Clinical trial NCT03444766
Conditions: Non-Small Cell Lung Cancer (NSCLC) Non-Small-Cell Lung Carcinoma Nonsmall Cell Lung Cancer Kidney Cancer Kidney Neoplasms Renal Cancer Renal Neoplasms
Sponsor: Bristol-Myers Squibb
Start date: 2018-03-06; Completion date: 2019-07-17
Enrollment: 100 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a study of nivolumab in participants with advanced Non-Small Cell Lung Cancer or Kidney Cancer in India.

Detailed description:

Arms: arm 1: administering nivolumab only
Interventions: intervention 1: Nivolumab
Intervention descriptions: intervention 1: specified dose on specified days

Protocol documents:
Prot_001.pdf: 
Page:
1
Protocol Number:
CA209887
IND Number:
N/A
EUDRACT Number
N/A
Date
16-Nov-2017
Clinical Protocol CA209887
Safety Study of Nivolumab for Selected Advanced Malignancies in India
Medical Monitor
Hardik Patel, MD 
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 
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authorized in writing by BMS. Any supplemental information (e.g., amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, e.g., a Contract Research 
Organization (CRO).
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Original Protocol
16-Nov-2017
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
 
 
 
 
 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
5 STUDY DESIGN....................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 Data Monitoring Committee and Other External Committees ................ 
5.2 Number of Participants ..................................................................................... 
5.3 End of Study Definition .................................................................................... 
 
 
6 STUDY POPULATION ............................................................................................ 
6.1 Inclusion Criteria .............................................................................................. 
6.2 Exclusion Criteria ............................................................................................. 
6.3 Lifestyle Restrictions ........................................................................................ 
6.4 Screen Failures .................................................................................................. 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
7 TREATMENT ........................................................................................................... 
7.1 Treatments Administered .................................................................................. 
7.2 Method of Treatment Assignment .................................................................... 
7.3 Blinding............................................................................................................. 
7.4 Dosage Modification ......................................................................................... 
7.4.1 Dose Delay and Resumption of Treatment Criteria for Nivolumab ........ 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
7.5.1 Preparation and administration .............................................................. 
7.5.1.1 Calculating the dose ....................................................................... 
7.5.1.2 Preparing the infusion .................................................................... 
7.5.2 Administration of Nivolumab ................................................................... 
7.5.2.1 Disposal .......................................................................................... 
7.5.3 Retained Samples for Bioavailability / Bioequivalence ........................... 
7.6 Treatment Compliance ...................................................................................... 
 
 
 
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7.8 Treatment After the End of the Study ............................................................... 
8 DISCONTINUATION CRITERIA ........................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Post Study Treatment Study Follow-up.................................................... 
8.2 Discontinuation from the Study ........................................................................ 
8.3 Lost to Follow-Up ............................................................................................. 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
9.1 Efficacy Assessments ........................................................................................ 
9.1.1 Imaging Assessment for the Study............................................................ 
9.2 Adverse Events ................................................................................................. 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.5 Pregnancy ................................................................................................ 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
9.2.8 Other Safety Considerations .................................................................... 
9.3 Overdose ........................................................................................................... 
9.4 Safety ................................................................................................................ 
9.4.1 Clinical Safety Laboratory Assessments .................................................. 
9.4.2 Imaging Safety Assessment ...................................................................... 
 
 
 
 
 
 
9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
10 STATISTICAL CONSIDERATIONS .................................................................... 
10.1 Sample Size Determination ............................................................................. 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
10.3.1 Efficacy Analyses ................................................................................... 
10.3.2 Safety Analyses....................................................................................... 
10.3.2.1 Primary Endpoint(s) ..................................................................... 
10.3.2.2 Secondary Endpoint(s) .................................................................. 
 
 
 
12 APPENDICES ......................................................................................................... 
 
 
APPENDIX 2 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
APPENDIX 3 NIVOLUMAB OPDYTA ..................................................................... 
 
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APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 5 STUDY GOVERANCE CONSIDERATIONS .................................... 
 
APPENDIX 6 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
 
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1
SYNOPSIS
Protocol Title: Safety Study of Nivolumab for Selected Advanced Malignancies in India
Study Phase: Phase 4
 
 
 
 
 
 
 
 
 
  
 
 
 
Study Population:
The study population includes:
•
adult patients with locally advanced or metastatic NSCLC after prior chemotherapy 
•
adult patients with advanced RCC after prior therapy.
Objectives and Endpoints:
Objective
Endpoint
Primary
•
To assess the safety and tolerability of 
nivolumab for the treatment of locally 
advanced or metastatic NSCLC after 
prior chemotherapy or advanced RCC 
after prior therapy
•
Incidence and severity of treatment 
related adverse events (AEs)
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Objective
Endpoint
Secondary
•
To estimate the incidence and severity 
of treatment-related select AEs in all 
treated participants. 
•
To estimate the incidence of all 
treatment-related serious adverse events 
(SAEs)
•
To estimate the incidence of AEs that 
lead to discontinuation of treatment 
with nivolumab. 
•
Incidence and severity of treatment-
related select AEs, as specified in 
Section 10.3.2 in all treated participants
•
Incidence of all treatment-related SAEs
•
Incidence of AEs that lead to 
discontinuation from treatment with 
nivolumab
Overall Design:
This is a Phase 4, open-label, single arm, multi-center, prospective safety study to be conducted in 
India with participants with either locally advanced or metastatic NSCLC (Stage IIIb/IV NSCLC) 
with squamous histology or non-squamous histology who have progressed during or after at least 
1 prior chemotherapy (N= 70) or advanced RCC who have progressed during or after at least 
1 prior therapy (N= 30). Potential participants will undergo screening evaluations to determine 
eligibility within 28 days prior to first dose. Participants who meet the protocol-defined 
inclusion/exclusion criteria will be prospectively enrolled in a sequential manner. All enrolled 
participants will be treated with nivolumab administered intravenously over 60 minutes at 3 mg/kg 
every 2 weeks. Each 14 day dosing period will constitute a cycle. Treatment will continue as long 
as clinical benefit is observed for a maximum of 24 weeks or until treatment is no longer tolerated 
by the participant or withdrawal of consent. The treatment period for this study is 26 weeks, which 
corresponds to 24 weeks of treatment and 2 weeks of follow-up after the final on-study dose of 
nivolumab. Participants who are observed to continue to receive clinical benefit from nivolumab 
at 26 weeks will continue treatment via commercial supply (provided by BMS) as long as clinical 
benefit is observed or until treatment is no longer tolerated by the participant. Any participant who 
discontinues treatment with nivolumab before 24 weeks on study will be followed for 100 days 
after discontinuation of study drug or for a total of 26 weeks from first on-study treatment with 
nivolumab, whichever is earliest.
Safety will be evaluated throughout the treatment period and during the follow up of participants 
who discontinue treatment before 24 weeks by physical exams including vital signs, AE/SAE 
monitoring, laboratory evaluations and recording of concomitant medications.  
Data analyses will be conducted only on the safety data collected within the maximum of the 
26 week study period, which will include safety collected during the follow-up of participants who 
discontinue treatment before 24 weeks.  
All SAEs after 26 weeks of study duration for patients on commercial nivolumab supply will be 
reported to India Health Authority as part of spontaneous reporting.
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Number of Participants: 
A total of 100 participants will be enrolled: 70 NSCLC and 30 RCC
Treatment Arms and Duration: All participants will be treated with nivolumab 3mg/kg IV q 2
weeks on Day 1 of each cycle. Each treatment cycle is 14 days long. The treatment period for all 
participants is a maximum of 26 weeks. Participants who are observed to continue to receive 
clinical benefit from treatment with nivolumab at 26 weeks may continue treatment via 
commercial supply (provided by BMS) as long as clinical benefit is observed or until treatment is 
no longer tolerated by the participant.
Study treatment:
Study Drug for CA209887
Medication
Potency
IP/Non-IP
Nivolumab
10 mg/mL concentrate for 
solution for infusion
IP
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2
SCHEDULE OF ACTIVITIES
Table 2-1:
CA209887 Screening procedures and assessments
Procedure
Screening Visit 
Notes
Screening visit will occur within 28 days before start of nivolumab
Eligibility Assessments
Informed Consent
X
IVRS
X
An Interactive voice recognition system (IVRS) will be used to assign participant numbers.
Inclusion/Exclusion Criteria
X
Medical History
X
Medical history will include smoking history, and comorbidities. Mutation status of EGFR 
and ALK will be collected if available. Additional biopsies for mutation status, if not 
previously tested, are not required.   
Safety Assessments
Physical Examination
X
Includes height, weight, and ECOG PS (Appendix 1). Full physical exam required at 
baseline.
Vital Signs 
X
Temperature, BP, HR, RR. Obtain vital signs at screening visit and within 72 hours of first 
dose
Assessment of Signs and 
Symptoms
X
After obtaining Informed Consent, assess all signs and symptoms within 14 days of first 
dose, prior to study treatment initiation
Concomitant medications
X
Within 14 days of first dose
Laboratory Tests
X
Laboratory Tests performed locally within 14 days prior to first dose (unless otherwise 
specified): CBC with differential, serum chemistry (BUN or serum urea level, serum 
creatinine, sodium, potassium, calcium, magnesium, phosphate, chloride, and glucose), liver 
function tests (AST, ALT, total bilirubin, alkaline phosphatase, albumin, LDH). TSH, free 
T3, free T4 (within 28 days prior to first dose), hepatitis B surface antigen (HBsAg) and 
hepatitis C antibody (HCV Ab) or HCV RNA.
Pregnancy Test
X
Within 24 hours prior to first dose for WOCBP only (serum or urine at the site).
ALT = alanine aminotransferase, AST = aspartate aminotransferase; BP = blood pressure; BUN = blood urea nitrogen; CBC = complete blood count; 
ECOG = Eastern Cooperative Oncology Group; HR = heart rate; LDH = lactate dehydrogenase; NCI CTCAE = National Cancer Institute Common Terminology 
Criteria for AEs; RR = respiratory rate, TSH = thyroid stimulating hormone, T3 = triiodothyronine, T4 = thyroxine; WOCBP = Women of Childbearing Potential
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Table 2-2:
CA209887: On-Study Procedures and assessments
Procedure
Each Cycle
(Every 2 weeks)
Notes
Safety Assessments
Physical Measurements
(including Performance Status)
X
Collect weight and ECOG Performance Status (Appendix 1) within 72 hours prior to dosing. 
Targeted physical examination may be performed if clinically indicated and is recommended to 
include cardiovascular, gastrointestinal, pulmonary and neurological exam for participants with 
brain metastases.  
Vital Signs
X
Within 72 hours prior to dosing, tests includes temperature, BP, HR and RR
Serious Adverse Event Assessment 
X
Assessed using NCI CTCAE v 4.0 (continuously monitored throughout treatment period)
Adverse Events Assessment
X
Assessed using NCI CTCAE v 4.0(continuously monitored throughout treatment period)
Review Concomitant Medication
X
Laboratory Tests
X a, b ,c d
CBCs with differential a Serum chemistry tests b and liver function tests c should be checked every 
cycle, and the results should be obtained prior to dosing. Thyroid Function Test (TFTs) d should be 
checked every 6 weeks.
Pregnancy Test
Every 4 weeks
Completed more frequently if required by local standards (serum or urine as required by standard 
of care at the site).
Clinical Drug Supplies
Administration of nivolumab (3 
mg/kg)
X
All enrolled participants continue treatment every 2 Weeks. Treatment should be continued as long 
as clinical benefit is observed for a maximum of 24 weeks or until treatment is no longer tolerated 
by the participant or withdrawal of consent. Record Study Drug Infusion start and stop
BP = blood pressure; CBC = complete blood count; ECOG = Eastern Cooperative Oncology Group; HR = heart rate; LDH = lactate dehydrogenase; 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for AEs; RR = respiratory rate.
a CBCs with differential includes white blood cell count, lymphocyte count, absolute neutrophil count, hemoglobin, hematocrit, and platelet count. Results to be
obtained prior to dosing on infusion days.
b Serum chemistry tests include blood urea nitrogen (BUN) or serum urea level, serum creatinine, sodium, potassium, calcium, magnesium, phosphate, chloride,
and glucose.
c
Liver function tests include AST, ALT, total bilirubin, alkaline phosphatase, albumin, LDH.
d Thyroid function testing including TSH (reflex to free T3 and free T4 if abnormal result).
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Table 2-3:
CA209887: Follow-up Procedures
Procedure
Follow-up phase
Follow-up Visit 1: 30 days (+/- 5 days) after last 
dose or on the date of discontinuation 
(+/- 5 days) if date of discontinuation is greater 
than 35 days after last dose. 
Follow up Visit 2: 70 days (+/- 5 days) after Follow 
up Visit 1.
Notes
Participants who discontinue on-study treatment with nivolumab 
before 24 weeks will be followed for 100 days after the last on-study 
dose of nivolumab or for a maximum of 26 weeks from the date of 
the first on-study dose of nivolumab, whichever occurs earliest. 
Safety Assessments
Physical measurements
X
 
Vital Signs
X
Temperature, BP, HR and RR
Adverse Events 
Assessment
X
All SAEs after 26 weeks of study duration for participants on 
commercial nivolumab supply will be reported to India Health 
Authority as part of spontaneous reporting.
Serious Adverse Event 
Assessment 
X
Review Concomitant
Medication
X
Laboratory Tests
X 
Laboratory tests as listed for on treatment assessment in Table 2-2.
Pregnancy Test
X
Completed more frequently if required by local regulations (serum or 
blood as required by standard of care at the site).
BP = blood pressure; ECOG = Eastern Cooperative Oncology Group; HR = heart rate; RR = respiratory rate.
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Clinical Protocol
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4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To assess the safety and tolerability of nivolumab for the treatment 
of locally advanced or metastatic NSCLC after prior chemotherapy 
or advanced RCC after prior therapy
•
Incidence and severity of 
treatment related AEs
Secondary
•
To estimate the incidence and severity of treatment-related select 
AEs in all treated participants. 
•
To estimate the incidence of all treatment-related SAEs 
•
To estimate the incidence of AEs that lead to discontinuation of 
treatment with nivolumab. 
•
Incidence and severity of 
treatment-related select AEs, 
as specified in Section 10.3.2
in all treated participants
•
Incidence of all treatment-
related SAEs
•
Incidence of AEs that lead to 
discontinuation from 
treatment with nivolumab
5
STUDY DESIGN
5.1
Overall Design
This is a Phase 4, open-label, single arm, multi-center, prospective safety study to be conducted 
in India with participants with either locally advanced or metastatic NSCLC (Stage IIIb/IV 
NSCLC) with squamous histology or non-squamous histology who have progressed during or 
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after at least 1 prior chemotherapy (N= 70) or advanced RCC who have progressed during or 
after at least 1 prior therapy (N= 30). Potential participants will undergo screening evaluations to 
determine eligibility within 28 days prior to first dose. Participants who meet the protocol 
defined inclusion/exclusion criteria will be prospectively enrolled in a sequential manner. All 
enrolled participants will be treated with nivolumab administered intravenously over 60 minutes 
at 3 mg/kg every 2 weeks. Each 14 day dosing period will constitute a cycle. Treatment will 
continue as long as clinical benefit is observed for a maximum of 24 weeks or until treatment is 
no longer tolerated by the participant or withdrawal of consent. The treatment period for this 
study is 26 weeks, which corresponds to 24 weeks of treatment and 2 weeks of follow-up after 
the final on-study dose of nivolumab. Participants who are observed to continue to receive 
clinical benefit from nivolumab at 26 weeks will continue treatment via commercial supply 
(provided by BMS) as long as clinical benefit is observed or until treatment is no longer tolerated 
by the participant. Any participant who discontinues treatment with nivolumab before 24 weeks 
on study will be followed for 100 days after discontinuation of study drug or for a total of 26 
weeks from first on-study treatment with nivolumab, whichever is earliest.
Safety will be evaluated throughout the treatment period and during the follow up of participants 
who discontinue treatment before 24 weeks by physical exams including vital signs, AE/SAE 
monitoring, laboratory evaluations and recording of concomitant medications.  
Data analyses will be conducted only on the safety data collected within the maximum of the 26 
week study period, which will include safety collected during the follow-up of participants who 
discontinue treatment before 24 weeks.  
All SAEs after 26 weeks of study duration for participants on commercial nivolumab supply will 
be reported to India Health Authority as part of spontaneous reporting.
The study design schematic is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schematic
Physical examinations, vital sign measurements, and clinical laboratory evaluations will be 
performed at selected times throughout the dosing interval and during follow-up for those 
participants who discontinue treatment before the end of the treatment period (24 weeks). 
Participants will be closely monitored for AEs throughout the study.
5.1.1
Data Monitoring Committee and Other External Committees
Not applicable.
5.2
Number of Participants
A total of 100 participants will be enrolled: 
•
70 participants with locally advanced or metastatic NSCLC after prior chemotherapy.
•
30 participants with advanced renal cell carcinoma (RCC) after prior therapy.
The sample size calculation is presented in Section 10.1.
5.3
End of Study Definition
The start of the trial is defined as the first visit of the first person as part of screening for the trial. 
The end of trial is defined as the last visit of the last participant. 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.  
In this trial, the study will be completed on the date on which safety data (primary endpoint) are
collected for the last participant on study. 
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6
STUDY POPULATION  
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants 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 
participant care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests and other requirements of the study.
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2) Type of Participant and Target Disease Characteristics
a) Locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior 
chemotherapy OR advanced renal cell carcinoma (RCC) after prior therapy.
b) Eastern Cooperative Oncology Arm (ECOG) (Appendix 1) performance status of ≤ 1
c) Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to 
randomization.
3) Age and Reproductive Status
a) Males and Females, ages ≥ 18 or age of majority
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 treatment.
c) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of treatment with nivolumab and 5 months 
after the last dose of study treatment. {i.e., 30 days (duration of ovulatory cycle) plus the 
time required for the investigational drug to undergo approximately 5 half-lives}.
d) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of study treatment with nivolumab and 7 
months after the last dose of study treatment {i.e., 90 days (duration of sperm turnover) 
plus the time required for the investigational drug to undergo approximately five half-
lives.}
e) 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 participants 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 4 which have a failure rate of < 1% when used consistently and correctly.
6.2
Exclusion Criteria
1) Medical Conditions
a) Women who are pregnant or breastfeeding
b) Women with a positive pregnancy test at enrollment or prior to administration of study 
medication
c) Participants with untreated, symptomatic central nervous system (CNS) metastases.
d) Participants with carcinomatous meningitis.
e) Participants with active, known or suspected autoimmune disease. Participants with type 
I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll
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f)
Participants with a condition requiring systemic treatment with either corticosteroids (> 
10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 
days of first dose of study drug. Inhaled or topical steroids, and adrenal replacement 
steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
g) Other active malignancy requiring concurrent intervention.
h) Participants with previous malignancies (except non-melanoma skin cancers, and the 
following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, 
melanoma, or breast) are excluded unless a complete remission was achieved at least 2 
years prior to study entry AND no additional therapy are ongoing and required during the 
study period with the exception of anti-estrogen/androgen therapy or bisphosphonates. 
Participants with other active malignancy requiring concurrent intervention are excluded.
i)
All toxicities attributed to prior anti-cancer therapy other than alopecia, fatigue, or 
peripheral neuropathy must have resolved to Grade 1 (NCI CTCAE version 4) or baseline 
before administration of study drug.
j)
Participants must have recovered from the effects of major surgery or significant 
traumatic injury at least 14 days before the first dose of study treatment.
k) Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be 
performed at sites where mandated locally.
2) Prior/Concomitant Therapy
a) Ongoing or planned administration of anti-cancer therapies other than those specified in 
this study
b) Use of corticosteroids or other immunosuppressive medications with exceptions detailed 
in the protocol consistent with nivolumab program.
c) Treatment with any investigational agent within 14 days of first administration of study 
treatment
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3) Physical and Laboratory Test Findings
a) WBC < 2000/mm3
b) Neutrophils < 1500/mm3
c) Platelets < 100*103/mm3
d) Hemoglobin < 9.0 g/dL
e) Serum creatinine > 1.5 x ULN or calculated creatinine clearance < 40 mL/min (using the 
Cockcroft-Gault formula)
f)
AST/ALT: > 3.0 x ULN
g) Total bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0x ULN)
h) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, e.g. Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative).Any serious or 
uncontrolled medical disorder or active infection with hepatitis that may be reactivated.
4) Allergies and Adverse Drug Reaction
a) History of severe hypersensitivity reactions to other monoclonal antibodies.
b) History of allergy or intolerance (unacceptable adverse event) to study drug components, 
or Polysorbate-80-containing infusions.
c) Participants with history of life-threatening toxicity related to prior immune therapy (eg. 
anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically 
targeting T-cell co-stimulation or immune checkpoint pathways) except those that are 
unlikely to re-occur with standard countermeasures (eg. Hormone replacement after 
adrenal crisis).
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to 
continue as a participant. Strict conditions apply and Bristol-Myers Squibb approval is 
required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required
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6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from 
regulatory authorities. Minimal information includes date of consent, demography, screen failure 
details, eligibility criteria, and any serious AEs.
6.4.1
Retesting During Screening or Lead-In Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (i.e., participant has not been randomized / has 
not been treated). If re-enrolled, the participant must be re-consented
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).
The most current result prior to enrollment is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2-1, CA209887 Screening 
Procedure and Assessments may be repeated in an effort to find all possible well-qualified 
participants. Consultation with the Medical Monitor may be needed to identify whether repeat 
testing of any particular parameter is clinically relevant.
7
TREATMENT
Participants should receive nivolumab at a dose of 3 mg/kg as a 60-minute IV infusion, on Day 1 
of each treatment cycle every 2 weeks for 24 weeks or until progression, unacceptable toxicity, 
withdrawal of consent, or the study ends, whichever occurs first. Participants should begin study 
treatment within 3 calendar days of enrollment.
Dosing calculations should be based on the body weight assessed at baseline. It is not necessary 
to re-calculate subsequent doses if the participant weight is within 10% of the weight used to 
calculate the previous dose. All doses should be rounded up or to the nearest milligram per 
institutional standard.
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation
Study 
treatment
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
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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.
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products.
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Table 7-1:
Study treatments for CA209887
Product Description / 
Class and Dosage 
Form
Potency
IP/Non-IMP
Blinded or Open 
Label
Packaging / 
Appearance
Storage Conditions
(per label)
Nivolumab Solution for 
Injectiona
100 mg (10 mg/mL 
concentrate)
IP
Open label
10 mL per vial
(5 or 10 vials per 
carton)
Store at 2○ - 8○ C Protect 
from light and freezing
a Nivolumab is labeled as BMS-936558-01 Solution for Injection 
NOTE: Medications used to treat BMS-936558 (nivolumab)-related infusion reactions are (eg, diphenhydramine, acetaminophen/paracetamol, corticosteroids) 
considered NIMPs (non-investigational products) and will not be provided by the sponsor. These will be obtained by the investigational sites as marketed 
product, which should be stored in accordance to the package insert. For further details related to these medications and nivolumab-related infusion reactions, 
please see Section 7.7.3
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7.1
Treatments Administered
Table 7.1-1:
Selection and Timing of Dose
Study Treatment
Unit dose 
strength(s)/Dosage 
level(s)
Dosage formulation
Frequency of 
Administration
Route of Administration
nivolumab
3 mg/kg
every 2 weeks 
IV
7.2
Method of Treatment Assignment
An IVRS will be used to assign participant numbers. 
All participants will receive treatment with nivolumab in an open-label fashion. Study treatment 
will be dispensed at the study visits as listed in Schedule of Activities (Section 2). 
7.3
Blinding
This is an open-label study, blinding procedures are not applicable.
7.4
Dosage Modification
There will be no dose escalations or reductions of nivolumab allowed. Participants may be dosed 
no less than 12 days from the previous dose during q2w cycles. Premedications are not 
recommended for the first dose of nivolumab.
Participants
should be carefully monitored for infusion reactions during nivolumab 
administration. If an acute infusion reaction is noted, participants should be managed according 
to Section 7.7.3.
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
participant tolerates the treatment. Dosing visits are not skipped, only delayed.
Nivolumab Injection, 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 1 mg/mL. 
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. 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles.
7.4.1
Dose Delay and Resumption of Treatment Criteria for Nivolumab
Dosing delay or discontinuation of nivolumab may be required based on individual safety and
tolerability. Guidelines for permanent discontinuation, withholding of doses and resumption of 
treatment are included in the Nivolumab India Prescribing Information (Appendix 3). 
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7.5
Preparation/Handling/Storage/Accountability
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 Participants. The investigational product must be dispensed only from official study sites 
by authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment 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 treatment arise, the study treatment
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (e.g., required diluents, administration sets).
7.5.1
Preparation and administration
7.5.1.1
Calculating the dose
The prescribed dose for the participant is given in mg/kg. Based on this prescribed dose,
calculate the total dose to be given. More than 1 vial of nivolumab concentrate may be needed
to give the total dose for the participant.
•
The total nivolumab dose in mg = the participant’s weight in kg × the prescribed dose in
mg/kg.
•
The volume of nivolumab concentrate to prepare the dose (mL) = the total dose in mg,
divided by 10 (the nivolumab concentrate strength is 10 mg/mL).
7.5.1.2
Preparing the infusion
Take care to ensure aseptic handling when you prepare the infusion. The infusion should be
prepared in a laminar flow hood or safety cabinet using standard precautions for the safe
handling of intravenous agents.
Nivolumab can be used for intravenous administration either:
•
without dilution, after transfer to an infusion container using an appropriate sterile syringe; or
•
after diluting to concentrations as low as 1 mg/mL. The final infusion concentration should
range between 1 and 10 mg/mL. Nivolumab concentrate may be diluted with either:
−
sodium chloride 9 mg/mL (0.9%) solution for injection; or
−
50 mg/mL (5%) glucose solution for injection.
STEP 1
−
Inspect the nivolumab concentrate for particulate matter or discoloration. Do not shake
the vial. Nivolumab concentrate is a clear to opalescent, colorless to pale-yellow liquid.
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Discard the vial if the solution is cloudy, is discolored, or contains particulate matter
other than a few translucent-to-white particles.
•
Withdraw the required volume of nivolumab concentrate using an appropriate sterile syringe.
STEP 2
•
Transfer the concentrate into a sterile, evacuated glass bottle or intravenous container (PVC
or polyolefin).If applicable, dilute with the required volume of sodium chloride 9 mg/mL
(0.9%) solution for injection or 50 mg/mL (5%) glucose solution for injection. Gently
mix the infusion by manual rotation. Do not shake.
7.5.2
Administration of Nivolumab
Nivolumab infusion must not be administered as an intravenous push or bolus injection.
Administer the nivolumab infusion intravenously over a period of 60 minutes.
Nivolumab infusion should not be infused at the same time in the same intravenous line with
other agents. Use a separate infusion line for the infusion.
Use an infusion set and an in-line, sterile, non-pyrogenic, low protein binding filter (pore size
of 0.2 μm to 1.2 μm).
Nivolumab infusion is compatible with:
•
PVC containers
•
Polyolefin containers
•
Glass bottles
•
PVC infusion sets
•
In-line filters with polyethersulfone membranes with pore sizes of 0.2 μm to 1.2 μm.
After administration of the nivolumab dose, flush the line with sodium chloride 9 mg/mL (0.9%)
solution for injection or 50 mg/mL (5%) glucose solution for injection.
7.5.2.1
Disposal
Do not store any unused portion of the infusion solution for reuse. Any unused medicinal product
or waste material should be disposed of in accordance with local requirements.
•
Further guidance and information for final disposition of unused study treatment are provided 
in Appendix 5.  
7.6
Treatment Compliance
Administration of nivolumab will be documented on the case report form, including start and 
stop time for each infusion. 
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7.7.2
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, 
delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
7.7.3
Treatment of Nivolumab-Related Infusion Reactions
Severe infusion reactions have been reported in clinical trials of nivolumab as specified in the 
Nivolumab India Prescribing Information (Appendix 3). In case of a severe or life-threatening 
infusion reaction, the nivolumab infusion must be discontinued and appropriate medical therapy 
administered. Participants with mild or moderate infusion reaction may receive nivolumab with 
close monitoring and use of premedication according to local treatment guidelines for 
prophylaxis of infusion reactions.
7.8
Treatment After the End of the Study
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study treatment. Study treatment 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. In this study, 
participants who are observed to continue to receive clinical benefit from treatment with 
nivolumab at the end of 26 weeks, may continue treatment via commercial supply, with 
nivolumab supplied by BMS. 
BMS reserves the right to terminate access to BMS supplied study treatment if any of the 
following occur: a) the study is terminated due to safety concerns; b) the development of 
nivolumab is terminated for other reasons, including but not limited to lack of efficacy and/or not 
meeting the study objectives; c) the participant can obtain medication from a government 
sponsored or private health program. In all cases BMS will follow local regulations
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8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment 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 participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant 
to provide this information
•
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 participant
•
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 (e.g., infectious disease) illness
Additional criteria for the discontinuation of nivolumab as recommended in the Nivolumab India 
Prescribing Information is presented in Appendix 3.
Refer to the Schedule of Activities for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In the event a normal healthy female participant becomes 
pregnant during a clinical trial, the study treatment must be discontinued immediately. In most 
cases, the study treatment will be permanently discontinued in an appropriate manner (e.g., dose 
tapering if necessary for participant safety). Please call the BMS Medical Monitor within 24 
hours of awareness of the pregnancy. If the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study treatment, a discussion between the 
investigator and the BMS Medical Monitor/designee must occur.
All participants who discontinue study treatment should comply with protocol specified follow-
up procedures as outlined in Section 2. The only exception to this requirement is when a 
participant withdraws consent for all study procedures including post-treatment study follow-up 
or loses the ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the 
treatment of either a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason 
for the discontinuation must be documented in the participant’s medical records and entered on 
the appropriate case report form (CRF) page.
8.1.1
Post Study Treatment Study Follow-up
Participants who discontinue study treatment before 24 weeks will be followed for 100 days after 
the last dose of nivolumab or for a total of 26 weeks from first on-study treatment with 
nivolumab whichever is earliest.
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Participants who continue to benefit clinically from nivolumab at 26 weeks will continue 
treatment via commercial supply (provided by BMS) as long as clinical benefit is observed or 
until treatment is no longer tolerated by the participant. AEs/SAEs for participants receiving 
commercial supply will be reported via spontaneous reporting.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment 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 participant specifically withdraws consent for any further contact with him/her or 
persons previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment 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 participant 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.
•
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate participants to determine and report their 
ongoing status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical 
records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain 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 participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’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 participant remains lost to follow-up, then the last known alive date 
as determined by the investigator should be reported and documented in the participant’s
medical records.
9
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and timing are summarized in the Schedule of Activities. 
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•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of informed consent may be utilized for screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has been 
performed within the timeframe defined in the Schedule of Activities.
9.1
Efficacy Assessments
This is a safety study of nivolumab, required as a post marketing commitment per condition of 
approval by the Indian Health Authority. Clinical benefit is not a formal assessment in this study.
However, clinical benefit will be assessed by the treating physician as part of routine practice in 
the decision to continue or discontinue treatment with nivolumab.
9.1.1
Imaging Assessment for the Study
Imaging assessment is not included in this study due to very short duration of treatment.
At the sponsor’s discretion, scans may be collected for review.
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 6.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or the study, or that caused the 
participant to discontinue before completing the study. 
Contacts for SAE reporting are specified in Appendix 6.
Immune-mediated 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.
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9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious AE information should begin at initiation of study treatment until 
the follow-up contact, at the time points specified in the Schedule of Activities (Section 2). 
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 participants.
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the participant’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, during treatment, and within 
100 days or a maximum of 26 weeks of discontinuation of dosing, whichever is earliest. If 
applicable, SAEs must be collected that relate to any later protocol-specified procedure (e.g., 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.
•
Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the appropriate section of the eCRF section.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 6. 
•
The investigator will submit any updated SAE data to the sponsor within 24 hours of this 
being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the 
study treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 6.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. (In order to prevent reporting bias, participants
should not be questioned regarding the specific occurrence of one or more AEs.)
9.2.3
Follow-up of AEs and SAEs
•
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section Appendix 6).
•
Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
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•
 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.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
Section 9.2 will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 6.
9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
•
An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
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. A SUSAR (Suspected, 
Unexpected Serious Adverse Reaction) is a subset of SAEs and will be reported to the 
appropriate regulatory authorities and investigators following local and global guidelines and 
requirements.
All SAEs must be collected that occur during the screening period and during the treatment 
period and within 100 days or a maximum of 26 weeks of discontinuation of dosing, whichever 
is earliest, as specified in the study design Section 5.1.
For participants assigned to treatment and never treated with study drug, SAEs should be 
collected for 30 days from the date of treatment assignment.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Appendix 6
In most cases, the study treatment will be permanently discontinued in an appropriate manner 
(e.g., dose tapering if necessary for participant safety). Please call the BMS Medical Monitor 
within 24 hours of awareness of the pregnancy.
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.
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Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee 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.
9.2.6
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 participant to have study treatment
discontinued or interrupted
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (e.g., anemia versus low hemoglobin value).
9.2.7
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 6 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.
9.2.8
Other Safety Considerations
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly.
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9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 9.2).
9.4
Safety
Safety will be assessed from the screening period, during the treatment phase and, for those 
participants who discontinue treatment before 24 weeks, during the follow up period. Safety 
assessments include physical exam, vital signs, AE/SAE assessments, recording of concomitant 
medications, and laboratory assessments.  For WOCBP, a pregnancy test (serum or urine) is also 
required 24 hours prior to the first dose and at least monthly during the treatment phase of the 
study.
Planned time points for all safety assessments are listed in the Schedule of Activities.
9.4.1
Clinical Safety Laboratory Assessments
The schedule of laboratory assessment to be conducted at screening, during treatment, and 
during follow up for those participants who discontinue treatment before 24 weeks of treatment 
is presented in Table 2-1, Table 2-2, and Table 2-3. Specific laboratory assessments to be 
performed throughout the study are listed in Table 9.4.1-1. 
•
Investigators must document their review of each laboratory safety report.
Table 9.4.1-1:
CA209887 - Laboratory Assessments
Hematology
Complete Blood Count (CBC) includes
Hemoglobin
Hematocrit
lymphocyte count, 
absolute neutrophil count (ANC)
Total leukocyte count, including differential
Platelet count
Serum Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Creatinine
Blood Urea Nitrogen (BUN) or serum urea level
Uric acid
Fasting glucose
Total Protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Magnesium
Creatinine clearance (CLcr)- screening only
Serology
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Table 9.4.1-1:
CA209887 - Laboratory Assessments
Hepatitis B surface antigen (HBsAg) and hepatitis C antibody (HCV Ab) or HCV RNA (screening only).
Other Analyses
Thyroid function testing including TSH (reflex to free T3 and free T4 if abnormal result).
Pregnancy test (WOCBP only: screening, every 4 week during treatment, and during follow up for those 
participants who discontinue treatment before 24 weeks as presented in Table 2-3
Follicle stimulating hormone (FSH) (screening only for women only) use as applicable
9.4.2
Imaging Safety Assessment
Not Applicable.
 
 
9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination
The study is projected to enroll a minimum of 100 participants (70 NSCLC participants and 30
RCC participants). The total sample size for this study is based on logistical considerations. The
sample size meets regulatory requirement for safety update submission.
In global clinical studies, treatment-related AEs of any grade occurred approximately 65% and of 
Grade 3-4 occurred approximately 10% in nivolumab users with NSCLC; treatment-related AEs 
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of any grade occurred approximately 80% and of grade 3-4 occurred approximately 20% in 
nivolumab users with RCC. Assuming these event rates, there is approximately 99% probability 
to observe at least 37 treatment-related AEs of any grade and approximately 84% probability to 
observe at least 5 treatment-related AEs of grade 3-4 in the 70 NSCLC participants; there is 
approximately 97% probability to observe at least 20 treatment-related AEs of any grade and 
approximately 88% probability to observe at least 4 treatment-related AEs of grade 3-4 in the 30
RCC participants.
Given the proposed sample size, the 95% confidence intervals for relevant AE rates are 
presented in Table 10.1-1
Table 10.1-1:
CA209887: Estimated Incidence Rates and 95% CIs
Incidence Rate (%)
Sample Size
Lower 95% CI (%)
Upper 95% CI (%)
5
30
0.36
19.71
70
1.22
13.01
100
1.64
11.28
10
30
2.11
26.53
70
4.12
19.52
100
4.90
17.62
20
30
7.71
38.57
70
11.39
31.27
100
12.67
29.18
30
30
14.73
49.40
70
19.62
42.13
100
21.24
39.98
40
30
22.66
59.40
70
28.47
52.41
100
30.33
50.28
50
30
31.30
68.70
70
37.80
62.20
100
39.83
60.17
60
30
40.60
77.34
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Table 10.1-1:
CA209887: Estimated Incidence Rates and 95% CIs
Incidence Rate (%)
Sample Size
Lower 95% CI (%)
Upper 95% CI (%)
70
47.59
71.53
100
49.72
69.67
70
30
50.60
85.27
70
57.87
80.38
100
60.02
78.76
Exact confidence interval based on Clopper-Pearson method.
10.2
Populations for Analyses
Table 10.2-1:
CA209887: Population for Analyses
Population
Description
All enrolled participants
All participants who sign informed consent and were registered into the IVRS.
All treated participants
All Participants who received any nivolumab. This is the primary population 
for safety analyses. Subpopulation analyses will be conducted by tumor type 
and tumor histology (SQ or NSQ in NSCLC).
10.3
Statistical Analyses
The study is intended to provide information regarding the safety profile for participants in India,
and will contribute additional information to the overall safety profile of nivolumab. Due to the 
small sample size, this study should not be directly compared to the data from any other country.
Unless specified otherwise, all analyses will be tabulated in 3 columns: NSCLC, RCC, and the 2
cancer types pooled.
10.3.1
Efficacy Analyses
Clinical benefit from treatment with nivolumab will not be analyzed in this study due to the very 
short duration of treatment. 
10.3.2
Safety Analyses
Data analyses will be conducted only on the safety data collected within the maximum of the 26 
week study period, which will include safety collected during the follow-up of participants who 
discontinue treatment before 24 weeks.  
All SAEs after 26 weeks of study duration for participants on commercial nivolumab supply will 
be reported to India Health Authority as part of spontaneous reporting.
10.3.2.1
Primary Endpoint(s)
The primary endpoint is the incidence and severity of all treatment-related adverse events. 
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10.3.2.2
Secondary Endpoint(s)
The secondary endpoints include:
1) Incidence and severity of all treatment-related select adverse events which are as follows: 
•
Pulmonary toxicity
•
Gastrointestinal toxicity (diarrhea or colitis)
•
Endocrinopathies
•
Hepatotoxicity (including asymptomatic LFT elevations)
•
Renal toxicity
•
Skin toxicity
•
Neurological toxicity
•
Hypersensitivity/infusion reactions
2) Incidence of serious treatment-related adverse events
3) Incidence and severity of adverse events that lead to discontinuation.
All safety data will be summarized and listed for all treated participants. All on-study AEs, 
SAEs, treatment-related AEs, treatment-related SAEs and select AEs will be summarized using 
worst grade per NCI CTCAE v4.0 by system organ class and Medical Dictionary for Regulatory 
Affairs (MedDRA) preferred term. On-study laboratory abnormalities 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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12
APPENDICES
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APPENDIX 2
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
adverse event
ALK
Alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
Aspartate aminotransferase
β-HCG
beta-Human Chorionic Gonadotrophin
BA/BE
bioavailability/bioequivalence
%BE
percent biliary excretion
BMS
Bristol-Myers Squibb
BP
blood pressure
BTLA
B and T lymphocyte attenuator
BUN
blood urea nitrogen
Ca++
calcium
CBC
complete blood count
CD28
cluster of differentiation 28
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
cm
centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
minimum observed concentration
CNS
Central nervous system
CRF
Case Report Form, paper or electronic
CTLA-4
cytotoxic T lymphocyte antigen-4
Ctrough
Trough observed plasma concentration
CV
coefficient of variation
CYP
cytochrome p-450
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Term
Definition
D/C
discontinue
dL
deciliter
ECG
electrocardiogram
EC50
half maximal effective concentration
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eg
exempli gratia (for example)
EGFR
estimated glomerular filtration rate.
F
bioavailability
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
g
gram
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
h
hour
HBsAg
hepatitis B surface antigen
HBV
Hepatitis B virus
HCO3-
bicarbonate
HCV ab
hepatitis C virus antibody
HCV RNA
hepatitis C virus ribonucleic acid
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
IC50
half maximal inhibitory concentration
ie
id est (that is)
IEC
Independent Ethics Committee
IL
interleukin
IMP
investigational medicinal products
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Term
Definition
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IU
International Unit
IV
intravenous
IVRS
interactive voice recognition system
kg
kilogram
L
liter
LDH
lactate dehydrogenase
mg
milligram
Mg++
magnesium
min
minute
mL
milliliter
mmHg
millimeters of mercury
MR
medical research
MS
mass spectrometry
MTD
maximum tolerated dose
μg
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
ng
nanogram
NIMP
non-investigational medicinal products 
NCI CTCAE
National Cancer Institute Common Terminology Criteria for AEs
NSCLC
non-small cell lung cancer
PD-1
programmed death-1
PS
Performance status
PT
prothrombin time
PTT
partial thromboplastin time
QC
quality control
RBC
red blood cell
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Term
Definition
RCC
renal cell carcinoma
RR
respiration rate
SAE
serious adverse event
SD
standard deviation
SOP
Standard Operating Procedures
Subj
subject
t
temperature
T
time
T3 
triiodothyronine 
T4
thyroxine
TCR
T-cell receptor
TSH
thyroid stimulating hormone
UV
ultraviolet
W
washout
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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SAP_000.pdf: 
Statistical Analysis Plan for 
 
Official Title of Study 
Safety Study of Nivolumab for Selected Advanced Malignancies in India 
NCT03444766 
07-May-2019