An Open Label Phase 2 Multi-cohort Trial of Nivolumab in Advanced or Metastatic Malignancies
Phase: PHASE2
Conditions: Cancer
Sponsor: Bristol-Myers Squibb

Page:
1
Protocol Number:
CA209627
IND Number:
100,052
EUDRACT Number
2016-000461-23
Date:
17-Mar-2016
Revised Date:
31-May-2018
Clinical Protocol CA209627
An Open-label Phase 2 Multi-cohort Trial of Nivolumab in Advanced or Metastatic 
Malignancies
(CheckMate 627: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 627)
Revised Protocol Number: 02
Study Director/Medical Monitor
Ibrahima Soumaoro, MD, MSc
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 
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 
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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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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 02
31-May-2018

Incorporated change as per Administrative Letter 03

Updated Medical Monitor information

Added minor changes to statistical section

Added language that Oncology TA was responsible for the design 
and conduct of the study and decisions regarding the protocol will be 
made with consultation with the Steering Committee

Added language for early stopping considerations
Revised 
Protocol 01
18-Jan-2018

Changed primary end point from Clinical Benefit Rate at week 16 
(CBR16) to Objective Response Rate (ORR). 

Statistical analysis is modified to include a pause rule and 
clarification of final analysis of each bin. 

Adverse Events were updated to include Immune-Mediated Adverse 
Events (IMAEs)

Vital signs were added to follow-up assessments

28 days screening window removed

Adenocarcinoma of the small bowel and Adrenocortical carcinoma 
were added to inclusion criteria

Additional tumor types were added to the exclusion criteria

Treatment duration for 24 months
Original 
Protocol
17-Mar-2016
Not applicable
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & 
Title
Description of Change
Brief Rationale
Section 4.5.1: Dose 
Delay Criteria
The bullet point regarding Grade 3 
lymphopenia was corrected to read 
“Grade 
3 
lymphopenia 
or 
asymptomatic amylase or lipase..”
 
Section 7: Data 
Monitoring 
Committee and other 
External Committees; 
Section 8: Statistical 
Considerations; 
Section 8.1: Sample 
Size Determination; 
Section 8.5: Interim 
Analysis; Section 
8.5.1: Pause Rule; 
Appendix 1 -
Statistical Analysis 
and Modeling, 
Section 3: Trial 
Logistics
Revised the decision rule that 
mandates stopping for early success 
to allow continuing enrollment for 
promising cohorts
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SYNOPSIS
Clinical Protocol CA209627
Protocol Title: An Open-label Phase 2 Multi-cohort Trial of Nivolumab in Advanced or Metastatic Malignancies
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product: 
Nivolumab (BMS-936558) 240 mg IV as a 30 minute infusion every 2 weeks for 8 cycles followed by nivolumab 
480 mg as a 30 minute infusion every 4 weeks beginning at cycle 9 until 24 months, disease progression, 
unacceptable toxicity or withdrawal of consent. 
Study Phase: 2
Research Hypothesis: Nivolumab monotherapy will improve objective tumor response in subjects with advanced 
or metastatic malignancies.
Objectives: 
Primary objective: 
To evaluate the investigator-assessed Objective Response Rate (ORR) of nivolumab monotherapy in advanced or 
metastatic malignancies
Secondary objectives: 

To assess duration of investigator-assessed clinical response (duration of response)

To assess time to response (TTR)

To assess clinical benefit rate (CBR)

To assess overall survival (OS) at one year

To assess safety of nivolumab in malignancies in this study 

To correlate clinical response and OS to programmed death-ligand 1 (PD-L1) expression 

To correlate clinical response and OS to MisMatch Repair (MMR) alterations
 
Study Design: This is an open-label, multicenter, phase 2 study of nivolumab monotherapy in subjects (18 years) 
with advanced or metastatic malignancies not previously evaluated with nivolumab. Enrollment includes up to
350 subjects. Subjects must have received previous standard of care for primary therapy or post primary therapy. 
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Study Design Schematic
a Tumor tissue will be evaluated for sufficient tumor that meet the minimum quality requirements, received by a 
central laboratory before first treatment
b Blood sample will be collected at screening or before first nivolumab administration
c Subjects will be treated until protocol-defined progression, unacceptable toxicity, 24 months of treatment, or 
withdrawal of consent
d Time interval between dose 8 and dose 9 is 2 weeks; time interval between dose 9 and dose 10 is 4 weeks
Study Population: Key Inclusion Criteria

Cohorts are comprised of tumor types which may include but are not limited to the following advanced or 
metastatic malignancies:
1.
Adenocarcinoma of the small bowel 
2.
Adrenocortical carcinoma 
3.
adenoid cystic carcinoma
4.
anal cancer
5.
biliary tract cancer (intrahepatic or extrahepatic cholangiocarcinoma gallbladder cancer, ampullary 
carcinoma)
6.
carcinoid after somatostatin analogs (SSA) (Ki67 less than 20%)
7.
cervix cancer (exocervix, squamous cell pathology)
8.
endometrial cancer (after primary treatment that includes radiation therapy. Subjects with tumors greater 
than 10% estrogen receptor positive pathology in the primary tumor are excluded) 
9.
histiocytoses (including Erdheim Chester disease, Langerhans cell histiocytosis) 
10. insulinoma
11. Lynch syndrome associated cancers (excluding hereditary nonpolyposis colorectal cancer [HNPCC]). 
12. medullary thyroid cancer
13. Merkel cell carcinoma (includes unresectable disease) 
14. nasopharyngeal carcinoma
15. neuroendocrine tumors (poorly differentiated, Ki67 greater than 20%) 
16. neuroendocrine tumors (well to moderately differentiated, Ki67 less than 20%)
17. non-lung small cell carcinoma (including small cell carcinoma of the ovary of pulmonary type or small cell 
ovarian cancer hypercalcemic type)
18. non squamous cell cancer of the head and neck (including cancer of the salivary gland) 
Confirmed 
diagnosis of 
malignancy
Tumor tissue 
and blood 
sample sent 
to central 
laboratory a,b
Nivolumab IV 240 mg
Q2 weeks for 8 doses
Nivolumab IV 480 mg
Q4 weeks until 
progressionc,d
Imaging & 
ORR 
evaluation 
at  Week 28
OS 
evaluation 
at 1 year
Screening
Treatment
Follow-up
OS and 
safety 
evaluation: 
100 days 
after the last 
nivolumab 
dose
Assessments
Imaging 
every 12 
weeks
Imaging at 
Week 8 & 
Week 16
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19. penile cancer
20. rare women's cancers (high grade, clear cell:-greater than 50% clear cell by pathology) 
21. soft-tissue sarcoma (including liposarcoma, leiomyosarcoma) 
22. malignant peripheral nerve sheath tumor-NF-1 
23. testicular cancer (chemotherapy resistant or recurrent within 2 years of primary therapy)
24. thymic carcinoma or invasive thymoma
25. thyroid cancer (anaplastic thyroid cancer as primary therapy)
26. thyroid cancer (papillary or follicular, after failing radioactive iodine [RAI] and after approved kinase 
inhibition [lenvatinib]) 
27. uterine sarcoma (excluding endometrial stroma sarcoma) 
28. vaginal cancer (squamous cell pathology)
29. vulvar cancer (squamous cell pathology)

Other (consult with BMS Medical Monitor before screening subjects in this group - for US only)

Adults 18 years of age

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Pathology report confirming diagnosis of malignancy. Subjects will have advanced or metastatic disease. In the 
case of anaplastic thyroid cancer, subjects may receive nivolumab as part of primary therapy.

Subjects must have measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) 
per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. 

Subjects must have received standard-of-care primary treatment for malignancy and standard-of-care for relapse 
or refractory disease, if treatment exists. For de novo metastatic disease, subjects with recurrent or refractory 
disease after standard-of-care (first-line or second-line [if treatment exists]) will be eligible for this trial. If there 
is no standard-of-care treatment for de novo metastatic disease (eg, metastatic carcinoid), subjects are eligible to 
enroll without prior first-line (or second-line) therapy. 

Mandatory tissue and blood collection for PD-L1 testing and MMR-deficiency testing. Tumor tissue (formalin-
fixed, paraffin embedded archival [< 3 months old] or recent acquisition) must be received by a central 
laboratory before first treatment. In order to receive treatment, the sample must meet the minimum quality 
requirements, as determined by the central laboratory. If the archival tissue is > 3 months old, a fresh biopsy 
will be required to obtain sufficient tissue sample for PD-L1 testing. Archival tissue samples are acceptable for 
MMR testing. A blood sample must be obtained before the first dose of nivolumab. Test results are not required 
for enrollment. (Note: Fine Needle Aspiration [FNA] and bone metastases samples are not acceptable for 
submission.) 
Key Exclusion Criteria

Subjects who require ongoing treatment with more than 10 mg of prednisone (or steroid equivalent, excluding 
inhaled or topical steroids) daily

Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibodies (including 
ipilimumab or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways).

Subjects with the following malignancies are excluded:
1.
adenocarcinoma of the colon
2.
adenocarcinoma of the pancreas 
3.
adenocarcinoma of the prostate 
4.
adenocarcinoma of the rectum
5.
endometrial cancers with greater than 10% estrogen receptor positive pathology in the primary tumor
6.
epithelial ovarian cancer
7.
breast cancer that is ER, PR positive or HER2 positive or triple-negative 
8.
esophageal cancer
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9.
gastric cancer
10. gastrointestinal stromal tumor (GIST)
11. hepatocellular carcinoma
12. Hodgkin's lymphoma
13. leptomeningeal disease
14. leukemia
15. melanoma
16. meningioma (low grade)
17. multiple myeloma
18. myelodysplastic syndrome
19. non-Hodgkin's lymphoma (except primary CNS lymphoma without leptomeningeal disease)
20. non-small cell lung cancer 
21. peritoneal carcinoma
22. primary CNS lymphoma
23. renal cell carcinoma 
24. small cell lung cancer
25. squamous cell carcinoma of the head and neck
26. squamous cell carcinoma of the skin
27. urothelial bladder cancer (urothelial [transitional cell] histology or mixed histologies)
28. carcinoma of unknown primary

Subjects with an active, known, or suspected autoimmune disease (Subjects may enroll with type I diabetes 
mellitus, hypothyroidism [only requiring hormone replacement], vitiligo, psoriasis, or alopecia not requiring 
systemic treatment.)

Subjects with previous malignancies (except non-melanoma skin cancers, and in situ cancers) are excluded 
unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is 
required or anticipated to be required during the study period.
Study Drug: includes Investigational [Medicinal] Products (IP/IMP) as listed:
Study Drug for CA209627
Medication 
Potency 
IP/Non-IP 
Nivolumab
BMS936558-01
40 mg/4 mL and 100 mg/10 mL solution 
in a single-dose vial.
IP
Study Assessments: The primary endpoint of this trial is investigator-assessed ORR of nivolumab monotherapy 
which is based on tumor assessments at baseline and then at 28 weeks from first dose of nivolumab. Clinical benefit 
will be defined. Tumor assessments will occur at week 8, week 16, week 28, and then every 12 weeks until disease 
progression, regardless of any dose delays. Adverse events will be assessed continuously during the study and for 
100 days after last trial dose of nivolumab.
Statistical Considerations:
Sample Size: Up to 350 subjects
Primary Endpoint: ORR analyses will be summarized for each tumor type. 
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Secondary Endpoints:

Duration of the response

TTR

CBR

Overall Survival (OS) at one year

Safety and Tolerability 
 
Analyses:
The final analysis for each group declares success if the Bayesian posterior probability that the treatment effect in 
that group (treatment compared to control) is above 80%.
DOR, TTR, CBR, and overall survival at 1 year will also be provided for each group.
Safety analyses will be performed by tumor group in all treated subjects. Descriptive statistics of safety will be 
presented using NCI CTCAE version 4.0. All AEs, drug-related AEs, SAEs and drug-related SAEs will be tabulated 
using worst grade per NCI CTCAE v4.0 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.
 
 
 
 
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02 ......................... 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
 
 
 
 
 
 
 
 
 
 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
 
 
 
 
 
 
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 ............................................................................... 
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 ........................................................... 
 
 
 
 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post-Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
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3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage of Study Drug ...................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Dose Delay Criteria ................................................................................. 
4.5.2 Criteria to Resume Treatment .................................................................. 
4.5.3 Treatment Discontinuation Criteria ........................................................ 
4.5.4 Nivolumab Treatment Beyond Disease Progression ............................... 
 
4.5.6 Treatment of Nivolumab-Related Infusion Reactions .............................. 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction or Return of Investigational Product ............................................. 
4.9 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 Objective Response Rate (ORR) .............................................................. 
5.4.2 Secondary Efficacy Assessments .............................................................. 
 
 
 
5.7 Retention of Tissue for Additional Research .................................................... 
5.8 Outcomes Research Assessments ..................................................................... 
5.9 Other 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 ............................................................................... 
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8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint..................................................................................... 
8.3.2 Secondary Endpoints ............................................................................... 
8.3.2.1 Duration of Response ...................................................................... 
8.3.2.2 TTR .................................................................................................. 
8.3.2.3 CBR ................................................................................................. 
8.3.2.4 Overall survival .............................................................................. 
8.3.2.5 Safety and Tolerability .................................................................... 
 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.3 Safety Analyses......................................................................................... 
 
 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
8.5.1 Pause Rule ............................................................................................... 
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 .................................................................... 
9.2 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 .................................................................................. 
 
 
APPENDIX 2 ECOG PERFORMANCE STATUS ..................................................... 
 
APPENDIX 4 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) 1.1 .......................................................................................................... 
APPENDIX 5 NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
CLASSIFICATION ................................................................................................ 
APPENDIX 6 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 7 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
 
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1.2
Research Hypothesis 
Nivolumab monotherapy will improve objective tumor response in subjects with advanced or 
metastatic malignancies.
1.3
Objectives(s)
1.3.1
Primary Objectives
To evaluate the investigator-assessed ORR of nivolumab monotherapy in advanced or metastatic 
malignancies
1.3.2
Secondary Objectives

To assess duration of investigator-assessed clinical response (duration of response)

To assess time to response (TTR)
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
To assess clinical benefit rate (CBR)

To assess overall survival (OS) at 1 year

To assess safety of nivolumab in malignancies in this trial

To correlate clinical response and OS to PD-L1 expression 

To correlate clinical response and OS to MMR alterations
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with consensus ethical principles derived from 
international guidelines including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS), International Ethical Guidelines 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) and applicable local 
requirements.
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 Sponsor or designee 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, patient 
emergency cards, advertisements, etc), 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 BMS-
936558 Nivolumab Investigator Brochure or product labeling information to be provided to 
subjects and any updates. 
The investigator, BMS, or designee 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 or designee 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 
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regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:

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. 

Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.

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. 

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.

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.

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, contracted representatives (eg, CRO), 
and regulatory authorities have direct access to subject records. 
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 2 study of nivolumab monotherapy in adult (≥ 18 years) 
subjects with advanced malignancies. Subjects must have received previous standard-of-care 
therapies (for primary therapy or post primary therapy). 
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Figure 3.1-1:
Study Design Schematic
a Tumor tissue will be evaluated for sufficient tumor tissue that meet the minimum quality requirements, received by 
a central laboratory before first treatment. 
b Blood sample will be collected at screening or before first nivolumab administration
c Subjects will be treated until confirmed progression, unacceptable toxicity, or 24 months of treatment (see 
Section 4.5.3)
d Time interval between dose 8 and dose 9 is 2 weeks; time interval between dose 9 and dose 10 is 4 weeks
Enrollment of up to 350 subjects is expected to require approximately 24 months. Interim 
monitoring and final analyses are planned. Subjects will receive study drug for the 
maximum treatment duration of 24 months. 
The start of the trial is defined as first visit for first subject screened. End of trial is defined as the 
last scheduled procedure shown in the Time & Events Schedule for the last subject. Study 
completion is defined as the final date on which data for the primary endpoint was or is expected 
to be collected, if this is not the same.
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 for the maximum treatment duration specified in 
protocol Section 3.1. Study drug 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.
Confirmed 
diagnosis of 
malignancy
Tumor tissue 
and blood 
sample sent 
to central 
laboratory a,b
Nivolumab IV 240 mg
Q2 weeks for 8 doses
Nivolumab IV 480 mg
Q4 weeks until 
progressionc,d
Imaging & 
ORR 
evaluation 
at  Week 28
OS 
evaluation 
at 1 year
Screening
Treatment
Follow-up
OS and 
safety 
evaluation: 
100 days 
after the last 
nivolumab 
dose
Assessments
Imaging 
every 12 
weeks
Imaging at 
Week 8 & 
Week 16
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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 to comply with scheduled visits, treatment schedule, laboratory 
tests, mandatory collection of archival or fresh tumor tissue (primary or metastatic) 
specimens, blood, and other requirements of the study. Mandatory tissue and blood 
collection is required for PD-L1 testing and for MMR deficiency testing. Tumor tissue 
(formalin-fixed, paraffin embedded archival or recent acquisition [< 3 months old]) must 
be received by a central laboratory before first treatment. If the archival tissue is > 3 
months old, a fresh biopsy will be required, to obtain sufficient tissue sample for PD-L1 
testing. Archival tissue samples are acceptable for MMR testing. In order to receive 
treatment, the sample must meet the minimum quality requirements, as determined by the 
central laboratory. A blood sample must be obtained before the first dose of nivolumab. 
Test results are not required for enrollment. (Note: Fine Needle Aspiration (FNA) and 
bone metastases samples are not acceptable for submission
c) Subject Re-enrollment: This trial permits the re-enrollment of a subject that has 
discontinued the study as a screening failure (the subject will not have received 
nivolumab). If re-enrolled, the subject must be re-consented.
2. Target Population
a) Subjects with pathologically confirmed locally advanced or metastatic disease. In the 
case of anaplastic thyroid cancer, subjects may receive nivolumab as part of primary 
therapy. Advanced or metastatic tumor types may include, but are not limited to the 
following:

Adenocarcinoma of the small bowel

Adrenocortical carcinoma

adenoid cystic carcinoma

anal cancer

biliary tract cancer (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder 
cancer, ampullary carcinoma)

carcinoid after somatostatin analogs (SSA) (Ki67 less than 20%)

cervix cancer (exocervix, squamous cell pathology)

endometrial cancer (after primary treatment that includes radiation therapy. Subjects 
with tumors with greater than 10% estrogen receptor positive pathology in the 
primary tumor are excluded) 

histiocytoses (including Erdheim Chester disease, Langerhans cell histiocytosis) 

insulinoma 
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
Lynch syndrome associated cancers (excluding hereditary nonpolyposis colorectal 
cancer [HNPCC]) (Please see Section 10)

medullary thyroid cancer

Merkel cell carcinoma (includes unresectable disease) 

mesothelioma

nasopharyngeal carcinoma

neuroendocrine tumors (poorly differentiated, Ki67 greater than 20%) 

neuroendocrine tumors (well to moderately differentiated, Ki67 less than 20%)

non-lung small cell carcinoma (including small cell carcinoma of the ovary of 
pulmonary type or small cell ovarian cancer hypercalcemic type)

non squamous cell cancer of the head and neck (including cancer of the salivary 
gland) 

penile cancer

rare women’s cancers (high grade, clear cell:-greater than 50% clear cell by 
pathology)

soft-tissue sarcoma [including liposarcoma, leiomyosarcoma]) 

malignant peripheral nerve sheath tumor NF-1 

testicular cancer (chemotherapy resistant or recurrent within 2 years of primary 
therapy)

thymic carcinoma or invasive thymoma

thyroid cancer (anaplastic thyroid cancer as primary therapy)

thyroid cancer (papillary or follicular, after failing radioactive iodine [RAI] and after 
approved kinase inhibition [lenvatinib]) 

uterine sarcoma (excluding endometrial stroma sarcoma) 

vaginal cancer (squamous cell pathology)

vulvar cancer (squamous cell pathology)
b) Other (please consult with BMS Medical Monitor before screening subjects in this group -
US only) 
c) Subjects must have received standard-of-care primary treatment for malignancy and 
standard-of-care for relapse or refractory disease, if treatment exists. For de novo 
metastatic disease, subjects with recurrent or refractory disease after standard-of-care 
(first-line or second-line [if treatment exists]) will be eligible for this trial. If there is no 
standard-of-care treatment for de novo metastatic disease (eg, metastatic carcinoid), 
subjects are eligible to enroll without prior first-line (or second-line) therapy. 
d) For subjects with brain metastases, there must be 1 evaluable lesion outside the brain. 
Subjects must not be receiving corticosteroids for brain metastasis.
e) Screening laboratory values must meet the following criteria (using CTCAE v4):
i)
WBC
2000/uL
ii) Neutrophils
1500/uL
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iii) Platelets
100x103/uL
iv) Hemoglobin
9.0 g/dL
v) Serum creatinine 1.5 x ULN or calculated creatinine clearance > 40 
mL/min (using the Cockcroft-Gault formula)
Female CrCl = (140- age in years) x weight (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)
vi) AST
3.0 x ULN 
vii) ALT
3.0 x ULN 
viii)
Total bilirubin 1.5 x ULN (except subjects with Gilbert Syndrome who 
must have a total bilirubin level of < 3.0x ULN). 
f)
Subjects must have measurable disease by CT or MRI per RECIST 1.1 criteria (see 
Appendix 4)
g) Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 (see Appendix 2)
h) Life expectancy weeks
3. Age and Reproductive Status
a) Adults, ages ≥ 18 
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 should use an adequate method to avoid pregnancy for 5 months (30 days plus 
the time required for nivolumab to undergo five half-lives) after the last dose of 
investigational drug.
e) Males who are sexually active with WOCBP must continue contraception for 7 months
(90 days plus the time required for nivolumab to undergo five half-lives) after the last 
dose of investigational drug. 
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must 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 on the use of highly effective methods of contraception (Appendix 6), 
which have a failure rate of < 1% when used consistently and correctly.
3.3.2
Exclusion Criteria
1. Target Disease Exclusions
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a) Subjects with:

adenocarcinoma of the colon

adenocarcinoma of the pancreas 

adenocarcinoma of the prostate 

adenocarcinoma of the rectum

endometrial cancers with greater than 10% estrogen receptor positive pathology in the 
primary tumor

epithelial ovarian cancer

breast cancer that is ER, PR positive breast cancer OR HER2 positive OR triple-
negative 

esophageal cancer

gastric cancer 


hepatocellular carcinoma

Hodgkin's lymphoma

leptomeningeal disease

leukemia

melanoma

meningioma (low grade)

multiple myeloma

myelodysplastic syndrome

non-Hodgkin's lymphoma (except primary CNS lymphoma without leptomeningeal 
disease)

non-small cell lung cancer 

peritoneal carcinoma

primary CNS lymphoma

renal cell carcinoma 

small cell lung cancer

squamous cell carcinoma of the head and neck

squamous cell carcinoma of the skin 

urothelial bladder cancer (urothelial [transitional cell] histology or mixed histologies)

carcinoma of unknown primary
2. Medical History and Concurrent Diseases
a) Subjects with previous malignancies (except non-melanoma skin cancers, and in situ 
cancers) are excluded unless a complete remission was achieved at least 2 years prior to 
study entry AND no additional therapy is required or anticipated to be required during the 
trial period.
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b) Active and untreated CNS metastases as determined by CT or MRI evaluation during 
screening and prior radiographic assessments. Subjects with CNS metastasis requiring 
corticosteroids are excluded from the trial.
c) Previously treated spinal cord compression must be clinically stable for ≥ 6 weeks prior 
to first dose of nivolumab
d) Uncontrolled pain
e) Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures 
f)
Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or 
corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use 
of bisphosphonate therapy or denosumab
h) Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibodies (including ipilimumab or any other antibody or drug specifically targeting 
T cell co-stimulation or checkpoint pathways).
i)
Subjects with an active, known or suspected autoimmune disease. Subjects with 
hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, 
psoriasis, or alopecia) not requiring systemic treatment, type I diabetes mellitus, or 
conditions not expected to recur in the absence of an external trigger are permitted to 
enroll.
j)
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalent) or other immunosuppressive medications within 14 days 
of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 
mg daily prednisone equivalent, are permitted in the absence of active autoimmune 
disease.
k) Known history of positive test of human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be 
performed at sites where mandated locally (eg, Germany). 
l)
Prior allogeneic bone marrow transplantation or prior solid organ transplantation
m) Any disease, metabolic dysfunction, physical examination finding, or clinical laboratory 
finding giving reasonable suspicion of a condition or event that contraindicates the use of 
the investigational drug or that may affect the interpretation of the results or render the 
subject at high risk from treatment complication
n) Subjects previously treated with investigational anticancer therapies less than 6 weeks 
prior to the first dose of nivolumab
o) Evidence of significant uncontrolled concomitant disease that could affect compliance 
with the protocol or interpretation of results (eg, significant liver disease, cirrhosis, 
uncontrolled major seizure disorder, psychiatric disorders, superior vena cava syndrome)
p) Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction within 3 months before first dose of 
nivolumab, unstable arrhythmias or unstable angina
q) Signs or symptoms of infection within 4 weeks before first dose of nivolumab, severe 
infections within 4 weeks before first dose of nivolumab including but not limited to 
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hospitalization for complications of infection, bacteremia or severe pneumonia, and/or 
received oral or IV antibiotics within 2 weeks before first dose of nivolumab
r)
All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of 
study drug. Subjects with toxicities attributed to prior anti-cancer therapy which are not 
expected to resolve and result in long lasting sequelae, such as neuropathy after platinum 
based therapy, are permitted to enroll.
s) Major surgical procedure within 28 days before first dose of nivolumab or anticipation of 
need for a major surgical procedure during the course of the study
t)
Treatment with botanical preparations (eg, herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 
2 weeks prior to randomization/treatment. Refer to Section 3.4.1 for prohibited therapies.
3. Physical and Laboratory Test Findings
a) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection, and/or detectable virus
b) Positive test for human immunodeficiency virus (HIV) 
4. Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
b) Known hypersensitivity to dacarbazine (DTIC) 
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated. (Note: under specific 
circumstances a person who has been imprisoned may be included as a subject. Strict 
conditions apply and Bristol-Myers Squibb approval is required.
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
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
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 or bilateral salpingectomy) 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 > 40 mIU/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 
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duration of the washout period below are suggested guidelines and the investigators should use 
their judgement in checking serum FSH levels. 

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. If the serum 
FSH level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
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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. (Note: Under specific circumstances, a participant who has been imprisoned may 
be permitted to continue as a participant. Strict conditions apply, and BMS approval is 
required).

Any event found in the Discontinuation criteria as outlined in Section 4.5.3.
Subjects discontinuing study treatment will remain on study for documentation of progression 
and death for up to one year.
In the case of pregnancy, the investigator must immediately notify the Sponsor or designee of 
this event. In most cases, the study drug will be permanently discontinued in an appropriate 
manner (eg, dose tapering if necessary for subject safety). Please contact the Sponsor or designee 
within 24 hours of awareness of the pregnancy. If the investigator determines a possible 
favorable benefit/risk ratio that warrants continuation of study drug, a discussion between the 
investigator and the Sponsor or designee must occur.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 
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 Section 5 until death or the conclusion of the 
study.
BMS may request that survival data be collected on all treated/randomized subjects outside of 
the protocol defined window (Table 5.1-4). At the time of this request, each subject will be 
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contacted to determine their survival status unless the subject has withdrawn consent for all 
contacts or is lost to follow-up.
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, if 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 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
Subjects should receive nivolumab at a dose of 240 mg as a 30 minute infusion on Day 1 of each 
2-week treatment cycle for 8 doses until progression, unacceptable toxicity, withdrawal of 
consent, the study ends, or until q4w dosing begins, whichever occurs first. Beginning with Dose 
9, subjects should receive nivolumab 480 mg as a 30 minute infusion every 4 weeks (3 days) 
until progression, unacceptable toxicity, withdrawal of consent, or the study ends, whichever 
occurs first. Subjects will receive study drug for the maximum treatment duration of 24 
months.
Study drug includes both Investigational [Medicinal] Product (IP/IMP) consist of the following:
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Table 4-1:
Study Drug for CA209627
Product 
Description / 
Class and Dosage 
Form
Potency
IP/Non-IMP
Blinded or Open 
Label
Packaging / 
Appearance
Storage 
Conditions
(per label)
Nivolumab 
BMS-936558-01
Solution for 
Injection
40 mg/4 mL 
and 100 mg 
(10 mg/mL)
IP
Open Label
Clear to 
opalescent 
colorless to pale 
yellow liquid. 
May contain 
particles
2 to C. 
Protect from 
light and 
freezing
There will be no dose escalations or reductions of nivolumab allowed. Subjects may be dosed no 
less than 12 days from the previous dose during q2w cycles. For q4w dosing cycles, subjects 
may be dosed within a 3 day window. Premedications are not recommended for the first dose 
of nivolumab.
Subjects should be carefully monitored for infusion reactions during nivolumab administration. 
If an acute infusion reaction is noted, subjects should be managed according to Section 4.5.6.
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
subject tolerates the treatment. Dosing visits are not skipped, only delayed.
Nivolumab Injection: 40 mg/4 mL and 100 mg/10 mL (10 mg/mL) 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron 
pore size, low-protein binding in-line filter at the protocol-specified doses. It is not to be 
administered as an IV push or bolus injection. Nivolumab injection can be infused undiluted 
(10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, 
USP to protein concentrations as low as 0.35 mg/mL. 
When the dose is fixed (eg, 240 mg flat dose), nivolumab injection can be infused undiluted or 
diluted so as not to exceed a total infusion volume of 120 mL. Nivolumab infusion must be 
promptly followed by a flush of diluent to clear the line. Instructions for dilution and infusion of 
nivolumab injection may be provided in the clinical protocol, pharmacy binder, or pharmacy 
reference sheet. Care must be taken to assure sterility of the prepared solution as the product 
does not contain any antimicrobial preservative or bacteriostatic agent. 
No incompatibilities have been observed between nivolumab injection and polyvinyl chloride 
(PVC), non-PVC/non-DEHP (di[2-ethylhexyl]phthalate) IV components, or glass bottles have 
been observed.
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 
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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. 
4.2
Non-investigational Product
Not applicable for this study.
4.3
Storage of Study Drug
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.
Please refer to Section 9.2.2 for guidance on IP records and documentation.
4.4
Method of Assigning Subject Identification
The subject number will be assigned through an interactive voice response system (IVRS) once 
the subject has signed the informed consent form and is registered. 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 that informed consent was obtained

Date of birth (year of birth only in Germany) 

Gender at birth

Tumor type
Once enrolled in IVRS, subjects that have met all eligibility criteria will be ready for treatment 
and drug vial assignment through the IVRS. The following information is required for drug vial 
assignment and treatment:

Subject number

Date of birth (year of birth only in Germany) 

Tumor Type

Confirmation of receipt of tumor tissue in archival (≤ 3 months old or new biopsy tissue) and 
blood samples by a central laboratory
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4.5
Selection and Timing of Dose for Each Subject
Subjects will receive treatment with nivolumab 240 mg as a 30 minute IV infusion on Day 1 of a 
treatment cycle every 2 weeks (14 days) for 8 doses until progression, unacceptable toxicity, 
withdrawal of consent, the study ends, or until Q4W dosing begins, whichever occurs first. 
Participants should begin study treatment within 3 calendar days of treatment assignment. 
Beginning with dose 9 (2 weeks following the 8th dose), subjects will receive treatment with 
nivolumab 480 mg as a 30 minute IV infusion every 4 weeks (28 days) (3 days) until 
progression, unacceptable toxicity, withdrawal of consent, maximum of 24 months of treatment, 
or the study ends, whichever occurs first.
If required for clinic scheduling, subjects may be treated up to 3 days before or after the 
scheduled date, ie, at intervals of not less than 12 days from the previous dose during Q2W 
cycles. For Q4W dosing cycles, participants may be dosed within a ±3 day window. A dose 
given more than 3 days after the intended dose date will be considered a delay. Subsequent 
treatments should be based on the actual date of administration of the previous dose of drug.
No dose escalations or reductions of nivolumab are allowed. Dosing visits are not skipped, only 
delayed.
There are no premedications recommended for nivolumab until infusion reactions have been
observed in the subject. Subjects should be carefully monitored for infusion reactions during 
nivolumab administration. If an acute infusion reaction is noted, subjects should be managed 
according to Section 4.5.6.
Dose delay criteria, criteria to resume treatment, and treatment discontinuation criteria can be
found in Section 4.5.1, Section 4.5.2, and Section 4.5.3, respectively.
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles.
4.5.1
Dose Delay Criteria
Nivolumab administration should be delayed for the following:

Grade 2 non-skin, drug-related adverse event with the exception of fatigue

Grade 2 drug-related creatinine, AST, ALT, or total bilirubin abnormalities 

Any Grade 3 skin, drug-related AE

Any Grade 3 drug-related laboratory abnormality with the following exceptions:

Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay 

Any Grade ≥ 3 AST, ALT, Total Bilirubin will require dose discontinuation (See Section 
4.5.3 for Treatment Discontinuation Criteria). 

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Subjects who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met.
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4.5.2
Criteria to Resume Treatment
Subjects may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to Grade 
≤1 or baseline, 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

For subjects with Grade 2 AST, ALT, and/or total bilirubin abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete.

Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the Medical Monitor or designee.

Subjects with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical 
Monitor or designee. Adrenal insufficiency requires discontinuation regardless of control 
with hormone replacement.
4.5.3
Treatment Discontinuation Criteria
Nivolumab treatment should be permanently discontinued for the following:

Any Grade 2 drug-related uveitis, 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 
laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, neurologic 
toxicity, hypersensitivity reactions, infusion reactions, and endocrinopathies:

Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, 
myocarditis, 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. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement. 

Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:

Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation

Grade ≥ 3 drug-related AST, ALT or total bilirubin requires discontinuation*

Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN

* In most cases of Grade 3 AST or ALT elevation, study drug(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that 
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warrants continuation of study drug(s), a discussion between the investigator and the BMS 
Medical Monitor/designee must occur.

Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or total bilirubin), except for the following events which do not 
require discontinuation:

Grade 4 neutropenia ≤ 7 days

Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase

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 drug-related endocrinopathy adverse events, such hyper- or hypothyroidism, or 
glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor.

Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, 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 from the previous dose, the BMS medical monitor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is delayed. Periodic study 
visits to assess safety and laboratory studies should also continue every 6 weeks or more 
frequently if clinically indicated during such dosing delays.

Dosing delays lasting > 6 weeks from the previous dose 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. Periodic study visits to assess safety and laboratory studies should also continue 
every 6 weeks or more frequently if clinically indicated during such dosing delays.

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.
4.5.4
Nivolumab Treatment Beyond Disease Progression
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of PD.48 Subjects treated with nivolumab will be 
permitted to continue nivolumab treatment beyond initial RECIST 1.1 defined PD until the 
maximum of 24 months from the first treatment, assessed by the investigator, as long as they 
meet the following criteria:

Investigator-assessed clinical benefit

Tolerance of study drug
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
Stable performance status

Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)

Subject provides written informed consent prior to receiving additional nivolumab treatment. 
All other elements of the main consent including description of reasonably foreseeable risks 
or discomforts, or other alternative treatment options will still apply.
A radiographic assessment/ scan should be performed within 6 weeks of initial investigator-
assessed progression to determine whether there has been a decrease in the tumor size or 
continued PD. The assessment of clinical benefit should be balanced by clinical judgment as to 
whether the subject is clinically deteriorating and unlikely to receive any benefit from continued 
treatment with nivolumab.
If the investigator believes the subject would receive clinical benefit by continuing nivolumab 
treatment after scans showing disease progression, the subject may continue to receive 
nivolumab treatment, remain on the trial, and monitored according to the Time and Events 
Schedule in Section 5.
When a subject receives nivolumab therapy beyond disease progression, further progression 
from initial progressive disease evaluation is defined as an additional 10% increase in tumor 
burden (with a minimum 5 mm absolute increase). This includes an increase in the sum of 
diameters of all target lesions and/or the diameters of new measurable lesions compared to the 
initial progressive disease evaluation. Nivolumab treatment should be discontinued permanently 
upon determination of further progression.
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least15 
mm). Any new lesion considered non-measureable at the time of initial progression may become 
measureable and therefore included in the tumor burden if the longest diameter increases to at 
least 10 mm (except for pathological lymph nodes which must have a short axis of at least 15 
mm). In situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm.
 
 
 
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4.5.6
Treatment of Nivolumab-Related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, 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. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the study medical monitor and reported 
as an SAE if it meets the criteria. Infusion reactions should be graded according to NCI CTCAE 
(Version 4) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated):

Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab administrations.
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but responds 
promptly to symptomatic treatment (eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic medications indicated for ≤ 
24 hours):

Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at bedside and monitor subject until resolution of symptoms. Corticosteroid 
and/or bronchodilator therapy may also be administered as appropriate. If the infusion is 
interrupted, then restart the infusion at 50% of the original infusion rate when symptoms 
resolve; if no further complications ensue after 30 minutes, the rate may be increased to 
100% of the original infusion rate. Monitor subject closely. If symptoms recur, then no 
further BMS-936558 will be administered at that visit.

For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab infusions. If necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
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For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae (eg, renal 
impairment, pulmonary infiltrates). Grade 4: Life threatening; pressor or ventilatory support 
indicated):

Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline and 
treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until 
the Investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery of the 
symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
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 eCRF.
4.8
Destruction or Return of Investigational Product
For this study, IP (those supplied by BMS, a vendor or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site (see below). 
If
Then
IP supplied by BMS (including its vendors)
Any unused IP supplied by BMS can only be destroyed 
after being inspected and reconciled by the responsible 
Study Monitor unless IP containers must be 
immediately destroyed as required for safety, or to 
meet local regulations (eg, cytotoxics or biologics).
It is the investigator’s or designee’s responsibility to arrange for disposal, 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. The following minimal standards must be 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.
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
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.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of IP provided by BMS (or its vendors). Destruction of non-IP sourced 
by the site, not supplied by BMS, is solely the responsibility of the investigator or designee.
Please refer to Section 9.2.2 for additional guidance on IP records and documentation.
4.9
Retained Samples for Bioavailability / Bioequivalence
Not applicable
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline CA209627
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior to first dose
Medical History
X
Including diagnostic pathology report
Prior Systemic Therapy
X
Safety Assessments
Physical Examination
X
Within 14 days prior to first dose
Physical Measurements
X
Include Height and Weight
Within 14 days prior to first dose
Vital Signs 
X
Temperature, BP, HR, and RR within 3 days of first dose
Performance Status (ECOG)
X
Within 14 days prior to first dose. See Appendix 2 for ECOG scale
Assessment of Signs and Symptoms
X
After obtaining Informed Consent, assess all signs and symptoms within 14 days prior to first dose.
Concomitant Medication Collection
X
Within 14 days prior to first dose
Serious Adverse Events assessment
Assessed using NCI CTCAE v. 4 (continuously evaluate after subject signs ICF)
Laboratory Tests
X
Screening local laboratory assessments should be done within 14 days prior to first dose and are to 
include: CBC with differential, Chemistry panel including LFTs (ALT, AST, total bilirubin, 
alkaline phosphatase), albumin, BUN or serum urea level, creatinine, Ca, Na, K, Cl, phosphate, 
LDH, glucose, and thyroid panel including TSH, free T3, and free T4.
The following screening local laboratory assessments should be done prior to first dose: Hepatitis 
B and C testing (HBV sAg and HCV Ab or HCV RNA).
HIV testing (Germany only)
X
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Table 5.1-1:
Screening Procedural Outline CA209627
Procedure
Screening
Visit
Notes
Pregnancy Test
X
Serum or urine pregnancy testing at screening visit and repeated within 24 hours of first dose.
 
 
 
 
 
 
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.

Prior to dosing for study drug vial assignment (call should be made within 3 days 
prior to dosing). 
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Table 5.1-2:
On-Treatment Assessments - Nivolumab 240mg/Q2 weeks CA209627
Procedure
Cycle 1 Day 1 
(C1D1)
(First dose)
Each Cycle 
(every 2 weeks) 
on Day 1
Notes: 
Safety Assessments
Physical Examination (including 
weight)
X
Targeted Physical Examination
X
Targeted examination must include at a minimum the following body 
systems: Cardiovascular, Gastrointestinal, and Pulmonary.
Weight must be collected. 
Within 3 days prior to dosing
Vital Signs 
X
X
Temperature, BP, RR, and HR. 
Obtain vital signs within 3 days prior to dosing.
ECOG Performance Status
X
X
See Appendix 2 for ECOG scale
Adverse Events Assessment
------- Continuously -------
Assessed using NCI CTCAE v. 4
Serious Adverse Event Assessments
------- Continuously -------
Assessed using NCI CTCAE v. 4.
Review of Concomitant Medications
X
X
Laboratory Tests
X
X
On-study local laboratory assessments should be done within 3 days prior to 
dosing for every cycle and to include: CBC with differential, Chemistry 
panel including LFTs (ALT, AST, total bilirubin, alkaline phosphatase), 
BUN or serum urea level, creatinine, Ca, Na, K, Cl, phosphate, LDH, and 
glucose. 
If > 14 days from screening, labs must be repeated. 
Thyroid Function Testing
See Notes
TSH (reflex to free T3 and free T4 if abnormal result) to be performed every 
6 weeks (1 week).
Pregnancy Test
X
See Notes
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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Table 5.1-2:
On-Treatment Assessments - Nivolumab 240mg/Q2 weeks CA209627
Procedure
Cycle 1 Day 1 
(C1D1)
(First dose)
Each Cycle 
(every 2 weeks) 
on Day 1
Notes: 
Efficacy Assessments 
Radiographic Tumor Assessment
See notes
See Appendix 4 (RECIST 1.1 Guidelines) for details regarding imaging 
methodology requirements and assessments
Radiographic tumor assessment must be performed on Week 8 (5 days), 
prior to the next cycle, at Week 16 prior to the start of 480 mg dosing, and at 
Week 28 prior to dosing. Cycles beyond Week 16 may be 5 days.
Clinical Drug Supplies
Administer Study Drug
X
X
Within 3 days from vial allocation, the subject must receive the first dose of 
study medication. Subjects may be dosed no less than 12 days between doses 
and no more than 3 days from the scheduled dose. Contact with IVRS for 
drug vial assignment.
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Table 5.1-3:
On-Treatment Assessments - Nivolumab 480mg/Q4 weeks CA209627
Procedure
Each Cycle (every 
4 weeks) on Day 1
Notes
Safety Assessments
Targeted Physical Examination
X
Targeted examination must include at a minimum the following body systems: 
Cardiovascular, Gastrointestinal, and Pulmonary.
Weight must be collected. Within 3 days before dosing
Vital Signs 
X
Temperature, BP, RR, and HR. 
Obtain vital signs within 3 days before dosing.
ECOG Performance Status
X
See Appendix 2 for ECOG scale
Adverse Events Assessment
X
Assessed using NCI CTCAE v. 4.0.
Serious Adverse Event Assessments
X
Assessed using NCI CTCAE v. 4.0.
Review of Concomitant Medications
X
Laboratory Tests
X
On-study local laboratory assessments should be done within 3 days prior to dosing for 
every cycle and to include: CBC with differential, Chemistry panel including LFTs 
(ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum urea level, creatinine, 
Ca, Na, K, Cl, phosphate, LDH, and glucose.
Thyroid Function Testing
X
TSH (reflex to free T3 and free T4 if abnormal result) to be performed every 8 weeks 
(1 week).
Pregnancy Test
X
Serum or urine every 4 weeks regardless of dosing schedule.
Efficacy Assessments
Radiographic Tumor Assessment
Every 12 weeks
See Appendix 4 (RECIST 1.1 Guidelines) for details regarding imaging methodology 
requirements and assessments
Radiographic tumor assessment must be performed q12 weeks ±5 days. Timing of 
radiographic assessments is based on timing from first dose.
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Table 5.1-3:
On-Treatment Assessments - Nivolumab 480mg/Q4 weeks CA209627
Procedure
Each Cycle (every 
4 weeks) on Day 1
Notes
Clinical Drug Supplies
Administer Study Drug
X
Within 3 days of schedule dose.
Contact with IVRS for drug vial assignment.
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Table 5.1-4:
Follow-Up Assessments - All Subjects CA209627
Procedure
Follow-Up Visits 
X01 (Day 35) (7 
Days) and X02 
(Day 100) a
(7 Days) after 
last dose
Survival 
Follow-Up 
Visits b Every 
12 weeks
Notes
Safety Assessments
Targeted Physical Examination
X
Targeted examination must include the Cardiovascular, Gastrointestinal, and 
Pulmonary body systems and examination to specific malignancy 
To assess for potential late emergent study drug related findings. 
Vital Signs
X
X
Adverse Events and Serious 
Adverse Events Assessment
X
All AEs and SAEs must be collected up to 100 days after study drug 
discontinuation. SAEs that relate to any later protocol specified procedure must 
be collected.
Review of Medical History and 
Subsequent Cancer Therapy 
Information 
X
X
Laboratory Tests
X
CBC with differential, Chemistry panel including LFTs (ALT, AST, total 
bilirubin, alkaline phosphatase), BUN or serum urea level, creatinine, Ca, Na, K, 
Cl, phosphate, LDH, and glucose.
Thyroid Function Testing
X
TSH (reflex to free T3 and free T4 if abnormal result)
Pregnancy Test
X
Serum or urine
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Table 5.1-4:
Follow-Up Assessments - All Subjects CA209627
Procedure
Follow-Up Visits 
X01 (Day 35) (7 
Days) and X02 
(Day 100) a
(7 Days) after 
last dose
Survival 
Follow-Up 
Visits b Every 
12 weeks
Notes
Efficacy Assessments
Radiographic Tumor 
Assessment
See notes
Only for subjects without progression and no longer on study therapy. If subject 
starts subsequent treatment, no assessment required
Subjects with a history of brain metastasis may have surveillance MRI 
approximately every 12 weeks or sooner if clinically indicated
Subject Status
Survival Status
X
X
Every 3 months after X02; may be accomplished by visit or phone contact, to 
update survival information and assess subsequent anti-cancer therapy.
NOTES:
a Subjects must be followed for at least 100 days after last dose of study treatment. Follow-up visit #1 occurs approximately 35 days (7 days) after the last 
dose or coinciding with the date of discontinuation (7 days) if date of discontinuation is greater than 30 days after last dose. Follow-up visit #2 occurs 
approximately 100 days (7 days) from last dose
b Survival Follow-up visits to occur every 3 months from Follow-up Visit 2. 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. Vital signs not required if follow-up is performed via telephone contact. 
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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 (ie, the most current result prior to 
Randomization) 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

National Cancer Institute Common Terminology Criteria for Adverse Events NCI CTCAE 
version 4.0

BMS-936558 Nivolumab Investigator Brochure 

Laboratory Manuals for collection and handling of blood and tissue specimens

Pharmacy Binder

Site manual for operation of interactive voice response system, including enrollment 
worksheets

Serious Adverse Event CRFs/eCRFs
5.3
Safety Assessments
At screening, a medical history will be obtained to capture relevant underlying conditions. The 
screening examinations should include weight, height, ECOG Performance Status, blood 
pressure (BP), heart rate (HR), respiration rate (RR), and temperature. 
Screening local laboratory assessments should be done within 14 days prior to treatment and are 
to include: CBC with differential, Chemistry panel including LFTs (ALT, AST, total bilirubin, 
alkaline phosphatase), BUN or serum urea level, creatinine, Ca, Na, K, Cl, phosphate, LDH, 
glucose, albumin, and thyroid panel including TSH, free T3, and free T4.
Screening pregnancy tests for WOCBP must be performed within 24 hours prior to the initial 
administration of study drug. 
The following screening local laboratory assessments should be done prior to treatment: 
Hepatitis B and C testing (HBV sAg and HCV Ab or HCV RNA).
While on-study the following local laboratory assessments will occur within 3 calendar days 
prior to each dose: CBC with differential, chemistry panel including LFTs (ALT, AST, total 
bilirubin, alkaline phosphatase), BUN or serum urea level, creatinine, Ca, Na, K, Cl, phosphate, 
LDH, glucose.
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Thyroid function testing (TSH;  reflexive fT3 and fT4 if abnormal during on-treatment testing) is 
to be done every 6 weeks (every 3 doses) for subjects receiving nivolumab at 240 mg q2w, then 
every 8 weeks (1 week) for subjects receiving nivolumab at 480 mg q4w (every other dose). If 
the patient demonstrated an active endocrinopathy during the nivolumab 240 mg dosing period, 
then thyroid function testing will be performed every 6 weeks (1 week) at the discretion of the 
treating physician.
On treatment pregnancy tests should be performed as per the schedule in the Time & Events 
table.
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase as well as during the first 2 safety follow-up visits. 
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.
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.
The start and stop time of the study therapy infusions and any interruptions or infusion rate 
reductions should be documented. 
Physical examinations are to be performed as clinically indicated. 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.
On treatment local laboratory assessments are to be completed within 3 calendar days prior to 
dosing.
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.
If a subject shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, 
fever) consistent with possible pulmonary adverse events, the subject should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in the BMS-936558 Nivolumab Investigator Brochure and Appendix 3.
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
Images will be collected centrally and may be reviewed by blinded independent central review 
(BICR) at a later date, or at any time during the study.  Image acquisition guidelines and 
submission process will be outlined in the CA209-627 Imaging Manual to be provided by the 
core lab. 
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Any additional imaging that may demonstrate tumor response or progression (including scans 
performed at unscheduled timepoints and/or at an outside institution) should be collected for 
RECIST 1.1 tumor assessment and submitted to the BICR.
Study evaluations will take place in accordance with Table 5.1-1, Table 5.1-2, Table 5.1-3, and 
Table 5.1-4 according to RECIST 1.1. CT with IV contrast are the preferred imaging modalities 
for assessing radiographic tumor response. In cases where contrast is contraindicated, a non-
contrast scan will suffice. Screening (baseline) tumor assessments of, chest, abdomen, pelvis, 
and all known / suspected sites of disease are to be performed prior to first dose. Subsequent 
assessments should include chest, abdomen, pelvis, and all known / suspected sites of disease 
using the same imaging method and technique as was used at baseline. 
For evaluating CNS metastasis, brain MRI is the required imaging method, and assessment is 
required during screening in subjects with a known history of treated brain metastases. All 
known sites of disease (including CNS) should be assessed at baseline and subsequent 
assessments using the same imaging method and technique. If more than 1 method is used at 
screening, then the most accurate method according to RECIST 1.1 should be used when 
recording data, and should again be used for all subsequent assessments. Bone scan, PET scan, 
or ultrasound is not adequate for assessment of RECIST 1.1 response. Previously treated CNS 
metastases are not considered measurable lesions for purposes of RECIST 1.1 determined 
response. Subjects with a history of brain metastasis should have surveillance MRI 
approximately every 12 weeks or sooner if clinically indicated. 
Radiographic tumor response will be assessed at Week 8 (days), Week 16 (days), and 
Week 28 (days), then every 12 weeks (days) until disease progression, beyond 
progression, lost to follow-up, or withdrawal of consent. Tumor assessments for all subjects 
should continue as per protocol even if dosing is interrupted. Tumor measurements should be 
made by the same investigator or radiologist for each assessment whenever possible. Change in 
tumor measurements and tumor response to guide ongoing study treatment decisions will be 
assessed by the investigator using the RECIST 1.1 criteria (see Appendix 4 for details of 
RECIST 1.1).49 Independent adjudication will resolve equivocal interpretations of imaging 
results.
Local radiologic assessment of tumor measurements will be used during the study for clinical 
management and investigator-assessed disease progression using RECIST 1.1 criteria. The same 
imaging modality used in screening must be used in all subsequent imaging assessments. 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.
5.4
Efficacy Assessments
5.4.1
Objective Response Rate (ORR) 
The primary endpoint is investigator-assessed ORR in all treated subjects. See Section 8.3.1. 
Please see Appendix 4 for RECIST 1.1.
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5.4.2
Secondary Efficacy Assessments
Secondary endpoints are DOR, TTR, CBR, and OS at 1 year. See Section 8.3.2 for the 
definitions of these endpoints. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.7
Retention of Tissue for Additional Research 
All residual blood and tissue samples will be retained by the BMS Biorepository for additional 
research purposes. No additional sampling is required. Additional research retention is 
mandatory for all subjects, except where prohibited by local laws and regulations. Details of 
sample collection and processing will be provided to the site in the procedure manual.
5.8
Outcomes Research Assessments
Not applicable.
5.9
Other Assessments 
Not applicable.
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 
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questioned regarding the specific occurrence of one or more AEs.) Care should be taken not to 
introduce bias when collecting AE and/or SAEs. Inquiry about specific AEs should be guided by 
clinical judgement in the context of known adverse events, when appropriate for the program or 
protocol. 
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and 
FDA Code of Federal Regulations 21 CFR Parts 312 and 320.
Immune-mediated (IM) adverse events are AEs consistent with an immune-mediated mechanism 
or immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which 
were exacerbated by the induction of autoimmunity. Information supporting the assessment will 
be collected on the participant’s case report form.
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.)

Admission for administration of anticancer therapy in the absence of any other SAEs 
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).
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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

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 BMS-936558 Nivolumab Investigator Brochure 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 nivolumab. 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 Sponsor 
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 
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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.) 
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 Sponsor or 
designee using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
BMS will be reporting adverse events to regulatory authorities and ethics committees according 
to local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320. 
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. 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.
All nonserious adverse events (not only those deemed to be treatment-related) should be 
collected continuously during the treatment period and for a minimum of 100 days following 
discontinuation of dosing.
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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 electronic) as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.

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 Sponsor or 
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.
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety). Please call the Sponsor or designee within 
24 hours of awareness of the pregnancy.
The investigator must immediately notify the Sponsor or designee of this event and complete and 
forward a Pregnancy Surveillance Form to Sponsor 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 
Sponsor or designee. In order for BMS to collect any pregnancy surveillance information from 
the female partner, the female partner must sign an informed consent form for disclosure of this 
information. 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.).
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6.6
Potential Drug Induced Liver Injury (DILI)
Hepatotoxicity, such as transaminase elevations and hepatitis, has been identified as an important 
risk for nivolumab. 
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.
A hepatic AE management algorithm that has been established (Appendix 3) and applied across 
the nivolumab program remains appropriate for managing drug-induced liver injury (DILI) 
cases. The experience to date shows that hepatic AEs, including possible DILI cases, were 
manageable using the established management algorithm and thus do not meaningfully alter the 
benefit/risk of nivolumab in the advanced malignancy populations.
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.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
A Steering Committee comprised of trial investigators, trial statisticians, and BMS physicians 
will be created to design the trial and govern the trial’s conduct, scope, and execution. No DMC 
will be formed for this trial. The oncology therapeutic area of BMS has primary responsibility 
for overall design and conduct of the study. Decisions regarding the study protocol will be made 
by the sponsor upon consultation with the steering committee.
8
STATISTICAL CONSIDERATIONS 
 
 
 
 
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Overview: This is a Phase 2 single-arm clinical trial that investigates nivolumab across multiple 
cancer types. At least 25 tumor types (groups) will be considered. If additional groups are 
identified in the course of the trial, they will be enrolled and will be included within the 
statistical analysis provided reasonable estimates of the control response rates can be identified. 
The trial is designed to estimate the underlying ORR of nivolumab in each tumor type (πg). 
Supporting secondary objectives include the duration of response, TTR, CBR, OS, and safety. 
All subjects will receive nivolumab.
A hierarchical model that borrows information across tumor subgroups will be used to strengthen 
the overall evidence within each subgroup. Using the hierarchical model, both continuous 
monitoring for futility and success will be undertaken throughout the study.
Regularly scheduled trial update analyses occur at most every 4 weeks. At each of these 
analyses, a Bayesian hierarchical model is fit across the data in all cohorts. For each cohort we 
determine the Bayesian posterior probability that the treatment effect in that cohort (treatment 
compared to historical control) is greater than 0 (eg, that treatment is better than control). 
Formally, if θg is the true log odds treatment effect for cohort g, we compute Pr(θg>0 | data) for 
each cohort g. At the regularly scheduled trial update analyses, each cohort may stop enrollment 
for success or futility. If a cohort stops enrollment, subjects currently in the cohort are all still 
followed to their primary endpoint.
Separate final analyses will be conducted for each cohort.  A final analysis for a group will occur 
after enrollment in that group is complete and after all subjects in that group have at least 28 
weeks follow-up. Once a group is stopped early for futility, the group will not be re-opened for 
further enrollment. The final analysis for a cohort declares success if the Bayesian posterior 
probability that the treatment effect in that cohort (treatment compared to historical control) is 
above 80%. For example, cohort g will be declared a success at cohort g’s final analysis if 
Pr(θg>0 | data) > 0.80. This posterior probability will incorporate the entire dataset at the time of 
analysis through the Bayesian Hierarchical Model.
Statistical Hypotheses: Let Yi be the response indicator for the ith subject. Define πg = Pr(Yi = 
1 | gi = g) as the underlying probability of response for group g for the experimental treatment 
and Rg as the assumed probability of response for group g within the (historical) control 
population. Transformation to the logit scale is applied for modeling purposes. Let θg be the 
mean log odds treatment effect, ie,
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θg=log (πg/(1-πg ))-log (Rg/(1-Rg )).
Thus, θg is the logistic regression coefficient for the treatment within tumor group g. The 
primary analysis is a set of group specific tests of θg>0 (equivalently, πg > Rg) meaning that the 
treatment is better than the assumed control rate within that group. Thus, the following 
hypotheses are tested for each tumor group g:
H0g : θg≤0,
H1g : θg>0.
The assumed control ORRs (Rg) vary by group and are provided in the Table 8-1 below.
Table 8-1:
Historical Control ORRs
Group 
Index 
Tumor Type
Assumed 
Control ORR 
(Rg)
1
Anal Cancer (squamous cell histology)
15%
2
Biliary Tract Cancer (includes nonresectable disease), intrahepatic or extrahepatic 
cholangiocarcinoma, gallbladder cancer, and ampullary carcinoma
10%
3
Carcinoid after SSAs (Ki67 < 20%)
7.5%
4
Squamous Cell Cancer of the Cervix (exocervix), Squamous Cell Cancer of the 
Vagina
20%
5
Endometrial Cancer (after primary treatment including RT). Subjects with tumors 
> 10% estrogen receptor positive pathology in the primary tumor are excluded.
20%
6
Non-squamous Cell Cancer of the Head and Neck (including Cancer of  the 
Salivary Gland, Adenoid Cystic Carcinoma)
10%
7
Histiocytoses (including Erdheim Chester Disease [macrophage disorder], 
Langerhans Cell Histiocytosis [LCH, dendritic cell disorder]
15%
8
Lynch Syndrome Associated Cancers (excluding HNPCC)
12.5%
9
Medullary Thyroid Cancer (after TKI [vandetanib or cabozantinib])
20%
10
Merkel Cell Carcinoma (includes unresectable disease)
15%
11
Mesothelioma
10%
12
Nasopharyngeal Carcinoma
17.5%
13
Neuroendocrine Tumors (poorly differentiated, Ki67 > 20%)
10%
14
Neuroendocrine Tumors (well to moderately differentiated) after SSAs or 
everolimus, including insulinomas 
15%
15
Non-Lung Small Cell Carcinoma (includes Small Cell Carcinoma of the ovary of 
pulmonary or hypercalcemic type) 
10%
16
Penile Cancer 
15%
17
Rare Women’s Cancers: Clear Cell (> 50% clear cell by pathology) 
5%
18
Soft-Tissue Sarcoma (including Liposarcoma, Leiomyosarcoma), Malignant 
10%
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Table 8-1:
Historical Control ORRs
Group 
Index 
Tumor Type
Assumed 
Control ORR 
(Rg)
Peripheral Nerve Sheath Tumor, NF-1
19
Testicular Cancer (chemotherapy resistant disease or relapsed within 2 years of 
primary therapy)
10%
20
Thymic Carcinoma or Invasive Thymoma 
10%
21
Thyroid Cancer (papillary or follicular), after failing RAI and approved kinase 
inhibition [lenvatinib]
15%
22
Thyroid Cancer: anaplastic first-line. In BRAF V600e positive subjects, 
investigators may administer nivolumab after vemurafenib.
5%
23
Uterine Sarcoma (excluding endometrial stromal sarcoma)
15%
24
Vulvar Cancer (post vulvectomy, cisplatin and radiotherapy)
15%
25
Adenoid Cystic Carcinoma
10%
8.1
Sample Size Determination
The maximum overall sample size across all tumor groups is 350 subjects. In addition, the 
maximum permitted sample size per group is 25 subjects, although a group with high posterior 
probability of success may be permitted a larger sample size at Sponsor discretion. Some groups 
will enroll more subjects than others. Simulation studies were conducted to evaluate the 
performance of the analysis under various assumptions for the distribution of true underlying 
ORRs across the tumor types. Operating characteristics including power and type I error were 
assessed.
When the treatment effects are similar across all tumor types, estimation efficiencies, due to 
borrowing, result in strong trial performance. When all groups are in truth effective, the 
individual groups generally exhibit power between 86.8% and 98.0%, under the scenario of odds 
ratio improvement of 3. When all groups are ineffective, the individual groups have between a 
2.1% and 9.5% chance of mistakenly declaring group success. In addition, the global type I error 
(proportion of trials that declare at least 1 group successful when none is effective) is controlled 
at 0.539. Full presentation and discussion of the simulation parameters, corresponding simulation 
results, and example trials are included in the Appendix 1.
8.2
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 1 dose of nivolumab. 
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8.3
Endpoints
8.3.1
Primary Endpoint 
ORR is defined as the number of participants with a best overall response of confirmed CR or 
PR divided by the number of all treated participants. Best overall response is defined as the best 
response designation, as determined by investigator, recorded between the date of first dose and 
the date of objectively documented progression per tumor-specific response criteria  or the date 
of subsequent therapy, whichever occurs first. For participants without documented progression 
or subsequent therapy, all available response designations will contribute to the BOR 
determination.
8.3.2
Secondary Endpoints
8.3.2.1
Duration of Response
DOR is defined as the time from first confirmed response (CR or PR) to the date of the first 
documented tumor progression as determined by investigator or death due to any cause, 
whichever occurs first. Participants who start subsequent therapy without a prior reported 
progression will be censored at the last evaluable tumor assessments prior to initiation of the 
subsequent anticancer therapy. Participants who die without a reported prior progression will be 
considered to have progressed on the date of their death. Participants who neither progress nor 
die will be censored on the date of their last evaluable tumor assessment. 
8.3.2.2
TTR
TTR is defined as the time from first dosing date to the date of the first confirmed response, as 
assessed by investigator.
8.3.2.3
CBR
CBR is defined as the number of participants with a best overall response of confirmed CR or 
PR, or stable disease divided by the number of all treated subjects.
8.3.2.4
Overall survival
OS is defined as the time from the first dosing date to the date of death. A participant who has 
not died will be censored at last known date alive. OS rate at 1 year is measured as the survival 
rate at 1 year from Kaplan-Meier curve of OS.
8.3.2.5
Safety and Tolerability
Safety and tolerability will be measured by the incidence of deaths, adverse events, serious 
adverse events, adverse events leading to discontinuation, immune-mediated adverse events, 
select adverse events, adverse events leading to dose delay, and specific laboratory abnormalities 
(worst grade) in each tumor group. Toxicities will be graded using the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
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8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographics and baseline disease characteristics including age, sex, race, weight, baseline 
disease diagnosis, and medical condition will be summarized using descriptive statistics by 
disease type.
8.4.2
Efficacy Analyses 
The final analysis for each group declares success if the Bayesian posterior probability that the 
treatment effect in that group (treatment compared to control) is above 80%. Formally: 
Pr(θg>Rg) > 0.80.
DOR, TTR, CBR, and overall survival at 1 year will also be provided for each group.
8.4.3
Safety Analyses
Safety analyses will be performed by tumor group in all treated subjects. Descriptive statistics of 
safety will be presented using NCI CTCAE version 4.0. All AEs, drug-related, AEs, SAEs and 
drug-related SAEs will be tabulated using worst grade per NCI CTCAE v4.0 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.
 
 
 
 
 
 
 
 
 
 
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8.4.6
Outcomes Research Analyses
Not applicable.
8.4.7
Other Analyses 
Not applicable. 
8.5
Interim Analyses 
Interim Monitoring will be conducted, at most, every 4 weeks. At each analysis, the groups will 
be evaluated for futility and success by comparing posterior quantities for the overall response 
rate to pre-specified early stopping criteria based on the hierarchical model based on population 
of subjects with at least 28 weeks of follow-up. The design may limit the maximum number of 
subjects per group to 25 subjects within the trial. Available resources will be used more 
effectively by enrolling subjects in groups that offer greater promise of efficacy. Internal 
assessment of the program will also take into consideration for the final decision of early 
stopping.
Early Futility: If there is a sufficiently low probability (20%) that the ORR in a group exceeds 
the historical rate Rg by at least 10%, then the group will stop enrollment early for futility.
Formally, enrollment will stop early for futility if:
Pr(πg > Rg+0.10) < 0.20
A group is only eligible for early stopping for futility once a minimum of 5 subjects have been 
evaluated for ORR in that group. 
Early Success: If there is a sufficiently high probability (95%) that the ORR in a group exceeds 
the historical rate Rg, then the group may stop enrollment early for success. Formally, 
enrollment may stop early for success if:
Pr(πg > Rg) > 0.95
A group is only eligible for early stopping for success once a minimum of eligible 8 subjects 
have been evaluated for ORR in that group.
8.5.1
Pause Rule 
The Bayesian hierarchical model incorporates information from all cohorts into each analysis, 
however the primary driver of the analysis for each cohort is the data from that specific cohort. 
Thus, it is important that enough data is available in each cohort where possible. To minimize the 
possibility of excessive enrollment imbalance between the groups, enrollment may be paused in 
a cohort at any time where 12 or more patients have enrolled, but have not had, yet, an 
opportunity to complete their 28 week evaluation visit (dropouts are not included in this 
calculation if they have no post-baseline tumor assessment). The pause may continue until at 
least 75% of the subjects in the cohort have reached 28 weeks follow-up or have discontinued 
due to disease progression.
In addition, based on considerations such as emerging external data, cohorts may be paused by 
Sponsor decision in consultation with Steering Committee.
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9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) 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 relevant approval/favorable opinion(s), the deviation or 
change will be submitted as soon as possible to:

IRB/IEC 

Regulatory Authority(ies), if applicable by local regulations per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority, 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 
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 or designee 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. Certain CRF pages and/or electronic files may serve as the 
source documents:
In addition, the study may be evaluated by BMS or designee 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 or designee. 
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 
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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. 
9.2
Records
9.2.1
Records Retention
The investigator (or head of the study site in Japan) 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 or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS or designee prior to destroying 
any records associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) 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, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee.
9.2.2
Study Drug Records 
Records for IP (whether supplied by BMS, its vendors, or the site) must substantiate IP integrity 
and traceability from receipt, preparation, administration, and through destruction or return. 
Records must be made available for review at the request of BMS/designee or a Health 
Authority.
If...
Then...
Supplied by BMS (or its vendors):
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 (e.g., lost, wasted) 
amount destroyed at study site, if applicable
amount returned to BMS
retain samples for bioavailability/bioequivalence, if 
applicable 
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If...
Then...
dates and initials of person responsible for 
Investigational Product dispensing/accountability, as 
per the Delegation of Authority Form.
BMS or designee 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 
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 Sponsor or designee 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 electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor of designee. 
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, 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. Subinvestigators in Japan may not be delegated the CRF 
approval task. 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 Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. 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:
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
Study Steering Committee chair or their designee
The data collected during this study are confidential and proprietary to BMS or designee. 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  or designee 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
Table 10-1:
Glossary of Terms
Term
Definition
Clinical Benefit Rate
Percentage of subjects who have achieved complete response, partial 
response, and stable disease to a therapy
Lynch Syndrome associated 
malignancies.
Subjects without a diagnosis of Lynch Syndrome, but with variations 
in the mismatch repair genes MLH1, MSH2, MSH6, PMS2, or 
germline deletions in the EPCAM gene 
or 
Subjects in whom molecular testing demonstrates the presence of 
MSI and/or abnormal expression of MMR proteins on IHC testing of 
tumors, without presence of characteristic germline mutations seen 
in LS.
Pseudoprogression
Pseudoprogression is paradoxical tumor growth which mimics tumor 
progression. Imaging and corresponding signs and symptoms identify 
pseudoprogression.
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11
LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AT
aminotransaminases
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
CBC
complete blood count
CBR
clinical benefit rate
CFR
Code of Federal Regulations 
CI
confidence interval
CNS
central nervous system
CRC
Colorectal cancer
CRF
case report form (paper or electronic)
eCRF
electronic case report form
CT
computed tomography
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
eg
exempli gratia (for example)
FDA
Food and Drug Administration
FFPE
formalin fixed paraffin embedded
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCVab
hepatitis C virus antibody
HIV
human immunodeficiency virus
HNPCC
Hereditary nonpolyposis colorectal cancer
HR
heart rate; hazard ratio
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Term
Definition
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IU
international unit
IV
intravenous
LDH
lactate dehydrogenase
LFT
liver function test
mg
milligram
min
minute
mL
milliliter
MMR
mismatch repair
MRI
magnetic resonance imaging
g
microgram
N
number of subjects or observations
N/A
not applicable
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIMP
non-investigational medicinal products 
ORR
Objective response rate
OS
overall survival
PD-L1
Programmed death-ligand 1
RECIST
Response Evaluation Criteria in Solid Tumors 
RR
respiration rate
SAE
serious adverse event
t
temperature
TSH
thyroid stimulating hormone
WBC
white blood cell
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Term
Definition
WOCBP
women of childbearing potential
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APPENDIX 2
ECOG PERFORMANCE STATUS
Table 1:
ECOG Performance Status
ECOG PERFORMANCE STATUS
Grade 
ECOG 
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, e.g., 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 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.
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APPENDIX 4
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) 1.1
1
EVALUATION OF LESIONS
Changes in tumor measurements and tumor responses will be assessed by the investigator using 
the RECIST 1.1 (Response Evaluation Criteria in Solid Tumors) criteria. (Eisenhauer, et al 2009.)
Source:  Eisenhauer et al New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1), European Journal of Cancer, 2009, Vol. 45, p 228-247
1.1
Assessment of overall tumor burden and measurable disease
To assess objective response or future progression, 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. When CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.2
Measurable lesions 
Measurable lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of the measurement to be recorded) with a minimum size of:
.
10 mm by CT/MRI scan - (CT/MRI scan slice thickness no greater than 5 mm)
.
10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)
 20 mm by chest x-ray
 Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.
1.3
Non-measurable lesions
 All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with 10 to < 15 mm short axis), 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 that in not 
measurable by reproducible imaging techniques.
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1.4
Special considerations regarding lesion measurability
1.4.1
Bone lesions
 Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or disappearance 
of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.
 Blastic bone lesions are non-measurable.
1.4.2
Cystic lesions
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions 
are present in the same subject, these are preferred for selection as target lesions.
1.4.3
Lesions with prior local treatment
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional 
therapy, are usually not considered measurable unless there has been demonstrated progression in 
the lesion.
1.5
Specifications by methods of measurements
1.5.1
Measurement of lesions
All measurements should be recorded in metric notation (mm). All baseline evaluations should be 
performed as close as possible to the beginning of the treatment.
1.5.2
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.
1.5.2.1
CT/MRI scan 
CT/MRI is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT/MRI scan is based on the assumption that 
CT/MRI slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness.
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1.5.2.2
Chest X-ray 
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions 
on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated 
lung.
1.5.2.3
Clinical lesions 
Clinical lesions will only be considered measurable when they are superficial and 10 mm 
diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. As previously noted, 
when lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the study.
1.5.2.4
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. 
1.5.2.5
Endoscopy, laparoscopy
The utilization of these techniques for objective tumor evaluation is not advised.
1.5.2.6
Tumor markers 
Tumor markers alone cannot be used to assess objective tumor response.  
1.6
Baseline documentation of ‘target’ and ‘non-target’ lesions
1.6.1
Target lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated
measurements.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted below, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
1.6.2
Lymph nodes
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
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Nodes that have a short axis < 10 mm are considered non-pathological and should not be recorded 
or followed.
1.7
Non-target lesions
All other lesions (or sites of disease) including pathological 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 record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).
1.8
Tumor Response evaluation 
1.8.1
Evaluation of target lesions
Complete Response (CR):  Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR):  At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progression).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
1.8.2
Special notes on the assessment of target lesions
1.8.2.1
Lymph nodes
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
Nodes that have a short axis <10 mm are considered non-pathological and should not be recorded 
or followed.
1.8.2.2
Target lesions that become ‘too small to measure’  
All lesions (nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g. 2 mm). If the radiologist is 
able to provide an actual measurement, that should be recorded, even if it is below 5 mm.
However, when such a lesion becomes difficult to assign an exact measure to then:
 if it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. 
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 if the lesion is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned (note: in case of a lymph node believed to be present and 
faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).
1.8.2.3
Target lesions that split or coalesce on treatment
 When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should 
be added together to calculate the target lesion sum. 
 As lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced 
such that they are no longer separable, the vector of the longest diameter in this instance should 
be the maximal longest diameter for the ‘coalesced lesion’.
1.9
Evaluation of non-target lesions 
While some non-target lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively at the time points specified in the protocol. 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis).
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered progression).
1.9.1
Special notes on assessment of non-target lesions
The concept of progression of non-target disease requires additional explanation as follows:
1.9.1.1
When the subject also has measurable disease
 To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. 
 A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
quality for unequivocal progression status.
1.9.1.2
When the subject has only non-measurable disease 
 To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening such that the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. 
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 A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status. 
 Because worsening in non-target disease cannot be easily quantified (by definition: if all 
lesions are non-measurable) a useful test that can be applied when assessing subjects for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e. an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, 
an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’.
 If ‘unequivocal progression’ is seen, the subject should be considered to have had overall PD 
at that point. 
1.9.1.3
Tumor markers
Tumor markers alone cannot be used to assess objective tumor responses. If markers are initially 
above the upper normal limit, however, they must normalize in order for a subject to be considered 
as having attained a complete response. 
1.10
New lesions  
The appearance of new malignant lesions denotes disease progression. The finding of a new lesion 
should be unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly important 
when the subject’s baseline lesions show partial or complete response. For example, necrosis of a 
liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the subject 
who has visceral disease at baseline and while on study has a CT or MRI brain scan ordered which 
reveals metastases. The subject’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan.
1.10.1
FDG-PET evaluation
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of the qualitative assessment of FDG-PET scanning to complement CT 
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scanning in assessment of progression (particularly possible ‘new’ disease). New lesions on the 
basis of FDG-PET imaging can be identified according to the following algorithm: 
 Negative FDG-PET at baseline, with a positive FDG-PET at follow-up might be a sign of PD 
based on a new lesion. However, other reasons for newly detected lesions with increased FDG-
PET uptake, such as inflammatory lymphnodes, should be taken into consideration.
 No FDG-PET at baseline and a positive FDG-PET at follow-up: 

If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD. 

If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial positive FDG-PET 
scan).

If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD.

Other reasons for newly detected lesions with increased FDG-PET uptake, such as 
inflammatory lymphnodes, should be taken into consideration.
1.11
Response Criteria
1.11.1
Time point response
A response assessment should occur at each time point specified in the protocol. 
For subjects who have measurable disease at baseline Table 2 provides a summary of the overall 
response status calculation at each time point.
Table 2:
Time point response: subjects with target (+/– non-target) disease.
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
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Table 2:
Time point response: subjects with target (+/– non-target) disease.
Target lesions
Non-target lesions
New lesions
Overall response
Any 
PD
Yes or No
PD
Any
Any 
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE =not evaluable.
For subjects who have non-measurable (therefore non-target) disease only, Table 3 is to be used.
Table 3:
Time point response: Subjects with non-target disease only
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as endpoint 
for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
CR = complete response, PD = progressive disease, and NE = not evaluable.
1.11.2
Missing assessments and not evaluable designation
When no imaging/measurement is done at all at a particular time point, the subject is not evaluable 
(NE) at that time point. If only a subset of lesion measurements are made at an assessment, the 
case is also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not have changed the assigned time point 
response.
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1.11.3
Confirmation of Scans and External Evaluation
 Verification of Response: Confirmation of response (CR or PR) is required. Confirmed CR 
or PR will be claimed only if the criteria for each are met at a subsequent timepoint 
(minimum 4 weeks after criteria for an objective response are first met).
 Verification of Progression: Progression of disease should be verified in cases where 
progression is equivocal. If repeat scans confirm PD, then progression should be declared using 
the date of the initial scan. If repeat scans do not confirm PD, then the subject is considered 
not to have progressive disease per RECIST 1.1.
 External Evaluation of scans: For all subjects, BMS will request the transfer of anonymized 
scans for a BMS internal or external evaluation through a third party. For tumor types where 
data from study CA209-032 will potentially be used for future NDA submissions, BMS will 
request the transfer of anonymized scans from all subjects with this tumor type for a BMS 
internal or external evaluation through a third party.
1.12
Best overall response: All time points
The best overall response is determined once all the data for the subject is known. It is defined as 
the best response designation, as determined by the investigator, recorded between the date of first 
treatment and the date of objectively documented progression per RECIST 1.1 or the date of 
subsequent therapy, whichever occurs first. For subjects without documented progression or 
subsequent therapy, all available response designations will contribute to the BOR assessment. 
The subject’s best overall response assignment will depend on the findings of both target and non-
target disease and will also take into consideration the appearance of new lesions.
Complete or partial responses may be claimed only if the criteria for each are met at a subsequent 
time point (minimum 4 weeks after criteria of objective response are first met). In this 
circumstance, the best overall response can be interpreted as in Table 4.
Table 4:
Best overall response when confirmation of CR and PR is required
Overall response
Overall response
BEST overall response
First time point
Subsequent time 
point
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
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Table 4:
Best overall response when confirmation of CR and PR is required
Overall response
Overall response
BEST overall response
First time point
Subsequent time 
point
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not evaluable.
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the subject had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
For purposes of this study, the minimum scan time from baseline for determination of SD will be 
6 weeks.
1.13
Duration of response
1.13.1
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study).
The duration of overall complete response is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented.
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1.13.2
Duration of stable disease  
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD).
1.13.3
Immune related Response Criteria
Immune related response criteria using unidimensional measurements may be used to describe 
tumor shrinkage following RECIST 1.1 defined disease progression Appendix 4. The 
methodology is the same as described above for RECIST 1.1 except:
 New lesions do not automatically denote disease progression
 The measurement of longest diameter of new measurable lesions are in included in the sum of 
the measurements of the original target lesions.
Best immune related responses, for subjects who have progression followed by tumor shrinkage 
are classified as irCR (disappearance of all lesions) or irPR (30% reduction from baseline).
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APPENDIX 5
NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
CLASSIFICATION
Class I. Patients with cardiac disease, but without resulting limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
Class II. Patients with cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal 
pain.
Class III. Patients with marked limitation of physical activity. They are comfortable at rest. Less 
that ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.
Class IV. Patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of heart failure or of the anginal syndrome may be present even at 
rest. If any physical activity is undertaken, discomfort is increased.
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APPENDIX 6
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female

A postmenopausal state 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 > 40 
mIU/mL to confirm menopause.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 months after the end of study 
treatment.*
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 

oral 

intravaginal 

transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulationb 

oral 

injectable 
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Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)c

Intrauterine device (IUD)c

Bilateral tubal occlusion

Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 

Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.

It is not necessary to use any other method of contraception when complete abstinence is 
elected. 

WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Unacceptable Methods of Contraception*

Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal Sponge with spermicide
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
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus interruptus).

Spermicide only

Lactation amenorrhea method (LAM)
* Local laws and regulations may require use of alternative and/or additional contraception 
methods.
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.

Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.

Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment.

Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end of 
treatment in the male participant.

Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of study treatment. 

Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 6.4 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
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APPENDIX 7
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number & Title
Description of Change
Brief Rationale
Cover page
Changed the Medical Monitor 
and associated contact 
information.
Synopsis, Investigational 
Product; Section 3.1, Study 
Design and Duration; Section 
3.2, Post-study Access to 
Therapy; Section 4, Study 
Drug; Section 4.5.4, Nivolumab 
Treatment Beyond Disease 
Progression
Added 24 month maximum 
duration
 
 
 
 
 
 
Synopsis, Research Hypothesis; 
Synopsis, Primary Objective; 
Section 1.2, Research 
Hypothesis; Section 1.3.1, 
Primary Objectives; Section 
8.3.1, Primary Endpoint
Changes the primary objective 
from clinical benefit rate to 
investigator-assessed objective 
response rate. 
 
 
Synopsis, Secondary 
Objectives; Section 1.3.2, 
Secondary Objectives; 
Added duration of response and 
time to response. 
 
Removed characterizing disease 
progression.
 
 
Synopsis, Schematic; Section 
3.1, Study Design and Duration
Aligned the frequency of scans 
and the primary objective to 
reflect the changes made to the 
protocol. 
 
 
Synopsis, Study Population, 
Key Inclusion Criteria; Section 
3.3.1, Inclusion Criteria
Added adenocarcinoma of the 
small bowel and adrenocortical 
carcinoma to the possible tumor 
types for inclusion. 
 
Removed option for measurable 
disease by disease-specific 
criteria
 
Provided additional information 
regarding required previous 
treatment. 
 
Changed the age of tissue sample 
from 4 months to 3 months. 
Synopsis, Study Population, 
Key Exclusion Criteria; Section 
3.3.2, Exclusion Criteria
Added adenocarcinoma of the 
colon, prostate, or rectum; 
gastrointestinal stromal tumor; 
meningioma; peritoneal 
carcinoma; primary CNS 
lymphoma, squamous carcinoma 
of the head and neck; squamous 
carcinoma of the skin; and 
carcinoma of unknown primary to 
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number & Title
Description of Change
Brief Rationale
the excluded malignancies. 
Removed gliomas. 
Synopsis, Study Assessments; 
Section 1.1.3, Rationale for 
Clinical Assessments at 28 
Weeks; Table 5.1-1, Flow 
Chart/Time and Events 
Schedule, Table 5.1-2, On-
treatment Assessments -
Nivolumab 240mg/Q2W 
CA209627
Changed the evaluation of the 
response at 16 weeks to 28 weeks.
The actual assessment timing 
have not changed. 
 
 
Synopsis, Primary Endpoint; 
Secondary Endpoints.
The primary and secondary 
objectives were updated to align 
with the changes made to the 
primary and secondary objectives. 
 
 
Synopsis, Analysis
The analyses were revised. 
 
 
 
Section 1.1.6, Duration of 
Treatment with Nivolumab
Section was added. 
 
 
 
 
 
 
Section 3.1, Study Design and 
Duration
Removed the sentence about 
survival data being collected for 1 
year after the first nivolumab 
dose.
 
Section 3.3.1, Inclusion Criteria
Changed duration of 
contraception use from 23 weeks 
to 5 months for women and 31 
weeks to 7 months for men. 
 
Section 3.3.2, Exclusion 
Criteria; Section 3.4.1, 
Prohibited and/or Restricted 
Treatments
Added a criterion to exclude 
treatment with botanical 
preparations
 
Section 4, Study Design 
Added directions to flush the 
infusion line after administration. 
 
Section 4.4, Method of 
Assigning Subject 
Identification
Clarified that only year of birth is 
collected in Germany. 
 
 
Provided additional details 
regarding tumor tissue collection. 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number & Title
Description of Change
Brief Rationale
Section 4.5, Selection and 
Timing of Dose for Each 
Subject
Added additional details 
regarding the dosing of the every 
2 weeks regimen and the every 4 
week regimen. 
. 
Section 4.5.1, Dose Delay 
Criteria
Updated the dose delay criteria
 
a.
Section 4.5.2, Criteria to 
Resume Treatment
Updated the criteria to resume 
treatment 
 
Section 4.5.3, Treatment 
Discontinuation Criteria
Updated the criteria to 
discontinue treatment. 
 
Section 4.5.4, Nivolumab 
Treatment Beyond Disease 
Progression
Language was revised 
 
Section 5.1, Flow Cart/Time 
and Events Schedule; Table 
5.1-1, Screening Procedural 
Outline 
Added a row for Serious Adverse 
Event Collection 
 
 
Changed the age of tissue samples 
from 4 months to 3 months
 
Section 5.1, Flow Cart/Time 
and Events Schedule; Table 
5.1-2, On-treatment 
Assessments - Nivolumab 
240mg/Q2 weeks CA209627
Added thyroid function testing 
and pregnancy testing beyond 
Cycle 1. 
 
 
Added notes regarding the timing 
of tumor assessments at Week 16 
and 28. The frequency of the 
assessments did not change. 
 
 
Section 5.1, Flow Cart/Time 
and Events Schedule, Table 
5.1-4, Follow-up Assessments -
All Subjects CA209627
Added vital signs
 
 
Section 5.3, Safety 
Assessments
Removed requirement for 
screening assessments to be 
performed within 28 days.
 
Section 5.3.1, Imaging 
Assessments for the Study
Added details regarding the 
collection and review of the 
Blinded Independent Central 
Review
 
Section 5.4.1, Objective 
Response Rate
Provided definition for the new 
primary endpoint.
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number & Title
Description of Change
Brief Rationale
Section 5.4.2, Secondary 
Assessments
Provided the new secondary 
endpoints and the location of the 
definitions. 
. 
Section 5.6.1, Collection of 
Tumor Tissue and Blood for 
Biomarker Analysis
Changes the age of tumor tissue 
sample to 3 months 
 
Section 6, Adverse Events
Added text to caution against 
introducing bias.
 
 
 
Added the definition of immune-
mediated adverse events
 
 
.
Section 8, Statistical 
Considerations; Section 8.1, 
Sample Size Determination
Change in primary endpoint and 
provided additional detail on the 
analysis. 
 
 
Section 8.2, Populations for 
Analysis
Removed the all evaluable 
analysis and removed the table of 
historical control benefit rates. 
 
Section 8.3.2.1, Duration of 
Response; Section 8.3.2.2, 
TTR, Section 8.3.2.3, CBR, 
Section 8.3.2.4, Overall 
Survival.
Sections were added. 
 
 
Section 8.3.2.5, Safety and 
Tolerability 
Clarified how safety and 
tolerability would be presented. 
 
 
 
 
Section 8.4, Analysis
Interim Monitoring was moved to 
Section 8.5, Interim Analyses.  
 
Section 8.4.2, Efficacy 
Analysis
Section was revised.
 
 
Section 8.4.3, Safety Analyses
More detail was added.  
 
 
Section 8.5, Interim Analyses
Incorporates text originally 
appearing in Section 8.4.
 
Section 8.5.1, Pause Rule
Section was added. 
 
 
 
Appendix 1, Statistical 
Analysis and Modeling 
Changed primary analysis to 
ORR
 
Revised Protocol No.: 02
Date: 31-May-2018
151
3.0
Approved
930100104
3.0
v

Clinical Protocol
CA209627
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number & Title
Description of Change
Brief Rationale
Appendix 2
ECOG Scale, Management 
Algorithms, RECIST Criteria, and 
New York Heart Association 
(NYHA) Functional 
Classification were separated into 
individual appendices.
 
Removed Response Criteria for 
Primary Central Nervous System 
. 
Appendix 3
Management Algorithms were 
updated. 
 
 
 
 
 
Appendix 6, Methods of 
Contraception
Updated the methods of 
contraception.
 
All
Minor formatting and 
typographical corrections
 
Revised Protocol No.: 02
Date: 31-May-2018
152
3.0
Approved
930100104
3.0
v