Clinical trial NCT02750514
Conditions: Advanced Cancer
Sponsor: Bristol-Myers Squibb
Start date: 2016-05-09; Completion date: 2020-01-29
Enrollment: 295 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether Nivolumab, in combination with other therapies, is effective in patients with advanced Non-Small Cell lung cancer

Detailed description:

Arms: arm 1: Nivolumab Monotherapy - Arm associated with this intervention is closed. Nivolumab is no longer given as an active comparator arm 2: Nivolumab in combination with Dasatinib arm 3: Nivolumab in combination with Relatlimab arm 4: Nivolumab in combination with Ipilimumab arm 5: Nivolumab in combination with BMS- 986205
Interventions: intervention 1: Nivolumab intervention 2: Dasatinib intervention 3: Relatlimab intervention 4: Ipilimumab intervention 5: BMS-986205
Intervention descriptions: intervention 1: Arm associated with this intervention is closed. Nivolumab is no longer given as an active comparator. intervention 2: None intervention 3: None intervention 4: None intervention 5: Specified dose on specified days

Protocol documents:
Prot_001.pdf: 
Page:
1
Protocol Number:
CA018001
IND Number:
IND 127,405
EUDRACT Number
2016-001835-11
Date:
10-Feb-2016
Revised Date:
22-Apr-2019
Clinical Protocol CA018001
A Phase 2, Fast Real-time Assessment of Combination Therapies in Immuno-ONcology Study in 
Subjects with Advanced Non-small Cell Lung Cancer (FRACTION-Lung)
Revised Lung Master Protocol: 07
Incorporates Administrative Letter: 01
Study Director / Medical Monitor
Praveen Aanur, MD, MPH
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 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).
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Clinical Protocol
CA018001
BMS-986217
FRACTION-Lung
Revised Protocol No.: 07
Date: 22-Apr-2019
2
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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Clinical Protocol
CA018001
BMS-986217
FRACTION-Lung
Revised Protocol No.: 07
Date: 22-Apr-2019
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 07
22-Apr-2019
Removed option to retreat after follow-up begins and removed
Response/Survival Follow-up periods. Inclusion criteria 2) c) ii) and 2) c) 
iii) were deemed no longer applicable and inclusion criterion 2) c) iv) was 
added. Additional research retention was aligned throughout the protocol. 
 
Appendix 04 (Revised Protocol Summary of Change History) was
added. Language (Inclusion Criteria, WOCBP, Adverse Events, Pregnancy)
was updated to align with the current BMS Protocol Model Document.
Administrative 
Letter 01
13-Nov-2019
Study Director/Medical Monitor was updated. Clarification was made that 
during screening of patients for Track 4, the results of the PD-L1 testing 
must be obtained by the site prior to randomization and communicated to 
the study team; study team will inform the site if randomization may occur.
Revised 
Protocol 06
12-Apr-2018
Removed stratification by PD-L1 expression in Track 4 and introduced the 
option of new randomization schedules in Sub-Protocols. Two-stage design 
may be used in Track 5, as opposed to a single-stage design, based on 
specific Sub-Protocols. Emphasis added to direct readers to Sub-Protocols 
for additional inclusion and exclusion criteria including the following: 
inclusion criteria 1c and 3. Emphasis added to direct readers to Sub-
Protocols for additional statistical considerations. Inclusion criteria 2.c.i was 
modified to note that EGFR testing must be performed using tumor tissue. 
Urinalysis added to the screening and the baseline for retreatment/re-
randomization procedural outlines. Added clarification that death resulting 
from disease progression within 100 days of discontinuation of dosing must 
be reported as an SAE within 24 hours. Minor formatting and typographical 
corrections.
Revised 
Protocol 05
16-Feb-2017
Incorporates Amendment 05
Amendment 05
16-Feb-2017
Removed the FRACTION-Lung nivolumab monotherapy treatment arm, 
including nivolumab monotherapy run-in, consolidated 3 tracks into 2 tracks 
(PD-1/PD-L1 treatment naïve and experienced), and simplified the study 
design accordingly. Clarified study assessments for pulse oximetry. 
Removed patient-reported outcome assessment of quality of life at 
screening, as this is also being performed at baseline. Updated data from the 
literature regarding anti-PD-1 and other targeted therapies. Updated 
eligibility criteria to clarify the population for Track 4 (ie, PD-1/PD-L1 
treatment naïve with up to 1 prior therapy for progressive or recurrent 
disease). Added sample size determination for Tracks 4 and 5 and simplified 
sample size determination for Tracks 1, 2, and 3. Added assessment 
schedule for retreatment/re-randomization in place of existing footnote, for 
clarity. Additionally, minor clarifications and typographical errors have also 
been made throughout the document.
Revised 
Protocol 04
13-Oct-2016
Incorporates Amendment 04
Amendment 04
13-Oct-2016
Removed the Treatment Procedural Outline tables (previously Table 5.1-2 
and Table 5.1-3) and added to Sub-Protocol A. Updated exclusion criteria to 
clarify all subjects with active CNS metastases are excluded. Clarified 
prohibition of concurrent neoplastic treatment. Corrected typographical 
errors and made minor clarifications also.
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FRACTION-Lung
Revised Protocol No.: 07
Date: 22-Apr-2019
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Document
Date of Issue
Summary of Change
Revised 
Protocol 03
21-Sep-2016
Incorporates Amendment 03
Amendment 03
21-Sep-2016
Updated to include Management Algorithms for Immuno-Oncology Agents 
(Appendix 3) that were not included in Revised Protocol 02.
Revised 
Protocol 02
27-Jul-2016
Incorporates Amendment 02
Amendment 02
27-Jul-2016
Updated to remove requirement for platinum based chemotherapy as one of 
the prior treatments for Tracks 1 and 2. Removed the option for less 
effective methods of birth control. The exclusion criteria for patients with 
CNS metastases was clarified. Section 3.5.1 was updated to remove the 
prohibition of receptor activator of nuclear kappa-B ligand inhibitors or 
bisphonates. The term “Pretreatment AEs” was changed to “Assessment of 
Baseline Signs and Symptoms”. Figure 8.1.3-1 was updated to fix a 
typographical error in the Stage 2 number of subjects (changed 15 to 23). 
Corrected typographical errors and made minor clarifications also. 
Revised 
Protocol 01
08-Apr-2016
Incorporates Amendment 01
Amendment 01
08-Apr-2016
Updated the statistical study design from a 2-stage design to a 4 stage 
design. Additionally, updates were made to the study design figures and 
tables to clarify retreatment and re-randomization options, including the 
procedures required for re-baselining prior to re-randomization and re-
treatment. 
 
Corrected typographical errors and made minor clarifications. also 
Original 
Protocol
10-Feb-2016
Not applicable
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FRACTION-Lung
OVERALL RATIONALE FOR REVISED PROTOCOL 07:
 
 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis
The text in the synopsis was updated.
 
Section 3.1.1 FRACTION-
Lung Track 4 (Naïve) and 
5 (Experienced) Design
Removal of option of retreatment for subjects with 
CR, PR, or SD who enter study follow up.
 
 
 
 
 
Section 3.1.1 FRACTION-
Lung Track 4 (Naïve) and 
5 (Experienced) Design,
Figure 3.1.1-1 Track 4 and 
5 Study Design
The option in the study schematic to “re-treat with 
current assigned study treatment, 1 time only 
(additional 6 cycles/24 weeks)” once the subject 
enters follow-up was removed.
Note b was adjusted to remove reference to 
Response and Survival Follow-up periods.
Note d was adjusted to remove retreatment options 
after progression once in follow-up.
 
 
 
 
 
Section 3.2 Study Phases
Updated the number of phases of the study from 4 
to 3 and removed reference to response/survival 
follow-up and re-treatment.
 
 
Section 3.2.3.1 Safety 
Follow-up
Section 3.6 
Discontinuation of 
Subjects Following any 
Treatment with Study Drug
Section 5.1 Flow 
Chart/Time and Events 
Schedule
Section 5.3 Safety 
Assessments
Section was updated to remove reference to 
retreatment.
 
 
 
 
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07
Section Number & 
Title
Description of Change
Brief Rationale
Section 3.2.3.2 Response 
Follow-up
Section 3.2.3.3 Survival 
Follow-up
Section 3.2.3.4 
Retreatment During 
Survival Follow-up
Sections were removed.
 
 
 
 
 
Section 3.4.1 Inclusion 
Criteria
The following 2 inclusion criteria were deemed no 
longer applicable:
Inclusion Criterion 2) c) ii) If tested for ALK 
translocations, use of an approved test is strongly 
encouraged.
Inclusion Criterion 2) c) iii) Subjects with unknown 
or indeterminate ALK status may be enrolled.
These criteria were replaced with Criterion 2) c) iv) 
“All subjects with nonsquamous histology must 
have been tested for ALK rearrangements. Use 
of an approved test is strongly encouraged.”
 
Section 3.4.1 Inclusion 
Criteria
Inclusion criteria 3 e) was modified to include fetal 
protection language as well as language clarifying 
that azoospermeric males are exempt from 
contraceptive requirements unless the potential 
exists for fetal toxicity due to study drug being 
present in seminal fluid, even if the participant 
has undergone a successful vasectomy or if the 
partner is pregnant.
 
 
Section 3.4.1 Inclusion 
Criteria
Addition of language:  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 and when applicable, the potential of 
fetal toxicity occurring due to transmission of 
study drug, present in seminal fluid, to a 
developing fetus, even if the participant has 
undergone a successful vasectomy or if the 
partner is pregnant.
 
 
 
Section 3.4.1 Inclusion 
Criteria
Additional details were added to the “Highly 
Effective Methods of Contraception.” “Less than 
Highly Effective Methods of Contraception” were 
added. It was clarified that “Male participants 
with female partners of childbearing potential 
are eligible to participate if they agree to 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.”
 
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07
Section Number & 
Title
Description of Change
Brief Rationale
Section 3.4.3 Women of 
Child Bearing Potential
A detailed description of women who are NOT of 
childbearing potential was added and the definition 
of “menopause” was replaced with the definition of 
“a postmenopausal state.”
 
 
Section 3.7 Post Study 
Drug Follow-up
Section was updated to remove reference to survival 
follow-up and indicate that subjects will be 
followed through Safety follow-up. Reference to 
retreatment was also removed.
 
 
 
 
 
 
 
 
 
 
Section 5.1 Flow 
Chart/Time and Events 
Schedule, Table 5.1-2
Table title was updated to remove reference to 
retreatment.
Procedure for “Subject Registration” was updated 
to remove reference to retreatment.
Procedure note for “Physical Examination” was 
updated to remove reference to retreatment.
Procedure note for “Mandatory Pretreatment Tumor 
Biopsy” was updated to remove reference to 
retreatment.
 
 
 
 
 
Section 5.1 Flow 
Chart/Time and Events 
Schedule, Table 5.1-3
Column “Response/Survival Follow-up” was 
removed from the table.
Procedure “Tumor Assessment” was shifted from 
Response/Survival Follow-up to Safety FU 3 (100 
Days).
Note b was removed.
 
 
.
Section 5.4 Efficacy 
Assessments
Section was updated to remove the performance of 
assessments “every 12 weeks during the response 
follow-up (subjects with CR, PR, or SD at study 
drug discontinuation)” and add the performance of 
assessments at the end of the follow-up period.
Section 5.4.3 Exploratory 
Efficacy Assessments
Section was updated to change collection of OS 
data from “up to 5 years from subject’s last dose” to
“the Safety Follow-up period.”
Section 5.7 Outcomes 
Research Assessments
Section was updated to change collection of EQ-5D 
from the “Survival” Follow-Up phase to the 
“Safety” Follow-Up phase.
 
 
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Date: 22-Apr-2019
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FRACTION-Lung
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07
Section Number & 
Title
Description of Change
Brief Rationale
Section 5.10 Additional 
Research Collection
Additional research retention was updated from 
“mandatory” to “encouraged.”
 
 
Section 6 Adverse Events
“Events Meeting the AE Definition” were added. 
“Events Not Meeting the AE Definition” were 
added. The brief causal relationship description was 
removed and replaced with “Assessment of 
Causality.”
In addition, prevention of reporting bias was 
removed and replaced with the following 
description: “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.”
Finally, language was added clarifying that if an 
event does not meet the definition of an AE, then it 
cannot be an SAE even if serious conditions are 
met.
 
 
Section 6.1 Serious 
Adverse Events
The following language was removed “Although
pregnancy, overdose, cancer, and potential DILI are 
not always serious by regulatory definition, these 
events must be handled as SAEs” and replaced with 
“Pregnancy and potential drug induced liver 
injury (DILI) must follow the same transmission 
timing and processes to BMS as used for SAEs.”
 
 
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Date: 22-Apr-2019
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07
Section Number & 
Title
Description of Change
Brief Rationale
Section 6.4 Pregnancy
Language was updated to indicate that continuation 
or reintroduction of study treatment in a pregnant 
subject must be discussed with the Medical 
Monitor. If pregnancy has ended and is confirmed, 
treatment may resume with proper approvals.
Language was added to indicate that the female 
partner of a male participant must sign an informed 
consent form for pregnancy surveillance 
information to be collected.
Fetal toxicity language was added:
In cases where a study drug can be present in 
seminal fluid, at exposures sufficient to 
potentially cause fetal toxicity, and if any sexual 
activity (e.g. vaginal, anal, oral) has occurred 
between a male participant and a pregnant 
WOCBP partner(s), the information should be 
reported to the Sponsor or designee, even if the 
male participant has undergone a successful 
vasectomy. In order for Sponsor or designee to 
collect any pregnancy surveillance information 
from the female partner, the female partner(s) 
must sign an informed consent form for 
disclosure of this information. Information on 
the pregnancy will be collected on the Pregnancy 
Surveillance Form.
 
 
Section 8.3.1 Primary 
Endpoints
Tumor assessments were updated to conclude at the 
completion of the safety follow-up period. 
Reference to retreatment therapy was removed.
 
 
 
 
 
Appendix 03
 
l 
.
Appendix 04
Appendix 04 Revised Protocol Summary of Change 
History was added.
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SYNOPSIS
Clinical Protocol CA018001
Protocol Title: A Phase 2, Fast Real-time Assessment of Combination Therapies in Immuno-ONcology Study 
in Subjects with Advanced Non-small Cell Lung Cancer (FRACTION-Lung)
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Specific IPs are listed in each FRACTION-Lung Sub-Protocol.
Specific dosing and treatment regimens for each FRACTION-Lung treatment combination and/or nivolumab 
monotherapy are outlined in each FRACTION-Lung Sub-Protocol.
Protocol-specified assessments are described in Table 5.1-1 (Screening Procedural Outline) and Table 5.1-3 (Follow-
up Procedural Outline). Procedures for Re-Randomization are listed in Table 5.1-2 (Baseline for Re-randomization 
Procedural Outline). Treatment Phase procedures are described in each FRACTION-Lung Sub Protocol. 
Follow Up visits at Days 30, 60, and 100 (+/- 7 days) should occur after the last dose of study drug or coinciding with 
the date of discontinuation 30 days, if date of discontinuation is greater than 30 days after the last dose, to monitor for 
AEs.
Approximately 1200+ subjects are expected to be treated over a 3 to 5 year period.
Study Phase: 2
Research Hypothesis: We hypothesize that combination of IO agents will demonstrate improved efficacy in subjects 
with recurrent NSCLC.
Objectives: The overall FRACTION-Lung study-wide objectives are presented in the following sections. Any 
changes to these objectives for specific treatments are specified in each FRACTION-Lung Sub-Protocol.
The primary objective is to assess the efficacy (objective response rate [ORR], duration of response [DOR], and 
progression-free survival rate [PFSR] at 24 weeks) of each FRACTION-Lung treatment combination in subjects with 
NSCLC.
The secondary objective is to investigate additional safety and tolerability of each FRACTION-Lung treatment 
combination in subjects with NSCLC.
Study Design: The FRACTION-Lung Master Protocol is a rolling, Phase 2, adaptive study that will evaluate the 
preliminary efficacy, safety, tolerability, PK, and pharmacodynamics of novel treatment combinations which will be 
described in FRACTION-Lung Sub-Protocols. 
The initial Sub-Protocol for FRACTION-Lung (nivolumab [BMS-936558] in combination with dasatinib [BMS-
354825], nivolumab in combination with BMS-986016 (anti-LAG-3 mAb) and, and nivolumab in combination with 
ipilimumab) will be described in the FRACTION-Lung Sub-Protocol A.
The FRACTION-Lung study has been designed for Recurrent NSCLC subjects.
Subjects will be enrolled into 1 of 2 tracks based on their previous exposure to PD-1/PD-L1 treatment (experienced 
or naïve).
Subjects will be enrolled in 1 of 2 tracks. Subjects who have not had prior anti-PD-1/PD-L1 therapy will be assigned 
to Track 4. Subjects who have had prior anti-PD-1/PD-L1 therapy will be assigned to Track 5.
Treatment Phase is defined in cycles each of 4 weeks duration. 
Tumor assessments will be conducted every 8 weeks (±1 week).
Details about track treatment are available in the protocol, Section 3.1.1.
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Study Population: 
In addition to the study-wide inclusion criteria noted in the FRACTION-Lung Sub-Protocols, which must be met for 
study participation, the following criteria are also required for participation.
1)
Target Population
a)
Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤1.
b)
Subjects must have histologic or cytologic confirmation of NSCLC (per the seventh International Association 
for the Study of Lung Cancer [IASLC]) with squamous or nonsquamous histology that is advanced 
(metastatic and/or unresectable)
c)
Subjects with known EGFR mutations or ALK rearrangements must have received EGFR or ALK inhibitors, 
respectively, prior to study entry.
d)
Track-specific eligibility criteria
i)
Track 4: Anti-PD-1/PD-L1 treatment-naïve subjects
(1) Subjects must be naïve to PD-1/PD-L1 therapy. 
ii)
Track 5: Anti-PD-1/PD-L1 treatment-experienced subjects
(1) Subjects must have had progressive or recurrent disease during or after anti-PD-1 or anti-PD-L1 
therapy and, in the opinion of the investigator, must be unlikely to benefit from nivolumab 
monotherapy. 
(2) Subjects who have had prior treatment with 1 of the agents (or any other IO agent that is directed 
against the same target) in any combination regimen in a Sub-Protocol are eligible for treatment on 
Track 5. 
(3) Subjects who have had prior combination treatment with the same IO agents (or IO agents that are 
directed against the same target) as 1 of the combination regimens in a FRACTION-Lung Sub-
Protocol are eligible for treatment on Track 5 but must be randomized to another IO combination 
regimen (as outlined in Section 3.4 Inclusion Criteria of each FRACTION-Lung Sub-Protocol).
iii) Tracks 4 and 5
(1) Subjects may have had up to 1 prior cytotoxic chemotherapy for advanced phase NSCLC.
(a) Subjects enrolled in FRACTION-lung prior to implementation of Amendment 5 who are re-
enrolling in Track 5 may have received 1 or more prior chemotherapies for progressive or 
recurrent disease.
(b) Maintenance therapy does not count as an additional line of treatment.
(2) Subjects should have been offered a platinum-based chemotherapy for NSCLC.
(a) The platinum-based chemotherapy may have been in the adjuvant, neoadjuvant, or recurrent 
setting.
In addition to the study-wide exclusion criteria noted in the FRACTION-Lung Sub-Protocols, which must be met for 
participation, the following criteria are also required for participation. 
1)
Target Population
a)
Subjects must not have known EGFR mutations that are sensitive to available targeted inhibitor therapy.
b)
Subjects must not have known ALK translocations that are sensitive to available targeted inhibitor therapy.
c)
Subjects must not have active CNS metastases. 
Study Drug: Includes both investigational [medicinal] products (IP/IMP) and non-investigational [medicinal] 
products (Non-IP/Non-IMP). Specific IPs are listed in each FRACTION-Lung Sub-Protocol.
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Study Assessments: 
AEs will be assessed continuously during the study and for 100 days after the last study drug treatment. AEs will be 
evaluated according to the NCI CTCAE Version 4.03 and should be followed per requirements in Sections 6.1.1 and 
6.2.1 of the FRACTION-Lung Master Protocol. Subjects should be followed until all treatment-related AEs have 
recovered to baseline or are deemed irreversible by the investigator.
Changes in tumor measurements and tumor responses will be assessed by the investigator using RECIST v1.1 criteria, 
and the time point of tumor assessments will be reported on the CRF based on the investigator's assessment using 
RECIST v1.1 criteria. 
Tumor assessments will be submitted to a third party radiology vendor on an ongoing basis; subject management is 
not dependent on third party review of tumor assessments.
 
 
 
 
The effects of lung cancer and its treatment on health status and quality of life will be assessed using the EQ-5D-3L 
and FLSI-12. Subjects will be asked to complete the EQ-5D and FLSI-12 during on-study clinic visits and the EQ-5D 
at designated visits during the Safety Follow-up Phase. 
Statistical Considerations:
Sample Size: Tracks 1 through 4 include a Multi-Stage adaptive design with 12-70 subjects/treatment arm, and use 
the Simon and Fleming statistical plan that gives early strong evidence of efficacy or futility that may be used to 
terminate an arm. In Track 5, a single stage design with 35 subjects/treatment arm is used.
With the implementation of Amendment 5, subjects will be enrolled in Tracks 4 and 5. The sample size for Track 4 is 
guided by a 2-stage design and for Track 5 is guided by a single-stage design. 
Endpoints: The primary objective of preliminary efficacy will be measured by ORR, DOR, and PFSR at 24 weeks 
based on RECIST v1.1 criteria. Tumor response will be based on tumor assessments at screening, every 8 weeks from 
the first dose until investigator assessed initial disease progression (per RECIST v1.1) or confirmed disease 
progression (defined as an additional 10% or greater increase in tumor burden volume from the time of initial 
progression [including all target lesions and new measurable lesions]), at the completion of safety follow-up, or until 
subjects withdraw from the study.
The assessment of safety will be based on the incidence of AEs, SAEs, AEs leading to discontinuation, and deaths. In 
addition, clinical laboratory test abnormalities will be examined.
AEs and laboratory values will be graded according to the current version of the NCI CTCAE 4.0.3.
Analyses: The following analyses will be performed: demographics and baseline characteristics, efficacy analyses, 
safety analyses, 
, outcomes 
research analyses, other analyses, and interim analyses.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07 ......................... 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
 
 
 
 
 
 
 
1.3 Research Hypotheses ........................................................................................ 
1.4 Objectives for FRACTION-Lung ..................................................................... 
1.4.1 Primary Objective .................................................................................... 
1.4.2 Secondary Objective ................................................................................ 
 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
1.5.1 Safety Monitoring on Study Therapy ....................................................... 
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 ............................................................................... 
3.1.1 FRACTION-Lung Track 4 (Naïve) and 5 (Experienced) Design ............. 
3.2 Study Phases ..................................................................................................... 
3.2.1 Screening.................................................................................................. 
3.2.2 Treatment ................................................................................................. 
3.2.3 Follow-up ................................................................................................. 
3.2.3.1 Safety Follow-up ............................................................................. 
3.3 Post-study Access to Therapy ........................................................................... 
3.4 Study Population ............................................................................................... 
3.4.1 Inclusion Criteria ..................................................................................... 
3.4.2 Exclusion Criteria .................................................................................... 
3.4.3 Women of Childbearing Potential ........................................................... 
 
 
 
 
 
 
3.6 Discontinuation of Subjects Following any Treatment with Study Drug ......... 
1
3
5
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CA018001
FRACTION-Lung
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3.7 Post Study Drug Follow-up .............................................................................. 
3.7.1 Withdrawal of Consent ............................................................................ 
3.7.2 Lost to Follow-up ..................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Noninvestigational Product ............................................................................... 
4.3 Storage and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Dose Reductions and Delays and Criteria to Resume Dosing ................ 
4.5.2 Permanent Treatment Discontinuation .................................................... 
4.5.3 Treatment Beyond Disease Progression .................................................. 
4.5.4 Management Algorithms for Immuno-oncology and Oncology Agents ... 
4.5.5 Treatment of Drug-related Infusion Reactions ........................................ 
4.6 Combination Treatment Arm Discontinuation Criteria .................................... 
4.7 Blinding/Unblinding ......................................................................................... 
4.8 Treatment Compliance ...................................................................................... 
4.9 Destruction of Study Drug ................................................................................ 
4.10 Return of Study Drug ...................................................................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Imaging Assessment for the Study............................................................ 
5.3.2 Laboratory Test Assessments ................................................................... 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Primary Efficacy Assessments ................................................................. 
5.4.2 Secondary Efficacy Assessments .............................................................. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.8 Other Assessments ............................................................................................ 
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5.9 Results of Central Assessments ........................................................................ 
5.10 Additional Research Collection ...................................................................... 
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 ................................................................. 
6.7 Other Safety Considerations ............................................................................. 
7 SAFETY MONITORING BOARD AND OTHER EXTERNAL COMMITTEES .. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.1.1 Sample Sizes for Tracks 4 and 5 .............................................................. 
8.1.1.1 Track 4 - Anti-PD-1/PD-L1 Treatment-naïve Subjects .................. 
8.1.1.2 Track 5 - Anti-PD-1/PD-L1 Treatment-experienced Subjects ........ 
8.1.2 Sample Sizes for Tracks 1, 2 and 3 .......................................................... 
8.1.2.1 Track 1.a and 1.c - Anti-PD-1/PD-L1 Treatment-naïve, PD-L1-
positive Subjects .................................................................................... 
8.1.2.2 Track 1.b - Anti-PD-1/PD-L1 Treatment-naïve, PD-L1-positive 
Subjects and Track 2 - Anti-PD1/PD-L1 Treatment-naïve, PD-L1-
negative Subjects ................................................................................... 
8.1.2.3 Track 3 - Anti-PD-1/PD-L1 Treatment-experienced Subjects ........ 
 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoints ................................................................................... 
8.3.2 Secondary Endpoints ............................................................................... 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.3 Safety Analyses......................................................................................... 
 
 
 
 
8.4.8 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
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9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 LIST OF ABBREVIATIONS .................................................................................. 
 
12 APPENDICES ......................................................................................................... 
APPENDIX 1 ECOG PERFORMANCE STATUS ..................................................... 
APPENDIX 2 RECIST V1.1 ........................................................................................ 
 
APPENDIX 4 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
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1.3
Research Hypotheses
We hypothesize that combination of IO agents will demonstrate improved efficacy in subjects with 
recurrent NSCLC.
1.4
Objectives for FRACTION-Lung
The overall FRACTION-Lung study-wide objectives are presented in the following sections. Any 
changes to these objectives for specific treatments are specified in each FRACTION-Lung 
Sub-Protocol.
1.4.1
Primary Objective

To assess the efficacy (ORR, duration of response [DOR], and progression-free survival rate 
[PFSR] at 24 weeks) of each FRACTION-Lung treatment combination in subjects with 
NSCLC
1.4.2
Secondary Objective

To investigate additional safety and tolerability of each FRACTION-Lung treatment 
combination in subjects with NSCLC
 
 
 
 
 
1.5
Overall Risk/Benefit Assessment
An overall risk/benefit assessment for each novel FRACTION-Lung treatment combination will 
be provided in each FRACTION-Lung Sub-Protocol.
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1.5.1
Safety Monitoring on Study Therapy 
Frequent safety assessments will be carried out by the Sponsor/BMS Medical Monitor (or 
designee) and investigators throughout the study to determine whether dose modification, 
additional safety measures, or termination of the combination arm, is required at any time. In 
addition, adverse events (AEs) and serious adverse events (SAEs) will be reviewed regularly by 
the BMS Medical Monitor (or designee) and the Pharmacovigilance group to look for trends and 
potential safety signals. Treatment of AEs will follow institutional guidelines and recommended 
management algorithms, as listed in the Investigator Brochures (IBs) and prescribing information, 
as applicable, for each combination agent, and provided as appendices to this protocol. Specific 
algorithms for the management of immune-related AEs are provided in Appendix 3 and are 
applicable to immune-related AEs for all FRACTION-Lung treatment combinations.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the US Code of Federal Regulations (CFR), 
Title 21, Part 50 (21CFR50).
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 (IRB)/Independent 
Ethics Committee (IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a breach 
of the conditions and principles of GCP in connection with the study or the protocol, which is 
likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects of 
the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The investigator
or BMS should also provide the IRB/IEC with a copy of the IB or product labeling information to
be provided to subjects, and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates, and other information 
(eg, expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures.
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2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form(s), which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:

Provide a copy of the consent form(s) 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 nontechnical 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(s) 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 informed 
consent form and, in the US, the subjects’ signed Health Insurance Portability and Accountability 
Act Authorization.
The consent form(s) must also include a statement that BMS 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.
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For the FRACTION Program, subjects should receive consent forms that include relevant 
information for all treatments to which they are eligible for enrollment; subjects will not receive 
consent forms that include data relevant to agents within the FRACTION Program that are not 
within the Sub-Protocol for which they are screened. Informed consents to Sub-Protocols which 
are closed, terminated early or in any way no longer in effect will not be provided to new subjects 
as an eligible treatment consent. Subjects in any follow-up phase for a Sub-Protocol which is 
closed or terminated will receive pertinent updated safety and risk information if it becomes 
known. Subjects in any follow-up phase may receive revised informed consent via mail and 
follow-up phone call by the investigator site.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a rolling, Phase 2, adaptive study that will evaluate the preliminary efficacy, safety, 
tolerability, PK, and pharmacodynamics of novel FRACTION-Lung treatment combinations in 
subjects with advanced NSCLC. The details pertaining to the specific treatment regimens are 
provided in each FRACTION-Lung Sub-Protocol.
A study design update occurred with the implementation of Amendment 5 due to the change in the 
standard of care for NSCLC. Data for a PD-1 inhibitor demonstrated a significant improvement in 
ORR, PFS, and overall survival compared to platinum-based chemotherapy in previously untreated 
metastatic NSCLC expressing ≥50% PD-L1 on tumor cells.28 In addition, nivolumab did not 
demonstrate a difference in PFS or overall survival compared to platinum-based doublet 
chemotherapy in first line metastatic NSCLC among patients with PD-L1 positive tumor (> 5%).29
Also, pembrolizumab combined with platinum doublet chemotherapy in patients with advanced,
chemotherapy-naïve NSCLC demonstrated a significantly improved response rate compared to 
chemotherapy alone.30 For this reason, the nivolumab monotherapy treatment in Tracks 1 and 2 
was removed, including the nivolumab run-in phase. This change eliminated differences between 
Track 1 and 2 and resulted in the establishment of a new Track of PD-1/PD-L1-naïve subjects 
(Track 4). Track 3 was modified in order to test immuno-oncology combinations in an earlier 
setting in subjects with a more intact immune system. This group of PD-1/PD-L1 experienced 
subjects was re-established as Track 5. Safety, efficacy, PK, and pharmacodynamic data from 
subjects enrolled in Tracks 1, 2, and 3 will be analyzed separately from subjects in Tracks 4 and 5.
Prior to implementation of Amendment 5, subjects were enrolled in 1 of 3 tracks depending on 
prior treatment and PD-L1 status (Tracks 1, 2, or 3). Following implementation of Amendment 5, 
subjects will be enrolled in 1 of 2 tracks following treatment for advanced NSCLC with ≤ 1 prior 
chemotherapy regimen and prior tyrosine kinase inhibitor (for subjects with a known epidermal 
growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] rearrangement). Subjects 
who are anti-PD-1 and anti-PD-L1 treatment naïve will be eligible for Track 4. Subjects who have 
had prior experience with anti-PD-1 or anti-PD-L1 treatment will be assigned to Track 5, as 
outlined in Figure 3.1-1 and described in Section 3.1.1. Treatment duration may extend to up to 
approximately six 4-week cycles (24 weeks) for both Tracks 4 and 5.
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Subjects in Tracks 4 and 5 will be treated until completion of the Treatment Phase (as outlined 
below), progression, toxicity, or protocol-specified discontinuation (see Section 4.5.2 and each 
FRACTION-Lung Sub-Protocol). The decision to continue treatment beyond the investigator-
assessed progression is possible (for up to completion of that Treatment Phase) and should be 
discussed with the BMS Medical Monitor (or designee) and documented in the study records 
(see Section 4.5.3). In addition, a subject with progressive disease (PD) will have several treatment 
options including continued treatment (for additional six 4-week cycles [approximately 24 weeks]
only) and/or entry into Track 5, assuming that he/she continues to fulfill all eligibility criteria at 
each new randomization point (see Section 3.1.1). Subjects receiving treatment on Tracks 1, 2, or 
3 prior to implementation of Amendment 5 will continue to receive treatment on their assigned 
track until completion, progression, toxicity, or protocol-specified discontinuation. Subjects in 
Tracks 1, 2, or 3 who experience PD during the Treatment Phase and continue to fulfill all entry 
criteria may be re-enrolled in Track 5 and re-randomized to a new combination other than that 
previously received, if applicable.
A 2-stage design will be used as a guide to evaluate the possibility of terminating an arm early in 
Track 4, and a single-stage design will be used in Track 5 (see Section 8.1; a 2-stage design may 
be used, also see Section 8.1 in specific Sub-Protocols). In Track 4, enrollment will be continued 
during initial efficacy evaluation (ie, with the indicated number of subjects at Stage 1) to allow
additional subjects to enroll to account for unexpected trial impact, such as response non-evaluable 
subjects due to early drop-out, design parameter change (eg, historical rate update), etc. The
number of subjects planned for enrollment may vary by track and is described in Section 8.1.
Subjects who continue to fulfill eligibility criteria may move from Track 4 into Track 5 or re-enter 
Track 5, as described in Section 3.1.1.
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Figure 3.1-1:
FRACTION-Lung Study Design
Note: Subjects will be considered PD-1/PD-L1-experienced if they have previously received at least 1 dose of a 
PD-1/PD-L1 inhibitor.
Note: Subjects in Tracks 1, 2, or 3 who experience PD during the Treatment Phase and continue to fulfill all entry 
criteria may be re-enrolled in Track 5 and re-randomized to a new combination other than that previously received, if 
applicable.
3.1.1
FRACTION-Lung Track 4 (Naïve) and 5 (Experienced) Design
A detailed study schematic for both Tracks 4 and 5 is presented in Figure 3.1.1-1. 
Subjects who are naïve to anti-PD-1 and anti-PD-L1 therapy will be enrolled into Track 4 and 
randomized to 1 of the FRACTION-Lung combination treatments. These subjects will receive 
their assigned treatment in Track 4 until completion of the Treatment Phase. 
Subjects who have received prior anti-PD-1 or anti-PD-L1 treatment will be enrolled in Track 5
and randomized to 1 of the FRACTION-Lung combination treatments. In addition, subjects who 
experience PD during the Treatment Phase in Tracks 4 or 5 and continue to fulfill all entry criteria 
may be re-enrolled in Track 5 and re-randomized to a new combination other than that previously 
received, if applicable. These subjects will receive their assigned study treatment in Track 5 until 
completion of the Treatment Phase. The number of subjects who enroll in Tracks 4 or 5 is described 
in Section 8.1.
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
Subjects with CR or PR at the end of the Track 4 or 5 Treatment Phase will have the option 
to:
a) Enter study follow-up or
b) Receive continued study treatment (at the discretion of the investigator) for a 
further six 4-week cycles (a further approximately 24 weeks; approximately 
48 weeks of total study treatment) with their Track 4 or 5 randomized combination 
treatments.

Subjects with SD at the end of the Track 4 or 5 Treatment Phase will have the option to:
a) Enter study follow-up,
b) Receive continued study treatment (at the discretion of the investigator) for a 
further six 4-week cycles (a further approximately 24 weeks; approximately 
48 weeks of total study treatment) with their Track 4 or 5 randomized combination 
treatments, or
c) Enter (or re-enter) Track 5, if eligible and if a new treatment combination is 
available, and be randomized to a new combination.

Subjects with SD who opt to continue study treatment upon completion of a total of twelve 
4-week cycles (approximately 48 weeks of study treatment)will have the option to: 
a) Enter study follow-up or
b) Enter (or re-enter) Track 5, if eligible and if a new treatment combination is 
available, and be randomized to a new combination

Subjects with PD during the Track 4 or 5 Treatment Phase will have the option to:
a) Enter study follow-up or
b) Enter (or re-enter) Track 5, if eligible and if a new treatment combination is 
available, and be randomized to a new combination, or
c) Continue study treatment beyond progression, if criteria in Section 4.5.3 are met, 
for up to completion of that Treatment Phase.
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Figure 3.1.1-1:
Track 4 and 5 Study Design Schematic
Note: This diagram presents the protocol-mandated treatment flow for Tracks 4 and 5. Alternatives must be discussed with the BMS Medical Monitor (or designee).
a Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) as defined by RECIST v1.1. Subjects who the investigator 
believes may still benefit from further therapy may, after consultation with the Sponsor/BMS Medical Monitor (or designee), continue with their assigned study 
treatment, 1 time only (for an additional six 4-week cycles [approximately 24 weeks] only).
b Safety Follow-up Phase.
c If subjects are eligible and if a new study treatment combination is available, they can enroll/re-randomize to a new combination.
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d Each individual subject may receive multiple therapies, including initial treatment, treatment beyond investigator-assessed progression (for up to completion of 
that Treatment Phase), continued treatment (for an additional six 4-week cycles [approximately 24 weeks] only), and/or entry into Track 5, assuming that the 
subject continues to fulfill all eligibility criteria at each new randomization point (see Section 3.1.1 for details).
e Subjects with PD during treatment may continue treatment beyond progression if criteria in Section 4.5.3 are met.
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3.2
Study Phases
Subjects will complete up to 3 phases of the study: screening, treatment, and safety follow-up 
within each track (not considering re-randomization), as described below:
3.2.1
Screening
Prior to screening for the protocol, investigative sites are required to determine if a subject is 
anti-PD-1/PD-L1 treatment-naïve or not through their Institutional database, subject medical 
history, or Institutional pre-screening process. Once determined, treatment experience is 
considered source data for this FRACTION-Lung study, and the subject must be provided with 
the FRACTION-Lung study IRB-approved written consent. The subject is then considered to have 
entered screening. The treatment status must be entered into the enrollment management system 
and subjects will be required to submit a tumor biopsy to score for PD-L1 status by a BMS 
approved and validated vendor in the Screening Phase; local laboratory results will not be 
accepted. Subjects must submit tumor biopsy material before randomization. Subjects may not be 
randomized before the results of their PD-L1 expression testing are known. As a result, there may 
be a small number of subjects (estimated no more than 10% to 15%) who are randomized but are 
subsequently found to be unevaluable for PD-L1 expression. 
The Screening Phase for each track will last for up to 28 days. The Screening Phase, also called 
enrollment, begins by establishing the subject’s initial eligibility and signing of the consent form. 
Subjects will be enrolled using Interactive Response Technology (IRT).
If a subject surpasses the 28-day window during the Screening Phase due to a study-related 
procedure (eg, scheduling of a tumor biopsy or waiting time for a study-related laboratory value), 
the subject must be re-consented, but does not need to be assigned a new subject identification 
number. In this situation, the fewest repeat procedures from the initial screening to qualify the 
subject, while maintaining safety and eligibility under the discretion of the BMS Medical Monitor
(or designee) and investigator, may be done to reduce any undue burden of procedure in this 
subject population.
Enrollment into all arms in each track will be competitive. 
3.2.2
Treatment 
The details of the treatment phase duration are provided in Section 3.1. Further details of the 
treatment administration are in each FRACTION-Lung Sub-Protocol. Study assessments are to be 
collected as outlined in the On-treatment Procedural Outline(s) specific to each FRACTION-Lung 
Sub-Protocol.  
For subjects on any track, assessment of response will be every 2 cycles (8 weeks ± 1 week) to be 
completed before the first dose in the next cycle. Assessments of PR and CR must be confirmed 
no less than 4 weeks following initial assessment. Tumor progression or response endpoints will 
be assessed using RECIST v1.1 criteria for solid tumors (see Appendix 2).
Treatment beyond progression may be allowed in select subjects with initial PD, as defined using 
RECIST v1.1 criteria, after discussion and agreement with the BMS Medical Monitor (or designee)
that the benefit/risk assessment favors continued administration of study therapy (eg, subjects are 
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continuing to experience clinical benefit, as assessed by the investigator, tolerating treatment, and 
meeting other criteria specified in Section 4.5.3).
Subjects will generally be allowed to continue study therapy until the first occurrence of either: 
1) completion of the maximum number of cycles, 2) PD, 3) clinical deterioration suggesting that 
no further benefit from treatment is likely, 4) intolerable toxicity, or 5) the subject meets criteria 
for discontinuation of study therapy, as outlined in protocol Section 4.5.2. Individual subjects with 
confirmed CR will be given the option to discontinue study therapy prior to completion of the
maximum number of cycles on a case-by-case basis after specific consultation and agreement 
between the investigator and BMS Medical Monitor (or designee) in settings where the benefit/risk 
ratio justifies discontinuation of study therapy. 
All subjects will be treated as per Section 3.1, unless criteria for study drug discontinuation are 
met earlier (Section 4.5.2). Upon completion of the Treatment Phase, all subjects will enter the 
Safety Follow-up Phase (Section 3.2.3 and Table 5.1-3).
3.2.3
Follow-up
3.2.3.1
Safety Follow-up
Upon completion of the Treatment Phase and once the decision is made to discontinue the subject 
from treatment, all subjects will complete the EOT visit and enter the Safety Follow-up Phase. 
For subjects that complete all scheduled cycles of therapy, EOT visit will be the same as the last 
scheduled and completed on-treatment visit and the start of Week 1 safety follow-up visit. For 
subjects that do not complete all scheduled cycles of therapy, EOT visit will be the most recent 
on-treatment visit (with all available safety and response data; does not need to be repeated) and 
will be considered the start of Week 1 safety follow-up visit.
After the EOT visit, all subjects will be evaluated for any new AEs for at least 100 days after the 
last dose of study drug, as specified in each FRACTION-Lung Sub-Protocol. Follow-up visits 
should occur at Days 30, 60, and 100 (7 days) after the last dose of study drug or coinciding with 
the date of discontinuation (7 days), if date of discontinuation is greater than 30 days after the 
last dose, to monitor for AEs. All subjects will be required to complete the 3 clinical safety 
follow-up visits, regardless of whether they start a new anti-cancer therapy, except for those 
subjects who withdraw consent for study participation or those subjects who are re-randomized.
3.3
Post-study Access to Therapy
At the end of the study, BMS will not continue to provide BMS-supplied study drug to 
subjects/investigator unless BMS chooses to extend the study. The investigator should ensure that 
the subject receives appropriate standard of care to treat the condition under study.
3.4
Study Population
For entry into the FRACTION-Lung Master Protocol, the following criteria MUST be met prior 
to dosing on Day 1. For entry into a treatment in a Sub-Protocol, additional treatment-specific
criteria, if applicable, must also be met.
No exceptions will be granted.
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In addition to the inclusion and exclusion guidelines noted below, please refer to the 
individual Sub-Protocols for additional requirements. As with the inclusion and exclusion 
criteria of the FRACTION-Lung Master Protocol, the inclusion and exclusion criteria of the 
FRACTION-Lung Sub-Protocols are also required to be followed.
3.4.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Subjects must be able to give self-consent and then sign and date an IRB/IEC-approved 
written informed consent in accordance with regulatory and institutional guidelines. This 
must be obtained before the performance of any protocol-related procedures that are not 
considered part of normal patient care.
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study.
c) Subjects must provide consent for mandatory tumor biopsy samples (ie, pretreatment, on 
treatment, and at progression; see Section 5.6.2.1). Requirements for collection of 
biomarkers, including tumor biopsy samples, may differ based on the sub-protocol. Please 
refer to the specific sub-protocol for specific requirements.
2) Target Population
a) Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status 
of ≤1 (see Appendix 1).
b) Subjects must have histologic or cytologic confirmation of NSCLC (per the seventh 
International Association for the Study of Lung Cancer [IASLC]31) with squamous or 
nonsquamous histology that is advanced (metastatic and/or unresectable)
i)
Prior adjuvant or neoadjuvant chemotherapy is permitted as long as the last 
administration of the prior regimen occurred at least 4 weeks prior to enrollment.
ii) Prior definitive chemoradiation for locally advanced disease is also permitted as long 
as the last administration of chemotherapy or radiotherapy (whichever was given last) 
occurred at least 4 weeks prior to enrollment.
c) Subjects with known EGFR mutations or ALK rearrangements must have received EGFR 
or ALK inhibitors, respectively, prior to study entry.
i)
All subjects with nonsquamous histology must have been tested for EGFR mutation 
status; use of an approved test is strongly encouraged. (Note: EGFR testing may only 
be performed on tumor tissue. Blood EGFR testing may not be used.) Subjects with 
nonsquamous histology and unknown or indeterminate EGFR status are excluded.
ii) Not applicable per Revised Protocol 07: If tested for ALK translocations, use of an 
approved test is strongly encouraged. 
iii) Not applicable per Revised Protocol 07: Subjects with unknown or indeterminate ALK 
status may be enrolled.
iv) All subjects with nonsquamous histology must have been tested for ALK 
rearrangements. Use of an approved test is strongly encouraged.
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d) Track-specific eligibility criteria
i)
Track 4: Anti-PD-1/PD-L1 treatment-naïve subjects
(1) Subjects must be naïve to PD-1/PD-L1 therapy.
ii) Track 5: Anti-PD-1/PD-L1 treatment-experienced subjects
(1) Subjects must have had progressive or recurrent disease during or after anti-PD-1 
or anti-PD-L1 therapy and, in the opinion of the investigator, must be unlikely to 
benefit from nivolumab monotherapy.
(2) Subjects who have had prior treatment with 1 of the agents (or any other IO agent 
that is directed against the same target) in any combination regimen in a 
Sub-Protocol are eligible for treatment on Track 5. 
(3) Subjects who have had prior combination treatment with the same IO agents (or IO 
agents that are directed against the same target) as 1 of the combination regimens 
in a FRACTION-Lung Sub-Protocol are eligible for treatment on Track 5 but must 
be randomized to another IO combination regimen (as outlined in Section 3.4
Inclusion Criteria of each FRACTION-Lung Sub-Protocol).
iii) Tracks 4 and 5
(1) Subjects may have had up to 1 prior cytotoxic chemotherapy for advanced phase 
NSCLC.
(a) Subjects enrolled in FRACTION-lung prior to implementation of Amendment 
5 who are re-enrolling in Track 5 may have received 1 or more prior 
chemotherapies for progressive or recurrent disease.
(b) Maintenance therapy does not count as an additional line of treatment.
(2) Subjects should have been offered a platinum-based chemotherapy for NSCLC.
(a) The platinum-based chemotherapy may have been in the adjuvant, neoadjuvant, 
or recurrent setting.
e) Subjects must have a life expectancy of at least 3 months following their most recent 
chemotherapy or immunotherapy for entry onto all tracks. 
i)
Subjects who wish to be re-randomized to a new combination treatment on Track 5
following progression on a prior treatment in Track 4 must have a life expectancy of at 
least 3 months following the last study treatment.
f)
Subjects receiving prior palliative radiotherapy to a non-central nervous system (CNS) 
lesion must have completed that therapy at least 2 weeks prior to the first dose of study 
drug. 
i)
Subjects with symptomatic tumor lesions at baseline who may require palliative 
radiotherapy within 4 weeks of the first dose of study drug are strongly encouraged to 
receive palliative radiotherapy prior to enrollment.
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g) Subjects must have at least 1 lesion with measurable disease as defined by RECIST v1.1 
criteria for solid tumors response assessment (see Appendix 2). 
i)
Subjects with lesions in a previously irradiated field as the sole site of measurable 
disease will be permitted to enroll, provided the lesion(s) have demonstrated clear 
progression and can be measured accurately.
h) Subjects with toxicity from any prior anti-cancer therapy must have their toxicity returned 
to Grade ≤1 (NCI Common Terminology Criteria for Adverse Events [CTCAE] Version 
4.03) or baseline before administration of study drug.
i)
Subjects Grade ≥2 with toxicities attributed to prior anti-cancer therapy that are not 
expected to resolve and result in long-lasting sequela, such as neuropathy after a 
platinum-based therapy, are eligible.
ii) Grade >1 alopecia or fatigue is permitted.
i)
Subjects must allow a pretreatment tumor biopsy, an on-treatment tumor biopsy, and a 
tumor biopsy at EOT/progression of disease (at acceptable clinical risk as judged by the 
investigator) for each treatment regimen. After signing the informed consent, subjects will 
be required to submit a fresh tumor biopsy with sufficient tissue for immunohistochemical 
staining to determine PD-L1 status. PD-L1 status will be performed by a BMS-approved 
and validated vendor using an approved assay. Local laboratory results for PD-L1 tumor 
status will not be accepted.
i)
Subjects who do not have accessible or suitable lesions are not eligible. 
(1) Biopsies may be collected from subjects with a single measureable lesion, as long 
as it is not an excisional biopsy. See details in Section 5.6.2.1.
ii) Subjects whose pretreatment biopsy is known prior to randomization to yield 
inadequate tissue quantity or quality will not be ineligible for treatment on Tracks 4 or 
5; however, re-biopsy is permitted.
iii) Study personnel must ensure that the archival tissue block or slides samples, if 
available, are located and shipped to the central laboratory within 6 weeks of signing 
the written informed consent. 
iv) The solid tumor tissue specimen must be a core-needle biopsy, excisional or incisional 
biopsy. Fine-needle biopsies, drainage of pleural effusions with cytospins, or punch 
biopsies are not considered adequate for biomarker review and randomization. Biopsies 
of bone lesions that do not have a soft tissue component or decalcified bone tumor 
samples are also not acceptable.
v) The biopsy at progression of disease after treatment on any track may function as the 
pretreatment biopsy for subsequent treatment on Track 5.
j)
Subjects with solid tumor histologies must have adequate organ function, as defined by the 
following:
i)
White blood cells 2,000/L (stable and discontinued growth factor more than 
4 weeks of the first study drug administration)
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ii) Neutrophils 1,500/L (stable off any growth factor within 4 weeks of the first study 
drug administration)
iii) Platelets 100103/L (transfusion to achieve this level is not permitted within 
2 weeks of the first study drug administration)
iv) Hemoglobin 9.0 g/dL (transfusion to achieve this level is not permitted within 
2 weeks of the first study drug administration)
v) Alanine 
aminotransferase 
(ALT) 
and 
aspartate 
aminotransferase 
(AST) 
3institutional upper limit of normal (ULN)
vi) Total bilirubin 1.5institutional ULN (except for subjects with Gilbert’s syndrome 
who must have normal direct bilirubin)
vii)Serum creatinine 1.5institutional ULN or creatinine clearance (CrCl) 50 mL/min 
(measured using the Cockcroft-Gault formula below):
Female CrCl =
(140 - age in years) weight in kg 0.85
72 serum creatinine in mg/dL
Male CrCl =
(140 - age in years) weight in kg 1.00 
72 serum creatinine in mg/dL
k)
Subjects must be able to comply with restrictions and prohibited activities/treatments 
listed in Section 3.5.1.
l)
Subject re-enrollment: This study permits the re-enrollment of a subject who has 
discontinued the study as a pretreatment failure (eg, subject has not been treated). If 
re-enrolled, the subject must be re-consented.
3) Age and Reproductive Status
In addition to the reproductive guidelines noted below, please refer to the individual Sub-
Protocols for additional requirements regarding reproductive guidelines. As with the 
inclusion and exclusion criteria of the FRACTION-Lung Master Protocol, the criteria of the 
FRACTION-Lung Sub-Protocols are also required to be followed.
a) Subjects must be males and females ≥18 years of age at the time of informed consent.
b) Subjects who are women of childbearing potential (WOCBP) must have a negative serum 
or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human 
chorionic gonadotropin) within 72 hours prior to the start of study drug.
c) Subjects who are women must not be breastfeeding.
d) Subjects who are WOCBP must agree to follow instructions for method(s) of contraception 
for the duration of treatment with study drug(s) plus 5 half-lives (T-HALF) of study drug 
plus 30 days (duration of ovulatory cycle).
i)
Subjects who are WOCBP who are continuously not heterosexually active are 
exempted from contraceptive requirements but still must undergo pregnancy testing as 
described in this section.
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e) Subjects who are males and who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception and fetal protection for the duration of 
treatment with study drug(s) plus 5 half-lives (T-HALF) of study drug(s) plus 90 days 
(duration of sperm turnover). In addition, male subjects must be willing to refrain from 
sperm donation during this time.
i)
Subjects who are azoospermic males are exempted from contraceptive requirements
unless the potential exists for fetal toxicity due to study drug being present in seminal 
fluid, even if the participant has undergone a successful vasectomy or if the partner is 
pregnant.
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 and 
when applicable, the potential of fetal toxicity occurring due to transmission of study drug, present 
in seminal fluid, to a developing fetus, even if the participant has undergone a successful 
vasectomy or if the partner is pregnant. Investigators shall advise on the use of highly effective 
methods of contraception, which have a failure rate of < 1% when used consistently and correctly.
At a minimum, all non-exempt subjects must agree to use 1 highly effective method of 
contraception:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Highly effective methods of contraception have a failure rate of < 1% when used consistently and 
correctly. WOCBP are expected to use one of the highly effective methods of contraception listed 
below. 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.
Contraceptive methods are as follows:
1) Progestogen only hormonal contraception associated with inhibition of ovulation (oral and 
injectable).
2) Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation (These methods of contraception cannot be used 
by WOCBP participants in studies where hormonal contraception is prohibited): oral (birth 
control pills), intravaginal (vaginal birth control suppositories, rings, creams, gels), 
transdermal.
3) Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
and/or implantation (This method of contraception cannot be used by WOCBP participants in 
studies where hormonal contraception is prohibited.)
4) Nonhormonal IUDs such as ParaGard
5) Bilateral tubal occlusion
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6) Vasectomized partner 

Vasectomized partner is a highly effective birth control method provided that partner is the 
sole sexual partner of the WOCBP trial participant and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used.
7) Intrauterine hormone-releasing system (IUS) (This method of contraception cannot be used by 
WOCBP participants in studies where hormonal contraception is prohibited.)
8) Sexual abstinence

Complete sexual abstinence is defined as the complete avoidance of heterosexual 
intercourse.

Complete abstinence is an acceptable form of contraception for all study drugs and must 
be used throughout the duration of the study treatment (plus 5 half-lives of the 
investigational drug plus 30 days).

It is not necessary to use any other method of contraception when complete abstinence is 
elected.

Subjects who choose complete abstinence must continue to have pregnancy tests as 
specified in Section 6.4. 

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the subject chooses to forego complete abstinence.

The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject.
LESS THAN HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Less than highly effective methods of contraception have a failure rate of > 1% per year when used 
consistently and correctly.
1) Male or female condom with or without spermicide.  Male and female condoms cannot be used 
simultaneously
2) Diaphragm with spermicide
3) Cervical cap with spermicide
4) Vaginal Sponge with spermicide
5) Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mechanism of action (This method of contraception cannot be used by WOCBP participants 
in studies where hormonal contraception is prohibited)
UNACCEPTABLE METHODS OF CONTRACEPTION
1) Periodic abstinence (calendar, symptothermal, post-ovulation methods)
2) Withdrawal (coitus interruptus)
3) Spermicide only
4) Lactation amenorrhea method (LAM)
Local laws and regulation may require use of alternative and/or additional contraception methods. 
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3.4.2
Exclusion Criteria
1) Target Population
a) Subjects must not have known EGFR mutations that are sensitive to available targeted 
inhibitor therapy, as per Section 3.4.1.
b) Subjects must not have known ALK translocations that are sensitive to available targeted 
inhibitor therapy, as per Section 3.4.1.
c) Subjects must not have active CNS metastases.
i)
Subjects with treated CNS metastases are eligible if they have neurologically returned 
to baseline (except for residual signs or symptoms related to the CNS treatment) for at 
least 2 weeks prior to the first dose of study drug. In addition, subjects must be either 
off corticosteroids, or on a stable or decreasing dose of ≤10 mg daily prednisone (or 
equivalent) for at least 2 weeks prior to the first dose of study drug.
ii) Subjects with small, untreated, asymptomatic CNS metastases without associated 
edema, shift, or requirement for steroids are eligible after discussion with the BMS 
Medical Monitor (or designee).
iii) The CNS must not be the only site of metastatic disease.
iv) Subjects must not have leptomeningeal disease or carcinomatous meningitis.
2) Medical History and Concurrent Diseases
a) Subjects must not have had previous malignancies (except nonmelanoma skin cancers and 
in situ cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma, 
or breast) 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.
b) Subjects must not have other active malignancy requiring concurrent intervention.
c) Subjects must not have received a prior organ allograft.
d) Subjects must not have received any anti-cancer therapy (eg, chemotherapy, radiotherapy, 
biologics, immunotherapies, or hormonal treatment), including investigational drugs, 
within 4 weeks prior to the first dose of study drug administration.
i)
Subjects who have received non-cytotoxic anti-cancer therapies (eg, prior use of
targeted therapy or hormonal therapy) and who completed treatment at least 4 weeks 
or 5 half-lives (whichever is shorter) prior to the first dose of study drug are eligible to 
enroll. However, if 5 half-lives is shorter than 4 weeks, agreement with the BMS 
Medical Monitor (or designee) is mandatory.
e) Subjects must not have active, known, or suspected autoimmune disease. 
i)
Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone 
replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring 
systemic treatment, or conditions not expected to recur in the absence of an external 
trigger are permitted to enroll.
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f)
Subjects must not have a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 
14 days of study drug administration. 
i)
Inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily prednisone 
equivalent, are permitted in the absence of active autoimmune disease.
g) Subjects must not have a history of life-threatening toxicity related to prior IO treatment.
i)
Subjects with toxicities that are unlikely to recur with standard countermeasures 
(eg, hormone replacement after adrenal crisis) are eligible.
h) Subjects must not have interstitial lung disease that is symptomatic or may interfere with 
the detection or management of suspected drug-related pulmonary toxicity.
i)
Subjects must not have uncontrolled or significant cardiovascular disease including, but 
not limited to, any of the following:
i)
Myocardial infarction or stroke/transient ischemic attack within the past 6 months
ii) Uncontrolled angina within the past 3 months
iii) Any history of clinically significant arrhythmias (such as ventricular tachycardia, 
ventricular fibrillation, or torsades de pointes)
iv) Corrected QT interval with Fridericia’s formula interval > 480 msec
v) History of other clinically significant heart disease (eg, cardiomyopathy, congestive 
heart failure with New York Heart Association functional classification III to IV, 
myocarditis, pericarditis, or significant pericardial effusion)
j)
Subjects who require daily supplemental oxygen therapy are excluded.
k) Subjects must not have a history of any acute or chronic hepatitis, as evidenced by a 
positive test for hepatitis B surface antigen (HBsAg) or a positive test for qualitative 
hepatitis C viral load (by polymerase chain reaction)
i)
Subjects with positive hepatitis C antibody and negative quantitative hepatitis C by 
polymerase chain reaction are eligible. 
ii) Subjects with a history of resolved hepatitis A virus infection are eligible.
l)
Subjects must not have evidence of active infection requiring antibacterial, antifungal, or 
antiviral therapy 7 days prior to initiation of study drug therapy.
m) Subjects must not have a known history of testing positive for human immunodeficiency 
virus (HIV) or known acquired immunodeficiency syndrome. 
i)
Testing for HIV must be performed at sites mandated by local requirements.
n) Subjects must not have known or suspected active tuberculosis.
o) Subject must not have had any major surgery within 4 weeks of study drug administration 
and must have recovered from the effects of major surgery or significant traumatic injury 
at least 14 days before the first dose of study drug.
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p) Subjects must not have received nononcology vaccines containing live virus for prevention 
of infectious diseases within 12 weeks prior to the first dose of study drug. 
i)
The use of inactivated seasonal influenza vaccines (eg, Fluzone®) will be permitted on 
study without restriction.
q) Subjects must not have received packed red blood cell or platelet transfusion within 
2 weeks prior to the first dose of study drug.
r)
Subjects must not have a known or underlying medical condition that, in the opinion of the 
investigator or Sponsor, could make the administration of study drug hazardous to the 
subjects or could adversely affect the ability of the subject to comply with or tolerate the 
study.
3) Allergies and Adverse Drug Reaction
a) Subjects must not have a history of allergy to nivolumab.
b) Subjects must not have a history of any significant drug allergy (such as anaphylaxis or 
hepatotoxicity) to prior anti-cancer immune-modulating therapies (eg, checkpoint 
inhibitors and T-cell co-stimulatory antibodies).
4) Other Exclusion Criteria
a) Subjects must not be prisoners or be involuntarily incarcerated.
b) Subjects must not be 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.
3.4.3
Women of Childbearing Potential
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.
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
Postmenopausal female

A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 in 
the absence of other biological or physiological causes. In addition, females under the age 
of 55 years must have a documented serum follicle-stimulating hormone (FSH) level > 40
mIU/mL to confirm menopause.
Females treated with hormone replacement therapy 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 hormone replacement therapy used. The durations
of the washout periods below are suggested guidelines, and the investigators should use their 
judgement in checking serum FSH levels:

1 week minimum for vaginal hormonal products (eg, rings, creams, and gels)

4 weeks minimum for transdermal products

8 weeks 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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3.6
Discontinuation of Subjects Following any Treatment with Study Drug
Subjects MUST discontinue IP (and noninvestigational product at the discretion of the 
investigator) for any of the following reasons:

Subject’s request to stop study treatment and/or participation in the study

Any clinical AE, laboratory abnormality, or intercurrent illness that, 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 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

Pregnancy

Documented disease progression as defined by RECIST v1.1 (see Appendix 2), unless the 
subject meets criteria for treatment beyond progression (Section 4.5.3), or the subject continues 
treatment by entering another track (Section 3.1)
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
Clinical deterioration while receiving active study therapy that, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
subject

Discretion of the investigator

Inability to comply with the protocol requirements

Protocol-defined reasons for discontinuation (see Section 4.5.2)
In the case of pregnancy, the investigator must immediately notify the BMS Medical Monitor (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 notify the BMS 
Medical Monitor (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 BMS Medical Monitor (or designee) must occur.
All subjects who discontinue IP should comply with protocol-specified follow-up procedures, as 
outlined in Table 5.1-3. The only exception to this requirement is when a subject 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 CRF page.
3.7
Post Study Drug Follow-up
In this study, OS is an exploratory 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 safety
follow-up data, as required and in line with Table 5.1-3, until death, withdrawal of consent, 
conclusion of the study, or to be randomized to a new treatment regimen in Track 5 if applicable.
3.7.1
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 the subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The withdrawal 
of consent should be explained in detail in the medical records by the investigator, as to whether 
the withdrawal is from further treatment with study drug only or also from study procedures and/or 
post-treatment study follow-up, and entered on the appropriate CRF page. In the event that vital 
status (whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only, as appropriately directed in accordance with local 
law.
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3.7.2
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 3 documented phone calls, faxes, 
texts, or emails as well as lack of response by subject to 1 registered mail letter. All attempts should 
be documented in the subject’s medical records. If it is determined that the subject has died, the 
site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study has 
been included in the subject’s informed consent, then the investigator may use a Sponsor-retained 
third-party representative to assist site staff with obtaining subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If, after all attempts, the subject remains 
lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both IP and noninvestigational product. Other drugs administered as part of 
the study that are critical to claims of efficacy (eg, background therapy, rescue medications) will 
be considered study drug. A table describing the study drugs and dosage information is provided 
in each Sub-Protocol.
For study drugs not provided by BMS and obtained commercially by the site, storage should be in 
accordance with the package insert, Summary of Product Characteristics (SmPC), or similar 
documentation.
4.1
Investigational Product
An IP, also known as investigational medicinal product in some regions, is defined as a 
pharmaceutical form of an active substance or placebo being tested or used as a reference in a 
clinical study, including products already with a marketing authorization but used or assembled 
(formulated or packaged) differently than the authorized form, or used for an unauthorized 
indication, or when used to gain further information about the authorized form.
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator to ensure that IP is only dispensed to study subjects. The IP must be dispensed 
only from official study sites by authorized personnel according to local regulations. 
Specific IPs are listed in each FRACTION-Lung Sub-Protocol.
4.2
Noninvestigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as 
noninvestigational products.
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Specific noninvestigational products, as applicable, are listed in each FRACTION-Lung 
Sub-Protocol.
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed 
and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
IP documentation (whether supplied by BMS or not) must be maintained, which includes all 
processes required to ensure drug is accurately administered. This includes documentation of drug 
storage, administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets).
Infusion-related supplies (eg, intravenous bags, in-line filters, 0.9% NaCl solution) will not be 
supplied by the Sponsor and should be purchased locally if permitted by local regulations.
Please refer to each Sub-Protocol, the current version of the IBs, and/or pharmacy reference sheets 
for complete storage, handling, dispensing, and infusion information.
For noninvestigational product, if marketed product is utilized, it should be stored in accordance 
with the package insert, SmPC, or similar.
4.4
Method of Assigning Subject Identification
This is an open-label study. All subjects must be assigned a patient identification number upon 
providing a signed IRB/IEC-approved written informed consent. During the screening visit, the 
investigative site will utilize the IRT for enrollment and receive a 5-digit patient identification 
number designated by BMS that will be unique across all sites. Enrolled subjects, including those 
not dosed, will be assigned sequential patient identification numbers starting with 00001 
(eg, 00001, 00002, 00003...00010). The patient identification number will ultimately comprise the 
site number and patient identification number. For example, the first subject screened 
(eg, enrolled) at Site Number 1 will have a subject identification number of 0001-00001. The 
following information is required for enrollment:

Date that informed consent was obtained

Date of birth

Gender at birth

IO Therapy and PD-1/PD-L1 Therapy Treatment Experience (Section 3.2.1)
Once enrolled in the IRT, enrolled subjects who have met all eligibility criteria will be ready to be 
randomized through the IRT. The following information is required for subject randomization:

Subject number

Date of birth
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Randomization subject schedules will be generated and maintained by the IRT vendor. At the 
conclusion of the trials, BMS will receive copies of all generated subject schedules from the 
vendor. Because of the nature of the study design, limited early access to the randomization 
information will be granted to the study team to facilitate early analyses for internal decision 
making (early termination of treatment arm, etc.).
Each subject who is randomized will be assigned a unique randomization number. This is not the 
primary identifier for the subject, but used for the randomization schedule. The primary identifier 
will be patient identification number described above, for use on the case report form and source 
documents. A subject being re-randomized will be assigned a different randomization number but 
will retain the same patient identification number. Randomization numbers will be assigned using 
a Central Randomization System in the order in which subjects qualify for treatment, not in the 
order of study enrollment. If, within a given track, treatment arms from more than 
one Sub-Protocol within the Master Protocol are simultaneously open to enrollment, then a new 
subject could be assigned to any of the open arms. New randomization schedules may be added 
for specific Sub-Protocols (randomization ratios will be specified in corresponding Sub-
Protocols). Subjects will be equally allocated to all existing randomization schedules within a 
given track. If the randomization ratio is not specified in the Sub-Protocol, subjects will be equally 
assigned to any of the open arms.
Pre-specified treatment arm caps (as described in Section 8.1) will be utilized to control the accrual 
for each combination arm under different tracks. In the event that one or more subjects go off-study 
without being evaluable for response (ie, with no on-study tumor measurements and no evidence 
of clinical progression or death due to disease progression), the enrollment cap for that arm may 
be correspondingly raised if needed to ensure that a sufficient number of evaluable subjects are 
available for decision making. If the decision is made to close any arm for safety concerns, the cap 
for that arm will be reduced to the current number of subjects already randomized. Accrual will be 
stopped immediately.
Specific instructions for randomization into the Central Randomization System will be provided 
in a separate manual.
4.5
Selection and Timing of Dose for Each Subject
Specific dosing and treatment regimens for each FRACTION-Lung treatment combination are 
outlined in each FRACTION-Lung Sub-Protocol.
4.5.1
Dose Reductions and Delays and Criteria to Resume Dosing
Tumor assessments for all subjects should continue as per protocol even if dosing is delayed.
Guidelines for dose reductions and delays due to toxicity and for resuming treatment for each 
FRACTION-Lung combination therapy are provided in each FRACTION-Lung Sub-Protocol.
4.5.2
Permanent Treatment Discontinuation
Criteria for permanent discontinuation for each FRACTION-Lung combination therapy are
provided in each FRACTION-Lung Sub-Protocol.
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4.5.3
Treatment Beyond Disease Progression
Accumulating evidence indicates that a minority of subjects treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD.32
Subjects will be permitted to continue on treatment beyond initial RECIST v1.1-defined PD as 
long as they meet the following criteria:

Investigator-assessed clinical benefit and no rapid disease progression

Subject continues to meet relevant eligibility criteria, as determined by the BMS Medical 
Monitor (or designee) in discussion with the investigator

Stable performance status

Subject is tolerating study treatment

Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
The decision to continue treatment beyond initial investigator-assessed progression should be 
discussed with the BMS Medical Monitor (or designee) and documented in the study records. A 
follow-up scan should be performed at the next scheduled imaging evaluation 8 weeks later (but 
no less than 4 weeks) 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. If 
the investigator feels that the subject continues to achieve clinical benefit by continuing treatment, 
the subject should remain on the study and continue to receive monitoring according to the Time 
and Events Schedule Table 5.1-1, Table 5.1-2, and the On-treatment Procedural Outline(s) specific 
to each FRACTION-Lung Sub-Protocol).
For subjects who continue study therapy beyond initial RECIST v1.1-defined PD, further 
progression is defined as an additional 10% increase in tumor burden volume from time of initial 
PD assessment. This includes an increase in all target lesions and/or the development of new 
measurable lesions. Study therapy should be discontinued in any subject for whom these criteria 
are met and should be documented. 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 least 15 mm). Any new lesion considered nonmeasureable at the time 
of initial progression may become measureable and, therefore, included in the tumor burden 
volume 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 that become measurable, these new 
lesions must demonstrate an absolute increase of at least 5 mm.
 
 
 
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4.5.5
Treatment of Drug-related Infusion Reactions
Treatment of drug-related infusion reactions for each FRACTION-Lung treatment combination 
therapy is provided in each FRACTION-Lung Sub-Protocol.
4.6
Combination Treatment Arm Discontinuation Criteria
In the event that 20% or more of study subjects in a novel FRACTION-Lung combination arm of 
a given track, at any given time, meet any of the toxicity criteria for permanent discontinuation (as 
described in Section 4.5.2), then consideration will be given to discontinue that FRACTION-Lung 
combination arm in that track. This will include early side effects seen with IO agents and longer 
term effects such as endocrinopathies. This action will be taken in consultation with the Safety 
Monitoring Board (SMB) and will consider other pertinent facts in coming to a decision, including 
toxicity profile of that combination seen outside FRACTION-Lung and subject benefit as 
measured by anti-tumor response.
Discontinuation of a combination arm in a given track for any reason WILL NOT lead to 
discontinuation for that combination in all tracks. Safety of all open-label combination arms in 
other tracks that contain the same agent (or agents) will be assessed by SMB and the Sponsor. In 
the event of serious, unexpected, or life-threatening emergent toxicities, relevant combination arms 
may then be modified to maintain the safety of subjects. Decisions on such steps and the 
re-initiation of any combination arms that had been stopped would be made by SMB in 
consultation with the Sponsor and relevant authorities (eg, IRB/IEC).
4.7
Blinding/Unblinding
Not applicable.
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4.8
Treatment Compliance
Study drug will be administered in the clinical facility by trained medical personnel. Treatment 
compliance will be monitored by drug accountability, as well as by recording administration of 
each study drug in subjects’ medical records and CRF.
4.9
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as partially 
used study drug containers, vials, and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible BMS Study Monitor (or designee), unless study drug containers must be immediately 
destroyed as required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s Standard Operating Procedures 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 BMS Study
Monitor (or designee) to review throughout the clinical trial period.

If conditions for destruction cannot be met, the responsible BMS Study Monitor (or designee) 
will make arrangements for return of study drug.

It is the investigator’s responsibility to arrange for disposal of all empty containers, provided
that procedures for proper disposal have been established according to applicable federal, state, 
local, and institutional guidelines and procedures and provided that appropriate records of 
disposal are kept.
4.10
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. The return of study 
drug will be arranged by the responsible study monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Study assessments and procedures are presented in Table 5.1-1 (Screening Procedural Outline),
Table 5.1-2 (Baseline for Re-randomization Procedural Outline), and Table 5.1-3 (Follow-up
Procedural Outline). Additional screening or follow-up requirements that are specific for 
individual study treatments are provided in each FRACTION-Lung Sub-Protocol. The 
On-treatment Procedural Outline(s) for each study treatment are included in each 
FRACTION-Lung Sub-Protocol.
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Table 5.1-1:
Screening Procedural Outline
Procedure
Screening 
Visita
Notes
Informed Consent
X
Obtain patient identification number via IRT after signing of the written informed consent.
Utilize IRT
X
To obtain patient identification number
Inclusion/Exclusion Criteria
X
Medical History
X
Includes risk factors (eg, smoking history, alcohol consumption, pleural effusion and 
pneumonitis)
Collect Data on Prior Anti-PD-1/PD-L1 
Therapy Exposure
X
Prior to screening for the protocol, investigative sites are required to determine subject 
exposure to anti-PD-1/PD-L1 therapy. Those data will be collected as part of the Screening 
Phase.
Physical Examination
X
Oxygen Saturation
X
Record at rest via pulse oximetry to establish baseline. 
If subject has oxygen saturation ≤90%, consult BMS Medical Monitor (or designee) prior to 
enrollment.
Vital Signs
X
Temperature, blood pressure, heart rate, and respiratory rate
Height and Weight
X
ECOG Performance Status
X
Pretreatment Medications
X
Medications taken within 14 days prior to treatment
Assessment of Baseline Signs and 
Symptoms
X
Within 14 days prior to first dose.
Serious Adverse Events
X
All SAEs must be collected from the date of the subject’s written consent until 100 days post-
discontinuation of dosing or subject’s participation in the study if the last scheduled visit 
occurs at a later time.
Chest X-ray
X
12-Lead ECG
X
ECGs should be recorded after the subject has been supine for at least 5 minutes. Record 
QTcF
Pregnancy Serum or Urine Test
X
Serum or urine, within 72 hours prior to first dose of assigned treatment
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Table 5.1-1:
Screening Procedural Outline
Procedure
Screening 
Visita
Notes
Serum Chemistry and Urinalysis
X
Within 14 days prior to first dose of assigned treatment (see Section 5.3.2)
Hematology
X
Complete blood count with differential and platelets, within 14 days prior to first dose of 
assigned treatment
Thyroid Function Panel
X
TSH, within 14 days prior to first dose of assigned treatment; if TSH is abnormal, then obtain 
free T3 and free T4.
Virology Tests
X
HBsAg or hepatitis C viral load, HIV (if required by local law), within 14 days prior to first 
dose of assigned treatment
Mandatory Pretreatment Tumor Biopsy
X
Biopsy must be performed during the Screening Phase in all subjects prior to first dose of 
assigned treatment. Sample(s) may be retained for additional research. Results of the PD-L1 
testing must be communicated to the Sponsor Team prior to randomization to determine if 
randomization may proceed.
Archival Tumor Block
X
An archival, formalin-fixed, paraffin-embedded tumor tissue block, or slides samples, is to be 
provided by all subjects, if available.
Disease assessments
X
Assessment should include the chest/abdomen/pelvis at a minimum, and should include other 
anatomic regions as indicated based on the subject’s tumor type and/or disease history.
a Within 28 days of first dose of assigned treatment
Abbreviations: T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone.
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Table 5.1-2:
Baseline for Re-randomization Procedural Outline (Following Implementation of Amendment 5)
Procedure
Days -1
to -28a
Notes
Utilize IRT
X
Subject Registration for Re-randomization
X
Ensure subject continues to meet eligibility for study treatment.
Physical Examination
X
If the re-randomization baseline physical examination is performed within 24 hours prior to 
dosing on Day 1, then a single examination may count as both the re-randomization baseline 
and predose evaluation.
Oxygen Saturation
X
Record at rest via pulse oximetry to establish baseline. 
If subject has oxygen saturation ≤90%, consult BMS Medical Monitor (or designee) prior to 
enrollment.
Vital Signs
X
Temperature, blood pressure, and heart rate
Weight
X
ECOG Performance Status
X
Assessment of Baseline Signs and 
Symptoms
X
If re-baseline or re-randomization occurs > 100 days after the last dose, signs and symptoms 
that occur up to 14 days prior to the next dose of study treatment should be recorded.
Serious Adverse Events
X
All SAEs must be collected from the date of the subject’s written consent until 100 days post-
discontinuation of dosing or subject’s participation in the study if the last scheduled visit 
occurs at a later time.
Chest X-ray
X
12-Lead ECG
X
ECGs should be recorded after the subject has been supine for at least 5 minutes. Record 
QTcF.
Pregnancy Serum or Urine Test
X
Serum or urine, within 72 hours prior to first dose of assigned treatment
Serum Chemistry and Urinalysis
X
See Section 5.3.2
Hematology
X
Includes complete blood count with differential including platelets
Thyroid Function Panel
X
Includes T3, T4, and TSH; if TSH is abnormal, then obtain free T3 and free T4
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Table 5.1-2:
Baseline for Re-randomization Procedural Outline (Following Implementation of Amendment 5)
Procedure
Days -1
to -28a
Notes
Virology Tests
X
Virology must be collected if > 6 months has passed since the previous assessment. Perform 
testing for HBsAg, hepatitis C antibody (if hepatitis C antibody is positive, reflex to hepatitis 
C RNA), or hepatitis C RNA. (Note: Testing for HIV-1 and HIV-2 must be performed at sites 
where mandated by local requirements.)
Mandatory Pretreatment Tumor Biopsy
X
Biopsy must be performed in all subjects within 28 (± 2 days) prior to first dose of assigned 
retreatment. If a biopsy is performed for another reason within that window, re-biopsy for 
purposes of re-randomization baseline is not necessary. Sample(s) may be retained for 
additional research. 
Disease assessments
X
Assessment should include the chest/abdomen/pelvis at a minimum, and should include other 
anatomic regions as indicated based on the subject’s tumor type and/or disease history.
a Within 28 days of first dose of assigned treatment
Abbreviations: ECG = electrocardiogram; QTcF = QT correction using Fridericia’s formula; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating 
hormone.
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Table 5.1-3:
Follow-up Procedural Outline
Safety Follow-up
Procedure
FU 1
30 Daysa
(± 7 Days) 
FU 2
60 Days
(± 7 Days)
FU 3
100 Days
(± 7 Days)
Notes
SAFETY ASSESSMENTS
Physical Examination 
X
X
X
ECOG Performance Status
X
Vital Signs and Weight
X
X
X
Includes body temperature, seated blood pressure, and 
heart rate. Blood pressure and heart rate should be 
measured after the subject has been resting quietly for 
at least 5 minutes.
Oxygen Saturation
X
As clinically indicated
Collected at rest via pulse oximetry
Laboratory Tests
X
X
To include serum chemistry and hematology
Monitor for Serious Adverse 
Events
X
X
X
All SAEs must be collected from the date of the 
subject’s written consent until 100 days post-
discontinuation of dosing or subject’s participation in 
the study if the last scheduled visit occurs at a later 
time
Review of Concomitant 
Medications
X
X
X
SAMPLE COLLECTION
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Table 5.1-3:
Follow-up Procedural Outline
Safety Follow-up
Procedure
FU 1
30 Daysa
(± 7 Days) 
FU 2
60 Days
(± 7 Days)
FU 3
100 Days
(± 7 Days)
Notes
EFFICACY ASSESSMENTS
Tumor Assessment
X
X
Assessed by RECIST v1.1 criteria (see Appendix 2)
Subjects with a history of brain metastasis should have 
a MRI or CT of the brain if clinically indicated. 
Subjects with a history of bone metastasis should have 
a bone scan if clinically indicated.
Subjects who have progressive disease will not require 
further assessments of response.
Collection of Survival Status 
and Subsequent Therapy 
Information
X
X
X
May be performed by phone contact or office visit 
 
a FU visits at Days 30, 60, and 100 (7 days) should occur after the last dose of study drug or coinciding with the date of discontinuation days, if date of 
discontinuation is greater than 30 days after the last dose, to monitor for AEs.
Abbreviations: FU = follow-up.
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5.2
Study Materials
The site will provide all required materials for the tests performed locally (eg, relevant clinical 
laboratory tests and urinalysis). The site will have a well-calibrated scale for recording body 
weight, a 12-lead electrocardiogram (ECG) machine, and calibrated sphygmomanometer and 
thermometer for vital signs assessments. A current and fully-stocked advanced cardiac life support 
cart will be immediately available on the premises. The site will have urine collection containers, 
a refrigerated centrifuge, a monitored and alarmed refrigerator, and freezer (-70°C or below), as 
well as containers and dry ice for shipment and storage of blood and urine samples. The site will 
provide all materials required for accurate source documentation of study activities and for housing 
the subjects during the study. The site will source marketed products from a single commercial lot.
BMS will provide a BMS-approved protocol (and any amendments or administrative letters, if 
required) and IBs for all IPs. CRFs (electronic or hard copy) will be provided by BMS. The central 
laboratory will provide labels and tubes for the collection of blood samples for PK/biomarker and 
genotyping analyses. Additionally, the IRT manual and pharmacy manual will be provided.
5.3
Safety Assessments
AEs will be assessed continuously during the study and for 100 days after the last study drug 
treatment. AEs will be evaluated according to the NCI CTCAE Version 4.03 and should be 
followed per requirements in Sections 6.1.1 and 6.2.1. AEs will be coded using the most current 
version of Medical Dictionary for Regulatory Activities (MedDRA) and reviewed for potential 
significance and importance. Subjects should be followed until all treatment-related AEs have 
recovered to baseline or are deemed irreversible by the investigator.
Protocol-specified assessments are described in Table 5.1-1 (Screening Procedural Outline), Table 
5.1-2 (Baseline for Re-randomization Procedural Outline), Table 5.1-3 (Follow-up Procedural 
Outline), and the On-treatment Procedural Outline(s) specific to each FRACTION-Lung 
Sub-Protocol.
5.3.1
Imaging Assessment for the Study
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the study investigator as per standard 
medical/clinical judgment.
5.3.2
Laboratory Test Assessments
A local laboratory will perform the analyses and will provide reference ranges for these tests. The 
clinical laboratory assessments are indicated in Table 5.3.2-1.
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Table 5.3.2-1:
Laboratory Test Assessments
Hematology
CBC with differential and platelets
Hemoglobin
Total leukocyte count, including differential
Hematocrit
Platelet count
Serum Chemistry
Aspartate aminotransferase (AST)
Total protein
Alanine aminotransferase (ALT)
Albumin
Total bilirubin
Sodium
Direct bilirubin (only if total bilirubin is elevated)
Potassium
Alkaline phosphatase
Chloride
Lactate dehydrogenase (LDH)
Carbon dioxide or bicarbonate
Creatinine
Calcium
Blood urea nitrogen (BUN) or urea
Phosphorus
Uric acid (screening only)
Magnesium
Glucose
Creatine kinase
Amylase
CrCl (screening only)
Lipase
C-reactive protein
Gamma-glutamyl transferase (only when alkaline phosphatase is abnormal)
Urinalysis
Protein
Leukocyte esterase
Glucose
Specific gravity
Blood
pH
Microscopic examination of the sediment if blood, protein, or leukocyte esterase are positive on the dipstick
Serology
Serum for hepatitis C antibody or hepatitis C RNA (if hepatitis C antibody is positive, reflex to hepatitis C RNA), 
HBsAg, and HIV-1 and HIV-2 antibodies (Testing for HIV-1 and HIV-2 antibodies must be performed at the sites 
mandated by local requirements.)
Other Analyses
Pregnancy test (WOCBP only)
TSH with reflex to free T3 and free T4, as applicable
FSH, if needed to document postmenopausal status, as defined in Section 3.4.3
Abbreviations: CBC = complete blood count; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating 
hormone.
Results of all laboratory tests required by this protocol must be provided to BMS, either recorded 
on the laboratory pages of the CRF or by another mechanism, as agreed upon between the 
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investigator and BMS (eg, provided electronically). If the units of a test result differ from those 
printed on the CRF, the recorded laboratory values must specify the correct units. Any abnormal 
laboratory test result considered clinically significant by the investigator must be recorded on the 
appropriate AE page of the CRF (see Section 6.3).
5.4
Efficacy Assessments
Disease assessment with contrast-enhanced CT scans acquired on dedicated CT equipment is 
preferred for this study. CT with contrast of the chest, abdomen, and pelvis are to be performed 
for tumor assessments. CT scans should be acquired with 5-mm slices with no intervening gap 
(contiguous). Should a subject have a contraindication for CT IV contrast, a non-contrast CT of 
the chest and a contrast-enhanced MRI of the abdomen and pelvis may be obtained. MRIs should 
be acquired with slice thickness of 5 mm with no gap (contiguous). Every attempt should be made 
to image each subject using an identical acquisition protocol on the same scanner for all imaging 
time points. Assessments will be performed at baseline and every 8 weeks (± 1 week) during the 
Treatment Phase until disease progression per RECIST v1.1 criteria (see Appendix 2) or confirmed 
disease progression for subjects treated beyond progression (defined as an additional 10% or 
greater increase in tumor burden volume from the time of initial progression [including all target 
lesions and new measurable lesions]), discontinuation of treatment, or withdrawal from study. 
Assessments will also be performed 30 days after discontinuation of study drug (ie, safety 
follow-up Visit 1; all subjects) and at the end of the follow-up period. Tumor assessments at other 
time points may be performed if the investigator is concerned about tumor progression. 
Assessments of PR and CR must be confirmed no less than 4 weeks following initial assessment. 
Assessment of tumor response will be reported by the investigator for appropriate populations of 
subjects, as defined by RECIST v1.1 criteria (see Appendix 2) for subjects with solid tumors. Same 
modality/scanner should be used for all assessments.
Changes in tumor measurements and tumor responses will be assessed by the investigator using 
RECIST v1.1 criteria.33 Investigators will also report the number and size of new lesions that 
appear while on study. The time point of tumor assessments will be reported on the CRF based on 
the investigator’s assessment using RECIST v1.1 criteria. (See Appendix 2 for specifics of 
RECIST v1.1 criteria to be utilized in this study.)
Tumor assessments will be submitted to a third party radiology vendor on an ongoing basis; subject 
management is not dependent on third party review of tumor assessments.
5.4.1
Primary Efficacy Assessments
The efficacy assessments will include the ORR (eg, PR plus CR), DOR, and PFSR at 24 weeks
based on assessment of tumor response using RECIST v1.1 criteria. 
5.4.2
Secondary Efficacy Assessments
Not applicable.
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5.8
Other Assessments
Not applicable.
5.9
Results of Central Assessments
Central assessments are not planned for this study; however, copies of all scans will be stored for 
possible future central analysis, if determined to be necessary by BMS. At the Sponsor’s discretion, 
scans may be collected centrally to be reviewed by independent radiologists.
5.10
Additional Research Collection
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 encouraged
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. 
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.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or results 
from other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical and 
scientific judgment of the investigator. Note that abnormal lab tests or other safety assessments 
should only be reported as AEs if the final diagnosis is not available. Once the final diagnosis 
is known, the reported term should be updated to be the diagnosis.

Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
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should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration will be 
considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.

The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a subject. 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.
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
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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.
6.1
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 that 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 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 1 of the other serious outcomes listed in the definition above). Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization. Potential drug-induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE.
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (See Section 6.1.1 for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint; if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as an SAE (see Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

A visit to the emergency room or other hospital department < 24 hours that does not result in 
admission (unless considered an important medical or life-threatening event)

Elective surgery planned prior to signing consent

Admissions as per protocol for a planned medical/surgical procedure

Routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)

Medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study. Appropriate documentation is required in these cases.
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
Admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)

Admission for administration of anti-cancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Certain SAEs will be collected as clinical events and not as SAEs, this will include the expected 
clinical outcomes of disease progression, disease metastasis. If death results from disease 
progression, and within 100 days of discontinuation of dosing or subject’s last scheduled visit, this 
SAE should also be reported within 24 hours.
Sections 5.6.1 and 5.6.2 in the Investigator Brochures (IBs) represent the Reference Safety 
Information to determine expectedness of SAEs 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 Phase and within 100 days of 
discontinuation of dosing. The investigator must report any SAE that occurs after these time 
periods and that is believed to be related to study drug or protocol-specified procedure. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE Report 
Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The preferred 
method for SAE data reporting collection is through the electronic CRF. The paper SAE 
Report/Pregnancy Surveillance Forms are only intended as a back-up option when the eCRF 
system is not functioning. In this case, the paper forms are to be transmitted via email or confirmed 
facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture, 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.
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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 BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as a serious adverse event.
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). 
All nonserious adverse events (not only those deemed treatment-related) are to be collected 
continuously during the treatment period and for a minimum of 100 days following the last dose 
of study treatment. 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (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 IP, it is subsequently discovered that a study subject is pregnant or 
may have been pregnant at the time of study exposure, including during 100 days or at least 
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5 half-lives (if longer) after study drug administration, the investigator must immediately notify 
the BMS Medical Monitor (or designee) of this event and complete and forward a Pregnancy 
Surveillance Form to BMS (or designee) within 24 hours and in accordance with the SAE reporting 
procedures described in Section 6.1.1.
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study treatment, or reinitiation of study treatment, a discussion between the investigator and the 
BMS Medical Monitor/designee must occur. If, for whatever reason, pregnancy has ended, 
confirmed by negative serum pregnancy test, treatment may be resumed (at least 3 weeks and not 
greater than 6 weeks after the pregnancy has ended), following approvals of participant/sponsor 
/IRB/EC, as applicable.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered, if indicated.
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 subject should be reported to BMS. 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.
In cases where a study drug can be present in seminal fluid, at exposures sufficient to potentially 
cause fetal toxicity, and if any sexual activity (e.g. vaginal, anal, oral) has occurred between a male 
participant and a pregnant WOCBP partner(s), the information should be reported to the Sponsor 
or designee, even if the male participant has undergone a successful vasectomy. In order for 
Sponsor or designee to collect any pregnancy surveillance information from the female partner, 
the female partner(s) must sign an informed consent form for disclosure of this information. 
Information on the pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details).
6.6
Potential Drug-induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential drug-induced liver injury (p-DILI) event. All occurrences 
of potential DILIs, meeting the defined criteria, must be reported as SAEs (see Section 6.1.1 for 
reporting details).
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Potential DILI is defined as the following: 

Aminotransferase (ALT or AST) elevation > 3institutional ULN
AND 

Total bilirubin > 2institutional ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase)
AND 

No other immediately apparent possible causes of aminotransferase elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, preexisting chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic, or cancer 
metastases. 
The key responsibilities for investigators during p-DILI assessment include the following: (i) early 
detection, medical evaluation (including the exclusion of other potential causes), and rapid 
laboratory confirmation of liver-related abnormalities and (ii) BMS notification of p-DILI cases 
via SAE forms. Following the gathering and assessment of relevant clinical information, BMS is 
responsible for the following: (iii) timely evaluation and triaging of p-DILI cases, (iv) expedited 
reporting of p-DILI cases, and (v) expanded review of p-DILI cases, including a detailed 
assessment of all available clinical information, investigations, and biochemical data.
Investigators are expected to monitor ongoing routine and ad hoc hepatic laboratory test results to 
rapidly determine whether a subject meets p-DILI criteria. They are expected to promptly notify 
BMS of all p-DILI cases. p-DILI cases may be identified by abnormal liver biochemistry values, 
whether or not they are accompanied by liver-related signs and/or symptoms. In both cases, 
expedited confirmation with repeat laboratory testing should occur within 3 business days using a 
Hepatic Laboratory Panel (ALT, AST, total bilirubin, and alkaline phosphatase). Any subject with 
an abnormal Hepatic Laboratory Panel that meets p-DILI criteria is a candidate for study drug 
discontinuation. Any confirmed p-DILI events must be reported (along with a description of the 
clinical findings) to BMS as an SAE within 24 hours of confirmation. 
An extensive clinical history, examination, and appropriate investigations should be obtained to 
exclude cholestatic and other apparent causes that may explain the observed abnormalities in liver 
function and/or hepatic signs and symptoms. Other apparent causes include, nonexhaustively and 
by way of example only, infectious diseases (such as active hepatitis A, B, and C), congenital 
diseases (such as Gilbert’s syndrome), neoplastic diseases (such as hepatocellular carcinoma), 
autoimmune diseases (such as primary biliary cirrhosis), and the use of concomitant hepatotoxic 
medications (such as antibiotics, the oral contraceptive pill, and herbal medicines). All 
investigations to exclude potential causes of liver function abnormalities or hepatic signs and/or 
symptoms should be guided by relevant factors such as the subject’s age, gender, clinical history, 
and signs and symptoms.
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6.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, ECG, x-ray 
filming, or 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
SAFETY MONITORING BOARD AND OTHER EXTERNAL COMMITTEES
Two independent committees may be utilized: a Safety Monitoring Board (SMB) and an 
Independent Review Committee (IRC).
The SMB will be established to provide safety monitoring and to provide advice to the Sponsor 
regarding actions the committee deems necessary for the continuing protection of subjects enrolled 
in the study. The SMB will meet at least twice per year concurrent with BMS internal continuous 
safety assessment. If needed, additional ad-hoc SMB meetings may be convened. Safety related 
data summary and listing (by study track and treatment arm as appropriate) will be provided to 
SMB to facilitate safety monitoring. The SMB will act in an advisory capacity to BMS and will 
monitor subject safety throughout the study. Additional details are provided in the SMB Charter.
The IRC may be established if needed. The IRC may review all available tumor assessment scans 
to determine response (RECIST v1.1 criteria). IRC-determined response may be used in the 
analyses of ORR, PFSR, and DOR.
8
STATISTICAL CONSIDERATIONS
Additional or Sub-Protocol-specific statistical considerations may be provided in Sub-
Protocols. Please refer to the specific Sub-Protocol for guidance.
8.1
Sample Size Determination
Sample sizes are guided by Simon 2-stage, single-stage or multi-stage designs as described in the 
subsequent sections and in Table 8.1-1. Because of the different patient populations and existing 
standard of care options under each track, different criteria apply to determine the number of 
patients for each stage and the strength of the efficacy signal required to proceed to the next stage. 
For sample size calculation and for simplicity of description, decision criteria for stopping or 
progressing to the next stage are based on the number of objective responses observed. However, 
since BOR does not necessarily capture the full extent of clinical benefit, and since response can 
be delayed or of short duration, the Sponsor will also review other aspects of clinical benefit which 
may better predict OS benefit, such as DOR and PFSR, as well as the relative performance of 
different combination arms, before making a final determination.
Additional subjects may be enrolled to account for subjects who may drop out of the study without 
being evaluable for response. For example, assuming a 25% dropout rate, up to 5 additional 
subjects per arm could be enrolled into Track 2 Stage 1 to achieve 20 “evaluable” subjects (with 
any over-enrollment counting towards Stage 2), while in Stage 2, an additional 4 subjects over the 
planned 15 could be enrolled to achieve 35 total evaluable subjects. Similarly in Track 3 Stage 1, 
up to 15 subjects may initially be enrolled to achieve 12 evaluable subjects.
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Although the sample size calculations are based on efficacy considerations, safety will also be 
continuously assessed, and will be taken into account in the decision to continue or terminate an 
arm. For example, 35 subjects per arm will result in 83% probability of detecting an AE that has a 
true rate of 5%.
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Table 8.1-1:
Multi-stage or Single-stage Design
Track
Stage 
1
n
Stage 1 Responders
Stage 
2 
n
Stage 2 Responders
Stage 
3 
n
Stage 3 
Responders
Stage 
4 
n
Stage 4 Responders
Futility 
Stop
Go to 
Stage 2
Futility 
Stop
Go to 
Stage 3
Efficacy 
Stop
Futility 
Stop
Go to 
Stage 4
Futility 
Stop
Efficacy 
Stop
1.b
20
≤ 3
≥ 4
15
≤ 6
≥ 7
≥ 11
15
≤ 11
≥ 12
20
≤ 13
≥ 14
2
20
≤ 2
≥ 3
15
≤ 4
≥ 5
≥ 9
15
≤ 8
≥ 9
20
≤ 9
≥ 10
3
12
≤ 1
≥ 2
23
≤ 5
≥ 6
4
(PD-L1 exp. 
< 1%)
19
≤ 3
≥ 4
17
≤ 10
≥ 11 
4
(PD-L1 exp. 
≥1% & < 50%)
28
≤ 11
≥ 12
13
≤ 20
≥ 21 
4
(PD-L1 exp. 
≥50%)
16
≤ 11
≥ 12
9
≤ 20
≥ 21
5
35
Note: n values presented in this table are per treatment arm.
Abbreviations: exp = expression.
With regard to sample size, subjects who are re-randomized to a different treatment will be counted once for each randomization; 
subjects who are re-treated within the same arm will only be counted once.
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8.1.1
Sample Sizes for Tracks 4 and 5
With the implementation of Amendment 5, subjects will be enrolled in Tracks 4 and 5. The sample 
size for Track 4 is guided by a 2-stage design and for Track 5 is guided by a single-stage design. 
Track 4 subjects will be stratified into 3 groups according to their PD-L1 expression level as 
assessed by the baseline tumor biopsy. Section 8.1.1.1 describes the sample size determination for 
all three strata in Track 4, while Section 8.1.1.2 describes the sample size determination for 
Track 5. 
8.1.1.1
Track 4 - Anti-PD-1/PD-L1 Treatment-naïve Subjects
Track 4 subjects will be enrolled into 1 of 3 strata based on their PD-L1 expression level as 
assessed by the baseline tumor biopsy. Subjects may in some cases be randomized before the 
results of their PD-L1 expression testing are known. As a result, there may be a small number of 
subjects (estimated no more than 10% to 15%) who are randomized but are subsequently found to 
be unevaluable for PD-L1 expression. Such unevaluable subjects may continue their randomized 
treatment but will not be counted towards the sample size for any of the three strata. Data for such 
subjects will be reported as if coming from a fourth stratum. In the situation that one or two of the 
strata has reached or is approaching full enrollment, the Sponsor may choose to require the results 
of PD-L1 testing to be available before randomizing additional subjects, to reduce the risk of 
over-enrollment.
Enrollment will be continued during initial efficacy evaluation (ie, with the indicated number of 
subjects at Stage 1) to allow additional subjects to enroll to account for unexpected trial impact, 
such as response non-evaluable subjects due to early drop-out, design parameter change 
(eg, historical rate update), etc. The number of responses given here is used as a guide for sample 
size calculation and for simplicity of description. Before making a decision to terminate or 
continue an arm, BMS will also review the totality of all available data, which includes: other 
aspects of efficacy that may help predict OS benefit, such as DOR and PFSR; clinical safety 
information; and biomarker data, as well as the relative performance of other treatment arms on a 
continuing basis.
Track 4 - Anti-PD-1/PD-L1 Treatment-naïve subjects with PD-L1 expression less than 1%
As shown in Table 8.1-1, a minimum of 19 subjects in each study treatment combination arm will 
be treated in Stage 1 for an initial evaluation of efficacy. If the number of responses observed in 
Stage 1 is ≤3/19, the study treatment combination arm would likely not be considered efficacious. 
In Stage 2, an additional 17 subjects will be treated. More than 10 responses observed at the end 
of Stage 2 would suggest the efficacy target has been met. The totality of efficacy data and response 
profile for each combination will be considered when making decisions to terminate or continue 
an arm. The operating characteristics of the Simon 2-stage design to be used as a guide are provided 
in Figure 8.1.1.1-1. With the stopping boundaries as shown in Table 8.1-1, if the combination has 
an ORR no better than the historical control (from nivolumab and ipilimumab combination data in 
Study CA209012) at 20%, then there is a 90% overall chance of declaring futility, with a 
46% chance of stopping at Stage 1; there is a 10% false positive rate. If the combination has an 
ORR equal to the target of 40%, then there is a 90% chance of declaring efficacy after Stage 2, 
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whereas if the ORR is equal to 35%, 30%, and 25%, there will be, respectively, 76%, 52%, and 
27% chance of declaring efficacy.
Figure 8.1.1.1-1:
Operating Characteristics of Simon 2-Stage Design for Track 4 
Subjects with PD-L1 Expression < 1% (Power = 90%, Alpha = 10%)
Track 4 - Anti-PD-1/PD-L1 Treatment-naïve Subjects with PD-L1 Expression ≥1% and 
< 50%
As shown in Table 8.1-1, a minimum of 28 subjects in each study treatment combination arm will 
be treated in Stage 1 for an initial evaluation of efficacy. If the number of responses observed in 
Stage 1 is ≤11/28, the study treatment combination arm would likely not be considered 
efficacious. In Stage 2, an additional 13 subjects will be treated. More than 20 responses observed 
at the end of Stage 2 would indicate the efficacy target has been met. The totality of efficacy data 
and response profile for each combination will be considered when making decisions to terminate 
or continue an arm. The operating characteristics of the Simon 2-stage design, used as a guide, are 
provided in Figure 8.1.1.1-2. With the stopping boundaries as shown in Table 8.1-1, if the 
combination has an ORR no better than the historical control (from nivolumab and ipilimumab 
combination data in Study CA209012) at 40%, then there is a 90% overall chance of declaring
futility, with a 55% chance of stopping at Stage 1; there is a 10% false positive rate. If the 
combination has an ORR equal to the target of 60%, then there is a 90% chance of declaring
efficacy after Stage 2, whereas if the ORR is equal to 55%, 50%, and 45%, there will be,
respectively, 74%, 50%, and 27% chance of declaring efficacy.
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Figure 8.1.1.1-2:
Operating Characteristics of Simon 2-Stage Design for Track 4 
Subjects with PD-L1 Expression Between 1% and < 50% (Power = 
90%, Alpha = 10%)
Track 4 - Anti-PD-1/PD-L1 Treatment-naïve Subjects with PD-L1 Expression ≥ 50%
As shown in Table 8.1-1, a minimum of 16 subjects in each study treatment combination arm will 
be treated in Stage 1 for an initial evaluation of efficacy. If the number of responses observed in 
Stage 1 is ≤11/16, the study treatment combination arm would likely not be considered 
efficacious. In Stage 2, an additional 9 subjects will be treated. More than 20 responses observed 
at the end of Stage 2 would indicate the efficacy target has been met. The totality of efficacy data 
and response profile for each combination will be considered when making decisions to terminate 
or continue an arm. The operating characteristics of the Simon 2-stage design, used as a guide, are 
provided in Figure 8.1.1.1-3. With the stopping boundaries as shown in Table 8.1-1, if the 
combination has an ORR no better than the historical control (from nivolumab and ipilimumab 
combination data in Study CA209012) at 70%, then there is a 90% overall chance of declaring
futility, with a 55% chance of stopping at Stage 1; there is a 10% false positive rate. If the 
combination has an ORR equal to the target of 90%, then there is a 90% chance of declaring
efficacy after Stage 2, whereas if the ORR is equal to 85%, 80%, and 75%, there will be,
respectively, 68%, 42%, and 21% chance of declaring efficacy.
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Figure 8.1.1.1-3:
Operating Characteristics of Simon 2-Stage Design for Track 4 
Subjects with PD-L1 Expression ≥ 50% (Power = 90%, Alpha = 10%)
8.1.1.2
Track 5 - Anti-PD-1/PD-L1 Treatment-experienced Subjects
It is not known whether PD-L1 expression levels affect response rates for combination therapy in 
anti-PD-1/PD-L1 experienced patients. Therefore, Track 5 participants will not be stratified on 
their PD-L1 expression levels; however, subset analyses may be performed. The sample size of 
35 participants for Track 5 is based on a 1-sided alpha of 0.1 for testing the null hypothesis that 
the ORR is equal to the null rate of 10%, and a power of 90% against the alternative hypothesis 
that the ORR is equal to the target rate of 30% (Table 8.1.1.2-1). Unlike in Track 4, participants 
whose PDL-1 status is unevaluable will count towards the sample size in Track 5.
Table 8.1.1.2-1:
Single-stage Design for Track 5
PD-L1 Stratum
Null ORR
Target ORR
Type 1 Error
Power
Sample size
All
0.1
0.3
0.1
0.9
35
Efficacy will be continuously monitored in all participants who are evaluable for response using 
the measurements described in Section 8.3.1. In Track 5, 8/35 responses would result in CIs for 
ORR which are strictly higher than 10%. If at any point it appears very unlikely that this track will 
meet its efficacy target, the Sponsor will consider closing that arm to further enrollment. Both 
subjects previously treated in Tracks 4 and 5 (re-randomized subjects) and new subjects who meet 
eligibility criteria are permitted to enter Track 5. Some slots in Track 5 will be reserved for 
re-randomized subjects to ensure that both types of subjects are enrolled in Track 5. 
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8.1.2
Sample Sizes for Tracks 1, 2 and 3
With the implementation of Amendment 5, enrollment in Tracks 1, 2, and 3 will cease. Sample 
size descriptions provided in Sections 8.1.2.1 through 8.1.2.3 are, therefore, applicable only until 
implementation of Amendment 5. The sample sizes for Tracks 1b and 2 are guided by a 4-stage 
design, whereas the sample size for Track 3 is guided by a Simon 2-stage design. 
8.1.2.1
Track 1.a and 1.c - Anti-PD-1/PD-L1 Treatment-naïve, PD-L1-positive 
Subjects
Week 8 Responders and Rapid Progressors
The number of subjects entering Track 1.a is not pre-specified but is determined by patient 
response to 8 weeks of nivolumab monotherapy. It is estimated that approximately 15% of subjects 
who enter Track 1 would enter Track 1.a. Similarly, the number of subjects who enter Track 1.c 
and are discontinued from treatment after Week 8 due to fast progression cannot be pre-specified.
It is estimated that approximately 10% of subjects who enter Track 1 would enter Track 1.c. The 
remaining 75% of subjects who enter Track 1 would enter Track 1.b. The actual percentage 
(number) of subjects entering Track 1.a and 1.c at the end of the Nivolumab Run-in Phase may be 
included in future Sub-Protocols based on experience from existing/on-going Sub-Protocol(s).
8.1.2.2
Track 1.b - Anti-PD-1/PD-L1 Treatment-naïve, PD-L1-positive Subjects
and Track 2 - Anti-PD1/PD-L1 Treatment-naïve, PD-L1-negative Subjects
For each combination arm under Tracks 1.b and 2, a four-stage approach will be used (nested 
Simon/Fleming). Initially, 20 subjects per combination arm will be treated in Stage 1, and 
preliminary efficacy will be assessed when those subjects are evaluable. If futility is demonstrated 
at that point, the corresponding arm will be terminated; otherwise an additional 15 Stage 2 subjects 
will be enrolled. At the end of Stage 2, the arm can be stopped for futility, continue to Stage 3, or 
be stopped for efficacy. Stage 3 will enroll 15 additional subjects, and when those subjects are 
evaluable for efficacy, the arm may be stopped for futility or proceed to Stage 4. Stage 4 will enroll 
20 subjects. The total potential enrollment for all 4 stages is 70 subjects per combination per Track. 
More details including the Track-specific criteria for stopping or continuing, are given below
Track 1.b - Anti-PD-1/PD-L1 Treatment-naïve, PD-L1-positive Subjects
Week 8 Inadequate Responders
The operating characteristics, futility stops, and efficacy boundaries of this design are provided in 
Figure 8.1.2.2-1. The stopping criteria specific to Track 1.b were selected via simulation to 
1) control the probability of stopping for efficacy if the true ORR is 14%
; and 2) maximize the probability of stopping for efficacy 
if the true ORR is 35%. With the stopping boundaries as shown in Table 8.1-1, if the combination 
has an ORR no better than the historical control at 14%, then there is a 97% overall chance of 
stopping for futility, with a 69% chance of stopping at Stage 1; there is a 3% false positive rate. If 
the combination has an ORR equal to the target of 35%, then it has a 93% chance of stopping for 
efficacy overall (power), with a 72% chance of declaring efficacy at Stage 2; whereas if the true 
ORR is 20%, 25%, or 30%, the power would be 25%, 55%, or 80% respectively. If at least 
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11 responses are observed at the end of Stage 2, then the lower limit of the 95% CI for ORR will 
be higher than the historical ORR of 14%. The CI is calculated using the Clopper-Pearson method.
Figure 8.1.2.2-1:
Operating Characteristics of Track 1b 4-Stage Design 
(Power =93%, Alpha = 3%)
Track 2 - IO Treatment-naïve, PD-L1-negative Subjects
The operating characteristics, futility stops, and efficacy boundaries of this design are provided in 
Figure 8.1.2.2-2. The stopping criteria specific to Track 2 were selected via simulation to 1) control 
the probability of stopping for efficacy if the true ORR is 10%; and 2) maximize the probability 
of stopping for efficacy if the true ORR is 30%.   With the stopping boundaries as shown in Table 
8.1-1, if the combination has an ORR no better than the historical control at 10% (
 
, then there is a 96% overall chance of stopping for futility, 
with a 67% chance of stopping at Stage 1; there is a 4% false positive rate. If the combination has 
an ORR of 30%, then there is a 95% chance of stopping for efficacy overall (power), with a 76% 
chance of stopping for efficacy at Stage 2; whereas if the true ORR is 15%, 20%, or 25%, the 
power would be 28%, 62%, or 85%, respectively. If at least 9 responses are observed at the end of 
Stage 2, then the lower limit of the 95% CI for ORR will be higher than the historical ORR of 10% 
(from nivolumab monotherapy data in Study CA209017). The CI is calculated using the 
Clopper-Pearson method.
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Figure 8.1.2.2-2:
Operating Characteristics of Track 2 4-Stage Design 
(Power =95%, Alpha = 4.4%)
8.1.2.3
Track 3 - Anti-PD-1/PD-L1 Treatment-experienced Subjects
For each combination arm under Track 3, the Simon 2-stage (optimal) design will be used. Initially,
12 subjects per combination arm will be treated in Stage 1 and preliminary efficacy will be assessed 
when those subjects are evaluable. If 1 or fewer responses is observed in Stage 1, the arm will be 
terminated for futility; otherwise, Stage 2 will be initiated and enroll an additional 23 subjects, for 
a total of 35 subjects per combination arm. 
The operating characteristics of this Simon 2-stage (optimal) design are provided in Figure 8.1.2.3-
1. With the stopping boundaries as shown in Table 8.1-1, if the combination has an ORR no better 
than 10%, then there is a 90% overall chance of stopping for futility, with a 66% chance of stopping 
at Stage 1; there is a 10% false positive rate. If the combination has an ORR equal to the target of 
30%, then it has a 90% chance of stopping for efficacy after Stage 2.
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Figure 8.1.2.3-1:
Operating Characteristics of Track 3 Simon 2-Stage Design 
(Power = 90%, Alpha = 10%)
Both subjects previously treated in Tracks 1 and 2 (re-randomized subjects) and new subjects who 
meet eligibility criteria are permitted to enter Track 3. Some slots in Track 3 will be reserved for 
re-randomized subjects to ensure that both types of subjects are enrolled in Track 3. At the 
initiation of the study, recruitment of re-randomized subjects will be limited to 7 subjects per 
Track 3 combination arm in Stage 1 (with 25% dropout rate considered). In Stage 2, recruitment 
of additional re-randomized subjects will be limited to 13 subjects out of the 29 additional subjects 
(with 25% dropout rate considered). The limited number of re-randomized subjects may be 
re-adjusted depending on the enrollment rates, the rate of progression in Tracks 1 to 3, and the 
number of currently open arms in Track 3.
 
 
 
 
 
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8.2
Populations for Analyses

All enrolled subjects include all subjects who signed the written informed consent and were
registered into the IRT.

All randomized subjects include all subjects who were randomized to any treatment arm of 
any track in this study.

All treated subjects include all subjects who received at least 1 dose of study drug.

 
 
 
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8.3
Endpoints
8.3.1
Primary Endpoints
The primary objective of preliminary efficacy will be measured by ORR, DOR, and PFSR at 
24 weeks based on RECIST v1.1 criteria. Tumor response will be based on tumor assessments at 
screening, every 8 weeks from the first dose until investigator assessed initial disease progression 
(per RECIST v1.1) or confirmed disease progression (defined as an additional 10% or greater 
increase in tumor burden volume from the time of initial progression [including all target lesions 
and new measurable lesions]), at the completion of safety follow-up, or until subjects withdraw 
from the study.

Best overall response (BOR) is defined as the best response designation over the round of 
treatment (with corresponding follow-up) as a whole, recorded between the dates of the first 
dose until the last tumor assessment prior to subsequent therapy (re-randomized therapy will 
be considered as subsequent therapy). CR or PR determinations included in the BOR 
assessment must be confirmed by a second scan performed no less than 4 weeks after the 
criteria for response are first met. For those subjects who have surgical resection, only pre-
surgical tumor assessments will be considered in the determination of BOR. 

ORR is defined as the proportion of all treated subjects whose BOR is either a CR or a PR.

DOR, computed for all treated subjects with a BOR of CR or PR, is defined as the time between 
the date of first response and the date of disease progression or death (death occurring after re-
treatment or re-randomization will not be included), whichever occurs first. 

PFSR at 24 weeks is defined as the proportion of treated subjects remaining progression free 
and surviving at 24 weeks. The proportion will be calculated by the Kaplan-Meier estimate, 
which takes into account censored data.
8.3.2
Secondary Endpoints
The assessment of safety will be based on the incidence of AEs, SAEs, AEs leading to 
discontinuation, and deaths. In addition, clinical laboratory test abnormalities will be examined.
AEs and laboratory values will be graded according to the current version of the NCI 
CTCAE 4.0.3.
 
 
 
 
 
 
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8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Frequency distributions of gender and race will be tabulated by treatment arm under each track for 
different subject populations. Summary statistics for age, body weight, and height will be tabulated 
by treatment arm under each track for different subject populations.
8.4.2
Efficacy Analyses
Treatments under each track for different populations will be analyzed independently. There is no 
intention to combine the same treatment across tracks for efficacy analyses.
Efficacy from re-treatment will be assessed and analyzed separately from the initial treatment. 
Subjects re-randomized into Track 3 or 5 will be combined with subjects originally randomized 
into Track 3 or 5 for efficacy analysis. 
In general, the following efficacy analyses will be performed. Listings of tumor measurements will 
be provided by subject and study day in each treatment arm under each track for different subject
populations. Individual subject’s BOR will be listed. ORR and corresponding 2-sided 95% exact 
CI will be provided. Median DOR and corresponding 2-sided 95% CI will be reported. PFSR at 
24 weeks will be estimated. The corresponding 95% CI will be derived. 
 
 
 
Time-to-event endpoints (DOR, PFS, PFSR, 
) will be analyzed using Kaplan-Meier 
method, and the corresponding CI will be derived based on Greenwood formula. Exact CI for ORR 
will be calculated by Clopper-Pearson method.
Specific analyses to be performed for each track are shown in Table 8.4.2-1.
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Table 8.4.2-1:
Analyses Planned for Each Track
Track
ORR
DOR
PFSR
Track 1.a
X
X
X
Track 1.c
Tracks 1.b and 2
End of Stages 1, 2, 3, and 4
X
X
X
Early Termination at Stage 1
X
Tracks 3 and 4
End of Simon Stage 2
X
X
X
Early Termination at Simon Stage 1
X
Track 5
X
X
X
8.4.3
Safety Analyses
All recorded AEs will be listed and tabulated by system organ class, preferred term, and treatment 
under each track for different populations and will be coded according to the most current version 
of MedDRA. Vital signs and clinical laboratory test results will be listed and summarized by 
treatment under each track for different populations. Any significant physical examination findings 
and clinical laboratory results will be listed. ECG readings will be evaluated by the investigator
and abnormalities, if present, will be listed.
Subjects receiving the same treatment in different tracks may be combined for safety analyses. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.4.8
Other Analyses
Not applicable.
8.5
Interim Analyses
Data from individual treatment under each track of this study may emerge at different times; timely 
decision (including early termination) for each individual treatment under different tracks is 
needed. Database lock and analysis for certain FRACTION-Lung combination arms will be 
performed when all subjects in these combination arms (under each track) have completed 
treatment and with sufficient follow-up. Potential interim analyses for each combination arm under 
each track are listed in Table 8.5-1. These interim analyses will be performed independent of each 
other.
Table 8.5-1:
Potential Interim Analyses
Track
Interim Analyses
Track 1.b Anti-PD-1/PD-L1 Treatment-naïve, PD-L1-positive 
Subjects Who Are Inadequate Responders by Week 8
End of Stage 1, end of Stage 2, end of Stage 3
Track 2 Anti-PD-1/PD-L1 Treatment-naïve, PD-L1-negative 
Subjects
End of Stage 1, end of Stage 2, end of Stage 3
Track 3 Anti-PD-1/PD-L1 Treatment-experienced Subjects
End of Simon Stage 1
Track 4 Anti-PD-1/PD-L1 Treatment-naïve Subjects
End of Simon Stage 1
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The SMB will have access to interim reports of safety and will provide advice to the Sponsor 
regarding arm termination due to safety concerns.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the subject: 
(1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study, if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a schedule 
of on-site visits for targeted review of study records.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. 
In addition, the study may be evaluated by BMS internal auditors and government inspectors who 
must be allowed access to CRFs, source documents, other study files, and study facilities. BMS 
audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities 
and promptly forward copies of inspection reports to BMS. 
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9.1.2.1
Source Documentation
The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
AE tracking/reporting, protocol-required assessments, and/or drug accountability records.
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
BMS representatives will provide quality investigational staff training prior to study initiation. 
Training topics will include, but are not limited to: GCP, AE reporting, study details and procedure, 
electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study and BMS will notify the investigator when the study records 
are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site. Records or logs must comply with 
applicable regulations and guidelines and should include:

Amount received and placed in storage area

Amount currently in storage area

Label identification number or batch number 

Amount dispensed to and returned by each subject, including unique subject identifiers

Amount transferred to another area/site for dispensing or storage

Nonstudy disposition (eg, lost, wasted) 

Amount destroyed at study site
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
Retained samples for bioavailability/bioequivalence, if applicable 

Dates and initials of person responsible for IP dispensing/accountability, as per the Delegation 
of Authority Form
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents, or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
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 electronic data capture tool, electronic CRFs will be prepared for all data 
collection fields, except for fields specific to SAEs and pregnancy, which will be reported on the 
paper or electronic SAE Report Form and Pregnancy Surveillance Form, respectively. Spaces may 
be left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator and 
who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review and 
approval/signature are completed electronically through the 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 training requirements and must 
only access the electronic data capture tool using the unique user account provided. User accounts 
are not to be shared or re-assigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory investigator must be selected to sign the clinical study report. Multiple clinical study 
reports for the FRACTION-Lung program may be generated to allow timely reporting of results 
for each completed FRACTION Sub-Protocol or results from a discontinued FRACTION-Lung 
treatment.
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For this protocol, the Signatory investigator will be selected, as appropriate, based on the following 
criteria:

Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications or 
abstracts arising from this study require approval by BMS prior to publication or presentation and 
must adhere to BMS publication requirements, as set forth in the approved Clinical Trial 
Agreement. All draft publications, including abstracts or detailed summaries of any proposed 
presentations, must be submitted to BMS at the earliest practicable time for review, but (at any 
event) not less than 30 days before submission or presentation, unless otherwise set forth in the 
Clinical Trial Agreement. BMS shall have the right to delete any confidential or proprietary 
information contained in any proposed presentation or abstract and may delay publication for up 
to 60 days for the purpose of filing a patent application.
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10
LIST OF ABBREVIATIONS
Term
Definition
ADA
anti-drug antibody
ALK
anaplastic lymphoma kinase
BOR
best overall response
CR
complete response
DILI
drug-induced liver injury
DOR
duration of response
EGFR
epidermal growth factor receptor
EOT
end of treatment
EQ-5D-3L
EuroQol 5-Dimension 3-Level Questionnaire
FLSI-12
Functional Assessment of Cancer Therapy - Lung Symptom Index-12
FRACTION
Fast Real-time Assessment of Combination Therapy in Immuno-ONcology (program)
FRACTION-Lung
the current study (CA018001) for which this document serves as the Master Protocol
FRACTION-Lung
Master Protocol
the current protocol, to which future FRACTION-Lung Sub-Protocols will be appended
FRACTION-Lung 
Sub-Protocol(s)
document(s) that will introduce additional novel FRACTION-Lung combination(s) 
and/or contemporaneous control treatments and will be appended to this 
FRACTION-Lung Master Protocol
FU
follow-up
GITR
glucocorticoid-induced tumor necrosis factor receptor-related gene
HRQoL
health-related quality of life
IFN
interferon gamma
IP
investigational product
IRC
independent review committee
IRT
Interactive Response Technology
ORR
objective response rate
OS
overall survival
PD
progressive disease 
PFS
progression-free survival
PR
partial response
SD
stable disease
SMB
Safety Monitoring Board
TKI
tyrosine kinase inhibitor
VAS
visual analog scale
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APPENDICES
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APPENDIX 1
ECOG PERFORMANCE STATUS
STATUS
SCALES
STATUS
KARNOFSKY
ZUBROD-
ECOG-WHO
Normal, no complaints
100
0
Normal activity
Able to carry on normal 
activities
Minor signs or symptoms of 
disease
90
1
Symptoms, but fully 
ambulatory
Normal activity with effort
80
Cares for self. Unable to carry 
on normal activity or to do 
active work
70
2
Symptomatic, but in 
bed < 50% of the day.
Requires occasional assistance, 
but able to care for most of his 
needs
60
Requires considerable 
assistance and frequent medical 
care
50
3
Needs to be in bed 
> 50% of the day, but 
not bedridden
Disabled. Requires special care 
and assistance
40
Severely disabled. 
Hospitalization indicated 
though death non imminent
30
4
Unable to get out of 
bed
Very sick. Hospitalization 
necessary. Active supportive 
treatment necessary
20
Moribund
10
Dead
0
5
Dead
 
 
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APPENDIX 2
RECIST V1.1
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:
1.1
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.
1.2
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.  
1.3
Special considerations regarding lesion measurability
1.3.1
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 
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considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above.

Blastic bone lesions are non-measurable.
1.3.2
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.
1.3.3
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. 
1.4
Specifications by methods of measurements
1.4.1
Measurement of lesions
All measurements should be recorded in metric notation (mm). All baseline evaluations should 
be performed as close as possible to the treatment start and never more than 28 days before the 
beginning of the treatment.
1.4.2
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.
1.4.2.1
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.
1.4.2.2
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.
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1.4.2.3
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.
1.4.2.4
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. 
1.4.2.5
Endoscopy, laparoscopy
The utilization of these techniques for objective tumor evaluation is not advised.
1.4.2.6
Tumor markers 
Tumor markers alone cannot be used to assess objective tumor response. 
2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
2.1
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.
2.1.1
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.
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2.2
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’).
3
TUMOR RESPONSE EVALUATION 
3.1
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.
3.1.1
Special notes on the assessment of target lesions
3.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded and should be measured in the same anatomical plane as the baseline examination, even 
if the nodes regress to below 10 mm on study. This means that when lymph nodes are included 
as target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met, 
since a normal lymph node is defined as having a short axis of < 10 mm.
3.1.1.2
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. 

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 
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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).   
3.1.1.3
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’.
3.2
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. 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) 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).
3.2.1
Special notes on assessment of non-target lesions
The concept of progression of non-target disease requires additional explanation as follows:
3.2.1.1
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. 
3.2.1.2
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. 

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 
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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. 
3.2.1.3
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. 
3.3
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.
3.3.1
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 
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 is a sign of PD 
based on a new lesion. 
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
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.
4
RESPONSE CRITERIA
4.1
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 1 provides a summary of the 
overall response status calculation at each time point.
Table 1.
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
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.
4.1.1
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 
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be made that the contribution of the individual missing lesion(s) would not have changed the 
assigned time point response.
4.1.2
Confirmation scans  

Verification of Response: Confirmation of PR and CR is required within 4 weeks to 
ensure responses identified are not the result of measurement error. To be assigned a 
status of CR or PR, changes in tumor measurements must be confirmed by consecutive 
repeat assessments that should be performed no less than 28 days after the criteria for 
response are first met. For this study, the next scheduled tumor assessment can meet this 
requirement.

Verification of Progression: Not required.
4.2
Best overall response: All timepoints
The best overall response is determined once all the data for the subject is known. It is the best 
response recorded from the start of the study treatment until objectively documented progression 
per RECIST1.1 or the date of subsequent anticancer therapy taking into account any requirement 
for confirmation. 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. 
Best response is defined as the best response across all time points with subsequent confirmation. 
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol (generally 4 weeks later). 
In this circumstance, the best overall response can be interpreted as specified in Table 2. When 
SD is believed to be best response, it must meet the protocol specified minimum time from 
baseline. Measurements must have met the SD criteria at least once after study entry at a 
minimum interval (not less than 4 weeks).
Table 2.
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 2.
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.
4.3
Duration of response
4.3.1
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.
4.3.2
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).
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APPENDIX 4
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 06, 12-Apr-2018
The FRACTION-Lung Master Protocol was revised with edits based on the addition of the 
FRACTION-Lung Sub-Protocol C.
Summary of key changes of Revised Protocol 06
Section Number & Title
Description of Change
Brief Rationale
Section 3.1: Study Design 
and Duration; Section 4.4
Removed stratification by PD-L1 
expression in Track 4 and introduced the 
option of new randomization schedules in 
Sub-Protocols.
 
 
Section 3.1: Study Design 
and Duration
Two-stage design may be used in Track 5, 
as opposed to a single-stage design, based 
on specific Sub-Protocols.
 
 
Section 3.4: Study Population
Emphasis added to direct readers to Sub-
Protocols for additional inclusion and 
exclusion criteria including the following: 
inclusion criteria 1c and 3.
 
 
Section 8: Statistical 
Considerations
Emphasis added to direct readers to Sub-
Protocols for additional statistical 
considerations.
 
 
Section 3.4: Study Population
Inclusion criteria 2.c.i was modified to 
note that EGFR testing must be performed 
using tumor tissue.
Table 5.1-1: Screening 
Procedural Outline; 
Table 5.1-2: Baseline for 
Retreatment/Re-
randomization Procedural 
Outline
Urinalysis added to the screening and the 
baseline for retreatment/re-randomization 
procedural outlines.
 
 
 
Section 6.1.1: Serious 
Adverse Event Collection 
and Reporting
Added clarification that death resulting 
from disease progression within 100 days 
of discontinuation of dosing must be 
reported as an SAE within 24 hours.
All
Minor formatting and typographical 
corrections.
 
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SAP_000.pdf: 
Official Title of Study: 
A Phase 2, Fast Real-time Assessment of Combination Therapies in Immuno-ONcology Study in 
Subjects with Advanced Non-small Cell Lung Cancer (FRACTION-Lung) 
 
NCT Number: NCT02750514 
 
Document Date (Date in which document was last revised): November 01, 2017 
 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A PHASE 2, FAST REAL-TIME ASSESSMENT OF COMBINATION THERAPIES IN 
IMMUNO-ONCOLOGY STUDY IN SUBJECTS WITH ADVANCED NON-SMALL CELL 
LUNG CANCER (REACTION-LUNG)
PROTOCOL(S) CA018001
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2
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................4
LIST OF FIGURES ....................................................................................................................6
2
STUDY DESCRIPTION ..........................................................................................8
2.1
Study Design ............................................................................................................8
2.1.1
Original Design (up to and includes Master Protocol Amemdment 4).......................9
2.1.1.1
FRACTION-Lung Track 1 Design - Anti-PD-1/PD-L1 Treatment-naïve, 
PD-L1-positive Subjects..........................................................................................11
2.1.1.2
FRACTION-Lung Track 2 Design - Anti-PD-1/PD-L1 Treatment-naïve, 
PD-L1-negative Subjects ........................................................................................14
2.1.1.3
FRACTION-Lung Track 3 Design - Anti-PD-1/PD-L1 Treatment-experienced 
Subjects ..................................................................................................................16
2.1.2
Current Design (Master Protocol Amendment 5)....................................................18
2.1.2.1
Fraction Lung Track 4 (Naive) and 5 (Experienced) Design ...................................19
2.2
Treatment Assignment............................................................................................22
2.3
Blinding and Unblinding.........................................................................................22
2.4
Protocol Amendments.............................................................................................22
2.5
Safety Monitoring Board ........................................................................................25
2.6
Independent Review Committee (IRC) ...................................................................25
3
OBJECTIVES ........................................................................................................25
3.1
Primary...................................................................................................................25
3.2
Secondary...............................................................................................................25
4
ENDPOINTS..........................................................................................................26
4.1
Primary Endpoint....................................................................................................26
4.1.1
Objective response rate (ORR) ...............................................................................26
4.1.2
Duration of Response (DOR)..................................................................................27
4.1.3
Progression Free Survival Rate (PFSR) at 24 Weeks ..............................................27
4.2
Secondary Endpoints ..............................................................................................29
5
SAMPLE SIZE AND POWER...............................................................................32
5.1
Sample Sizes for Tracks 4 and 5 .............................................................................34
5.1.1
Track 4 - Anti-PD-1/PD-L1 Treatment-naïve Subjects ............................................34
5.1.2
Track 5 - Anti-PD-1/PD-L1 Treatment-experienced Subjects..................................37
5.2
Sample Sizes for Tracks 1, 2 and 3 .........................................................................38
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5.2.1
Track 1.a and 1.c - Anti-PD-1/PD-L1 Treatment-naïve, PD-L1-positive 
Subjects ..................................................................................................................38
5.2.2
Track 1.b - Anti-PD-1/PD-L1 Treatment-naïve, PD-L1-positive Subjects and 
Track 2 - Anti-PD-1/PD-L1 Treatment - naïve, PD-L1 -negative Subjects...............38
5.2.2.1
Track 1.b - Anti-PD-1/PD-L1 Treatment-naïve, PD-L1-positive Subjects................38
5.2.2.2
Track 2 - Anti-PD-1/PD-L1 Treatment-naïve, PD-L1-negative Subjects..................39
5.2.3
Track 3 - Anti-PD-1/PD-L1 Treatment-experienced Subjects..................................40
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................42
6.1
Study Periods..........................................................................................................42
6.1.1
Study Periods for Treatment Arms Under Tracks 2, 3, 4 and 5................................42
6.1.1.1
Baseline Period ......................................................................................................43
6.1.1.2
Post Baseline Period...............................................................................................43
6.1.2
Study Periods for Treatment Arms under Track 1 ...................................................44
6.1.2.1
Baseline Period ......................................................................................................44
6.1.2.2
Run-in Period.........................................................................................................44
6.1.2.3
Post Run-in Period .................................................................................................45
6.1.2.4
Additional Period information ................................................................................45
6.2
Treatment Regimens...............................................................................................45
6.3
Populations for Analyses ........................................................................................46
7
STATISTICAL ANALYSES..................................................................................46
7.1
General Methods ....................................................................................................47
7.2
Study Conduct........................................................................................................47
7.2.1
Study information ...................................................................................................47
7.2.2
Accrual...................................................................................................................47
7.2.3
Relevant Protocol Deviations..................................................................................47
7.3
Study Population ....................................................................................................48
7.3.1
Subject Disposition.................................................................................................48
7.3.2
Demographics and Other Baseline Characteristics.................................................48
7.4
Extent of Exposure .................................................................................................49
7.4.1
Study Therapy.........................................................................................................49
7.4.2
Modification of Study Therapy................................................................................51
7.5
Efficacy..................................................................................................................52
7.5.2
Additional analyses for Track 1.b and 2..................................................................54
7.6
Safety.....................................................................................................................54
7.6.1
Deaths ....................................................................................................................55
7.6.2
Serious Adverse Events...........................................................................................56
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy.................................56
7.6.4
Adverse Event Leading to Dose Reduction (Dasatinib and BMS-986205 
specific)..................................................................................................................56
7.6.5
Adverse Event Leading to Dose Delay ....................................................................56
7.6.6
Overall Adverse Events...........................................................................................57
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7.6.7
Select Adverse Event...............................................................................................57
7.6.7.1
Incidence of Select AE ............................................................................................57
7.6.7.2
Time to onset of Select AE.......................................................................................58
7.6.8
Immune Mediated Adverse Events (IMAE)..............................................................58
7.6.8.1
Incidence of IMAE..................................................................................................59
7.6.8.2
Time to onset of IMAE ............................................................................................59
7.6.9
Multiple Events.......................................................................................................60
7.6.10
Clinical Laboratory Evaluations.............................................................................60
7.6.10.1
Abnormal Hepatic Test...........................................................................................60
7.6.10.2
Abnormal Thyroid Test...........................................................................................61
7.6.11
Vital Signs and Other Safety Evaluation .................................................................61
 
8
CONVENTIONS....................................................................................................66
9
CONTENT OF REPORTS .....................................................................................67
10
OTHER INFORMATION ......................................................................................67
10.1
Select Adverse Events Definition And Conventions................................................67
10.1.1
Time to onset definition...........................................................................................70
10.2
Immune Mediated adverse events definition and conventions .................................72
11
DOCUMENT HISTORY........................................................................................73
LIST OF TABLES
Table 1-1:
Potential Interim Analyses of Efficacy......................................................8
Table 2.4-1:
Master Protocol Amendment ..................................................................22
Table 2.4-2:
Sub Protocol A Amendment ...................................................................24
Table 4.1.1-1:
Tumor Assessments for BOR Consideration...........................................27
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Table 4.1.3-1:
Censoring Scheme for Progression (for DOR and PFS Derivation).........28
Table 4.3.3-1:
Samples for ADA endpoint consideration...............................................31
Table 5-1:
Multi-Stage or Single-stage Design ........................................................33
Table 5.1.2-1:
Single-stage Design for Track 5..............................................................37
Table 5.3-1:
Probability That Estimated Ratio of On-treatment to Pre-treatment 
(Baseline) Value Is Within 20% of True Value.......................................42
Table 6.1.2.4-1:
Analysis Period information for Track 1.................................................45
Table 7.4.1-1:
Study Therapy Parameter Definitions - Nivolumab Monotherapy...........49
Table 7.4.1-2:
Study Therapy Parameter Definitions - Nivolumab + Dasatinib..............49
Table 7.4.1-3:
Study Therapy Parameter Definitions - Nivolumab + BMS-986016........50
Table 7.4.1-4:
Study Therapy Parameter Definitions - Nivolumab + Ipilimumab...........50
Table 7.4.1-5:
Study Therapy Parameter Definitions - Nivolumab + BMS-986205........50
Table 7.5-1:
Analyses Planned for Each Track ...........................................................52
Table 10.1-1:
Select Adverse Event..............................................................................67
Table 10.1.2-1:
Derivation of Clustered Select AE..........................................................71
Table 10.2-1:
Immune-Mediated Adverse Event Definition..........................................72
Table 11-1:
Document History ..................................................................................73
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LIST OF FIGURES
Figure 2.1.1-1:
FRACTION-Lung Original (Tracks 1-3) Study Design...........................10
Figure 2.1.1.1-1:
Track 1 Design Schematic - Anti-PD-1/PD-L1 Treatment-naïve, 
PD-L1-positive Subjects.........................................................................13
Figure 2.1.1.2-1:
Track 2 Design Schematic - Anti-PD-1/PD-L1 Treatment-Naive, 
PD-L1-negative Subjects........................................................................15
Figure 2.1.1.3-1:
Track 3 Design Schematic - Anti-PD-1/PD-L1 Treatment-
experienced Subjects ..............................................................................17
Figure 2.1.2-1:
Fraction-Lung Current (Track 4 and 5) Study Design .............................18
Figure 2.1.2.1-1:
Track 4 and 5 Study Design Schematic:..................................................20
Figure 5.1.1-1:
Operating Characteristics of Simon 2-Stage Design for Track 4 
Subjects with PD-L1 Expression < 1% (Power = 90%, Alpha = 
10%).......................................................................................................35
Figure 5.1.1-2:
Operating Characteristics of Simon 2-Stage Design for Track 4 
Subjects with PD-L1 Expression Between 1% and < 50% (Power = 
90%, Alpha = 10%)................................................................................36
Figure 5.1.1-3:
Operating Characteristics of Simon 2-Stage Design for Track 4 
Subjects with PD-L1 Expression ≥ 50% (Power = 90%, Alpha = 
10%).......................................................................................................37
Figure 5.2.2.1-1:
Operating Characteristics of Track 1b 4-Stage Design (Power = 
93%, Alpha = 3%)..................................................................................39
Figure 5.2.2.2-1:
Operating Characteristics of Track 2 4-Stage Design (Power = 
95%, Alpha = 4.4%)...............................................................................40
Figure 5.2.3-1:
Operating Characteristics of Track 3 2-Stage Design (Power = 
90%, Alpha = 10%)................................................................................41
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The FRACTION Program will consist of several FRACTION studies, each in a specific tumor 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Research Hypothesis:  
It is anticipated that combination of IO agents will demonstrate improved efficacy in subjects with
recurrent NSCLC.
Schedule of Analyses:
Safety data from this study will be monitored by an independent Safety Monitoring Board (SMB). 
Details are specified in the SMB charter.
Interim analysis for individual treatment arm under each track per design (Single stage, Simon 2-
stage or multi-stage) may be performed when appropriate number of subjects are treated and 
followed. These interim analyses will be performed independent of each other. Additional interim 
analyses on safety and efficacy may be performed at various times prior to study completion in 
order to facilitate program decisions and to support scientific publications or presentations. 
Potential interim analyses of efficacy for each combination arm under each track are listed in Table 
1-1. No formal inferences requiring any adjustment to statistical significance level will be 
performed. Additional survival analysis may be performed beyond analysis for the final CSR and 
presented in a CSR addendum.
Table 1-1:
Potential Interim Analyses of Efficacy
Track
Interim Analyses
Track 3 Anti-PD-1/PD-L1 Treatment-experienced Subjects
End of Simon Stage 1
Track 4 Anti-PD-1/PD-L1 Treatment-naïve Subjects 
End of Simon Stage 1
Due to early termination of Track 1, 2 and 3 per Master Protocol amendment 5 and the limited 
number of subjects treated under Track 1 and 2 per treatment arm, interim analyses for these two 
tracks will focus on safety. Track 5 used single stage design, only interim analyses for safety may 
be performed.
2
STUDY DESCRIPTION
2.1
Study Design
This is a rolling, Phase 2, adaptive study that will evaluate the preliminary efficacy, safety, 
tolerability, PK, and pharmacodynamics of novel FRACTION-Lung treatment combinations in 
subjects with advanced NSCLC.
A study design update occurred with the implementation of Amendment 5 due to the change in the 
standard of care for NSCLC. Prior to implementation of Amendment 5, subjects are enrolled in 1 
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of 3 tracks depending on prior treatment and PD-L1 status (Tracks 1, 2, or 3) (see Section 2.1.1). 
Post implementation of Amemdment 5, subjects will be enrolled in 1 of 2 tracks depending on 
prior treament (Track 4 and 5) (see Section 2.1.2).
2.1.1
Original Design (up to and includes Master Protocol Amendment 4)
Anti-PD-1/PD-L1 naive subjects are assigned into Track 1 and 2. Track 1 is for subjects whose 
tumor expresses programmed death-ligand 1 (PD-L1), and Track 2 is for subjects whose tumor 
does not express PD-L1 (as outlined in Figure 2.1.1-1). Subjects who have had prior anti-
PD-1/PD-L1 therapy and have been offered platinum-based chemotherapy (and received prior TKI 
if their tumor contained an EGFR mutation or ALK rearrangement) are assigned to Track 3 as 
outlined in Figure 2.1.1-1.
Subjects in Track 1 have a nivolumab Run-in phase with nivolumab administrated every 2 weeks 
for four treatments. Following the nivolumab Run-in phase, these subjects enter Track 1.a or 1.b 
and begin the Treatment phase, or Track 1.c and begin follow-up. The Treatment phase is defined 
in cycles each of 4 weeks duration. Subjects on Track 1.a receive treatment cycles for a maximum 
of 2 years. Subjects on Track 1.b receive 6 cycles each of 4 weeks duration (a total 24 weeks). 
Subjects on Track 2 and 3 do not have a nivolumab Run-in phase and begin on the Treatment 
phase defined as 6 cycles each of 4 weeks duration (a total of 24 weeks). Tumor assessments are 
conducted every 8 weeks (±1 week).
For Track 1 only, subjects with inadequate response to the therapy are randomized after the 
nivolumab Run-in phase; responders continue nivolumab and rapid progressors are off treatment 
and enter follow-up Phase. 
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Figure 2.1.1-1:
FRACTION-Lung Original (Tracks 1-3) Study Design
Note* Subjects will be considered PD-1/PD-L1-experienced if they have previously received at least 1 cycle of therapy 
with a PD-1/PD-L1 inhibitor. 
Abbreviations: Response = Response by RECIST v 1.1 criteria
Subjects in Figure 2.1.1-1: Tracks 1-3 are treated until completion of the Treatment phase, 
progression, toxicity, or protocol-specified discontinuation. Except for Track 1.a and 1.c, the 
decision to continue treatment beyond investigator-assessed progression is possible (for 6 
additional cycles only) and should be discussed with the BMS Medical Monitor (or designee) and 
documented in the study records. A subject with progressive disease (PD) has several treatment 
options including continued treatment (for additional 6 cycles only) and/or entry into Track 3, 
assuming that he/she continues to fulfill all entry criteria at each new randomization point and is 
not considered a “rapid progressor.” 
In Track 1.b or 2, a 4-stage design is used to evaluate the possibility of expanding the combination 
arms and the nivolumab monotherapy arm and the possibility of terminating a combination arm 
early. In Track 3, a Simon 2-stage (optimal) design is used to evaluate the possibility of terminating 
an arm early. The number of subjects planned for enrollment may vary by track and is described 
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in Section 5. Subjects who continue to fulfill entry criteria may move from Tracks 1 or 2 into Track 
3, as described in Sections 2.1.1.1.1and 2.1.1.2.
2.1.1.1
FRACTION-Lung Track 1 Design - Anti-PD-1/PD-L1 Treatment-naïve, 
PD-L1-positive Subjects
A detailed study schematic for Track 1 is presented in Figure 2.1.1.1-1.
Subjects who are naïve to IO therapy and have a positive PD-L1 tumor status (defined by ≥1% of 
the membranous tumor staining for PD-L1) are enrolled into Track 1 and receive nivolumab 
monotherapy every 2 weeks for 4 treatments in the nivolumab Run-in phase. Based on results from 
the first tumor assessment (i.e, after the first 8 weeks of therapy), subjects are categorized as 
follows with treatment as designated:
•
Responder (subjects with tumor response of ≥30% [i.e., at least 30% reduction in target lesion 
burden] continue nivolumab monotherapy as the contemporaneous control therapy in Track 
1.a.
•
Inadequate responder (subject with tumor response of < 30% [i.e., less than 30% reduction in 
target lesion burden] are randomized into Track 1.b. 
•
Rapid progressor (subjects deemed by either the treating physician or BMS medical Monitor 
(or designee) to have no reasonable possibility of response to further immunotherapy, such as 
a subject whose lesions have increased in size by > 50%) are off treatment (Track 1.c) and 
enter study follow-up.
FRACTION-Lung Track 1.a Design 
Responders to treatment on Track 1 nivolumab Run-in phase at the first tumor assessment (i.e., at 
8 weeks) enter Track 1.a and continue nivolumab monotherapy for a total of 2 years. Subjects are 
not allowed nivolumab monotherapy treatment beyond 2 years.
•
Subjects with CR, PR, or SD at the completion of the treatment phase in Track 1.a (after 
receiving nivolumab monotherapy for a total of 2 years) enter study follow-up.
•
Subjects with PD during the Track 1.a treatment phase have the option to: 
•
Enter study follow-up or
•
Enter Track 3, if eligible and a treatment combination is available, and be randomized to 
combination treatment.
•
Subjects with rapid progression (as defined above) are taken off study treatment and enter 
study follow up.
FRACTION-Lung Track 1.b Design 
Inadequate responders to study treatment on Track 1 nivolumab Run-in phase at the first tumor 
assessment (i.e., at 8 weeks) have the option to be randomized into Track 1.b to nivolumab 
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monotherapy or to one of the novel FRACTION-Lung combinations. These subjects receive their 
assigned treatment in Track 1.b until completion of the treatment phase.
•
Subjects with CR or PR at the end of the Track 1.b Treatment phase enter study follow-up. 
•
Subjects with SD at the end of the Track 1.b Treatment phase have the option to: 
•
Enter study follow-up,
•
Receive continued treatment (at the discretion of the investigator) for a further 6 cycles (12 
cycles total treatment) with their Track 1.b randomized combination treatment or nivolumab 
monotherapy, or
•
Enter Track 3, if eligible and if a new treatment combination is available, and be randomized 
to a new combination.
•
Subjects with SD who opt to continue treatment upon completion of a total of 12 cycles of 
treatment have the option to:
•
Enter study follow-up
•
Enter Track 3, if eligible and if a new treatment combination is available, and be randomized 
to a new combination.
•
Subjects with PD during the Track 1.b Treatment phase have the option to: 
•
Enter study follow-up or
•
Enter Track 3 if eligible and if a new treatment combination is available, and be randomized 
to a new combination.
•
Subjects with rapid progression (as defined above) are taken off study treatment and enter 
study follow-up.
•
Subjects who elect to re-treat with their Track 1.b randomized combination treatment are
allowed to do so one time only. Upon completion of the Track 1.b retreatment, these subjects 
have the option to 
•
a)  Enter study follow-up or
•
b)  Enter Track 3 and be randomized to a new combination 
•
Subjects with CR, PR or SD who enter study follow-up and subsequently progress within 
12 months of their last study dose have the option to be considered for retreatment with the 
same treatment pending a discussion of this option with the investigator and BMS Medical 
Monitor (or designee). Subjects who fail retreatment, or are deemed by the investigator not to
be appropriate for retreatment, have the option to:
•
Enter study follow-up or
•
Enter Track 3, if eligible and if a new treatment combination is available, and be randomized 
to a new combination.
FRACTION-Lung Track 1.c Design 
Subjects with rapid progression (as defined above) should be discontinued from study treatment 
and enter study follow-up.
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Figure 2.1.1.1-1:
Track 1 Design Schematic - Anti-PD-1/PD-L1 Treatment-naïve, PD-L1-positive Subjects
Note: This diagram presents the protocol-mandated treatment flow for Track 1. Alternatives must be discussed with the BMS Medical Monitor (or designee).
a Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) as defined by RECIST v1.1
b Safety follow-up phase, followed by Response/Survival Follow-up phase.
c Each individual subject may receive multiple therapies, including initial treatment, treatment beyond investigator-assessed progression, continued treatment (for an additional 6 
cycles only), retreatment after progression (for an additional 6 cycles only), and/or entry into Track 3, assuming the subject continues to fulfill all eligibility criteria at each new 
randomization point.
d For subjects with PD, retreatment with the assigned therapy (for an additional 6 cycles only) pending discussion with the BMS Medical Monitor (or designee).
Abbreviations: Resp = response; Txt = treatment.
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2.1.1.2
FRACTION-Lung Track 2 Design - Anti-PD-1/PD-L1 Treatment-naïve, 
PD-L1-negative Subjects
A detailed study schematic for Track 2 is presented in Figure 2.1.1.2-11
Subjects who are naïve to IO therapy and have a negative PD-L1 tumor status (defined by < 1% 
of the membranous tumor staining for PD-L1) are enrolled into Track 2 and randomized to
nivolumab monotherapy or to 1 of the FRACTION-Lung combination treatments. These subjects 
receive their assigned treatment in Track 2 until completion of the Treatment phase.
•
Subjects with CR or PR at the end of the Track 2 Treatment phase enter study follow-up. 
•
Subjects with SD at the end of the Track 2 Treatment phase have the option to: 
•
Enter study follow-up,
•
Receive continued treatment (at the discretion of the investigator) for a further 6 cycles (12 
cycles total treatment) with their Track 2 randomized combination treatment or nivolumab 
monotherapy, or
•
Enter Track 3 if eligible and if a new treatment combination is available, and be randomized 
to a new combination.
•
Subjects with SD who opt to continue treatment upon completion of a total of 12 cycles of 
treatment have the option to:
•
Enter study follow-up or
•
Enter Track 3, if eligible and if a new treatment combination is available, and be randomized 
to a new combination.
•
Subjects with PD during the Track 2 Treatment phase have the option to: 
•
Enter study follow-up or
•
Enter Track 3, if eligible and if a new treatment combination is available, and be randomized 
to a new combination.
•
Subjects with rapid progression (as defined above) are taken off study treatment and enter 
study follow-up.
Subjects with CR, PR or SD who enter study follow-up and subsequently progress within 12 
months of their last study dose have the option to be considered for retreatment with the same 
treatment pending a discussion of this option with the investigator and BMS Medical Monitor (or 
designee). Subjects who fail retreatment, or are deemed by the investigator not to be appropriate 
for retreatment, have the option to:
a) Enter Study follow-up or
b) Enter Track 3, if eligible and if a new treatment combination is available, and be 
randomized to a new combination.
•
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Figure 2.1.1.2-1:
Track 2 Design Schematic - Anti-PD-1/PD-L1 Treatment-Naive, PD-L1-negative Subjects
Note: This diagram presents the protocol-mandated treatment flow for Track 2. Alternatives must be discussed with the BMS Medical Monitor (or designee).
a Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) as defined by RECIST v1.1
b Safety follow-up phase, followed by response/survival follow-up phase.
c Each individual subject may receive multiple therapies including initial treatment, treatment beyond investigator-assessed progression, continued treatment (for an additional 
6 cycles only), retreatment after progression (for an additional 6 cycles only), and/or entry into Track 3, assuming that the subject continues to fulfill all eligibility criteria at each 
new randomization point
d For subjects with PD, retreatment with the assigned therapy (for an additional 6 cycles only) pending discussion with the BMS Medical Monitor (or designee).
Abbreviations: Txt = treatment.
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2.1.1.3
FRACTION-Lung Track 3 Design - Anti-PD-1/PD-L1 Treatment-
experienced Subjects
A detailed study schematic for Track 3 is presented in Figure 2.1.1.3-11. 
Subjects who have received anti-PD-1/PD-L1 therapy are enrolled into Track 3 and randomized 
to one of the FRACTION-Lung treatment combinations (nivolumab monotherapy is not a 
treatment option under Track 3).
In addition, subjects who were treated in Track 1 or Track 2 and continue fulfill all entry criteria
can be enrolled in Track 3 and randomized to a new combination other than that previously 
received, if applicable. These subjects receive their assigned treatment in Track 3 until completion 
of the treatment phase. 
•
Subjects with CR or PR at the end of the Track 3 Treatment phase enter study follow-up. 
•
Subjects with SD at the end of the Track 3 Treatment phase have the option to: 
•
Enter study follow-up,
•
Receive continued treatment (at the discretion of the investigator) for a further 6 cycles (total 
of 12 cycles of treatment) with their Track 3 randomized treatment, or
•
Re-enter Track 3, if eligible and if a new combination is available, and be randomized to a new 
combination 
•
Subjects with SD who opt to continue treatment upon completion of a total of 12 cycles of 
treatment have the option to:
•
Enter study follow-up or
•
Re-enter Track 3, if eligible and if a new treatment combination is available, and be 
randomized to a new combination.
•
Subjects with PD during the Track 3 Treatment phase have the option to: 
•
Enter study follow-up or
•
Re-enter Track 3, if eligible and if a new treatment combination is available, and be 
randomized to a new combination.
•
Subjects with rapid progression (as defined above) are taken off study treatment and enter 
study follow-up.
Subjects with CR, PR or SD who enter study follow-up and subsequently progress within 12 
months of their last study dose have the option to be considered for retreatment with the same 
treatment pending a discussion of this option with the investigator and BMS Medical Monitor (or 
designee). Subjects who fail retreatment, or are deemed by the investigator not to be appropriate 
for re-induction, have the option to:
a) Enter Study follow-up or
•
Re-enter Track 3, if eligible and if a new treatment combination is available, and be 
randomized to a new combination.
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Figure 2.1.1.3-1:
Track 3 Design Schematic - Anti-PD-1/PD-L1 Treatment-experienced Subjects
a Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) as defined by RECIST v1.1
b Safety follow-up phase, followed by response/survival follow-up phase.
c Each individual subject may receive multiple therapies, including initial treatment, treatment beyond investigator-assessed progression, continued treatment (for an additional 
6 cycles only), retreatment after progression (for an additional 6 cycles only), and/or re-entry into Track 3, assuming that the subject continues to fulfill all eligibility criteria at 
each new randomization point. 
Note: subjects will be randomized to a combination other than the previously received Track 3 (and/or Track 1 or Track 2) combination treatment, if applicable.
d For subjects with PD, retreatment with the assigned therapy (for an additional 6 cycles only) pending discussion with the BMS Medical Monitor (or designee).
•
Abbreviations: Txt = treatment.
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2.1.2
Current Design (Master Protocol Amendment 5)
Subjects will be enrolled in 1 of 2 tracks following treatment for advanced NSCLC with ≤ 1 prior 
chemotherapy regimen and prior TKI (for subjects with a known EGFR or ALK rearrangement). 
Subjects who are naïve to anti-PD-1 and anti-PD-L1 therapy will be enrolled into Track 4. Subjects 
who have received prior anti-PD-1 or anti-PD-L1 treatment will be enrolled in Track 5, as outlined 
in Figure 2.1.2-11.
Figure 2.1.2-1:
Fraction-Lung Current (Track 4 and 5) Study Design
Note:  Subjects will be considered PD-1/PD-L1-experienced if they have previously received at least 1 dose of a PD-
1/PD-L1 inhibitor 
Analysis in Track 4 will be stratified by PD-L1 expression (< 1%, ≥ 1% and < 50%, and ≥ 50%)
Subjects in Tracks 1, 2, or 3 who experience PD during the treatment phase and continue to fulfill all entry criteria 
may be re-enrolled in Track 5 and re-randomized to a new combination other than that previously received, if 
applicable.
Subjects in Tracks 4 and 5 will be treated until completion of the treatment phase, progression, 
toxicity, or protocol-specified discontinuation. The decision to continue treatment beyond the 
investigator-assessed progression is possible (for up to completion of that treatment phase) and 
should be discussed with BMS medical monitor (or designee) and documented in the study records. 
Subjects receiving treatment on Tracks 1, 2 or 3 prior to implementation of Amendment 5 will 
continue to receive treatment on their assigned track until completion, progression, toxicity, or 
protocol-specified discontinuation. Subjects in Tracks 1, 2 or 3 who experience PD during the 
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treatment phase and continue to fulfill all entry criteria may be re-enrolled in Track 5 and re-
randomized to a new combination other than that previously received, if applicable.
2.1.2.1
Fraction Lung Track 4 (Naive) and 5 (Experienced) Design
A detailed study schematic for both Tracks 4 and 5 is presented in Figure 2.1.2.1-1.
Subjects with CR or PR at the end of the Track 4 or 5 Treatment Phase will have the option to:
•
Enter study follow-up or
•
Receive continued study treatment (at the discretion of the investigator) for a further six 4-
week cycles (a further approximately 24 weeks; approximately 48 weeks of total study 
treatment) with their Track 4 or 5 randomized combination treatments.
•
Subjects with SD at the end of the Track 4 or 5 Treatment Phase will have the option to:
•
Enter study follow-up,
•
Receive continued study treatment (at the discretion of the investigator) for a further six 4-
week cycles (a further approximately 24 weeks; approximately 48 weeks of total study 
treatment) with their Track 4 or 5 randomized combination treatments, or
•
Enter (or re-enter) Track 5, if eligible and if a new treatment combination is available, and be 
randomized to a new combination.
•
Subjects with SD who opt to continue study treatment upon completion of a total of twelve 
4-week cycles (approximately 48 weeks of study treatment)will have the option to: 
•
Enter study follow-up or
•
Enter (or re-enter) Track 5, if eligible and if a new treatment combination is available, and be 
randomized to a new combination
•
Subjects with PD during the Track 4 or 5 Treatment Phase will have the option to:
•
Enter study follow-up or
•
Enter (or re-enter) Track 5, if eligible and if a new treatment combination is available, and be 
randomized to a new combination, or
•
Continue study treatment beyond progression, for up to completion of that Treatment Phase.
•
Subjects with CR, PR or SD who enter study follow-up and subsequently have PD within
12 months of their last study dose will have the option to be considered for re-treatment with 
the same treatment pending a discussion of this option with the investigator and BMS Medical 
Monitor (or designee). Subjects who fail retreatment, or are deemed by the investigator not to 
be appropriate for retreatment, will have the option to:
•
Enter study follow-up or
•
Enter (or re-enter) Track 5, if eligible and if a new combination is available, and be randomized 
to a new combination.
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Figure 2.1.2.1-1:
Track 4 and 5 Study Design Schematic:
Note: This diagram presents the protocol-mandated treatment flow for Tracks 4 and 5. Alternatives must be discussed with the BMS Medical Monitor (or designee).
a Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) as defined by RECIST v1.1. Subjects who the investigator 
believes may still benefit from further therapy may, after consultation with the Sponsor/BMS Medical Monitor (or designee), continue with their assigned study 
treatment, 1 time only (for an additional six 4-week cycles [approximately 24 weeks] only).
b Safety Follow-up Phase, followed by Response/Survival Follow-up Phase.
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c If subjects are eligible and if a new study treatment combination is available, they can enroll/re-randomize to a new combination.
d Each individual subject may receive multiple therapies, including initial treatment, treatment beyond investigator-assessed progression (for up to completion of 
that Treatment Phase), continued treatment (for an additional six 4-week cycles [approximately 24 weeks] only), retreatment after progression (for an additional 
six 4-week cycles [approximately 24 weeks] only), and/or entry into Track 5, assuming that the subject continues to fulfill all eligibility criteria at each new 
randomization point.
e For subjects with PD within follow-up, retreatment with the assigned therapy (for an additional six 4-week cycles [approximately 24 weeks] only) is pending 
discussion with the BMS Medical Monitor (or designee).
f Subjects with PD during treatment may continue treatment beyond progression if criteria are met.
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2.2
Treatment Assignment
Randomization schedules will be generated and maintained by IRT vendor. At the conclusion of 
the trial, BMS will receive copies of all generated schedules form the vendor. Because of the nature 
of the study design, limited early access to the randomization information will be granted to the 
study team to facilitate early analyses for internal decision making (early termination of treatment 
arm, etc.).
Each subject who is randomized will be assigned a unique randomization number. This is not the 
primary identifier for the subject, but used for the randomization schedule. A subject being re-
randomized will be assigned a different randomization number but will retain the same patient 
identification number. Randomization numbers will be assigned using a Central Randomization 
System in the order in which subjects qualify for treatment, not in the order of study enrollment. 
If, within a given track, treatment arms from more than one sub-protocol within the Master 
Protocol are simultaneously open to enrollment, then a new subject could be assigned to any of 
the open arms. 
Pre-specified treatment arm caps will be utilized to control the accrual for each combination arm 
under different tracks. In the event that one or more subjects go off-study without being evaluable 
for response (i.e., with no on-study tumor measurements and no evidence of clinical progression 
or death due to disease progression), the enrollment cap for that arm may be correspondingly raised 
if needed to ensure that a sufficient number evaluable subjects are available for decision making. 
If the decision is made to close any arm for safety concerns, the cap for that arm will be reduced 
to the current number of subjects already randomized. Accrual will be stopped immediately.
Specific instructions for randomization into the Central Randomization System will be provided 
in a separate manual.
2.3
Blinding and Unblinding
Not applicable.
2.4
Protocol Amendments
All available Master Protocol amendments are shown in Table 2.4-1
Table 2.4-1:
Master Protocol Amendment
Protocol Amendment
Date
Purpose
Amendment 1
08-Apr-2016
1) Updated the study design from a 2-stage design 
to a 4-stage design with corresponding updates to 
study design figures
 
3) corrected typographical errors and made minor 
clarifications
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Table 2.4-1:
Master Protocol Amendment
Protocol Amendment
Date
Purpose
Amendment 2
27-Jul-2016
1) Remove requirement for platinum based 
chemotherapy as one of the prior treatments for 
tracks 1 and 2.
2) Remove the option for less effective methods of 
birth control.
3) Clarify the exclusion criteria for patients with 
CNS metastases.
4) Update Section 3.5.1 to remove the prohibition 
of receptor activator of nuclear kappa-B ligand 
inhibitors or bisphonates.
5) Change the term “Pretreatment AEs” to 
“Assessment of Baseline Signs and Symptoms”.
6) Update Figure 8.1.3-1 to fix a typographical 
error in the Stage 2 number of subjects (change 15 
to 23)
Amendment 3
21-Sep-2016
 
Amendment 4
13-Oct-2016
1) Remove the Treatment Procedural tables 
(previously Table 5.1-2 and Table 5.1-3) 
2) Update exclusion criteria to clarify all subjects 
with active CNS metastases are excluded. 
3) Clarify prohibition of concurrent neoplastic 
treatment.  
Amendment 05
16-Feb-2017
1) Removed the FRACTION-Lung nivolumab 
monotherapy treatment arm, including nivolumab 
monotherapy run-in, consolidated 3 tracks into 2
tracks (PD-1/PD-L1 treatment naïve and 
experienced), and simplified the study design 
accordingly. 
2) Clarified study assessments for pulse oximetry. 
Removed patient-reported outcome assessment of 
quality of life at screening, as this is also being 
performed at baseline. 
3) Updated data from the literature regarding anti-
PD-1 and other targeted therapies. 
4) Updated eligibility criteria to clarify the 
population for Track 4 (ie, PD-1/PD-L1 treatment 
naïve with up to 1 prior therapy for progressive or 
recurrent disease). 
4) Added sample size determination for Tracks 4 
and 5 and simplified sample size determination for 
Tracks 1, 2, and 3. 
5) Added assessment schedule for retreatment/re-
randomization in place of existing footnote, for 
clarity. 
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Table 2.4-1:
Master Protocol Amendment
Protocol Amendment
Date
Purpose
6) Minor clarifications and typographical errors 
have also been made throughout the document.
Sub Protocol A (originally named Sub Protocol 1) was provided at initiation of the study with 
detailed treatment information for nivolumab monotherapy, nivolumab in combination with
dasatinib therapy, nivolumab in combination with BMS-986016 therapy, and nivolumab in 
combination with ipilimumab. Sub Protocol B was provided after Master Protocol Amendment 5 
with detailed treatment information for nivolumab in combination with BMS-986205 (IDO
inhibitor) therapy.
All available Sub Protocol A amendments are shown in Table 2.4-2
Table 2.4-2:
Sub Protocol A Amendment
Sub Protocol A amendment
Date
Purpose
Amendment 1
08-Apr-2016
1) Added cardiac troponin and additional ECG 
monitoring for the nivolumab and BMS-986016 
combination. Additional language with regards to 
cardiac troponin monitoring and management of 
changes has been included.
2) Added Hepatitis B core antibody test to the 
procedural outline.
3) Minor clarifications and typographical errors 
have also been made throughout the document.
Amendment 2                        
13-Oct-2016
1) Added a new Fraction-Lung combination 
treatment (nivolumab in combination with 
ipilimumab) throughout the Sub-Protocol.
2) Moved Table 5.1-1 and 5.51-1 into Sub-
Protocol from Fraction-lung Master Protocol and 
combined Table 5.1-2 with full Treatment 
Procedural outline table (previously included in 
the Fraction-Lung Master Protocol) Sub-Protocol 
A.
3) Added text regarding additional hepatitis B 
serology tests in Table 5.1-2, clarifying that these 
are for subjects in the nivolumab and dasatinib 
Fraction-Lung combination only.
4) Updated Sub-Protocol identification from Sub-
Protocol 01” to Sub-Protocol A”.
5) Updated content to be consistent with the 
current guidance for the Fraction-Lung 
combination treatments.
Amendment 3
16-Feb-2017
1) Removed the FRACTION-Lung nivolumab 
monotherapy treatment arm, including nivolumab 
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Table 2.4-2:
Sub Protocol A Amendment
Sub Protocol A amendment
Date
Purpose
monotherapy run-in, and simplified the study 
design accordingly. 
2) Clarified study assessments for vital signs and 
pulse oximetry. 
3) Updated information regarding nivolumab 
experience and approvals and nivolumab in 
combination with dasatinib were added.
4) Dosing descriptions were consolidated, and the 
timing of dasatinib administration relative to 
nivolumab infusion was updated. 
5) The eligibility criteria regarding pleural or 
pericardial effusion were clarified, as were the 
PK and immunogenicity assessments and 
analyses. 
6) Minor clarifications and typographical errors 
have also been made throughout the document.
2.5
Safety Monitoring Board
A safety monitoring board (SMB) was established to provide safety monitoring and to provide 
advice to the Sponsor regarding actions the committee deems necessary for the continuing 
protection of subjects enrolled in the study. The SMB meets at least twice per year concurrent with 
BMS internal continuous safety assessment. If needed, additional ad-hoc SMB meetings may be 
convened. Safety related data summary and listings (by study track and treatment arm as 
appropriate) are provided to the SMB to facilitate safety monitoring. The SMB acts in an advisory 
capacity to BMS and monitors subject safety throughout the study. Additional details are provided 
in the SMB Charter.
2.6
Independent Review Committee (IRC)
An IRC is established. The IRC may review all available tumor assessment scans to determine 
response (RECIST v1.1 criteria). IRC-determined response and progression may be used in the 
analyses of objective response rate [ORR], progression free survival rate [PFSR] and duration of 
response [DOR].
3
OBJECTIVES
3.1
Primary
•
To assess the efficacy (ORR, DOR, and PFSR at 24 weeks) of each FRACTION-Lung 
treatment combination in subjects with NSCLC
3.2
Secondary
•
To investigate additional safety and tolerability of each FRACTION-Lung treatment 
combination in subjects with NSCLC
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4
ENDPOINTS
4.1
Primary Endpoint
The primary objective of preliminary efficacy will be measured by ORR, DOR, and PFSR at 24 
weeks based on RECIST Version 1.1 criteria. Tumor response will be based on tumor assessments 
at screening, every 8 weeks from first dose until investigator assessed initial disease progression 
(per RECIST 1.1) or confirmed disease progression (defined as an additional 10% or greater 
increase in tumor burden volume from the time of initial progression [including all target lesions 
and new measurable lesions]), at the completion of follow-up or every 12 weeks from completion 
of follow-up until 2 years after last dose of study drug, or until subjects withdraw from the study.
4.1.1
Objective Response Rate (ORR)
ORR is defined as the total number of subjects whose best overall response (BOR) is either a 
complete response (CR) or partial response (PR) divided by the total number of treated subjects. 
BOR for a subject will be assessed by investigator per RECIST1.1.
BOR is the best response designation over the round of treatment (with corresponding follow-up) 
as a whole, recorded between the dates of the first dose until the last tumor assessment prior to 
subsequent anticancer therapy (see Table 4.1.1-1). For subjects who received retreatment of their 
initial therapy or are re-randomized to new combination therapy, the retreatment therapy and re-
randomized therapy will be considered as subsequent anticancer therapy. CR or PR determinations 
included in the BOR assessment must be confirmed by a second scan performed at least 4 weeks 
after the criteria for response are first met. For those subjects who have surgical resection of 
target/non-target/new lesion, only pre-surgical tumor assessments will be considered in the 
determination of BOR.
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Table 4.1.1-1:
Tumor Assessments for BOR Consideration
Track
Baseline Tumor Assessment
On-treatment Tumor Assessments to be Considered
Track 1
Latest tumor assessment prior 
to first dose of nivolumab
From first dose date of nivolumab, up to last tumor assessment 
prior to subsequent anticancer therapy a (including tumor 
assessments done in nivolumab run-in)
Track 
2/3/4/5
Latest tumor assessment prior 
to randomization
From first dose date of randomized treatment, up to last tumor 
assessment prior to subsequent anticancer therapy a
a Retreatment with the same therapy after the initial treatment period and re-randomized treatment are considered 
subsequent anticancer therapy
Note: For Track 1 subjects received combination therapy, a set of exploratory efficacy endpoints may be used for 
exploratory efficacy analysis. For such set of efficacy endpoints, latest tumor assessment prior to randomization 
(end of Nivolumab run-in) will be used as baseline; all tumor assessment post randomization (and prior to sub-
sequent therapy) will be used as on-treatment tumor assessments.
ORR and BOR of Retreatment (considering all tumor assessments from first dose date of 
retreatment, up to last tumor assessment prior to subsequent anticancer therapy) may be assessed 
as exploratory endpoints for exploratory analyses.
4.1.2
Duration of Response (DOR)
DOR, computed for all treated subjects with a BOR of CR or PR, is defined as the time between 
the date of first response and the date of first documented disease progression as determined by 
RECIST 1.1 or death due to any cause (death occurring after retreatment or randomization to new 
combination treatment will not be considered), whichever occurs first.
(DOR = disease 
progression date/death date -first response date + 1)
Subjects who started subsequent anticancer therapy without a prior reported progression will be 
censored at the last evaluable tumor assessment on or prior to initiation of the subsequent 
anticancer therapy. Subjects who drop out study without documented progression will be censored 
at the last evaluable tumor assessment. For subjects received retreatment or randomized to new 
combination treatment, the retreatment therapy and newly randomized therapy will be considered 
as subsequent anticancer therapy. Progression censor derivation details are presented in Table 
4.1.3-1.
DOR of Retreatment may be assessed as exploratory endpoints for exploratory analyses.
4.1.3
Progression Free Survival Rate (PFSR) at 24 Weeks
The PFSR at 24 weeks is defined as the proportion of treated subjects remaining progression free 
and surviving at 24 weeks since the first dosing date. The proportion will be calculated by the 
Kaplan-Meier estimate which takes into account censored data.
PFS for a subject is defined as the time from the first dosing date to the date of first objectively 
documented disease progression or death due to any cause (death occurring after retreatment or 
randomization to new combination treatment will not be considered), whichever occurs first. (PFS 
= disease progression date/death date - first dose date +1). For subjects treated under Track 1
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combination therapy, first dosing date of nivolumab monotherapy will be used. (Subjects with 
RECIST 1.1 progression prior to receiving combination therapy will be excluded from the primary 
analysis)
Subjects who died without a reported prior progression will be considered to have progressed on 
the date of their death. Subjects who remained alive and have not progressed will be censored on 
the last evaluable tumor assessment date. Subjects who started subsequent anticancer therapy 
without a prior reported progression will be censored at the last tumor assessment on or prior to 
initiation of the subsequent anticancer therapy. Subjects who did not have any post-baseline tumor 
assessment and did not die will be censored on the date of first dose of study medication. For 
subjects who received retreatment with their initial treatment or were re-randomized to another 
treatment, the retreatment therapy and re-randomized therapy will be considered as subsequent 
anticancer therapy. (See Table 4.1.3-1)
Table 4.1.3-1:
Censoring Scheme for Progression (for DOR and PFS Derivation)
Situation
Date of Progression or Censoring
Outcome
No baseline tumor assessment
First dosing date a
Censored
No post-baseline tumor assessments 
and no death b
First dosing date a
Censored
Documented progression c
Date of first documented progression per RECIST 1.1
Progressed
No progression c and no death b
Date of last evaluable tumor assessment on or prior to
subsequent anti-cancer therapy
Censored
New anticancer therapy, tumor-
directed radiotherapy, or tumor-
directed surgery received without 
progression reported prior or on the 
same day
Date of last evaluable tumor assessment on or prior to the 
date of initiation of subsequent therapy
Censored
Death b without progression
Date of death
Progressed
a First dosing date for Track 1.a, 1.c, 2, 3, 4, and 5; first nivolumab run-in dose date for Track 1.b
b
Death occurring after retreatment or randomization to new combination treatment or other subsequent therapy 
will not be considered.
c
Progression occurring after subsequent therapy (including retreatment and randomized to new combination 
treatment) will not be considered.
 
 
 
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4.2
Secondary Endpoints
The assessment of safety will be based on the incidence of adverse events (AEs), serious adverse 
events (SAEs), adverse events leading to discontinuation, and deaths. In addition clinical 
laboratory test abnormalities will be examined.
AEs and laboratory values will be graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Event (CTCAE) version 4.0.3.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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a 5-point scale ranging from 0 (not at all) to 4 (very much). In addition to a total score based on 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5
SAMPLE SIZE AND POWER
Sample sizes are guided by Simon 2-stage, single-stage or multi-stage designs as described in 
Table 5-1. Because of the different patient populations and existing standard of care options under 
each track, different criteria apply to determine the number of patients for each stage and the 
strength of the efficacy signal required to the next stage. 
For sample size calculation and for simplicity of description, decision criteria for stopping or 
progressing to the next stage are based on the number of objective responses observed. However, 
since BOR does not necessarily capture the full extent of clinical benefit, and since response can 
be delayed or of short duration, the Sponsor will also review other aspects of clinical benefit which 
may better predict OS benefit, such as DOR and PFSR, as well as the relative performance of 
different combination arms, before making a final determination.
Additional subjects may be enrolled to account for subjects who may drop out of the study without 
being evaluable for response. For example, assuming a 25% dropout rate, up to 5 additional 
subjects per arm could be enrolled into Track 2 Stage 1 to achieve 20 “evaluable “ subjects (with 
any over-enrollment counting towards Stage 2), while in Stage 2, an additional 4 subjects over  the 
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planned 15 could be enrolled to achieve 35 total evaluable subjects. Similarly in Track 3 Stage 1, 
up to 15 subjects may initially be enrolled to achieve 12 evaluable subjects.
Although the sample size calculations are based on efficacy considerations, safety will also be 
continuously assessed, and will be taken into account in the decision to continue or terminate an 
arm. Thirty-five subjects per arm in Stage 1 and 2 combined will result in 83% probability of 
detecting an AE that has a true rate of 5%.
Table 5-1:
Multi-Stage or Single-stage Design
Track
Stage 
1
Stage 1 
Responders
Stage 
2
Stage 2 Responders
Stage 
3
Stage 3 
Responders
Stage 
4
Stage 4 
Responders
n
Futil
ity 
Stop
Go to 
Stage 
2
n
Futil
ity 
Stop
Go to 
Stage 
3
Effic
acy 
Stop
n
Futil
ity 
Stop
Go to 
Stage 
4
n
Futil
ity 
Stop
Effic
acy 
Stop
1.b
20
≤ 3
≥ 4
15
≤ 6
≥ 7
≥ 11
15
≤ 11
≥ 12
20
≤ 13
≥ 14
2
20
≤ 2
≥ 3
15
≤ 4
≥ 5
≥ 9
15
≤ 8
≥ 9
20
≤ 9
≥ 10
3
12
≤ 1
≥ 2
23
≤ 5
≥ 6
4
(PD-L1 
exp. 
< 1%)
19
≤ 3
≥ 4
17
≤ 10
≥ 11 
4
(PD-L1 
exp. 
≥1% 
& 
< 50%)
28
≤ 11
≥ 12
13
≤ 20
≥ 21 
4
(PD-L1 
exp. 
≥50%)
16
≤ 11
≥ 12
9
≤ 20
≥ 21
5
35
Note: n values presented in this table are per treatment arm.
Abbreviations: exp = expression.
With regards to sample size, subjects who are re-randomized to a different treatment will be 
counted once for each randomization; subjects who are re-treated within the same arm will only 
be counted once.
With the implementation of Amendment 5, enrollment in Tracks 1, 2, and 3 will cease. Sample 
size descriptions provided in Section 5.2 are, therefore, applicable only until implementation of 
Amendment 5. 
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5.1
Sample Sizes for Tracks 4 and 5
With the implementation of Amendment 5, subjects will be enrolled in Tracks 4 and 5. The sample 
size for Track 4 is guided by a 2-stage design and for Track 5 is guided by a single-stage design. 
Track 4 subjects will be stratified into 3 groups according to their PD-L1 expression level as 
assessed by the baseline tumor biopsy. Section 5.1.1 describes the sample size determination for 
all three strata in Track 4, while Section 5.1.2 describes the sample size determination for Track
5. 
5.1.1
Track 4 - Anti-PD-1/PD-L1 Treatment-naïve Subjects
Track 4 subjects will be enrolled into 1 of 3 strata based on their PD-L1 expression level as 
assessed by the baseline tumor biopsy. Subjects may in some cases be randomized before the 
results of their PD-L1 expression testing are known. As a result, there may be a small number of 
subjects (estimated no more than 10% to 15%) who are randomized but are subsequently found to 
be unevaluable for PD-L1 expression. Such unevaluable subjects may continue their randomized 
treatment but will not be counted towards the sample size for any of the three strata. Data for such 
subjects will be reported as if coming from a fourth stratum. In the situation that one or two of the 
strata has reached or is approaching full enrollment, the Sponsor may choose to require the results 
of PD-L1 testing to be available before randomizing additional subjects, to reduce the risk of 
over-enrollment.
Enrollment will be continued during initial efficacy evaluation (ie, with the indicated number of 
subjects at Stage 1) to allow additional subjects to enroll to account for unexpected trial impact, 
such as response non-evaluable subjects due to early drop-out, design parameter change (eg,
historical rate update), etc. The number of responses given here is used as a guide for sample size 
calculation and for simplicity of description. Before making a decision to terminate or continue an 
arm, BMS will also review the totality of all available data, which includes: other aspects of 
efficacy that may help predict OS benefit, such as DOR and PFSR; clinical safety information; 
and biomarker data, as well as the relative performance of other treatment arms on a continuing 
basis.
Track 4 - Anti-PD-1/PD-L1 Treatment-naïve subjects with PD-L1 expression less than 1%
As shown in Table 5-1, a minimum of 19 subjects in each study treatment combination arm will 
be treated in Stage 1 for an initial evaluation of efficacy. If the number of responses observed in 
Stage 1 is ≤3/19, the study treatment combination arm would likely not be considered efficacious. 
In Stage 2, an additional 17 subjects will be treated. More than 10 responses observed at the end 
of Stage 2 would suggest the efficacy target has been met. The totality of efficacy data and response 
profile for each combination will be considered when making decisions to terminate or continue 
an arm. The operating characteristics of the Simon 2-stage design to be used as a guide are provided 
in Figure 5.1.1-1. With the stopping boundaries as shown in Table 5-1, if the combination has an 
ORR no better than the historical control (
 
) at 20%, then there is a 90% overall chance of declaring futility, with a 46%
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chance of stopping at Stage 1; there is a 10% false positive rate. If the combination has an ORR 
equal to the target of 40%, then there is a 90% chance of declaring efficacy after Stage 2, whereas 
if the ORR is equal to 35%, 30%, and 25%, there will be, respectively, 76%, 52%, and 27% chance 
of declaring efficacy.
Figure 5.1.1-1:
Operating Characteristics of Simon 2-Stage Design for Track 4 
Subjects with PD-L1 Expression < 1% (Power = 90%, Alpha = 10%)
Track 4 - Anti-PD-1/PD-L1 Treatment-naïve Subjects with PD-L1 Expression ≥ 1% and 
< 50%
As shown in Table 5-1, a minimum of 28 subjects in each study treatment combination arm will 
be treated in Stage 1 for an initial evaluation of efficacy. If the number of responses observed in 
Stage 1 is ≤11/28, the study treatment combination arm would likely not be considered efficacious. 
In Stage 2, an additional 13 subjects will be treated. More than 20 responses observed at the end 
of Stage 2 would indicate the efficacy target has been met. The totality of efficacy data and 
response profile for each combination will be considered when making decisions to terminate or 
continue an arm. The operating characteristics of the Simon 2-stage design, used as a guide, are 
provided in Figure 5.1.1-2. With the stopping boundaries as shown in Table 5-1, if the combination 
has an ORR no better than the historical control (
 
) at 40%, then there is a 90% overall chance of declaring futility, with a 
55% chance of stopping at Stage 1; there is a 10% false positive rate. If the combination has an 
ORR equal to the target of 60%, then there is a 90% chance of declaring efficacy after Stage 2, 
whereas if the ORR is equal to 55%, 50%, and 45%, there will be, respectively, 74%, 50%, and 
27% chance of declaring efficacy.
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Figure 5.1.1-2:
Operating Characteristics of Simon 2-Stage Design for Track 4 
Subjects with PD-L1 Expression Between 1% and < 50% (Power = 
90%, Alpha = 10%)
Track 4 - Anti-PD-1/PD-L1 Treatment-naïve Subjects with PD-L1 Expression ≥ 50%
As shown in Table 5-1, a minimum of 16 subjects in each study treatment combination arm will 
be treated in Stage 1 for an initial evaluation of efficacy. If the number of responses observed in 
Stage 1 is ≤11/16, the study treatment combination arm would likely not be considered efficacious. 
In Stage 2, an additional 9 subjects will be treated. More than 20 responses observed at the end of 
Stage 2 would indicate the efficacy target has been met. The totality of efficacy data and response 
profile for each combination will be considered when making decisions to terminate or continue 
an arm. The operating characteristics of the Simon 2-stage design, used as a guide, are provided in 
Figure 5.1.1-3. With the stopping boundaries as shown in Table 5-1, if the combination has an 
ORR no better than the historical control (
 
) at 70%, then there is a 90% overall chance of declaring futility, with a 55%
chance of stopping at Stage 1; there is a 10% false positive rate. If the combination has an ORR 
equal to the target of 90%, then there is a 90% chance of declaring efficacy after Stage 2, whereas 
if the ORR is equal to 85%, 80%, and 75%, there will be, respectively, 68%, 42%, and 21% chance 
of declaring efficacy.
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Figure 5.1.1-3:
Operating Characteristics of Simon 2-Stage Design for Track 4 
Subjects with PD-L1 Expression ≥ 50% (Power = 90%, Alpha = 10%)
5.1.2
Track 5 - Anti-PD-1/PD-L1 Treatment-experienced Subjects
It is not known whether PD-L1 expression levels affect response rates for combination therapy in 
anti-PD-1/PD-L1 experienced patients. Therefore, Track 5 participants will not be stratified on 
their PD-L1 expression levels; however, subset analyses may be performed. The sample size of 35
participants for Track 5 is based on a 1-sided alpha of 0.1 for testing the null hypothesis that the 
ORR is equal to the null rate of 10%, and a power of 90% against the alternative hypothesis that 
the ORR is equal to the target rate of 30% (Table 5.1.2-1). Unlike in Track 4, participants whose 
PDL-1 status is unevaluable will count towards the sample size in Track 5.
Table 5.1.2-1:
Single-stage Design for Track 5
PD-L1 Stratum
Null 
ORR
Target 
ORR
Type 1 Error
Power
Sample size
All
0.1
0.3
0.1
0.9
35
Efficacy will be continuously monitored in all participants who are evaluable for response using 
the measurements described in Section 4.1. In Track 5, 8/35 responses would result in CIs for 
ORR which are strictly higher than 10%. If at any point it appears very unlikely that this track will 
meet its efficacy target, the Sponsor will consider closing that arm to further enrollment.  Both 
subjects previously treated in Tracks 4 and 5 (re-randomized subjects) and new subjects who meet 
eligibility criteria are permitted to enter Track 5. Some slots in Track 5 will be reserved for 
re-randomized subjects to ensure that both types of subjects are enrolled in Track 5.
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5.2
Sample Sizes for Tracks 1, 2 and 3
With the implementation of Amendment 5, enrollment in Tracks 1, 2, and 3 will cease. Sample 
size descriptions provided in Sections5.2.1 through 5.2.3 are, therefore, applicable only until 
implementation of Amendment 5. The sample sizes for Tracks 1b and 2 are guided by a 4-stage 
design, whereas the sample size for Track 3 is guided by a Simon 2-stage design.
5.2.1
Track 1.a and 1.c - Anti-PD-1/PD-L1 Treatment-naïve, PD-L1-positive 
Subjects
Week 8 Responders and Rapid Progressors
The number of subjects entering Track 1.a is not pre-specified but is determined by patient 
response to 8 weeks of nivolumab monotherapy. It is estimated that approximately 15% of subjects 
who enter Track 1 would enter Track 1.a. Similarly the number of subjects who enter Track 1.c 
and discontinued from treatment after Week 8 due to fast progression cannot be pre-specified. It 
is estimated that approximately 10% of subjects who enter Track 1 would enter Track 1.c. The 
remaining 75% of subjects who enter Track 1 would enter Track 1.b.
5.2.2
Track 1.b - Anti-PD-1/PD-L1 Treatment-naïve, PD-L1-positive Subjects 
and Track 2 - Anti-PD-1/PD-L1 Treatment - naïve, PD-L1 -negative 
Subjects
For each combination arm under Tracks 1.b and 2, a four-stage approach will be used (nested 
Simon/Fleming).  Initially 20 subjects per combination arm will be treated in Stage 1, and 
preliminary efficacy will be assessed when those subjects are evaluable. If futility is demonstrated 
at that point, the corresponding arm will be terminated; otherwise an additional 15 Stage 2 subjects 
will be enrolled. At the end of Stage 2, the arm can be stopped for futility, continue to Stage 3, or 
be stopped for efficacy. Stage 3 will enroll 15 additional subjects, and when those subjects are 
evaluable for efficacy, the arm may be stopped for futility or proceed to Stage 4. Stage 4 will enroll 
20 subjects. The total potential enrollment for all 4 Stages is 70 subjects per combination per Track. 
More details including the Track-specific criteria for stopping or continuing, are given in Section 
5.2.2.1 and 5.2.2.2. The nivolumab monotherapy arm will enroll the same number of subjects as 
its largest corresponding combination arm.
Historical ORRs from nivolumab Phase 3 clinical studies are used for the initial sample size 
assessment and sizes for the multi-stage approach are based on Simon/Fleming-like single-arm 
efficacy and futility boundaries. However the ORR from the nivolumab monotherapy control arm 
will also be considered in the final decision making process. Sample sizes may be re-adjusted using 
the observed ORR in the nivolumab monotherapy arms if those differ substantially from historical 
rates, and so the final sample size may deviate from the original assessment.
5.2.2.1
Track 1.b - Anti-PD-1/PD-L1 Treatment-naïve, PD-L1-positive Subjects
Week 8 Inadequate Responders
As shown in Table 5-1, a minimum of 20 subjects per combination arm will be treated in Stage 1 
for an initial evaluation of efficacy. If the number of responses observed in Stage 1 is ≤3/20, the 
combination arm would be terminated for futility, otherwise enrollment to Stage 2 will continue, 
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and an additional 15 subjects will be treated. If the total number of responses at the end of Stage 2
is ≤ 6/35, the arm will be terminated for futility; if there are ≥ 11/35 responses the arm will be 
terminated for efficacy; while if the total number of response is ≥ 7/25 but ≤ 10/35, Stage 3 will 
be initiated. Stage 3 will enroll 15 subjects, and if the total number of response is then ≤ 11/50, 
then the arm will stop for futility; otherwise Stage 4 will be initiated and enroll 20 additional 
subjects.
The operating characteristics of this design are provided in Figure 5.2.2.1-1. The stopping criteria 
specific to Track 1.b were selected via simulation to 1) control the probability of stopping for 
futility if the true ORR is 14%; and 2) maximize the probability of stopping for efficacy if the true 
ORR is 35%. With the stopping boundaries as shown in Figure 5.2.2.1-1, if the combination has 
an ORR no better than the historical control at 14%, then there is a 97% overall chances of stopping 
for futility, with a 69% chance of stopping at Stage 1; there is a 3% false positive rate. If the 
combination has an ORR equal to the target of 35%, then it has a 93% chance of stopping for 
efficacy overall (power), with a 72% chance of declaring efficacy at Stage 2; whereas if the true 
ORR is 20%, 25% or 30%, the power would be 25%, 55%, or 80% respectively.
Figure 5.2.2.1-1:
Operating Characteristics of Track 1b 4-Stage Design (Power = 93%, 
Alpha = 3%)
If at least 11 responses are observed at the end of Stage 2, then the lower limit of the 95% 
confidence interval (CI) for ORR will be higher than the historical ORR of 14%. The CI is 
calculated using the Clopper-Pearson method.
5.2.2.2
Track 2 - Anti-PD-1/PD-L1 Treatment-naïve, PD-L1-negative Subjects
As shown in Table 5-1, a minimum of 20 subjects in each combination arm will be treated in Stage 
1 for an initial evaluation of efficacy. If the number of responses observed in Stage 1 is ≤ 2/20, the 
combination arm would be terminated for futility, otherwise enrollment to Stage 2 will continue, 
and an additional 15 subjects will be treated. If the total number of responses at the end of Stage 2 
is ≤ 4/35, the arm will be terminated for futility; if there are ≥ 9/35 responses the arm will be 
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terminated for efficacy; while if the total number of responses is ≥ 5/35 but < 9/35, Stage 3 will be 
initiated. Stage 3 will enroll 15 subjects, and if the total number of response is then ≤ 8/50, the arm 
will stop for futility; otherwise Stage 4 will be initiated and enroll 20 additional subjects.
The operating characteristics of this design are provided in Figure 5.2.2.2-1. The stopping criteria 
specific to Track 2 were selected via simulation to 1) control the probability of stopping for futility 
if the true ORR is 10%; and 2) maximize the probability of stopping for efficacy if the true ORR 
is 30%. With the stopping boundaries as shown in Figure 5.2.2.2-1, if the combination has an ORR 
no better than the historical control at 10%, then there is a 96% overall chance of stopping for 
futility, with a 67% chance of stopping at Stage 1; there is a 4% false positive rate. If the 
combination has an ORR of 30%, then there is a 95% chance of stopping for efficacy overall 
(power), with a 76% chance of stopping for efficacy at Stage 2; whereas if the true ORR is 15%, 
20%, or 25%, the power would be 28%, 62%, or 85%, respectively.
Figure 5.2.2.2-1:
Operating Characteristics of Track 2 4-Stage Design (Power = 95%, 
Alpha = 4.4%)
If at least 9 responses are observed at the end of Stage 2, then the lower limit of the 95% CI for 
ORR will be higher than the historical ORR of 10%. The CI is calculated using the Clopper-
Pearson method.
5.2.3
Track 3 - Anti-PD-1/PD-L1 Treatment-experienced Subjects
For each combination arm under Track 3, the Simon 2-stage (optimal) design will be used. 
Initially, 12 subjects per combination arm will be treated in Stage 1 and preliminary efficacy will 
be assessed when those subjects are evaluable. If 1 or fewer responses is observed in Stage 1, the 
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arm will be terminated for futility; otherwise, Stage 2 will be initiated and enroll an additional 23 
subjects, for a total of 35 subjects per combination arm. 
The operating characteristics of this Simon 2-stage (optimal) design are provided in Figure 5.2.3-
1. With the stopping boundaries as shown in Table 5-1, if the combination has an ORR no better 
than 10%, then there is a 90% overall chance of stopping for futility, with a 66% chance of stopping 
at Stage 1; there is a 10% false positive rate. If the combination has an ORR equal to the target of 
30%, then it has a 90% chance of stopping for efficacy after stage 2.
Figure 5.2.3-1:
Operating Characteristics of Track 3 2-Stage Design (Power = 90%, 
Alpha = 10%)
Both subjects previously treated in any track (re-randomized subjects) and new subjects who meet 
eligibility criteria are permitted to enter Track 3. Some slots in Track 3 will be reserved for re-
randomized subjects to ensure that both types of subjects are enrolled in Track 3. At the initiation 
of the study, recruitment of re-randomized subjects will be limited to 7 subjects per Track 3 
combination arm in Stage 1 (with 25% drop out rate considered). In Stage 2, recruitment of 
additional re-randomized subjects will be limited to 13 subjects out of the 29 additional subjects 
(with 25% drop out rate considered). The limited number of re-randomized subjects may be re-
adjusted depending on the enrollment rates, the rate of progression in Tracks 1 to 3, and the number 
of currently open arms in Track 3.
 
 
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2
 
 
 
 
 
 
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
6.1.1
Study Periods for Treatment Arms Under Tracks 2, 3, 4 and 5
Under Tracks 2, 3, 4 and 5, each treatment assignment will go through two study periods: baseline 
period and post baseline period.
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6.1.1.1
Baseline Period
Baseline evaluations or events will be defined as evaluations or events that occur before the date 
and time of the first dose of study treatment (and within 28 days of first dose date). 
In cases where the time (onset time of event or evaluation time and dosing time) is missing or not 
collected, the following definitions will apply:
•
Pre-treatment AEs will be defined as AEs with an onset date prior to but not including the day 
of the first dose of study treatment
•
Baseline evaluations (laboratory tests, pulse oximetry and vital signs) will be defined as 
evaluations with a date on or prior to the day of first dose of study treatment
If there are multiple valid assessments, the assessment that is closest to day (and time if collected) 
of the first dose of study treatment will be used as the baseline in the analyses. If multiple 
assessments are collected at the same date (and time if collected), the assessment with the latest 
database entry date (and time if collected) will considered as baseline. If same database entry date 
(and time if collected) or database entry date not available, the assessment with the latest 
modification date will be considered as baseline.
6.1.1.2
Post Baseline Period
Post baseline period is further characterized into Treatment, and Retreatment Periods.
Treatment Period
Treatment Period starts with the first dose date-time of study treatment and includes continued 
treatment [additional 24 week treatment] as agreed between investigator and BMS medical 
monitor.
 On-treatment AEs will be defined as AEs with an onset date-time on or after the date-time 
of the first dose of study treatment (or with an onset date on or after the day of first dose 
of study treatment if time is not collected or is missing). For subjects who are off treatment
(off treatment date available), AEs will be counted as on-treatment if event occurred within 
100 days of the last dose of study medication and prior to first dose of retreatment or 
randomized new combination treatment (if exist). For subjects who are still on study 
treatment (off treatment date not available), all available post baseline AEs will be counted 
as on-treatment.
 On-treatment evaluations (laboratory tests, pulse oximetry and vital signs) will be defined 
as evaluations taken after the day (and time, if collected and not missing) of first dose of 
study treatment. For subjects who are off treatment (off treatment date available), 
evaluations will be counted as on-treatment if evaluation is taken within 100 days of the 
last dose of study medication and on or prior to first dose of retreatment or randomized 
new combination treatment (if exist). For subjects who are still on study treatment (off 
treatment date not available), all available post baseline evaluations will be considered as 
on-treatment.
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Primary analysis of safety endpoints will be based on the treatment period. AEs and other 
evaluations reported during the retreatment period will be listed and summarized separately (if 
exist). 
Optional Retreatment Period
Optional Retreatment Period starts with the first dose date-time of retreatment.
 On-retreatment AEs, will be defined as AEs with an onset date-time on or after the date-
time of the first dose of retreatment (or with an onset date on or after the day of first dose 
retreatment if time is not collected or is missing). For subjects who are off treatment in the 
retreatment period (off treatment date available), AEs will be counted as on retreatment if 
event occurred within 100 days of the last dose of retreatment and prior to first dose of 
randomized new combination treatment (if exist). For subjects who are still on retreatment 
of study medication (off treatment date not available), all available AEs with onset date-
time on or after the date-time of first dose of retreatment will be counted as on-retreatment.
 On-retreatment evaluations (laboratory tests, pulse oximetry and vital signs) will be 
defined as evaluations taken after the day (and time, if collected and not missing) of first 
dose of retreatment. For subjects who are off treatment in the retreatment period (off 
treatment date available), evaluations will be counted as on-retreatment if evaluation is 
taken within 100 days of the last dose of retreatment and on or prior to first dose of re-
randomized treatment (if exist). For subjects who are still on retreatment (off treatment 
date not available), all available evaluations taken after the day of first dose of retreatment 
will be considered as on-retreatment.
6.1.2
Study Periods for Treatment Arms under Track 1
Under Track 1, each subject may go through three study periods: Baseline Period, Run-in Period
and Post Run-in Period.
6.1.2.1
Baseline Period
Same definition and derivation rule as stated in Section 6.1.1.1 will be applied.
6.1.2.2
Run-in Period
Run-in period starts with the first dose date-time of nivolumab and end by the first dose date-time 
of study medication after Week 8 tumor assessment.
 Run-in Period AEs will be defined as AEs with an onset date-time on or after the date-time 
of the first dose of nivolumab (or with an onset date on or after the day of first dose of 
initial study treatment if time is not collected or is missing). For subjects who are off 
treatment during the Run-in Period (off treatment date available), AEs will be counted for
Run-in Period if event occurred within 100 days of the last dose of nivolumab prior to week 
8 tumor assessment. For subjects who enter into the Post Run-in Period, all post baseline 
AEs will be counted for Run-in Period if event occurred prior to first dose date-time of 
study medication post week 8 tumor assessment. 
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 Run-in Period evaluations (laboratory tests, pulse oximetry and vital signs) will be defined 
as evaluations taken after the day (and time, if collected and not missing) of first dose of 
study treatment. For subjects who are off treatment during Run-in Period, evaluations will 
be counted for Run-in Period if evaluation is taken within 100 days of the last dose of study
medication prior to week 8 tumor assessment. For subjects who entered into Post Run-in 
Period, all post baseline evaluations taken on or prior to first dose data-time of study 
medication post week 8 tumor assessment will be included in Run-in period. 
6.1.2.3
Post Run-in Period
Post Run-in Period starts with the first dose date-time of study medication post week 8 tumor 
assessment scan (for subjects treated in Track 1.b, this is the first dose of study medication after 
randomization).
Post Run-in period can be further characterized into Treatment, and Retreatment Periods. Same 
definition and derivation rule as stated in section 6.1.1.2 will be applied.
6.1.2.4
Additional Period information
Analysis period to be used for Track 1 are listed below and summarized in Table 6.1.2.4-1
Track 1 Nivolumab monotherapy
Including subjects treated with nivolumab monotherapy only under track 1.a, 1.b, 1.c or still in 
nivolumab run-in. Run-in and post Run-in period will be combined as Post Baseline period. The 
same definition and derivation rule as stated in section 6.1.1.2 will be applied. First dose date-time 
of nivolumab will be used. Overall two periods: Baseline Period, and Post Baseline Period.
Track 1 combination therapy
Including subjects treated with nivolumab run-in, followed by combination therapy. Post Run-in 
Period is further characterized into Treatment, and Retreatment Periods. Same definition and 
derivation rule as stated in section 6.1.1.2 will be applied. Run-in and post Run-in period will be 
combined as Post Baseline period. Overall two periods: Baseline Period, and Post Baseline Period.
Table 6.1.2.4-1:
Analysis Period Information for Track 1
Track 
Period Used for Analysis
Period Defined in Section 6.1
Track 1 nivolumab 
monotherapy
Baseline Period
Baseline Period
Post Baseline Period
Run-in Period + Post Run-in Period
Track1
Combination therapy
Baseline Period
Baseline Period 
Post Baseline Period 
Run-in Period + Post  Run-in Period 
6.2
Treatment Regimens
Treatments included in Sub-Protocol A:
Trt N: Nivolumab 240 mg Q2W IV
Trt ND: Nivolumab 240 mg Q2W IV + Dasatinib 100 mg QD Oral
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Trt NB: Nivolumab 240 mg Q2W IV + BMS-986016 20 mg Q2W IV
Trt NI: Nivolumab 240 mg Q2W IV + Ipilimumab 1 mg/kg Q6W IV
Treatments included in Sub-Protocol B:
Trt NO: Nivolumab 480 mg Q4W IV + BMS-986205 (IDO) 100mg QD Oral
Additional treatment regimens will be added per future Sub-Protocol.
The treatment group “as randomized” will be retrieved from the IRT system, if applicable. The 
treatment group “as treated” will be the same as the arm as randomized by IRT, if applicable. 
However, if a subject received the incorrect drug for the entire period of treatment, the subject’s 
treatment group will be defined as the incorrect drug the subject actually received.
6.3
Populations for Analyses
•
All Enrolled Subjects: All subjects who signed an informed consent form
•
All Randomized Subjects: All subjects who were randomized to any treatment arm in the study.
•
All Treated Subjects: All subjects who received at least one dose of any study medication 
•
Pharmacokinetic Subjects: All subjects who received at least one dose of investigational 
product component and have corresponding evaluable plasma or serum concentration data 
•
Immunogenicity Subjects: All subjects who received at least one dose of investigational 
product component and have corresponding evaluable immunogenicity assessment (i.e., 
baseline and at least one post baseline assessment)
•
Biomarker Subjects: All treated subjects with available biomarker data 
•
PD-L1+ Subjects: All treated subjects with positive PD-L1 tumor status at baseline (defined 
by ≥1% of the membranous tumor staining for PD-L1)
•
PD-L1- Subjects: All treated subjects with negative PD-L1 tumor status at baseline (defined 
by < 1% of the membranous tumor staining for PD-L1)
•
PD-L1 Unknown Subjects: All treated subjects with unknown PD-L1 tumor status at baseline 
•
PD-L1 + H Subjects: All treated subjects with high PD-L1 expression at baseline (defined by 
≥50% of the membranous tumor staining for PD-L1)
•
PD-L1 + L Subjects: All treated subjects with low PD-L1 expression at baseline (defined by ≥
1% and < 50% of the membranous tumor staining for PD-L1)
•
Retreatment Subjects: Subjects who received retreat of original treatment
•
Re-Randomized Subjects: Subjects who were randomized and received new combination 
treatment under Track 3 or 5
•
Outcome Research Subjects: All subjects who received at least one dose of investigational 
product component and have corresponding evaluable assessment (i.e., baseline and at least 
one subsequent assessment while on treatment)
•
7
STATISTICAL ANALYSES
All analyses will be performed in SAS using version 9.2 or higher. Some figures will be generated 
using S-Plus.
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7.1
General Methods
Continuous variables will be summarized using descriptive statistics, ie, medians, minimums, 
maximums, means and standard deviations. Categorical variables will be summarized by 
frequencies and percentages. Percentages will be rounded and may not always add up to 100. If a 
missing category is not being presented in the data display, only those subjects with non-missing 
values for the parameter being assessed are included in the percentage calculation.
Time to event distributions (i.e., progression free survival, overall survival) will be estimated using 
Kaplan Meier techniques. When appropriate, the median along with 95% confidence interval (CI) 
will be estimated based on Brookmeyer and Crowley methodology4 (using log-log transformation 
for constructing the confidence intervals). Rates at fixed time points (e.g., PFSR at 24 weeks) will 
be derived from the Kaplan Meier estimate along with their corresponding log-log transformed 
95% CIs5. Confidence intervals for binomial proportions will be derived using the Clopper-
Pearson method6.
7.2
Study Conduct
7.2.1
Study Information
•
Listing:
 Batch number 
7.2.2
Accrual
The following will be presented on the All Enrolled Subjects.
Summary:
 Number (%) of subjects accrued by country and investigational site: include country, site 
number, number of subjects enrolled, and number of subjects treated by Track
 Number (%) of subjects accrued per month: include number of subjects enrolled, and 
number of subjects treated by Track
Listing:
 Subjects accrued by country and investigational site
7.2.3
Relevant Protocol Deviations
The following programmable deviations will be considered as relevant protocol deviations and a 
listing will be provided.
Eligibility:
 Subjects without measurable disease at baseline 
 Subjects with misclassified PD-L1 status for Tracks 1 and 2
 Subjects with prior anti-PD-1/PD-L1 treatment for Tracks 1, 2 and 4
 Subjects without prior anti-PD-1/PD-L1 treatment for Tracks 3 and 5
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On-study:
 Subjects treated differently than randomized (subjects who received the wrong treatment 
for the entire treatment period, excluding the never treated)
7.3
Study Population
7.3.1
Subject Disposition
Summary:
The number (%) of subjects of the following will be summarized on All Enrolled Subjects. 
−
Subjects assigned to Tracks 1, 2, 3, 4, and 5
−
Screen failure Subjects  with reason
•
The number (%) of subjects of the following will be summarized on the All Treated Subjects. 
−
Subjects discontinued treatment with reason
−
Subjects entered into follow up
−
Subjects entered into Track 3 or 5 (re-randomized subjects)
−
Subjects off study
−
Subjects received re-treatment
Listing:
•
Screen Failure Subjects with reason 
•
Treated subjects with off treatment reason (by Track and treatment)
7.3.2
Demographics and Other Baseline Characteristics
Summary:
Descriptive statistics will be summarized the following baseline characteristics for all treated 
subjects by treatment, and track.
•
Age (in years) ; Age  category (<65, ≥65); Gender; Race; Ethnicity
•
Height; Weight; ECOG PS 
•
Disease characteristics such as histology, stage and disease status
•
Mutation status (EGFR, ALK, K-RAS, etc.)
•
Prior therapy (surgery, radiotherapy, systemic therapy--setting, number of regimen prior to this 
study (including subsequent therapy received during follow-up of treatment prior to re-
randomized treatment if exist), number of regimens within this study, etc.)
•
Baseline PD-L1 status
•
Smoking status
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•
All relevant data, generally variables listed above by treatment and track.
•
Subject General medical history will be listed by treatment and track
•
Subject abnormal baseline physical exam results will be listed by treatment and track
7.4
Extent of Exposure
The extent of exposure will be characterized according to the number of subjects exposed, the 
duration of exposure, and the dose to which they were exposed. Analyses in this section will be 
performed on the All Treated Subjects “as treated”. Extent of Exposure will be assessed separately 
for treatment and retreatment.
7.4.1
Study Therapy
Summary:
Descriptive statistics will be provided by study medication, treatment (treatment and retreatment) 
and track for the following.
•
Number of doses, if appropriate
•
Duration of therapy (days) = last dose date - first dose date + XX
•
Cumulative dose (unit)= the sum of all actual doses that a subject received
•
Dose intensity (unit) = cumulative dose/duration of therapy
•
Relative dose intensity (%) = (dose intensity / planned dose)*100
−
Categories: <50%; 50 - < 70%; 70 - < 90%; 90 - < 110%;  ≥ 110%
Exposure parameter derivation for each treatment are show in Table 7.4.1-1, Table 7.4.1-2, Table 
7.4.1-3, Table 7.4.1-4 and Table 7.4.1-5. More Tables will be added with new treatments added 
into the study through sub-protocol.
Table 7.4.1-1:
Study Therapy Parameter Definitions - Nivolumab Monotherapy
Nivolumab
Dosing Schedule per Protocol
240 mg every 2 weeks
Cumulative Dose 
Cum Dose (mg) is the sum of the doses (mg) administered to a subject 
during the treatment period.
Relative Dose Intensity (%)
{Cum dose (mg)/[(Last dose date - Start dose date + 14) × (240/14) ]} × 100
Duration of Therapy
Last dose date - Start dose date +14
Note: Last dose date, Start dose date, Cumulative dose will be chosen/derived for corresponding treatment periods 
(treatment, retreatment).
Table 7.4.1-2:
Study Therapy Parameter Definitions - Nivolumab + Dasatinib
Nivolumab
Dasatinib
Dosing Schedule per Protocol
240 mg every 2 weeks
100 mg QD
Cumulative Dose 
Cum Dose (mg) is the sum of the doses (mg) administered to a subject during 
the treatment period.
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Table 7.4.1-2:
Study Therapy Parameter Definitions - Nivolumab + Dasatinib
Nivolumab
Dasatinib
Relative Dose Intensity (%)
{Cum dose (mg)/[(Last dose date -
Start dose date + 14) × (240/14) ]} ×
100
{Cum dose (mg)/[(Last dose date -
Start dose date + 1) × (100) ]} × 100
Duration of Therapy
Last dose date - Start dose date +14
Last dose date - Start dose date +1
Note: Last dose date, Start dose date, Cumulative dose will be chosen/derived for corresponding treatment periods 
(treatment, retreatment).
Table 7.4.1-3:
Study Therapy Parameter Definitions - Nivolumab + BMS-986016
Nivolumab
BMS-986016
Dosing Schedule per Protocol
240 mg every 2 weeks
20 mg every 2 weeks
Cumulative Dose 
Cum Dose (mg) is the sum of the doses (mg) administered to a subject during 
the treatment period.
Relative Dose Intensity (%)
{Cum dose (mg)/[(Last dose date -
Start dose date + 14) × (240/14) ]} ×
100
{Cum dose (mg)/[(Last dose date -
Start dose date + 14) × (20/14) ]} ×
100
Duration of Therapy
Last dose date - Start dose date +14
Last dose date - Start dose date +14
Note: Last dose date, Start dose date, Cumulative dose will be chosen/derived for corresponding treatment periods 
(treatment, retreatment).
Table 7.4.1-4:
Study Therapy Parameter Definitions - Nivolumab + Ipilimumab
Nivolumab
Ipilimumab
Dosing Schedule per Protocol
240 mg every 2 weeks
1 mg/kg every 6 weeks
Cumulative Dose 
Cum Dose (mg) is the sum of the 
doses (mg) administered to a 
subject during the treatment period.
Cum Dose (mg/kg) is the sum of 
the total doses delivered 
(mg)/weight (kg) to a subject 
during the treatment period.
Relative Dose Intensity (%)
{Cum dose (mg)/[(Last dose date -
Start dose date + 14) × (240/14) ]} 
× 100
{Cum dose (mg/kg)/[(Last dose 
date - Start dose date + 42) × (1/42) 
]} × 100
Duration of Therapy
Last dose date - Start dose date +14
Last dose date - Start dose date +42
Note: Last dose date, Start dose date, Cumulative dose will be chosen/derived for corresponding treatment periods 
(treatment, retreatment).
Table 7.4.1-5:
Study Therapy Parameter Definitions - Nivolumab + BMS-986205
Nivolumab
BMS-986205
Dosing Schedule per Protocol
480 mg every 4 weeks
100 mg QD
Cumulative Dose 
Cum Dose (mg) is the sum of the doses (mg) administered to a subject during 
the treatment period.
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Table 7.4.1-5:
Study Therapy Parameter Definitions - Nivolumab + BMS-986205
Nivolumab
BMS-986205
Relative Dose Intensity (%)
{Cum dose (mg)/[(Last dose date -
Start dose date + 28) × (480/28) ]} ×
100
{Cum dose (mg)/[(Last dose date -
Start dose date + 1) × (100) ]} × 100
Duration of Therapy
Last dose date - Start dose date +28 
Last dose date - Start dose date +1
Note: Last dose date, Start dose date, Cumulative dose will be chosen/derived for corresponding treatment periods 
(treatment, retreatment).
Listing:
•
Drug administration of study medication
•
Duration of therapy, cumulative dose, and relative dose intensity, etc.
Figure:
•
Kaplan-Meier curve of Duration of treatment by treatment/retreatment under each track. 
Median duration of treatment and associated 95% CI will be provided. 
7.4.2
Modification of Study Therapy
Summary:
The following will be provided by treatment and Track.
•
Number (%) of subjects with dose delay with the reason, number of dose delayed per subject, 
Number (%) of subjects with omission with the reason
•
Number (%) of subjects with dose reduction with reason, number (%) of subjects with a dose
reduction to dose level -1 and dose level -2 (dasatinib and BMS-986205 specific)
•
Infusion related modification (nivolumab, BMS-986016 and ipilimumab specific)
−
Number (%) of subjects with at least one infusion interruption along with the reason
−
Number of infusion interruptions per subject
−
Number (%) of subjects with at least one IV infusion rate reduction along with the reason
•
Listing:
•
All relevant information on dose modification listed above
•
 
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7.5
Efficacy
The primary efficacy analyses will be performed on All Treated Subjects. All analysis listed below 
will be performed for treatment period. Some of the analysis may be performed for retreatment
period if deemed appropriate. Treatment under each track for different population will be analyzed 
independently. Treatment across tracks may be combined for exploratory analysis if appropriate.
Subjects re-randomized into Track 3 or 5 will be combined with subjects originally randomized 
into Track 3 or 5 for primary efficacy analyses. Sub-group analysis of re-randomized subjects in 
Track 3 or 5 may be performed. After implementation of Master Protocol Amendment 5, 
enrollment to Track 1, 2, and 3 were ceased. Due to design change, the following treatment groups
may be pooled together for efficacy analysis: Treatment under Track 2 (PD-L1 -) may be pooled 
with Track 4 PD-L1- treatment group.
Specific efficacy analyses to be performed for each track are shown in Table 7.5-1
Table 7.5-1:
Analyses Planned for Each Track
Track
Situation
ORR
TTR
DOR
PFSR
OS
Track 1, 2, 3 and 5
End of stage 1, 2, or end of study
X
X
X
X
X
Early termination at stage 1 or early 
termination of track/treatment
Track 4
End of stage 1 and 2
X
X
X
X
X
Early termination at stage 1
X
X
The following outputs related to ORR, 
, DOR, PFS and 
 will be produced accordingly.
Summary:
The following will be summarized by treatment under each Track or across Tracks. Summary will 
also be done by PD-L1 status under Track 4.
•
ORR with corresponding 2-sided 95% CI along with each category of BOR
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•
DOR with median (95% CI) and range (min, max). The number of subjects still in response at 
the time of database lock will be indicated. This summary includes responders (BOR of CR or 
PR) only
•
 
•
PFSR at specified timepoints (Week 24)
•
 
 
 
 
Figure:
•
Percent change from baseline in target lesions (aka spider plot)
•
Maximum reduction in baseline target lesions (aka waterfall plot)
•
K-M plot of DOR for responders only 
•
Swimmer plot of 
, DOR, and 
 for responders only
•
K-M plot of PFS
•
Listing:
The following will be listed by treatment under each Track.
•
Tumor lesion measurements
•
Tumor evaluation at each visit
•
Subject level efficacy for all treated subjects- tumor best overall response (BOR), maximum 
response in tumor burden, PFS
•
Duration of response for responders - BOR, 
, response 
duration, 
 
 
 
 
 
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7.5.2
Additional Analyses for Track 1.b and 2
Due to early termination of Track 1 and 2 through Master Protocol amendment 5, the analysis 
specified in this section for Track 1.b and 2 will not be performed as originally planned.
A descriptive odds ratio and estimate of the difference in ORRs, along with corresponding two-
sided 95% CIs will be provided to evaluate difference between the 2 randomized arms 
(combination arm and nivolumab arm) at the end of each stage by Track.
A descriptive hazard ratio and corresponding two-sided 95% CIs of PFS and OS will be estimated 
in a Cox proportional hazard model using treatment as a single covariate to evaluate difference 
between the two arms at the end of each stage by Track.
Subset analyses of efficacy using the factors specified in Section 7.5.1 may be explored. The odds 
ratio of ORR and corresponding 95% CI may be presented for each subgroup in a forest plot.
Forest plots of PFS and OS hazard ratios (along with 95% CI) may be produced for each level of 
the subgroups. 
 
 
7.6
Safety
Analysis of safety will be based on All Treated Subjects, if not otherwise specified, and presented 
by treatment (“as treated”) under each Track or combined across Tracks.
Adverse events (AEs) will be coded according to the most current version of MedDRA and be 
graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Drug-related AEs are those events with relationship to study drug “Related” as recorded on the 
CRF. If the relationship to study drug is missing, the AE will be considered as drug-related. 
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Serious adverse events consist of AEs deemed serious by the investigator and flagged accordingly 
in the CRF and clinical database.
Adverse events leading to study drug discontinuation are AEs with action taken =”Drug was 
discontinued”.
Listing of adverse events will include all enrolled subjects as SAEs and deaths are collected 
pretreatment. Summaries of adverse events will include all on-treatment adverse events as defined 
in Section 6.1. Adverse events occurring after treatment or retreatment will be summarized 
separately.
When reporting adverse events by CTC grade, summary tables will be provided based on the event 
with worst CTC grade. In the AE summary tables, unless otherwise specified, subjects will only 
be counted (1) once at the preferred term (PT) level, (2) once at the system organ class (SOC) 
level, and (3) once in the ‘Total subject’ row at their worst CTC grade, regardless of SOC or PT.
The AE tables will list the SOCs (ordered by descending frequency) and PTs (ordered by 
descending frequency within each SOC) for each treatment group.
Analyses that take into account the multiple occurrences of a given adverse event will be conducted 
(see Section 7.6.9). To prepare these analyses, the CRF data will be processed according to 
standard BMS algorithms7 in order to collapse adverse event records into unique records based on 
the preferred term. This data will be presented as the rate per 100 person-years of exposure. These 
analyses will take into account all on-treatment events (allowing more than 1 event per subject) 
and the total exposure time. When specified the 95% CI of the rate per 100 person-year of exposure 
will be derived using normal approximation and variance estimation proposed in Cook and 
Lawless8.
The analysis of laboratory results will be based on All Treated Subjects. Laboratory results will be 
categorized according to NCI CTCAE (version 4.03) grade. Summaries of laboratory results 
include baseline and on-treatment results as defined in Section 6.1. Clinical laboratory data will 
be first analyzed using US conventional units. Analyses will be repeated using International 
System of Units (SI).
7.6.1
Deaths
•
Summary:
All deaths during the study will be summarized for cause of deaths by treatment under each Track 
or combined across Track. Death will be summarized under the most recent study treatment and 
track prior to death.
In addition, death within 100 days of last dose of treatment or last dose of re-treatment will be 
summarized for cause of deaths.
•
Listing:
All recorded deaths for All Enrolled subjects will be listed by treatment under each Track. Death 
will be listed under the most recent study treatment and track prior to death. Death date, cause of 
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death, study treatments (start/stop date) (including all prior and current study treatments), days 
since last dose, and days since first dose of study drug will be included in the listing. 
7.6.2
Serious Adverse Events
Serious adverse events will be summarized by treatment under each Track or combined across 
Tracks.
•
Summary:
•
Overall summary of SAEs by worst CTC grade (grade 1, 2, 3, 4, 3-4, 5, unknown, total) 
presented by SOC/PT
•
•
Overall summary of drug-related SAEs by worst CTC grade (grade 1, 2, 3, 4, 3-4, 5, 
unknown, total) presented by SOC/PT
•
Listing:
By-subject SAE listing will be provided for the All Enrolled Subjects.
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy
Adverse events leading to study drug discontinuation will be summarized by treatment under each 
Track or combined across Tracks.
Summary:
•
Overall summary of AEs leading to discontinuation by worst CTC grade (grade 1, 2, 3, 4, 3-4, 
5, unknown, total) presented by SOC/PT
•
Overall summary of drug-related AEs leading to discontinuation by worst CTC grade (grade 
1, 2, 3, 4, 3-4, 5, unknown, total) presented by SOC/PT
Listing:
•
By-subject AEs leading to discontinuation listing will be provided.
7.6.4
Adverse Event Leading to Dose Reduction (Dasatinib and BMS-986205
specific)
•
Adverse events leading to dasatinib or BMS-986205 dose reduction will be summarized for 
nivolumab + dasatinib or nivolumab + BMS-986205 treatment under each Track or combined 
across Tracks.
Summary:
•
Overall summary of AEs leading to dose reduction by worst CTC grade (grade 1, 2, 3, 4, 3-4, 
5, unknown, total) presented by SOC/PT
Listing:
•
By-subject AEs leading to dose reduction listing will be provided.
7.6.5
Adverse Event Leading to Dose Delay 
•
Adverse events leading to dose delay will be summarized by treatment under each Track or 
combined across Tracks.
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•
Overall summary of AEs leading to dose delay by worst CTC grade (grade 1, 2, 3, 4, 3-4, 5, 
unknown, total) presented by SOC/PT
Listing:
•
By-subject AEs leading to dose delay listing will be provided.
•
7.6.6
Overall Adverse Events
•
Adverse events will be summarized by treatment under each Track or combined across Tracks.
Summary:
•
Overall summary of any AEs by worst CTC grade (grade 1, 2, 3, 4, 3-4, 5, unknown, total) 
presented by SOC/PT
•
Overall summary of drug-related AEs by worst CTC grade (grade 1, 2, 3, 4, 3-4, 5, unknown, 
total) presented by SOC/PT
•
Overall summary of any AEs that required immune modulating medication by worst CTC 
grade (grade 1, 2, 3, 4, 3-4, 5, unknown, total) presented by SOC/PT
•
Listing:
 All recorded Adverse Events will be listed.
 By-subject listing of AEs requiring immune modulating concomitant medication will be 
provided.
7.6.7
Select Adverse Event
Unless otherwise specified, analyses will be performed by select AE category. Some analyses may 
also be repeated by subcategory of endocrine events (Table 10.1-1)
7.6.7.1
Incidence of Select AE
Selected AE will be summarized by treatment group under each Track or combined across Tracks 
for each category/subcategory:
Summary:
•
Overall summary of any select AEs by worst CTC grade (grade 1, 2, 3, 4, 3-4, 5, unknown, 
total) presented by Category or subcategory/PT
•
Overall summary of any drug-related select AEs by worst CTC grade (grade 1, 2, 3, 4, 3-4, 5, 
unknown, total) presented by Category or subcategory/PT
•
Overall summary of any serious select AEs by worst CTC grade (grade 1, 2, 3, 4, 3-4, 5, 
unknown, total) presented by Category or subcategory/PT
•
Overall summary of any drug-related serious select AEs by worst CTC grade (grade 1, 2, 3, 4, 
3-4, 5, unknown, total) presented by Category or subcategory/PT
•
Overall summary of any select AEs leading to discontinuation by worst CTC grade (grade 1, 
2, 3, 4, 3-4, 5, unknown, total) presented by Category or subcategory/PT
•
Overall summary of any drug-related select AEs leading to discontinuation by worst CTC 
grade (grade 1, 2, 3, 4, 3-4, 5, unknown, total) presented by Category or subcategory/PT
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Listing:
•
By subject select AEs listing will be provided.
7.6.7.2
Time to Onset of Select AE
Time to onset of the following specific events will be graphically displayed for each 
category/subcategory of select AE using the Kaplan-Meier technique:
 Time to onset of any grade select AE by treatment under each Track or across Tracks
 Time to onset of grade 3-5 select AE by treatment under each Track or across Tracks
 Time to onset of any grade drug-related select AE by treatment under each Track or across 
Tracks
 Time to onset of grade 3-5 drug-related select AE by treatment under each Track or across 
Tracks
Rates (derived from the graph) by landmark time points will be tabulated for these specific events 
and for each treatment under each Track or across Tracks.
Additional details regarding the time to onset definition and censoring rules are described in 
Section 10.1.1.
 
 
 
 
 
7.6.8
Immune Mediated Adverse Events (IMAE)
Immune Mediated Adverse Events consist of a list of preferred terms grouped by specific category 
(see Table 10.2-1) AEs that may differ from or be more severe than AEs caused by non-
immunotherapies and AEs whose early recognition and management may mitigate severe toxicity 
are included as IMAEs. The IMAEs and the categories are defined by the Sponsor and the list that 
is the most current at the time of analysis will be used. Changes may be made to this list with each 
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new version of MedDRA prior to database lock. Categories of IMAEs may include subcategories 
(e.g. adrenal disorders, diabetes, pituitary disorders, and thyroid disorders are subcategories of the 
endocrine event category).
Unless otherwise specified, analyses will be performed by IMAE category. Some analyses may 
also be repeated by subcategory of endocrine events.
7.6.8.1
Incidence of IMAE
IMAE will be summarized by treatment under each Track and across Tracks.
Summary:
•
Overall summary of any IMAEs by worst CTC grade (grade 1, 2, 3, 4, 3-4, 5, unknown, total) 
presented by Category or subcategory/PT
•
Overall summary of any drug-related IMAEs by worst CTC grade (grade 1, 2, 3, 4, 3-4, 5, 
unknown, total) presented by Category or subcategory/PT
•
Overall summary of any serious IMAEs by worst CTC grade (grade 1, 2, 3, 4, 3-4, 5, unknown, 
total) presented by Category or subcategory/PT
•
Overall summary of any drug-related serious IMAEs by worst CTC grade (grade 1, 2, 3, 4, 3-
4, 5, unknown, total) presented by Category or subcategory/PT
•
Overall summary of any IMAEs leading to discontinuation by worst CTC grade (grade 1, 2, 3, 
4, 3-4, 5, unknown, total) presented by Category or subcategory/PT
•
Overall summary of any drug-related IMAEs leading to discontinuation by worst CTC grade 
(grade 1, 2, 3, 4, 3-4, 5, unknown, total) presented by Category or subcategory/PT
•
Listing:
By subject IMAE listing will be provided.
7.6.8.2
Time to Onset of IMAE
Time to onset of the following specific events will be graphically displayed for each 
category/subcategory of IMAE using the Kaplan-Meier technique:
 Time to onset of any grade IMAE by treatment under each Track or across Tracks
Additional details regarding the time to onset definition and censoring rules are described in time 
to onset definition subsection of Section 10.1.1
 
 
 
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7.6.9
Multiple Events
Summary:
Analysis may be performed by treatment and retreatment separately. The following summary 
tables will be provided:
•
Total number and rate (exposure adjusted, ie, patient-year event rate) of occurrences for all 
AEs 
•
For Select and/or IMAE AEs:
−
The number of subjects experiencing an AE once or multiple times by treatment arm under 
each track or across tracks
Listing:
 Unique instances of all AEs, ie, after duplicates have been eliminated and overlapping and 
contiguous occurrences of the same event (ie, same PT) have been collapsed.
7.6.10
Clinical Laboratory Evaluations
The analysis population for each laboratory test is restricted to treated subjects who underwent that 
laboratory test.
The following laboratory tests will be included for the analysis:
 Hematology: hemoglobin (HB), platelets, white blood counts (WBC), absolute neutrophils 
count (ANC) and lymphocyte count (LYMPH).
 Serum chemistry: ALT, AST, alkaline phosphatase (ALP), total bilirubin and creatinine
 Electrolytes: sodium (high and low), potassium (high and low), calcium (high and low), 
magnesium (high and low).
Summary:
The number (%) of subjects with the following will be summarized by treatment under each Track 
or combined across Track, using the worst CTC grade on-treatment (as defined in section 6.1) per 
subject.
•
Post-baseline grade
•
Grade change from baseline
•
Descriptive statistics of laboratory test result and their changes from baseline by treatment and 
study day 
Listing:
•
A by-subject listing of these laboratory parameters will be provided. Laboratory abnormality 
criteria and laboratory results outside of normal range will be listed.
7.6.10.1
Abnormal Hepatic Test
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The number of subjects with the following laboratory abnormalities from on-treatment evaluations 
(as defined in Section 6.1) will be summarized by treatment under each Track or combined across 
Track:
•
ALT or AST > 3 x ULN, > 5 x ULN, > 10 x ULN and > 20 x ULN
•
Total bilirubin > 2 x ULN
•
Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
•
Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
Figure:
•
Scatter plot of Total bilirubin peak vs AST peak
•
Scatter plot of Total bilirubin peak vs ALT peak
On-treatment peak total bilirubin and on-treatment peak AST/ALT may or may not happen on the 
same day of liver testing. 
•
Listing:
•
A by-subject listing of these specific abnormalities will be provided.
7.6.10.2
Abnormal Thyroid Test
Summary:
The number of subjects with the following laboratory abnormalities from on-treatment evaluations 
(as defined in Section 6.1) will be summarized by treatment under each Track or combined across 
Track:
•
TSH value > ULN and 
−
With baseline TSH value ≤ ULN
−
At least one T3/T4 test value < LLN
•
Low TSH < LLN and 
−
With baseline TSH value ≥ LLN
−
At least one T3/T4 test value > ULN
•
Listing:
A by subject listing of these specific abnormalities will be provided.
7.6.11
Vital Signs and Other Safety Evaluation
Listing:
•
Vital signs
•
pulse oximetry (i.e. % oxygen saturation)
•
ECG measures
−
Individual QTcF, PR, QRS or ΔQTcF values will be listed.
•
ECG abnormalities
•
Diagnostic procedures
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•
Medical treatment procedures
 
 
•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8
CONVENTIONS
The following conventions may be used for imputing partial dates for analyses requiring dates:
AE onset date following Adverse Event Domain Requirements Specification9
AE resolution/end date (these conventions may change)
 If only the day of the month is missing, the last day of the month will be used to replace 
the missing day
 If the day and month are missing or a date is completely missing, it will be considered as 
missing
Non-study medication date
following Non-Study Medication Domain Requirements 
Specification10
Death date
 If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. The imputed date will be compared to the last known date alive and the 
maximum will be considered as the death date.
 If month or the year is missing, the death date will be imputed as the last known date alive. 
If the date is completely missing but the reason for death is present (as in death module of 
CRF) the death date will be imputed as the last known date alive.
Disease progression date
 If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day
 If the day and month are missing or a date is completely missing, it will be considered as 
missing
 In case of the date of death is present and complete, the imputed progression date will be 
compared to the date of death. The minimum of the imputed progression date and date of 
death will be considered as the date of progression.
Other partial date, the following conventions may be used:
 If only the day of the month is missing, the 15th of the month will be used to replace the 
missing day
 If both the day and the month are missing, “July 1” will be used to replace the missing 
information
 If a date is completely missing, it will be considered as missing
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The following conversion factors will be used to convert days to months or years: 1 month = 
30.4375 days and 1 year = 365.25 days.
Duration (e.g., duration response, time to response, etc) will be calculated as follows:
Duration = (Last date - first date +1)
9
CONTENT OF REPORTS
All analyses described in this SAP will be included in final Clinical Study Report(s) (per data 
availability). Multiple Clinical Study Reports may be produced depending on the maturity of 
different treatment arm under each Track. Refer to the Data Presentation Plan for mock-ups of all 
tables and listings.
10
OTHER INFORMATION
10.1
Select Adverse Events Definition And Conventions
The select Adverse Events (select AEs) consist of a list of preferred terms grouped by specific 
category (e.g. pulmonary events, gastrointestinal events categories) and by subcategory (e.g. 
thyroid disorders, diabetes, pituitary, adrenal disorders subcategories). These categories and 
subcategories are defined by the Sponsor and the list that is most current at the time of analysis 
will be used.  Also changes may be made to this list with each new version of MedDRA.
For information, the select adverse events defined at the time of finalization of the first version of 
the document are listed in Table 10.1-1 using MedDRA version 18.  The final list used for the 
clinical study report will be included in an Appendix of the CSR.
Table 10.1-1:
Select Adverse Event
Category
Subcategory
Preferred Terms
Endocrine Adverse Event
ADRENAL 
DISORDER 
ADRENAL INSUFFICIENCY
ADRENAL SUPPRESSION
BLOOD CORTICOTROPHIN DECREASED
BLOOD CORTICOTROPHIN INCREASED
HYPOTHAIAMIC PITUITARY ADRENAL AXIS 
SUPPRESSION
SECONDARY ADRENOCORTICAL INSUFFICIENCY
DIABETES
DIABETES MELLITUS
DIABETIC KETOACIDOSIS
LATENT AUTOIMMUNE DIABETES IN ADULTS
PITUITARY 
DISORDER
HYPOPHYSITIS
THYROID 
DISORDER 
AUTOIMMUNE THYROIDITIS
BLOOD THYROID STIMULATING HORMONE 
DECREASED
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Table 10.1-1:
Select Adverse Event
Category
Subcategory
Preferred Terms
BLOOD THYROID STIMULATING HORMONE 
INCREASED
HYPERTHYROIDISM
HYPOTHYROIDISM
THYROID FUNCTION TEST ABNORMAL
THYROIDITIS
THYROIDITIS ACUTE
THYROXINE DECREASED
THYROXINE FREE DECREASED
THYROXINE FREE INCREASED
THYROXINE INCREASED
TRI-IODOTHYRONINE INCREASED
Hypersensitivity/Infusion 
Reactions
ANAPHYLACTIC REACTION
ANAPHYLACTIC SHOCK
BRONCHOSPASM
HYPERSENSITIVITY
INFUSION RELATED REACTION
Gastrointestinal Adverse 
Events
COLITIS
COLITIS ULCERATIVE
DIARRHOEA
ENTERITIS
ENTEROCOLITIS
FREQUENT BOWEL MOVEMENTS
GASTROINTESTINAL PERFORATION
Hepatic Adverse Event
ACUTE HEPATIC FAILURE
ALANINE AMINOTRANSFERASE INCREASED
ASPARTATE AMINOTRANSFERASE INCREASED
AUTOIMMUNE HEPATITIS
BILIRUBIN CONJUGATED INCREASED
BLOOD ALKALINE PHOSPHATASE INCREASED
BLOOD BILIRUBIN INCREASED
DRUG-INDUCED LIVER INJURY
GAMMA-GLUTAMYLTRANSFERASE INCREASED
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Table 10.1-1:
Select Adverse Event
Category
Subcategory
Preferred Terms
HEPATIC ENZYME INCREASED
HEPATIC FAILURE
HEPATITIS
HEPATITIC ACUTE
HEPATOTOXICITY
HYPERBILIRUBINAEMIA
LIVER DISORDER
LIVER FUNCTION TEST ABNORMAL
LIVER INJURY
TRANSAMINASES INCREASED
Pulmonary Adverse Events
ACUTE RESPIRATORY DISTRESS SYNDROME
ACUTE RESPIRATORY FAILURE
INTERSTITIAL LUNG DISEASE
LUNG INFILTRATION
PNEUMONITIS
Renal Adverse Events
BLOOD CREATININE INCREASED
BLOOD UREA INCREASED
CREATININE RENAL CLEARANCE DECREASED
HYPERCREATININAEMIA
NEPHRITIS
NEPHRITIS ALLERGIC
NEPHRITIS AUTOIMMUNE
RENAL FAILURE
RENAL FAILURE ACUTE
RENAL TUBULAR NECROSIS
TUBULOINTERSTITIAL NEPHRITIS
URINE OUTPUT DECREASED
Skin Adverse Events
BLISTER
DERMATITIS
DERMATITIS EXFOLIATIVE
DRUG ERUPTION
ECZEMA
ERYTHEMA
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Table 10.1-1:
Select Adverse Event
Category
Subcategory
Preferred Terms
ERYTHEMA MULTIFORME
EXFOLIATIVE RASH
PALMAR-PLANTAR ERYTHRODYSAESTHESIA 
SYNDROME
PHOTOSENSITIVITY REACTION
PRURITUS
PRURITUS ALLERGIC
PRURITUS GENERALISED
PSORIASIS
RASH
RASH ERYTHEMATOUS
RASH GENERALISED
RASH MACULAR
RASH MACULO-PAPULAR
RASH PAPULAR
RASH PRURITIC
SKIN EXFOLIATION
SKIN HYPOPIGMENTATION
SKIN IRRITATION
STEVERNS-JOHNSON SYNDROME
TOXIC EPIDERMAL NECROLYSIS
URTICARIA
VITILIGO
Source: MedDRA version 18
10.1.1
Time to Onset Definition
Time-to onset of select AE (any grade) for a specific category (i.e. pulmonary events, 
gastrointestinal events, ...) is defined as the time between the day of the first dose of study treatment  
and the onset date of the earliest select AE (of any grade) in this category.
If the subject did not experience a select AE (of any grade) in the category, time-to onset will be 
censored at the maximum follow-up time of all subjects in their respective treatment group (i.e.
for subjects without an event, follow-up time is defined from first dosing date up to last dosing 
date +100 days or first dose date of retreatment/re-randomized treatment, whichever is earliest, if 
subjects are off treatment and followed for at least 100 days or started retreatment/re-randomized 
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treatment) , otherwise it is defined up to the last known alive date). The resulting Kaplan-Meier 
plot will represent the cumulative rate of the select AE (any grade) in the category over time.
Time-to onset of select AE (grade 3-5) for a specific category is defined similarly but restricted to 
grade 3-5 select AEs.
Time-to onset of drug-related (grade 3-5 or any grade) select AE for a specific category is defined 
similarly but restricted to drug-related select AEs.
Time-to onset for a specific subcategory is defined similarly but restricted to event of this 
subcategory.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.2
Immune Mediated Adverse Events Definition and Conventions
The Immune Mediated Adverse Events (IMAE) consist of a list of preferred terms grouped by 
specific category (e.g. pulmonary events, gastrointestinal events categories). These categories are 
defined by the Sponsor and the list that is most current at the time of analysis will be used. Also 
changes may be made to this list with each new version of MedDRA.
For information, the IMAE defined at the time of finalization of the first version of the document 
are listed in Table 10.2-1 using MedDRA version 18. The final list used for the clinical study report 
will be included in an Appendix of the CSR.
Table 10.2-1:
Immune-Mediated Adverse Event Definition
Category
Preferred Terms
ADRENAL INSUFFICIENCY
ADRENAL INSUFFICIENCY
DIABETES MELLITUS
DIABETES MELLITUS
DIABETIC KETOACIDOSIS
DIARRHEA/COLITIS
COLITIS
DIARRHOEA
ENTEROCOLITIS
HEPATITIS
ALANINE AMINOTRANSFERASE INCREASED
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Table 10.2-1:
Immune-Mediated Adverse Event Definition
Category
Preferred Terms
ASPARTATE AMINOTRANSFERASE INCREASED
AUTOIMMUNE HEPATITIS
BLOOD ALKALINE PHOSPHATASE INCREASED
BLOOD BILIRUBIN INCREASED
HEPATITIS
HEPATITIS ACUTE
HEPATOTOXICITY
HYPERBILIRUBINAEMIA
HYPERSENSITIVITY
HYPERSENSITIVITY
INFUSION RELATED REACTION
HYPERTHYROIDISM
HYPERTHYROIDISM
HYPOTHYROIDISM/THYROIDITIS
AUTOIMMUNE THYROIDITIS
HYPOTHYROIDISM
THYROIDITIS
THYROIDITIS ACUTE
NEPHRITIS AND RENAL DYSFUNCTION
BLOOD CREATININE INCREASED
NEPHRITIS
NEPHRITIS ALLERGIC
RENAL FAILURE
RENAL FAILURE ACUTE
TYBULOINTERSTITIAL NEPHRITIS
PNEUMONITIS
INTERSTITIAL LUNG DISEASE
PNEUMONITIS
RASH
RASH
RASH MACULO-PAPULAR
THYROIDITIS
AUTOIMMUNE THYROIDITIS
THYROIDITIS
THYROIDITIS ACUTE
11
DOCUMENT HISTORY
Table 11-1:
Document History
Version Number
Author(s)
Description
1.0
Initial version  -Mar-2016
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Table 11-1:
Document History
Version Number
Author(s)
Description
2.0
Incorporate Master Protocol amendment 2,3 and 4, incorporate Sub 
Protocol A amendment 1 and 2 (with addition of nivolumab + 
ipilimumab combination arm)
3.0
Incorporate Master Protocol amendment 5 and incorporate Sub 
Protocol B 
 
 
 
 
 
 
 
 
 
 
 
3.0
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