CRR of 57%, and PRR of 
29%. The median duration of response was reported as 12.6 months. The most common adverse 
event 
reported 
was 
peripheral 
sensory 
neuropathy, 
neutropenia,
diarrhea, 
pyrexia, 
thrombocytopenia, cough and vomiting. 16
Brentuximab vedotin has also shown efficacy in other lymphoid malignancies. Ongoing trials in 
different NHL are exploring its full potential. Brentuximab vedotin is currently being developed 
by Seattle Genetics for the treatment of hematological malignancies. 
1.1
Study Rationale
Study CA209436 is an open label, multi center Phase 1/2 study to investigate the safety and 
efficacy of nivolumab in combination with brentuximab vedotin in subjects with relapsed, 
refractory Diffuse Large B Cell Lymphoma (DLBCL), Peripheral T Cell Lymphoma (PTCL) all 
subtypes excluding Anaplastic Large Cell Lymphoma (ALCL), Cutaneous T Cell Lymphoma
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(CTCL) Mycosis Fungoides (MF), Sezary Syndrome (SS), Primary Mediastinal B Lymphoma 
(PMBL) and Mediastinal Gray Zone Lymphoma (MGZL).
Harnessing host immune response is an important antitumor strategy. In this context reversing the 
effects of exhaustive T cells by checkpoint blockade agents is being actively explored as an 
effective immune therapy in clinical trials. It has been advocated that optimal T cell-based 
antitumor immunity requires both CD8+ T cells acting as cytolytic effector cells and CD4+ Th1 
cells to sustain antitumor response. Additionally it has been suggested that PD-1 blockade can 
restore robust Th1 immunity and T cell activation, hence abolish immunosuppression in the tumor 
microenvironment.2,5Although immune therapies including check point blockade appear effective 
anti cancer therapies, concerns remains for enhancing efficacy due to limitation of single agent 
activity which has been observed in certain tumor types. Some of the strategies to enhance the 
efficacy of immune therapies include improving the quality of effector cells and to reveal 
additional tumor antigens.2 The MHC class II antigen processing pathway is altered in cancer 
thereby precluding efficient presentation of T cell epitopes.2 Hence one strategy to increase 
efficacy of check point blockade is by combining with agents which possess the ability to enhance 
the effects of MHC Class II molecules to increase antigen presentation. It is therefore postulated 
that nivolumab and brentuximab vedotin combination will have additive and synergistic 
mechanism of actions.
Brentuximab vedotin will mediate its effects through induction of apoptosis.
Brentuximab vedotin may provide synergy by inducing ICD. Induction of ICD may enhance and 
increase the expression of the co stimulatory molecule CD86 and MHC Class II antigens. These 
effects may result in augmenting the effects of nivolumab.
Nivolumab by inducing robust Th 1 immunity and T cell activation, will result in augmenting host 
anti tumor immune response.
Collectively this combination has a high potential of becoming an effective novel therapy in 
lymphoid malignancies with unmet medical need.
1.1.1
Unmet medical need in DLBCL
DLBCL is the most common form of NHL. With the standard first line chemo immunotherapy 
(anthracycline based regimen and rituximab), 67% of subjects are alive at a median follow up of 
4 years.17 This implies that approximately 30-40% of subjects either relapse after standard therapy 
or demonstrate presence of refractory disease. At the time of relapse, the standard of care is to 
offer high dose therapy with autologous transplant to subjects who demonstrate chemo sensitive 
disease. The salvage chemotherapy is comprised of platinum or cytarabine based regimens in 
combination with rituximab. Most studies have demonstrated CRR with salvage regimen ranging 
from 20-40%.18,19 The Landmark PARMA study has established autologous transplant as a 
standard treatment modality in the management of relapsed DLBCL for subjects demonstrating 
chemo sensitive disease. The PARMA trial demonstrated the rate of Event Free Survival (EFS) of 
46% for subjects in the transplant group versus 12% in the group which received chemotherapy 
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without transplant.20 Subjects who do not respond to salvage therapy have an extremely poor 
outcome with a median survival of only 4 months with 4% alive at 1 year.21 Furthermore, only 20-
25% subjects after autologous transplant sustain durable responses. Treatment options following 
failure of transplant or for chemo refractory subjects are finite. This underscores the urgent need 
for effective therapy for subjects with relapsed refractory DLBCL. Several novel agents are 
emerging and have shown activity in relapsed DLBCL.22 Nivolumab has demonstrated activity as 
a single agent in subjects with relapsed refractory DLBCL. A total of 11 subjects with relapsed 
DLBCL were treated with nivolumab. Nivolumab was administered at a dose of 1mg/kg 
intravenously followed by 3mg/kg intravenously in the expansion cohort until disease progression 
or unacceptable toxicities. The trial reported an ORR of 36%, CRR of (9%), PRR of (27%), and 
(27%) SD. The median duration of response was 17 weeks (range 6-44.1+) at a median follow up 
of 23 weeks (range 3-69.0+). Overall the study treatment was well tolerated and majority of 
adverse event reported were grades 1-2.9 Results from a phase II study in subjects with NHL has 
demonstrated efficacy of brentuximab vedotin in subjects with relapsed DLBCL. There were a
total of 49 subjects with relapsed DLBCL, brentuximab vedotin was administered at 1.8 mg/kg 
intravenously every 3 weeks. Subjects who achieved SD or better could continue treatment until 
disease progression, unacceptable toxicity or study closure. Subjects with relapsed DLBCL were 
noted to have an ORR of 44%, with (17%) achieving Complete Remission (CR) in subjects with 
CD30 expression. The median duration of response was reported as 16.6 months in subjects with 
CR. Significant activity of brentuximab vedotin was noted across a range of CD 30 expression.23
An important observation from a majority of the trials of novel agents in relapsed DLBCL is that 
they have limited single agent activity, suggesting the need of adjuncts to improve quality of 
response. Trials with novel agent combinations are needed to address an important unmet medical
need in this patient population. 
1.1.2
Rationale for nivolumab and brentuximab vedotin in relapsed DLBCL
Since the outcome remains dismal for relapsed refractory DLBCL, incorporation of novel agents 
is key to identify and improve therapy. Research elucidating molecular characterization in DLBCL 
is emerging to provide insight which can facilitate drug development to improve outcomes. The 
International Prognostic Index (IPI) is used to delineate subjects into prognostic subgroups based 
on clinical prognosticators however it lacks biological insight which attributes to the heterogeneity 
of the disease. Gene- expression profile has yielded important prognostic and biological 
information for DLBCL. The Leukemia and Lymphoma Profiling Project (L&LPP) using 
microarray identified two independent groups with distinct gene expression profiles based on 
hierarchical clustering.24,25 The two groups based on Cell of Origin (COO) include the Germinal 
Center subtype (GC) and Activated B Cell like (ABC) or non-Germinal center (non GC) subtype. 
Subjects with ABC are noted to have inferior outcomes as compared to the GC subtype. In an 
updated analysis from the L&LPP, in subjects with DLBCL treated with Rituximab, 
Cyclophosphamide, Adriamycin, Oncovin, Prednisone(R-CHOP) two gene signatures were 
identified. The favorable signature stromal 1 demonstrated genes related with extracellular matrix 
and histiocytic infiltration. The stromal signature 2 which was associated with worse prognosis 
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was reflective of genes linked with angiogenesis and surrounding macrophages.26,27 This suggests
role of tumor microenvironment in DLBCL pathology. Relapsed NHL is often treated with 
allogeneic transplant, underpinning the role of adaptive immunotherapies in this setting.28
Eradication of immune tolerance in this patient population may provide an important therapeutic 
strategy. This is further supported by activity of check point blockade agents such as anti PD1 in 
relapsed DLBCL. In a phase II trial of subjects with relapsed DLBCL undergoing autologous 
transplant, pidilizumab an anti PD-1 monoclonal antibody was administered for measurable 
disease following transplant. The therapeutic benefit of anti-PD1 was manifested by a CRR of 
34% and ORR of 51% among subjects with measurable disease.10 Likewise, Nivolumab has 
demonstrated activity in heavily pre treated group of subjects with relapsed DLBCL with an ORR 
of 36%.9
CD 30 is a membrane glycoprotein associated with the TNF receptor (TNFR) superfamily. There 
is suggestion that CD30 stimulation results in cell cycle arrest, apoptosis and activation of the 
prosurvival transcription factor NF-ദB.29 CD30 is expressed in several lymphoid malignancies.
Results from a retrospective analysis of 167 cases of archived tissue from subjects with DLBCL, 
demonstrated variable CD30 expression measured by immunohistochemistry (IHC). Twenty one 
percent (95% confidence interval [CI]: 14.8-27.1%) of these cases expressed CD30, and in 52% 
of samples CD30 expression was noted in > 80% of tumor cells.30 Multivariate analysis performed 
in Bcl2+ DLBCL showed that higher frequency of CD30 expression was observed in samples with 
non- GC subtype, and in subjects < 47 years old. Another group examined CD30 expression in 
subjects with de novo DLBCL using IHC. A total of 385 cases of formalin fixed paraffin embedded 
DLBCL in tissue microarray were examined. Using a > 0% cut off, CD30 expression was predicted 
of superior 5 year progression free within R-CHOP treated germinal center B cell like DLBCL 
(86% versus 64%, p=0.020). Epstein - Barr virus (EBV) was identified in 11 (3%) of cases in the 
non-
GCB/ABC subtype DLBCL (p=0.001).31
International DLBCL Rituximab-CHOP 
Consortium Program evaluated 903 cases of de novo DLBCL. It was reported that approximately 
14% of subjects with DLBCL express CD30. The subjects with CD30 expression DLBCL had 
superior Overall Survival (OS) and PFS regardless of the COO. In multivariate analysis, 
controlling other variables, including B symptoms, tumor size, IPI, COO classification and TP53 
mutational status, absence of CD30 expression remained an independent inferior predictor of 
overall survival Hazard Ratio [HR] of 3.03; 95% Confidence Interval [CI], 1.33-6.89; P = .0082) 
and Progression Free Survival (PFS) (HR of 2.89; 95% CI, 1.35-6.20; P = .0064).The molecular 
elucidation in this group using gene expression profiling depicted up regulation of genes encoding 
negative regulators of NF țB activation and lymphocyte survival, and down regulation of genes 
encoding B-cell receptor signaling and proliferation, as well as prominent cytokine and stromal 
signatures in CD30 expressed DLBCL subjects, suggesting a distinct molecular basis for its 
favorable outcome.32 Although the report is suggestive of favorable prognosis in de novo frontline
R-CHOP treated subjects with CD30 expressed DLBCL, the prognostic implications of CD30 
expressed DLBCL in relapsed setting remains unclear and some report suggest association with 
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CD30 expression as an adverse prognosticator.33 Results from a phase II study in subjects with 
NHL has demonstrated efficacy of brentuximab vedotin in subjects with relapsed DLBCL.23
Based on these observations, it is postulated that combined immune modulation with 
antibody-mediated PD-1 immune-checkpoint blockade nivolumab and brentuximab vedotin may 
result in additive activity and synergistic activity translating into improved clinical outcomes in 
subjects with relapsed DLBCL. 
1.1.3
Unmet medical need in Peripheral T Cell NHL (PTCL)
PTCL is a heterogeneous group of aggressive T cell NHL which carries a poor prognosis. The 
incidence of PTCL is < 1 case per 100, 000 people in the United States. Despite being a rare tumor 
PTCL accounts for substantial numbers of death worldwide.34 PTCL encompasses several 
different types, among which the most frequent subtypes are PTCL- Not Otherwise Specified
(NOS-25.9%) and Angioimmunoblastic T cell Lymphoma (AITL-18.5%). Historically the 
treatment of PTCL has comprised of integration of cytotoxic chemotherapy combination such as 
CHOP in the frontline treatment. The outcome for subjects with PTCL remains dismal with a 
reported 5 year overall survival of only 37%.35,36 More intensive chemotherapeutic regimens such 
as ACVBP (dose-intensified doxorubicin, Cyclophosphamide, Vindesine, Bleomycin and 
Prednisone) have been employed for younger subjects with superior event free survival and overall 
survival albeit at the expense of increase in toxicities.36 The majority of subjects with PTCL 
require many lines of therapies with ultimate dismal outcomes. Recently integration of novel 
agents in the management of PTCL has been employed with the aim to improve outcomes in this 
highly aggressive disease group. Pralatrexate is a novel folate antagonist which exerts its effects 
by binding to the reduced folate carrier. Pralatrexate has demonstrated activity in subjects with 
relapsed PTCL. The phase II PROPEL (Pralatrexate in Patients with Relapsed or Refractory T-cell 
Lymphoma) trial demonstrated activity of pralatrexate in subjects with relapsed refractory PTCL. 
The total number of subjects treated were 111 with a median of 3 prior therapies. Pralatrexate was 
administered at a dose of 30mg/m2/week for 6 weeks in 7 weeks cycle. Approximately 63% of 
subjects were refractory to their last therapies. The reported ORR was 29%, CRR of 11% with a 
median duration of response of 10.1 months. The median PFS and OS were 3.5 and 14.1 months 
respectively.37 Important toxicities include mucositis and thrombocytopenia. Pralatrexate was 
approved by the United States Food and Drug Administration as a single agent for the treatment 
of relapsed refractory PTCL. Romidepsin, one of the Histone Deacetylase Inhibitor (HDACi), has 
also demonstrated activity in the treatment of relapsed PTCL. In a phase II trial with 131 subjects 
with PTCL, romidepsin was administered at a dose of 14mg/m2 intravenous infusion on days 1, 
8 and 15 of a 28 days cycle. The ORR was 25%, CRR 15% and the median duration of response 
was 17 months with the longest ongoing response at 34 months. The most common adverse events 
include cytopenias and infections along with nausea and fatigue.38 Brentuximab vedotin has 
demonstrated promising activity in patient with relapsed ALCL. In a phase II trial 58 subjects with 
ALCL were treated with brentuximab vedotin at 1.8 mg/kg intravenously every 3 weeks. The ORR 
was 86%, CRR 57% and PRR 29%. The median duration of response was 12.6 months.16 Horwitz 
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et al also demonstrated activity of brentuximab vedotin in subjects with relapsed CD30+ PTCL. 
In this phase II study the total number of subjects with PTCL NOS=22 and AITL n=13. The ORR 
was 41% (8CR, 6PR) in subjects with PTCL NOS and the ORR was 54% (5 Complete Response, 
2 Partial Response) in subjects with AITL.39 Nivolumab has also demonstrated activity in subjects 
with T NHL (n=23) the ORR has been reported as 17% with PRR for 4(17%), SD for 10(43%). In 
this phase I study the total number of subjects with PTCL was 5. Nivolumab was administered at 
1mg/kg intravenously every 2 weeks and at 3 mg/kg intravenously every 2 weeks in the expansion 
cohort until unacceptable toxicities or disease progression. The ORR for the PTCL cohort was 
40% and PRR (40%) Importantly, the duration of response appears durable in the responding 
group.9
The overall prognosis of PTCL remains poor, marked with multiple relapses and OS at 10 year of 
10-15%, hence there remains a vital need to develop effective therapies. The availability of novel 
agents allows for exploring combination with scientific rationale to improve not only response 
rates but also durability of responses.
1.1.4
Rationale for nivolumab combination with brentuximab vedotin in PTCL
PTCL encompasses several subtypes originating from the post thymic T lymphocytes mature 
T cells.40 The scarcity of cases of PTCL, diverse morphology and lack of diagnostic markers are 
some of the factors for impeding the progress in the molecular and genetic characterization in 
PTCL.40,41 With the exception of ALCL which harbors the specific genetic abnormality
t(2;5)(p23;q35), other subtypes of PTCL lack specific genetic abnormalities.40,42 The cellular 
inception of several of the subtypes of PTCL remains obscure or appears to be heterogeneous. At 
the present time approximately 50% of PTCL cases are not classifiable.41 Majority of PTCL NOS 
are related to the CD4 helper cells and a minority are analogous to CD8 cytotoxic cells. T follicular 
helper cells (TFH) have been identified as the cell of origin for a few subtypes of PTCL including 
AITL.43,44 The AITL neoplastic cells are identified as clonal mature DE CD4+ T cells which 
express numerous TFH markers such as; CXCL13, PD1, ICOS, CD200 and BCL6.40 Studies 
incorporating gene expression profiling have began to delineate biological and prognostic 
subgroups to elucidate pathobiology in PTCL.45 Iqbal et al recently examined gene expression 
profiling in 372 PTCL cases. The group demonstrated high expression of several signatures 
association with the tumor microenvironment in subjects with AITL. The genes in the signature 
depicted strong associated with angiogenesis and vascular endothelial function or cell migration. 
Furthermore, 2 major subgroups in PTCL NOS were recognized. The 2 subgroups include GATA3 
with high expression of GATA3 and target genes (CCR4, IL18RA, CCL3, and IFNڜ) and the 
TBX21 with high expression of TBX2I, EOMES, and CXCR3, IL2RB, CCL3 and IFNڜ). The 
enrichment in these subgroups depicts gene signatures related to proliferation (MYC), mTOR 
(PI3K), IFNڜ induced genes and NFKB gene signatures. The presence of GATA3 profile was 
noted to be associated with inferior outcomes.46
The role of immunosuppressive 
microenvironment in PTCL was further validated by a study by Wilcox et al. Tumor biopsies were 
evaluated for the expression of PD-L1 (B7-H1) from subjects with CTCL and PTCL. 
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Approximately 50% of T cell NHL cases examined depicted expression of PD-L1. The expression 
was noted in the cells within the microenvironment such as the monocyte derived cells, dendritic 
cells and the macrophages.47 Collectively these observations suggest strong influence of pro 
inflammatory and immunosuppressive microenvironment in PTCL.47
In this context PD-1 modulation may provide a benefit by enhancing immune responses in subjects 
with PTCL. Results from a phase I trial are indicative of activity of nivolumab in PTCL. 
Additionally brentuximab vedotin appears active in PTCL, hence combination of these agents may 
provide a novel combination which will result in improving quality of responses. 
1.1.5
Unmet medical need in CTCL Mycosis Fungoides (MF) and Sezary 
Syndrome (SS)
The incidence of CTCL in the United States is 6.4/million/year. MF and SS comprise 53 % of 
CTCL cases per year. Treatment for CTCL is stage dependent, with local therapies used for early 
stage and systemic therapies employed for extensive or relapsed diseases.48 The response to 
systemic therapy for relapsed disease is often ephemeral and underscores the need for developing 
effective agents in this disease.49 Numerous chemotherapeutic agents have shown activity in 
MF/SS. Gemcitabine has demonstrated CRR of 11-51% with duration of response of 
10-15 months.50 Pegylated liposomal doxorubicin has shown an ORR of 88% with disease free 
survival of 13 months.51 Additionally combination chemotherapy CHOP has shown an ORR of 
66% in subjects with CTCL.52 Biological agents such as anti CD52 monoclonal antibody 
alemtuzumab and the fusion toxin denileukin diftitox targeting the interleukin 2 receptor and 
bexarotene have also demonstrated activity in CTCL (MF/SS).53,54.Recently novel agents such as 
HDACi (romidepsin and vorinostat) have been approved for the treatment of MF/SS.55,56
Romidepsin has demonstrated activity in subjects with CTCL. Results from a phase II trial in 
96 subjects with CTCL demonstrated an ORR was reported as 34% & CRR 6%. The median 
duration of response was 15 months. Romidepsin was administered as an intravenous infusion at 
a dose of 14mg/m2 on days 1, 8 and 15 every 28 days. The commonly reported adverse events 
reported were mild and mainly involving the gastrointestinal tract which included nausea, fatigue, 
infections, vomiting and decrease in white blood cells57. Vorinostat is another HDACi for the 
treatment of CTCL in subjects who have failed prior therapies. The pivotal study was a single 
agent vorinostat at an oral dose of 400 mg daily. The total number of subjects in this phase II trial 
was 74. The trial demonstrated an ORR of 30%, the estimated median duration of response was 
168 days. The most common adverse events were diarrhea, fatigue, nausea and anorexia.58
Nivolumab has demonstrated activity in subjects with CTCL. In the phase I trial with nivolumab
the total number of subjects with CTCL (MF) was 13. Nivolumab was administered at 1 mg/kg 
intravenously followed by 3 mg kg intravenously every 2 weeks in the expansion cohort. The 
response for MF cohort was an ORR of 15% with PRR of (2, 15%) and SD in (9, 69%) subjects. 
Importantly, the duration of response appears durable in the responding group. Overall the therapy 
is well tolerated with majority of adverse events reported as grades 1-2.9
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Brentuximab vedotin has also demonstrated activity in subjects with CD30+ CTCL. In a phase II 
trial of 32 subjects with relapsed CTCL, brentuximab vedotin was administered at a dose of 
1.8 mg/kg every 3 week up to 8 cycles with optional extension of additional 8 cycles for the 
responding subjects. The ORR was 70% (21/30), responses were observed in all clinical stages. 
Additionally 54% of subjects were progression free at 12 months. The median maximum CD30 
expression by IHC of all subjects was 13 %( range 0-100%; 6 had < 5%), the median was noted to 
be higher in responders (CRR/PRR) 15%, versus non responders 3% (p = 0.037) It was also 
demonstrated that subjects with CD30 expression less than 5% had a lower likelihood of clinical 
response (17% versus 83%; p=0.0046). Overall the therapy was well tolerated with majority of 
adverse events reported as grades 1-2.59
There remains a significant need for new active agents in the therapy of CTCL as the outcomes 
continue to be poor for the majority of subjects with recurring disease and relapses due to limited 
duration of responses. 
1.1.6
Rationale for nivolumab and brentuximab vedotin in CTCL (MF/SS)
With increased understanding of disease biology and the integration of novel agents in the 
treatment of NHL, the outcomes have improved. The progress is impeding in the management of 
T cell NHL, it is likely that elucidation of pathobiology will help to integrate novel agents in this 
disease to improve outcomes. Evidence is suggestive that the elements of microenvironment such 
as stromal cells, dermal fibroblasts, vascular endothelial cells, infiltrating T cells, macrophages, 
mast cells produce different types of growth factors, cytokines and chemokines which cause
disease progression in subjects with CTCL.60 Recent reports have shown increased expression of 
ICR and the associated ligands in subjects with T NHL. Wilcox et al demonstrated increased 
expression of B7-H1 (PD-L1, CD274) a member of the co stimulatory/co inhibitory ligands by the 
tumor cells, monocytes and the tumor infiltrating monocytes within the tumor microenvironment. 
The report also highlighted the role of PD-L1 in the suppression of host immunity by promoting 
induction of T regulatory FoxP3+ cells and inhibiting the effects of immune T cells in subjects
with TNHL including CTCL and PTCL47. In another report from Kantekure et al the expression 
of PD-1 and PD-L1 in subjects with different stages of CTCL were examined. The study identified
PD-1 as an important immunosuppressive protein, promoting immune inhibition in subjects with 
CTCL.61 This suggests that PD-1 modulation by treatment with a PD-1 blocking antibody may 
result in clinical benefits by enhancing host immune response. Results from a Phase I trial in 
hematological malignancies are suggestive of activity of anti PD1 (Nivoulmab) in subjects with T 
NHL. Subjects with CTCL (MF/SS) have demonstrated variable expression of CD30. 
Brentuximab vedotin has demonstrated activity in CTCL (MF/SS).59
Given that nivolumab and brentuximab vedotin have demonstrated activity in subjects with CTCL 
(MF/SS), the combination has the potential of demonstrating increased activity which may 
translate into improving quality of responses in this patient population.
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1.1.7
Unmet Need in Primary Mediastinal B Lymphoma (PMBL)
PMBL is a distinct type of Non Hodgkin Lymphoma NHL derived from the thymic B cells62
PMBL is a rare NHL which compromises only 2-4 % of NHL and 10% of cases of DLBCL. PMBL 
affects subjects in the third and fourth decade of life with a female predominance63. The 
therapeutic approach to PMBL remains an active area of debate. Chemo immunotherapy is used 
in the frontline treatment with promising responses. However prognosis is poor for subjects who 
relapse following front line therapy62. The increased efficacy of dose dense regimens in this 
disease suggests that this requires a unique therapeutic approach62. During the pre- rituximab era, 
reports with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP-like)
chemotherapy and radiation consolidation demonstrated suboptimal outcomes manifested by early 
progression and poor salvage options64. In the current chemo immunotherapy era, reports 
integrating rituximab with CHOP or third-generation regimens (eg, methotrexate, leucovorin, 
doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin [MACOP-B]) have 
resulted in favorable outcomes with cure rates generally in the range of 80% compared with 
approximately 50% in the past62,65 ,66 ,67. The Mab thera International (MinT) study, an important 
study in high grade B cell lymphomas. This study also included subjects with PMBL. In this study, 
subjects were treated with CHOP-like chemotherapy with or without rituximab. The number of 
subjects with PMBL was 87. The study demonstrated that rituximab treatment resulted in 
significantly improved rate of CR (90 versus 54 %) decrease in the rate of progression (3 versus 
24 %) and increase in the rate of 3 years event free survival (78 versus 52%) and overall survival 
(89 versus 78)68.
There has also been interest in intensifying chemotherapy with integration of dose dense regimen. 
In this context, results from a single center Phase II prospective study appear promising for the 
treatment of PMBL. In this study, total number of subjects with newly diagnosed PMBL was 51.
Subjects were treated with six to eight cycles of dose-adjusted etoposide, doxorubicin, 
cyclophosphamide, vincristine, prednisone, and rituximab (da-EPOCH-R). All subjects were 
supported with growth factors and antimicrobial prophylaxis trimethoprim-sulfamethoxazole. 
After a median follow-up of 63 months, the reported rates of event-free and overall survival at five 
years were 93 percent and 97 percent (95% CI 81-99%), respectively. Approximately 10-30% of 
patients relapse after first line therapy. There is no standard therapy for relapsed or refractory 
PMBL. The general approach is to salvage subjects with chemo immunotherapy and if subjects 
demonstrate chemo sensitivity, consolidate with high dose therapy and hematopoietic stem cell 
transplant64.  Prior to the immunotherapy era, the outcomes reported were inferior with salvage 
therapy in PMBL as compared to DLBCL;  ORR 25% PMBL vs 48% in DLBCL, 2 year survival 
15% PMBL vs 34% DLBCL64. Outcomes have improved in the rituximab era, 4 year PFS 69% 
have been reported65,69. In a retrospective study, a total of 44 subjects with relapsed/refractory 
PMBL were treated with high dose therapy and autologous stem cell transplant (ASCT). 
Approximately 41% of the subjects were refractory to front line treatment. The ORR after 
HDT/ASCT was 77% with CR of 63.6%. With a median follow-up of 53.5 months the OS and 
PFS at 4 years were 70 and 61% respectively. The OS at 4 years was 61% for subjects with primary 
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refractory disease69. It has been observed that the outcomes remain dismal for subjects with chemo 
refractory disease and for subjects who relapse after ASCT, underscoring the need for novel agents 
in this disease62,64. Pembrolizumab, a check point inhibitor, which has demonstrated activity in 
relapsed PMBL. In a phase IB study subjects with relapsed PMBL were treated with single agent 
pembrolizumab. The total number of subjects with relapsed PMBL was 16. The study reported 
ORR of 38%, with 6% CR, the median DOR was not reached, range (.03-17 months), additionally 
6/16= 38% subjects progressed. The median follow up was 5 months70. The single agent activity 
of pembrolizumab appears less promising in PMBL as compared to its single agent activity in 
relapsed classical HL, where ORR were reported as 65%70,71. This suggests, perhaps efficacy can 
be improved by combining novel agents. Another novel agent, BV has also demonstrated activity 
in PMBL. In a phase II study of subjects with relapsed DLBCL, 6 subjects were enrolled with the 
diagnosis of relapsed PMBL. The subjects were treated with single agent BV. The median follow 
up was 6.6 months for all subjects participating in the study (range 2.2-22.7+). Preliminary 
evidence of activity of BV were reported in subjects with PMBL, out of 6 subjects, 1 subject 
demonstrated CR, 3 subjects demonstrated Stable Disease (SD) and 2 subjects progressed. 
Important to note that this is a small cohort of subjects treated with single agent BV76. BV has also 
been used in frontline treatment of PMBL in combination with chemo immunotherapy72.
1.1.8
Rationale for nivolumab combination with brentuximab vedotin in 
PMBL
PMBL is derived from medullary thymic B cell. PMBL has a B cell phenotype and expresses 
CD20, CD79a, CD30, CD10, CD23, BCL6 where as CD15 is negative62,63. The CD30 expression 
is dim as compared to cHL. Gene expression profiling has demonstrated similarities among PMBL 
and nodular sclerosing Hodgkin Lymphoma (NSHL)63. Some of the common genetic aberrations 
reported include abnormalities on chromosomes 9p and 2p. The PD1 ligand genes, PD-L1 and 
PD-L2 are located on chromosome 9p24.1.73 Chromosome 9p24.1 amplification and increased 
expression of the PD-1 ligands has been reported in Classical Hodgkin Lymphoma (cHL) and 
PMBCL cell lines.74
Some
studies have demonstrated and identified 9P24.1/CD274 
(PD-L1)/PDCD1LG2(PD-L2), copy gain and increased expression of the PD-1 ligands in 65% of 
PMBLs74. In another molecular analysis of PMBL and DLBCL, twenty-three of 32 (72%) PMBLs 
but only 1 of 37 (3%) DLBCLs were noted to demonstrate expression of PD-L2 by 
Immunohistochemistry (IHC). These findings are highly suggestive of the presence of 9p24 
genetic aberration in subjects with PMBL.  This has critical implication for drug development, as 
these constitute important targets based on the inhibition of PD1 receptors and the PD1 ligand 
PDL1 and PDL2 for PMBL73,75.
Given the variable expression of C30 that is observed in PMBL along with presence of 9p24 
amplification, there is rationale to combine BV with nivolumab in PMBL.
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1.1.9
Unmet Medical Need in Mediastinal Gray Zone Lymphoma (MGZL)
MGZL is an extremely rare form of NHL. MGZL affects, the majority of the time, the mediastinum 
of young subjects with a male propensity 62,76. The World Health Organization recognizes MGZL 
a rare lymphoma with features analogous and intermediate between NSHL and PMBL62. The 
clinical characteristics and treatment have not been formulated and standardized due to the scarcity 
of the disease. Subjects with MGZL are treated with chemo immunotherapy similar to PMBL. The 
outcomes are inferior as compared to subjects with PMBL and NSHL 62,77. In a prospective study 
where subjects were treated with infusional dose-adjusted etoposide, doxorubicin and 
cyclophosphamide with vincristine, prednisone and rituximab (da-EPOCH-R), the event free 
survival and overall survival were 62% and 74% at 59 months median follow up77. Although the 
numbers are small, there is evidence of activity with BV in subjects with MGZL. In a phase II 
study of subjects with relapsed DLBCL, 6 subjects were enrolled with the diagnosis of relapsed 
MGZL. The subjects were treated with single agent BV. The median follow up was 6.6 months 
for all subjects participating in the study (range 2.2-22.7+). Preliminary evidence of activity of BV 
were reported in subjects with MGZL. For the 6 patients with MGZL enrolled on this study,
responses reported were 1 CR and 2 PRs76. Due to low incidence of this lymphoma, there is 
scarcity of data on the treatment in the front line and relapsed setting. Most subjects are treated 
similar to relapsed PMBL77.
1.1.10
Rationale for nivolumab combination with brentuximab vedotin in 
MGZL
Since the outcome remains dismal for relapsed refractory MGZL, incorporation of novel agents is 
needed to improve outcomes in therapy. MGZL similar to PMBL, expresses CD 20 and CD30. 
The expression of CD 30 is dim and variable and the expression of CD 20 is low. The molecular 
characterization of mediastinal grey zone lymphoma is an area of research. Molecular analysis has 
demonstrated amplifications in 2p16.1 (REL/BCL11A locus) as well as alteration of the 
JAK2/PDL2 locus. Alterations affecting the JAK2/PDL2 locus in 9p24 have been reported in 55% 
of subjects with MGZL78. Additionally studies suggest similarities in the epigenetic characteristics 
in PMBL, NSHL and MGZL. 
Given the variable expression of C30 that is observed in MGZL along with presence of 9p24 
amplification, there is rationale to combine BV with nivolumab in MGZL.
1.1.11
Rationale for permitting continued treatment in select cases of PD
Immune therapies have been noted to be associated with atypical responses known as tumor flare 
or immune related response.79,80 There is increasing evidence that subjects treated with immune 
therapies including checkpoint inhibitors may manifest disease progression (by conventional 
response criteria) before demonstrating clinical objective responses and/or stable disease. Ongoing 
clinical trials with nivolumab have reported this phenomenon in approximately 10% of subjects.81
Similar response has also been observed with other immune therapies. Treatment with antiviral 
agent in combination with interleukin-12 demonstrated evidence of objective responses after an 
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initial Progressive Disease (PD) in a patient with human immunodeficiency virus related kaposi 
sarcoma.82 The exact etiology for this phenomenon remains unknown. There is suggestion that 
enhanced inflammation within tumors results in increase in tumor size which may manifest as 
enlarged index lesions and as newly visible small non-index lesions. Over time, both the malignant 
and inflammatory portions of the mass may then decrease leading to overt signs of clinical 
improvement. Alternatively, in some individuals, the kinetics of tumor growth may initially 
outpace anti-tumor immune activity. With sufficient time, the anti tumor activity will dominate 
and become clinically apparent. Given the observation of this phenomenon, subjects will be 
allowed to continue study therapy (nivolumab and brentuximab vedotin) after initial 
investigator-assessed Response Evaluation Criteria (Lugano Lymphoma 2014, Response Criteria 
in MF/SS; consensus Global Response Score) defined progression.83,84 If the subjects are assessed 
to be deriving clinical benefit and if they continue to meet the following criteria;
1. Investigator-assessed clinical benefit
2. Stable performance status
3. Treatment beyond disease progression will not delay an imminent intervention to prevent 
serious complications of disease progression
4. Subject will be re-consented for treatment beyond progressive disease
5. Tolerance of study drug
1.1.12
Rationale and Aims for Biomarker Assessments
The biological basis of nivolumab in the treatment of oncological disease is to modulate the 
immune system to both generate and restore a durable anti-tumor response leading to clearance of 
tumor. The nivolumab clinical data supports the hypothesis that inhibition of the PD 1 pathway 
results in rejection of tumor by the host immune system. Additionally, in the lymphoid 
malignancies, PD-1 blockade in the tumor microenvironment appears a biologically important 
parameter to correlate with response. Brentuximab vedotin has shown to execute anti tumor effects 
by inducing cell death and apoptosis, along with immune modulation through induction of ICD. 
Understanding the biology of tumor microenvironment both pre and post treatment will be crucial 
for evaluating the role of combination in modulation of the immune system and its response to 
PD-1 blockade. In this context, relevant biomarker panels will be obtained in this trial, see 
Section 5.6.  
The precise mechanisms by which nivolumab exerts its anti-tumor activity is unclear, however, 
particular cell types, such as effector T cells and regulatory T cells are critical for the anti-tumor 
response. The 9p24 amplicon induces JAK2, and gene dose dependent JAK-STAT induces 
PD-1ligand transcription. Effects of nivolumab on JAK/STAT pathway (pJAK2, pSTAT1 and 
pSTAT3), will be evaluated in DLBCL and T NHL.
Therefore, the major questions that will be addressed are: 
•
Does expression of PD-L1 on tumor cells prior to therapy correlate with clinical efficacy to 
combination therapy?
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•
Can we define distinct pharmacodynamic markers of combination therapy in the peripheral 
compartment?
•
How does nivolumab in combination with brentuximab vedotin alter the activating and 
negative costimulatory molecules on immune cells in the periphery and at the tumor site? Are 
there any distinct mechanisms of resistance to nivolumab?
•
Does the composition and phenotype of the tumor microenvironment correlate with clinical 
efficacy?
•
Does the treatment with brentuximab vedotin enhance effects of nivolumab?
•
Is there a correlation between the effects of combination therapy and immune related genes, 
cytokines and signaling pathways?
1.1.13
Rationale for Study Design
CA209436 is a Phase I/II open-label study of nivolumab combined with brentuximab vedotin to 
evaluate the safety and efficacy in subjects with relapsed and/or refractory DLBCL, PTCL
(excluding ALCL) and CTCL (MF/SS). CD30 expression t 1% by IHC is a prerequisite for all 
subjects participating in this study. A dose limiting toxicity (DLT) evaluation period will be 
conducted for the first 6 subjects during cohort A (Dose Evaluation Phase). In this cohort the first 
dose of brentuximab vedotin 1.8 mg/kg will be given on Cycle 1 Day 1. The first dose of nivolumab 
240 mg flat dose will be given on Cycle 1 Day 8. Subsequent to cycle 1, both drugs will be 
administered on the first day of the new cycle. Brentuximab vedotin will be administered first as 
a 30-minute infusion followed by a minimum 30-minute rest. Nivolumab will then be administered 
as a 30-minute infusion. By administering brentuximab vedotin, a directly cytotoxic agent which 
also induces ICD, it is anticipated that the tumor associated antigens will be released and available 
for presentation to cytotoxic T cells, which may enhance effects of nivolumab. Given the long 
half-life of nivolumab, there is no rationale to continue staggered dosing beyond Cycle 1. 
In Cohort A, the safety of the combination treatment will be evaluated by the BMS study team
along with the Seattle Genetics study team and the investigators participating in the trial prior to 
expansion of enrollment to evaluate treatment effect in Cohort B, as detailed in Section 4.5.1
After 6 DLT-evaluable subjects have been followed throughout the first 6 weeks of treatment, or 
at the point that 2 or more subjects experience a DLT, whichever comes first, the study team will 
review the available data and provide any of the following recommendations, that may include but 
are not limited to:
1. If one or none (d 1) of the 6 subjects experience a DLT, the expansion cohort will begin with 
brentuximab vedotin 1.8 mg/kg Cycle 1 Day 1 and nivolumab 240 mg flat dose on Cycle 1 
Day 8. 
2. If two or more (t 2) of the 6 subjects are determined to have had a DLT based on the protocol 
definition (refer to section 4.5.1), the following options will be considered
a.
To repeat Cohort A of the study and treat up to 6 additional subjects at the same drug doses 
and schedule previously tested 
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b. To repeat Cohort A of the study and treat up to 6 additional subjects at a reduced dose of 
brentuximab vedotin 1.2 mg/kg;
c.
Administration of the combination treatment on Day 1 of every cycle, including cycle 1
d. To close the study to additional enrollment. 
Cohort B of the study will further characterize safety and evaluate the antitumor activity of
brentuximab vedotin combined with nivolumab in subjects with relapsed and/or refractory
DLBCL, PTCL (excluding ALCL), PMBL, MGZL and CTCL (MF/SS) who have failed prior 
chemotherapy or autologous transplant or are ineligible for autologous transplant. The Expansion 
Phase (Cohort B) plans to treat approximately 130 subjects.
If the combination of nivolumab and brentuximab vedotin is considered safe based on the DLT 
evaluation, nivolumab will be a 240 mg flat dose for the expansion cohort q 3 weeks administered 
as a 30-minute infusion.
1.1.13.1
Rationale for Dose Selection 
Brentuximab Vedotin
The recommended dose for brentuximab vedotin per its prescribing information is 1.8 mg/kg via 
intravenous (IV) infusion administered every 3 weeks (first day of every treatment cycle). This 
dose and schedule was evaluated in two pivotal phase 2 studies in subjects with CD30-positive 
hematologic malignancies.
Nivolumab
In both Cohorts A and B, the first dose of nivolumab 240 mg flat via 30 minute IV infusion will 
be given on Cycle 1 Day 8. Subsequent to cycle 1, both drugs will be administered on the first day 
of the new cycle (every 3 weeks). The rationales for using the flat dose, every 3 week dosing 
intervals, and 30-minute infusion times are provided in section 1.1.13.2, section 1.1.13.3, and 
section 1.1.13.4.
1.1.13.2
Flat Dose Rationale
The flat dose of 240 mg was selected based on clinical data and modeling and simulation 
approaches using population PK (PPK) and exposure-response analyses of data from studies in 
multiple tumor types (melanoma, non-small-cell lung cancer [NSCLC], and renal cell carcinoma 
[RCC]) where body weight normalized dosing (mg/kg) has been used.
PPK analyses have shown that the PK of nivolumab is linear with proportional exposure over a 
dose range of 0.1 to 10 mg/kg, and no differences in PK across ethnicities and tumor types were 
observed. Nivolumab clearance and volume of distribution were found to increase as the body 
weight increases, but less than the proportional with increasing weight, indicating that mg/kg 
dosing represents an over-adjustment for the effect of body weight on nivolumab PK. The PPK 
model previously developed using data from NSCLC subjects has recently been updated, using 
data from 1544 subjects from 7 studies investigating nivolumab in the treatment of melanoma, 
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NSCLC, and RCC. In this dataset, the median (minimum - maximum) weight was 77 kg 
(35 kg - 160 kg) and thus, an approximately equivalent dose of 3 mg/kg for an 80 kg subject, 
nivolumab 240 mg flat dose was selected for future investigation. To predict relevant summary 
exposures of nivolumab 240 mg flat, the PPK model was used to simulate 100 virtual trials, with 
1000 subjects per treatment arm (240 mg flat dose or 3 mg/kg) randomly sampled from 
aforementioned pooled database of cancer subjects. Because no differences in PK were noted 
across ethnicities and tumor types, these simulated melanoma and NSCLC data are applicable to 
subjects with other tumor types. The simulated geometric mean Cavgss predicted for 240 mg flat 
dose every 2 week are predicted to be similar for all subjects in reference to 80 kg subjects 
receiving 3 mg/kg every 2 week.
Nivolumab is safe and well tolerated up to 10 mg/kg every 2 week dose level. Adverse events have 
been broadly consistent across tumor types following monotherapy and have not demonstrated 
clear dose-response or exposure-response relationships. Additionally, the simulated median and 
95th prediction interval of nivolumab summary exposures across body weight range (35 - 160 kg) 
are predicted to be maintained below the corresponding observed highest exposure experienced in 
nivolumab ie, 95th percentile following nivolumab 10 mg/kg every 2 week from clinical study 
CA209003. Thus, while subjects in the lower body weight ranges would have greater exposures 
than 80 kg subjects, the exposures are predicted to be within the range of observed exposures at
doses (up to 10 mg/kg every 2 week) used in the nivolumab clinical program, and are not 
considered to put subjects at increased risk. For subjects with greater body weights, the simulated 
ranges of exposures are also not expected to affect efficacy, because the exposures predicted 
following administration of a 240 mg flat dose every 2 week are on the flat part of the exposure-
response curves for previously investigated tumors, melanoma and NSCLC.
1.1.13.3
Every 3 Week Dosing Interval Rationale
For previously approved indications of melanoma and NSCLC and for other indications currently 
being investigated using the flat dose, the dosing frequency for nivolumab monotherapy is 3 mg/kg 
and 240 mg flat dose, respectively, every 2 weeks. Nivolumab over a dose range of 0.3 mg/kg to 
10 mg/kg has been studied as monotherapy and in combination in several tumor types using an 
every 3 weeks dosing regimen. It has been demonstrated that following administration of 
nivolumab 0.3 mg/kg, 2 mg/kg, and 10 mg/kg every 3 weeks, > 90% receptor occupancy (RO) is 
achieved beginning with the first cycle. Because nivolumab will be administered in combination 
with brentuximab vedotin, which has every 3 week dosing and the supporting RO data, the 
nivolumab dosing regimen in this study will be 240 mg flat dose administered every 3 weeks with 
brentuximab vedotin.
1.1.13.4
Thirty Minute Infusion Time Rationale
Long infusion times place a burden on subjects and treatment centers. Establishing that nivolumab 
can be safely administered using shorter infusion times of 30 minutes duration in subjects will 
diminish the burden provided no change in safety profile. Previous clinical studies show that 
nivolumab has been administered safely over 60 minutes at doses ranging up to 10 mg/kg over 
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long treatment duration. In Study CA209010, (a Phase 2, randomized, double blinded, 
dose-ranging study of nivolumab in subjects with advanced/metastatic clear cell RCC) a dose 
association was observed for infusion site reactions and hypersensitivity reactions (1.7% at 
0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). All the events were grade 1-2 and were 
manageable. An infusion duration of 30 minutes for 240 mg flat dose of nivolumab (~ 30% of the 
dose provided at 10 mg/kg) is not expected to present any safety concerns compared to the prior 
experience at 10 mg/kg nivolumab dose infused over a 60 minute duration.
1.2
Research Hypothesis 
The study will investigate the hypothesis that brentuximab vedotin can be safely combined with 
nivolumab. Additionally the study will investigate that the combination can result in a clinical 
meaningful ORR in subjects with relapsed/refractory DLBCL, relapsed/refractory PTCL (all 
subtypes excluding ALCL), relapsed/refractory PMBL, relapsed/refractory MGZL
and 
relapsed/refractory CTCL (MF/SS).
1.3
Objectives(s)
The purpose of this study is to evaluate the safety profile, tolerability and antitumor activity
following administration of nivolumab in combination with brentuximab vedotin in subjects with 
the diagnosis of relapsed/refractory DLBCL, PTCL (all subtypes excluding ALCL), PMBL. 
MGZL and CTCL (MF/SS).
1.3.1
Primary Objectives
•
To evaluate the safety and tolerability of the combination of nivolumab and brentuximab 
vedotin in subjects with the diagnosis of relapsed, refractory DLBCL, PTCL (all subtypes 
excluding ALCL), PMBL, MGZL and CTCL (MF/SS).
•
To assess the clinical benefit of nivolumab and brentuximab vedotin combination regimen in 
subjects with the diagnosis of relapsed/refractory DLBCL, relapsed/refractory PTCL
(excluding 
ALCL), 
relapsed/refractory 
PMBL, 
relapsed/refractory 
MGZL 
and 
relapsed/refractory CTCL (MF/SS) (CD30 expression t 1% by IHC is a prerequisite for all 
subjects participating in this study), as measured by ORR, defined as the proportion of subjects 
achieving either a PR or CR. In subjects with relapsed/refractory DLBCL, relapsed/refractory
PTCL, relapsed/refractory PMBL, relapsed/refractory MGZL the response will be assessed
according to Lugano Classification 2014. For subjects with relapsed/refractory CTCL,
response will be assessed according to consensus Global Response Score as per the consensus
statement of the International Society for Cutaneous Lymphoma.
1.3.2
Secondary Objectives
•
To assess overall duration of response (DOR) of the brentuximab vedotin and nivolumab 
combination regimen based on investigators assessments.
•
To assess the CRR with the nivolumab and brentuximab vedotin combination regimen and the 
duration of CR based on investigators assessments. 
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•
To assess PFS based on investigators assessments and OS of the brentuximab vedotin and 
nivolumab combination regimen.
1.3.3
Exploratory Objectives
•
To assess the Indeterminate response (IR) per Lymphoma Response to Immunomodulatory 
therapy Criteria (LYRIC) 85 in subjects with DLBCL, PTCL, PMBL, MGZL and CTCL (if 
applicable). 
•
To assess CD30 expression and correlate with response, and to assess PD-L1/L2 status and 
correlate it with response.
•
To characterize the molecular effects of the brentuximab vedotin and nivolumab combination 
regimen on tumor cells and the immune response; and identify biomarkers of response or 
resistance to the combination.
•
To assess tumor microenvironment and peripheral immune status
•
To characterize pharmacokinetics of nivolumab and brentuximab vedotin and explore 
exposure-response relationships.
•
To characterize the immunogenicity of nivolumab and brentuximab vedotin following 
combination therapy.
•
To evaluate changes in general health status assessed by the EQ-5D 3L (Cohort B only).
1.4
Product Development Background
1.4.1
Clinical Pharmacology Summary (Nivolumab)
The pharmacokinetics (PK) of nivolumab was studied in subjects over a dose range of 0.1 to 
10 mg/kg administered as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. The 
geometric mean (% CV%) clearance (CL) was 9.5 mL/h (49.7%), geometric mean volume of 
distribution at steady state (Vss) was 8.0 L (30.4%), and geometric mean elimination half-life 
(t1/2) was 26.7 days (101%). Steady-state concentrations of nivolumab were reached by 12 weeks 
when administered at 3 mg/kg Q2W, and systemic accumulation was approximately 3-fold. The 
exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg 
administered every 2 weeks. The clearance of nivolumab increased with increasing body weight. 
The PPK analysis suggested that the following factors had no clinically important effect on the CL 
of nivolumab: age (29 to 87 years), gender, race, baseline LDH, PD-L1. A PPK analysis suggested 
no difference in CL of nivolumab based on age, gender, race, tumor type, baseline tumor size, and 
hepatic impairment. Although ECOG status, baseline glomerular filtration rate (GFR), albumin, 
body weight, and mild hepatic impairment had an effect on nivolumab CL, the effect was not 
clinically meaningful. When nivolumab is administered in combination with ipilimumab, the CL 
of nivolumab was increased by 24%, whereas there was no effect on the clearance of ipilimumab.
Full details on the clinical pharmacology aspects of nivolumab can be found in the Investigator
Brochure.
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1.4.2
Clinical Pharmacology Summary (Brentuximab Vedotin)
The PK of brentuximab vedotin was assessed in phase 1 and 2 trials in oncology patients. 
Maximum serum concentrations of brentuximab vedotin antibody-drug conjugate (ADC) were 
generally observed close to the end of the 30 minute IV infusion. ADC exposures increased 
approximately dose proportionally from 1.2 to 2.7 mg/kg, and there was minimal to no 
accumulation upon multiple-dosing on a Q3W schedule. Serum ADC concentrations declined in a 
multi-phasic manner, with a terminal half-life of approximately 4 to 6 days. The mean Vss of the 
ADC was approximately 6 – 10 L, suggesting limited or modest extravascular distribution. 
Following administration of brentuximab vedotin, free or unconjugated MMAE levels were 
quantifiable in plasma, though at concentrations that were markedly (roughly 1/10th to 1/40th on 
a molar basis) lower than those of the ADC. Maximum plasma MMAE concentrations were 
attained approximately 1 to 3 days after the infusion. MMAE exposures decreased by 
approximately 20% to 50% with continued administration of brentuximab vedotin (relative to the 
first dose). Based on a population PK analysis, gender, age and race do not have a meaningful 
effect on the PK of brentuximab vedotin. Patients with hepatic impairment (Child-Pugh class A to 
C) exhibited a trend toward moderate decreases in ADC exposures, but increases in MMAE 
exposures of approximately 2.3 - fold. ADC and MMAE exposures were not meaningfully altered 
by mild or moderate renal impairment; however, severe renal impairment (CrCl < 30 mL/min) was 
associated with a trend toward moderate decreases in ADC exposures, but increases in MMAE 
exposures of approximately 1.9 - fold.
Further details on the clinical pharmacology of brentuximab vedotin can be found in the 
Investigator Brochure.
1.4.3
Safety Summary (Nivolumab)
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 8,600 subjects treated to date. Overall, the 
safety profile of nivolumab monotherapy as well as combination therapy is manageable and 
generally consistent across completed and ongoing clinical trials with no MTD reached at any dose 
tested up to 10 mg/kg. There was no pattern in the incidence, severity, or causality of AEs to 
nivolumab dose level. Most AEs were low-grade (Grade 1 to 2) with relatively few related high-
grade (Grade 3 to 4) AEs. Most high-grade events were manageable with the use of corticosteroids 
or hormone replacement therapy (endocrinopathies) as instructed in the management algorithms 
provided in Appendix 6 and nivolumab investigator brochure. The spectrum, frequency, and 
severity of drug-related AEs were generally similar across the dose levels tested. A review of the 
safety data by tumor type (RCC, NSCLC, mCRPC, CRC, and melanoma) also did not show any 
clinically meaningful differences in the proportion of subjects with AEs noted across tumor type. 
Although tumor progression was the most common cause of mortality, there were 3 drug-related 
deaths associated with grade 3-4 pneumonitis. Pneumonitis (any grade) occurred in 12 of 306 
subjects (4%), and grade 3-4 pneumonitis occurred in 4 subjects (1%), with clinical presentations 
ranging from asymptomatic radiographic abnormalities to progressive, diffuse pulmonary 
infiltrates associated with cough, fever, and/or dyspnea. No clear relationship between the 
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occurrence of pneumonitis and tumor type, dose level, or treatment duration was noted. In 9 of 12 
subjects, pneumonitis was reversible with treatment discontinuation and/or immunosuppression 
(glucocorticoids, infliximab, mycophenolate). 
Nivolumab, at 1 or 3 mg/kg, has an acceptable safety profile in subjects with relapsed or refractory 
hematologic malignancy. The following were the key safety findings for 105 subjects treated with 
nivolumab monotherapy in CA209039 as of 15-Apr-2015:
1. The most frequently reported drug-related AEs (> 10% of subjects) were fatigue (16.2%) and
rash (10.5%). The majority were Grade 1-2 in severity.
2. The most frequently reported drug-related SAE was pneumonitis (4.8%).
3. Drug-related AEs leading to discontinuation were reported for 14.3% of subjects. The most
frequently reported AE leading to discontinuation were pneumonitis (2.9%).
4. The most frequently reported drug-related select AE categories were skin (19.0%), GI (9.5%), 
and pulmonary (9.5%). The most frequently reported (t 5% of total treated subjects) drug-
related select AEs were rash (10.5%), pneumonitis (9.5%), pruritus (9.5%), and diarrhea 
(8.6%). Drug-related select AEs were mostly Grade 1-2 in all categories.
5. Most deaths were due to disease progression. One death was reported due to study drug toxicity 
(The subject with non Hodgkin’s lymphoma [small lymphocytic lymphoma] in the 3 mg/kg 
treatment group died due to Grade 5 pneumonitis with onset 10 days after the subject received 
the only dose of nivolumab).
Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are also available in the Investigator Brochure (IB).
1.4.4
Safety Summary (Brentuximab Vedotin)
Two pivotal phase 2 studies evaluating the efficacy and safety of brentuximab vedotin as a single 
agent were performed in patients with relapsed or refractory Hodgkin lymphoma (HL) and 
systemic anaplastic large cell lymphoma (ALCL) (Studies SG035-0003 and SG035-0004, 
respectively). Treatment-emergent adverse events (AEs) occurring in t 20% of HL and systemic 
ALCL patients in the phase 2 studies were peripheral sensory neuropathy (45%), fatigue (43%),
nausea (41%), diarrhea (34%), pyrexia (31%), upper respiratory tract infection (31%), neutropenia 
(21%), and vomiting (20%). These events were primarily Grade 1 or 2, with the exception of 
neutropenia, for which Grade 3 and Grade 4 events were reported for 13% and 7% of patients, 
respectively. Similar patterns and incidences of AEs were generally observed for HL and ALCL 
patients.
A phase 3, randomized, placebo-controlled study evaluating efficacy and safety of brentuximab 
vedotin in the treatment of patients with HL who are at risk of disease progression following 
autologous stem cell transplant (ASCT) has been completed (SGN35-005). A total of 329 patients 
were randomized (164 patients to brentuximab vedotin and 165 to placebo) and there were 
327 patients who received study treatment (167 patients received at least 1 dose of brentuximab 
vedotin and 160 patients received placebo). AEs that had a higher relative risk of occurring in 
patients in the brentuximab vedotin arm of Study SGN35-005 compared with patients in the 
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placebo arm (as indicated by a relative risk >1 and confidence intervals 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.
Additional oncology clinical studies, compassionate-use programs, and postmarketing use have 
contributed further brentuximab vedotin safety data. Notable adverse events observed with 
brentuximab vedotin treatment of various cancers to date include peripheral neuropathy, infusion-
related 
reactions, 
and 
cytopenias; 
and, 
less 
commonly, 
progressive 
multifocal 
leukoencephalopathy (PML), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), 
tumor lysis syndrome (TLS), acute pancreatitis, pulmonary toxicity, and hepatotoxicity. In 
addition, concomitant use of brentuximab vedotin and bleomycin is contraindicated due to 
pulmonary toxicity that occurred in some patients receiving this combination of treatments.
1.5
Overall Risk/Benefit Assessment
Subjects with relapsed/refractory Non Hodgkin Lymphoma (DLBCL, PTCL, CTCL, PMBL and 
MGZL) after progression on systemic therapy represent an area of substantial unmet medical need. 
Allogeneic Stem Cell Transplant has the potential to offer cure in this patient population, majority 
of subjects are ineligible for this treatment due to age, refractory disease status or lack of suitable 
stem cell donor. Additionally allogeneic stem cell transplant has significant risk of associated 
morbidity and mortality. Although a significant numbers of novel agents are emerging in the 
treatment of relapsed NHL, the duration of response remains short with the majority as single 
agents. Therefore the development of new approaches is needed in relapsed NHL. The clinical 
activity of nivolumab observed to date in heavily pretreated subjects with solid tumors as well as 
early results in NHL and HL suggests the potential for improved clinical outcomes for these 
subjects. Additionally brentuximab vedotin has demonstrated promising activity in HL and NHL. 
Nivolumab and brentuximab vedotin also have the potential for clinically relevant adverse events 
including pulmonary toxicity, hepatotoxicity, diarrhea/colitis, endocrinopathies, nephrotoxicity, 
peripheral neuropathy and cytopenias. To date, serious AEs have been manageable with prompt 
diagnosis and initiation of corticosteroids, dose interruption, and adequate supportive care with 
both agents. Together the data suggest a positive benefit-risk potential, supporting a Phase I/II
study to further assess the safety and efficacy of nivolumab and brentuximab vedotin combination 
in subjects with relapsed, refractory DLBC, PTCL (excluding ALCL), CTCL (MF/SS), PMBL & 
MGZL.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
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The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a breach 
of the conditions and principles of GCP in connection with the study or the protocol, which is 
likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects of 
the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements) and any other written information to be provided to subjects. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other information 
(eg, expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1. Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 
2. Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study.
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3. Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion. 
4. Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
5. If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject.
6. Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct
access to subject records. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The subject 
must also be informed about the nature of the study to the extent compatible with his or her
understanding, and should this subject become capable, he or she should personally sign and date 
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or 
her written consent, but who is capable of forming an opinion and assessing information to refuse 
participation in or to be withdrawn from, the clinical study at any time should be considered by 
the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is an open-label, multicenter phase I/II study of nivolumab in combination with brentuximab 
vedotin designed to evaluate the safety and efficacy in subjects with the diagnosis of 
relapsed/refractory DLBCL, PTCL (excluding ALCL), CTCL (MF/SS), PMBL, and MGZL. 
The study will consist of three phases: Screening, Treatment and Follow-up. The treatment phase 
is divided in two parts: Cohort A consists of the Dose Evaluation Phase and Cohort B is the 
Expansion Phase.
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It is anticipated that 170 subjects will be enrolled in the United States, Canada and Europe for the 
entire study (Cohort A and Cohort B combined). All subjects will undergo a screening period to 
determine eligibility within 28 days prior to initial dosing.
Dose Evaluation Phase (Cohort A)
The Dose Evaluation Phase (Cohort A) will include a dose limiting toxicity (DLT) evaluation for 
the dose level of brentuximab vedotin 1.8 mg/kg intravenously in combination with nivolumab 
240 mg flat dose intravenously in a q 3 week cycle. Refer to section 4.5.1 for further details.
In cycle 1, brentuximab vedotin 1.8mg/kg will be administered on day 1 where as nivolumab 
240 mg flat dose will be administered on day 8. Subsequent to cycle 1, both drugs will be 
administered on the first day of the new cycle. Brentuximab vedotin will be administered first as 
a 30-minute infusion followed by a minimum 30-minute rest. Nivolumab will then be administered 
also as a 30-minute infusion.  
The DLT evaluation period, which consists of the first dose of study drug through the first 6 weeks 
of treatment, will be conducted in the first 6 treated subjects (all comers). Decisions to enroll up 
to 6 additional subjects onto the same dose of brentuximab vedotin 1.8 mg/kg in combination with 
nivolumab 240 mg flat dose intravenously every 3 weeks or at a reduced dose of brentuximab 
vedotin at 1.2 mg/kg will be based on the safety data reviewed throughout the DLT evaluation
period.
If any of the first 6 treated subjects discontinue treatment for reasons other than a DLT but prior 
to completing the DLT evaluation period, then they will be replaced. Subjects enrolled to Cohort 
A will be monitored for DLT throughout the DLT evaluation period. Refer to section 4.5.1 for 
DLT definition. 
After 6 DLT-evaluable subjects have been followed throughout the first 6 weeks of treatment, or 
at the point that 2 or more subjects experience a DLT, whichever comes first, the study team will 
review the available data and provide any of the following recommendations that may include but 
are not limited to:
1) If one or none (d 1) of the 6 subjects experience a DLT, the expansion cohort will begin with 
brentuximab vedotin 1.8 mg/kg Cycle 1 Day 1 and nivolumab 240 mg flat dose on Cycle 1 
Day 8. 
2) If two or more (t 2) of the 6 subjects are determined to have had a DLT based on the protocol 
definition (refer to section 4.5.1), the following options will be considered
a) To repeat Cohort A of the study and treat up to 6 additional subjects at the same drug doses 
and schedule previously tested 
b) To repeat Cohort A of the study and treat up to 6 additional subjects at a reduced dose of
brentuximab vedotin 1.2 mg/kg;
c) Administration of the combination treatment on Day 1 of every cycle, including cycle 1
d) To close the study to additional enrollment.
NOTE: Doses may not be increased to above 1.8 mg/kg brentuximab vedotin or nivolumab 
240 mg flat dose.
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On review of all available data, the study team may determine that the classification of DLT was 
not appropriate for one or more of the subjects, in which case enrollment may resume if the target 
of 6 DLT-evaluable subjects has not yet been reached. However, if 2 or more subjects were
determined to have experienced DLTs, then expansion will not occur as the next step. Based on 
the study team’s recommendations, up to 6 additional subjects may be enrolled in Cohort A at the 
same drug dose levels and schedule or at a modified treatment (described above in this section). 
These additional subjects will then be assessed for DLT in the same manner described above to 
determine if it is appropriate to move to the Expansion Phase (Cohort B). If it is determined by the 
study team that due to safety concerns no additional dose levels or schedules should be enrolled, 
then the study will be closed to enrollment.
There is no planned interim analysis (IA). However, all available efficacy and safety data will be 
used to select the recommended brentuximab vedotin dose and treatment schedule that will be 
further evaluated in the Expansion Phase (Cohort B).
Expansion Phase (Cohort B)
The Expansion Phase will consist of a single-arm phase II study which will expand enrollment at 
the recommended dose level and treatment schedule as deemed safe by the study team in Cohort A. 
An additional 40 subjects in DLBCL (cohort B1), 30 subjects in PTCL (cohort B2) 20 subjects in 
CTCL (cohort B3), 30 subjects in PMBL (cohort B4) and 10 subjects in MGZL (cohort B5) will 
be enrolled to complete this evaluation. 
If one or none (d 1) of the 6 subjects in cohort A experience a DLT, the expansion cohort will 
begin with brentuximab vedotin 1.8 mg/kg Cycle 1 Day 1 and nivolumab 240 mg flat dose on 
Cycle 1 Day 8. Subsequent to cycle 1, both drugs will be administered on the first day of the new 
cycle. Brentuximab vedotin will be administered first as a 30-minute infusion followed by a 
minimum 30-minute rest. Nivolumab will be then be administered as a 30-minute infusion. If two 
or more (t 2) of the 6 subjects are determined to have had a DLT based on the protocol definition 
(refer to section 4.5.1) treatment modification or enrollment closure will be considered, as 
described above.
All subjects in the study (Cohort A and Cohort B) will be allowed to be treated until disease 
progression or unacceptable toxicity as described in Section 4.5.3 and Section 4.5.5. If during 
therapy it appears that a subject is benefiting from the combination but experiencing toxicities 
related to one agent that would require permanent treatment discontinuation, then they have the 
option to continue therapy with the single agent not attributing to toxicities.
Subjects that present progressive disease during treatment may be allowed to be treated beyond 
progression until further progression is observed. Refer to Section 4.5.9 for further details.
Once subjects discontinue from study treatment for any reason, subjects will enter the follow-up 
phase of the study. During follow-up long-term safety, survival status, disease progression, 
subsequent anticancer therapy and occurrence of other primary malignancy data will be collected. 
Follow-up visit 1 (X01) and follow-up visit 2 (X02) will be in person visits and all subsequent 
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follow-up visits may be done in person or by phone. All treated subjects will be followed for 
survival at least every 3 months until death or lost to follow-up. Subjects with residual toxicity G
t 2 at the time of discontinuation must follow these until resolved to at least G1, end of study or 
deemed irreversible, whichever occurs first. Subjects who discontinue for reasons different than 
progressive disease must continue to perform tumor assessments as described in Section 5.4 until 
disease progression is documented. 
The primary endpoint for Cohort B will be investigator-assessed ORR for all five tumor types. 
Primary endpoint analysis will occur 8 months after the last patient receives their first treatment 
(LPFT). Depending on the enrollment for each disease cohort, the analysis may be done at different 
times for each cohort, or at the same time for the five cohorts. The study design schematic is 
presented in Figure 3.1-1.
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Figure 3.1-1:
Study Design Schematic
3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug (brentuximab vedotin and nivolumab). Study drug 
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will be provided via an extension of the study, a rollover study requiring approval by responsible 
health authority and ethics committee or through another mechanism at the discretion of BMS. 
BMS reserves the right to terminate access to BMS supplied study drug if any of the following 
occur: a) the marketing application is rejected by responsible health authority; b) the study is 
terminated due to safety concerns; c) the subject can obtain medication from a government 
sponsored or private health program; or d) therapeutic alternatives become available in the local 
market.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent form 
in accordance with regulatory and institutional guidelines. This must be obtained before 
the performance of any protocol related procedures that are not part of normal subject care.
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests and other requirements of the study.
c) Each participant must be informed about the nature of the study to the extent compatible 
with his or her understanding. Should a participant become capable or reach the age of 
majority, his or her consent should be obtained as soon as possible. The explicit wish of a 
participant who is a minor or unable to give his or her written consent, but who is capable 
of forming an opinion and assessing information to refuse participation in, or to be 
withdrawn from, the clinical study at any time should be considered by the investigator
d) Minors who are judged to be of an age of reason as determined by local requirements 
should also give their assent. The assent should be documented based on local 
requirements. Continued assent should be documented when important new information 
becomes available that is relevant to the participant’s assent.
2. Target Population
a) Subject must be 18 years of age or older ( for PMBL  15 years or older)
b) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1, see 
Appendix 1.
c) All subjects in this study are required to have expression of CD30 t 1% in the tumor or 
tumor infiltrating lymphocytes (TILs) by local immunohistochemistry prior to the first 
dose. 
d) Histological confirmation of the following NHL subtypes is permitted: 
i)
DLBCL by standard immunopathology, relapsed/refractory disease as follows: 
(1) Subjects with relapsed and/or refractory DLBCL or Transformed Lymphoma (TL) 
after high-dose conditioning chemotherapy and ASCT, or subjects with relapsed 
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and/or refractory DLBCL or TL after at least 2 prior multi-agent chemotherapy 
regimens if ASCT ineligible. 
(2) Subjects with Richter’ s transformation (TL)
(transformed chronic lymphoid 
leukemia into DLBCL) are allowed to participate in this study
ii) PTCL with immunopathological and molecular biological diagnosis, all subtypes with 
the exception of ALCL
(1) PTCL must be relapsed and/or refractory disease after 1 or more lines of standard 
systemic therapy 
iii) CTCL (MF/SS subtypes only) with diagnosis of MF/SS by immunopathological and 
molecular, biological criteria 
(1) CTCL must be relapsed and/or refractory disease after 1 or more lines of standard 
systemic therapy
(2) Stage IB-IV per TNMB modified International Society of Cutaneous Lymphoma 
(ISCL) and WHO-EORTC staging criteria (Appendix 3).
iv) PMBL must be relapsed/refractory disease after high-dose conditioning chemotherapy 
and ASCT, or subjects with relapsed and/or refractory PMBL after at least 2 prior 
multi-agent chemotherapy regimens if ASCT ineligible
v) MGZL must be relapsed/refractory disease after high-dose conditioning chemotherapy 
and ASCT, or subjects with relapsed and/or refractory MGZL after at least 2 prior 
multi-agent chemotherapy regimens if ASCT ineligible 
e) Evaluable tumor tissue (archived or new biopsy) must be provided for biomarker analysis 
as FFPE tumor block or a minimum of 20 slides. Bone marrow aspirate and biopsy and 
peripheral blood are not to be submitted for evaluable tumor tissue. In order to be treated, 
the sample must meet the minimum quality requirements, as determined by the central 
laboratory during the screening period.
f)
All subjects with PTCL, DLBCL, PMBL and MGZL must have measurable disease 
defined as:
i)
At least 1 measurable site of disease according to the Lugano Classification 2014 
(Appendix 2). (Criteria does not apply for CTCL).
g) Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been treated). If 
re-enrolled, the subject must be re-consented.
3. Physical and Laboratory Test Findings
a) Screening laboratory values must meet these following criteria: 
i)
Absolute neutrophil count (ANC) t 1.0 x 109cells/L (ie, t 1000/ L)
ii) Platelets t 50 x 109cells/L (ie, t 50,000/L) without transfusion support within 14 days 
prior to test
iii) Hemoglobin t 8.5 g/dL without transfusion support within 7 days prior to test
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iv) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) d 2.5 x upper 
limit of normal (ULN)
v) Serum bilirubin d 1.5 X ULN (unless due to Gilbert’s syndrome, in which case the cut 
off is < 3.0 x ULN)
vi) Calculated creatinine clearance of t 30 mL/min/1.73m2 measured using the Cockcroft-
Gault formula below:
Female CrCl = (140 - age in years) x weight in kg x 0.85
   72 x serum creatinine in mg/dL
Male CrCl = (140 - age in years) x weight in kg x 1.00
72 x serum creatinine in mg/dL
4. Age and Reproductive Status
a) Males and Females, t 18 years of age, inclusive (for PMBL   15 years or older)
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study drug (s) plus approximately 5 half-lives of study drug plus 30 days 
(duration of ovulatory cycle) for a total of 23 weeks post-treatment completion. .(Note: 
half-life of nivolumab is greater than brentuximab vedotin) 
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug (s) plus 
approximately 5 half-lives of the study drug plus 90 days (duration of sperm turnover) for 
a total of 31 weeks post-treatment completion.
f)
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However they must still undergo pregnancy 
testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the 
use of highly effective methods of contraception. Highly effective methods of contraception have 
a failure rate of < 1% when used consistently and correctly.
At a minimum, subjects must agree to the use of two methods of contraception, with one method 
being highly effective.
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3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Location of the NHL in the central nervous system (CNS)
2. Medical History and Concurrent Diseases
a) Subjects with history of progressive multifocal leukoencephalopathy (PML)
b) Any positive test for hepatitis B virus, including HBs Ag+ or anti-HBc+, or positive test 
for hepatitis C virus indicating acute or chronic infection (including anti-HCV+ or presence 
of HCV-RNA)
c) Positive test for human immunodeficiency virus (HIV)
d) Pre-existing neuropathy of t grade 2
e) Any active grade 3 or higher (per the National Cancer Institute’s Common Terminology 
Criteria for Adverse Events [NCI CTCAE], version 4.03) viral, bacterial or fungal infection 
within 2 weeks prior to the first dose of brentuximab vedotin; routine antimicrobial 
prophylaxis is permitted.
f)
Documented history of cerebral vascular event (stroke or transient ischemic attack), 
unstable angina, myocardial infarction or cardiac symptoms with New York Heart 
Association Class III-IV within 6 months prior to the first dose of the study drugs
g) Subjects with an active, known or suspected autoimmune disease. 
NOTE: Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone 
replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring 
systemic treatment, or conditions not expected to recur in the absence of an external 
trigger are permitted to enroll.
h) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
first dose
NOTE: Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune disease.
i)
Known history of pancreatitis
j)
Other serious underlying medical condition that, in the opinion of the investigator, would 
impair the ability to receive or tolerate the planned treatment and follow-up
k) History of another primary invasive malignancy that has not been in remission and is 
requiring therapy in the last 3 years 
3. Prohibited Treatments and/or Therapies
a) Prior exposure to brentuximab vedotin
b) Prior exposure to anti-PD1, anti-PDL1, anti-PD-L2, anti-CD137 or anti- CTLA-4 antibody,
or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways
c) Concurrent enrollment in another therapeutic investigational clinical study
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d) History of hypersensitivity reactions to monoclonal antibody therapy 
e) Prior exposure to anti-CD30 directed treatment 
f)
Nitrosoureas within 6 weeks of first dose
g) Chemotherapy within 4 weeks of first dose
h) Therapeutic antibodies within 4 weeks of first dose
i)
Radio- or toxin-immunoconjugates within 10 weeks of first dose
j)
Radiation therapy within 3 weeks of first dose, or chest radiation d 12 weeks prior to first 
dose 
k) Investigational agents within 3 weeks of first dose
l)
Carmustine (BCNU) > 1000 mg received as part of pre-transplant conditioning regimen
m) Received an allogeneic hematopoietic Stem Cell Transplant
n) Topical and targeted therapies; such as histone deacetylase inhibitors (HDAC inhibitors), 
anti-folate antagonist, nucleoside analogs or retinoids such as bexarotene,  topical nitrogen 
mustard 
4. Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Women who are pregnant or breastfeeding
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
A Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In addition, 
females under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40mIU/mL to confirm menopause.
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
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judgement in checking serum FSH levels. If the serum FSH level is > 40 mIU/ml at any time 
during the washout period, the woman can be considered postmenopausal:
•
1 week minimum for vaginal hormonal products (rings, creams, gels)
•
4 week minimum for transdermal products
•
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug related 
adverse event):
•
Immunosuppressive agents
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 3.4.2.1)
•
Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents)
3.4.2
Other Restrictions and Precautions
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days of first dose are 
excluded. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune disease.
It is the local imaging facility’s responsibility to determine, based on subject attributes (eg, allergy 
history, diabetic history and renal status), the appropriate imaging modality and contrast regimen 
for each subject. Imaging contraindications and contrast risks should be considered in this 
assessment. Subjects with renal insufficiency should be assessed as to whether or not they should 
receive contrast and if so, what type and dose of contrast is appropriate. Specific to MRI, subjects 
with 
severe 
renal 
insufficiency 
(ie, 
estimated 
glomerular 
filtration 
rate 
(eGFR) 
< 30 mL/min/1.73m2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast should 
not be given to this subject population. In addition, subjects are excluded from MRI if they have 
tattoos, metallic implants, pacemakers, etc.   
The ultimate decision to perform MRI in an individual subject in this study rests with the site 
radiologist, the investigator and the standard set by the local Ethics Committee.
3.4.2.1
Permitted Therapy
Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
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daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-
type hypersensitivity reaction caused by a contact allergen) is permitted.
Concomitant palliative and supportive care for disease related symptoms (including 
bisphosphonates and RANK-L inhibitors) is allowed if initiated prior to first dose of study therapy. 
Palliative radiotherapy must have been completed at least 3 weeks prior to first dose. Palliative 
radiation therapy is allowed on study, study treatment must be held 2 weeks prior to and 2 weeks 
post treatment. 
The use of platelet and/or red blood cell supportive growth factors or transfusions when applicable 
is allowed. The use of colony stimulating factors for the treatment of neutropenia per institutional 
practice is permitted during therapy.
Routine premedication for infusion reactions should not be administered prior to the first dose of 
study drug(s). However, subjects who experience an infusion-related reaction may receive 
subsequent treatment with premedication as described in Section 4.5.6.
Subjects who are receiving strong CYP3A4 inhibitors concomitantly with brentuximab vedotin 
should be closely monitored for adverse reactions.
Routine prophylaxis with vaccines is permitted prior to study entry; it is recommended that 
vaccines used do not contain live micro-organisms.
3.5
Discontinuation of subjects following any treatment with study drug
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Subject’s request to stop study treatment
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
•
Additional protocol specific reasons for discontinuation Section 4.5.5 and Section 4.5.3
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug and it is allowed by local regulations, a discussion between 
the investigator and the BMS Medical Monitor/designee must occur.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Table 5.1-3. The only exception to this requirement is when a subject 
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withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow up
In this study, overall survival is a key endpoint of the study. Post study follow-up is of critical 
importance and is essential to preserving subject safety and the integrity of the study. Subjects who 
discontinue study drug must continue to be followed for collection of outcome and/or survival 
follow-up data as required and in line with Table 5.1-3 until death, withdrawal of consent, lost to 
follow-up or the conclusion of the study.
In addition, subjects who discontinue study therapy by proceeding to allogeneic SCT or ASCT 
will require tumor assessment (CR or non-CR) by the investigators according to the Lugano 
Classification 2014 (DLBCL/PTCL) and consensus Global Response Score (CTCL) on day 100, 
at 6 months, 1 year and every year thereafter from the date of stem cell infusion until the first 
non-CR after SCT is documented. For the subjects who discontinue study therapy by proceeding 
to allogeneic SCT, documentation of acute and chronic GVHD will be simultaneously collected
see Appendix 5 for more details.
Subjects who discontinue study drug may continue to be followed. BMS may request that survival 
data be collected on all treated subjects outside of the 3 month specified visit schedule. At the time 
of this request, each subject will be contacted to determine their survival status unless the subject 
has withdrawn consent for all contact.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a subject 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In the 
event that vital status (whether the subject is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in accordance 
with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up 
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is defined by the inability to reach the subject after a minimum of three documented phone calls, 
faxes, or emails as well as lack of response by subject to one registered mail letter. All attempts 
should be documented in the subject’s medical records. If it is determined that the subject has died, 
the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study has 
been included in the subject’s informed consent, then the investigator may use a Sponsor-retained 
third-party representative to assist site staff with obtaining subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If after all attempts, the subject remains 
lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
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Table 4-1:
Study Drugs for CA209436
Product Description / 
Class and Dosage Form
Potency
IP/Non-IMP
Blinded or Open 
Label
Packaging/
Appearance
Storage Conditions
(per label)
BMS-936558-01 
Solution for Injection*
100 mg
(10 mg/mL)
IP
OPEN LABEL
Clear to opalescent 
colorless to pale yellow 
liquid. May contain 
particles.
2-8°C. Protect from 
light and freezing.
Brentuximab Vedotin
Powder for Injection
50mg 
IP
OPEN LABEL
White to off-white 
lyophilized 
preservative-free cake 
or powder in a single-
use vial for 
reconstitution. 
2-8°C. Protect from 
light.  
*May be labeled as either “BMS-936558-01” or “Nivolumab”.
Premedications or medications used to treat infusion-related reactions should be sourced by the investigative sites if available and 
permitted by local regulations
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to 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.
In this protocol, investigational products are:
•
Nivolumab (BMS-936558) 
•
Brentuximab Vedotin
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products. 
Not applicable for this study.
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed
and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
4.3.1
Brentuximab Vedotin
Brentuximab vedotin will be administered every 21 (q 3 weeks) days by IV infusion given over 
approximately 30 minutes. In the absence of infusion-related reactions, the infusion rate for all 
subjects should be calculated in order to achieve a 30 minute infusion period. Brentuximab vedotin 
must not be administered as an IV push or bolus nor mixed with other medications. Brentuximab 
vedotin will be administered first as a 30 minute infusion followed by a minimum 30 minute rest 
prior to the nivolumab infusion.
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Dosing is based on subject’s actual body weight. Doses must be adjusted for subjects who 
experience a t 10% change in weight from baseline. Other dose adjustments for changes in body 
weight are permitted per institutional standard. An exception to weight-based dosing is made for 
subjects weighing greater than 100 kg; doses will be based on 100 kg for these individuals.
Rounding is permissible within 5% of the nominal dose.
Refrigeration should be set at 2–8°C for storage of vials and solutions containing brentuximab 
vedotin. The controlled location must be accessible only to the pharmacist, the investigator, or a 
designated person. Brentuximab vedotin does not contain preservatives; therefore, opened and 
reconstituted vials of brentuximab vedotin should be used as soon as possible. If not used 
immediately, the in-use storage should not be longer than 24 hours. It is recommended that 
brentuximab vedotin vials and solutions be protected from direct sunlight until the time of use.
Reconstituted vials and solutions must not be shaken.
Drug product vials may be labeled as brentuximab vedotin, the United States adopted name 
(USAN) and the International Nonproprietary Name (INN), or as SGN 35, the compound code; 
the 2 names can be used interchangeably.
Brentuximab vedotin vials are provided via single-use containers. Any partially used vials or 
diluted dosing solutions should be discarded using appropriate institutional drug disposal 
procedures.
Brentuximab vedotin should be reconstituted with 10.5mL of Sterile Water for Injection, United 
States Pharmacopeia (USP) or equivalent (see Pharmacy Binder for details) for a final 
concentration of 5mg/mL. The vial should be gently swirled until the contents are completely 
dissolved. The vial must not be shaken. The reconstituted drug product should be inspected 
visually for any particulate matter and discoloration.
The required volume of reconstituted drug product should be diluted into an infusion bag. The bag 
should be gently inverted to mix the solution. The bag must not be shaken. Prior to administration, 
the reconstituted and diluted drug product should be inspected visually for any particulate matter 
and discoloration.
Detailed drug preparation and drug accountability instructions for brentuximab vedotin are 
provided in the Pharmacy Binder.
4.3.2
Nivolumab
Nivolumab will be administered every 21 days (q 3weeks) by IV infusion given over 
approximately 30 minutes. Nivolumab (BMS-936558) vials must be stored at a temperature of 2°C 
to 8°C and should be 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.
For details on prepared drug storage and use time of nivolumab under room temperature/light and 
refrigeration, please refer to the BMS-936558 (nivolumab) IB section for “Recommended Storage 
and Use Conditions” and/or pharmacy reference sheets.
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At the end of the infusion, flush the line.
For both study drugs, infusion-related supplies (eg, IV bags, in-line filters, 0.9% NaCl solution) 
will not be supplied by the sponsor and should be purchased locally if permitted by local 
regulations. 
Please refer to the current version of the IB and/or pharmacy reference sheets for complete storage, 
handling, dispensing, and infusion information for BMS-936558 (nivolumab).
4.4
Method of Assigning Subject Identification
After the subject’s initial eligibility is established and informed consent has been obtained, the 
subject must be enrolled into the study by calling an IVRS to obtain the subject number. Every 
subject that signs the informed consent form must be assigned a subject number in IVRS. Specific 
instructions for using IVRS will be provided to the investigational site in a separate document. 
The investigator (or designee) will register the subject for enrollment by following the enrollment 
procedures established by BMS. The following information is required for enrollment:
•
Date of informed consent
•
Date of birth
•
Gender at birth
•
Lymphoma Disease Diagnosis (DLBCL, PTCL, CTCL, PMBL, MGZL)
A separate call will need to be placed to assign eligible subjects their first treatment once the tumor 
tissue submitted to the central laboratory has gone through the quality assessment and the 
information is available in the IVRS.
4.5
Selection and Timing of Dose for Each Subject
There will be 2 parts to this study. During the Dose Evaluation Phase (Cohort A) six eligible 
subjects will be enrolled and treated with brentuximab vedotin (IV) 1.8 mg/kg as the starting dose 
and may be reduced to 1.2 mg/kg if toxicities described in Table 4.5.3-1 are observed. Subjects 
enrolled to Cohort A will be treated with a combination of brentuximab vedotin and nivolumab 
240 mg flat dose (IV) of every 3 week cycle. In cycle 1, brentuximab vedotin will be administered 
on day 1 where as nivolumab will be administered on day 8. Subsequent to cycle 1, both drugs 
will be administered on the first day of the new cycle. Brentuximab vedotin will be administered 
first as a 30-minute infusion followed by a minimum 30-minute rest. Nivolumab will be then be 
administered as a 30-minute infusion 
The starting dose of brentuximab vedotin 1.8 mg/kg is to be given over approximately 30 minutes
intravenously. In the absence of infusion related reaction, the infusion rate for all subjects should 
be calculated in order to achieve a 30-minute infusion period. Dosing calculations should be based 
on the subject’s actual body weight. If the subject’s weight on the day of dosing differs by > 10% 
from the previous weight used to calculate the required dose, a corrected dose must be recalculated. 
Other dose adjustments for changes in body weight are permitted per institutional standard. All 
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doses should be rounded to the nearest milligram. Brentuximab vedotin may be reduced to 
1.2mg/kg if toxicities described in Table 4.5.3-1 are observed. The Cohort B will open with a 
proposed dosing regimen with cycle duration of 21 days (3 weeks). Brentuximab vedotin will be 
administered based on the dose identified in Cohort A (1.8 mg/kg or 1.2 mg/kg) and nivolumab 
will be given over 30 min intravenously at a 240 mg flat dose.
An exception to weight-based brentuximab vedotin dosing is made for subjects weighing greater 
than 100 kg; doses will be based on 100kg for these individuals. Rounding is permissible within 
5% for the nominal dose.
There will be no dose escalations or reductions of nivolumab allowed. There are no premedications 
recommended for nivolumab on the first cycle. If an acute infusion reaction is noted, subjects 
should be managed according to Section 4.5.6.
First dose of nivolumab will be administered on Cycle 1 Day 8, which is only 2 weeks away from
Cycle 2 Day 1. For safety reasons, subjects may be dosed no less than 12 days between doses. For 
all other cycles, treatment is to occur within 3 days of the scheduled dosing date. Dose given after 
the 3 day window is considered a dose delay. Treatment may be delayed for up to a maximum of 
6 weeks from the previous dose. Refer to Section 4.5.4 for further details.
Subjects will be monitored continuously for AEs while on study. Treatment modifications 
(eg, dose delay, interruption or discontinuation) will be based on specific laboratory and AE 
criteria (further details described in Section 4.5.3 and Section 4.5.4).
4.5.1
Dose Evaluation Phase: (Cohort A)
The Dose Evaluation Phase (Cohort A) will include a dose limiting toxicity (DLT) evaluation for 
the dose level of brentuximab vedotin 1.8 mg/kg intravenously in combination with nivolumab 
240 mg flat dose intravenously in a q 3 week cycle. In cycle 1, brentuximab vedotin 1.8 mg/kg 
will be administered on day 1 where as nivolumab 240 mg flat dose will be administered on day 8. 
Subsequent to cycle 1, both drugs will be administered on the first day of the new cycle. 
Brentuximab vedotin will be administered first as a 30-minute infusion followed by a minimum 
30-minute rest. Nivolumab will be then be administered as a 30-minute infusion.  
The DLT evaluation will be conducted in the first 6 treated subjects (all comers). Decisions to 
enroll up to 6 additional subjects onto the same dose of brentuximab vedotin 1.8 mg/kg in 
combination with nivolumab 240 mg flat dose intravenously every 3 weeks or at a reduced dose 
of brentuximab vedotin at 1.2 mg/kg will be based on the safety data reviewed throughout the DLT 
evaluation period. The DLT evaluation period consists of the first dose of study drug through the 
first 6 weeks of treatment.
If any of the first 6 treated subjects discontinue treatment for reasons other than a DLT, prior to 
completing the DLT evaluation period, then they will be replaced. These subjects will be 
monitored for DLT throughout the DLT evaluation period (DLT definition is provided further 
below in this section). After 6 DLT-evaluable subjects have been followed through the end of the 
DLT evaluation period, or at the point that 2 or more subjects experience a DLT, whichever comes 
first, the study team will review the available data. The BMS study team along with Seattle 
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Genetics study team and the investigators participating in the trial, will review all of the available 
safety data and provide any of the following recommendations that may include, but are not limited 
to:
1. One or none (d 1) of the 6 subjects experience a DLT, the expansion cohort will begin with 
brentuximab vedotin 1.8 mg/kg Cycle 1 Day 1 and nivolumab 240 mg flat dose on Cycle 1 
Day 8. Subsequent to cycle 1, both drugs will be administered on the first day of the new cycle. 
Brentuximab vedotin will be administered first as a 30-minute infusion followed by a minimum 
30 minute rest. Nivolumab will be then be administered as a 30 min infusion.
2. If two or more (t 2) of the 6 subjects are determined to have had a DLT based on the protocol 
definition, the following options will be considered
a.
To repeat Cohort A of the study and treat up to 6 additional subjects at the same drug 
doses and schedule previously tested 
b. To repeat Cohort A of the study and treat up to 6 additional subjects at a reduced dose 
of brentuximab vedotin 1.2 mg/kg;
c.
Administration of the combination treatment on Day 1 of every cycle, including cycle 1
d. To close the study to additional enrollment. 
NOTE: Doses may not be increased to above 1.8 mg/kg brentuximab vedotin or nivolumab 
240 mg flat dose
On review of all available data, the study team may determine that the classification of DLT was 
not appropriate for one or more of the subjects, in which case enrollment may resume if the target 
of 6 DLT-evaluable subjects has not yet been reached. However, if 2 or more subjects were 
determined to have experienced DLTs, then expansion will not occur as the next step. Based on 
the study team’s recommendations, up to 6 additional subjects may be enrolled in Cohort A at the 
same drug doses and schedule or at a modified treatment (described above in this section). These 
additional subjects will then be assessed for DLT in the same manner described above to determine 
if it is appropriate to move to the Expansion Phase (Cohort B). If it is determined by the study 
team that due to safety concerns no additional dose levels or schedules should be enrolled, then 
the study will be closed to enrollment.
Dose Limiting Toxicity
The incidence of dose limiting toxicities assessed in the first 6 DLT-evaluable subjects beginning 
Cycle 1 Day 1 through the first 6 weeks of treatment will determine whether the combination, 
nivolumab with brentuximab vedotin is tolerable. A subject will be considered evaluable for DLT 
if they have received at least one dose of either drug in the first 6 weeks of treatment. However, if 
the subject discontinues treatment for reasons other than a DLT prior to completing the DLT 
evaluation period, then they are not considered DLT evaluable and will be replaced. DLT should 
not be AEs considered by the investigator to be disease related. For the purpose of this study, DLTs 
are defined as any study drug-related toxicity (brentuximab vedotin or nivolumab) that requires 
either a dose reduction or delay of more than 7 days of either study drug in Cycle 2 or delays the 
Cycle 3 Day 1 administration of combined treatment by more than 7 days. The DLT evaluation 
period consists of the first dose of study drug through the first 6 weeks of treatment. The IBs for 
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brentuximab vedotin and nivolumab individually describe adverse events commonly observed 
relative to either agent (ie, neutropenia or peripheral neuropathy with brentuximab vedotin; 
immune-mediated adverse events with nivolumab), as well as less common serious findings. 
However, the final decision regarding causality is at the discretion of the Investigator. 
There is no planned interim analysis (IA). However, all available efficacy and safety data will be 
used to select the recommended dose that will be further evaluated in the Expansion Phase 
(Cohort B).
4.5.2
Premedication
Routine premedication should not be administered for the prevention of infusion-related reactions 
prior to the first dose of study drug(s). However, subjects should be carefully monitored for 
infusion reactions during administration of study drug(s). If an acute infusion reaction is noted, 
subjects should be managed according to Section 4.5.6.
Subjects should be individually evaluated to assess the need for tumor lysis prophylaxis prior to 
the first dose of brentuximab vedotin. Subjects should receive prophylaxis as appropriate per the 
institutional standards.
4.5.3
Dose Modifications for Brentuximab Vedotin
Table 4.5.3-1 describes the recommended dose modifications for brentuximab vedotin treatment 
associated toxicity. Doses reduced for brentuximab vedotin-related toxicity should not be 
re-escalated without discussion with the sponsor. Dose escalation of brentuximab vedotin beyond 
1.8 mg/kg is not permitted.
Dose reductions below 1.2mg/kg are not allowed, and toxicities should be managed with dose 
delays.
If brentuximab vedotin treatment is delayed for any reason, nivolumab must also be delayed until 
the subject has appropriately recovered and is able to resume the combination treatment on the 
first day of the subsequent cycle. Nivolumab should only be given alone in case a decision has 
been made to permanently discontinue brentuximab vedotin.
Table 4.5.3-1:
Dose Modifications for Brentuximab Vedotin
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Peripheral 
Neuropathy
Continue at same 
dose level
Reduce dose to 
1.2 mg/kg and 
resume treatmenta
Withhold (delay) until 
toxicity resolves to 
d Grade 2 or baseline, 
then resume treatment 
at 1.2 mg/kg or 
discontinue if 
reduction has already 
occurred.
Discontinue treatment
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Table 4.5.3-1:
Dose Modifications for Brentuximab Vedotin
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Non-hematologic 
(except peripheral 
neuropathy)
Continue at same
dose level
Continue at same
dose level
Withhold (delay) dose 
until toxicity is 
d Grade 2 or has 
returned to baseline, 
then resume treatment 
at the same dose levelb
Withhold dose until 
toxicity is d Grade 2 or 
has returned to 
baseline, then reduce 
dose to 1.2 mg/kg and 
resume treatment, or 
discontinue at the 
discretion of the 
investigatora,b, c
Hematologicd
Continue at same 
dose level
Continue at same 
dose level
Withhold (delay) until toxicity resolves to 
d Grade 2 or baseline, then resume treatment at 
the same dose levele. Growth factor support 
(G-CSF or GM-CSF) should be considered for 
subsequent cycles. If Grade 4 neutropenia recurs 
despite growth factor support, consider 
discontinuation or dose reduction to 1.2 mg/kg.
a Dose reductions below 1.2 mg/kg are not allowed, and toxicities should be managed with dose delays.
b Subjects who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study treatment without dose 
delay.
c Treatment should be discontinued for subjects who experience Grade 4 infusion-related reactions.
d Support with blood product transfusions allowed per institutional standard of care.
e Subjects who develop Grade 3 or 4 lymphopenia may continue study treatment without dose delay.
Subjects who discontinue nivolumab due to a related AE may continue treatment with brentuximab 
vedotin monotherapy until disease progression or unacceptable toxicity. Similarly, subjects who 
discontinue brentuximab vedotin due to related AE may choose to continue on nivolumab 
monotherapy. In the Cohort A, if toxicity is observed during the DLT evaluation period that 
requires discontinuation of study treatment, both compounds must be discontinued.
4.5.4
Dose Modifications for Nivolumab
4.5.4.1
Nivolumab Dose Delays
Dose delay criteria apply for all drug-related AEs. Nivolumab must be delayed until treatment can 
resume (see Section 4.5.4.2)
Nivolumab administration should be delayed for the following:
•
Any Grade t 2 non-skin, drug-related AE, with the following exceptions:

Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay
•
Any Grade 3 skin, drug-related AE
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•
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, leukopenia, AST, ALT, total bilirubin, or asymptomatic amylase or lipase:

Grade 3 lymphopenia or leukopenia does not require dose delay.

If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade t 2 toxicity.

If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade t 3 toxicity.
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
4.5.4.2
Criteria to Resume Nivolumab Dosing
Subjects may resume treatment with nivolumab when the drug-related AE(s) resolve to Grade d 1 
or baseline value, with the following exceptions:
•
Subjects may resume treatment in the presence of Grade 2 fatigue 
•
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity 
•
Subjects with baseline AST/ALT or total bilirubin in the Grade 1 toxicity range who require 
dose delays for reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume 
treatment in the presence of Grade 2 AST/ALT OR total bilirubin
•
Subjects with combined Grade 2 AST/ALT AND
total bilirubin values meeting 
discontinuation parameters (Section 4.5.5) should have treatment permanently discontinued
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed
•
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment.
If nivolumab treatment is delayed for any reason, brentuximab vedotin must also be delayed until 
the subject has appropriately recovered and is able to resume the combination treatment on the 
first day of the subsequent cycle. Brentuximab vedotin should only be given alone in case a 
decision has been made to permanently discontinue nivolumab.
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in Section 4.5.5.
4.5.4.3
Nivolumab Dose Reductions and Escalations
There will be no dose escalations or reductions of nivolumab allowed.
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4.5.5
Nivolumab Treatment Discontinuation
Nivolumab treatment should be permanently discontinued for the following:
•
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment 
•
Any Grade 3 non-skin, drug-related AE lasting > 7 days, with the following exceptions for 
drug-related laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
hypersensitivity reactions, and infusion reactions:

Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity reaction, or 
infusion reaction of any duration requires discontinuation

Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation

Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except: 
i Grade 3 drug-related thrombocytopenia > 7 days or associated with clinically 
significant bleeding requires discontinuation
i Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation: 
•
AST or ALT > 8 x ULN
•
Total bilirubin > 5 x ULN
•
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
•
Any Grade 4 drug-related AE or laboratory abnormality, except for the following events which 
do not require discontinuation:

Grade 4 neutropenia d 7 days

Grade 4 lymphopenia or leukopenia

Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset

Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations, or radiographic signs of pancreatitis. It is recommended to consult with the 
BMS Medical Monitor for Grade 4 amylase or lipase abnormalities

Grade 4 drug-related endocrinopathy AEs such as adrenal insufficiency, ACTH 
(Adrenocorticotropic Hormone) deficiency, hyper- or hypothyroidosis, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (steroids, thyroid hormones) or glucose controlling agents, respectively, may 
not require discontinuation after discussion with and approval from the BMS Medical 
Monitor
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Any dosing delay lasting > 6 weeks from the previous dose with the following exceptions:

Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. Prior to re-initiating treatment in a subject with a dosing delay lasting > 6 
weeks, the BMS medical monitor must be consulted. Tumor assessments should continue 
as per protocol even if dosing is delayed. 

Dosing delays > 6 weeks that occur for non-drug-related reasons may be allowed if 
approved by the BMS medical monitor. Prior to re-initiating treatment in a subject with a 
dosing delay lasting > 6 weeks, the BMS medical monitor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is delayed.
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued nivolumab 
dosing.
•
Disease progression as determined by investigator assessment following the guidelines given 
in Appendix 2 and Appendix 4 with the exception described in Section 4.5.9.
•
Subject who initiated the preparative regimen for allogeneic SCT or ASCT any time after the 
first dose of nivolumab treatment
•
Initiation of antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
radiation therapy except for palliative radiation therapy, or standard or investigational agents 
for treatment of cancer)
Subjects who discontinue nivolumab due to a related AE may continue treatment with brentuximab 
vedotin monotherapy until disease progression or unacceptable toxicity. The same applies in case 
subjects discontinue brentuximab vedotin due to related AE and chose to continue on nivolumab 
monotherapy. During Cohort A, however, if subject meets discontinuation criteria within the DLT 
evaluation period, both drugs must be discontinued. 
4.5.5.1
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab is considered an immuno-oncology agent 
in this protocol. Early recognition and management of AEs associated with immuno-oncology 
agents may mitigate severe toxicity. Management algorithms have been developed to assist 
investigators in assessing and managing the following groups of AEs:
Gastrointestinal
Renal
Pulmonary
Hepatic
Endocrinopathies
Skin
Neurological
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For subjects expected to require more than 4 weeks of corticosteroids or other immunosuppressants 
to manage an AE, consider recommendations provided in the algorithms. These algorithms are 
found in Appendix 6 and the Nivolumab IB. Discussions with the BMS Medical Monitor on how 
to apply these algorithms are strongly encouraged. The guidance provided in these algorithms 
should not replace the Investigator’s medical judgment but should complement it.
4.5.6
Treatment of Infusion Related Reactions (nivolumab/brentuximab 
vedotin)
Infusion-related reactions may occur during the infusion of study treatment(s). The infusion should 
be administered at a site properly equipped and staffed to manage anaphylaxis should it occur. All 
supportive measures consistent with optimal patient care should be given throughout the study 
according to institutional standards. Supportive measures may include extending the infusion time 
and/or administering medications for infusion-related reactions.
Infusion or hypersensitivity reactions may occur to either brentuximab vedotin or nivolumab. If 
such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthalgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. Infusion 
reactions should be graded according to NCI CTCAE (Version 4.03) guidelines.
Subjects who experience a Grade 1 or Grade 2 infusion-related reaction should be premedicated 
for subsequent infusions. Premedication should be given at least 30 minutes prior to dosing study 
drug(s) and should include an antihistamine and corticosteroid. Recommended doses are:
diphenhydramine 25-50 mg IV (or equivalent) and methylprednisolone 40 mg IV (or equivalent).
In addition, acetaminophen/paracetamol 325 to 1000 mg and ranitidine 50 mg IV may be given. If 
the onset of a reaction occurs during an infusion, the infusion may be interrupted for treatment of 
the infusion-related reaction, including treatment with antihistamines, corticosteroids, and/or 
bronchodilator therapy, as appropriate. Subjects who experience a Grade 3 infusion-related 
reaction to brentuximab vedotin or nivolumab may potentially receive additional treatment with 
the study drug(s) at the discretion of the investigator after discussion with the sponsor.
If anaphylaxis or a Grade 4 infusion-related reaction occurs, administration of the implicated 
agent(s) (brentuximab vedotin and/or nivolumab) should be immediately and permanently 
discontinued.
In case of late-occurring hypersensitivity symptoms to nivolumab (eg, appearance of a localized 
or generalized pruritus within 1 week after nivolumab treatment), symptomatic treatment may be 
given (eg, oral antihistamine or corticosteroids).
4.5.7
Management of Suspected PML
Signs and symptoms of PML may include altered mental status, motor deficits such as hemiparesis 
or ataxia, visual disturbances, or higher cortical dysfunction such as dysphasia or agnosia. See the 
brentuximab vedotin (IB) for further details.
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If PML is suspected, hold further dosing of brentuximab vedotin and nivolumab and undertake a 
diagnostic work-up including (but not limited to):
•
Neurologic examinations, as warranted
•
Brain radiologic features by magnetic resonance imaging (MRI)
•
PCR analysis: John Cunningham virus (JCV) DNA detectable in cerebrospinal fluid
If PML is confirmed, permanently discontinue treatment with brentuximab vedotin and nivolumab.
4.5.8
Guidelines for Assessment and Initial Management of Tumor Lysis 
Syndrome
The possibility of tumor lysis syndrome cannot be ruled out for the subjects with lymphoma. 
Therefore, adequate management such as hydration and/or the use of allopurinol is recommended 
in the subjects who have risk factor of potential tumor lysis syndrome, for example the subjects 
with high tumor burden, reflected by high serum LDH levels, or bulky disease, or those with 
preexisting renal failure.
4.5.9
Treatment Beyond Disease Progression
4.5.9.1
Circumstances in which post-progression treatment is permitted
Subjects meeting progression defined by relapsed disease (after CR) or progressive disease 
(after PR, SD) per 2014 Lugano Classification  & the Lymphoma Response to Immunomodulatory 
therapy Criteria (LYRIC) 85for DLBCL/PTCL/PMBL/MGZL (Appendix 2) or modified Severity 
Weighted Assessment Tool (mSWAT) and Global Response Score in CTCL criteria (Appendix 4)
may continue receiving study medication beyond investigator-assessed progression as long as they 
meet the following criteria:
•
Investigator-assessed clinical benefit
•
Stable performance status 
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression 
•
Subjects will be re-consented for treatment beyond progressive disease
•
Tolerance of study drug. 
The decision to continue treatment beyond investigator-assessed progression should be discussed 
with the BMS Medical Monitor and documented in the study records. The assessment of clinical 
benefit should take into account whether the subject is clinically deteriorating and unlikely to 
receive further benefit from continued treatment. 
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CA209436
BMS-936558
nivolumab
4.5.9.2
Assessment Schedule for the Subjects with Post-progression 
Treatment
The subject should continue to receive monitoring according to  the Lymphoma Response to
Immunomodulatory therapy Criteria (LYRIC) a minimum of 12 weeks On-Treatment Assessments 
on Table 5.1-2. Radiographic assessment described in section 5.4.1 should be performed when 
subjects continue post progression treatment as outlined in appendix 2.
4.5.9.3
Discontinuation due to “Further Progression”
Subjects should discontinue study therapy upon evidence of further progression, defined as an 
additional 10% or greater increase in tumor burden volume from time of initial progression 
(including all target lesions and new measurable lesions, increase in tumor burden without a 5mm 
absolute increase does not require discontinuation) from previous PET-CT, CT and/or MRI.
•
The tumor burden volume from time of initial progression should be used as the reference 
baseline for comparison with the post-progression assessment.
•
New lesions are considered measurable at the time of initial progression if the long axis is more 
than 15 mm regardless of the short axis. Increase in tumor burden without a 5mm absolute 
increase does not require discontinuation.
•
Any new lesion considered non-measurable at the time of or after initial progression may 
become measurable and therefore included in the tumor burden determination.
4.5.9.4
Efficacy Assessment for Subjects who Discontinue Study Drug during 
Post-Progression Treatment
When subjects stop post-progression treatment, no additional radiographic assessment will be 
required and they will continue in the follow-up phase of the study (Table 5.1-3). The subjects 
who proceed to allogeneic SCT or ASCT will be followed with specific tumor assessment on 
day 100, at 6 months, 1 year and every year thereafter from the date of stem cell infusion until the 
first non-CR after SCT is documented.
4.6
Blinding/Unblinding
Not applicable.
4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and CRF. 
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site. 
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BMS-936558
nivolumab
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as required 
for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. The return of study 
drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
4.10
Retained Samples for Bioavailability / Bioequivalence
Not Applicable
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CA209436
BMS-936558
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule
Table 5.1-1:
Screening Assessments (CA209436)
Procedure
Screening
Visit
Notes (Screening procedures are to occur within 28 days from first dose unless 
otherwise specified)
Eligibility Assessment
Informed Consent
X
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening
Medical History
X
Prior Systemic Therapy
X
Safety Assessments
Complete Physical Examination
X
Include assessment of lymph node areas (eg, submandibular, cervical, supraclavicular, 
axillary, or inguinal lymph node), abdominal organs (eg, spleen) and neurological 
examination
Skin evaluations using m SWAT for CTCL
Physical Measurements
X
Include height, weight and ECOG Performance Status
Vital Signs and oxygen saturation
X
Temperature, BP, HR, and O2 saturation by pulse oximetry at rest (also monitor amount of 
supplemental oxygen if applicable).
Assessment of Signs and Symptoms
X
Required for the 14 days prior to first dose
Concomitant Medication Collection
X
Required for the 14 days prior to first dose, 
Laboratory Tests
X
CBC with differential, Chemistry panel including LDH, AST, ALT, ALP, albumin, total 
bilirubin, BUN or serum urea level, uric acid, creatinine, Ca, Mg, Na, K, Cl, glucose, 
amylase, lipase, TSH, Free T3, Free T4 within 14 days prior to first dose.
Hepatitis B surface antigen (HBV sAg), and hepatitis C antibody (HCV Ab) or HCV 
ribonucleic acid (RNA) within 28 days prior to first dose.
HIV test within 28 days prior to first dose
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CA209436
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Table 5.1-1:
Screening Assessments (CA209436)
Procedure
Screening
Visit
Notes (Screening procedures are to occur within 28 days from first dose unless 
otherwise specified)
Urinalysis
X
Total protein, glucose, blood, leukocyte esterase, specific gravity, and pH, within 14 days 
prior to first dose
Pregnancy Test
X
For WOCBP only and must be done within 24 hours of first dose.
Efficacy/Biomarker Assessment
Radiographic Tumor Assessment CT 
chest, CT/MRI abdomen, pelvis and other 
known sites of disease ( also required for 
CTCL)
FDG PET-CT (DLBCL, PTCL, PMBL & 
MGZL only)
X
To be performed within 28days prior to first dose.
Contrast enhanced CT chest, CT/MRI abdomen, pelvis and other known sites of disease. 
Brain MRI for CNS assessment (only if clinically indicated). Non-contrast CT chest and MRI 
abdomen/pelvis acceptable if CT with contrast is contra-indicated. Modality should remain 
the same for each subject throughout the study
FDG PET-CT will be used for response assessment for DLBCL, PTCL, PMBL and MGZL
only. Refer to section 5.4.3.3
Blood tumor burden assessment 
(SS-CTCL only)
X
Required only for CTCL Sezary Syndrome for assessment of tumor burden and baseline 
staging. Refer to section 5.4.3.6 and Appendix 3 for further details
Modified Severity Weighted Assessment 
Tool
X
Required for subjects with Cutaneous T Cell Lymphoma. Refer to Appendix 4.
Medical Photography
X
Suggested for subjects with Cutaneous T Cell Lymphoma only. Refer to Section 5.4.3.5
CD30 Expression
X
CD30 expression t 1% in tumor or TILs must be confirmed by local IHC testing prior to first 
dose. 
It will also be done centrally and assessed retrospectively. 
Bone Marrow Biopsy & Aspirate
See Note
Bone Marrow assessment is not required for DLBCL/CTCL/PMBL/MGZL subjects unless 
clinically indicated. It is recommended for PTCL subjects if there is clinical suspicion for 
disease involvement in the bone marrow. Refer to section 5.4.4 for further details.
Only if clinically indicated, bone biopsy & aspirate collected during screening are acceptable.
If a biopsy and/or aspirate is performed during treatment, submission for biomarker analyses 
is optional. Refer to Table 5.6-1 for further details.
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Date: 14-Sep-2016
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CA209436
BMS-936558
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Table 5.1-1:
Screening Assessments (CA209436)
Procedure
Screening
Visit
Notes (Screening procedures are to occur within 28 days from first dose unless 
otherwise specified)
Tumor tissue submission
X
Submission of tumor tissue (FFPE tumor tissue block or a minimum of 20 unstained slides, 
obtained during the screening phase or collected as a standard of care procedure prior to 
obtaining informed consent) is mandatory. Tumor tissue must have been collected within 20 
months from screening, while slides must have been cut within 6 months from screening.
In order to be treated, the sample must meet the minimum quality requirements, as 
determined by the central laboratory during the screening period.
Biopsy samples should be excisional, incisional or core needle. Refer to Section 5.6.1 and 
also to Table 5.6-1 for further details.
Serum/plasma
X
Specification of test performed is described in Table 5.6-1
IVRS/Clinical Drug Supplies
Phone calls to IVRS
X
Phone calls must be made to IVRS as follows:
For subject number assignment at the time informed consent is obtained and trigger 1st 
shipment of drug. Refer to section 4.4 for further details.
Revised Protocol No.: 01
Date: 14-Sep-2016
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CA209436
BMS-936558
nivolumab
Table 5.1-2:
On Treatment Procedures (CA209436)
On treatment procedures 
Procedure
Cycle 1
Day 1
Cycle 1
Day 8
Cycle 2 & 
Beyond, Day 1
Notes
All windows proposed are calendar days. Procedures must be 
done within 72h prior to dosing unless otherwise specified.
Safety Assessments
Targeted Physical Examination
X
X
Include assessment of lymph node areas (eg, submandibular, 
cervical, supraclavicular, axillary, or inguinal lymph node), 
abdominal organs (eg, spleen) and neurological examination
Skin evaluation using mSWAT scoring for CTCL
Refer to section 5.3 for further details.
Vital Signs and Oxygen 
Saturation
X
X
X
Temperature, BP, HR, O2 saturation by pulse oximetry at rest
(also monitor amount of supplemental oxygen if applicable) prior 
to dosing and at any time a subject has any new or worsening 
respiratory symptoms. Refer to section 5.3 for further details. 
Adverse Events Assessment
---------------------Continuously--------------------------
Assessed using NCI CTCAE v. 4.03
Review of Concomitant 
Medications
X
X
X
Physical Measurements
X
X
X
Includes weight and ECOG status
Laboratory Tests
X
X
To be done within 72 hours prior to dosing and include: CBC 
with differential, uric acid, BUN or serum urea level, creatinine, 
Ca, Mg, K, Cl, Na, amylase, lipase, glucose, AST, ALT, total 
bilirubin, alkaline phosphatase, albumin, LDH.
Thyroid Function Testing
See Note
TSH (reflex to free T3 and free T4 if abnormal result) to be 
performed at every other cycle (C3, C5, etc). Refer to section 5.3
for further details.
Pregnancy Test 
(WOCBP only)
X
See Note
Serum or urine within 24 hours prior to first dose and then at 
least once every 4 weeks regardless of dosing schedule.
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Date: 14-Sep-2016
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Clinical Protocol
CA209436
BMS-936558
nivolumab
Table 5.1-2:
On Treatment Procedures (CA209436)
On treatment procedures 
Procedure
Cycle 1
Day 1
Cycle 1
Day 8
Cycle 2 & 
Beyond, Day 1
Notes
All windows proposed are calendar days. Procedures must be 
done within 72h prior to dosing unless otherwise specified.
Efficacy/Biomarker Assessments
Radiographic Tumor Assessment
•
CT chest, CT/MRI of 
abdomen, pelvis and any 
other known sites of disease
(required for CTCL) 
FDG PET-CT (DLBCL, PTCL, 
PMBL & MGZL only)
See Note
Tumor assessments will occur at Week 6 and Week 12 continuing 
every 9 weeks (+/- 1 week) for the subsequent 4 tumor 
assessment timepoints, regardless of dosing schedule. After the 
first year, tumor assessments are to occur every 12 weeks 
(+/- 2 weeks) until disease progression is documented. Patients 
with treatment beyond progression should be evaluated at 
minimum every 12 weeks (see appendix 2). Radiographic 
evaluations in subjects with CTCL will be performed as clinically 
indicated by the disease stage.
FDG PET-CT is the method of assessment for DLBCL, PTCL, 
PBML & MGZL subjects. Subjects with PET-Avid lesions at 
baseline should be followed with PET, subjects with non-Pet avid 
lesions and lesions on CT scans at baseline should be followed 
with CT Scans.
Refer to section 5.4 for further details.
Blood tumor burden assessment 
(SS-CTCL only)
See Note
Only required to confirm CR in CTCL SS subjects in case blood 
was positive for tumor cells at screening. Refer to section 5.4.3.6.
Modified Severity Weighted 
Assessment Tool 
See Note
Required for subjects with Cutaneous T Cell Lymphoma as part 
of disease assessment. To be completed at each visit. Refer to 
Appendix 4 for further details.
Medical Photography
See Note
Suggested for subjects with Cutaneous T Cell Lymphomas as part 
of disease assessment. To be done along with the radiographic 
assessment timepoints. Refer to section 5.4.3.5 for further details.
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Date: 14-Sep-2016
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CA209436
BMS-936558
nivolumab
Table 5.1-2:
On Treatment Procedures (CA209436)
On treatment procedures 
Procedure
Cycle 1
Day 1
Cycle 1
Day 8
Cycle 2 & 
Beyond, Day 1
Notes
All windows proposed are calendar days. Procedures must be 
done within 72h prior to dosing unless otherwise specified.
Bone Marrow Aspirate and 
Biopsy
See Note
Bone Marrow assessment is not required for 
DLBCL/CTCL/PMBL/MGZL subjects unless clinically 
indicated. It is recommended for PTCL subjects if there is clinical 
suspicion for disease involvement in the bone marrow.
If a biopsy and/or aspirate is performed during treatment, 
submission for biomarker analyses is optional. Refer toTable 5.6-
1 for further details.
Required to confirm complete response (CR) in subjects with 
bone marrow disease at screening.
Additional Biomarker Samples
•
Tumor biopsy
•
Blood 
See Note
See Note
See Note
See Table 5.6-1 for collection of samples for biomarker studies
Outcomes Research Questionnaire
EQ-5D 3L Questionnaire
X
X
Subjects will be asked to complete the EQ-5D 3L prior to study 
drug administration and before any clinical activities. Refer to 
section 5.7 for more information.
To be completed only for subjects enrolled in the Expansion 
Phase (Cohort B).
PK and Immunogenicity Assessments
PK and Immunogenicity Samples
See Table 5.6-1 for sampling details.
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Clinical Protocol
CA209436
BMS-936558
nivolumab
Table 5.1-2:
On Treatment Procedures (CA209436)
On treatment procedures 
Procedure
Cycle 1
Day 1
Cycle 1
Day 8
Cycle 2 & 
Beyond, Day 1
Notes
All windows proposed are calendar days. Procedures must be 
done within 72h prior to dosing unless otherwise specified.
Clinical Drug Supplies
Administer Study Drug
Brentuximab 
vedotin
Nivolumab
X
Brentuximab vedotin will be administered at C1D1 and 
Nivolumab will be administered on C1D8. At all subsequent 
cycles, both study drugs will be administered on the same day. 
Brentuximab vedotin will be administered first followed by a 
minimum 30 minute rest. Nivolumab will be administered second. 
Refer to Section 4.5 for further details.
IVRS should be called within 3 days prior to study drug 
administration to receive vial assignment.
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CA209436
BMS-936558
nivolumab
Table 5.1-3:
Follow-up Assessments (CA209436)
Follow-up Assessments (CA209436)
Procedure
Follow Up, Visits 1 
and 2a
(X01 & X02)
Survival 
Follow-Up 
Visitsb
Notes
Safety Assessments
Targeted Physical Examination
X
Lymph node areas (eg, submandibular, cervical, 
supraclavicular, axillary, or inguinal lymph node), 
abdominal organs (eg,spleen) and neurological 
examination
Skin evaluation with mSWAT scoring in CTCL
Adverse Events Assessment
X
Laboratory Tests
X
Required for X01: CBC with differential, uric acid, 
serum urea level, serum creatinine, sodium, potassium, 
calcium, magnesium, chloride, glucose, AST, ALT, 
total bilirubin, alkaline phosphatase, LDH, TSH (reflex 
to free T3, free T4 for abnormal TSH result).  
Panel should also be performed at X02 if X01 results 
were abnormal.
Pregnancy Test
(WOCBP only) 
X
Serum or urine
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CA209436
BMS-936558
nivolumab
Table 5.1-3:
Follow-up Assessments (CA209436)
Follow-up Assessments (CA209436)
Procedure
Follow Up, Visits 1 
and 2a
(X01 & X02)
Survival 
Follow-Up 
Visitsb
Notes
Efficacy Assessments
Radiographic Tumor Assessment
CT chest, CT/MRI abdomen,
pelvis, and any other known sites of disease
FDG PET-CT (DLBCL,CTCL, PMBL &MGZL
only)
X
X
Only for subjects without documented progression since 
first dose of study therapy
Tumor assessments will occur at Week 6 and Week 12 
continuing every 9 weeks (+/- 1 week) for the 
subsequent 4 tumor assessment timepoints, regardless of 
dosing schedule. After the first year, tumor assessments 
are to occur every 12 weeks (+/- 2 weeks) until disease 
progression is documented.
FDG PET-CT is required for assessment of
DLBCL/PTCL/PMBL/MGZL subjects
NOTE: Subjects proceeding to allogeneic SCT or ASCT
will be assessed on Day 100, at 6 months, 1 year and 
every year thereafter from the date of stem cell infusion 
until the first non-CR after SCT is documented. Refer to 
section 5.4for further details.
Blood tumor burden assessment (SS-CTCL only
See note
See note
Only required to confirm CR in CTCL SS subjects in 
case blood was positive for tumor cells at screening. 
Refer to section 5.4.3.6 for details.
Modified Severy Weighted Assessment Tool for 
subjects with Cutaneous T Cell Lymphoma
See note
See note
Required for subjects with Cutaneous T Cell 
Lymphoma as part of disease assessment. Refer to 
Appendix 4 for details.
Medical Photography
See note
See note
Suggested for subjects with Cutaneous T Cell 
Lymphomas as part of disease assessment. To be done 
along with the radiographic assessment for all of those 
respective timepoints. Refer to section 5.4.3.5 for 
details.
Revised Protocol No.: 01
Date: 14-Sep-2016
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Clinical Protocol
CA209436
BMS-936558
nivolumab
Table 5.1-3:
Follow-up Assessments (CA209436)
Follow-up Assessments (CA209436)
Procedure
Follow Up, Visits 1 
and 2a
(X01 & X02)
Survival 
Follow-Up 
Visitsb
Notes
GVHD Assessments
Only for subjects who proceed to allogeneic SCT. To be 
assessed on Day 100, at 6 months, at 1 year and every 
1 year thereafter from the date of stem cell infusion 
until the first non-CR after SCT is documented. Refer to 
Appendix 5 for further details.
Subsequent Anticancer Therapy
X
X
Other Primary Malignancies
X
X
Biomarker Assessments
Serum, Tumor Biopsy, Bone Marrow 
Aspirate/biopsy
See Note
Optional biomarker samples collected at time of 
progression. See Table 5.6-1 for biomarker sampling 
details 
Pharmacokinetic/Immunogenicity Assessments
PK and Immunogenicity samples
X
See Table 5.5.1-1 for PK and immunogenicity sampling 
details
Outcomes Research Assessments
EQ-5D 3L Questionnaire
X
X
EQ-5D-3L questionnaires administered during survival 
follow-up will be completed in clinic or via phone 
contact. Refer to section 5.7 for more information.
To be completed only for subjects enrolled in the 
Expansion Phase (Cohort B).
Revised Protocol No.: 01
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Clinical Protocol
CA209436
BMS-936558
nivolumab
Table 5.1-3:
Follow-up Assessments (CA209436)
Follow-up Assessments (CA209436)
Procedure
Follow Up, Visits 1 
and 2a
(X01 & X02)
Survival 
Follow-Up 
Visitsb
Notes
Subject Status
Survival Status
X
X
Survival follow-up visits are expected to occur every 
3 months after X02; may be accomplished by visit, 
phone contact or email, to update survival information 
and assess subsequent anti-cancer therapy.
BMS may request that survival data be collected on all 
treated subjects outside of the 3 month specified
window. At the time of this request, each subject will be 
contacted to determine their survival status unless the 
subject has withdrawn consent for all contact.
a Follow-up visit 1 (X01) = 35 days from the last dose +/- 7 days. Follow-up visit 2 (X02) = 80 days (+/- 7 days) from follow-up visit X01.
b Survival Follow-up visits to occur every 3 months from X02. BMS may request that survival data be collected on all treated subjects outside of the 3 month 
specified window. At the time of this request, each subject will be contacted to determine their survival status unless the subject has withdrawn consent for all 
contact.
Revised Protocol No.: 01
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CA209436
BMS-936558
nivolumab
5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening or Lead-
in period will be permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result and is the value by which study inclusion will be 
assessed, as it represents the subject’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified subjects. Consultation with 
the Medical Monitor may be needed to identify whether repeat testing of any particular parameter
is clinically relevant.
5.2
Study Materials
•
NCI CTCAE version 4.03
•
Nivolumab IB
•
Brentuximab Vedotin IB
•
Pharmacy Binder
•
Laboratory manuals for collection and handling of blood (including PKs, biomarker and 
immunogenicity) and tissue specimens
•
Site manual for operation of IVRS, including enrollment worksheet
•
Manual for submission of local laboratory data 
•
Serious Adverse Events (or eSAE) case report forms
•
EQ-5D 3L questionnaires 
•
Pregnancy Surveillance Forms
5.3
Safety Assessments
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include weight, height, ECOG Performance Status, blood pressure 
(BP), heart rate (HR), temperature, and oxygen saturation by pulse oximetry at rest (also monitor 
amount of supplemental oxygen if applicable) and should be performed within 28 days prior to 
first dose. 
Physical examination will be performed as clinically indicated and clinical signs and symptoms 
are to be collected within 14 days of first dose. For subjects with CTCL, a skin examination 
following the mSWAT should be included. During the on-treatment visits, a target physical 
examination is acceptable and it should include the assessment of the lymph node areas, abdominal 
organs (eg, spleen), neurological assessment and skin lesions if applicable. If there are any new or 
worsening clinically significant changes since the last exam, report changes on the appropriate 
non-serious or serious adverse event page.  
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CA209436
BMS-936558
nivolumab
Pregnancy testing (urine or serum) must be done in WOCBP only and within 24 hours of first dose 
and at least every 4 weeks (+/- 3days) thereafter regardless of dosing schedule. 
Baseline local laboratory assessments must be done within 14 days prior to first dose to include 
CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum urea 
level, creatinine, uric acid, Ca, Mg, Na, K, Cl, LDH, glucose, albumin, amylase, lipase and
urinalysis (total protein, glucose blood, leukocyte esterase, specific gravity and pH).
Baseline local laboratory assessments for Hep B and C testing (HBV sAg, HCV Ab or HCV RNA)
must be done within 28 days prior to first dose. 
On treatment oxygen saturation by pulse oximetry should be obtained within 72 hours prior to 
dosing and at any time a subject has any new or worsening respiratory symptoms. A reading at 
rest should be obtained at each time point. If a subject shows changes on pulse oximetry or other 
pulmonary-related signs (eg, hypoxia, fever) or symptoms (eg, dyspnea, cough) consistent with 
possible pulmonary adverse events, the subject should be immediately evaluated to rule out 
pulmonary toxicity. An algorithm for the management of suspected pulmonary toxicity can be 
found in Appendix 6 and the nivolumab IB.
Thyroid function testing is to be done at every other cycle (approximately every 6 weeks, unless 
treatment delays are observed) for subjects receiving study drug. At baseline TSH, Free T3 and 
Free T4 will be performed within 14 days of first dose. During treatment TSH will be done (with 
reflexive Free T4 and Free T3 if TSH results are abnormal) within 72 hours prior to dosing. 
On treatment local laboratory assessments should be done within 72 hours prior to dosing; and 
will include CBC with differential, BUN or serum urea level, serum creatinine, sodium, potassium, 
calcium, magnesium, chloride, amylase, lipase, glucose, AST, ALT, total bilirubin, alkaline 
phosphatase and LDH.
Local laboratory assessments are to be performed for the Follow-up X01 visit and include CBC 
with differential, uric acid, serum urea level, uric acid, albumin, creatinine, sodium, potassium, 
calcium, magnesium, chloride, glucose, AST, ALT, total bilirubin, alkaline phosphatase, LDH, 
TSH (reflex to free T3, free T4 for abnormal TSH result). This panel should be repeated at Follow-
up visit X02 if Follow-up visit X01 results were abnormal.
For subjects who discontinue study therapy by proceeding to allogeneic SCT, documentation of 
acute and chronic GVHD will be captured on Day 100, at 6 months, 1 year and every year 
thereafter from the date of stem cell infusion until the first non-CR after SCT is documented.
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase. During the Follow-Up Phase at Visits X01 and X02, 
toxicity assessments should be done in person. Follow-up visit 1 (X01) is to occur 35 days from 
the last dose +/- 7 days. Follow-up visit 2 (X02) is to occur 80 days (+/- 7 days) from follow-up 
visit X01. Once subjects reach the survival follow-up phase, either in-person visits or documented 
telephone calls/email correspondence to assess the subject’s status are acceptable. Survival visits 
should occur every 3 months. BMS may request that survival data be collected on all treated 
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subjects outside of the 3 month specified window. At the time of this request, each subject will be 
contacted to determine their survival status unless the subject has withdrawn consent for all 
contact. 
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.03.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on site/local 
labs until all study drug related toxicities resolve, return to baseline, or are deemed irreversible.
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
5.3.1
Imaging Assessment for the Study
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment.
At the sponsor’s discretion, scans may be collected centrally to be reviewed by independent 
radiologists.
5.4
Efficacy Assessments
DLBCL, PTCL, PMBL and MGZL Efficacy Assessment:
The primary efficacy assessment is Objective Response (OR). Objective Response is defined as a 
subject achieving either a PR or CR according to the Lugano Classification 2014 and Lymphoma
Response to Immunomodulatory therapy Criteria (LYRIC) (Appendix 2) and will be based on
investigator assessed response. Efficacy assessment for DLBCL, PTCL, PMBL and MGZL will 
be primarily derived from the FDG PET-CT performed according to the timepoints described in 
Table 5.1-1 Table 5.1-2 and Table 5.1-3. Subjects with PET-Avid lesions at baseline should be 
followed with PET, subjects with non-Pet avid lesions and lesions on CT scans at baseline should 
be followed with CT Scans. Tumor assessment (CR or non-CR) will be assessed by the investigator 
according to the Lugano Classification 2014.  
CTCL Efficacy Assessment:
Efficacy assessment for Cutaneous T Cell lymphomas will include CT/MRI for visceral disease 
assessment and peripheral lymph nodes at the pre-determined timepoints described in Table 5.1-1
Table 5.1-2 and Table 5.1-3. The consensus Global Response Score assessment to evaluate disease 
activity will also be completed at every tumor assessment time point to assess extent of disease. 
Medical photographies are recommended to document the appearance of skin lesions throughout 
the study. The mSWAT will be used to assess skin involvement, it is preferable that the mSWAT 
assessments should be performed by the same investigator at all time points to eliminate inter-
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observer variability for a given patient. Lymphoma Response to Immunomodulatory therapy
Criteria (LYRIC) will be used where clinically indicated (Appendix 2).
Whole blood must be included for assessment of SS-CTCL at baseline to evaluate blood tumor 
burden. In the case the blood is confirmed to be positive for tumor cells, it must be reassessed at 
the time of response documentation, prior to its confirmation. 
All subjects treated are expected to be followed for disease progression. Subjects that discontinue 
treatment for other reasons different from disease progression must continue to perform tumor 
assessments as described in Table 5.1-3 until disease progression is documented. 
The primary analysis of the study will be performed 8 months after the last subject has received 
the first dose of study medication, or earlier if that subject discontinues study therapy. After the 
cut off for the primary analysis, subjects who are receiving study treatment can continue treatment 
per protocol until progression, unacceptable toxicity, withdrawal of consent, or other reasons as 
listed in Section 3.5.
Once subjects discontinue study therapy by proceeding to allogeneic SCT or ASCT, they will not 
undergo radiographic assessments at the predetermined timepoints described in Table 5.1-3.
Instead, they will be evaluated on Day 100, at 6 months, 1 year and every year thereafter from 
the date of stem cell infusion until the first non-CR after SCT is documented.
Sites are required to have available on site all of the on-study tumor scans.
5.4.1
Radiographic Assessments
Baseline assessments should be performed within 28 days prior to the first dose, utilizing FDG 
PET-CT, CT or MRI. CT scans are preferred for CTCL. In addition to chest, abdomen, pelvis, all 
known sites of disease should be assessed at baseline. FDG PET-CT will be performed for 
assessment throughout the study for subjects with DLBCL, PTCL, PMBL and MGZL. Low dose 
or attenuation correction CT portions of a combined FDG PET-CT are of limited use in 
anatomically based efficacy assessments and it is therefore suggested that they should not be 
substituted for dedicated diagnostic contrast enhanced CT scans for anatomically based 
measurements. However, if a site can document that the CT performed as part of a FDG PET-CT 
is of identical diagnostic quality to a diagnostic CT with oral contrast, (+/- IV contrast) then the 
adequate dose CT of the FDG PET-CT can be used for tumor measurements. Subjects with CTCL 
are to perform the CT scans described above in addition to medical photographies if appropriate 
for disease assessment.
Subjects will be evaluated for tumor response by FDG PET-CT, or CT/MRI at week 6 and week 12 
continuing every 9 weeks (+/- 1 week) for the subsequent 4 tumor assessment timepoints, 
regardless of dosing schedule. After the first year, tumor assessments are to occur every 12 weeks 
(+/- 2 weeks) until disease progression is documented.
Tumor assessments for ongoing study treatment decisions will be completed by the investigator 
using the Lugano Classification 2014 for Diffuse Large B Cell Lymphomas and Peripheral T Cell 
Lymphomas. Refer to Appendix 2 for further details. For Cutaneous T Cell Lymphomas, response 
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should be assessed by the consensus Global Response Score. Refer to Appendix 4 for further 
details.
5.4.2
Assessment of Overall Tumor Burden and Measurable Disease
To serially evaluate tumor response to therapy, it is necessary to estimate the overall tumor burden 
at baseline and use this as a comparator for subsequent measurements. Measurable disease is 
defined by the presence of at least one measurable tumor lesion. 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows in Section 5.4.2.1 and Section 5.4.2.2.
5.4.2.1
Measurable Lesions
Measurable lesions must be accurately measured in at least two perpendicular dimensions. For 
subjects staged with PET-CT (DLBCL, PTCL, PMBL and MGZL), focal uptake in nodal and 
extranodal sites that is in keeping with lymphoma, according to the distribution and/or CT 
characteristics, is considered involvement with lymphoma, including spleen, liver, bone, thyroid, 
and so on. For subjects staged with CT, up to six of the largest target nodes, nodal masses, or other 
lymphomatous lesions that are measurable in two diameters (longest diameter [LDi] and shortest 
diameter) should be identified from different body regions representative of the patient’s overall 
disease burden and include mediastinal and retroperitoneal disease, if involved. A measurable node 
must have a LDi greater than 15 mm. Measurable extranodal disease (eg, hepatic nodules) may be 
included in the six representative, measured lesions. For extranodal measurable lesion the LDi 
must be greater than 10 mm. All other lesions (including nodal, extranodal, and assessable disease) 
should be followed as non measurable disease (eg, cutaneous, GI, bone, spleen, liver, kidneys, 
pleural or pericardial effusions, ascites). In subjects in whom a discordant histology or malignant 
transformation is suspected, a PET-CT may identify the optimal site to biopsy for confirmation.
For subjects with CTCL measurable, skin lesions are defined as papules, plaques and patches 
covering t 10% of the skin surface (T2). Lymph nodes are qualified as abnormal if > 15 mm in 
diameter.
5.4.2.2
Non-Measurable Lesions
Non-measurable lesions will be all other lesions, including small lymph nodes (longest diameter 
d 15 mm) as well as truly non-measurable lesions. Lesions considered truly non-measurable 
include: leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical exam and that is not measurable by reproducible imaging techniques.
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5.4.3
Specifications by Method of Assessment
5.4.3.1
Measurement of Lesions
All measurements should be recorded in the eCRF in metric notation (mm). All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 
28 days before the beginning of treatment.
5.4.3.2
Method of Assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
5.4.3.3
FDG PET-CT, CT Scan and MRI
Contrast-enhanced Computed Tomography (CT) scans acquired on dedicated CT equipment are
preferred for response assessment of subjects with CTCL or DLBCL/PTCL/PMBL/MGZL
subjects without FDG avid tumors in this study. CT with contrast of the chest, abdomen and pelvis 
(as clinically indicated) are to be performed for tumor assessments at week 6 and week 12 
continuing every 9 weeks (+/- 1 week) for the subsequent 4 tumor assessment timepoints, 
regardless of dosing schedule. After the first year, tumor assessments are to occur every 12 weeks 
(+/- 2 weeks) until disease progression is documented. CT scans should be acquired with 5mm 
slices with no intervening gap (contiguous). When CT scans have slice thickness greater than 
5 mm, the minimum size for a measurable lesion should be twice the slice thickness.
Should a subject have a contraindication for CT IV contrast, a non-contrast CT of the chest and a 
contrast enhanced MRI of the abdomen and pelvis may be obtained. MRIs should be acquired with 
slice thickness of 5 mm with no gap (contiguous). 
Every attempt should be made to image each subject using an identical acquisition protocol on the 
same scanner for all imaging time points.
FDG PET-CT with oral contrast and intravenous contrast will be performed for assessment 
throughout the study for patients with DLBCL, PTCL, PMBL and MGZL. If however CT is low 
dose and intravenous contrast is not available, then sites may obtain additional CT with oral and 
intravenous contrast. 
Note on CT component of a PET-CT scanner: Combined modality scanning such as with PET-CT 
is increasingly used in clinical care. Low dose or attenuation correction CT portions of a combined 
PET-CT are of limited use in anatomically based efficacy assessments and it is therefore suggested 
that they should not be used. Site should document that the CT performed as part of a PET-CT is 
of identical diagnostic quality to a diagnostic CT (with IV and oral contrast). In certain cases where 
the CT portion of the PET-CT scan is low dose, then a diagnostic CT scan with oral and 
intravenous contrast should be performed.
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MRI of the brain should be done at baseline if CNS involvement is suspected to rule out active 
disease. Scans during on-study treatment and follow up periods are required only as clinically 
indicated for new signs and symptoms that suggest central nervous system (CNS) involvement.
5.4.3.4
Clinical Lesions
Clinical lesions (nodal, extranodal) will only be considered measurable when they are superficial 
and t 15 mm diameter as assessed using calipers. As previously noted, when lesions can be 
evaluated both by clinical exam and imaging, imaging evaluation should be undertaken since it is 
more objective.
In regards to CTCL, skin evaluation will be performed using the m SWAT scoring system. It is 
recommended that the mSWAT at the bedside should be performed by the same investigator at all 
time points. If the same investigator cannot perform all the assessments, then all personnel grading 
the same patient must have completed prior training, ideally before study initiation.
5.4.3.5
Medical Photography (Skin lesions only)
Medical photography with ruler measurements for documentation of skin lesions are 
recommended in subjects with CTCL.
5.4.3.6
Whole Blood (SS-CTCL only)
Peripheral blood flow cytometry to evaluate for SS cell at screening and at response confirmation 
is required in subjects with CTCL(SS).
5.4.3.7
Target Lesions
At baseline, up to 6 of the largest dominant nodes or nodal masses meeting the criteria for 
measurable lesions given in Section 5.4.2 should be identified as target lesions and their 
measurements recorded. Other measurable lesions will be designated as non-target lesions.
A sum of the product of the diameters (SPD) will be calculated for all target lesions and recorded 
as the baseline SPD. The baseline SPD will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease.
5.4.3.8
Non-Target Lesions
All other lesions (or sites of disease) including non-measurable lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’. 
In addition, it is possible to record multiple non-target lesions involving the same organ as a single 
item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or multiple liver 
nodules’).
5.4.4
Bone Marrow Assessments
Bone marrow assessments are not mandatory in the study, unless clinical suspicion is high. In
subjects with PTCL, if there is clinical suspicion for bone marrow involvement, it is recommended 
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to obtain a bone marrow aspirate and biopsy at the time of screening. All subjects may volunteer 
to undergo bone marrow biopsy and aspirate at any time during therapy if clinically indicated for 
DLBCL, CTCL, PMBL and MGZL. 
Only if clinically indicated, bone marrow biopsy and aspirate performed within 90 days prior to 
obtaining consent or fresh sample collected during screening are acceptable options. If a bone 
marrow biopsy/aspirate is performed during the screening period, consider submitting a bone 
marrow aspirate sample for biomarker analyses. For subjects that perform bone marrow 
assessment at screening and there is marrow involvement confirmed, a bone marrow biopsy and 
aspirate will be required to confirm a CR, and submission of bone marrow aspirate samples is 
optional as detailed in Table 5.6-1.
In addition to efficacy assessments, additional, optional, bone marrow biopsy and aspirate samples 
may be collected and submitted for biomarker studies as detailed in Table 5.6-1.
5.4.5
Disease Response Evaluation
The determination of disease response to study treatment will be made using Lugano Classification 
2014 in subjects with DLBCL, PTCL, PMBL and MGZL (Appendix 2). Responses in CTCL will 
be evaluated using consensus Global Response Score by the investigators (Appendix 4).
For CTCL Response Evaluation, the consensus Global Response Score will be used incorporating 
skin, lymph nodes, viscera and blood. The mSWAT score will be used to evaluate and score skin 
lesions, and to assist in skin response evaluation. 
5.5
Pharmacokinetic and Immunogenicity Assessments
Samples for PK and immunogenicity assessments will be collected for all subjects receiving 
nivolumab and brentuximab vedotin as described in Table 5.5.1-1. All time points are relative to 
the start of study drug administration. After cycle 1 (once both study drugs of the combination are 
administered on the same day), predose samples are to be collected relative to the start of 
brentuximab vedotin. All on-treatment time points are intended to align with days on which study 
drug is administered, if dosing occurs on a different day, the PK and immunogenicity sampling 
should be adjusted accordingly. Further details of sample collection, processing, and shipment will 
be provided in the laboratory procedures manual.
5.5.1
Pharmacokinetics:  Collection and Processing
A detailed schedule of PK and immunogenicity evaluations for nivolumab and brentuximab
vedotin is provided in Table 5.5.1-1. PK samples will be analyzed for nivolumab and brentuximab
vedotin by validated ligand binding assays. Immunogenicity samples will be analyzed for anti-
nivolumab antibodies by a validated immunogenicity assay; samples may also be analyzed for 
neutralizing antibodies by a validated method. Serum samples may be analyzed by an exploratory 
method that measures anti-drug antibodies for technology exploration purposes; exploratory 
results will not be reported. Serum samples designated for PK or biomarker assessments may also 
be used for immunogenicity analysis if required (eg, insufficient volume for complete 
immunogenicity assessment or to follow up on suspected immunogenicity related AE).
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Table 5.5.1-1:
Nivolumab Pharmacokinetic and Immunogenicity Sampling 
Schedule - Cohort A and Cohort B
Study Day
Event 
(Relative to Start of 
Infusion/Event)
Time 
(Relative to Start 
of the Infusion
treatment)
Hour:Min
Nivolumab 
PK Blood 
Sample
Nivolumab 
Immunogenicity 
Sample
Cycle 1 Day 8
Predosea
00:00
X
X
Cycle 2 Day 1
Predosea
00:00
X
X
Cycle 3 Day 1
Predosea
00:00
X
X
Cycle 5 Day 1
Predosea
00:00
X
X
Day 1 of every 6th cycle
thereafter (every 18 weeks) 
until discontinuation of 
study treatmentb
Predosea
00:00
X
X
First 2 Follow-up visits-
X01 & X02
X
X
a Predose samples should be taken just prior to the administration. It is acceptable to collect the predose sample for 
nivolumab and brentuximab vedotin at the same time, as long as it is collected prior to the start of the infusion. If 
the infusion is delayed and a pre-dose sample was already collected, there is no need to collect an additional pre-
dose sample.
b For subjects during second year of treatment and beyond, PK collections will occur every 24 weeks instead of every 
18 weeks.
Table 5.5.1-2:
Brentuximab Vedotin Pharmacokinetic and Immunogenicity 
Sampling Schedule - Cohort A and Cohort B
Study Day
Event 
(Relative to Start 
of Infusion/Event)
Time 
(Relative to Start 
of Brentuximab 
Vedotin 
Infusion)
Hour:Min
Brentuximab 
Vedotin PK 
Blood Sample
Brentuximab 
Vedotin 
Immunogenicity 
Sample
Cycle 1 Day 1 
Predosea
00:00
X
X
Cycle 2 Day 1
Predoseb
00:00
X
X
Cycle 3 Day 1
predoseb
00:00
X
X
Cycle 5 Day 1
predoseb
00:00
X
X
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Table 5.5.1-2:
Brentuximab Vedotin Pharmacokinetic and Immunogenicity 
Sampling Schedule - Cohort A and Cohort B
Study Day
Event 
(Relative to Start 
of Infusion/Event)
Time 
(Relative to Start 
of Brentuximab 
Vedotin 
Infusion)
Hour:Min
Brentuximab 
Vedotin PK 
Blood Sample
Brentuximab 
Vedotin 
Immunogenicity 
Sample
Day 1 of every 6th cycle 
thereafter (every 18 weeks) 
until discontinuation of study 
treatmenta
predoseb
00:00
X
X
First 2 Follow-up visits- X01 & 
X02
X
X
a For subjects during second year of treatment and beyond, PK collections will occur every 24 weeks instead of every 
18 weeks.
b Predose samples should be taken just prior to the administration (preferably within 30 minutes). It is acceptable to 
collect the predose sample for nivolumab and brentuximab vedotin at the same time, as long as it is collected prior 
to the start of the infusion. If the infusion is delayed and a pre-dose sample was already collected, there is no need 
to collect an additional pre-dose sample.
5.6
Biomarker Assessments
Peripheral blood, tumor tissue and bone marrow aspirate/biopsy will be collected prior to therapy 
and at selected timepoints on treatment as outlined in Table 5.6-1, unless restricted by local 
requirements.
Table 5.6-1:
Biomarker Sampling Schedule (CA209436)
Collection Timing
Plasma and 
Seruma
PBMC
Tumor Biopsy
Bone Marrow 
Aspirate/Biopsyb
Whole 
Blood
Study Day
Soluble 
Biomarkers
Immuno-
phenotyping
(FFPE)
(Fresh)
SNP
Screening
Xc
X
Xd
Cycle 1 Day 1
X
X
X
X
Cycle 2 Day 1
X
X
Cycle 3 Day1
X
X
Cycle 4 Day 1
X
X
Cycle 7 Day1
X
X
CR Evaluation
X
X
Xe
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Table 5.6-1:
Biomarker Sampling Schedule (CA209436)
Collection Timing
Plasma and 
Seruma
PBMC
Tumor Biopsy
Bone Marrow 
Aspirate/Biopsyb
Whole 
Blood
Study Day
Soluble 
Biomarkers
Immuno-
phenotyping
(FFPE)
(Fresh)
SNP
During Treatment 
(when clinically 
indicated)
Xf
X
Xf
Follow-up Visit X01
X
X
Xd
Upon Progressiong
X
X
X
X
X
a All biomarker samples may be obtained within 3 days prior to the indicated time.
b Fresh tumor biopsy collections may be performed at screening or cycle 1 for flow-cytometry analysis of TILs. Such 
fresh biopsies for TILs analysis are optional but strongly encouraged. If screening or cycle 1 day 1 fresh tumor 
collection for TILs flow-cytometry analysis is perform, on-study collections are also optional but encouraged.
c Subjects may undergo tumor biopsy during screening or submit archival tumor tissue collected prior to obtaining 
informed consent. Tumor tissue must have been collected within 20 months from screening, while slides must have 
been cut within 6 months from screening. Refer to section 5.6.1 for further details. In order to be treated, the sample 
must meet the minimum quality requirements, as determined by the central laboratory during the screening period.
d In subjects with PTCL where clinical suspicion for marrow involvement is high, bone marrow biopsy and aspirate 
collected within 90 days prior to obtaining consent or fresh sample during screening are acceptable. Submission of 
bone marrow aspirate is encouraged if available. Submission of bone marrow biopsy specimens is not required at 
any point in this study.
e If the bone marrow was involved by lymphoma prior to or at baseline, a bone marrow biopsy and aspirate will be 
required to confirm a CR. Submission of bone marrow aspirate is encouraged.
f All subjects may volunteer to undergo tumor and/or bone marrow biopsies at any time during therapy if clinically 
indicated. When tumor biopsy is performed, submission of tumor biopsy is encouraged.
g Samples from subjects that have confirmed progression are optional.
5.6.1
Biomarker Sampling
Tumor Biopsy:
Tumor biopsy specimens will be obtained to characterize immune cell populations and expression 
of selected tumor markers. 
Biopsy samples should be excisional, incisional or core needle. Fine needle biopsies are not 
allowed because the architecture of the tumor in its microenvironment cannot be assessed.
Tumor tissue (obtained during the screening phase or collected as a standard of care procedure 
prior to obtaining informed consent) must be provided for biomarker analysis. Subjects with 
relapsed disease must provide a recent biopsy sample within 20 months from screening, while 
slides have been cut within 6 months from screening. 
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In order for subjects to be treated, the sample must meet the minimum quality requirements, as 
determined by the central laboratory during the screening period. Minimum of 1 FFPE tumor tissue 
block (preferred) OR a minimum of 20 FFPE unstained sections are required for assessment of 
PD-L1 status and other biomarker evaluations.
All subjects may volunteer to undergo tumor biopsy at any time during therapy if clinically 
indicated (eg, upon progression). When tumor biopsy is performed, submission of tumor biopsy is 
optional, but encouraged for the purposes of understanding mechanisms of resistance to therapy.
Fresh tumor biopsy collections may be performed at screening or cycle 1 day 1 for flow-cytometry 
analysis of TILs. Such fresh tumor biopsies for TILs analysis are optional but strongly encouraged. 
If screening or cycle 1 day 1 fresh tumor collection for TILs flow-cytometry is performed, on-
study collections are also optional but encouraged.  
Plasma and Serum
Soluble Biomarkers
Soluble factors, such as cytokines, chemokines, soluble receptors, and antibodies to tumor antigens 
will be characterized and quantified by immunoassays in serum. 
Plasma samples will be collected and assessed for additional cytokines and soluble factors, 
including soluble PD-L1 if possible.
PBMC
Immunophenotyping
The proportion of specific lymphocyte subsets and expression levels of T cell co-stimulatory 
markers in peripheral blood mononuclear cell (PBMC) preparation will be quantified by flow 
cytometry. Analyses may include, but not necessarily be limited to, the proportion of T, B, and 
NK cells, proportion of memory and effector T cell subsets, and expression levels of PD 1, PD L1, 
PD-L2, ICOS, and Ki67
Whole Blood
Single Nucleotide Polymorphism (SNP) Analysis
In order to identify potential polymorphisms associated with safety and efficacy of nivolumab, 
selected genes will be evaluated for single nucleotide polymorphisms (SNP). Analysis will be 
limited to sequence polymorphisms linked to genes associated with the PD-1/PD-L1 pathway and 
activated T cell phenotype, including PD-1, PD-L1, PD-L2, and CTLA-4. A blood sample will be 
obtained at Day 1, unless restricted by local requirements
Bone Marrow Biopsy and Aspirate
If clinical suspicion of bone marrow involvement, disease manifestation in the bone marrow will 
be evaluated in subjects with PTCL (Section 5.4.4) within 90 days prior to start of study therapy. 
If disease is observed in the bone marrow prior to or during screening, bone marrow aspirate will 
be required if CR is considered during the treatment phase of the study. Bone marrow aspirates 
will be obtained using institutional standards for these procedures. Samples will be assessed for 
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phenotypic and functional status of immune cells and tumor cells. (Screening and during treatment 
as described in Table 5.6-1).
Samples from bone marrow aspirates that may be performed at screening and during CR evaluation 
(only for subjects who had marrow involvement at study entry) are encouraged to be submitted for 
biomarker assessment. These will be utilized to assess the phenotypic and functional status of 
immune cells and tumor cells.
All subjects may volunteer to undergo bone marrow biopsy and aspirate at any time during therapy 
if clinically indicated. When bone marrow biopsy is done, submission of bone marrow aspirate is 
encouraged.
5.6.2
Detailed Biomarkers
The biomarkers described below will be analyzed by third party vendors to the extent possible 
considering that tumor tissue provided by some of the subjects may be insufficient to complete the 
full panel of biomarkers proposed in this protocol. 
•
PD-L1: Proprietary IHC analysis (Screening only)
•
Immunecell subsets: Lymphocyte subsets and expression levels of T cell co-stimulatory 
markers (by flow cytometry). Analyses may include, but not be limited to, the proportion of 
T-, B-, and NK-cells, proportion of memory- and effector T-cell subsets, and expression levels 
of PD 1, PD L1, PD L2, ICOS, CD 30, CD153 and Ki67. Analysis of the diversity of the T-cell 
repertoire in correlation to clinical activity.
•
Tumor gene and phenotype: Analysis (by IHC, RNASeq, GEP, qRT-PCR, miRNA, 
methylation, or mutational analyses) of disease heterogeneity and subtypes and implication of 
the data as response predictors to study therapy. (Screening only)
•
Cell of origin: Cell of origin evaluation will be done by for subjects with diagnosis of relapsed 
DLBCL. Additionally, BCL2 and MYC will be assessed for double hit lymphoma. (Screening 
only)
•
Molecular mechanisms of action and resistance to the study drugs: Expression profiling 
of immune-related genes, mutational analysis, and immune related signaling pathway gene 
expression profiling. Analysis includes, genes associated with immune-related pathways, such 
as T cell activation and antigen processing and presentation (Screening only and other 
timepoints if tumor material is made available)
•
PD-1 expression and nivolumab binding effects of combination therapy on survival 
pathways (NF-kB,) as well as survival signals from the microenvironment. Tumor samples 
obtained from bone metastases are not considered acceptable for PD-L1 testing because the 
PD-L1 assay does not include a decalcification step. For any cases where the only tumor tissue 
available is from a bone metastasis lesion, please discuss further with the study Medical 
Monitor
•
Biomarkers of clinical response: Multiplex- and enzyme-linked immunosorbent assay 
(ELISA) of tumor antigen-specific responses associated with clinical response by including 
cytokines, chemokines, soluble receptors, and antibodies to tumor antigens quantified. 
Analyses include but are not limited to, soluble CD25, soluble PD-1, soluble LAG 3, CXCL 
9, and soluble PD-L1. (Screening and during treatment as described in Table 5.6-1)
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Single nucleotide polymorphisms (SNP) associated with safety and efficacy of study therapy. 
SNP analysis will be limited to genes associated with the PD1/PD-L1 pathway and genes 
associated with CD30 and TNF receptors and apoptosis. 
•
Characterization of tumor infiltrating lymphocytes (TILs)
and tumor antigens. 
Immunohistochemistry (IHC) will be used to assess the number and composition of immune 
infiltrates in order to define the immune cell subsets present within formalin-fixed, paraffin 
embedded (FFPE) tumor tissue before and after exposure to therapy. These IHC analyses will 
include, but not necessarily be limited to, the following markers: CD4, CD8, FOXp3, PD-1, 
PD-L1, and PD-L2.
•
Flow cytometry of TIL from bone marrow aspirates, tumor biopsies and lymph nodes will be 
assessed for the proportion of T, B, and NK cells, proportion of memory and effector T cell 
subsets, and expression levels of PD 1, PD L1, PD-L2, ICOS, and Ki67. Where available, 
immune cells from tumor and lymph node biopsies will be isolated and cryopreserved. For 
functional assessment, including proliferation and intracellular cytokines such as IFN-gamma 
and TNF-alpha.
•
Characterization of tumor genotype and phenotype: Gene mutations, chromosomal 
translocations, aberrant expressions, and epigenetic modifications within tumor cells will be 
characterized and explored by IHC and RNA/DNA analysis of tumor biopsies. Associations 
of altered tumor cell genetic structure with nivolumab efficacy will be performed.
•
Characterization of T cell repertoire: As described above, DNA sequencing will be 
performed on pre- and post treatment tumor tissue to assess the composition of the T cell 
repertoire. DNA will be isolated from either the FFPE tumor block or from RNAlater, or 
equivalent preparations. 
Complete instructions on the collection, processing, handling, and shipment of all samples 
described herein will be provided in a separate procedure manual at the time of study initiation.
5.7
Outcomes Research Assessments
General health-related quality of life will be collected with the EQ-5D 3L during Expansion Phase 
(Cohort B) as outlined in the assessment schedule in Table 5.1-2 and Table 5.1-3
Outcomes research data including health related quality of life (QoL) and patient reported 
symptom burden provide a more complete understanding of the impact of treatment by 
incorporating the subjects’ perspective. These data will be used to assess the impact of nivolumab 
combined with brentuximab vedotin as reported by subjects with DLBCL (cohort B1), PTCL
(cohort B2) and CTCL (cohort B3).
The EQ-5D 3L is a standardized instrument for self-reported health status comprised of 
5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety, plus a visual 
analog rating scale (VAS). 
Subjects will be asked to complete the EQ-5D 3L before study drug administration and any clinical 
activities are performed during visits to the study clinics at on-study visits. . During follow-up and 
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survival-follow-up assessments, the EQ-5D 3L may be administered via telephone contact.
Validated questionnaires will be provided in the subject’s preferred language.
5.8
Other Assessments 
5.8.1
Immunogenicity Assessments
Serum samples collected at time points identified in Table 5.5.1-1 will be analyzed by a validated 
immunogenicity assays. Additional characterization (ie, neutralizing antibodies) for any detected 
anti-drug antibodies (ADA) response to nivolumab and/or brentuximab vedotin may also be 
performed using a validated functional cell-based assay. All on-treatment PK timepoints are 
intended to align with days on which nivolumab and brentuximab vedotin are administered. If it 
is known that dose(s) is/are going to be delayed, then the predose sample should be collected just 
prior to the delayed dose(s). However, if a predose sample(s) is/are collected, but the dose is 
subsequently delayed, additional predose sample(s) should not be collected. Selected serum 
samples may be analyzed by an exploratory method that measures antinivolumab antibodies for 
technology exploration purposes; exploratory results will not be reported.
In addition, serum samples designated for PK or biomarker assessments may also be used for 
immunogenicity analysis if required (eg, if there is insufficient volume for complete 
immunogenicity assessment or to follow up on suspected immunogenicity related AE). 
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess all
adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
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6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
•
results in death
•
is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
•
requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect 
•
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 6.1.1
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
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admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason).

Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur during the screening period and within 
100 days of the last dose of study drug. If applicable, SAEs must be collected that relate to any 
later protocol-specified procedure (eg, a follow-up skin biopsy). 
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
(or designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE Report 
Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The preferred 
method for SAE data reporting collection is through the eCRF. The paper SAE/pregnancy 
surveillance forms are only intended as a back-up option when the eCRF system is not functioning.
In this case, the paper forms are to be transmitted via email or confirmed facsimile (fax) 
transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
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If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to BMS 
(or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug until 100 days 
from the last dose of study drug .Nonserious AE information should also be collected from the 
start of a placebo lead-in period or other observational period intended to establish a baseline status 
for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). 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. All identified nonserious AEs must be recorded and described on the nonserious AE 
page of the CRF (paper or electronic).
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the subject to have study drug discontinued 
or interrupted
•
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 5 half 
lives after product administration, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form to BMS 
Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Section 6.1.1.
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In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough discussion 
of benefits and risk with the subject
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
of awareness of the event and in accordance with SAE reporting procedures described in 
Section 6.1.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
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 (see Section 6.1.1 for reporting details.).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury is defined as: 
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
6.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
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DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Not Applicable.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
•
In the Dose Evaluation Phase (Cohort A), 6 -12 subjects will be treated (Section 4.5.1). The 
number of subjects is not based on statistical power considerations. If less than 1/3 of 6 subjects 
experience a DLT, the upper limit of the 80% 1-sided exact confidence interval for the true 
DLT rate will not be greater than 42%. If less than 1/3 of 12 subjects experience a DLT, the 
upper limit of the 1-sided 80% exact confidence interval (CI) for the true DLT rate will not be 
greater than 41.2%. 
•
In the Expansion Phase (Cohort B), a total of 130 subjects will be treated, with 40 subjects in 
cohort B1 (DLBCL), 30 subjects in cohort B2 (PTCL), 20 subjects in B3 (CTCL), 30 subjects 
in cohort B4 (PMBL) and 10 subjects in cohort B5 (MGZL). 

Given 40 subjects in DLBCL, the one-sided 90% confidence interval (ie, two-sided 80% 
confidence interval) for the ORR is 48.6% - 70.6% if we assume an observed ORR rate of 
60%. The lower bound of the 90% CI excludes 40%, which is the null hypothesis ORR rate 
for PTCL. 

Given 30 subjects in PTCL, the one-sided 90% confidence interval (ie, two-sided 80% 
confidence interval) for the ORR is 46.7% - 72.3% if we assume an observed ORR rate of 
60%. The lower bound of the 90% CI excludes 40%, which is the null hypothesis ORR rate 
for PTCL. 

Given 20 subjects in CTCL, the one-sided 90% confidence interval (ie, two-sided 80% 
confidence interval) for ORR is 63.9% - 91.0% if we assume an observed ORR rate of 
80%. The lower bound of the 90% CI excludes 60%, which is the null hypothesis ORR rate 
for CTCL.

Given 30 subjects in PMBL, the one-sided 90 % confidence interval (ie, two-sided 80% 
confidence interval) for the ORR is 37.0% - 63.0% if we assume an observed ORR rate of 
50%. The lower bound of the 90% CI excludes 30%, which is the null hypothesis ORR rate 
for PMBL. 

Given 10 subjects in MGZL, the one-sided 90 % confidence interval (ie, two-sided 80% 
confidence interval) for the ORR is 11.6% - 55.2% if we assume an observed ORR rate of 
50%. The lower bound of the 90% CI excludes 10%, which is the null hypothesis ORR rate 
for MGZL.
Table 8.1-1 summarizes the 90% exact CI for different targeted ORRs and sample sizes. The 
targeted ORR of 60% in DLBCL and PTCL and 80% in CTCL, and null hypothesis ORR rate 
of 40% in DLBCL and PTCL and 60% in CTCL are based on the historical data and the activity 
of brentuximab vedotin and nivolumab as single agents from phase I and phase II studies.
19,39,86,87
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Table 8.1-1:
One-sided 90% Exact CI for different number 
of subjects in each cohort
If the observed ORR rate is 60% in Cohort B1 and 
B2
Power
N=30
[46.7% - 72.3%] 
82%
N=40
[48.6% - 70.6%]
87%
If the observed ORR rate is 80% in Cohort B3
N=20
[63.9% - 91.0%]
62 % 
If the observed ORR rate is 50% in Cohort B4
N=30
[37.0% - 63.0%]
81 %
If the observed ORR rate is 30% in Cohort B5
N=10
[11.6% - 55.2%]
61%
Also, If we have 20 subjects in Cohort B3, assuming true ORR is 80%, there will be approximately 
62% power to reject null hypothesis that the true ORR is <= 60%, considering a one-sided alpha 
of 10%. Given a very low prevalence of CTCL, 20 subjects in cohort III is considered as feasible 
and adequate for a phase II signal detecting trial. Sample size of 30 subjects in Cohort B2 and 40 
subjects in Cohort B1 are corresponding to power of 82% and 87% respectively to reject null 
hypothesis that the true ORR is <= 40% assuming true ORR is 60% and considering a one-sided 
alpha of 10%. If we have 30 subjects in Cohort B4, assuming true ORR is 50%, there will be 
approximately 81% power to reject null hypothesis that the true ORR is <= 30%, considering a 
one-sided alpha of 10%. Finally if we have 10 subjects in Cohort B5, assuming true ORR is 30%, 
there will be approximately 61% power to reject null hypothesis that the true ORR is <= 10%, 
considering a one-sided alpha of 10%.
If the screening failure rate is 20%, we would need to enroll 170 subjects to have 136 patients 
treated (130 in Cohort B, 6 in Cohort A). If Cohort A needs 6-12 more treated subjects, we would 
need to enroll 8-15 more subjects accordingly.
8.2
Populations for Analyses
In each cohort the following populations will be defined:
•
All Enrolled Subjects: All subjects who signed an informed consent form and were registered
into the IVRS.
•
All Treated Subjects: All subjects who received at least one dose of any of the study drugs. 
This is the primary population for safety and efficacy analyses. This dataset will be used for 
baseline demographics and efficacy and safety analyses.
•
PK Subjects: Subjects with available serum time-concentration data from treated subjects 
dosed with nivolumab and/or brentuximab vedotin.
•
HEOR subjects: treated subjects who have an assessment at screening/baseline and at least 
1 follow-up assessment
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Immunogenicity subjects: treated subjects who have an assessment at screening/baseline and
at least 1 follow-up assessment
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary safety endpoints include incidence of deaths, adverse events, serious adverse events, 
adverse events leading to discontinuation, adverse events leading to dose delay, drug-related 
adverse events and specific laboratory abnormalities (worst grade). Toxicities will be graded using 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03.
The primary efficacy endpoint is ORR. It is defined as the number of subjects with a best overall
response (BOR) of confirmed CR or PR divided by the number of treated subjects. The BOR is 
defined as the best response designation recorded between the date of first dose and the date of 
initial objectively documented progression or the date of subsequent therapy, whichever occurs 
first. Allogeneic SCT and ASCT will be considered as subsequent therapy. In subjects with 
relapsed refractory DLBCL, relapsed refractory PTCL, relapsed refractory PMBL and relapsed 
refractory MGZL the response (CR, PR, PD, and progression) will be assessed according to 
Lugano Classification 2014. For subjects with relapsed refractory CTCL, response will be assessed 
according to consensus Global Response Score as per the consensus statement of the International 
Society for Cutaneous Lymphoma. A CR must have been confirmed by scans, including a negative 
Positron Emission Tomography (PET) to be considered for CR in subjects with PTCL, DLBCL, 
PMBL and MZGL. In subjects with PTCL, if the bone marrow was compromised at baseline, a 
bone marrow must also be negative at the time of CR. In CTCL CT scans (chest, neck, abdomen 
and pelvis), blood flow for SS cells and m SWAT skin scoring along with medical photography 
will be performed at baseline and at the end of the treatment for response evaluation. The 
investigator will perform tests that will allow evaluation of response to therapy according to 
corresponding disease criteria in Appendix 2 and Appendix 4. The analysis of the primary endpoint 
will occur approximately 8 months after the last enrolled subject’s first dose of study therapy.
Depending on the enrollment for each disease cohort, the analysis may be done at different times
for each cohort, or at the same time for the three cohorts.
8.3.2
Secondary Endpoint(s)
The secondary endpoints are DOR, CR rate, duration of CR, PFS and OS.
DOR will be calculated from the date of initial documentation of a response (CR, or PR) to the 
date of first documented evidence of progressive disease (or relapse for subjects who experience 
CR during the study) or death. Subjects who are progression-free and alive or have unknown status 
will be censored at the last tumor assessment. For subjects who received subsequent therapy prior 
to documented progression, duration of response will be censored on the last tumor assessment 
date prior to subsequent therapy. Allogeneic SCT and ASCT will be considered as subsequent 
therapy.
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The CR rate is defined as the number of subjects with a BOR of CR divided by the number of 
treated subjects. The duration of CR will only be evaluated in subjects with BOR of CR and is 
defined as the time from first documentation of CR to the date of initial documented progression 
or death due to any cause, whichever occurs first. Censoring will be applied as per DOR definition.
PFS is defined as the time from the date of first dose of study drug until the date of first documented 
evidence of progressive disease (or relapse for subjects who experience CR during the study) or 
death, whichever comes first. Subjects who are progression-free and alive or have unknown status 
will be censored at the last tumor assessment. For subjects who received subsequent therapy prior 
to documented progression, it will be censored on the last tumor assessment date prior to 
subsequent therapy.
OS is defined as the time from the date of first dose of study drug until the date of death 
(any reason). If the subject is alive or the vital status is unknown, the subject will be censored at 
the date the subject was last known to be alive.
8.3.3
Exploratory Endpoint(s)
The Indeterminate response will be assessed per the Lymphoma Response to Immunomodulatory 
therapy Criteria (LYRIC). The exploratory biomaker objectives are to assess CD30 expression and 
correlate with response, and to assess PD-L1/L2 status and correlate it with response etc. These 
biomarker endpoints are discussed in detail in Section 5.6. The exploratory objectives also include 
characterizing pharmacokinetics (PK) and the immunogenicity of nivolumab and brentuximab
vedotin following combination therapy. The nivolumab and brentuximab vedotin concentration, 
PK parameter and inmmunogenicity endpoints are discussed in details in Section 5.5.  
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics of patient will be summarized for each cohort and also 
for all treated subjects.
8.4.2
Efficacy Analyses
All analyses will be performed separately for each cohort and also for all treated subjects combined 
with same treatment dosage (ie, safety cohort subjects with different dose from the expansion
cohort will not be combined). 
The ORR will be summarized by binomial response rates and their corresponding two-sided 80% 
exact CIs using the Clopper-Pearson method. The same analysis will be performed for CR rate.
The DOR will be summarized by cohort for subjects who achieve confirmed PR or CR using the 
Kaplan-Meier (KM) product-limit method. Median values of DOR, along with two-sided 95% CI 
using log-log transformation method and range, will also be calculated. The same analysis will be 
performed for duration of CR, PFS and OS at 1 year. Detailed analyses on efficacy endpoints will 
be presented in the statistical analyses plan.
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8.4.3
Safety Analyses
Safety analyses will be performed in all treated subjects. Descriptive statistics of safety will be 
presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. All on-study AEs, drug-related, AEs, SAEs and drug-related SAEs 
will be tabulated using worst grade per NCI CTCAE v4.03 criteria by system organ class and 
MedDRA preferred term. On-study lab parameters including hematology, chemistry, liver 
function, thyroid function, and renal function will be summarized using worst grade per NCI 
CTCAE v4.03 criteria. 
In addition to separate analyses per cohort, safety analyses will be performed all treated subjects 
combined. If safety cohorts subject have different doses, the safety results will be presented by 
cohorts and by dose.
8.4.4
Pharmacokinetic Analyses
The nivolumab and brentuximab vedotin concentration data obtained in this study may be 
combined with data from other studies in the clinical development programs to develop or refine 
existing population PK models. These models may be used to evaluate the effects of intrinsic and 
extrinsic covariates on the PK of nivolumab or brentuximab vedotin and to determine measures of 
individual exposure (such as steady-state peak, trough, and time-averaged concentration). In 
addition, model determined exposures may be used for exposure-response analyses. Results of 
population PK and exposure response-analyses will be reported separately.
8.4.5
Biomarker Analyses
Summary statistics for peripheral blood and tumor biomarker activity such as, but not limited to 
CD30, PD-L1/L2 expression levels and their corresponding changes (or percent changes) from 
baseline will be tabulated by planned study visit to assess pharmacodynamic effects. In addition, 
the time course of biomarker outcomes will be investigated graphically; if there is indication of 
meaningful pattern across time, further analysis may be performed to characterize the relationship. 
Results from peripheral blood and tumor biomarkers will be tabulated and associations between 
biomarkers and efficacy or safety measures will be assessed. Methods such as, but not limited to,
logistic regression will be used to explore possible associations between measures of peripheral
blood, tumor biopsies and clinical outcome. More details of biomarker analyses will be described 
in the statistical analysis plan.
8.4.6
Outcomes Research Analyses
Subject’s overall health state on a visual analog scale (EQ-VAS) at each assessment time point 
will be summarized using descriptive statistics (N, mean, standard deviation, median, first and
third quartiles, minimum, maximum). Proportion of subjects reporting problems for the 5 EQ-5D
3L dimensions at each assessment time point will be summarized by level of problem. Percentages
will be based on number subjects assessed at assessment time point.
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A by-subject listing of EQ-5D 3L with the problem levels for each of the 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort and anxiety/depression), health state 
(5 dimensions digits combined in a 5-digit number) and EQ-VAS will be provided.
8.4.7
Other Analyses 
8.4.7.1
Immunogenicity Analyses
Immunogenicity may be reported for ADA positive status (such as persistent positive, neutralizing 
positive, only last sample positive, baseline positive and other positive) and ADA negative status, 
relative to baseline. Effect of immunogenicity on safety, efficacy, biomarkers and PK may be 
explored. Additional details will be described in the SAP.
8.5
Interim Analyses
No formal interim analysis is planned. Interim analyses may be conducted if it is necessary in order 
to make decisions regarding further development. Summaries and listings of efficacy and safety 
will be provided. Interim analyses will not impact the study conduct and the trial will continue as 
planned.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to:
•
IRB/IEC for review and approval/favorable opinion
•
BMS
•
Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the subject: 
(1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
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currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a schedule 
of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable.
In addition, the study may be evaluated by BMS internal auditors and government inspectors who 
must be allowed access to CRFs, source documents, other study files, and study facilities. BMS 
audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to BMS. 
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and procedure, 
electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
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9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product and 
the following non-investigational product(s). Records or logs must comply with applicable 
regulations and guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number 
•
amount dispensed to and returned by each subject, including unique subject identifiers
•
amount transferred to another area/site for dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for bioavailability/bioequivalence, if applicable 
•
dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
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understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all data 
collection fields except for fields specific to SAEs and pregnancy, which will be reported on the 
paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be left 
blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator and 
who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review and 
approval/signature is completed electronically through the BMS electronic data capture tool. The 
investigator must retain a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements and 
must only access the BMS electronic data capture tool using the unique user account provided by 
BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
•
External Principal Investigator designated at protocol development
•
Subject recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (eg, among top quartile of enrollers from a specified region or country)
The data collected during this study are confidential and proprietary to BMS. Any publications or 
abstracts arising from this study must adhere to the publication requirements set forth in the clinical 
trial agreement (CTA) governing [Study site or Investigator] participation in the study. These 
requirements include, but are not limited to, submitting proposed publications to BMS at the 
earliest practicable time prior to submission or presentation and otherwise within the time period 
set forth in the CTA.
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10
GLOSSARY OF TERMS
Not applicable.
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LIST OF ABBREVIATIONS
Term
Definition
ABC
Activated B cell like
ACTH
Adrenocorticotropic Hormone
ACVBP
Doxorrubicin, cyclophosphamide, vindesine, bleomycin and prednisone
ADC
Antibody-drug conjugate
AE
adverse event
AIDS
Acquired immunodeficiency syndrome
AITL
Angioimmunoblastic T Cell Lymphoma
ALCL
Anaplastic Large Cell Lymphoma
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCT
Autologous Stem Cell Transplant 
AST
aspartate aminotransferase
AT
Aminotransferase (ALT or AST)
BA
Bioavailability
BCNU
bis-chloroethylnitrosourea (Carmustine)
BE
Bioequivalence
BMI
body mass index
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BUN
blood urea nitrogen
BV
Brentuximab Vedotin
C
Celsius
Ca
Calcium
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
C1
Chloride
CrCl
creatinine clearance
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Term
Definition
CL/CLR
Clearance/renal clearance
Cm
Centimeter
CMV
Cytomegalovirus
CNS
Central nervous system
COO
Cell of Origin
CR
Complete remission
CRC
Colorectal Cancer
CrCl
Creatinine Clearance
CRF
Case Report Form, paper or electronic
CRR
Complete response rate
CT
Computed tomograhpy
CTLA
Cytotoxic T-Lymphocyte Antigen
CTA
Clinical Trial Agreement 
CTCAE
Common Terminology Criteria for Adverse Events
CTCL
Cutaneous T Cell Lymphoma
DILI
drug induced liver injury
dL
Deciliter
DLBCL
Diffuse large B-Cell lymphoma
DLT
Dose Limiting Toxicity
DOR
Duration of response 
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EFS
Event Free Survival
eg
exempli gratia (for example)
ELISA
enzyme-linked immunosorbent assay
EORTC
European Organization of Research and Treatment of Cancer
ER
Endoplasmic Reticulum Stress
eSAE
Electronic Serious Adverse Event 
ESR
Expedited Safety Report
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Term
Definition
FDA
Food and Drug Administration
FDG
Fludeoxyglucose
FFPE
Formalin-Fixed Parafin-Embedded
FSH
follicle stimulating hormone
g
Gram
GC
Germinal Center subtype
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
G-CFS
Growth factor support
GVHD
Graft versus host disease
h
Hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
Human chorionic gonadotropin
HCV
hepatitis C virus
HCO3-
Bicarbonate
HDACi
Histone deacetylase Inhibitor
HD-ASCT
High dose autologous stem cell transplant
HER2
Human epidermal growth factor receptor 2
HIPAA
Health Insurance Portability and Accountability Act 
HIV
Human Immunodeficiency Virus
HL
Hodgkin lymphoma
HR
heart rate
HRT
hormone replacement therapy
HuMAb
Fully-human monoclonal antibody
IB
Investigational Brochure
ICD
Immunogenic cell death
ICR
Immune checkpoint receptors
ICH
International Conference on Harmonisation 
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Term
Definition
ICF
Informed Consent Form
ie
id est (that is)
IEC
Independent Ethics Committee
Ig
Immuneglobulin
IHC
Immunohistochemistry
IMP
investigational medicinal products
IND
Investigational New Drug
INN
International Nonproprietary Name
IPI
International prognostic index
IR 
Indeterminate Response
IRB
Institutional Review Board
ISCL
International Society for Cutaneous Lymphoma
IU
International Unit
IUD
Intrauterine device
IV
Intravenous
IVRS
Interactive voice response system
JCV
John Cunningham virus
K+
Potassium
kg
Kilogram
L
Liter
LDH
lactate dehydrogenase
LFT
Liver function test
LPFT
Last Patient First Treatment
mAbs
monoclonal antibodies
mCRPC
Metastatic Castration-Resistance Prostate Cancer
MF
Mycosis Fungoides
mg
Milligram
Mg++
Magnesium
MGZL
Mediastinal Gray Zone Lymphoma 
MHC
Major Histocompatibility Complex
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Term
Definition
min
Minute
MRI
Magnetic resonance imaging
mL
Milliliter
MLR
mixed lymphocyte reaction
mm
Millimeter
MMAE
Monomethyl auristatin E 
mmHg
millimeters of mercury
mSWAT
Modified Severity Weighted Tool
MTD
maximum tolerated dose
Pg
Microgram
N
number of subjects or observations
Na
Sodium
N/A
not applicable
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse 
Events
NFkB
Natural Factor țB
ng
Nanogram
NIMP
non-investigational medicinal products 
NIV
Nivolumab
NHL
Non-Hodgkin lymphoma
NK
Natural Killer
Non GC
Non germinal center subtype
NOS
Not otherwise specified
NSCLC
Non small cell lung cancer
ORR
Objective response rate
OS
Overall survival 
PBMC
peripheral blood mononuclear cells
PD
Progressive Disease
PD-1
Programmed death-1 receptor
PET
Positron emission tomography
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Term
Definition
PFS
Progression free survival 
PK
pharmacokinetics
PPK
Population PK
PMBL
Primary Mediastinal B Lymphoma 
PML
Progressive multifocal leukoencephalopathy 
PR
Partial response 
PRR
Partial response rate
PS
Performance Status
PTCL
Peripheral T Cell Lymphoma
q
Every 
Q2W
Every 2 weeks
qPCR
Quantitative real-time polymerase chain reaction
RBC
red blood cell
RCC
Renal cell carcinoma
R-CHOP
Rituximab plus cyclophosphamide, doxorubicin, vincristine, 
prednisone/prednisolone
RO
Receptor Occupancy
RT-PCR
Reverse transcription- polymerase chain reaction
SAE
serious adverse event
SCT
Stem cell transplant 
SD
Stable Disease
SmPC
Summary of product characteristics 
SNP
Single nucleotide polymorphisms
SOP
Standard Operating Procedures
SS
Sézary Syndrome
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
TCR
T-cell receptor
TFH
T Follicular helper cells
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Term
Definition
T-HALF
Half life
TIL
tumor infiltrating lymphocytes
USAN
United States Adopted Name
USP
Unites States Pharmacopeia
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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12
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b-cell lymphoma is associated with decreased overall survival and the non- germainal center 
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the United States, 1992-2001. Blood 107:265-76, 2006
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38 Coiffier B, Pro B, Prince HM, et al: Results from a pivotal, open-label, phase II study of 
romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. 
J Clin Oncol 30:631-6, 2012
39 Horwitz SM, Advani RH, Bartlett NL, et al: Objective responses in relapsed T-cell lymphomas 
with single-agent brentuximab vedotin. Blood 123:3095-100, 2014
40 Gaulard P, de Leval L: The microenvironment in T-cell lymphomas: emerging themes. Semin 
Cancer Biol 24:49-60, 2014
41 Gaulard P, de Leval L: Pathology of peripheral T-cell lymphomas: where do we stand? Semin 
Hematol 51:5-16, 2014
42 Iqbal J, Weisenburger DD, Greiner TC, et al: Molecular signatures to improve diagnosis in 
peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. 
Blood 115:1026-36, 2010
43 Piccaluga PP, Agostinelli C, Califano A, et al: Gene expression analysis of peripheral T cell 
lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets. J Clin 
Invest 117:823-34, 2007
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44 Piccaluga PP, Agostinelli C, Califano A, et al: Gene expression analysis of 
angioimmunoblastic lymphoma indicates derivation from T follicular helper cells and vascular 
endothelial growth factor deregulation. Cancer Res 67:10703-10, 2007
45 Dupuis J, Boye K, Martin N, et al: Expression of CXCL13 by neoplastic cells in 
angioimmunoblastic T-cell lymphoma (AITL): a new diagnostic marker providing evidence 
that AITL derives from follicular helper T cells. Am J Surg Pathol 30:490-4, 2006
46 Iqbal J, Wright G, Wang C, et al: Gene expression signatures delineate biological and 
prognostic subgroups in peripheral T-cell lymphoma. Blood 123:2915-23, 2014
47 Wilcox RA, Feldman AL, Wada DA, et al: B7-H1 (PD-L1, CD274) suppresses host immunity 
in T-cell lymphoproliferative disorders. Blood 114:2149-58, 2009
48 Kim YH, Liu HL, Mraz-Gernhard S, et al: Long-term outcome of 525 patients with mycosis 
fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. 
Arch Dermatol 139:857-66, 2003
49 Trautinger F, Knobler R, Willemze R, et al: EORTC consensus recommendations for the 
treatment of mycosis fungoides/Sezary syndrome. Eur J Cancer 42:1014-30, 2006
50 Zinzani PL, Baliva G, Magagnoli M, et al: Gemcitabine treatment in pretreated cutaneous T-
cell lymphoma: experience in 44 patients. J Clin Oncol 18:2603-6, 2000
51 Wollina U, Dummer R, Brockmeyer NH, et al: Multicenter study of pegylated liposomal 
doxorubicin in patients with cutaneous T-cell lymphoma. Cancer 98:993-1001, 2003
52 Molin L, Thomsen K, Volden G, et al: Combination chemotherapy in the tumour stage of 
mycosis fungoides with cyclophosphamide, vincristine, vp-16, adriamycin and prednisolone 
(cop, chop, cavop): a report from the Scandinavian mycosis fungoides study group. Acta Derm 
Venereol 60:542-4, 1980
53 Bernengo MG, Quaglino P, Comessatti A, et al: Low-dose intermittent alemtuzumab in the 
treatment of Sezary syndrome: clinical and immunologic findings in 14 patients. 
Haematologica 92:784-94, 2007
54 Foss FM, Ihde DC, Breneman DL, et al: Phase II study of pentostatin and intermittent high-
dose recombinant interferon alfa-2a in advanced mycosis fungoides/Sezary syndrome. J Clin 
Oncol 10:1907-13, 1992
55 Olsen EA, Kim YH, Kuzel TM, et al: Phase IIb multicenter trial of vorinostat in patients with 
persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 
25:3109-15, 2007
56 Rasheed WK, Johnstone RW, Prince HM: Histone deacetylase inhibitors in cancer therapy. 
Expert Opin Investig Drugs 16:659-78, 2007
57 Whittaker SJ, Demierre MF, Kim EJ, et al: Final results from a multicenter, international, 
pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 28:4485-
91, 2010
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58 Duvic M, Talpur R, Ni X, et al: Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic 
acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 109:31-9, 2007
59 Kim YHT, M. Rozati, S. et al: Phase II investigator-initiated Study of Brentuximab Vedotin in 
Mycosis Fungoides or Sezary Syndrome: Final Results Show Significant Clinical Activity and 
Suggest Correlation with CD30 Expression. Blood Abstract:804, 2014
60 Miyagaki T, Sugaya M: Immunological milieu in mycosis fungoides and Sezary syndrome. J 
Dermatol 41:11-8, 2014
61 Kantekure K, Yang Y, Raghunath P, et al: Expression patterns of the immunosuppressive 
proteins PD-1/CD279 and PD-L1/CD274 at different stages of cutaneous T-cell 
lymphoma/mycosis fungoides. Am J Dermatopathol 34:126-8, 2012
62 Dunleavy K, Wilson WH: Primary mediastinal B-cell lymphoma and mediastinal gray zone 
lymphoma: do they require a unique therapeutic approach? Blood 125:33-9, 2015
63 Steidl C, Gascoyne RD: The molecular pathogenesis of primary mediastinal large B-cell 
lymphoma. Blood 118:2659-69, 2011
64 Kuruvilla J, Pintilie M, Tsang R, et al: Salvage chemotherapy and autologous stem cell 
transplantation are inferior for relapsed or refractory primary mediastinal large B-cell 
lymphoma compared with diffuse large B-cell lymphoma. Leuk Lymphoma 49:1329-36, 2008
65 Hamlin PA, Portlock CS, Straus DJ, et al: Primary mediastinal large B-cell lymphoma: optimal 
therapy and prognostic factor analysis in 141 consecutive patients treated at Memorial Sloan 
Kettering from 1980 to 1999. Br J Haematol 130:691-9, 2005
66 Zinzani PL, Stefoni V, Finolezzi E, et al: Rituximab combined with MACOP-B or VACOP-B 
and radiation therapy in primary mediastinal large B-cell lymphoma: a retrospective study. 
Clin Lymphoma Myeloma 9:381-5, 2009
67 Dunleavy K, Pittaluga S, Maeda LS, et al: Dose-adjusted EPOCH-rituximab therapy in primary 
mediastinal B-cell lymphoma. N Engl J Med 368:1408-16, 2013
68 Pfreundschuh M, Trümper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, 
Walewski J, Zinzani PL, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, 
López-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, 
Loeffler M, MabThera International Trial Group: CHOP-like chemotherapy plus rituximab 
versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-
B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) 
Group. Lancet Oncol. 2006;7(5):379
69 Aoki T, Suzuki R, Kuwatsuka Y, et al: Long-term survival following autologous and 
allogeneic stem cell transplantation for blastic plasmacytoid dendritic cell neoplasm. Blood 
125:3559-62, 2015
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70 Zinzani PLR, V. Moskowitz, C.H. et al: Phas 1B Study of Pembrolizumab in patients with 
relapsed refractory Primary Mediastinal Large B-Cell Lymphoma: KEYNOTE-013. EHA. 
Abstract S797
71 Armand PS, M.A. Ribrag, V. et al: PD-1 Blockade with Pembrolizumab in Patients with 
Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Safety, Efficacy, and 
Biomarker Assessment. Blood 126, 2015
72 Jakub Svoboda, MD, Lauren E. Strelec, BA*, Sunita Dwivedy Nasta, MD*, Daniel J. 
Landsburg, MD, Anthony R. Mato, MD*, Barbara Pro, Stefan Klaus Barta, MD, MRCP, MS4, 
Nirav N. Shah, MD, Sarah Jordan Nagle, MD*, Elise A. Chong, MD, Ellen Napier, NP*, 
Samantha Garrett* and Stephen J. Schuster, MD: Brentuximab Vedotin in Combination with 
Multi-Agent Chemotherapy Is Well Tolerated and Shows Promising Activity As Frontline 
Treatment for Primary Mediastinal B-Cell Lymphoma).  Abstract # 2694 Blood:
73 Green MR, Monti S, Rodig SJ, 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 
116:3268-77, 2010
74 Chapuy B, Roemer MG, Stewart C, et al. Title: Targetable genetic features of primary 
testicular and primary central nervous system lymphomas. Source: Blood, 2015.
75 Shi M, Roemer MG, Chapuy B, 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 38:1715-23, 2014
76 Jacobsen ED, Sharman JP, Oki Y, et al: Brentuximab vedotin demonstrates objective responses 
in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood 
125:1394-402, 2015
77 Wilson WH, Pittaluga S, Nicolae A, et al: A prospective study of mediastinal gray-zone 
lymphoma. Blood 124:1563-9, 2014
78 Eberle FC, Salaverria I, Steidl C, et al: title :Gray zone lymphoma: chromosomal aberrations 
with immunophenotypic and clinical correlations. source: Mod Pathol 24:1586-97, 2011.
79 Chanan-Khan A, Miller KC, Lawrence D, et al: Tumor flare reaction associated with 
lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical 
response. Cancer 117:2127-35, 2011
80 Wolchok JD, Hoos A, O'Day S, et al: Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412-20, 2009
81 (BMS) B-MS: Investigator Brochure Nivolumab BMS-936558 MDX 1106 Version 13, 2014
82 Little RF, Pluda JM, Wyvill KM, et al: Activity of subcutaneous interleukin-12 in AIDS-
related Kaposi sarcoma. Blood 107:4650-7, 2006
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83 Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, 
and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. 
J Clin Oncol 32:3059-68, 2014
84 Olsen EA, Whittaker S, Kim YH, et al: Clinical end points and response criteria in mycosis 
fungoides and Sezary syndrome: a consensus statement of the International Society for 
Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the 
Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment 
of Cancer. J Clin Oncol 29:2598-607, 2011
85 Cheson BD, Ansell S, Schwartz L, et al: Refinement of the Lugano classification response 
criteria for lymphoma in the era of immunomodulatory therapy. Blood, 2016
86 Bartlett NL, Chen R, Fanale MA, et al: Retreatment with brentuximab vedotin in patients with 
CD30-positive hematologic malignancies. J Hematol Oncol 7:24, 2014
87 Horwitz SM: Romidepsin for previously treated patients with peripheral or aggressive T-cell 
lymphomas. Clin Adv Hematol Oncol 10:333-4, 2012
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APPENDIX 1
ECOG PERFORMANCE STATUS 
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5
Dead
Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. 
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APPENDIX 2
2014 LUGANO CLASSIFICATION: STAGING AND RESPONSE 
EVALUATION (DIFFUSE LARGE B CELL LYMPHOMA, 
PERIPHERAL T CELL LYMPHOMA, PRIMARY MEDIASTINAL B 
LYMPHOMA & MEDIASTINAL GRAY ZONE LYMPHOMA).
Table 1:
Revised Criteria for Response Assessment
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*The recommendations from Lugano Classification is to use a 5 point scale to assess the metabolic 
response in PET-CT based response.
Response Evaluation in DLBCL, PTCL, PMBL & MGZL:
CR (Complete Remission)
The designation of CR requires all of the following be met:
1) Complete disappearance of all detectable clinical evidence of disease.
a) PET-CT-based response: A score of d 3 is considered to represent complete metabolic 
response.
b) CT based response: Target node/nodal masses must regress to d 1.5 cm in LDi, with no 
extrlymphatic sites of disease.
Organ involvement: Absence of organomegaly (Table 3).
2) Bone marrow: No evidence of FDG- avid disease in marrow. If there was evidence of 
involvement of bone marrow with lymphoma at screening/baseline and a biopsy was 
performed (PTCL), a bone marrow biopsy will be required to confirm CR.
3) The presence of residual symptoms in the absence of detectable disease by imaging does not 
preclude the designation of CR.
PR (Partial Remission)
The designation of PR requires all of the following:
1) PET-CT based response: Score of 4 or 5, provided reduced uptake compared with base line 
and absence of structural progression development on CT Scan.
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2) CT based response: t 50% regression in SPD of upto 6 measurable nodal and extranodal 
lesions (Table 3) .
3) Splenic and hepatic nodules must regress by t 50% in length beyond normal.
Bone marrow : reduced uptake compared with baseline. If there is evidence of nodal response but 
persistent focal changes in the marrow consider further evaluation (Table 3).
SD (Stable Disease)
SD is defined as the following:
1) PET-CT based response: no metabolic response, score of 4 or 5 with no significant changes 
from baseline.
2) CT based response: < 50% decrease from baseline, absence of new lesions (Table 3). 
3) Bone marrow: no change from baseline.
PD: Relapsed Disease (after CR)/Progressive Disease (after PR, SD)
1) PET-CT based response: Score of 4 or 5 with increase in intensity from baseline or interim 
scan/ or any new FDG avid focus consistent with malignant lymphoma (Table 3).
2) CT based response: New node, new or recurrent splenomegaly,progression of existing lesions 
(Table 3).
IR (INDETERMINATE RESPONSE)
A patient will be considered to have Indeterminate Response (IR) in one or more of the 3 following 
circumstances
1) Increase in overall tumor burden (as assessed by SPD) of t 50% of up to 6 measurable lesions 
in the first 12 weeks of therapy, without clinical deterioration (IR(1))
2) Appearance of new lesions; or growth of one or more existing lesion(s) of t 50% at any time 
point during treatment occurring in the context of lack of overall progression (<50% increase) 
of overall tumor burden, as measured by SPD of up to 6 lesions at any time during the treatment 
(IR(2))
3) Increase in FDG uptake of one or more lesion(s) without a concomitant increase in lesion size 
or number (IR(3))
It is possible that, at a single time point a subject could fulfill criteria for both IR(1 or 2) AND 
IR(3): for example, there could be a new FDG-avid lesion in the absence of overall progression
(IR(2)), and, at the same time, increase in FDG uptake of a separate lesion (IR(3)). In such cases, 
the designation of IR(1 or 2) should take priority (eg, IR(2))
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Follow-up of IR
1) In patients categorized as having any of the above types of IR, it is mandatory to obtain a repeat 
imaging after an additional 12 weeks (or earlier if clinically indicated). At that time, response 
should be re-evaluated and the patient should be considered to have true PD if the SPD of 
target lesion has increased further, with the considerations below:
2) In the case of IR(1), the comparison should be between the first IR(1) and the current SPD, 
with an increase of >10% constituting PD. In addition there should be an increase of > 5 mm 
(in either dimension) of at least one lesion for lesions < 2 cm, and 10 mm for lesions > 2 cm, 
to be consistent with the Lugano classification (3)(Table 2). The 10% threshold is empiric but 
designed to account for variability in measurement (37), especially when taken along with the 
minimum increase. If the target SPD increase is < 10%, the response would still be categorized 
as IR(1), and the patient could continue treatment until a subsequent scan shows either true PD 
(> 10% increase from first IR(1) time point and an increase of > 5mm in either dimension of 
at least one lesion) or response (>50% decrease from baseline). In this situation, it is reasonable 
to repeat imaging in 4-8 weeks of the original IR(1) timepoint to ensure absence of significant 
further increase.
3) In the case of IR(2), the new or growing lesion(s) (unless biopsy proven to be benign) should 
be added to the target lesion(s), up to a total of no more than 6 total lesions. If the SPD of the 
newly defined set of target lesions has increased > 50% from the nadir value which may 
precede the IR time point. The patients is considered to have PD.
4) In the case of IR(3), since inflammatory responses may result in an increase in the standardized 
uptake value of a lesion, the patient will not be considered to have PD unless there is evidence 
of PD by an increase in lesion size or the development of new lesions, as noted above
5) Importantly, if a patient is assessed as having IR and then “true” PD at a subsequent time point 
(without an intervening objective response between IR and PD), the IR assessment should 
subsequently be corrected to PD for reporting purposes to the date of the prior designation of 
IR
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APPENDIX 3
CUTANEOUS T CELL LYMPHOMA ISCL/EORTC STAGING 
CRITERIA
Table 2:
Modified ISCL/EORTC 
Revisions to the TNMB 
Classification of MF/SS
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APPENDIX 4
MODIFIED SEVERITY WEIGHTED ASSESSMENT TOOL / 
GLOBAL RESPONSE SCORE
Table 3:
Modified Severity Weighted Assessment Tool
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Table 4:
Response in Skin
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Table 5:
Response in Lymph Nodes*
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Table 6:
Response in Viscera
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Table 7:
Response in Blood*
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Table 8:
Global Response Score
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Response Evaluation in CTCL:
Response in CTCL will be evaluated based on the involvement of different sites (lymph nodes, 
viscera, skin and blood) using the TNMB staging (as clinically indicated) and will be incorporated 
in the Global Response Score. The m SWAT will be used for skin scoring.
All responses to be designated as CR or PR, should be documented for at least 4 weeks in duration. 
No CR can be ascribed to a study drug while a patient remains on concomitant therapy (such as 
topical steroids) with known efficacy in MF/SS.
In certain cases to document CR a biopsy may be required if there are limitations on Spiral CT 
scan or MRI examination for lymph node or viscera evaluation and if it is deemed necessary.
Blood evaluation for Sezary syndrome: The absolute number of CD4+ CD26- determined on flow 
cytometry will be used to assess blood involvement. A normal value for CD+ CD26- or 
CD4+CD7- cells by flow cytometry is lower than 15%.
Response in skin:
m SWAT for skin soring/evaluation, to track skin tumor burden.
CR: 100% clearance of skin lesions. 
PR: 50%-99% clearance of skin disease from baseline without new tumors (T3) in patients with 
T1, T2 or T4 only skin disease. (t 50% reduction in the mSWAT score compared with baseline).
Stable disease: < 25% increase to < 50% clearance in skin disease.from baseline without new 
tumors (T3) in patients with T1, T2, or T4 only skin disease. (Less than 50% reduction to less than 
25% increase in the mSWAT score compared with baseline).
Progressive disease: > 25% increase in skin disease from baseline or new tumors (T3) in patients 
with T1, T2 or T4 only skin disease or Loss of response: in those with complete or partial response, 
increase of skin score of greater than the sum of nadir plus 50% baseline score. Relapse is any 
disease recurrence in those with complete response. (t 25% increase in the mSWAT score from 
baseline).
Response in the lymph nodes will be assessed using a Spiral CT Scan or MRI.
CR: all lymph nodes d 1.5 cm in greatest transverse (long axis) diameter by method used to assess 
lymph nodes at baseline or biopsy negative for lymphoma; in addition, lymph nodes that were 
N3 classification and d 1.5 cm in their long axis and > 1 cm in their short axis at baseline, must be 
d 1 cm in their short axis or biopsy negative for lymphoma.
PR: cumulative reduction t 50% of the SPD of each abnormal lymph node at baseline and no new 
lymphnode > 1.5 cm in the diameter of the long axis or > 1.0 cm in the diameter of the short axis 
if the long axis is 1-1.5 cm diameter.
SD: fails to attain the criteria for CR, PR, and PD.
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PD: > 50% increase in SPD from baseline of lymph nodes or any new node > 1.5 cm in the long 
axis or > 1 cm in the short axis if 1-1.5 cm in the long axis that is proven to be N3 histologically 
or loss of response: > 50% increase from nadir in SPD of lymph nodes in those with PR.
Relapse is any new lymph node > 1.5 cm in the long axis in those with CR proven to be N3 
histologically.
Response in the viscera will be assessed using a Spiral CT Scan or MRI:
CR: (viscera): liver , spleen or any organ considered involved at baseline should not be enlarged 
on physical exam and should be considered normal by imaging; no nodules should be present on 
imaging of liver or spleen; any post treatment mass must be determined by biopsy to be negative 
for lymphoma.
PR: t 50% regression in any splenic or liver nodules, or in measureable disease (SPD) in any 
organs abnormal at baseline; no increase in size of liver or spleen and no new sites of involvement.
SD: Fails to attain the criteria for CR, PR, or PD.
PD: > 50% increase in size (SPD) of any organs involved at baseline or new organ involvement or 
loss of response: > 50% increase from nadir in the size (SPD) of any previous organ involvement 
in those with PR.
Relapse new organ involvement in those with CR.
Response in blood will be performed with peripheral blood flow cytometry.
CR: B0 (absence of blood involvement).
PR: > 50% decrease in quantitative measurements of blood tumor burden from baseline in those 
with high tumor burden at baseline (B2).
SD: Fails to attain criteria for CR, PR, or PD.
PD: B0 to B2 or > 50% increase from baseline and at least 5,000 neoplastic cells/L36 or loss of 
response: in those with PR who were originally B2 at baseline, > 50% increase from nadir and at 
least 5,000 neoplastic cells/L.
Relapse Increase of neoplastic blood lymphocytes to t B1 in those with CR.
* SPD: sum of the maximum linear dimension major axis x longest perpendicular dimension minor 
axis.
*B1: Low tumor burden (> 5%, B1a=clone negative, B1b= clone positive).
B2: High tumor burden t 1000/L Sezary cells with positive clone.
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IR (INDETERMINATE RESPONSE)*
A patient will be considered to have Indeterminate Response (IR) in one or more of the 3 following 
circumstances
1) Increase in overall tumor burden (as assessed by SPD) of t 50% of up to 6 measurable lesions 
in the first 12 weeks of therapy, without clinical deterioration (IR(1))
2) Appearance of new lesions; or growth of one or more existing lesion(s) of t 50% at any time 
point during treatment occurring in the context of lack of overall progression (<50% increase) 
of overall tumor burden, as measured by SPD of up to 6 lesions at any time during the treatment 
(IR(2))
3) Increase in FDG uptake of one or more lesion(s) without a concomitant increase in lesion size 
or number (IR(3))
It is possible that, at a single time point a subject could fulfill criteria for both IR(1 or 2) AND 
IR(3): for example, there could be a new FDG-avid lesion in the absence of overall progression 
(IR(2)), and, at the same time, increase in FDG uptake of a separate lesion (IR(3)). In such cases, 
the designation of IR(1 or 2) should take priority (eg, IR(2)
Follow-up of IR
1) In patients categorized as having any of the above types of IR, it is mandatory to obtain a repeat 
imaging after an additional 12 weeks (or earlier if clinically indicated). At that time, response 
should be re-evaluated and the patient should be considered to have true PD if the SPD of 
target lesion has increased further, with the considerations below:
2) In the case of IR(1), the comparison should be between the first IR(1) and the current SPD, 
with an increase of >10% constituting PD. In addition there should be an increase of > 5 mm 
(in either dimension) of at least one lesion for lesions < 2 cm, and 10 mm for lesions > 2 cm, 
to be consistent with the Lugano classification (3)(Table 2). The 10% threshold is empiric but 
designed to account for variability in measurement (37), especially when taken along with the 
minimum increase. If the target SPD increase is < 10%, the response would still be categorized 
as IR(1), and the patient could continue treatment until a subsequent scan shows either true PD 
(> 10% increase from first IR(1) time point and an increase of > 5mm in either dimension of 
at least one lesion) or response (>50% decrease from baseline). In this situation, it is reasonable 
to repeat imaging in 4-8 weeks of the original IR(1) timepoint to ensure absence of significant 
further increase.
3) In the case of IR(2), the new or growing lesion(s) (unless biopsy proven to be benign) should 
be added to the target lesion(s), up to a total of no more than 6 total lesions. If the SPD of the 
newly defined set of target lesions has increased > 50% from the nadir value which may 
precede the IR time point. The patients is considered to have PD.
4) In the case of IR(3), since inflammatory responses may result in an increase in the standardized 
uptake value of a lesion, the patient will not be considered to have PD unless there is evidence 
of PD by an increase in lesion size or the development of new lesions, as noted above
5) Importantly, if a patient is assessed as having IR and then “true” PD at a subsequent time point 
(without an intervening objective response between IR and PD), the IR assessment should 
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subsequently be corrected to PD for reporting purposes to the date of the prior designation of 
IR
*Lymphoma Response to Immunomodulatory therapy Criteria (LYRIC) (Appendix 2) will be 
applied as clinically applicable
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APPENDIX 5
ACUTE GVHD GRADING AND STAGING
Table 9:
Extent of Organ Involvement
Stage
Skin
Liver
Gut
1
Rash on < 25% of skina
Bilirubin 2 - 3 mg/dLb
Diarrhea > 500 mL/dayc or 
persistent nausead
2 
Rash on 25 - 50% of skin 
Bilirubin 3 - 6 mg/dL 
Diarrhea > 1000 mL/day 
3 
Rash on > 50% of skin 
Bilirubin 6 - 15 mg/dL 
Diarrhea > 1500 mL/day 
4 
Generalized erythroderma with 
bullous formation 
Bilirubin >15 mg/dL 
Severe abdominal pain with or 
without ileus 
Gradee
I 
Stage 1 - 2 
None 
None 
II 
Stage 3 or 
Stage 1 or 
Stage 1 
III 
--
Stage 2 - 3 or 
Stages 2 - 4 
IVf
Stage 4 
Stage 4 
--
a Use burn chart to determine extent of rash.
b Range given as total bilirubin. Downgrade one stage if an additional cause of elevated bilirubin has been 
documented.
c Volume of diarrhea applies to adults. For pediatric patients, the volume of diarrhea should be based on body surface 
area. Downgrade one stage if an additional cause of diarrhea has been documented.
d Persistent nausea with histologic evidence of GVHD in the stomach or duodenum.
e Criteria for grading given as minimum degree of organ involvement required to confer that grade.
f Grade IV may also include lesser organ involvement with an extreme decrease in performance status.
Table 10:
Percent Body Surfaces
Body Area
Percent
Total Percentage
Each Arm 
9%
18%
Each Leg 
18%
36%
Chest & Abdomen 
18%
18%
Back 
18%
18%
Head 
9%
9%
Pubis 
1%
1%
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Stage of Chronic GVHD
Limited: Localized skin involvement resembling localized scleroderma with or without liver 
involvement; no other organ involvement.
Extensive: Generalized skin and/or multiple organ involvement.
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APPENDIX 6
MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS
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SAP_001.pdf: 
Statistical Analysis Plan for 
 
Official Title of Study 
A PHASE I/ II STUDY TO EVALUATE THE SAFETY AND PRELIMINARY EFFICACY 
OF NIVOLUMAB IN COMBINATION WITH BRENTUXIMAB VEDOTIN IN SUBJECTS 
WITH RELAPSED REFRACTORY NON HODGKIN LYMPHOMAS WITH CD30 
EXPRESSION CHECKMATE 436: CHECKPOINT PATHWAY AND NIVOLUMAB 
CLINICAL TRIAL EVALUATION 
NCT02581631 
 
08-March-2017 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A PHASE I/ II STUDY TO EVALUATE THE SAFETY AND PRELIMINARY EFFICACY 
OF NIVOLUMAB IN COMBINATION WITH BRENTUXIMAB VEDOTIN IN SUBJECTS 
WITH RELAPSED REFRACTORY NON HODGKIN LYMPHOMAS WITH CD30 
EXPRESSION CHECKMATE 436: CHECKPOINT PATHWAY AND NIVOLUMAB 
CLINICAL TRIAL EVALUATION
PROTOCOL CA209436
VERSION # 1.0
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................5
LIST OF FIGURES ....................................................................................................................5
2
STUDY DESCRIPTION ..........................................................................................7
2.1
Study Design ............................................................................................................7
2.2
Treatment Assignment..............................................................................................9
2.3
Blinding and Unblinding.........................................................................................10
2.4
Protocol Amendments.............................................................................................10
2.5
Data Monitoring Committee ...................................................................................10
3
OBJECTIVES ........................................................................................................10
3.1
Primary...................................................................................................................10
3.2
Secondary...............................................................................................................10
4
ENDPOINTS..........................................................................................................11
4.1
Primary Endpoints..................................................................................................11
4.2
Secondary Endpoints ..............................................................................................11
5
SAMPLE SIZE AND POWER...............................................................................14
5.1
Sample Size Determination.....................................................................................14
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................15
6.1
Study Periods..........................................................................................................15
6.2
Treatment Regimens...............................................................................................15
6.3
Populations for Analyses ........................................................................................15
7
STATISTICAL ANALYSES..................................................................................16
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7.1
General Methods ....................................................................................................16
7.2
Study Conduct........................................................................................................17
7.2.1
Accrual...................................................................................................................17
7.2.2
Relevant Protocol Deviations..................................................................................17
7.3
Study Population ....................................................................................................17
7.3.1
Subject Disposition.................................................................................................17
7.3.2
Demographics and Other Baseline Characteristics.................................................18
7.3.3
Medical History......................................................................................................19
7.3.4
Prior Therapy.........................................................................................................19
7.3.5
Baseline Examinations............................................................................................20
7.4
Extent of Exposure .................................................................................................20
7.4.1
Administration of Study Therapy.............................................................................20
7.4.2
Modifications of Study Therapy ..............................................................................21
7.4.2.1
Dose Delays ...........................................................................................................21
7.4.2.2
Infusion Interruptions and Rate Changes:...............................................................21
7.4.2.3
Discontinuation of Study Therapy...........................................................................21
7.5
Efficacy Analyses...................................................................................................22
7.5.1
Primary Efficacy Endpoint......................................................................................22
7.5.2
Secondary Efficacy Endpoints.................................................................................22
7.5.3
Other Efficacy Analyses..........................................................................................23
7.5.3.1
Efficacy for Subjects Treated Beyond Progression and Subjects with 
Indeterminate Response..........................................................................................24
7.6
Safety Analyses ......................................................................................................24
7.6.1
Dose Limiting Toxicities.........................................................................................24
7.6.2
Deaths ....................................................................................................................24
7.6.3
Serious Adverse Events...........................................................................................24
7.6.4
Adverse Events Leading to Discontinuation of Study Therapy.................................25
7.6.5
Adverse Events Leading to Dose Delay of Study Therapy........................................25
7.6.6
Adverse Events .......................................................................................................25
7.6.7
Adverse Events by Subgroups .................................................................................25
7.6.8
Multiple Events.......................................................................................................25
7.6.9
Adverse Events of Special Interest ..........................................................................25
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7.6.9.1
Transplant ..............................................................................................................25
7.6.10
Clinical Laboratory Evaluations.............................................................................25
7.6.10.1
Hematology ............................................................................................................25
7.6.10.2
Serum Chemistry ....................................................................................................25
7.6.11
Vital Signs and Pulse Oximetry...............................................................................26
7.6.13
Pregnancy ..............................................................................................................26
7.6.14
Clinical Safety Program (CSP)...............................................................................26
 
7.10
Interim Analyses.....................................................................................................28
8
CONVENTIONS....................................................................................................29
9
CONTENT OF REPORTS .....................................................................................30
10
DOCUMENT HISTORY........................................................................................30
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LIST OF TABLES
Table 4.2-1:
Censoring Scheme for PFS.....................................................................12
Table 5.1-1:
Two-sided 80% Exact CI for different number of subjects in each 
cohort.....................................................................................................15
Table 7.4.1 -1:
Administration of Study Therapy: Definition of Parameters....................20
Table 10-1:
Document History ..................................................................................30
LIST OF FIGURES
Figure 2.1-1:
Study Design Schematic...........................................................................9
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2
STUDY DESCRIPTION
2.1
Study Design
This is an open-label, multicenter phase I/II study of nivolumab in combination with brentuximab 
vedotin designed to evaluate the safety and efficacy in subjects with NHL subtype of DLBCL, 
PTCL (excluding ALCL), PMBL, MGZL and CTCL(MF/SS). 
The study will consist of three phases: Screening, Treatment and Follow-up. The treatment phase 
is divided in two parts: Cohort A consists of the Dose Evaluation Phase and Cohort B is the 
Expansion Phase. 
It is anticipated that 170 subjects will be enrolled in the United States, Canada and Europe for the 
entire study (Cohort A and Cohort B combined). All subjects will undergo a screening period to 
determine eligibility within 28 days prior to initial dosing.
Dose Evaluation Phase (Cohort A)
The Dose Evaluation Phase (Cohort A) will include a dose limiting toxicity (DLT) evaluation for 
the dose level of brentuximab vedotin 1.8mg/kg intravenously in combination with nivolumab 
240mg flat dose intravenously in a q 3 week cycle. 
In cycle 1, brentuximab vedotin 1.8mg/kg will be administered on day 1 where as nivolumab 
240mg flat dose will be administered on day 8. Subsequent to cycle 1, both drugs will be 
administered on the first day of the new cycle. Brentuximab vedotin will be administered first as 
a 30-minute infusion followed by a minimum 30-minute rest. Nivolumab will then be administered 
also as a 30-minute infusion.
The DLT evaluation period, which consists of the first dose of study drug through the first 6 weeks 
of treatment, will be conducted in the first 6 treated subjects (all comers). Decisions to enroll up 
to 6 additional subjects onto the same dose of brentuximab vedotin 1.8mg/kg in combination with 
nivolumab 240mg flat dose intravenously every 3 weeks or at a reduced dose of brentuximab 
vedotin at 1.2mg/kg will be based on the safety data reviewed throughout the DLT evaluation 
period. After 6 DLT-evaluable subjects have been followed through the first 6 weeks of treatment, 
or at the point that 2 or more subjects experience a DLT, whichever comes first, the study team 
will review the available data and provide recommendations.
Expansion Phase (Cohort B)
The Expansion Phase will assess the combination of nivolumab and brentuximab vedotin and will 
consist of a single-arm phase II study which will expand enrollment at the recommended dose 
level and treatment schedule as deemed safe by the study team in Cohort A. An additional 
40 subjects in DLBCL (cohort B1), 30 subjects in PTCL (cohort B2), 20 subjects in CTCL (cohort 
B3) 30 subjects in PMBL (cohort B4) and 10 subjects in MGZL (cohort B5) will be enrolled to 
complete this evaluation.
All subjects in Cohort A and Cohort B will be allowed to be treated until disease progression or 
unacceptable toxicity as described in Protocol Section 4.5.3 and Section 4.5.5. If during therapy it 
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appears that a subject is benefiting from the combination but experiencing toxicities related to one 
agent that would require permanent treatment discontinuation, then they have the option to 
continue therapy with the single agent not attributing to toxicities.
Subjects that present progressive disease during treatment may be allowed to be treated beyond 
progression until further progression is observed.
Once subjects discontinue from study treatment for any reason, subjects will enter the follow-up 
phase of the study.
The study design schematic is presented in Figure 2.1-1
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Figure 2.1-1:
Study Design Schematic
2.2
Treatment Assignment
After the subject’s initial eligibility is established and informed consent has been obtained, the 
subject must be enrolled into the study by calling an IVRS to obtain the subject number. Every 
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subject that signs the informed consent form must be assigned a subject number in IVRS. Specific 
instructions for using IVRS will be provided to the investigational site in a separate document. 
2.3
Blinding and Unblinding
Not applicable. This is an open-label study.
2.4
Protocol Amendments
Amendments 01, 02 and 03 are site specific.
This SAP is based on the Revised Protocol 01 dated 14-Sep-2016. It incorporates Amendment 04. 
This amendment allowed additional cohorts of subjects with relapsed PMBL & MGZL to 
participate in the expansion cohort. Additionally, the amendment also defined Indeterminate 
response (IR) criteria and described changes in the biomarker section. Minor clarification in the
inclusion, exclusion criteria and clarification of dose adjustment for brentuximab vedotin for grade 
3 neurological toxicity have also been made.
The SAP will be updated in the future if any amendment to the protocol is made that has impact 
on the analyses.
2.5
Data Monitoring Committee
Not applicable.
3
OBJECTIVES
3.1
Primary
To evaluate the safety and tolerability of the combination of nivolumab and brentuximab in 
subjects with the diagnosis of relapsed, refractory DLBCL, PTCL (all subtypes excluding ALCL) 
and PMBL, MGZL and CTCL(MF/SS) 
To assess the clinical benefit of nivolumab and brentuximab vedotin combination regimen in 
subjects with the diagnosis of relapsed/refractory DLBCL, relapsed/refractory PTCL (excluding 
ALCL), relapsed/refractory PMBL, relapsed/refractory MGZL and relapsed/refractory CTCL 
(MF/SS) (CD30 expression ≥1% by IHC is a prerequisite for all subjects participating in this 
study), as measured by ORR, defined as the proportion of subjects achieving either a PR or CR. 
3.2
Secondary
•
To assess overall duration of response (DOR) of the brentuximab vedotin and nivolumab 
combination regimen based on investigators assessments
•
To assess the complete response rate (CRR) with the combination regimen and the duration of 
CR based on investigators assessments. 
•
To assess PFS based on investigator assessment and OS of the brentuximab vedotin and 
nivolumab combination regimen.
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4
ENDPOINTS
4.1
Primary Endpoints
The primary safety endpoints include DLT, incidence of deaths, adverse events, serious adverse 
events, adverse events leading to discontinuation, adverse events leading to dose delay, drug-
related adverse events and specific laboratory abnormalities (worst grade). Toxicities will be 
graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.
The primary efficacy endpoint is ORR. It is defined as the number of subjects with a best overall 
response (BOR) of CR or PR divided by the number of treated subjects. The BOR is defined as 
the best response designation recorded between the date of first dose and the date of initial 
objectively documented progression or the date of subsequent therapy, whichever occurs first. 
Allogeneic SCT and ASCT will be considered as subsequent therapy. In subjects with relapsed 
refractory DLBCL, relapsed refractory PMBL, relapsed refractory MGZL and relapsed refractory 
PTCL the response (CR, PR, SD and progression) will be assessed according to Lugano 
Classification 2014. A CR must have been confirmed by scans, including a negative Positron 
Emission Tomography (PET) to be considered for CR in subjects with PTCL, PMBL, MGZL and 
DLBCL. For subjects with relapsed refractory CTCL, response will be assessed according to 
consensus Global Response Score as per the consensus statement of the International Society for 
Cutaneous Lymphoma. 
4.2
Secondary Endpoints
The secondary endpoints are DOR, CR rate, duration of CR, PFS and OS. All these endpoints are 
based on Lugano classification 2014 and Global Response score for the CTCL subjects. 
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DOR will be calculated from the date of initial documentation of a response (CR, or PR) to the 
date of first documented evidence of progressive disease (or relapse for subjects who experience 
CR during the study) or death due to any cause, whichever occurs first. Subjects who are 
progression-free and alive or have unknown status will be censored at the last tumor assessment. 
For subjects who received subsequent therapy prior to documented progression, duration of 
response will be censored on the last tumor assessment date prior to or on subsequent therapy.
Allogeneic SCT and ASCT will be considered as subsequent therapy.
The CR rate is defined as the number of subjects with a BOR of CR divided by the number of 
treated subjects. The duration of CR will only be evaluated in subjects with BOR of CR and is 
defined as the time from first documentation of CR to the date of relapse or death due to any cause, 
whichever occurs first. Censoring will be applied as per DOR definition.
PFS is defined as the time from the date of first dose of study drug until the date of first documented 
evidence of progressive disease (or relapse for subjects who experience CR during the study) or 
death due to any cause, whichever comes first. Subjects who are progression-free and alive or have 
unknown status will be censored at the last tumor assessment. Subjects who did not have any on-
study tumor assessments and did not die will be censored on the date of first treatment. For subjects 
who received subsequent therapy prior to documented progression, it will be censored on the last 
tumor assessment date prior to or on subsequent therapy.
Table 4.2-1:
Censoring Scheme for PFS
Situation
Date of Progression or Censoring
Outcome
No baseline tumor assessments 
First dose date
Censored
No on study tumor assessments and no 
death 
First dose date
Censored
New anticancer treatment started 
without a prior reported progression or 
death 
Date of last evaluable tumor assessment prior to 
or on the date of initiation of the subsequent 
anti-cancer therapy
Censored 
Progression documented at scheduled or 
unscheduled visit and no new anticancer 
treatment started before
Date of the first documented tumor progression
Progressed
Subject progression free and no new 
anticancer treatment started 
Date of last tumor assessment
Censored
Death without prior progression and no 
new anticancer treatment started
Date of death
Progressed
OS is defined as the time from the date of first dose of study drug until the date of death (any 
reason). If the subject is alive or the vital status is unknown, the subject will be censored at the 
date the subject was last known to be alive.
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5
SAMPLE SIZE AND POWER
5.1
Sample Size Determination
•
In the Dose Evaluation Phase (Cohort A), 6 -12 subjects will be treated. The number of subjects 
is not based on statistical power considerations. If one or less (<=1) of 6 subjects experience a 
DLT, the upper limit of the 80% 1-sided exact confidence interval for the true DLT rate will 
not be greater than 42%. If 3 or less (≤3) of 12 subjects experience a DLT, the upper limit of 
the 1-sided 80% exact confidence interval (CI) for the true DLT rate will not be greater than 
41.2%. 
•
In the Expansion Phase (Cohort B), A total of 130 subjects will be treated, with 40 subjects in 
cohort B1 (DLBCL), 30 subjects in cohort B2 (PTCL) and 20 subjects in B3 (CTCL), 
30 subjects in cohort B4 (PMBL) and 10 subjects in cohort B5 (MGZL).
−
Given 40 subjects in DLBCL, the two-sided 80% confidence interval for the ORR is 48.6% 
- 70.6% if we assume an observed ORR rate of 60%. The lower bound of CI excludes 40%, 
which is the null hypothesis ORR rate for PTCL. 
−
Given 30 subjects in PTCL, the two-sided 80% confidence interval for the ORR is 46.7% 
- 72.3% if we assume an observed ORR rate of 60%. The lower bound of the  CI excludes 
40%, which is the null hypothesis ORR rate for PTCL. 
−
Given 20 subjects in CTCL, the two-sided 80% confidence interval for ORR is 63.9% -
91.0% if we assume an observed ORR rate of 80%. The lower bound of the CI excludes 
60%, which is the null hypothesis ORR rate for CTCL. 
−
Given 30 subjects in PMBL, the two-sided 80% confidence interval for the ORR is 37.0% 
- 63.0% if we assume an observed ORR rate of 50%. The lower bound of the CI excludes 
30%, which is the null hypothesis ORR rate for PMBL. 
−
Given 10 subjects in MGZL, the two-sided 80% confidence interval for the ORR is 11.6% 
- 55.2% if we assume an observed ORR rate of 30%. The lower bound of the CI excludes 
10%, which is the null hypothesis ORR rate for MGZL.
Table 5.1-1 summarizes the 80% exact CI for different targeted ORRs and sample sizes. 
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Table 5.1-1:
Two-sided 80% Exact CI for different number 
of subjects in each cohort
If the observed ORR rate is 60% in Cohort B1 and B2
N=30
[46.7% - 72.3%] 
N=40
[48.6% - 70.6%]
If the observed ORR rate is 80% in Cohort B3
N=20
[63.9% - 91.0%]
If the observed ORR rate is 50% in Cohort B4
N=30
[37.0% - 63.0%]
If the observed ORR rate is 30% in Cohort B5
N=10
[11.6% - 55.2%]
If the screening failure rate is 20%, we would need to enroll 170 subjects to have 136 patients 
treated (130 in Cohort B, 6 in Cohort A). If Cohort A needs 6-12 more treated subjects, we would 
need to enroll 8-15 more subjects accordingly.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
See Core Safety SAP.
6.2
Treatment Regimens
Subjects will receive brentuximab vedotin (BV) 1.8mg/kg and nivolumab 240mg flat dose or BV
1.2mg/kg and nivolumab 240mg flat dose. 
6.3
Populations for Analyses
•
All Enrolled Subjects: All subjects who signed an informed consent form and were registered 
into the IVRS. 
•
All Treated Subjects: All subjects who received at least one dose of any of the study drugs. 
This is the primary population for safety and efficacy analyses. This dataset will be used for 
baseline demographics and efficacy and safety analyses.
•
Response Evaluable Subjects: Treated subjects whose tumor measurements (PET CT or 
CT/MRI) were made at baseline and at least one on-study tumor assessment.
 
 
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7
STATISTICAL ANALYSES
7.1
General Methods
All analyses will be performed on the all treated subjects and will be conducted separately for the 
NHL subtype groups (DLBCL, CTCL, PTCL, PMBL, MGZL). 
As there was only one dose explored in the dose evaluation cohort A (brentuximab vedotin 
1.8mg/kg and nivolumab 240mg) subjects from cohort A (dose evaluation) and cohort B (dose 
expansion) will be combined for all analyses, unless otherwise noted. A couple of safety analysis 
will be conducted on the cohort A subjects only to support the dose evaluation process (see 
Section 7.6.1). 
The bulleted titles in the following subsections describe tabulations of discrete variables, by the 
frequency and proportion of subjects falling into each category, grouped by cohort. Percentages 
given in these tables will be rounded and, therefore, may not always sum to 100%. Continuous
variables will be summarized by cohort using the mean, standard deviation, median, minimum and 
maximum values.
Time to event distribution (i.e. progression free survival, overall survival and duration of response) 
will be estimated using Kaplan Meier techniques. 
Median survival time along with 95% CI will be constructed based on a log-log transformed CI 
for the survivor function S(t)4,5. Rates at fixed timepoints will be derived from the Kaplan Meier 
estimate and corresponding confidence interval will be derived based on Greenwood formula6 for 
variance derivation and on log-log transformation applied on the survivor function S(t)7.
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7.2
Study Conduct
7.2.1
Accrual
The accrual pattern will be summarized per country, investigational site and per month for all 
enrolled subjects. First dosing date, country, investigational site will be presented in a by subject 
listing of accrual.
7.2.2
Relevant Protocol Deviations
The relevant Protocol Deviations will be summarized for all treated subjects. A subject listing will 
also be produced. Relevant deviation implies a potential major impact on the interpretability of the 
main results of the study. Criteria for relevant deviations are listed below:
At entrance:
•
Wrong diagnosis based on Exclusion/inclusion
•
Do not have Measurable disease at baseline (not appliacable to CTCL)
 
 
 
On-study: 
Use of the following prohibited medications during the study (unless utilized to treat a drug related 
adverse event):
•
Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents)
7.3
Study Population
7.3.1
Subject Disposition
The total number of subjects enrolled (treated or not treated) will be presented along with the
reason for not being treated.
Number of subjects who discontinued study treatment along with corresponding reason will be 
tabulated.
A subject listing for all treated subjects will be provided showing the subject’s first and last dosing 
date, off study date and reason for going off-study. A subject listing for subjects not treated will 
also be provided, showing the subject’s race, gender, age, consent date and reason for not being 
treated.
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7.3.2
Demographics and Other Baseline Characteristics
The following demographic and baseline characteristics of patient will be summarized. Listings 
will also be provided.
Baseline demographics:
•
Age (descriptive statistics)
•
Age category (< 65, ≥65 to <75, ≥75 to <85, ≥85)
•
Gender, race, ethnicity
Baseline physical measurements
•
ECOG, height, and  weight
Other baseline characteristics: 
•
smoking status
•
region (US/Canada, Europa and rest of the world)
•
initial disease diagnosis 
−
DLCL: DLCL or transformed lyphoma,
−
CTCL: Mycosis Fungoides (MF), Sezary Syndrome (SS)
−
PTCL: Angioimmunoblastic T Cell Lymphoma, Peripheral T Cell Lymphoma-NOS, 
Peripheral T Cell Lymphoma-Other
•
stage of disease at initial diagnosis
•
Disease status at study entry(relapsed, refractory or relapsed and refractory).
•
Some disease characteristics will be reported depending on the NHL subtype:
DLBCL: 
•
international prognostic index (IPI) score at diagnosis,
•
cell type involved at diagnosis and study entry.
CTCL:
•
disease diagnosis at study entry: Mycosis Fungoides (MF), Sezary Syndrome (SS), other. 
PTCL: no specific characteristics
PMBL: no specific characteristics
MGZL: no specific characteristics
•
Time from Initial Disease Diagnosis to 
(< 1 year, 1 - < 2 year, 2 - < 3 year, 
3 - < 4 year, 4 - < 5 year, ≥ 5 year)
•
Lymphoma PET scan (yes/no), Lugano classification 5 point scale Lesion sites, Max SUV
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•
All lesions (Investigator Tumor Assessments at Baseline): sites of diseases, number of disease 
sites per subject
•
Target Lesions (Investigator Tumor Assessments at Baseline): Presence of target lesions, site 
of target lesion, sum of product diameters of target lesions.
•
Lymphoma involvement in bone marrow at baseline (Yes/No/Not Available)
•
baseline efficacy assessement for CTCL: % BSA involvement, blood involved by peripheral 
blood cytometry, lymph node involved and tumor involved
7.3.3
Medical History
General medical history will be listed by subject and pretreatment events will be tabulated. 
7.3.4
Prior Therapy 
The following will be summarized:
•
Number of subjects by type of prior therapy received (excluding preparative regimen for 
ASCT): 
−
Immunotherapy by Monoclonal Antibodies
−
Steroid
−
Chemotherapy – Anthracyclines
−
Chemotherapy – Other than Anthracyclines
−
Kinase Inhibitors
−
Immunomodulary Derivatives
−
Radioimmunotherapy
−
Other
•
Number of prior systemic regimen received (0, 1, 2, 3, ≥ 4), excluding preparative regimen for 
ASCT subjects 
•
Number of subjects per type of regimen for first and second lines of therapy (e.g. R-CHOP, 
ICE).For CTCL number of subjects per type of regimen by line of therapy where the 
combination of drugs within a regimen will be the concatenation of drugs by alphabetical order 
(e.g. gemcitabine)
•
Number of subjects with prior ASCT and type of regimen received for preparation to ASCT 
(e.g. Carmustine / Cytarabine / Etoposide / Mephalan) and number of subjects ASCT 
ineligible.
•
Best response to most recent prior regimen (CR vs. PR vs. SD vs. Relapse/PD vs. Unable to 
Determine vs. Not reported) 
•
Prior radiotherapy (yes or no)
•
Prior surgery (yes or no)
By subjects will also list the systemic therapy, details about ASCT and details about surgery and 
radiotherapy.
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7.3.5
Baseline Examinations
Percentage of subjects with abnormal baseline physical examination will be tabulated by 
examination criteria. A by-subject listing will also be provided.
7.4
Extent of Exposure
Analyses in this section will be performed on all treated subjects.
7.4.1
Administration of Study Therapy
The following parameters will be summarized (descriptive statistics) for each drug separately:
•
Number of doses received 
•
Cumulative dose 
•
relative dose intensity
•
Duration of treatment: duration of treatment will be presented using a Kaplan-Meier curve 
whereby the last dose date will be the event date for subjects who discontinued study therapy. 
Subjects who are still on study therapy will be censored on their last dose date. Median duration 
of treatment and associated 95% CI will be provided.
A by-subject listing of dosing of study medication (record of study medication, infusion details, 
dose change) and a listing of batch number will be also provided.
Below table summarizes the key parameters used to calculate dosing data.
Table 7.4.1 -1:
Administration of Study Therapy: Definition of Parameters
Nivolumab
Brentuximub Vedotin
Dosing schedule 
per protocol
Day 1, 240mg every 3 weeks (except cycle 1
C1D8)
1.8mg/kg (or 1.2mg/kg) every 3 weeks
Dose
Dose is defined as total dose administered.
Dose administered in mg at each dosing date 
are collected on the CRF.
Dose (mg/kg) is defined as total dose 
administered (mg)/most recent weight. Dose 
administered in mg at each dosing date and 
most recent weight are collected on the 
CRF.
Cumulative Dose
Cum dose (mg) is sum of the doses (mg) 
administered to a subject during the 
treatment period.
Cum dose (mg/kg) is sum of the doses 
(mg/kg) administered to a subject during the 
treatment period.
Duration of 
treatment  
Last dose date - Start dose date + 1
Last dose date - Start dose date + 1
Relative Dose 
intensity
If only one dose of nivolumab
Cum dose (mg)/[(Last dose date of 
nivolumab - Start dose date of nivolumab + 
14) x 240 /14] x 100
Cum dose (mg/kg)/[(Last dose date of BV -
Start dose date of BV + 21) x 1.8 /21] x 100
or 
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Table 7.4.1 -1:
Administration of Study Therapy: Definition of Parameters
Nivolumab
Brentuximub Vedotin
If more than 1 dose of nivolumab
[Cum dose (mg) / (Last dose date of 
nivolumab - Start dose date of nivolumab + 
21)] x [(14+(number of nivolumab doses-1)
* 21 / 240 * number of nivolumab doses] x 
100
7.4.2
Modifications of Study Therapy
There will be no dose escalations or reductions of nivolumab allowed. Brentuximab Vedotin may 
reduce dose to 1.2mg/kg. Brentuximab. Dose reduction as reported by the investigator will be 
summarized along with reason for reduction.
7.4.2.1
Dose Delays
Treatment may be delayed for up to a maximum of 6 weeks from the last dose. If one of the study 
drug is delayed for any reason the other drug must also be delayed. A dose will be considered as 
actually delayed if the delay is exceeding 3 days as of cycle 2 onwards (i.e., greater than or equal 
to 4 days from scheduled dosing date). Length of delay is defined as (duration of previous cycle 
in days - 21). Dose delays will be divided into following categories: 4 - < 8 days, 8 - < 15 days, 
15 - < 42, ≥ 42 days. Reason for dose delay will be retrieved from CRF dosing pages.
The following parameters will be summarized by drug:
•
Number of subjects with at least one dose delayed, number of dose delayed per subject, Length 
of Delay and Reason for Dose Delay
7.4.2.2
Infusion Interruptions and Rate Changes:
Each nivolumab or brentuximab vedotin infusion can be interrupted and/or the IV infusion rate 
can be reduced. This information will be retrieved from CRF. The following parameters will be 
summarized for each drug:
•
Number of subject with at least one dose infusion interrupted, number of infusions interrupted 
per subject and reason for the interruptions.
•
Number of subject with at least one IV infusion rate reduction, number of IV infusion rate 
reduction per subject and reason for the interruptions.
7.4.2.3
Discontinuation of Study Therapy
The number and percentage of subjects who have discontinued all study drugs and reason for 
discontinuation will be summarized by treatment group and overall using the subject status eCRF 
page from end of treatment. 
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In addition, subjects who discontinued one drug, while continuing treatment with the other study 
drug, will be summarized based on the dose modification CRF. The reason for discontinuing a 
specific drug from the combination will also be summarized. 
 
 
 
 
7.5
Efficacy Analyses
7.5.1
Primary Efficacy Endpoint
The primary endpoint ORR will be summarized for all treated subjects by binomial response rate 
and its corresponding two-sided 80% exact CIs using the Clopper-Pearson method.
BOR categories will be tabulated. 
7.5.2
Secondary Efficacy Endpoints
The CR will be analyzed using the same statistical method as ORR.
The DOR will be summarized for subjects who achieve PR or CR using the Kaplan-Meier (KM) 
product-limit method. Median values of DOR, along with two-sided 95% CI using log-log 
transformation method. Range of DOR will also be calculated. The same analysis will be 
performed for duration of CR.
The time to response (TTR), time from the first dose to the first response date will also be 
summarized. Note that TTR was not listed as a secondary endpoint in the protocol.
PFS will be summarized descriptively using the Kaplan-Meier (KM) product-limit method. KM 
curve of PFS will be generated. Median values of PFS, along with two-sided 95% CIs (based on 
the log-log transformation), will be calculated. PFS rates at 6 and 12 months (and two-sided 95% 
CIs) may be reported in function of the the minimum follow-up at time of analyses. Subject listings 
of PFS will be produced.
The source of progression (death vs. progression) will be summarized. The status of subjects who 
are censored in the PFS Kaplan-Meier analysis will be tabulated using following categories:
•
Received subsequent anti-cancer therapy 
•
Still on-treatment
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•
Progression-free in follow-up
•
Off-study: (lost to follow-up, withdrew consent, other).
OS will be analyzed using the same statistical method as PFS. Median values of OS, survival rates 
at 6 and 12 months along with two-sided 95% CIs may be reported in function of the minimum 
follow-up at time of analyses. 
The status of subjects who are censored in the OS Kaplan-Meier analysis will be tabulated using
the following categories:
•
On-study (on-treatment and not progressed, on-treatment progressed, in follow-up);
•
Off-study: (lost to follow-up, withdrew consent, etc.).
Subject Follow-up
The extent of follow-up for survival defined as the time between first dose date and last known
date alive (for subjects who are alive) or death date (for subjects who died) will be summarized
descriptively (mean, standard deviation, median, first and third quartiles, minimum, maximum)
for all treated subjects.
Follow-Up Therapy
The following information pertaining to subsequent therapies will be summarized:
•
Systemic therapy by drug name
•
Hematopoietic stem cell transplantation (Allogeneic, Autologous)
•
Surgery
•
Radiotherapy
A subject listing of follow-up therapy will be produced for subjects who had any subsequent
therapy.
 
 
 
 
 
 
 
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7.6
Safety Analyses
Safety analyses will be performed in all treated subjects. Descriptive statistics of safety will be 
presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. All on-study AEs, drug-related, AEs, SAEs and drug-related SAEs 
will be tabulated using worst grade per NCI CTCAE v4.03 criteria by system organ class and 
MedDRA preferred term. On-study lab parameters including hematology, chemistry, liver 
function, thyroid function, and renal function will be summarized using worst grade per NCI 
CTCAE v4.03 criteria. Details are in the Core Safety SAP v3.0.
7.6.1
Dose Limiting Toxicities
The DLT evaluation period, which consists of the first dose of study drug through the first 6 weeks 
of treatment, will be conducted in the first 6 treated subjects. 
DLTs are defined as any study drug-related toxicity (brentuximab vedotin or nivolumab) that 
requires either a dose reduction or delay of more than 7 days of either study drug in Cycle 2 or 
delays the Cycle 3 Day 1 administration of combined treatment by more than 7 days. 
Cohort A subjects who have a related AE that require either discontinuation, dose reduction or 
delay of more than 7 days of either study drug in Cycle 2 or delays the Cycle 3 Day 1 will be 
categorized as experiencing DLT.
•
Number of subjects with dose limiting toxicities will be tabulated (cohort A, all treated 
subjects)
•
A listing will be provided of those subjects containing their reasons for drug discontinuations, 
delay or reduction and total number of courses received (Cohort A, All treated subjects)
7.6.2
Deaths
See Core Safety SAP
7.6.3
Serious Adverse Events
See Core Safety SAP
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7.6.4
Adverse Events Leading to Discontinuation of Study Therapy
See Core Safety SAP
7.6.5
Adverse Events Leading to Dose Delay of Study Therapy
See Core Safety SAP
7.6.6
Adverse Events
See Core Safety SAP
7.6.7
Adverse Events by Subgroups
See Core Safety SAP
7.6.8
Multiple Events
See Core Safety SAP
7.6.9
Adverse Events of Special Interest
See Core Safety SAP
7.6.9.1
Transplant
Number and percentage of subjects by response category (CR, non-CR, unable to determine) will 
be provided at the time of transplant and at the 100 days, 6 months and 1 year timepoints after 
transplant for subjects undergoing subsequent allogeneic SCT and autologous SCT separately. 
Denominators will be based on subjects with assessment available by timepoint.
For subjects undergoing allogeneic SCT, number and percentage of subjects with GVHD will be 
provided at the 100 days, 6 months and 1 year timepoints: chronic limited, chronic extensive, acute 
(grade I, II, III, IV, unknown). Denominators will be based on subjects undergoing allogeneic SCT 
with assessment available by timepoint.
7.6.10
Clinical Laboratory Evaluations
The analysis population for each laboratory test is restricted to treated subjects who underwent that 
laboratory test.
7.6.10.1
Hematology
See Core Safety SAP
7.6.10.2
Serum Chemistry
See Core Safety SAP
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7.6.11
Vital Signs and Pulse Oximetry
See Core Safety SAP
7.6.13
Pregnancy
By-subject listing of pregnancy tests results will be provided 
7.6.14
Clinical Safety Program (CSP)
See Core Safety SAP
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.8.2.2
Evaluation of associations between CD30 at baseline and efficacy 
measures 
Analyses for ORR (BOR):
•
Box plots of CD30 expression versus BOR will be generated for all CD30 evaluable subjects
•
A logistic regression model of ORR (responder, non-responder) will be produced with baseline 
CD30 expression as continuous covariate.
Analyses of PFS and OS:
•
A Cox proportional hazards model of OS will be produced with Baseline CD30 expression as 
continuous variable.
•
A Cox proportional hazards model of PFS will be produced with Baseline CD30 expression as 
continuous variable.
 
 
 
 
 
 
7.10
Interim Analyses
No formal interim analysis is planned. Interim analyses may be conducted if it is necessary in order 
to make decisions regarding further development. Summaries and listings of efficacy and safety 
will be provided. Interim analyses will not impact the study conduct and the trial will continue as 
planned. 
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8
CONVENTIONS
The following conventions may be used for imputing partial dates for analyses requiring dates:
•
For missing and partial adverse event onset dates, imputation will be performed using the 
Adverse Event Domain Requirements Specification9. 
•
Missing and partial Non-Study Medication Domain dates will be imputed using the derivation 
algorithm described in 4.3.3 of BMS Non-Study Medication Domain Requirements 
Specification10.
For death dates, the following conventions will be used for imputing partial dates:
•
If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day. The imputed date will be compared to the last known date alive and the maximum will be 
considered as the death date.
•
If the month or the year is missing, the death date will be imputed as the last known date alive. 
If the date is completely missing but the reason for death is present the death date will be 
imputed as the last known date alive 
For date of progression, the following conventions will be used for imputing partial dates:
•
If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day*.
•
If the day and month are missing or a date is completely missing, it will be considered as 
missing.
•
In case of the date of death is present and complete, the imputed progression date will be 
compared to the date of death. The minimum of the imputed progression date and date of death 
will be considered as the date of progression.
•
For other partial/missing dates, the following conventions may be used:
•
If only the day of the month is missing, the 15th of the month will be used to replace the 
missing day.
•
If both the day and the month are missing, “July 1” will be used to replace the missing 
information.
•
If a date is completely missing, it will be considered as missing.
The following conversion factors will be used to convert days to months or years: 
1 month = 30.4375 days and 1 year = 365.25 days.
Duration (e.g. time from first diagnosis of NSCLC to first dosing date, duration response, and time 
to response) will be calculated as follows:
Duration = (Last date - first date + 1)
All statistical analyses will be carried out using SAS (Statistical Analysis System software, SAS
Institute, North Carolina, USA) unless otherwise noted.
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9
CONTENT OF REPORTS
All analyses describe in this SAP will be included in the final Clinical Study Report. Refer to the 
Data Presentation Plan for mock-ups of all tables and listings. Analyses of the different NHL 
subtype may not be conducted all at the same time depending on accrual in the different group.
10
DOCUMENT HISTORY
Table 10-1:
Document History
Version Number
Author(s)
Description
1.0
Initial version: January 31, 2017 
 
 
 
 
 
 
 
 
 
 
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