Clinical trial NCT06094296
Conditions: NSCLC
Keywords: Pharmacokinetics BMS-986315 Nivolumab Platinum doublet chemotherapy NSCLC Lung cancer
Sponsor: Bristol-Myers Squibb
Start date: 2023-11-27; Completion date: 2024-08-08
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of BMS-986315 plus nivolumab in combination with platinum-based doublet chemotherapy (PDCT) versus nivolumab in combination with PDCT in the first-line treatment of Stage IV or recurrent non-small cell lung cancer (NSCLC).

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None
Interventions: intervention 1: BMS-986315 intervention 2: Nivolumab intervention 3: Pemetrexed intervention 4: Cisplatin intervention 5: Carboplatin intervention 6: Paclitaxel
Intervention descriptions: intervention 1: Specified dose on specified days intervention 2: Specified dose on specified days intervention 3: Specified dose on specified days intervention 4: Specified dose on specified days intervention 5: Specified dose on specified days intervention 6: Specified dose on specified days

Protocol documents:
Prot_SAP_000.pdf: 
Official Title of Study: 
A Randomized, Double-blind, Phase 2 Study of BMS-986315 and Nivolumab in Combination 
with Chemotherapy versus Nivolumab in Combination with Chemotherapy as First-line 
Treatment for Participants with Stage IV or Recurrent Non-small Cell Lung Cancer (NSCLC) 
 
NCT Number: NCT06094296 
Document Date (Date in which document was last revised): 21 Jun 2023 
 
 
 


Page:
1
Protocol Number:
CA0471009
Date:
21-Jun-2023
CLINICAL PROTOCOL CA0471009
A Randomized, Double-blind, Phase 2 Study of BMS-986315 and Nivolumab in Combination 
with Chemotherapy versus Nivolumab in Combination with Chemotherapy as First-line 
Treatment for Participants with Stage IV or Recurrent Non-small Cell Lung Cancer (NSCLC)
Compound: BMS-986315
Brief Title: A Phase 2 Study of BMS-986315 and Nivolumab in Combination with Chemotherapy 
in Participants with First-line Stage IV or Recurrent NSCLC 
Medical Monitor Name and Contact Information:
24-hr Emergency Telephone Number
USA:
International:
Sponsor Name and Legal Registered Address:
Bristol-Myers Squibb Company
Route 206 & Province Line Road
Lawrenceville, NJ 08543
Bristol-Myers Squibb Services Unlimited Company
Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
REGULATORY AGENCY IDENTIFIER NUMBER(S)
IND: 145,968
EudraCT/EU Trial Number: 2022-503007-22-00
UTN: U1111-1282-5699
Clinical Trial Physician – Medical Monitor
Bristol-Myers Squibb Company
3551 Lawrenceville Rd
Princeton, NJ 08540
Phone:
email: 
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Clinical Protocol
CA0471009
BMS-986315
NKG2A
Date: 21-Jun-2023
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company (BMS) and its global affiliates. 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. References to BMS in this protocol may apply to partners to which BMS 
has transferred obligations (eg, a Contract Research Organization [CRO]).  
© 2023 Bristol-Myers Squibb Company
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Clinical Protocol
CA0471009
BMS-986315
NKG2A
DOCUMENT HISTORY
Document
Date of Issue
Summary of Changes
Original Protocol
21-Jun-2023
Not applicable.
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TABLE OF CONTENTS
TITLE PAGE................................................................................................................
DOCUMENT HISTORY..............................................................................................
TABLE OF CONTENTS..............................................................................................
1 PROTOCOL SUMMARY.........................................................................................
2 SCHEDULE OF ACTIVITIES..................................................................................
3 INTRODUCTION .....................................................................................................
3.1 Study Rationale.................................................................................................
3.2 Background.......................................................................................................
3.2.1 First-line Immunotherapy(ies) in Combination with Chemotherapy in 
NSCLC ........................................................................................................
3.2.2 Preclinical Activity of BMS-986315 in Combination with Nivolumab....
3.2.3 BMS-986315 Preliminary Clinical Activity and Safety ...........................
3.3 Benefit/Risk Assessment ..................................................................................
3.3.1 Risk Assessment .......................................................................................
3.3.2 Benefit Assessment...................................................................................
3.3.3 Overall Benefit/Risk Conclusion..............................................................
4 OBJECTIVES AND ENDPOINTS...........................................................................
5 STUDY DESIGN.......................................................................................................
5.1 Overall Design ..................................................................................................
5.1.1 Data Monitoring Committee and Other Committees...............................
5.2 Number of Participants .....................................................................................
5.3 End of Study Definition....................................................................................
5.4 Scientific Rationale for Study Design...............................................................
5.4.1 Rationale for Choice of Control Arm.......................................................
5.4.2 Rationale for ORR as a Primary Endpoint in Part 2...............................
5.4.3 Rationale for 2-year Duration of Treatment............................................
5.5 Justification for Immunotherapy Dose(s) .........................................................
5.5.1 Nivolumab................................................................................................
5.5.2 BMS-986315 ............................................................................................
5.6 Rationale for Exploratory Biomarker Research................................................
5.7 Rationale for Optional Future Research ...........................................................
6 STUDY POPULATION............................................................................................
6.1 Inclusion Criteria ..............................................................................................
6.2 Exclusion Criteria .............................................................................................
6.3 Lifestyle Restrictions ........................................................................................
6.4 Screen Failures..................................................................................................
6.4.1 Re-testing During Screening or Lead-in Period......................................
7 STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .......................
7.1 Study Interventions Administered ....................................................................
7.1.1 Immunotherapy Dosing............................................................................
7.1.2 Chemotherapy Dosing .............................................................................
7.1.2.1 Paclitaxel and Carboplatin.............................................................
7.1.2.2 Pemetrexed and Cisplatin...............................................................
7.1.2.3 Pemetrexed and Carboplatin..........................................................
7.1.2.4 Optional Continuation Maintenance ..............................................
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Clinical Protocol
BMS-986315
CA0471009
NKG2A
Date: 21-Jun-2023
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7.2 Assignment to Study Intervention ....................................................................
7.3 Blinding.............................................................................................................
7.4 Dosage Modification.........................................................................................
7.4.1 Dose Modification Criteria for Immunotherapy......................................
7.4.2 Dose Delay Criteria for Chemotherapy...................................................
7.4.3 Dose Reductions.......................................................................................
7.4.3.1 Dose Reduction for Immunotherapy...............................................
7.4.3.2 Dose Reduction for Chemotherapy.................................................
7.4.3.3 Chemotherapy: Dose Reductions for Hematologic Toxicity ..........
7.4.3.4 Chemotherapy: Dose Reductions for Non-hematologic Toxicities.
7.4.4 Criteria to Resume Dosing.......................................................................
7.4.4.1 Criteria to Resume Treatment with Immunotherapy ......................
7.4.4.2 Criteria to Resume Treatment with Chemotherapy ........................
7.4.5 Management Algorithms for Immuno-Oncology Agents .........................
7.4.6 Dose-limiting Toxicities...........................................................................
7.4.7 Treatment of Immunotherapy Infusion Reactions....................................
7.5 Preparation/Handling/Storage/Accountability..................................................
7.5.1 Retained Samples for Bioavailability/Bioequivalence/Biocomparability
7.6 Study Intervention Compliance ........................................................................
7.7 Concomitant Therapy........................................................................................
7.7.1 Prohibited and/or Restricted Treatments.................................................
7.7.2 Other Restrictions and Precautions.........................................................
7.7.2.1 Imaging Restrictions and Precautions............................................
7.7.3 Permitted Therapy ...................................................................................
7.7.3.1 Palliative Local Therapy.................................................................
7.8 Continued Access to Study Intervention After the End of the Study ...............
8 DISCONTINUATION CRITERIA ...........................................................................
8.1 Discontinuation of Study Intervention..............................................................
8.1.1 Immunotherapy Treatment Beyond Disease Progression........................
8.1.2 Post-study Intervention Study Follow-up.................................................
8.2 Discontinuation From the Study.......................................................................
8.2.1 Individual Discontinuation Criteria ........................................................
8.3 Lost to Follow-up..............................................................................................
9 STUDY ASSESSMENTS AND PROCEDURES.....................................................
9.1 Efficacy Assessments........................................................................................
9.1.1 Imaging Assessment for the Study............................................................
9.1.1.1 Methods of Measurement................................................................
9.1.1.2 Imaging and Clinical Assessment...................................................
9.1.1.3 BICR Confirmation of Progression or Recurrence ........................
9.2 Adverse Events .................................................................................................
9.2.1 Period and Frequency for Collecting AE and SAE Information .............
9.2.2 Method of Detecting AEs and SAEs.........................................................
9.2.3 Follow-up of AEs and SAEs.....................................................................
9.2.4 Regulatory Reporting Requirements for SAEs.........................................
9.2.5 Pregnancy ................................................................................................
9.2.6 Laboratory Test Result Abnormalities.....................................................
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Clinical Protocol
BMS-986315
CA0471009
NKG2A
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9.2.7 Potential Drug-induced Liver Injury .......................................................
9.2.8 Other Safety Considerations....................................................................
9.2.9 AEs of Special Interest.............................................................................
9.3 Overdose ...........................................................................................................
9.4 Safety ................................................................................................................
9.4.1 Physical Examinations.............................................................................
9.4.2 Vital Signs and Oxygen Saturation..........................................................
9.4.3 Electrocardiograms .................................................................................
9.4.4 Clinical Safety Laboratory Assessments..................................................
9.4.5 Imaging Safety Assessment ......................................................................
9.5 Pharmacokinetics and Immunogenicity............................................................
9.5.1 Pharmacokinetic Sample Collection Windows........................................
9.6 Immunogenicity Assessments...........................................................................
9.7 Biomarkers........................................................................................................
9.7.1 Biomarker Assessments in Tumor............................................................
9.7.2 Biomarker Assessments in Peripheral Blood...........................................
9.7.2.1 Whole Blood for Immunophenotyping ............................................
9.7.2.2 Exploratory Serum Biomarkers ......................................................
9.7.2.3 Plasma for Circulating Tumor DNA...............................................
9.7.2.4 Whole Blood DNA/RNA Analysis....................................................
9.7.2.5 Peripheral Blood Mononuclear Cells (PBMCs).............................
10 STATISTICAL CONSIDERATIONS ....................................................................
10.1 Statistical Hypotheses.....................................................................................
10.2 Sample Size Determination.............................................................................
10.3 Analysis Sets...................................................................................................
10.4 Statistical Analyses.........................................................................................
10.4.1 Efficacy Endpoint(s)...............................................................................
10.4.2 Safety Endpoint(s)..................................................................................
10.4.3 Other Analyses.......................................................................................
10.5 Interim Analyses for Part 2.............................................................................
11 REFERENCES ........................................................................................................
12 APPENDICES .........................................................................................................
APPENDIX 1 LIST OF ABBREVIATIONS...............................................................
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS .................................
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW-UP, AND REPORTING .......................................................................
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION.....................................................................
APPENDIX 5 ECOG PERFORMANCE STATUS .....................................................
APPENDIX 6 IMAE MANAGEMENT ALGORITHMS ...........................................
APPENDIX 7 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS ........................
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Clinical Protocol
BMS-986315
CA0471009
NKG2A
Date: 21-Jun-2023
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BMS-986315
NKG2A
1
PROTOCOL SUMMARY
Protocol Title:
A Randomized, Double-blind, Phase 2 Study of BMS-986315 and Nivolumab in Combination 
with Chemotherapy Versus Nivolumab in Combination with Chemotherapy as First-line 
Treatment for Participants with Stage IV or Recurrent Non-small Cell Lung Cancer (NSCLC)
Brief Title:
A Phase 2 Study of BMS-986315 and Nivolumab in Combination with Chemotherapy in 
Participants with First-line Stage IV or Recurrent NSCLC
Rationale:
This study aims to assess the clinical efficacy and to establish the safety of combination therapy 
of BMS-986315, nivolumab, and platinum doublet chemotherapy versus nivolumab and 
platinum-based doublet chemotherapy in the first-line treatment of Stage IV or recurrent NSCLC. 
Despite the success of therapeutic approaches targeting the checkpoint pathways in NSCLC, many 
patients do not benefit, potentially due to other immune resistance mechanisms. One such 
resistance mechanism stems from the interaction between the inhibitory receptor natural killer 
group 2 member A (NKG2A) and its ligand, MHC class I antigen E (HLA-E). CD94/NKG2 is a 
family of C-type lectin receptors that may stimulate or inhibit the cytotoxic activity of natural killer 
(NK) cells through recognition of nonclassical major histocompatibility complex (MHC) 
glycoproteins class I. NKG2A, commonly linked with CD94, is an inhibitory receptor that contains 
2 immunoreceptor tyrosine-based inhibitory motif domains that recruit src homology 2 domain-
containing protein tyrosine phosphatase 1 (SHP-1) and SHP-2, leading to the dephosphorylation 
of tyrosine kinase substrates, which results in the inhibition of NK and T-cell responses. NKG2A 
expression is specific to cytotoxic immune cells (effector/memory cluster of differentiation 8+ 
[CD8+], NK, NKT, and γδT cells), and it is increased in tumor-infiltrating CD8+ T and NK cells. 
HLA-E is physiologically expressed in most human tissues at low levels, and overexpression of 
HLA-E has been correlated to worse prognosis in several tumor types. In parallel, NKG2A 
expression is higher in NK cells found in breast cancer and NSCLC as compared to normal tissue. 
As for T-cells, NKG2A expression has been correlated with worse survival in patients with 
colorectal cancer. NKG2A null NK cells had higher cytotoxicity against HLA-E-expressing tumor 
cells compared to NKG2A+ cells, highlighting the inhibitory capacity of NKG2A. 
Thus, an NKG2A antagonistic antibody, such as BMS-986315, 
 could have a unique advantage of restoring both T and NK cell 
responses. Since NKG2A levels on tumor-infiltrating CD8+ T-cells are associated with high PD-
1 expression, the combination of BMS-986315 and anti-PD-1 may overcome anti-PD-1 resistance 
in patients with advanced solid tumors that express HLA-E. 
In the ongoing Phase 1 study CA047004, 
, BMS-986315
monotherapy and in combination with nivolumab showed a tolerable safety profile with no 
dose-limiting toxicities (DLTs) observed 
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CA0471009
BMS-986315
NKG2A
 
 
 Recent data from COAST, a Phase 2 study, showed that an anti-NKG2A mAb, 
monalizumab, in combination with durvalumab (anti-PD-L1 monoclonal antibody) is safe and 
showed preliminary efficacy in locally advanced NSCLC post-concurrent chemoradiation. 
Nivolumab, BMS-986315, and chemotherapy each have non-overlapping anti-cancer mechanisms 
and may have synergistic and/or additive activity as combination therapy, with few overlapping 
toxicities. 
 
Objectives and Endpoints:
Table 1:
Objectives and Endpoints
Objectives
Endpoints
Part 1: Safety Lead-in
•
To assess the safety and tolerability of BMS-
986315
administered in combination with 
nivolumab 
and 
platinum-based 
doublet 
chemotherapy in participants with histologically 
confirmed Stage IV or recurrent NSCLC in first-
line setting.
•
Incidence of AEs, TRAEs, SAEs (per CTCAE v5), AEs 
meeting protocol-defined DLT criteria, AEs leading to 
discontinuation, and death.
Part 2: Primary
•
To compare the objective response rate (ORR) of 
BMS-986315 and nivolumab in combination 
with platinum-based doublet chemotherapy 
versus nivolumab and platinum-based doublet 
chemotherapy in participants with histologically 
confirmed Stage IV or recurrent NSCLC in first-
line setting.
•
ORR assessed by blinded independent central review 
(BICR) is defined as the proportion of participants who 
achieve a best response of CR or PR using the RECIST 
1.1 criteria.
Part 2: Secondary
•
To evaluate the progression-free survival (PFS)
of BMS-986315 and nivolumab in combination 
with platinum-based
doublet chemotherapy 
compared to nivolumab and platinum-based 
doublet chemotherapy.
•
PFS assessed by BICR is defined as the time between 
the date of randomization and the first date of 
documented progression, per RECIST 1.1 criteria or 
death due to any cause, whichever occurs first.
•
To assess the safety and tolerability of 
BMS-986315 and nivolumab in combination 
with platinum-based doublet chemotherapy 
compared to nivolumab and platinum-based 
doublet chemotherapy.
•
Incidence of AEs, TRAEs, SAEs (per CTCAE v5), AEs 
meeting protocol-defined DLT criteria, AEs leading to 
discontinuation, and death.
•
To evaluate other efficacy endpoints including 
duration of response (DoR), time to objective 
response (TTR), and disease control rate (DCR) 
of BMS-986315 and nivolumab in combination 
•
DoR assessed by BICR is defined as the time between 
the date of first documented response (CR or PR) to the 
date of the first documented progression as determined 
by RECIST 1.1 criteria or death due to any cause, 
whichever occurs first.
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BMS-986315
NKG2A
Table 1:
Objectives and Endpoints
Objectives
Endpoints
with chemotherapy compared to nivolumab and 
chemotherapy
•
TTR assessed by BICR is defined as the time between 
the date of randomization and the first confirmed 
documented response (CR or PR) per RECIST 1.1 
criteria.
•
DCR assessed by BICR is defined as the proportion of 
participants who achieve a best response of CR, PR, or 
SD using the RECIST 1.1 criteria.
•
To characterize the PK of BMS-986315 in 
combination with nivolumab and chemotherapy.
•
To 
characterize 
the 
immunogenicity 
of 
BMS-986315 in combination with nivolumab 
and chemotherapy.
•
Summary of PK parameters: Cmax, Tmax, AUC(0-T), 
and other parameters as appropriate
•
Incidence of anti-drug antibodies to BMS-986315
when 
in 
combination 
with 
nivolumab 
and 
chemotherapy.
Abbreviations: AUC(0-T), Area under the serum concentration-time curve from time zero to time of last quantifiable 
concentration; AE, adverse event; BICR, blinded independent central review; Cmax, Maximum observed serum 
concentration; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; DCR, disease 
control rate; DLT, dose-limiting  toxicity; DoR, duration of response; NSCLC, non-small cell lung cancer; ORR, 
objective response rate; PFS, progression free survival; PK, pharmacokinetics; PR, partial response, RECIST, 
Response Evaluation Criteria in Solid Tumors; SAE, serious adverse event; SD, stable disease; Tmax, Time of 
maximum observed serum concentration; TRAE, treatment-related adverse event; TTR, time to response.
Overall Design:
This study is composed of 2 parts: Part 1: Safety Lead-in for 2 dose levels of BMS-986315
administered in combination with nivolumab and platinum-based doublet chemotherapy, and 
Part 2: randomization to BMS-986315 in combination with nivolumab and platinum-based doublet 
chemotherapy, or the control arm of nivolumab and platinum-based doublet chemotherapy. The 
study design schema is shown in Figure 1.
Part 1: Safety Lead-in
BMS-986315 450 mg
 or 900 mg
 and nivolumab 360 mg in 
combination with histology-based platinum doublet chemotherapy will be administered 
intravenously at Day 1 of every 3 week cycle for 4 cycles, followed by BMS-986315 and 
nivolumab combination for up to 2 years. This Safety Lead-in will be evaluated for safety and 
tolerability in a dose-escalation sequence based on dose-limiting toxicities (DLTs), using Bayesian
optimal interval (BOIN) design to guide escalation decisions, and the overall assessment of 
available safety, pharmacokinetic (PK), and pharmacodynamic data. The Part 2 randomization 
phase will be initiated upon the safety evaluation of the protocol-defined DLT and overall safety 
assessment of Part 1.
Part 2
 
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Part 2 of the study will start with randomization 
 
 
 
Arm A: Nivolumab 360 mg every 3 weeks (Q3W) + 4 cycles of histology-based platinum doublet 
chemotherapy
Arm B: BMS-986315 900 mg Q3W + nivolumab 360 mg Q3W + 4 cycles of histology-based 
platinum doublet chemotherapy 
Arm C: BMS-986315 450 mg Q3W + nivolumab 360 mg Q3W + 4 cycles of histology-based 
platinum doublet chemotherapy
Histology-based platinum doublet chemotherapy will be as follows:
•
Squamous histology: Carboplatin area under the concentration-time curve (AUC) 6 + 
paclitaxel 200 mg/m2 Q3W
•
Non-squamous histology: Carboplatin AUC 5 or 6 or cisplatin 75 mg/m2 + pemetrexed 
500 mg/m2 Q3W (optional maintenance therapy with 500 mg/m2 Q3W pemetrexed alone).
Treatment will continue until disease progression, unacceptable toxicity, or other reasons as 
specified in the protocol, and the maximum duration of treatment for nivolumab and BMS-986315 
will be 2 years (24 months) from first dose for BMS-986315 and nivolumab, whichever comes 
first. 
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Number of Participants:
Part 1: Safety Lead-in
participants will be enrolled in the safety Lead-in phase. 
 
 
Part 2: 
 participants will be randomized 
 
Study Population:
Key Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply: 
•
Ages 18 or older
•
Participants must have a life expectancy of at least 3 months 
•
Participants must have histologically confirmed NSCLC per the 8th International Association 
for the Study of Lung Cancer classification of squamous or non-squamous histology with Stage 
IV or recurrent disease following multimodal therapy for locally advanced disease.
•
No prior systemic anti-cancer treatment (including tyrosine kinase inhibitors) given as primary 
therapy for advanced or metastatic disease. Prior adjuvant or neoadjuvant chemotherapy for 
early-stage lung cancer is permitted if completed at least 6 months prior to initiating study 
treatment.
•
Eastern Cooperative Oncology Group Performance Status of 0 or 1. 
•
Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Key Exclusion Criteria
•
Participants with central nervous system metastases as the only disease site will be excluded.
•
Participants with known epidermal growth factor receptor (EGFR) mutation, ALK receptor 
tyrosine kinase (ALK) translocation, and ROS proto-oncogene 1 (ROS1) fusion which are 
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Clinical Protocol
CA0471009
BMS-986315
NKG2A
sensitive to available targeted inhibitor therapy are excluded. 
.
•
Participants with known gene mutations including neurotrophic tyrosine receptor kinase
(NTRK) fusion, mesenchymal epithelial transition (MET) exon 14 skipping mutation, B-Raf
proto-oncogene (BRAF) V600E mutation, or RET proto-oncogene (RET) rearrangement, 
which are sensitive to available targeted inhibitor therapy are excluded. If the test status is 
unknown or indeterminate for these 4 genes, the participants are eligible.
•
 
Study Intervention for CA0471009 
Intervention Name
Unit Dose 
Strength(s)
IP/IMP/Non-IP/
Non-IMP/AxMP 
BMS-986315 Concentrate for Solution for Infusion
mg/mL
IMP, Open-label (Part 1)
IMP, Blinded (Part 2)
Nivolumab (BMS-936558) Solution for Injection
10 mg/mL
IMP, Open label
Pemetrexed Powder for Concentrate for Solution for Infusiona
500 mg per vial
IMP, Open label
Cisplatin Concentrate for Solution for Infusiona
1 mg/mL
IMP, Open label
Carboplatin Concentrate for Solution for Infusiona
10 mg/mL
IMP, Open label
Paclitaxel Concentrate for Solution for Infusiona
6 mg/mL
IMP, Open label
Abbreviations: AxMP, Auxiliary Medicinal Product; IMP, Investigational Medicinal Product; IP, Investigational 
Product; Non-IMP and Non-IP, Non-investigational Medicinal Product.
a These products may be obtained by the investigational sites as local commercial product in certain countries if 
allowed by local regulations. In these cases, products may be a different pack size/potency than listed in the table. 
These products should be prepared/stored/administered in accordance with the package insert or summary of 
product characteristics (SmPC).
Statistical Methods:
It is expected that the objective response rate (ORR) with first-line Stage IV or recurrent NSCLC 
randomized to BMS-986315 with nivolumab in combination with chemotherapy will be improved 
as compared to participants receiving nivolumab in combination with chemotherapy.
In Part 1, the dose escalation will utilize the BOIN method to guide dose-escalation decisions.
Changes in tumor measurements will be assessed by blinded independent central review (BICR),
and tumor responses determined using RECIST v1.1 criteria. 
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A detailed description of the statistical analyses will be described in the statistical analysis plan.
Data Monitoring Committee: Yes
An internal, independent Data Assessment Committee will be used in this study.
Other Committee: Yes 
A BICR committee will be used in this study.
Brief Summary:
Study Intervention Duration: Each dosing cycle lasts 3 weeks (21 days). Study intervention is 
administered on Day 1 ± 3 days, and the maximum duration of treatment for nivolumab and 
BMS-986315 will be up to 2 years.
Study Visit Frequency: Study intervention will be given Q3W. 
 
 
 
 
 
 
 
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2
SCHEDULE OF ACTIVITIES
Study assessments and procedures are presented in
In the event that multiple procedures are required at a single time point, the electrocardiogram
(ECG) may be obtained up to 15 minutes earlier, vital signs may be obtained up to 10 minutes
earlier or later, and clinical laboratory samples may be obtained up to 5 minutes earlier than the
nominal time point, ensuring that the pharmacokinetic (PK) samples can be collected on time.
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3
INTRODUCTION
Study CA0471009 is a randomized, double-blind, Phase 2 study of BMS-986315 and nivolumab 
in combination with chemotherapy versus nivolumab in combination with chemotherapy as first-
line treatment for participants with Stage IV or recurrent non-small cell lung cancer (NSCLC).
BMS-986315 is a fully human immunoglobulin G1.3 (IgG1.3) monoclonal antibody (mAb) that 
binds 
 to human natural killer group 2 member A (NKG2A)
 
 
This study aims to provide preliminary evidence of clinical efficacy and to establish the safety of 
combination therapy of BMS-986315, nivolumab, and histology-based platinum doublet 
chemotherapy (PDCT) in the first-line treatment of Stage IV or recurrent NSCLC via a 2-part
design: a safety lead-in for 2 dose levels of BMS-986315 administered in combination with 
nivolumab and PDCT (Part 1), and a randomization part for 2 dose levels of BMS-986315 in 
combination with nivolumab and PDCT, and the control arm of nivolumab and PDCT (Part 2).
3.1
Study Rationale
The most extensively studied immune-modulating molecules are agents blocking checkpoint 
molecules, such as programmed cell death 1 (PD-1) and cytotoxic T lymphocyte–associated 
antigen 4 (CTLA-4). Inhibition of these negative regulatory receptors, referred to as immune 
checkpoint blockade, results in the enhanced activation of T-cell responses and potent antitumor 
activity in preclinical models. In first-line therapy of programmed death-ligand 1 (PD-L1)
expressing metastatic NSCLC patients, monotherapy of pembrolizumab, an anti-PD-1 monoclonal 
antibody (mAb), or a combination of nivolumab and ipilimumab, the PD-1 and CTLA-4 dual 
blockade respectively, provided clinical evidence of improvement in overall survival (OS) in Phase
3 trials Keynote 042 1 and CheckMate 227.2 In metastatic NSCLC, regardless of PD-L1 expression 
level, pembrolizumab plus chemotherapy, or nivolumab plus ipilimumab plus 2 cycles of 
chemotherapy have been approved to improve overall survival in all comers with acceptable and 
manageable safety profiles in Phase 3 trials Keynote 189,3 Keynote 407,4 and CheckMate 9LA.5
Despite the above success of therapeutic approaches targeting the checkpoint pathways in NSCLC, 
many patients do not benefit, potentially due to other immune resistance mechanisms. One such 
resistance mechanism stems from the interaction between the inhibitory receptor natural killer 
group 2 member A (NKG2A) receptor and its ligand, HLA-E. CD94/NKG2 is a family of C-type 
lectin receptors that may stimulate or inhibit the cytotoxic activity of NK cells through recognition 
of nonclassical major histocompatibility complex (MHC) glycoproteins class I. NKG2A, 
commonly linked with CD94, is an inhibitory receptor that contains 2 immunoreceptor tyrosine-
based inhibitory motif (ITIM) domains that recruit SHP-1 and SHP-2, leading to the 
dephosphorylation of tyrosine kinase substrates, which results in the inhibition of NK and T-cell 
responses. NKG2A expression is specific to cytotoxic immune cells (effector/memory CD8+, NK, 
NKT, and γδT cells), and it is increased in tumor-infiltrating CD8+T and NK cells. HLA-E is 
physiologically expressed in most human tissues at low levels, and overexpression of HLA-E has 
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been correlated to worse prognosis in several tumor types. In parallel, NKG2A expression is higher 
in NK cells found in breast cancer and NSCLC as compared to normal tissue. As for T cells, 
NKG2A expression has been correlated with worse survival in patients with colorectal cancer. 
NKG2A null NK cells had higher cytotoxicity against HLA-E-expressing tumor cells compared 
to NKG2A+ cells, highlighting the inhibitory capacity of NKG2A.
Thus, an NKG2A antagonistic antibody, such as BMS-986315, 
 
could have a unique advantage of restoring both T and NK cell 
responses. Since NKG2A levels on tumor-infiltrating CD8+ T cells are associated with PD-1 high 
expression, the combination of BMS-986315 and anti-PD-1 may overcome anti-PD-1 resistance 
in patients with advanced solid tumors that express HLA-E. 
In the ongoing Phase 1 study, CA047004, 
,8 BMS-986315
monotherapy cohort and in combination with nivolumab showed a tolerable safety profile with no 
dose-limiting toxicities (DLTs) 
 
 
 
 Recent data from COAST,6 a Phase 2 study, showed that an anti-NKG2A mAb,
monalizumab, in combination with durvalumab is safe and showed preliminary efficacy in locally 
advanced NSCLC post-concurrent chemoradiation. Nivolumab, BMS-986315, and chemotherapy 
each have non-overlapping anti-cancer mechanisms and may have synergistic and/or additive 
activity as combination therapy, with few overlapping toxicities. 
 
 
 
. The inclusion/exclusion criteria (Section 6.1, Section 6.2) 
in this study recapitulate a participant population who would typically be eligible to receive anti-
PD-1 and chemotherapy-based combination treatment.
3.2
Background
A detailed description of the chemistry, pharmacology, efficacy, and safety of BMS-986315 is 
provided in the Investigator’s Brochure (IB)8 and information for nivolumab is provided in the 
nivolumab IB. For prescribing information and administration instructions on pemetrexed, 
paclitaxel, cisplatin, and carboplatin, please refer to the current label and package insert that is 
applicable to the applicable geographic region.
3.2.1
First-line Immunotherapy(ies) in Combination with Chemotherapy in 
NSCLC
NSCLC remains the leading cause of cancer-related mortality worldwide, accounting for 
approximately 18% of all cancer deaths.7 Until recently, the treatment of patients with advanced 
NSCLC whose tumors did not have a targetable genetic alteration was cytotoxic chemotherapy 
alone. The introduction of immune checkpoint inhibitors targeting the PD-1 signaling pathway in 
the treatment of patient with NSCLC has had a significant effect on participant survival. 
Pembrolizumab combined with chemotherapy has been approved by the US Food and Drug 
Administration (FDA) in the front-line setting and has demonstrated an improvement in OS in 
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NSCLC participants as compared to chemotherapy alone.1 Although not approved by the FDA for 
use in the front-line setting for NSCLC, nivolumab in combination with histology-based PDCT
was recently studied in Part 2 of the Phase 3 trial.1 A summary of the efficacy results was presented 
at the European Society for Medical Oncology (ESMO) Immuno-Oncology (I-O) in 2019. Across 
all randomized, squamous (SQ), and non-squamous (NSQ) populations, there were clinically 
meaningful improvements with nivolumab + chemotherapy in OS, objective response rate (ORR), 
and progression-free survival (PFS) although in the primary endpoint population (NSQ), the results 
were not statistically significant. Specifically, OS results favored the nivolumab + chemotherapy 
arm in all randomized participants with median OS 18.3 m versus 14.7 m, OS hazard ratio (HR) 
0.81 (95% confidence interval [CI], 0.67–0.97), and participants with SQ NSCLC with median OS 
18.3 m vs 12.0 m, HR 0.69 (95% CI, 0.50–0.97). However, despite these advances, many patients 
do not benefit, potentially due to other immune resistance mechanisms.
To this end, dual immunotherapies in combination with histology-based chemotherapy have been 
developed and shown to improve efficacy outcomes with a manageable safety profile. Study 
CA2099LA5 which evaluated nivolumab plus ipilimumab in combination with PDCT vs PDCT in 
a similar population of first-line NSCLC participants, reported a hazard ratio (HR) for OS of 0.66
(95% CI, 0.55-0.80). Similarly, the current Phase 2 CA0471009 study evaluates BMS-986315, a
novel antagonistic antibody to NKG2A, in combination with nivolumab plus PDCT in NSCLC in 
the first-line setting.
3.2.2
Preclinical Activity of BMS-986315 in Combination with Nivolumab
The mechanism of action and preclinical functional activity of BMS-986315 are detailed in the 
IB8. Briefly, BMS-986315 is a fully human IgG1.3 mAb that binds 
 
 to human NKG2A 
 
 
 
 
 
 
 
 
 
 
 
 
 The antitumor therapeutic activity of anti-
NKG2A mAb was also studied using an anti-mouse NKG2A (mNKG2A) mAb.
 
 
 
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3.2.3
BMS-986315 Preliminary Clinical Activity and Safety
BMS-986315 is currently being evaluated in the first-in-human study, CA047004. 
 
, Part 1A and 1B of Study CA047004 were open and evaluating 
the dose escalation of BMS-986315 as monotherapy (Part 1A) and in combination with nivolumab 
(Part 1B). The dose-escalation Phase in combination with cetuximab (Part 1C) is not open to 
enrollment8.
In Part 1A BMS-986315 monotherapy, 
 
 The majority of AEs reported were Grade 1 or 2. 
 
 
 
 
 
 
 There were no reported treatment-related serious AEs. 
 
 
 
In Part 1B BMS-986315 in combination with nivolumab,
 
 no DLTs reported. 
 
 
 
 
 
 
At this time, no formal clinical efficacy evaluations have been conducted.
3.3
Benefit/Risk Assessment
Extensive details on the safety profile of BMS-986315, nivolumab, and chemotherapy agents 
(pemetrexed, paclitaxel, cisplatin, and carboplatin) are available in the IBs, and/or the current label 
and package insert that is applicable for the investigator’s geographic region and, will not be 
repeated herein.
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3.3.1
Risk Assessment
As described in Section 3.2.3, BMS-986315 showed a tolerable safety profile with no dose-
limiting toxicities (DLTs) 
 
 
Nivolumab, BMS-986315, and PDCT each have non-overlapping anti-cancer mechanisms with 
few overlapping toxicities. Based on available safety data for BMS-986315 as monotherapy and 
in combination with nivolumab 8,9as well as the known safety profile of nivolumab plus PDCT
10,11, the BMS-986315 + nivolumab + PDCT triplet therapy is expected to have manageable 
toxicity with no new serious AE categories expected, and 
 
In combination therapy, BMS-986315 may potentiate immune-mediated adverse events (IMAEs) 
caused by nivolumab. The safety profile of nivolumab is characterized by immune-related 
toxicities such as diarrhea, rash, pneumonitis, liver toxicity and endocrinopathies. The frequency 
and types of IMAEs associated with nivolumab are similar across multiple tumor types and are 
further described in the Reference Safety Information in the IB (BMS-986315 Investigator 
Brochure v2).
Participants who develop IMAEs may require prolonged treatment with high-dose corticosteroids 
and other immunosuppressive agents. This could increase the risk of opportunistic infections. 
IMAE management algorithms in the protocol recommend antibiotic prophylaxis against 
opportunistic infections in such situations (see Appendix 6). Due to the potential risk of 
exaggerated inflammatory response, participants with auto-immune disorders, who are at risk for 
flare of autoimmunity, will be excluded.
Whether nivolumab, PDCT, and/or BMS-986315 administration increases the risk for contracting 
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or increases the severity 
or duration of symptoms is currently unknown. This unknown risk must be considered when 
enrolling a participant. No additional safety monitoring or routine screening tests will be required 
due to the SARS-CoV-2 pandemic. Participants with recent or acute infections will be excluded 
or delay start of treatment. If a participant has a confirmed SARS-CoV-2 infection while on study 
intervention, dose delay or interruption of study intervention is required to meet the criteria for 
resuming study intervention. (see Section 7.4.4)
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3.3.2
Benefit Assessment
There remains a need to improve long-term outcomes in participants with first-line Stage IV
NSCLC. As described in the BMS-986315 Investigator’s Brochure,9 preclinical studies 
demonstrated that combination blockade of PD-1 and NKG2A had improved antitumor activity 
than either reagent alone. In the ongoing Phase 1 study, CA047004, BMS-986315 monotherapy 
and in combination with nivolumab, showed a tolerable safety profile with no DLTs observed 
 
.8 Recent data from COAST6 a Phase 2 study, showed that an anti-
NKG2A mAb, monalizumab, in combination with durvalumab is safe and showed preliminary 
efficacy in locally advanced NSCLC post-concurrent chemoradiation.6 Nivolumab, BMS-986315, 
and PDCT each have non-overlapping anti-cancer mechanisms and may have synergistic and/or 
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additive activity as combination therapy, with few overlapping toxicities. 
 
 
 
.
3.3.3
Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants in this study, the potential 
risks identified in association with combination therapy of BMS-986315 with nivolumab plus 
PDCT are justified by the anticipated benefits that may be afforded to participants with first-line
Stage IV NSCLC.
An independent, internal Data Assessment Committee (DAC) (see Section 5.1.1) will evaluate 
safety based on all available data with particular attention to: (i) AEs or other safety trends whose 
character, severity, and/or frequency suggest that participants would be exposed to an 
unreasonable and significant risk of illness or injury; (ii) new non-clinical data suggesting 
unreasonable and significant risk of illness or injury. In addition to the DAC, the Bristol-Myers 
Squibb Company (BMS) Safety Management Team (SMT) routinely monitors for actual or 
potential issues related to participant safety, including clinical trial data, information from 
literature, and non-clinical toxicology reports, which could result in a change in the medical risk-
benefit balance associated with study treatment. In this study, the SMT will also use quantitative 
approaches for continuous safety monitoring of specific AE signals (eg, Grade 3 to Grade 4 
treatment-related AEs). If a safety signal is detected by the SMT, then an ad hoc DAC meeting 
may occur to assess the risk/benefit and make recommendations about the safety.
If such evaluation suggests that the benefit/risk profile of the study has become unfavorable to 
participants, the Sponsor will pause enrollment and/or treatment until further evaluation of data, 
and interaction with the appropriate Health Authority(ies) can take place on potential actions. Such 
actions may include (but are not limited to) study continuation, substantial amendment, or 
termination of the study.
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4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints [Estimands]
Objectives
Endpoints
Part 1: Safety Lead-in
•
To assess the safety and tolerability of BMS-
986315
administered in combination with 
nivolumab 
and 
platinum-based 
doublet 
chemotherapy, in participants with histologically 
confirmed Stage IV or recurrent NSCLC in first-
line setting.
•
Incidence of AEs, TRAEs, SAEs (as per CTCAE v5), 
AEs meeting protocol-defined DLT criteria, AEs 
leading to discontinuation, and death.
Main Estimand for the Primary Objective
•
Treatment: BMS-986315 450 mg Q3W + nivolumab 360 mg Q3W+ histology-based chemotherapy Q3W
 and BMS-986315 900 mg Q3W + Nivolumab 360 mg Q3W + Histology-based Chemotherapy Q3W 
•
Population: Participants with Stage IV or Recurrent Non-Small Cell Lung Cancer (NSCLC)
•
Variable: Occurrence of AEs, TRAEs, SAEs (as per CTCAE v5), AEs meeting protocol-defined DLT criteria,
AEs leading to discontinuation, and death. 
•
Intercurrent events (strategy): AEs meeting protocol-defined DLT criteria (principal stratum strategy).  
Occurrence of AEs, TRAEs, SAEs (as per CTCAE v5), AEs leading to discontinuation, and death (while on 
treatment).
•
Population-level summary: Adverse event (AE) incidence rate
Part 2: Primary
•
To compare the objective response rate (ORR) of 
BMS-986315 and nivolumab in combination 
with platinum-based doublet chemotherapy 
versus nivolumab and platinum-based doublet 
chemotherapy in participants with histologically 
confirmed Stage IV or recurrent NSCLC in first-
line setting.
•
ORR assessed by blinded independent central review 
(BICR) is defined as the proportion of participants who 
achieve a best response of CR or PR using the RECIST 
1.1 criteria. 
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Table 4-1:
Objectives and Endpoints [Estimands]
Objectives
Endpoints
Main Estimand for the Primary Objective
•
Treatment: Nivolumab 360 mg Q3W + Histology-based Chemotherapy Q3W (Arm A), and BMS-986315 
900 mg Q3W + Nivolumab 360 mg Q3W + Histology-based Chemotherapy Q3W (Arm B), and 
BMS-986315 450 mg Q3W + Nivolumab 360 mg Q3W + Histology-based Chemotherapy Q3W (Arm C)
•
Population: Participants with Stage IV or Recurrent Non-Small Cell Lung Cancer (NSCLC)
•
Variable: Best overall response (BOR), defined as the best response, as determined by BICR recorded between 
the date of randomization and the date of first objectively documented progression per RECIST 1.1
•
Intercurrent events (strategy): Early discontinuation of study treatment (treatment policy); initiation of 
subsequent anti-cancer therapy (excluding allowed palliative radiotherapy/surgery to non-target/non-thoracic 
sites) (treatment policy)
•
Population-level summary: ORR, defined as the number of randomized participants who achieve a BOR of 
confirmed complete response (CR) or confirmed partial response (PR) based on BICR assessments (using 
RECIST 1.1) divided by the number of all  Uandomized participants in each treatment group, will be provided 
with a 95% exact confidence interval (CI). For the difference of ORR between arms, a 2-sided 90% exact CI
will be provided for Arm A vs. Arm B. For ORR differences between Arm A vs. Arm C or between Arm B vs. 
Arm C a 95% CI will be provided.
Part 2: Secondary
•
To evaluate the progression-free survival (PFS) 
of BMS-986315 and nivolumab in combination 
with platinum-based doublet chemotherapy 
compared to nivolumab and platinum-based 
doublet chemotherapy
•
PFS assessed by BICR is defined as the time between 
the date of 
randomization and the first date of 
documented progression, as per RECIST 1.1 criteria or 
death due to any cause, whichever occurs first.
Main Estimand for the Key Secondary Objective
•
Treatment: Nivolumab 360 mg Q3W + Histology-based Chemotherapy Q3W (Arm A), and BMS-986315 
900 mg Q3W + Nivolumab 360 mg Q3W + Histology-based Chemotherapy Q3W (Arm B), and
BMS-986315 450 mg Q3W + Nivolumab 360 mg Q3W + Histology-based Chemotherapy Q3W (Arm C) 
•
Population: Participants with Stage IV or Recurrent Non-Small Cell Lung Cancer (NSCLC)
•
Variable: PFS, defined as the time between the date of randomization and the first date of documented 
progression, determined by BICR assessments (using RECIST 1.1), or death due to any cause, whichever occurs 
first
•
Intercurrent events (strategy): Early discontinuation of study treatment (treatment policy); initiation of 
subsequent anti-cancer therapy (excluding allowed palliative radiotherapy/surgery to non-target/non-thoracic 
sites) prior to progressive disease or death ( hypothetical strategy)
•
Population-level summary: Kaplan Meier (KM) estimated HR, median survival time and landmark survival 
rate of PFS
•
To assess the safety and tolerability of 
BMS-986315 and nivolumab in combination 
with platinum-based doublet chemotherapy 
compared to nivolumab and platinum-based 
doublet chemotherapy.
•
Incidence of AEs, TRAEs, SAEs (as per CTCAE v5), 
AEs meeting protocol-defined DLT criteria, AEs 
leading to discontinuation, and death
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Table 4-1:
Objectives and Endpoints [Estimands]
Objectives
Endpoints
Main Estimand for the Secondary Objective
•
Treatment: Nivolumab 360 mg Q3W + Histology-based Chemotherapy Q3W (Arm A), and BMS-986315 
900 mg Q3W + Nivolumab 360 mg Q3W + Histology-based Chemotherapy Q3W (Arm B), and BMS-
986315 450 mg Q3W + Nivolumab 360 mg Q3W + Histology-based Chemotherapy Q3W (Arm C)  
•
Population: Participants with Stage IV or Recurrent Non-Small Cell Lung Cancer (NSCLC)
•
Variable: Incidence of AEs, TRAEs, SAEs (as per CTCAE v5), AEs meeting protocol-defined DLT criteria,
AEs leading to discontinuation, and death 
•
Intercurrent events (strategy): Early discontinuation of study treatment (while on treatment)
•
Population-level summary:  Adverse event (AE) incidence rate
•
To evaluate other efficacy endpoints including 
duration of response (DoR), time to objective 
response (TTR), and disease control rate (DCR)
of BMS-986315 and nivolumab in combination 
with chemotherapy compared to nivolumab and 
chemotherapy
•
DoR assessed by BICR is defined as the time between 
the date of first documented response (CR or PR) to the 
date of the first documented progression as determined 
by RECIST 1.1 criteria or death due to any cause, 
whichever occurs first.
•
TTR assessed by BICR is defined as the time between 
the date of randomization and the first confirmed 
documented response (CR or PR) per RECIST 1.1 
criteria.
•
DCR assessed by BICR is defined as the proportion of 
participants who achieve a best response of CR, PR, or 
SD using the RECIST 1.1 criteria.
•
To characterize the PK of BMS-986315 in 
combination with nivolumab and chemotherapy
•
To characterize the immunogenicity of BMS-
986315 in combination with nivolumab and 
chemotherapy
•
Summary of PK parameters: Cmax, Tmax, AUC(0-T), 
and other parameters as appropriate
•
Incidence of anti-drug antibodies to BMS-986315
when 
in 
combination
with 
nivolumab 
and 
chemotherapy
•
Part 2: Exploratory
•
To characterize the PK and immunogenicity of 
nivolumab in combination with BMS-986315
and chemotherapy.
•
Summary measure of trough nivolumab concentrations
•
Incidence of anti-drug antibodies to nivolumab 
•
To explore the pharmacodynamic (PD) activity 
of BMS-986315 and nivolumab in combination 
with 
chemotherapy
via 
assessment 
of 
translational biomarkers 
•
Summary of measures of change (or % change) from 
baseline for tumor and peripheral biomarkers of 
immune activation and associations with antitumor 
activity
•
To explore potential associations between 
antitumor activity and select biomarker measures 
in the tumor and peripheral blood prior to 
treatment
•
Summary of associations between baseline levels of 
select biomarkers and antitumor activity such as, but 
not limited to, tumoral PD-L1 
 
 
•
ORR, PFS, DoR, TTR, OS in randomized participants 
defined by tumor PD-L1 expression 
 
 based on RECIST v1.1 by 
BICR and investigator’s assessment
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Table 4-1:
Objectives and Endpoints [Estimands]
Objectives
Endpoints
•
To explore the relationship between BMS-
986315 and select biomarkers in tumor and 
peripheral blood
•
Associations between BMS-986315 concentrations 
and tumor and peripheral biomarkers
•
To evaluate the overall survival (OS) of BMS-
986315 and nivolumab in combination with 
chemotherapy compared to nivolumab and 
chemotherapy
•
OS in all randomized participants
•
1-year OS rate is defined as the percentage of 
randomized participants still alive at one year from first 
dose
•
To explore potential associations between 
image-based features, including, but not limited 
to, heterogeneity, shape,
and/or volumetric 
changes, and antitumor activity
•
Summary of measures of image-based feature changes, 
including, but not limited to, heterogeneity, shape 
and/or volume, from baseline for every timepoint until 
progression
or study treatment discontinuation, 
whichever occurs later, or withdrawal consent of tumor 
assessment, or death.
Abbreviations: AUC(0-T), Area under the serum concentration-time curve from time zero to time of last quantifiable 
concentration; AE, adverse event; BICR, blinded independent central review; BOR, best overall response; CI, 
confidence interval; 
; Cmax, Maximum observed serum concentration; CR, complete 
response; CTCAE, Common Terminology Criteria for Adverse Events; DCR, disease control rate; DF, Degree of 
fluctuation; DLT, dose-limiting toxicity; DoR, duration of response; 
; HR, hazard 
ratio;
; NSCLC, non-small cell lung cancer; ORR, objective response rate; 
PD, pharmacodynamic; PD-L1, programmed-death ligand 1; PFS, progression free survival; PK, pharmacokinetics; 
PR, partial response, Q3W, every 3 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious 
adverse event; SD, stable disease; Tmax, Time of maximum observed serum concentration; TRAE, treatment-related 
adverse event; TTR, time to response.
5
STUDY DESIGN
5.1
Overall Design
This multi-center, randomized trial will evaluate the efficacy and safety of the combination of 
BMS-986315 plus nivolumab and PDCT vs nivolumab and PDCT in adults with untreated Stage 
IV or recurrent non-small cell lung cancer (NSCLC). This study will be carried out in 2 parts: Part 
1: Safety lead-in for 2 dose levels of BMS-986315 administered in combination with nivolumab 
and chemotherapy, and Part 2: randomization to BMS-986315 in combination with nivolumab and 
PDCT or the control arm of nivolumab and PDCT. 
The study design schema is presented in 
.
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Part 1: Safety Lead-in
BMS-986315 450 mg
 or 900 mg
 and nivolumab 360 mg in 
combination with histology-based PDCT will be administered intravenously (IV) at day 1 of every 
3-week (Q3W) schedule for 4 cycles, followed by BMS-986315 and nivolumab combination (and 
optional pemetrexed maintenance therapy for nonsquamous participants) for up to 2 years. This 
Safety lead-in part will be evaluated for safety and tolerability in a dose escalation sequence based 
on dose-limiting toxicities (DLTs) within the 
 evaluation period, using Bayesian optimal 
interval (BOIN) design to guide escalation decisions, and the overall assessment of available 
safety, PK, and pharmacodynamic data.
During Part 1, approximately 6 participants (and up to 12) will be treated at each dose level. For 
all dose escalation cohorts, a sentinel participant approach will be used with a 5-day interval 
between the treatment initiation of the first participant and the treatment of subsequent participants 
in that dose level. Initially, 3 participants will be enrolled at the start of each dose-escalation cohort, 
in accordance with the sentinel participant approach above. However, to allow for any unforeseen 
discontinuations (such as disease progression) before the 
 DLT period 
 is 
completed, an extra participant may be enrolled in each dose escalation cohort. Cohort tolerability 
assessment and subsequent dose recommendation will occur when 
 participants 
within a cohort have completed a 
 DLT period or have been sufficiently followed, based 
on the BOIN design, to make an escalation decision depending on the number of DLTs so far. 
Dose de-esclation decision may be made as early as  subjects have completed the DLT period 
based on totality of data. Any toxicities that occur beyond the DLT period will be considered in 
making dose level decisions and/or dose level modifications. Additional information on DLTs can 
be found in Section 7.4.6.
Part 2
Part 2 of the study will start with randomization 
 
 
 
 
 
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Arm A: Nivolumab 360 mg Q3W + 4 cycles of histology-based PDCT
Arm B: BMS-986315 900 mg Q3W + nivolumab 360 mg Q3W + 4 cycles of histology-based 
PDCT
Arm C: BMS-986315 450 mg Q3W + nivolumab 360 mg Q3W + 4 cycles of histology-based 
PDCT
Histology-based platinum doublet chemotherapy will be as follows:
•
Squamous histology: Carboplatin under the concentration-time curve (AUC) 6 + paclitaxel 
200 mg/m2
•
Non-squamous histology: Carboplatin AUC 5 or 6 or cisplatin 75 mg/m2 + pemetrexed 
500 mg/m2 (optional maintenance therapy with 500 mg/m2 Q3W pemetrexed)
Planned BMS-986315 dose levels may be modified and intermediate dose levels of BMS-986315 
utilized, based upon the totality of the data and outcome of the safety-lead in (Part 1) and continued 
safety monitoring in Part 2.
If, based on the dose safety data in Part 1, the regimen including BMS-986315 900 mg 
 
 is confirmed to be safe, then this dose level will be evaluated in Part 2 of the trial 
 
. If, based on the dose safety data, the regimen including BMS-986315 900 
mg is not confirmed to be safe, but the regimen including BMS-986315 450 mg 
 is 
confirmed to be safe, an intermediate dose level may be tested. 
 (900 mg) would be 
reduced by 25% or greater. The highest dose level that is confirmed to be safe in the safety lead-
in will be evaluated in Part 2.
Treatment will continue until disease progression, or unacceptable toxicity, or other reasons as 
specified in the protocol, and the maximum duration of treatment for with BMS-986315 and 
nivolumab will be for up to 2 years (24 months) since the first dose for BMS-986315 and 
nivolumab, whichever comes first.
The investigator must decide prior to randomization whether the participant with non-squamous 
histology will receive cisplatin, if eligible. This information will be captured in the study database. 
Participants with non-squamous histology who have stable disease or response after induction 
chemotherapy are permitted to receive optional pemetrexed maintenance therapy.
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Dose reductions are not permitted for BMS-986315 and nivolumab. All participants will be treated 
until progression, presence of intolerable toxicities, withdrawal of consent, or study end, 
whichever comes first. Continuous safety evaluations and tumor assessments will guide the 
decision to treat a participant with additional cycles of study therapy if the participant has 
confirmed clinical benefit.
In all study parts, participants with unconfirmed stable disease (SD), partial response (PR), or 
complete response (CR) at the end of a given cycle will continue to the next treatment cycle. 
Participants will be allowed to continue study treatment until the first occurrence of any of the 
following:
•
Progressive disease defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
per investigator assessment, unless participants meet criteria for treatment beyond progression
•
Clinical deterioration suggests that no further benefit from treatment is likely
•
Intolerability to therapy
•
Participant meets criteria for discontinuation of study treatment
•
Efficacy assessments for the antitumor activity of BMS-986315 and nivolumab in combination 
with chemotherapy will be based on tumor measurements, using RECIST v1.1, with computed 
tomography (CT) and/or magnetic resonance imaging (MRI), as appropriate. Assessments will be 
performed 
 
 
Physical examinations, vital sign measurements, 12-lead electrocardiograms (ECGs), and clinical 
laboratory evaluations will be performed at selected times throughout the dosing interval. 
Participants will be closely monitored for AEs throughout the study. 
5.1.1
Data Monitoring Committee and Other Committees
An independent, internal Data Assessment Committee (DAC) will be used for this study. The DAC 
will be composed of Sponsor employees who are independent of the CA0471009 study team.
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The DAC charter will describe the procedures related to the committee operations in greater detail. 
The DAC will review data from Part 2 of the study and not the safety lead-in, Part 1.
The DAC will  provide general oversight and safety considerations during the study. The DAC
will provide advice to the CA0471009 study team regarding actions the committee deems 
necessary for the continuing protection of participants enrolled in this study. The DAC will be 
charged with assessing such actions in light of an acceptable benefit-risk profile for BMS-986315, 
nivolumab, and chemotherapy. The DAC will act in an advisory capacity and will monitor 
participant safety data of the study.
In addition to the independent DAC, BMS has in place a multi-layered process for ensuring 
participant safety through close collaboration of study site investigators, the BMS study team, and 
the BMS Worldwide Patient Safety (WWPS)-led SMT.
 
The minutes of the DAC meetings will be documented in the Trial Master File. The SMT will not 
share responsibilities with the independent DAC. Decisions on safety, toxicity, and benefit-risk 
will be solely the responsibility of the BMS CA0471009 study team and therapeutic area
leadership and will take account of the totality of the data available and in consideration of any 
DAC recommendations.
A Blinded Independent Central Review (BICR) is recommended by regulatory agencies in 
situations where clinical site image interpretation is variable and results of image measurements 
are important for eligibility determination, safety, and/or efficacy endpoints. Specifically, BICR
of scans may mitigate bias regarding endpoint assessment due to the subjectivity involved in lesion 
measurement and interpretation of tumor response and progression. Sites should submit all images 
to BICR on a continuing basis. However, should the BICR interpretation be in conflict with the 
local evaluation, treatment decisions will be based on investigator assessment and not the BICR 
assessment.
5.2
Number of Participants
Part 1: Safety Lead-in
participants will be enrolled in the safety lead-in phase. 
 
Part 2:
participants will be randomized 
 
.
5.3
End of Study Definition
The start of the study is defined as the first participant’s first visit, or first participant screened, or 
scheduled procedure shown in the Schedule of Activities (see Section 2). 
End of trial is defined as the last participant last visit or scheduled procedure shown in the Schedule 
of Activities (see Section 2) for the last participant, whichever occurs later.
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Study completion is defined as the final date on which data for the primary endpoint was or is 
expected to be collected if this is not the same.
A participant is considered to have completed the study if he/she has completed the last procedure 
shown in the Schedule of Activities.
The primary completion date is defined as the date on which the last data point is collected for the 
study’s primary endpoint. If the study has multiple primary endpoints, the primary completion date 
is the date on which the last data point is collected for the last primary endpoint. End of study is 
defined as the last participant’s last visit.
5.4
Scientific Rationale for Study Design
Despite the latest success of therapeutic approaches targeting the checkpoint pathways in NSCLC, 
many patients do not benefit, potentially due to other immune resistance mechanisms. One such 
resistance mechanism stems from the interaction between inhibitory receptor natural killer group 
2 member A (NKG2A) receptor and its ligand, HLA-E. CD94/NKG2 is a family of C-type lectin 
receptors that may stimulate or inhibit cytotoxic activity of NK cells through recognition of 
nonclassical major histocompatibility complex (MHC) glycoproteins class I. NKG2A, commonly 
linked with CD94, is an inhibitory receptor that contains 2 immunoreceptor tyrosine-based 
inhibitory motif (ITIM) domains that recruit SHP-1 and SHP-2, leading to the dephosphorylation 
of tyrosine kinase substrates, which results in the inhibition of NK and T cell responses. NKG2A 
expression is specific to cytotoxic immune cells (effector/memory CD8+, NK, NKT, and γδT 
cells), and it is increased in tumor-infiltrating CD8+T and NK cells. HLA-E is physiologically 
expressed in most human tissues at low levels, and overexpression of HLA-E has been correlated 
to worse prognosis in several tumor types. In parallel, NKG2A expression is higher in NK cells 
found in breast cancer and NSCLC as compared to normal tissue. As for T cells, NKG2A 
expression has been correlated with worse survival in patients with colorectal cancer. NKG2A null 
NK cells had higher cytotoxicity against HLA-E expressing tumor cells compared to NKG2A+ 
cells, highlighting the inhibitory capacity of NKG2A.
5.4.1
Rationale for Choice of Control Arm
In metastatic NSCLC, regardless of PD-L1 expression level, pembrolizumab plus chemotherapy, 
or nivolumab plus ipilimumab plus two cycles of chemotherapy have been approved to improve 
overall survival in all comers with acceptable and manageable safety profiles in Phase 3 trials 
Keynote 189, Keynote 407, and CheckMate 9LA. In CA209-012 12, a multi-arm Phase 1 safety 
study of nivolumab in chemotherapy-naive NSCLC, 56 participants were administered nivolumab 
in combination with gemcitabine/cisplatin, pemetrexed/cisplatin, or carboplatin/paclitaxel. The 
overall response rate (ORR) with the different combinations ranged from 42% to 50%. Nivolumab 
in combination with chemotherapy was studied in Part 2 of the Phase 3 trial CA209227. A 
summary of the efficacy results was presented at the European Society for Medical Oncology 
(ESMO) I-O in 2019. Across all randomized, squamous (SQ), and nonsquamous (NSQ) 
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populations, there were clinically meaningful improvements with nivolumab + chemotherapy in 
OS, ORR, and PFS, although in the primary endpoint population (NSQ), the results were not 
statistically significant. Specifically, OS results favored the nivolumab + chemotherapy arm in all 
randomized participants with median OS 18.3 month vs 14.7 month, HR 0.81 (95% CI, 0.67–0.97) 
and participants with SQ NSCLC with median OS 18.3 month vs 12.0 month, HR 0.69 (95% CI, 
0.50–0.97). A trend towards improvement was seen in participants with NSQ NSCLC, with OS 
HR 0.86 (95.62% CI, 0.69–1.08; P = 0.1859); median OS 18.8 month vs 15.6 month; and 12-
month OS rates 67.3% vs 59.2%. Progression-free survival and objective response rates also 
favored nivolumab + chemotherapy in NSQ, SQ, and all randomized participants. Grade 3 and 4 
treatment-related adverse events occurred in 45% and 35% of all participants treated with 
nivolumab + chemotherapy and chemotherapy alone, respectively. The study design of 
CA0471009 aims to establish the contribution of BMS-986315 to the overall treatment of the 
triplet combination in NSCLC patients, so nivolumab in combination with chemotherapy is chosen 
as the control arm of the study.
5.4.2
Rationale for ORR as a Primary Endpoint in Part 2
ORR is an acceptable Phase 2 endpoint in oncology studies in NSCLC that allows results to be 
assessed earlier when compared with survival-based endpoints. Early access to ORR data is 
necessary due to the rapidly changing landscape in NSCLC and is considered sufficient to establish 
proof-of-concept to help guide further development of the investigational agent(s). An advantage 
of ORR over survival-based endpoints is the direct attribution of tumor response to therapy 
because in the absence of treatment, spontaneous tumor regression is highly unlikely. Furthermore, 
ORR has been demonstrated to be a potential surrogate endpoint for checkpoint inhibitor therapies 
in NSCLC 13. A meta-analysis of 14 trials analyzed over 10,000 participants with advanced 
NSCLC submitted to the US Food and Drug Administration (FDA) between 2003 and 2013. In 
the patient-level responder analyses, this study demonstrated that patients who achieved a response 
had better PFS and OS compared with nonresponders (PFS: HR, 0.40; 95% CI, 0.38 to 0.42; OS: 
HR, 0.40; 95% CI, 0.38 to 0.43).14 Consistently, another meta-analysis including 36 trials for first-
line NSCLC also showed statistically significant association between OS and ORR across the trials
(R2 = 0.35; 95% CI, 0.13 to 0.57).15
In a meta-analysis conducted using pooled data from 63 trials and 78 immune checkpoint therapy 
treatment arms (n > 30,000), representing 15 different tumor types across different lines of 
therapies, including NSCLC, ORR, and 6-month DoR, was shown to be prognostic for 12-month 
OS.16 The primary ORR assessment will be performed by BICR in Part 2 and will be further 
characterized by the durability and depth of responses to establish the contribution of components 
of BMS-986315 and nivolumab.
5.4.3
Rationale for 2-year Duration of Treatment
The optimal duration of immunotherapy is an important question and continues to be investigated. 
The immunotherapy interventions in Study CA0471009 include nivolumab alone or nivolumab 
plus BMS-986315. The 2-year duration of treatment is mainly based on nivolumab, the backbone 
of immunotherapies, and is considered to have an optimal benefit-risk profile in studying the 
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investigational immunotherapies in this study. Clinical trials across different tumor types in the 
nivolumab development program indicate that most of the responses occur early, with a median 
time to response of 2 to 4 months,17,18,19,20,21 and emerging data suggest that benefit can be 
maintained in the absence of continued treatment. A recent analysis in a melanoma study suggests 
the majority of patients who discontinue nivolumab for toxicity maintain disease control in the 
absence of further treatment.22,23
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long-term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in participants with previously treated advanced solid tumors 
(including 129 participants with NSCLC), specified a maximum treatment duration of 2 years. 
Among 16 participants with NSCLC who discontinued nivolumab after completing 2 years of 
treatment, 12 participants were alive > 5 years later and remained progression free without any 
subsequent therapy. In the CA209003 NSCLC cohort, the OS curve begins to plateau after 2 years, 
with an OS rate of 25% at 2 years and 18% at 3 years.24 These survival outcomes are similar to 
Phase 3 studies in previously treated NSCLC, in which nivolumab treatment was continued until 
progression or unacceptable toxicity (2-year OS rates of 23% and 29%, and 3-year OS rates of 
16% to 18% for squamous and non-squamous NSCLC, respectively) .Taken together, these data 
suggest that treatment beyond 2 years is unlikely to confer additional clinically meaningful benefit 
and that the risk of progression after discontinuing treatment at 2 years is low.
In contrast, a shorter duration of nivolumab of only 1 year was associated with an increased risk 
of progression in previously treated participants with NSCLC, suggesting that treatment beyond 
1 year is likely needed. In CA209153, participants with previously treated advanced NSCLC who 
completed 1 year of nivolumab therapy were randomized to either continue or stop treatment, with 
the option of retreatment upon progression. Among 163 participants still on treatment at 1 year 
and without progression, those who were randomized to continue nivolumab had significant 
improvement in PFS compared with those who were randomized to stop treatment, with median 
PFS (post-randomization) not reached versus 10.3 months, respectively (HR = 0.42, 95% 
confidence interval [CI], 0.25 to 0.71). With a median follow-up of 14.9 months post-
randomization, there also was a trend for participants on continued treatment to live longer (OS 
HR = 0.63, 95% CI, 0.33 to 1.20). Of note, the PFS curves in both groups plateau approximately 
1 year after randomization (ie, 2 years after treatment initiation), suggesting that there may be 
minimal benefit in extending treatment beyond a total of 2 years.25
Collectively, these data suggest that there is minimal, if any, benefit derived from continuing I-O 
treatment beyond 2 years in advanced tumors. However, though immunotherapy can be well 
tolerated, participants will be at risk for additional toxicity with longer-term treatment. Therefore, 
in this study, treatment will be given for a maximum of 2 years from the start of study treatment.
5.5
Justification for Immunotherapy Dose(s)
Two BMS-986315 doses, 450 mg Q3W and 900 mg Q3W, were selected to be evaluated in co-
administration with nivolumab 360 mg Q3W plus chemotherapy.
 
. 
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In addition, both immunotherapy drugs will be co-administered as a single IV infusion. The PK 
and 
 
 
PK samples will be collected for BMS-986315. 
Nivolumab pre-dose samples will be collected until the end of the 2-year treatment period and end 
of infusion (EOI) samples up to Cycle 5.
5.5.1
Nivolumab
Nivolumab PK has been extensively studied in multiple tumor types, including melanoma, 
NSCLC, RCC, classical Hodgkin’s lymphoma, squamous cell cancer of the head and neck, 
colorectal cancer, and urothelial carcinoma, and has been safely administered at doses up to 
10 mg/kg Q2W. Nivolumab monotherapy was originally approved as a body weight-based dose 
of 3 mg/kg Q2W and was updated to 240 mg Q2W, 360 mg Q3W, or 480 mg Q4W in various
indications.26 Less frequent 360 mg Q3W and 480 mg Q4W dosing regimens can reduce the 
burden to participants of frequent, lengthy IV treatments and allow the combination of nivolumab 
with other agents using alternative dosing regimens.
5.5.2
BMS-986315 
Based on the totality of available data (eg, safety, PK, and pharmacodynamic [PD]) from 
preclinical murine studies and dose escalation of BMS-986315 as monotherapy and in combination 
with nivolumab in Study CA047004, 2 doses of BMS-986315 (450 mg Q3W and 900 mg Q3W) 
were selected to be evaluated with nivolumab 360 mg Q3W and chemotherapy in the proposed 
study, CA0471009. The 2 selected dosing regimens have adequate exposure separation to evaluate 
the differences between the dosing regimens. Both BMS-986315 and nivolumab will be co-
administered as a single IV infusion. 
In the ongoing study, CA047004, the highest dosing regimen currently evaluated is 
mg
 
as monotherapy and in combination with nivolumab 
 mg
. This dosing regimen was 
considered tolerable with no observed DLTs. 
 
 
 
The geometric means of maximum observed serum concentration (Cmax) and AUC appear to 
increase dose proportionally. A linear extrapolation was used to estimate the equivalent Q3W 
doses using the PK data from CA047004.
In addition, preclinical data were utilized to aid in the selection of these two dosing regimens. An 
integrated analysis of all available PK/ receptor occupancy (RO)/antitumor efficacy data in mouse 
syngeneic models was conducted. 
 
 
 
 
 
 
 
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5.6
Rationale for Exploratory Biomarker Research
 
 To evaluate 
the mechanism of action of BMS-986315 in combination with nivolumab and chemotherapy and 
explore potential pharmacodynamic and predictive markers for clinical response, comprehensive 
blood- and tumor-based patient selection and PD biomarker assessments are planned in this study. 
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Baseline and pharmacodynamic measures may also be correlated to clinical outcomes. All relevant 
PD data collected, which display a change from baseline, and their associations with PK may be 
explored in PK/PD analysis to derive a quantitative relationship. The biomarker data may also be 
evaluated for associations with efficacy, safety, and/or select AEs. 
Biomarker samples may also be used for research to develop methods, assays, prognostics, and/or 
diagnostics.
Digital imaging samples including CT/MRI scans will be used for research related to treatment 
efficacy using more advanced image analysis techniques.
5.7
Rationale for Optional Future Research
Future research may be performed using residual samples originally collected for another test 
required in this study from consented participants only. Future research is intended to allow for 
research aimed at emergent or future questions that are not addressed elsewhere in the protocol 
and may include research that is unrelated to the study intervention(s) and/or disease under study. 
 
 
 
 Such future research may also lead to the 
development of new diagnostic tests. The participant’s decision to participate in this optional 
future research will not impact his/her ability to participate in the main study.
6
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
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6.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1) Signed Written Informed Consent
a) Participants must have signed and dated an Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC)-approved written informed consent form (ICF) in accordance with 
regulatory, local, and institutional guidelines. This must be obtained before the 
performance of any protocol-related procedures that are not part of normal patient care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
and laboratory testing.
2) Type of Participant and Target Disease Characteristics
a) Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1 at screening and 
confirmed prior to randomization.
b) Participants must have a life expectancy of at least 3 months at the time of first dose.
c) Participants must have histologically confirmed NSCLC per the 8th International 
Association for the Study of Lung Cancer classification of squamous or non-squamous 
histology with Stage IV or recurrent disease following multimodal therapy for locally 
advanced disease.
d) No prior systemic anti-cancer treatment (including tyrosine kinase inhibitors) given as 
primary therapy for advanced or metastatic disease.
e) Prior definitive chemoradiation for locally advanced disease is permitted as long as the last 
administration of chemotherapy or radiotherapy (whichever was given last) occurred at 
least 6-months prior to enrollment.
f)
Prior adjuvant or neoadjuvant chemotherapy for early-stage lung cancer is permitted if 
completed at least 6-months prior to initiating study treatment.
g) Prior palliative radiotherapy to non-central nervous system (CNS) lesions must have been 
completed at least 2 weeks prior to treatment. Participants with symptomatic tumor lesions 
at baseline that may require palliative radiotherapy within 4 weeks of first treatment are 
strongly encouraged to receive palliative radiotherapy prior to treatment.
h) Participants must have measurable disease by CT or MRI per Response Evaluation Criteria 
in Solid Tumors (RECIST) v1.1 (Appendix 7).
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i)
Target lesions may be located in a previously irradiated field if there is documented 
radiographic disease progression in that site after the completion of radiation therapy.
3) Age of Participant
a) Participant must be 18 years old or local age of majority inclusive at the time of signing 
the ICF.
4) Reproductive Status
Investigators shall counsel women of childbearing potential (WOCBP), and male participants 
who are sexually active with WOCBP, on the importance of pregnancy prevention, the 
implications an unexpected pregnancy, and 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.
The investigator shall evaluate the effectiveness of the contraceptive method in relationship to 
the first dose of study intervention.
Local laws and regulations may require the use of alternative and/or additional contraception
methods.
−
Female Participants:
♦Women of childbearing potential (WOCBP) must have a negative highly sensitive
serum or urine pregnancy test (minimum sensitivity of 25 IU/L or equivalent units of 
human chorionic gonadotrophin) within 24 hours prior to the first dose of study drug.
♦If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive
♦Additional requirements for pregnancy testing during and after study intervention are 
in Section 2 Schedule of Activities.
♦The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy
♦Women who are not of childbearing potential (see Appendix 4) are exempt from 
contraceptive requirements.
♦WOCBP must agree to follow instructions for method(s) of contraception as described 
below and included in the ICF.
♦WOCBP are permitted to use hormonal contraception methods. 
♦A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least 1 of the following conditions applies: (1) Is not a WOCBP OR (2) Is a WOCBP 
and using a contraceptive method that is highly effective (failure rate of <1% per year), 
for the duration of treatment with BMS-986315 and nivolumab plus 5 months after last 
dose of these immunotherapies. A female participant who is a WOCBP must use a 
contraceptive method that is highly effective (failure rate of < 1% per year), for the 
duration of chemotherapy plus 7 months after last dose of chemotherapy (applicable to 
paclitaxel, pemetrexed, and carboplatin) or a total of 14 months after the last dose of 
cisplatin, or a duration specified by the local labels of the chemotherapy drugs received, 
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whichever is longer; and agrees not to donate eggs (ova, oocytes) for the purpose of 
reproduction for the same time period as contraception requirements listed above.
♦Female participants who are not WOCBP must have documented proof that they are 
not of childbearing potential.
−
Male Participants:
♦Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception as described below and included in the ICF.
♦Male participants are required to use a condom during the intervention period and for 
at least 6-months after the last chemotherapy (applicable to paclitaxel, pemetrexed, and 
carboplatin) dose of study intervention (or a total of 11 months for male participants 
receiving cisplatin), whichever is longer.
♦Male participants with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile vaginal intercourse or use a male condom during each episode of 
penile penetration during the intervention period and for at least 6-months after the last
chemotherapy (applicable to paclitaxel, pemetrexed, and carboplatin) dose of study 
intervention (or a total of 11 months for male participants receiving cisplatin), 
whichever is longer.  
♦Male participants must refrain from donating sperm during the intervention period and 
for at least 6-months after the last chemotherapy (applicable to paclitaxel, pemetrexed, 
and carboplatin) dose (or a total of 11 months for male participants receiving cisplatin), 
whichever is longer. 
♦Azoospermic males are not exempt from contraceptive requirements and will be 
required to always use a latex or other synthetic condom during any sexual activity 
(eg, vaginal, anal, oral) with WOCBP, even if the participant has undergone a 
successful vasectomy or if the partner is pregnant.
♦Female partners of male participants should be advised to use a highly effective method 
of contraception during the study intervention period and for at least at least 6-months 
after the last chemotherapy (applicable to paclitaxel, pemetrexed, and carboplatin) dose 
of study intervention (or a total of 11 months for male participants receiving cisplatin), 
whichever is longer.
♦Breastfeeding partners, should be advised to consult their health care providers about 
using appropriate highly effective contraception during the time the participant is 
required to use condoms.
5)
6.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
6) Medical Conditions
a) Mutation Status:
i.
Epidermal growth factor receptor (EGFR) mutations which are sensitive to 
available targeted inhibitor therapy (including, but not limited to, deletions in exon 
19 and exon 21 [L858R] substitution mutations) are excluded. 
 
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ii.
ALK receptor tyrosine kinase (ALK) and ROS proto-oncogene 1 (ROS1)
translocations which are sensitive to available targeted inhibitor therapy are 
excluded. All participants with NSQ histology must have been tested for ALK and 
ROS1 mutation status; use of an FDA-approved or local Health Authority-approved
test is strongly encouraged. 
 
iii.
Participants with other known gene mutations, including NTRK fusion, MET exon 
14 skipping mutation, B-Raf proto-oncogene (BRAF) V600E mutation, or RET 
rearrangement, which are sensitive to available targeted inhibitor therapy are 
excluded. If the test status is unknown or indeterminate for these four genes, the 
participants are eligible.
b) Participants with primary CNS disease, or tumors with CNS metastases as the only disease 
site, will be excluded.
c) Participants with untreated CNS metastases, except for either of the following two 
situations:
(1) The CNS metastases are asymptomatic and do not require immediate treatment.
(2) The CNS metastases have been treated and participants have neurologically 
returned to baseline (except for residual signs or symptoms related to the CNS 
treatment). In addition, participants must have been either off corticosteroids or on 
a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent) for at least 
2 weeks prior to randomization. Brain imaging performed within 28 days prior to 
randomization must document radiographic stability of CNS lesions and should be 
performed after completion of any CNS-directed therapy. 
d) Participants with leptomeningeal metastases (carcinomatous meningitis.)
e) Participants with concomitant second malignancies (except history of prior early-stage 
basal/squamous cell skin cancer, or noninvasive or in situ cancers who have undergone 
definitive treatment) are excluded unless a complete remission was achieved at least 2 years 
prior to study entry, and no additional therapy is required or anticipated to be required 
during the study period.
f)
Participants with an active, known, or suspected autoimmune disease. Participants with 
type 1 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.
g) Conditions requiring systemic treatment with either corticosteroids > 10 mg daily (QD)
prednisone equivalents or other immunosuppressive medications within 14 days of study 
drug administration, except for adrenal replacement steroid doses > 10 mg QD prednisone 
equivalent in the absence of active autoimmune disease.
h) Prior organ allograft.
i)
Uncontrolled or significant cardiovascular disease.
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j)
Any positive test result for hepatitis B virus or hepatitis C virus (HCV) indicating presence 
of virus (eg, hepatitis B surface antigen [Australia antigen] positive, or hepatitis C antibody 
[anti-HCV] positive [except if HCV-ribonucleic acid (RNA) negative]).
k) Known 
human 
immunodeficiency 
virus 
(HIV) 
positive 
with 
an 
acquired 
immunodeficiency syndrome-defining opportunistic infection within the last year, or a 
current CD4 count <350 cells/μL. Participants with HIV are eligible if they have received 
antiretroviral therapy (ART) for at least 4 weeks prior to randomization as clinically 
indicated while enrolled on study and continue on ART as clinically indicated. CD4 counts 
and viral load of these participants should be monitored per standard of care by a local 
health care provider.
l)
Participants with serious or uncontrolled medical disorders.
m) Participants must have recovered from the effects of major surgery or significant traumatic 
injury at least 14 days before first treatment.
n) Participants with interstitial lung disease that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonary toxicity.
o) Participants with history of myocarditis, regardless of etiology.
p) Known medical condition that, in the investigator’s opinion, would increase the risk 
associated with study participation or study drug administration or interfere with the 
interpretation of safety results.
q) Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 
days for severe/critical illness and not recovered prior to first dose of study drug.
Note: Coronavirus disease 2019 (COVID-19) polymerase chain reaction (PCR) viral 
testing may be required prior to randomization based on specific country/regional 
guidelines, and the result of this testing may impact study participation. Testing results 
should be discussed with the Medical Monitor to confirm eligibility.
7) Tumor Tissue Requirements
 
8) Reproductive Status
a) Women who are breastfeeding.
b) Women who are pregnant.
9) Prior/Concomitant Therapy
a) Inability to comply with restrictions and prohibited treatments as listed in Section 7.7: 
Concomitant Therapy.
c) Treatment with anti-NKG2A agents.
d) Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, extensive non-palliative radiation therapy, or standard or investigational 
agents for the treatment of NSCLC.)
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e) Participants who have received a live/attenuated vaccine within 30 days before first 
treatment.
f)
Treatment with botanical preparations (eg, herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 2 
weeks prior to randomization/treatment. Refer to Section 7.7.1 for prohibited therapies.
g) Participants currently in other interventional trials, including those for COVID-19, may not 
participate in BMS clinical trials until the protocol-specific washout period is achieved. If 
a study participant has received an investigational COVID-19 vaccine or other 
investigational product designed to treat or prevent COVID-19 prior to screening, 
enrollment must be delayed until the biologic impact of the vaccine or investigational 
product is stabilized, as determined by discussion between the investigator and the Medical 
Monitor.  
10) Physical and Laboratory Test Findings
a) Participants with ≥Grade 2 peripheral neuropathy.
b) Left ventricular ejection fraction (LVEF) assessment with documented LVEF < 50% by 
either transthoracic echocardiogram (TTE) or multiple gated acquisition (MUGA) scan 
(TTE preferred test) within 6-months prior to start of study treatment. 
c) White blood cells < 2000/μL (SI units: < 2× 109/L). 
Note: If white blood cells > upper limit of normal (ULN), investigations and clinical work-
up (eg, chest X-ray, C-reactive protein [CRP], procalcitonin, blood and urine culture) for 
presence of sub-clinical or clinical infection, and antibiotic treatment as needed, is 
recommended prior to randomization. All active infections diagnosed must resolve to 
baseline prior to first dose of study treatment.
d) Absolute neutrophil count (ANC) < 1500/μL (SI units: < 1.5× 109/L).
Note: If ANC > ULN, investigations and clinical work-up (eg, chest X-ray CRP, 
procalcitonin, blood and urine culture) for presence of sub-clinical or clinical infection, and 
antibiotic treatment as needed, is recommended prior to randomization. All active 
infections diagnosed must resolve to baseline prior to first dose of study treatment.
e) Platelets < 100,000/μL (SI units: < 100× 109/L).
f)
Hemoglobin < 9.0 g/dL (SI units: < 90 g/L).
g) Creatinine clearance (CrCl) < 50 mL/min (measured or calculated using the Cockcroft-
Gault formula).
h) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT): > 3.0 x ULN (>5× 
ULN if liver metastases are present).
i)
Total bilirubin (TB) > 1.5× ULN (except participants with Gilbert syndrome who must 
have a TB level of < 3.0× ULN).
11) Allergies and Adverse Drug Reactions
a) History of allergy or hypersensitivity to study drug components.
b) Any contraindication to any of the study drugs. Investigators should refer to local package 
insert or summary of product characteristics (SmPC).
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12) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: Under certain specific 
circumstances and only in countries where local regulations permit, a person who has been 
imprisoned may be included or permitted to continue as a participant. Strict conditions 
apply, and Sponsor approval is required.)
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
c) Any other serious or uncontrolled medical disorder, active infection, physical exam 
finding, laboratory finding, altered mental status, or psychiatric condition that, in the 
opinion of the investigator, would limit a participant's ability to comply with the study 
requirements, substantially increase risk to the participant, or impact the interpretability of 
study results.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study
participants and that the results of the study can be used. It is imperative that participants fully
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently randomized in the study/included in the analysis population. 
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, as applicable, and to respond to queries from regulatory authorities. 
Minimal information includes date of consent, demography, screen failure details, eligibility 
criteria, and any serious adverse events (SAEs) that occurred following consent.
6.4.1
Re-testing During Screening or Lead-in Period
This study permits the re-enrollment of a participant who has discontinued the study as a screen 
failure (ie, participant has not been randomized/has not been treated). If re-enrolled, the participant
must be re-consented.
The most current result prior to randomization is the value by which study inclusion will be 
assessed because it represents the participant’s most current clinical state.
Laboratory parameters and/or assessments that are included in 
, Screening Procedural
Outline, may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
Testing for asymptomatic SARS-CoV-2 infection, for example by reverse transcription-
polymerase chain reaction (RT-PCR) or viral antigen, is not required. However, some participants 
may develop suspected or confirmed symptomatic SARS-CoV-2 infection or be discovered to 
have asymptomatic SARS-CoV-2 infection during the screening period.  In such cases, 
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participants may be considered eligible for the study after meeting all inclusion/exclusion criteria 
related to active infection, and after meeting the following criteria:
•
At least 10 days (20 days for severe/critical illness) have passed since symptoms first appeared 
or positive RT-PCR or viral antigen test result
•
At least 24 hours have passed since last fever without the use of fever-reducing medications
•
Acute symptoms (eg, cough, shortness of breath) have resolved 
•
In the opinion of the investigator, there are no COVID-19-related sequelae that may place the 
participant at a higher risk of receiving investigational treatment
•
Negative follow-up SARS-CoV-2 RT-PCR or viral antigen test based on institutional, local or 
regional guidelines
7
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo,
procedure(s), or medical device intended to be administered to a study participant according to the 
study protocol.
Study intervention includes both Investigational [Medicinal] Product (IP/IMP) and 
Non-investigational/Auxiliary [Medicinal] Product (Non-IP/Non-IMP/AxMP) as indicated in
Table 7.1-1.
An IP, also known as an IMP 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 
from the authorized form, used for an unauthorized indication, or when used to gain further 
information about the authorized form.
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis may be considered Non-
IMPs/AxMPs.
7.1
Study Interventions Administered
During Part 1 and Part 2, participants will receive one of the treatment regimens by arm described 
in Table 7.1-1 and Table 7.1-2. BMS-986315 will be administered in a blinded manner, while 
nivolumab and chemotherapy will be unblinded. Dose reductions are not permitted for 
immunotherapy study treatments.
The chemotherapy products used in this clinical trial are authorized and will be used in accordance 
with the terms of their marketing authorizations.
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Table 7.1-1:
Study Intervention(s) Administered
Type/
Intervention 
Name/
Dose 
Formulation
Unit Dose 
Strength(s)
IMP/Non-IMP/
AxMP
Blinded or 
Open-label Use
Sourcing
Packaging 
and Labeling
Current/
Former 
Name(s) or 
Alias(es)
BMS-986315 
Concentrate for 
Solution for 
Infusion
mg/mL
IMP, Open-label 
Part 1)
IMP, Blinded
(Part 2)
Centrally 
Provided by 
Sponsor
Vial (one or 
more vials per 
carton)
Anti-NKG2A
Nivolumab 
Solution for
Injection
10 mg/mL
IMP, Open-label
Centrally 
Provided by 
Sponsor
Vial (one or 
more vials per 
carton)
Opdivo
(BMS-
936558)
Pemetrexed 
Powder for 
Concentrate for 
Solution for 
Infusiona
500 mg per 
vial
IMP, Open-label
Centrally 
Provided by 
Sponsor/Locally 
Sourced by Study 
Site
Vial (one or 
more vials per 
carton)
Pemetrexed
Cisplatin 
Concentrate for 
Solution for 
Infusiona
1 mg/mL
IMP, Open-label
Centrally 
Provided by 
Sponsor/Locally 
Sourced by Study 
Site
Vial (one or 
more vials per 
carton)
Cisplatin
Carboplatin 
Concentrate for 
Solution for 
Infusiona
10 mg/mL
IMP, Open-label
Centrally 
Provided by 
Sponsor/Locally 
Sourced by Study 
Site
Vial (one or 
more vials per 
carton)
Carboplatin
Paclitaxel 
Concentrate for 
Solution for 
Infusiona
6 mg/mL
IMP, Open-label
Centrally 
Provided by 
Sponsor/Locally 
Sourced by Study 
Site
Vial (one or 
more vials per 
carton)
Paclitaxel
Abbreviations: IMP, Investigational Medicinal Product; Non-IMP/AxMP, Non-investigational/Auxiliary Medicinal 
Product; NKG2A, natural killer group 2 member A.
a These products may be obtained by the investigational sites as local commercial product in certain countries if 
allowed by local regulations. In these cases, products may be a different pack size/potency than listed in the table. 
These products should be prepared/stored/administered in accordance with the package insert or summary of product 
characteristics (SmPC).
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Table 7.1-2:
Study Arm(s)
Arm Title/Arm Type
Intervention Description/
Dosage Levels
Route of Administration
Part 1 Safety Lead-in: 
BMS-986315 450 mg Q3W
Nivolumab 360 mg Q3W
4 Cycles of Histology-based 
Chemotherapy Q3Wa
IV Infusion
Part 1 Safety Lead-in: 
BMS-986315 900 mg Q3W
Nivolumab 360 mg Q3W
4 cycles of Histology-based 
Chemotherapy Q3Wa
IV Infusion
Part 2: Arm A a
Nivolumab 360 mg Q3W
4 cycles of Histology-based 
Chemotherapy Q3W
IV Infusion
Part 2: Arm B a
BMS-986315 900 mg Q3W
Nivolumab 360 mg Q3W
4 cycles of Histology-based 
Chemotherapy Q3W
IV Infusion
Part 2: Arm C a
BMS-986315 450 mg Q3W
Nivolumab 360 mg Q3W
4 cycles of Histology-based 
Chemotherapy Q3W
IV Infusion
Abbreviations: AUC, area under the concentration-time curve; 
; IV, intravenous; Q3W: every 3 
weeks; SQ, squamous.
a Histology-based chemotherapy: NSQ (non-squamous): Carboplatin AUC 5 or 6 or cisplatin 75 mg/m2 + 
pemetrexed 500 mg/m2 (optional maintenance therapy with 500 mg/m2 Q3W pemetrexed alone). SQ: paclitaxel 
200 mg/m2 + carboplatin AUC 6.
7.1.1
Immunotherapy Dosing
Participants will receive nivolumab and BMS-986315, followed by chemotherapy on Day 1 of 
every 3-week cycle. In Part 1 and Part 2 Arms B and C, nivolumab will be co-administered with
BMS-986315 in a single bag IV over approximately 60 minutes. Arm A participants will receive 
nivolumab IV over 60 minutes. 
 
 
 
 Participants should be carefully monitored for infusion reactions during co-
administration. If an acute infusion reaction is noted, participant should be managed according to 
Section 7.4.7. The 4 cycles of chemotherapy will be administered in all arms per Section 7.1.2. At 
the time of completion of the 4 cycles of chemotherapy, participants who have not experienced 
disease progression will continue to receive immunotherapy Q3W starting on Day 1 of the 
following cycle:
•
There will be no dose escalations or reductions of immunotherapy allowed.
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•
Premedications are not recommended for the first dose of immunotherapy.
•
Participants should receive immunotherapy until progression, unacceptable toxicity, 
withdrawal of consent, completion of 2 calendar years (24 months) of treatment, or the study 
ends, whichever occurs first.
•
Doses of immunotherapy may be interrupted, delayed, or discontinued, depending on how well 
the participant tolerates the treatment according to Section 7.4.1.
•
Dosing visits must not be skipped, only delayed. See Section 7.4 and Section 8.1.
•
The assessment for discontinuation of immunotherapy should be made separately from the 
assessment to discontinue chemotherapy.
•
If criteria for discontinuation of immunotherapy are met, PDCT may continue until 4 cycles 
have been completed.
•
If criteria for discontinuation of PDCT are met, immunotherapy may continue until progression 
or unacceptable toxicity, whichever occurs first.
•
If a participant meets criteria for discontinuation and investigator is unable to determine 
whether the event is related to all or any 1 study drug, the participant should discontinue all 
study drugs and be taken off the treatment phase of the study.
The immunotherapy injections can be infused undiluted or diluted. If needed, infusions can be 
flushed with diluent to complete the dose and clear the line before starting the chemotherapy 
infusion(s).
The second infusion will always be the chemotherapy study drug(s) and will start after the infusion 
line has been flushed, filters changed, and the participant has been observed to ensure no infusion 
reaction has occurred. The time between immunotherapy and chemotherapy infusions is expected 
to be approximately 30 minutes but may be more or less depending on the situation. Instructions 
for dilution and infusion of immunotherapy injections will be provided in the Pharmacy Manual. 
Care must be taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent. For details on prepared drug storage, 
preparation, and administration, please refer to the IBs and/or Pharmacy Manual. The selection 
and timing of dose for each participant is provided in Table 7.1-2 Table 7.1-1 and Table 7.1-2.
7.1.2
Chemotherapy Dosing
In all 3 study arms, 4 cycles of the histology-based PDCT option selected by the investigator will 
be administered on Day 1 Q3W. Participants with NSQ histology may also receive optional 
maintenance therapy with 500 mg/m2 pemetrexed alone on Day 1 of each 3-week cycle until 
disease progression or unacceptable toxicity, or other reasons specified in the protocol (Section 
8.1.2).
Histology-based PDCT:
•
Squamous histology: Carboplatin AUC 6 + paclitaxel 200 mg/m2
•
Non-squamous histology: Carboplatin AUC 5 or 6 or cisplatin 75 mg/m2 + pemetrexed 500 
mg/m2 (optional maintenance therapy with 500mg/m2 Q3W pemetrexed)
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•
All chemotherapy agents’ preparation, premedication, administration, monitoring, and 
management of complications are to follow local prescription guidelines and regulations. The dose 
of chemotherapy may be capped per local standards.
Note:  The investigator must decide prior to randomization whether or not a participant with NSQ 
histology will receive cisplatin, if eligible.
7.1.2.1
Paclitaxel and Carboplatin
Participants will receive paclitaxel 200 mg/m2 as a 180-minute IV infusion with carboplatin at a 
dose of AUC 6 as a 30-minute IV infusion on Day 1 of a 3-week cycle, or at doses per the local 
prescribing information. The infusion time can follow local institutional standards.
Paclitaxel dosing calculations should be based on the body surface area calculation. The dose may 
remain the same if the participant’s weight is within 10% of the baseline weight or prior dose 
weight.
Carboplatin should be given following paclitaxel on Day 1 of each cycle, and the carboplatin dose 
will be calculated using the Calvert formula as follows:
Carboplatin dose (mg) = target AUC × (CrCl [mL/min] + 25)
CrCl calculation is based on the Cockcroft-Gault formula and should include the most recent serum 
creatinine and most recent weight. NOTE:  If calculation of the CrCl by the Cockcroft-Gault 
formula yields a result of > 125 mL/min, then a CrCl should be calculated by an alternative formula 
per institutional standards or capped at 125 mL/min.
The dose of carboplatin may be capped per local standards.
Premedications for use with paclitaxel include the following:
•
Oral or IV corticosteroid should be given according to local standard at a dose equivalent to 
dexamethasone 20 mg 12 hours and 6 hours prior to paclitaxel administration (oral or IV).
•
IV diphenhydramine (or its equivalent) 50 mg and H2-blocker (per local standard of care) 
should be administered 30 to 60 minutes prior to paclitaxel infusion.
•
Doses of paclitaxel and/or carboplatin may be interrupted, delayed, reduced, or discontinued,
depending on how well the participant tolerates the treatment.
•
7.1.2.2
Pemetrexed and Cisplatin
Pemetrexed dosing calculations should be based on the body surface area calculation. The dose 
may remain the same if the participant’s weight is within 10% of the weight used to calculate the 
previous dose.
Premedications for use with pemetrexed include the following:
•
Oral or IV corticosteroid should be given according to local standards at a dose equivalent to 
dexamethasone 4 mg twice daily (BID) on the day prior to, the day of, and the day after the 
administration of pemetrexed.
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•
Oral folic acid 350 to 1000 mcg daily should be given starting 1 week prior to the first dose of 
pemetrexed, with at least 5 doses of folic acid administered in the 7 days prior to the first dose. 
Oral folic acid should be continued daily throughout the treatment with pemetrexed and for 21 
days after the last dose of pemetrexed. Intramuscular (IM) injection of vitamin B12 1000 mcg 
should be given approximately 1 week prior to the first dose of pemetrexed and repeated every 
3 cycles thereafter during pemetrexed treatment. Subsequent injections of vitamin B12 may be 
given on the same day as pemetrexed (participant with NSQ histology may begin folic acid 
and vitamin B12 prior to randomization in anticipation of pemetrexed).
•
Antiemetic premedication will be administered according to local standards. Recommended 
antiemetic treatments are dexamethasone (dosing according to local standards; an equivalent 
dose of another corticosteroid may be substituted) and a 5-HT3 receptor antagonist (type per 
investigator discretion and local standards of care). Additional use of antiemetic 
premedications may be employed at the discretion of the investigator.
•
Participants will receive pemetrexed at a dose of 500 mg/m2 as a 10-minute IV infusion on Day 1
with cisplatin at a dose of 75 mg/m2 infusion as per local standard practice on Day 1 of a 3-week 
treatment cycle for up to 4 cycles.
Dosing calculations should be based on the body surface area calculation and may be capped per 
local standards. The dose may remain the same if the participant’s weight is within 10% of the 
baseline weight or prior dose weight.
Cisplatin will be administered to participants at least 30 minutes following the end of the 
pemetrexed infusion. Pretreatment hydration for cisplatin can follow local standard of care or use 
1 to 2 liters of fluid (per local standards) infused IV for 8 to 12 hours prior to cisplatin infusion
(recommended). Adequate hydration and urinary output must be maintained for at least 24 hours 
following cisplatin administration. Administration and monitoring should be performed according 
to local standards. Use of mannitol following the cisplatin infusion should also follow local 
standards of care.
Doses of pemetrexed and/or cisplatin may be interrupted, delayed, reduced, or discontinued,
depending on how well the participant tolerates the treatment. See Section 7.4.2, Section 7.4.3, 
and Section 8.1 for more details.
All participants who will receive cisplatin should have audiometric testing performed prior to 
initiation of therapy and prior to subsequent doses of cisplatin, or as per local standards of care.
Participants who discontinue cisplatin alone may, at the investigator’s discretion, be switched to 
pemetrexed/carboplatin for the remainder of the PDCT (up to 4 cycles in total). Dosing for 
pemetrexed/carboplatin for such participants should follow the instructions in Section 7.1.2.3.
7.1.2.3
Pemetrexed and Carboplatin
Pemetrexed dosing calculations should be based on the body surface area calculation. The dose 
may remain the same if the participant’s weight is within 10% of the weight used to calculate the 
previous dose.
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Premedications for use with pemetrexed:
•
Oral or IV corticosteroid premedication for pemetrexed should be given according to local 
standards at a dose equivalent to dexamethasone 4 mg BID on the day prior to, the day of, and 
the day after the administration of pemetrexed.
•
Oral folic acid 350 to 1000 mcg daily should be given starting 1 week prior to the first dose of 
pemetrexed, with at least 5 doses of folic acid administered in the 7 days prior to the first dose. 
Oral folic acid should be continued daily throughout the treatment with pemetrexed and for 21 
days after the last dose of pemetrexed. IM injection of vitamin B12 1000 mcg should be given 
approximately 1 week prior to the first dose of pemetrexed and repeated every 3 cycles 
thereafter during pemetrexed treatment. Subsequent injections of vitamin B12 may be given 
on the same day as pemetrexed (participant with NSQ histology may begin folic acid and 
vitamin B12 prior to randomization in anticipation of pemetrexed).
•
Participants will receive pemetrexed at a dose of 500 mg/m2 as a 10-minute IV infusion on Day 1, 
followed by carboplatin at a dose of AUC 5 or 6 as a 30-minute IV infusion on Day 1 of a 3-week 
treatment cycle, for up to 4 cycles.
Pemetrexed dosing calculations should be based on the body surface area calculation. The dose 
may remain the same if the participant’s weight is within 10% weight used to calculate the previous 
dose.
The carboplatin dose will be calculated using the Calvert formula as follows:
Carboplatin dose (mg) = Target AUC × (CrCl [mL/min] + 25)
CrCl calculation is based on the Cockcroft-Gault formula (see inclusion criterion in Section 6.1) 
and should include the most recent serum creatinine and most recent weight. NOTE: If calculation 
of the CrCl by the Cockcroft-Gault formula yields a result of > 125 mL/min, then a CrCl should 
be calculated by an alternative formula per institutional standards or capped at 125 mL/min.
Doses of pemetrexed and/or carboplatin may be interrupted, delayed, reduced, or discontinued,
depending on how well the participant tolerates the treatment. All chemotherapy agents’ 
preparation, premedication, administration, monitoring, and management of complications are to 
follow local prescription guidelines and regulations. The dose of chemotherapy may be capped per 
local standards.
7.1.2.4
Optional Continuation Maintenance
After Cycle 4 of chemotherapy, participants with NSQ histology who have SD or response are 
permitted to receive pemetrexed 500 mg/m2 Q3W alone as maintenance therapy until disease 
progression, unacceptable toxicity, or the maximum duration of treatment (2 years) has been 
reached.
7.2
Assignment to Study Intervention
After the participant’s initial eligibility is established and informed consent has been obtained, the 
participant must be enrolled into the study via the Interactive Response Technology (IRT). Specific 
instructions for using IRT will be provided to the investigational site in a separate document. The 
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investigator or designee will register the participant for enrollment by following the enrollment 
procedures established by BMS. The following information is required for enrollment:
•
Date that informed consent was obtained
•
Date of birth (specifically the year of birth)
•
All eligible participants will be initially assigned to Part 1 (Safety Lead-in) until the decision is 
made to start Part 2.
Once enrolled in IRT, enrolled participants who have met all eligibility criteria will be randomized 
through IRT. The following information is required for participant randomization:
•
Participant number
•
Date of birth (specifically the year of birth)
•
Gender
•
Histology (SQ or NSQ)
−
Participants with mixed histology should be classified according to the predominant
histology
−
Participants with adenosquamous histology should be classified as NSQ histology
7.3
Blinding
Part 1 of the study is an open-label safety lead-in with no randomization. 
Part 2 is a randomized, double-blind study. 
 
 
Access to treatment codes will be restricted from all participants and site and 
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BMS personnel or their designee prior to primary database lock or the decision to unblind the 
study. 
If program-wide decision(s), including but not limited to, regulatory interactions, requires further 
discussion for the IA results, restricted study team members will be unblinded to the study data to 
support the discussion. Site-facing Sponsor personnel will not be unblinded to maintain study 
integrity. Personnel who will have the access to the IA results to support these activities will be 
documented in the trial master file prior to access of the results.
Blinding of study intervention assignment is critical to the integrity of this clinical study. However, 
in the event of a medical emergency or pregnancy in an individual participant in which knowledge 
of the IP is critical to the participant’s management, the blind for that participant may be broken 
by the investigator. The participant’s safety takes priority over any other considerations in 
determining whether a treatment assignment should be unblinded.
Before breaking the blind of an individual participant’s treatment, the investigator should 
determine that the unblinded information is necessary (ie, that it will alter the participant’s 
immediate management). In many cases, particularly when the emergency is clearly not related to 
the IP, the problem may be properly managed by assuming that the participant is receiving the IP. 
It is highly desirable that the decision to unblind treatment assignment be discussed with the 
Medical Monitor, but the investigator always has ultimate authority for the decision to unblind. 
The actual task of unblinding can be delegated by the investigator to a designee assigned the task 
on the Delegation of Authority. The Principal Investigator or appointed designee should only 
perform the emergency unblinding after the decision to unblind the participant has been 
documented.
For this study, the method of unblinding for emergency purposes is by IRT transaction by which 
the site users can unblind a participant in the event of an emergency. Please consult the IRT manual 
for further information on how to unblind in an emergency. 
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind.
Any request to unblind a participant for non-emergency purposes should be discussed with the 
Medical Monitor.
The designated staff of BMS may be unblinded (obtain the randomization codes) prior to database 
lock to facilitate the bioanalytical analysis of PK samples and immunogenicity. A bioanalytical 
scientist in the Bioanalytical Sciences department of BMS (or a designee in the external central 
bioanalytical laboratory) will be unblinded to (may obtain) the randomized treatment assignments 
in order to minimize unnecessary bioanalytical analysis of samples. 
7.4
Dosage Modification
No dose reductions or escalations for immunotherapy are permitted.
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7.4.1
Dose Modification Criteria for Immunotherapy
All AEs/SAEs must be graded using Common Terminology Criteria for Adverse Events (CTCAE) 
v5. 
The criteria for dose delay, resumption, and discontinuation for immunotherapy have been 
integrated to apply to immunotherapy treatment with either nivolumab or nivolumab plus BMS-
986315, henceforth referred to as immunotherapy. Delay immunotherapy dosing for any AE, 
laboratory test result abnormality, or intercurrent illness which, in the judgment of the investigator, 
warrants delaying the dose of study medication. Specific management guidelines (dose delay, 
resumption, and discontinuation) for expected AEs and SAEs for nivolumab and nivolumab + 
BMS-986315 combination therapy can be found in 
. Additional information on 
management of AEs and SAEs nivolumab and nivolumab + BMS-986315 combination therapy is 
found in Appendix 6:
For participants who require delay of immunotherapy, re-evaluate weekly, or more frequently, if 
clinically indicated, and resume dosing when criteria to resume treatment are met (see 
Section 7.4.4). Continue tumor assessments per protocol even if dosing is delayed. The decision 
for immunotherapy dose delay, resumption, and discontinuation should apply to both nivolumab 
and BMS-986315 in participants receiving nivolumab + BMS-986315 combination therapy.
The assessment for dose delays of immunotherapy should be made separately from the assessment 
to delay chemotherapy.
Study treatment must also be delayed for SARS-CoV-2 infection, either confirmed or suspected.
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7.4.2
Dose Delay Criteria for Chemotherapy
Chemotherapy drugs should be delayed for any of the events listed below. The delay should occur 
on treatment Day 1 
•
Absolute neutrophil count (ANC) < 1500/μL (SI units: < 1.5 × 109/L)
•
Platelets < 100,000/μL (SI units: < 100 × 109/L)
•
Any Grade ≥ 2 non-skin, non-hematologic, drug-related AE (excluding Grade 2 alopecia, 
Grade 2 fatigue, and Grade 2 laboratory test result abnormalities (abnormality))
•
Any Grade ≥ 3 skin, drug-related AE
•
Any Grade ≥ 3 drug-related laboratory abnormality, with the following exceptions for
lymphopenia, AST, ALT, or TB:
−
Grade 3 lymphopenia does not require dose delay.
−
Delay dosing if AST or ALT increases to > 3x and ≤ 5x upper limit of normal (ULN) or 
Tbili increases to > 1.5x and ≤ 3x ULN, regardless of baseline value.
−
In participants with liver metastasis, delay dosing if (1) Baseline AST/ALT is >1x and ≤3x 
ULN and increases to >5x and ≤10x ULN; (2) Baseline AST/ALT is >3x and ≤5x ULN 
and increases to >8x and ≤10x ULN
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the investigator, 
warrants delaying the dose of study medication. Investigators should consult local labeling for the 
chemotherapy drugs being administered to any given participant for additional guidance on dose 
delays.
Dose modifications listed are specific to US Prescribing Information (USPI). Variations may apply 
per local label. Participants receiving cisplatin with pemetrexed must discontinue cisplatin if the 
calculated CrCl decreases to < 50 mL/min (based on the Cockcroft-Gault formula). The other drug 
(pemetrexed) may be continued, and the platinum agent may, at the investigator’s discretion, be 
switched to carboplatin for the rest of the cycles when the participant meets re-treatment criteria. 
Note that pemetrexed can only be administered if CrCl is ≥45 mL/min (calculated per Cockcroft 
Gault formula).
If a participant receiving carboplatin with paclitaxel must discontinue carboplatin, paclitaxel may 
be continued at the investigator’s discretion.
If any non-hematologic AE meeting the dose delay criteria above is felt to be related to only 
1 particular agent in the PDCT regimen, then that agent alone may be omitted for that cycle while 
the other agent is given. In order to maintain synchronized dosing of the regimen, the omitted
agent should be resumed with the next scheduled cycle once the AE has improved and re-
treatment criteria are met. Please refer to Section 7.4.3.2 to determine if dose reduction of the 
resumed agent is required.
If both drugs in the PDCT regimen are delayed, then the participant should be re-evaluated
weekly or more frequently if clinically indicated until re-treatment criteria are met (as per
Section 7.4.4.2).
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Study treatment must also be delayed for SARS-CoV-2 infection, either confirmed or suspected.
Dosing of immunotherapy and both chemotherapy agents should be delayed if any criteria for
immunotherapy or both PDCT agents are met.
7.4.3
Dose Reductions
7.4.3.1
Dose Reduction for Immunotherapy
No dose reductions for immunotherapy are permitted.
7.4.3.2
Dose Reduction for Chemotherapy
Dose reductions for chemotherapy may be required and will be performed according to Section 
7.4.2 or per institutional guidelines. Chemotherapy dose reductions are permanent; once the dose
of any chemotherapy agent is reduced, it may not be re-escalated in subsequent cycles, except 
as noted when starting pemetrexed maintenance therapy. The dose reductions for each agent
in the PDCT regimen are not linked and may be adjusted independently as summarized in Table 
7.4.3.2-1.
Table 7.4.3.2-1:
Dose Reduction for Chemotherapy
Dose Level
Carboplatin
Pemetrexed
Paclitaxel
Cisplatin
Starting dose
AUC 6 or AUC 5
500 mg/m2
200 mg/m2
75 mg/m2
First dose 
reduction
AUC 5 (if starting dose is AUC 6) or AUC 
4 (if starting dose is AUC of 5)
375 mg/m2
150 mg/m2
56 mg/m2
Second dose 
reduction
AUC 4 (if starting dose is AUC 6) or AUC 
3 (if starting dose is AUC 5)
250 mg/m2
100 mg/m2
38 mg/m2
Third dose 
reduction
Discontinue
Discontinue
Discontinue
Discontinue
Abbreviation: AUC, area under the concentration-time curve.
Dose modifications listed are specific to US prescribing information (USPI). Variations may apply 
per local label.
Any participant with 2 prior dose reductions for 1 agent who experiences a toxicity that would 
cause a third dose reduction must be discontinued from that agent.
7.4.3.3
Chemotherapy: Dose Reductions for Hematologic Toxicity
Dose modifications for hematologic toxicities (according to CTCAE v5) are summarized in Table 
7.4.3.3-1. Dose adjustments are based on nadir blood counts (assessed as per local standards) since 
the preceding drug administration. Dose level adjustments for PDCT are relative to that of the 
preceding administration. Generally, both chemotherapy agents in the PDCT regimen should be 
dose reduced together for hematologic toxicity. After the first cycle, growth factors may be used 
to assist hematologic recovery. For incidences of chemotherapy-induced anemia or cancer-
associated anemia, red blood cell transfusions are recommended. In participants who refuse RBC 
transfusions, erythropoiesis-stimulating agents may be administered as per local standards.
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Use local standards of care for other previously described supportive measures. Additionally, 
prophylactic antibiotics may be used according to local standards of care. Investigators are strongly 
recommended to have a high index of suspicion for infection and consider starting broad spectrum 
antibiotics early for any fever or signs of infection in participants with neutropenia. Please report 
any antibiotic or growth factor use on the electronic Case Report Form (eCRF).
Dose modifications listed are specific to USPI. Variations may apply per local label.
Table 7.4.3.3-1:
Dose Modifications for Hematologic Toxicity (Based on Nadir 
Counts)
Toxicity
Carboplatin
Paclitaxel
Pemetrexed
Cisplatin
Neutrophil Count Decreased
Grade 4
(< 500/mm3 or < 0.5 × 109/L)
Reduce
1 dose level
Reduce
1 dose level
Reduce
1 dose level
Reduce
1 dose level
Platelet Count Decreased
Grade 3
(< 50,000 - 25,000/mm3;< 50.0 - 25.0 × 109/L)
Reduce
1 dose level
Reduce
1 dose level
Reduce
1 dose level
Reduce
1 dose level
Grade 4
(< 25,000/mm3; < 25.0 × 109/L)
Reduce
1 dose level
Reduce
1 dose level
Reduce
1 dose level
Reduce
1 dose level
7.4.3.4
Chemotherapy: Dose Reductions for Non-hematologic Toxicities
Dose adjustments for chemotherapy for non-hematologic toxicities during treatment are described 
in Section 7.4.3.2. All dose reductions should be made based on the worst-grade toxicity. 
Participants experiencing any of the toxicities during the previous cycle should have chemotherapy 
delayed until retreatment criteria are met, and then reduced for all subsequent cycles by 1 dose 
level or discontinued as appropriate. Dose levels for the 2 drugs in the PDCT regimen are not 
linked and may be reduced independently, as summarized.
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Table 7.4.3.4-1:
Dose Adjustments for Chemotherapy for Non-hematologic Toxicities
Toxicity
Carboplatin
Paclitaxel
Pemetrexed
Cisplatin
Febrile neutropenia
Grade ≥ 3
Reduce 1 dose level
Reduce 1 dose level
Reduce 1 dose level
Reduce 1 dose level
Diarrhea
Grade ≥ 3
No change
Reduce 1 dose level
Reduce 1 dose level
No change
Allergic reactiona
Grade ≥ 3
Discontinue
Discontinue
Discontinue
Discontinue
Neuropathy
Grade 2
Reduce 1 dose level
Reduce 1 dose level
No change
Reduce 1 dose level
Neuropathy
Grade 3-4
Discontinue
Discontinue
Discontinue
Discontinue
CrCl < 50 mL/min
No change
Discontinue if CrCl < 20 
mL/ min
No change
Discontinue
Other Grade ≥ 3 toxicity
(except for fatigue and transient arthralgia 
and myalgia)
Adjust as medically 
indicated
Adjust as medically 
indicated
Adjust as medically 
indicated
Adjust as medically 
indicated
Abbreviations: CrCl, creatinine clearance; USPI, US Prescribing Information.
a Only the drug(s) causing the hypersensitivity reaction or acute infusion reaction (≥ Grade 3) require(s) discontinuation. All other drugs may be continued.
Note: Dose modifications listed are specific to USPI. Variations may apply per local label.
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7.4.4
Criteria to Resume Dosing
7.4.4.1
Criteria to Resume Treatment with Immunotherapy
Participants may resume treatment with study drug if they have completed AE management 
(ie, corticosteroid taper) or are on ≤ 10 mg prednisone or equivalent and meet the requirements per 
. 
Participants with SARS-CoV-2 infection (either confirmed or suspected) may resume treatment 
after all of the following: 1) at least 10 days (20 days for severe/critical illness) have passed since 
symptoms first appeared or positive test result (eg, RT-PCR or viral antigen); 2) resolution of acute 
symptoms (including at least 24 hours have passed since last fever without fever-reducing
medications), 3) evaluation by the investigator with confirmation that there are no sequelae that 
would place the participant at a higher risk of receiving investigational treatment, and
4) consultation by the Medical Monitor. For suspected cases, treatment may also resume if 
SARS-CoV-2 infection is ruled out and other criteria to resume treatment are met.
Prior to re-initiating treatment in a participant with a dosing delay lasting > 8 weeks, the Medical 
Monitor (or designee) must be consulted. Continue tumor assessments per protocol even if dosing 
is delayed. Continue periodic study visits to assess safety and laboratory studies every 8 weeks or 
more frequently if clinically indicated during such dosing delays.
7.4.4.2
Criteria to Resume Treatment with Chemotherapy
Participants may resume treatment with chemotherapy when the ANC returns to ≥ 1500/μL 
(SI units: ≥ 1.5 × 109/L), the platelet count returns to ≥ 100,000/μL (SI units: ≥ 100 × 109/L), and 
all other drug-related toxicities have returned to baseline or Grade 1 (or Grade 2 for alopecia and 
fatigue).
If a participant fails to meet criteria for re-treatment, then re-treatment should be delayed, and the 
participant should be re-evaluated weekly or more frequently as clinically indicated. Any 
participant who fails to recover from toxicity attributable to chemotherapy to baseline or Grade 1 
(except Grade 2 alopecia and fatigue) within 6 weeks from the last dose given should discontinue 
the drug(s) that caused the delay.
When resuming chemotherapy treatment, please follow the dose-reduction recommendations in 
Section 7.4.3.2.
Participants with SARS-CoV-2 infection (either confirmed or suspected) may resume treatment 
after all of the following: 1) at least 10 days (20 days for severe/critical illness) have passed since 
symptoms first appeared or positive test result (eg, RT-PCR or viral antigen); 2) resolution of acute 
symptoms (including at least 24 hours passed since last fever without fever reducing medications), 
3) evaluation by the investigator with confirmation that there are no sequelae that would place the 
participant at a higher risk of receiving investigational treatment, and 4) consultation by the 
Medical Monitor. For suspected cases, treatment may also resume if SARS-CoV-2 infection is 
ruled out and other criteria to resume treatment are met.
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7.4.5
Management Algorithms for Immuno-Oncology Agents
I-O agents are associated with AEs that can differ in severity and duration than AEs caused by 
other therapeutic classes. Nivolumab and BMS-986315 are considered IO agents in this protocol. 
Because of the potential for clinically meaningful TRAEs requiring early recognition and prompt 
intervention, management algorithms have been developed to assist investigators in assessing and 
managing the following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary (note for participants with dyspnea, complete blood count should be measured)
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
•
Myocarditis
•
•
The above algorithms are included in Appendix 6 of this protocol.
7.4.6
Dose-limiting Toxicities
For the purpose of guiding decisions regarding dose escalation in Part 1 (Safety Lead-in), DLTs 
will be defined based on the incidence, intensity, and duration of the AEs for which no clear 
alternative cause is identified and will exclude events clearly related to disease progression or 
intercurrent illness.
Participants experiencing a DLT that is attributed to immunotherapy alone will be allowed to stop 
immunotherapy (both nivolumab and BMS-986315) and continue chemotherapy. Participants who 
withdraw from the study during the DLT evaluation period for reasons other than a DLT may be 
replaced with a new participant at the same dose level.
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•
Safety lead-in participants should discontinue treatment if they experience any adverse event, 
laboratory abnormality, or intercurrent illness (regardless of causality) which, in the opinion of the 
investigator, presents a substantial clinical risk to the participant with continued immunotherapy 
with or without chemotherapy. Such discontinuation, however, will not be considered a DLT 
unless it meets at least one of the DLT criteria defined above. Treatment delay, dose modifications, 
and discontinuation criteria (Section 7.4) are to be followed for the management of safety lead-in 
participants.
7.4.7
Treatment of Immunotherapy Infusion Reactions
Since nivolumab and BMS-986315 contain only human immunoglobulin protein sequences, they 
are unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if 
such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion 
reactions should be reported within 24 hours to the BMS Medical Monitor and reported as an SAE 
if criteria are met. Infusion reactions should be graded according to National Cancer 
Institute (NCI) CTCAE v5 guidelines. 
Treatment recommendations are provided below and may be modified based on local treatment
standards and guidelines, as appropriate:
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not
indicated):
Remain at bedside and monitor participant until recovery from symptoms. The following
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg (or
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equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before
additional immunotherapy administrations.
For Grade 2 symptoms (moderate reaction requires therapy or infusion interruption but
responds
promptly
to symptomatic
treatment [eg, antihistamines,
nonsteroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for ≤ 24 hours):
Stop the infusion, begin an IV infusion of normal saline, and treat
the participant with
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 mg to
1000 mg; remain at bedside and monitor participant until resolution of symptoms. Corticosteroid
and/or bronchodilator therapy may also be administered as appropriate. If the infusion is
interrupted, then restart the infusion at 50% of the original infusion rate when symptoms resolve;
if no further complications ensue after 30 minutes, the rate may be increased to 100% of the
original infusion rate. Monitor participant
closely. If symptoms recur, then no further
immunotherapy will be administered at that visit. Administer diphenhydramine 50 mg IV and
remain at bedside and monitor the participant until resolution of symptoms. The amount of study
drug infused must be recorded on the eCRF.
For
future
infusions,
the
following
prophylactic
premedications
are
recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg
should be administered at least 30 minutes before immunotherapy infusions. If necessary,
corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used.
For Grade 3 or 4 symptoms (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae [eg, renal impairment,
pulmonary infiltrates]. Grade 4: Life threatening; pressor or ventilatory support indicated):
Immediately discontinue infusion of immunotherapy. Begin an IV infusion of normal saline and
treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1000
solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected
slowly for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone
100
mg IV (or equivalent), as needed. Participant should be monitored until the investigator
is comfortable that the symptoms will not recur. Immunotherapy will be permanently
discontinued. Investigators should follow their institutional guidelines for the treatment of
anaphylaxis. Remain at bedside and monitor participant until recovery of the symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral
antihistamine or corticosteroids).
7.5
Preparation/Handling/Storage/Accountability
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 participants. The IP must be dispensed 
only from official study sites by authorized personnel according to local regulations.
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The product storage manager should ensure that the study intervention is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by the Sponsor. If 
concerns regarding the quality or appearance of the study intervention arise, the study intervention
should not be dispensed, and the Sponsor should be contacted immediately.
Study intervention not supplied by the Sponsor will be stored in accordance with the package 
insert.
IP/IMP/Non-IMP/AxMP documentation (whether supplied by the Sponsor or not) must be 
maintained and must include all processes required to ensure the 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).
All study intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff.
The investigator, institution, head of the medical institution (where applicable), or authorized site 
staff is responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition of records).
Only participants enrolled in the study may receive study intervention, and only authorized site 
staff may supply, prepare, or administer study intervention.
Further guidance and information for the final disposition of unused study interventions are 
provided in Appendix 2.
7.5.1
Retained Samples for Bioavailability/Bioequivalence/Biocomparability
At the time of receipt of the IP by the investigator or designee, the Sponsor will specify the 
appropriate number of containers or units to select for retention, the conditions of sample storage, 
required duration of sample retention, and provisions for returning or disposing of the IP. When 
samples are selected, containers or units should be placed in packaging with a tamper-evident seal 
provided by the Sponsor or sourced by the site. Package labeling should clearly identify the 
contents as retention samples and state that the IP should be stored in the restricted area with 
limited access.
Additional details regarding the retention process will be provided in the Pharmacy Manual (or in 
other written documentation) provided to the site.
7.6
Study Intervention Compliance
Treatment compliance will be monitored by drug accountability as well as the participant’s 
medical record and eCRF. This will be source data verified by the BMS Unblinded Site Monitor 
through regularly scheduled monitoring visits.
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7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug-related 
AE):
•
 
 
•
Treatment with anti-NKG2A agents other than the study drug.
•
Any
concurrent 
anti-neoplastic 
therapy.
(ie, 
chemotherapy, 
hormonal 
therapy, 
immunotherapy, extensive non-palliative radiation therapy, or standard or investigational 
agents for the treatment of NSCLC)
•
Any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio, and 
measles, mumps, rubella) during treatment and until 100 days post last dose.
•
Immunosuppressive doses of systemic corticosteroids. (except as stated in Section 7.7.3)
•
Any botanical preparation (eg, herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study or provide supportive care. Use of marijuana and its derivatives 
for treatment of symptoms related to cancer or cancer treatment are permitted if obtained by 
medical prescription or if its use (even without a medical prescription) has been legalized 
locally.
•
Administration of investigational SARS-CoV-2 vaccines is not allowed during the study. 
Participants may receive approved SARS-CoV-2 vaccines while continuing on study treatment 
at the discretion of the Investigator.
•
Treatment of active SARS-CoV-2 infections or high-risk exposures, including use of 
investigational therapies, is allowed and should be discussed with the Medical Monitor. No 
concomitant medications (prescription, over-the-counter, or herbal) are to be administered 
during study unless they are prescribed for treatment of specific clinical events. Any 
concomitant therapies must be recorded on the CRF.
The investigator must also adhere to the contraindications, precautions, and drug interactions 
found in the USPI or local label for each of the chemotherapy agents.
7.7.2
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization are excluded. Inhaled or topical steroids and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
For participants who need to undergo elective surgery (not tumor related) during the study, it is 
recommended to hold study drug(s) for at least 2 weeks before and 2 weeks after surgery, or until 
the participant recovers from the procedure, whichever is longer. Prior to resuming study drug 
treatment, surgically-related AEs should resolve to ≤ Grade 1 or baseline and participant must 
meet relevant eligibility criteria as determined by the BMS Medical Monitor in discussion with 
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the Investigator. The BMS Medical Monitor must be consulted prior to re-initiating treatment in a 
participant with a dosing interruption lasting > 8 weeks after the last dose.
7.7.2.1
Imaging Restrictions and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes 
(eg, allergy history, diabetic history, and renal status), the appropriate imaging modality and 
contrast regimen per imaging study. Imaging contraindications and contrast risks are to be 
considered in this assessment. Participants with renal insufficiency are to be assessed as to whether 
they should receive contrast and if so, which contrast agent and dose are appropriate. Specific to 
magnetic resonance imaging (MRI), participants with severe renal insufficiency (ie, estimated 
glomerular filtration rate < 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic 
fibrosis; therefore, MRI contrast is contraindicated. In addition, participants may be excluded from 
MRI if they have tattoos, metallic implants, pacemakers, etc. These restrictions will be outlined in 
the Imaging Manual.
Gentle hydration before and after IV contrast should follow local standard of care. The ultimate 
decision to perform MRI in an individual participant enrolled in this study rests with the site 
radiologist, the investigator, and standards set by the local Ethics Committee.
7.7.3
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). 
Adrenal replacement steroid doses > 10 mg daily prednisone are permitted. 
A brief (less than 3 weeks) course of corticosteroids for prophylaxis (eg, contrast dye allergy) or 
for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by 
a contact allergen) is permitted.
Regular concomitant use of bisphosphonates and RANK-L inhibitors for prevention or reduction
of skeletal-related events in participants with bone metastases is allowed if initiated prior to first 
dose of study treatment.
Prior palliative radiotherapy must have been completed at least 2 weeks prior to treatment.
7.7.3.1
Palliative Local Therapy
Palliative local therapy, including palliative radiation therapy and palliative surgical resection, to 
symptomatic non-target bone lesions, skin lesions, or CNS lesions is permitted prior to 
discontinuation of study treatment for participants who do not have evidence of overall clinical or 
radiographic progression per RECIST v1.1. Palliative local therapy to lesions causing hemoptysis 
may also be permitted prior to discontinuation of study treatment in participants who do not have 
evidence of overall clinical or radiographic progression per RECIST v1.1, provided that the lesions 
undergoing palliative local therapy are not the only sites of measurable disease and the case is 
discussed with and approved by the BMS Medical Monitor.
Participants requiring palliative local therapy should be evaluated for objective evidence of disease 
progression prior to the initiation of such therapy, particularly if the most recent tumor assessment 
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was more than 4 weeks prior to the start of local therapy. If progression per RECIST v1.1 is 
identified on any tumor assessments prior to the initiation of palliative local therapy, then 
participants must either discontinue study drug treatment or they must meet criteria to continue 
treatment beyond progression (Section 8.1.1) in order to resume immunotherapy after palliative 
local therapy. If radiographic progression per RECIST v1.1 is identified prior to the initiation of 
palliative local therapy, sites must request a BICR from the third-party radiologist. However, the 
initiation of palliative local therapy need not be delayed awaiting the assessment by the BICR.
The potential for overlapping toxicities with radiotherapy and immunotherapy currently is not 
known; however, anecdotal data suggest that it is tolerable. As concurrent radiotherapy and the 
immunotherapy regimens evaluated in this study have not been formally evaluated, whenever 
palliative radiotherapy is required for a tumor lesion, then immunotherapy should be withheld for 
at least 1 week before, during, and 1 week after radiation. Participants should be closely monitored 
for any potential toxicity during and after receiving radiotherapy, and AEs should resolve to Grade 
≤ 1 prior to resuming immunotherapy.
7.8
Continued Access to Study Intervention After the End of the Study
At the conclusion of the study, if the study intervention is not available as an approved treatment 
in the local country, participants who continue to demonstrate clinical benefit will be eligible to 
receive BMS-supplied study intervention for maximum treatment duration as specified in 
Section 7.1. 
BMS reserves the right to terminate access to BMS-supplied study treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b) the development of nivolumab or 
BMS-986315 is terminated for other reasons, including, but not limited to, lack of efficacy and/or 
not meeting the study objectives; c) the participant can obtain medication from a government-
sponsored or private health program. In all cases, BMS will follow local regulations.
8
DISCONTINUATION CRITERIA
The discontinuation of specific sites or of the study as a whole is detailed in Appendix 2.
8.1
Discontinuation of Study Intervention
Participants MUST discontinue IP (and Non-IMP/AxMP at the discretion of the investigator) for 
any of the following reasons as listed below.  Also refer to Section 7.4 for more information on 
study intervention discontinuation.
•
Participant’s request to stop study intervention. Participants who request to discontinue study 
intervention will remain in the study and must continue to be followed for protocol-specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by the participant 
to provide this information.
•
Any clinical AE, laboratory test result abnormality, or intercurrent illness which, in the opinion 
of the investigator, indicates that continued participation in the study is not in the best interest 
of the participant.
•
Termination of the study by the Sponsor.
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•
Loss of ability to freely provide consent through imprisonment or involuntary incarceration for 
treatment of either a psychiatric or physical illness (eg, infectious disease). (Note: Under 
specific circumstances and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply, and 
Sponsor approval is required.)
•
Pregnancy (refer to Section 9.2.5).
•
Significant noncompliance with protocol (eg, procedures, assessments, medications, etc). The 
investigator should discuss such issues with the Medical Monitor.
All participants who discontinue study intervention should comply with protocol-specified follow-
up procedures as outlined in Section 2: Schedule of Activities. The only exception to this 
requirement is when a participant withdraws consent for all study procedures, including post-
treatment study follow-up, or loses the ability to consent freely (eg, is imprisoned or involuntarily 
incarcerated for the treatment of either a psychiatric or physical illness).
If study intervention is discontinued prior to the participant’s completion of the study, the reason 
for the discontinuation must be documented in the participant’s medical records per local 
regulatory requirements in each region/country and entered on the appropriate CRF page.
8.1.1
Immunotherapy Treatment Beyond Disease Progression
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of disease progression.
Participants treated with immunotherapy (nivolumab [± BMS-986315]) will be permitted to 
continue treatment beyond initial RECIST v1.1-defined progression disease, assessed by the 
investigator as long as they meet the following criteria:
•
Investigator-assessed clinical benefit
•
Tolerance of study treatment
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
•
Participant provides written informed consent prior to receiving additional immunotherapy
treatment. All other elements of the main consent including description of reasonably 
foreseeable risks or discomforts or other alternative treatment options will still apply.
Radiographic assessment/scan(s) should continue in accordance with the Schedule of Activities 
for the duration of the treatment beyond progression and should be submitted to the central imaging 
vendor The assessment of clinical benefit should be balanced by clinical judgment as to whether 
the participant is clinically deteriorating and unlikely to receive any benefit from continued 
treatment with immunotherapy.
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If the investigator feels that the immunotherapy treated participant continues to achieve clinical 
benefit by continuing treatment, the participant should remain on the trial and continue to receive 
monitoring according to the Schedule of Activities (see Section 2).
For the participants who continue immunotherapy beyond progression, further progression is 
defined as an additional 10% increase in tumor burden with a minimum 5-mm absolute increase 
from time of initial PD. This includes an increase in the sum of diameters of all target lesions and/ 
or the diameters of new measurable lesions compared to the time of initial PD. Immunotherapy 
treatment should be discontinued permanently upon documentation of further progression.
New lesions are considered measurable 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 nonmeasurable at the time of initial progression may become 
measurable and therefore included in the tumor burden if the longest diameter increases to at least 
10 mm (except for pathological lymph nodes, which must have a short axis of at least 15 mm). In 
situations where the relative increase in total tumor burden by 10% is solely due to inclusion of 
new lesions which become measurable, these new lesions must demonstrate an absolute increase 
of at least 5 mm.
8.1.2
Post-study Intervention Study Follow-up
In this study, ORR and PFS are key endpoints of the study. Post-study follow-up is of critical 
importance and is essential to preserving participant safety and the integrity of the study. 
Participants who discontinue study intervention must continue to be followed (in this study or a 
rollover study) for collection of outcome and/or survival follow-up data as required and in line 
with Section 5: Study Design until death or the conclusion of the study.
If progression as per BICR has not occurred before treatment discontinuation, tumor assessments 
should continue according to the Schedule of Activities,
.
Participants should undergo 100 days of safety follow-up post last dose of study drug.
BMS may request that survival data be collected on all randomized participants outside of the 
protocol-defined window (see Section 5.1.1). At the time of this request, each participant will be 
contacted to determine their survival status unless the participant has withdrawn consent for all 
contacts or is lost to follow-up.
8.2
Discontinuation From the Study
Participants who request to discontinue study intervention will remain in the study and must 
continue to be followed for protocol-specified follow-up procedures. The only exception to this is 
when a participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by the participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator as to whether the withdrawal is from further treatment with study intervention only 
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or also from study procedures and/or post-treatment study follow-up, and entered on the 
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
•
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
•
8.2.1
Individual Discontinuation Criteria
•
A participant may withdraw completely from the study at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. Stopping study 
intervention is not considered withdrawal from the study.
•
At the time of discontinuing from the study, if possible, an early termination visit should be 
conducted, as shown in the Schedule of Activities (Section 2). See the Schedule of Activities 
for data to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed.
•
The participant will be permanently discontinued from both the study intervention and the 
study at that time.
•
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
•
8.3
Lost to Follow-up
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant. 
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of 3 
documented phone calls, faxes, or emails, as well as lack of response by participant to 1 
registered mail letter. All attempts should be documented in the participant’s medical records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
•
If the investigator’s use of a third-party representative to assist in the follow-up portion of the 
study has been included in the participant’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining the participant’s 
contact information or other public vital status data, such as public health registries and 
databases, 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, to obtain updated contact information.
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•
If, after all attempts, the participant remains lost to follow-up, then the last known alive date 
as determined by the investigator should be reported and documented in the participant’s 
medical records.
•
9
STUDY ASSESSMENTS AND PROCEDURES
Images will be submitted to a central imaging vendor for BICR at any time during the study. Prior 
to scanning first participant, sites should be qualified and understand the image acquisition 
guidelines and submission process as outlined in the CA0471009 Imaging Manual provided by the 
central imaging vendor.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug-
induced liver enzyme evaluations) will be monitored during the follow-up phase via on-site/local 
labs until all study drug-related toxicities resolve, return to baseline, or are deemed irreversible.
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, 
fever) consistent with possible pulmonary AEs, the participant should be immediately evaluated 
to rule out pulmonary toxicity, according to the suspected pulmonary toxicity management 
algorithm in the BMS-986315 and nivolumab IBs.
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
9.1
Efficacy Assessments
9.1.1
Imaging Assessment for the Study
Images will be submitted to a central imaging vendor for blinded independent central review 
(BICR) at any time during the study. Prior to scanning the first participant, sites should be qualified 
and understand the image acquisition guidelines and submission process as outlined in the Imaging 
Manual provided by the central imaging vendor. 
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9.1.1.1
Methods of Measurement
Contrast-enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all other known and/or 
suspected sites of disease should be performed for tumor assessments. Images should be acquired 
with slice thickness of 5 mm or less with no intervening gap (contiguous). Every attempt should 
be made to image each participant using an identical acquisition protocol on the same scanner for 
all imaging time points. Tumor measurements should be made by the same investigator or 
radiologist for each assessment whenever possible. Changes in tumor measurements and tumor 
response to guide ongoing study treatment decisions will be assessed by the investigator using the 
RECIST 1.1 criteria. In case of a contraindication for either contrast agent or MRI (eg,
incompatible pacemaker), it), it is strongly recommended to use the following guidance:
If a participant has a contraindication for CT intravenous contrast, then a non-contrast CT of the 
chest and a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected sites of 
disease should be obtained.  
If a participant has a contraindication for both MRI and CT intravenous contrasts, then a 
non‑contrast CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other 
known/suspected sites of disease should be obtained. 
If a participant has a contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT intravenous contrast, then a non-contrast CT of the chest, abdomen, pelvis, 
and other known/suspected sites of disease is acceptable.
Use of CT component of a Positron emission tomography–computed tomography (PET-CT)
scanner: Combined modality scanning such as with PET‑CT is increasingly used in clinical care 
and is a modality/technology that is in rapid evolution; therefore, the recommendations outlined 
here may change rather quickly with time. At present, low-dose or attenuation correction CT 
portions of a combined PET-CT are of limited use in anatomically based efficacy assessments and 
it is therefore suggested that they should not be substituted for dedicated diagnostic contrast 
enhanced CT scans for anatomically based RECIST 1.1 measurements. However, if a site can 
document that the CT performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast) then the CT portion of the PET-CT can be used for 
RECIST 1.1 measurements. Note, however, that the PET portion of the CT introduces additional 
data which may bias an investigator if it is not routinely or serially performed.
Bone scans or PET scans are not adequate for assessment of RECIST 1.1 response in target lesions. 
In selected circumstances where such modalities are the sole modality used to assess certain non-
target organs, those non-target organs may be evaluated less frequently. For example, bone scans 
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may need to be repeated only when complete response is identified in target disease or when 
progression in bone is suspected.
Bone scans may be collected per local standards, as clinically indicated.
MRI of brain (without and with contrast) should be acquired as outlined in Section 2 (Schedule of 
Activities). CT of the brain (without and with contrast) can be performed if MRI is contraindicated.
9.1.1.2
Imaging and Clinical Assessment
Tumor assessments should continue on the protocol-defined imaging schedule regardless if dosing 
is delayed or discontinued. Changes in tumor measurements and tumor responses will be assessed 
by the same investigator or designee using RECIST 1.1 criteria. Investigators will report the 
number and size of new lesions that appear while on study. The timepoint of tumor assessments 
will be reported on the eCRF based on the investigator’s assessment using RECIST1.1 criteria 
(See Appendix 8 for specifics of RECIST 1.1 criteria to be used in this study). Assessments of PR 
and CR must be confirmed at least 4 weeks (28 days) after initial responseA best overall response 
(BOR) of SD requires a minimum of 35 days on study from randomization to the date of the first 
imaging assessment.
9.1.1.3
BICR Confirmation of Progression or Recurrence
Sites should submit all scans to the central imaging vendor on a rolling basis throughout the 
duration of the study. BICR of scans will occur on a rolling basis, blinded to treatment arm, clinical 
data, and investigator assessment of submitted scans. When progression per RECIST v1.1 criteria 
is assessed by the investigator, the site will inform the central imaging vendor in order for BICR 
assessment of progression to be performed. The BICR will be completed, and the results provided 
to the site as specified in the imaging vendor documents, provided there are no pending imaging 
queries to the site. All details on the timelines and associated process requirements will be outlined 
in the Imaging Manual.
Participants whose progression is not confirmed by the BICR will be required to continue tumor 
assessments (if clinically feasible) according to the protocol-specified schedule or sooner if 
clinically indicated. Also, if participants discontinue treatment without radiographic progression, 
tumor assessments will continue according to the protocol-specified schedule, as noted in Section 
2 (Schedule of Activities) until progression has been confirmed by BICR.
All study treatment decisions will be based on the investigator’s assessment of tumor images and 
not on the BICR assessment.
9.2
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant.
The investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following up
on AEs that are serious, considered related to the study intervention or the study, or that caused 
the participant to discontinue before completing the study. 
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IMAEs are AEs consistent with an immune-mediated mechanism or immune-mediated component 
for which non-inflammatory etiologies (eg, infection or tumor progression) have been ruled out. 
IMAEs can include events with an alternate etiology which were exacerbated by the induction of 
autoimmunity. Information supporting the assessment will be collected on the participant’s eCRF.
Use CTCAE v5 definitions and grading for safety reporting of all AEs and SAEs on the Case 
Report Form.
Refer to Appendix 3 for SAE reporting.
9.2.1
Period and Frequency for Collecting AE and SAE Information
The IB represents the reference safety information to determine expectedness of SAEs for 
expedited reporting.
All AEs and SAEs must be collected from the time of signing the consent, including those thought 
to be associated with protocol-specified procedures and within 100 days of discontinuation of 
dosing. All SAEs and all AEs (SAEs and non-serious AEs) associated with confirmed or suspected 
SARS-CoV-2 infection must be collected from the date of the participant’s written consent until 
100 days following discontinuation of dosing. For participants randomized and never treated with 
study drug, SAEs should be collected for 30 days from the date of randomization.
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 (eg, a follow-up skin biopsy).
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF module.
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated in 
Appendix 3.
The investigator will submit any updated SAE data to the Sponsor or designee within 24 hours of 
updated information being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
intervention or study participation, the investigator must promptly notify the Sponsor.
The method of evaluating and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. Care should be taken not to introduce bias when collecting AEs and/or 
SAEs. Inquiry about specific AEs should be guided by clinical judgment in the context of known 
AEs, when appropriate for the program or protocol.
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Every AE must be assessed by the investigator with regard to whether it is considered immune 
mediated. For events which are potentially immune mediated, additional information will be 
collected on the participant’s eCRF.
All non-serious AEs (not only those deemed to be treatment related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
of study treatment.
9.2.3
Follow-up of AEs and SAEs
•
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).
•
Follow-up is also required for non-serious AEs that cause interruption or discontinuation of 
study intervention and for those present at the end of study intervention as appropriate.
•
All identified non-serious AEs must be recorded and described on the non-serious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory test result abnormalities that are reported/identified during the study.
•
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
Section 9.2), will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3) or for 
suspected cases, until SARS-CoV-2 infection is ruled out.
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal obligations 
and ethical responsibilities toward the safety of participants and the safety of a product under 
clinical investigation are met.
An investigator who receives an investigator safety report describing SAEs or other specific safety 
information (eg, summary or listing of SAEs) from the Sponsor will file it along with the 
Investigator’s Brochure and will notify the IRB/IEC, if appropriate, according to local 
requirements.
The Sponsor or designee must report AEs to regulatory authorities and ethics committees 
according to local applicable laws and regulations. A suspected, unexpected serious adverse 
reaction (SUSAR) is a subset of SAEs and must be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study intervention, it is discovered that a female participant is 
pregnant or may have been pregnant at the time of study intervention exposure including at least 
5 months after the last dose of immunotherapy, 7 months after the last dose of chemotherapy 
(applicable to paclitaxel, pemetrexed, and carboplatin) or 14 months after the last dose of cisplatin,
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the investigator must immediately notify the Sponsor Medical Monitor/designee of this event and 
complete and forward a Pregnancy Surveillance Form to the Sponsor designee within 24 hours of 
awareness of the event and in accordance with SAE reporting procedures described in Appendix 3.
In all cases, the study intervention will be discontinued in an appropriate manner (eg, dose tapering 
if necessary for participant safety).
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. Protocol-required procedures for study discontinuation and follow-up must 
be performed.
Any pregnancy that occurs in a female partner of a male participant at the time of study 
intervention exposure (see Section 6) including 6-months after last dose of chemotherapy 
(applicable to paclitaxel,  pemetrexed, and carboplatin) or a total of 11 months after the last dose 
for male participants receiving cisplatin should be reported to the Sponsor or designee. For the 
Sponsor or designee to collect any pregnancy surveillance information from the female partner, 
the female partner must sign an ICF for disclosure of this information. Information on this 
pregnancy will be collected and recorded on the Pregnancy Surveillance Form.
If any sexual activity involving penile intercourse (eg, vaginal, anal, oral) has occurred between a 
male participant and a pregnant partner(s) without the use of a condom for the duration of treatment 
with BMS-986315 and nivolumab and chemotherapy, and for a total of 6-months after last dose 
of chemotherapy (applicable to paclitaxel,  pemetrexed, and carboplatin) or a total of 11 months 
after the last dose for male participants receiving cisplatin should be reported to the Sponsor or 
designee even if the male participant has undergone a successful vasectomy (refer to Section 6 for 
details). In order for Sponsor or designee to collect any pregnancy surveillance information from 
the female partner, the female partner(s) must sign an ICF for disclosure of this information. 
Information on the pregnancy will be collected on the Pregnancy Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the Adverse Events –
Non-serious and Serious Events CRF page. 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 requires the participant to have study intervention
discontinued or interrupted
•
Any laboratory test result abnormality that requires the participant to receive specific 
corrective therapy
•
It is expected that, wherever possible, the clinical rather than the laboratory term will be used by 
the reporting investigator (eg, anemia vs low hemoglobin value).
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9.2.7
Potential Drug-induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory test result abnormalities 
should occur prior to the reporting of a potential drug-induced liver injury (DILI) event. All 
occurrences of potential DILIs meeting the defined criteria must be reported as SAEs (see
Section 9.2 and Appendix 3).
A potential DILI is defined as follows: 
•
Aminotransferase (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) 
elevation > 3× upper limit of normal (ULN)
•
AND
•
Total bilirubin > 2× 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, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic.
•
9.2.8
Other Safety Considerations
Any significant worsening of conditions noted during interim or final physical examinations, ECG, 
radiographic imaging, or any other potential safety assessment required or not required by the 
protocol should also be recorded as a non-serious AE or SAE, as appropriate, and reported 
accordingly.
9.2.9
AEs of Special Interest
Not applicable. 
9.3
Overdose
For this study, any dose of immunotherapy greater than the planned dose within a 24-hour period 
will be considered an overdose. Overdoses that meet the regulatory definition of an SAE will be 
reported as SAEs (see Appendix 3).
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. Overdoses that meet the regulatory 
definition of an SAE will be reported as SAEs (see Appendix 3.)
9.4
Safety
Planned time points for all safety assessments are listed in Section 2: Schedule of Activities.
9.4.1
Physical Examinations
Refer to Section 2: Schedule of Activities.
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9.4.2
Vital Signs and Oxygen Saturation
Refer to Section 2: Schedule of Activities. Vital signs include oxygen saturation, body 
temperature, respiratory rate, seated blood pressure, and seated heart rate. Blood pressure and 
heart rate should be measured after the participant has been resting quietly for at least 5 minutes. 
9.4.3
Electrocardiograms
Refer to Section 2: Schedule of Activities.
9.4.4
Clinical Safety Laboratory Assessments
•
Investigators must document their review of each laboratory safety report.
•
Local laboratory tests may be used to guide clinical decisions and determine eligibility for
dosing.
•
A local laboratory will perform the analyses and will provide reference ranges for these tests.
•
During screening and treatment, unless otherwise indicated 
, results
of clinical laboratory tests must be reviewed prior to dosing.
Clinical safety laboratory assessments are provided in 
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9.4.5
Imaging Safety Assessment
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 per standard 
medical/clinical judgment. See Section 7.7.2.1 for additional details.
9.5
Pharmacokinetics and Immunogenicity
Pharmacokinetic and immunogenicity (IMG) assessment data for BMS-986315 in combination 
with nivolumab and chemotherapy in Parts 1 and 2 will be collected from study participants 
assigned to the study 
. All time points are relative to the 
start of BMS-986315 administration. All on-treatment time points are intended to align with days 
on which study drug is administered; if dosing occurs on a different day, the PK and IMG sampling 
should be adjusted accordingly. If it is known that a dose is going to be delayed, then the pre-dose 
sample should be collected just prior to the delayed dose. However, if a pre-dose sample is 
collected but the dose is subsequently delayed, an additional predose sample should not be 
collected. 
 
. Pharmacokinetic parameters of BMS-986315 will be derived, if feasible, from serum 
concentration versus time data following Cycle 1 Day 1 and Cycle 5 Day 1. Trough concentrations 
of nivolumab will be summarized. PK parameters that will be assessed are shown in Table 9.5-1.
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Table 9.5-1:
Pharmacokinetic Parameters to be Assessed
Cmax
Maximum observed serum concentration
Tmax
Time of maximum observed serum concentration
AUC(0-T)
Area under the serum concentration-time curve from time zero to time of last quantifiable 
concentration
AUC(TAU)
Area under the serum concentration-time curve in 1 dosing interval
Ctau
Serum concentration at the end of a dosing interval
Ctrough
Trough observed serum concentrations (this includes pre-dose concentrations [C0] and Ctau)
PK Parameters of BMS-986315 that May be Assessed Following the Dose Administration in Cycle 5 Day 1
Css-avg
Average serum concentration over a dosing interval (AUC[TAU]/tau) at steady state
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to AUC(TAU) after the first dose.
DF
Degree of fluctuation or fluctuation index (to be calculated at steady state)
T-HALFeff
Effective elimination half-life that explains the degree of AUC accumulation observed
Nivolumab
Ctrough
Trough observed serum concentrations (this includes pre-dose concentrations [C0] and Ctau)
Individual participant PK parameter values will be derived by non-compartmental methods by 
using a validated PK analysis program. Actual times will be used for the analyses.
Sparse nivolumab concentration-time data will be collected and may be used in an integrated 
population PK or exposure-response (ER) analysis along with data from other nivolumab studies, 
which will be the subject of a separate report. BMS-986315 PK and biomarker data may be utilized 
in a population PK, PKPD, or ER analysis. 
Treatment assignments will be released to the bioanalytical laboratory in order to minimize 
unnecessary analysis and/or reanalysis of PK/IMG samples. Separate samples will be collected for 
PK and IMG assessments. 
Concentration and anti-drug antibodies (ADA) (anti-BMS-986315 and anti-nivolumab) analyses 
for BMS-986315 and nivolumab will be performed by using validated immunoassays.  Samples 
with a positive ADA response may also be analyzed for neutralizing ADA response to BMS-
986315 and/or nivolumab. Neutralizing ADA testing is conditional upon assay availability. ADA 
effects on safety, efficacy, and PK may be evaluated, if applicable.
Bioanalytical samples designated for assessments (eg, immunogenicity, PK, or biomarker) from 
the same collection time point may be used interchangeably for analyses, if required (including,
but not limited to insufficient volume for complement assessment, to follow-up on suspected 
immunogenicity related AE, etc). Additionally, residual bioanalytical samples will be archived for 
up to 20 years after the end of the study or the maximum period allowed by applicable law and 
may be used for potential exploratory bioanalysis (including, but not limited to analysis of drug-
ADA immune complexes, metabolite analyses, etc) and/or for additional method purposes 
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(including but not limited to cross validation, ADA/PK selectivity, cut point, etc.). Further details 
of sample collection, processing, and shipment will be provided in the laboratory/procedure 
manual. Blood samples should be drawn from a site other than the infusion site (ie, contralateral 
arm) on days of infusion. If the infusion was interrupted, the interruption details will also be 
documented on the CRF. Further details of sample collection, processing, and shipment will be 
provided in the laboratory/procedure manual.
9.5.1
Pharmacokinetic Sample Collection Windows
It is expected that every effort be made to collect PK samples at the times indicated in the protocol.
The following time window serve as a guideline for PK sample collections:
•
9.6
Immunogenicity Assessments 
Antibodies to BMS-986315 and nivolumab will be evaluated in serum samples collected from all 
participants who receive a dose of the respective drugs. Additionally, serum samples should be 
collected at the final visit from participants who discontinued study intervention or were 
withdrawn from the study.
Pre-dose samples will be collected on all participants prior to the administration of the first dose 
to determine baseline status; any sampling time points that coincide with dosing should have 
samples drawn for immunogenicity before the administration of the drug; samples must be drawn 
from a site other than the infusion site (ie. contralateral arm) on the day of infusion Samples that 
are confirmed positive will be titered.  All samples collected for detection of anti-drug antibodies 
will also be evaluated for serum concentrations of the drug to enable interpretation of the anti-drug 
antibody data.  
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Samples may be stored for up to 20 years after the end of the study or the maximum period allowed 
by applicable law (or according to local regulations) at a facility selected by the Sponsor to enable 
further analysis of immune responses to BMS-986315.
9.7
Biomarkers
Biomarkers are increasingly playing a key role in the development of cancer therapeutics. By 
evaluating treatment-induced changes in molecular markers measured in tissue and body fluids, 
the activity of experimental agents may be assessed and the details of their mechanisms of action 
may be elucidated. To explore potential pharmacodynamic and predictive markers for clinical 
response to BMS-986315 in combination with nivolumab and chemotherapy, the following 
samples for biomarker research are required and will be collected from all participants in this study 
as specified: (i) tumor tissue, (ii) serum, (iii) plasma, and (iv) whole blood.
 
 
Blood and tumor tissue samples will be collected in this study at baseline and on 
treatment to identify markers associated with clinical activity and mechanism of action of BMS-
986315 in combination with nivolumab and chemotherapy. Biomarker samples will be stored in 
the Sponsor-designated storage facility. The manager of these samples will ensure that they are 
properly used throughout their usable life and will destroy the samples at the end of the scheduled 
storage period, no longer than 20 years after the end of the study or the maximum period allowed 
by applicable law. Complete instructions on the collection, processing, handling, and shipment of 
all samples described herein will be provided to sites in a separate Laboratory Manual.
9.7.1
Biomarker Assessments in Tumor
Tumor tissues may be analyzed by IHC assays to determine the abundance of TILs and expression 
of immunoregulatory proteins
 
 
. Baseline and 
pharmacodynamic measures may also be correlated to clinical outcomes.
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9.7.2
Biomarker Assessments in Peripheral Blood
Blood samples will be collected prior to and during treatment from all participants. These blood 
samples may be assessed for changes in quantity or phenotype of immune cell subsets, changes in 
soluble factors 
, cytokines and chemokines, changes in immune 
cell functionality, changes in gene expression, and/or circulating tumor DNA (ctDNA). These 
biomarkers may be used to assess pharmacodynamic changes by dose, and potential associations 
with efficacy measures. Several sample analyses will be completed and are described briefly 
below.
9.7.2.1
Whole Blood for Immunophenotyping
Flow cytometry may be used to assess baseline and serial on-treatment alterations in 
composition/activation status of immune-cell subsets present in the whole blood samples obtained
from all participants in each treatment arm. Lymphocyte subsets to be assayed may include, but 
not be limited to, CD8+ and CD4+ T-cell subsets, NK cells and sub-populations of those cells as 
defined by the expression of activation, exhaustion, or signaling markers, 
. 
9.7.2.2
Exploratory Serum Biomarkers 
Serum factors including cytokines, chemokines, and other relevant immunomodulatory soluble 
factors may be determined by different immunoassay methods. Examples of specific analytes to 
be assessed may include, but are not limited to, factors induced by IFN-γ signaling 
 
, cytolytic markers 
. The impact of baseline level of soluble circulating proteins and the serial on-treatment 
alterations may be correlated to clinical outcomes.
9.7.2.3
Plasma for Circulating Tumor DNA
Plasma samples will be collected at specific time points indicated 
. Baseline plasma 
ctDNA levels may be assessed for association with tumor mutational burden (TMB) and/or
potential association with efficacy. Dynamic changes in ctDNA levels may also be evaluated for 
the patient response to treatment. 
9.7.2.4
Whole Blood DNA/RNA Analysis
Whole blood collected from participants prior to study treatment initiation may be used to generate
genomic DNA for the understanding of genetic variation analyses. 
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. Whole exome or whole-
genome sequencing methods may be used for this analysis.
Genomic expression analysis of RNA derived from whole blood collected pre treatment and on
study may provide information on the broad effects of BMS-986315 combined with nivolumab 
and chemotherapy versus nivolumab with chemotherapy alone on gene expression that regulates 
immune modulation. 
9.7.2.5
Peripheral Blood Mononuclear Cells (PBMCs)
Whole blood samples may be collected for isolation and cryopreservation of PBMCs. 
 
 
 
 These cryopreserved samples 
may be used for functional activation tests or for additional assays if new biology suggests analysis 
beyond the immunophenotyping described above. 
10
STATISTICAL CONSIDERATIONS
10.1
Statistical Hypotheses
It is expected that the objective response rate (ORR) with first-line Stage IV or recurrent NSCLC 
randomized to the BMS-986315 with nivolumab in combination with chemotherapy will be 
improved as compared to participants receiving nivolumab in combination with chemotherapy.
10.2
Sample Size Determination
The sample size of the study is calculated to have a sufficient probability of making the correct 
decision and have a low probability of making an incorrect decision.
•
Part 1 safety lead-in: 
participants will be enrolled in the safety lead-in 
Phase. 
 
 A Bayesian optimal interval design (BOIN) with overdose control will be 
used to safeguard participants' safety.
•
Part 2, 
participants will be randomized 
 
 
 
 
The experimental arm may 
be dropped if no additional benefit compared to control arm is seen. In such a case, the 
study will be terminated.
 
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10.3
Analysis Sets
For the purposes of analysis, the following populations are shown in Table 10.3-1:
Table 10.3-1: Population Description
Population
Description
Enrolled
All participants who sign informed consent and obtained a participant number.
Randomized
All participants who were randomized using IRT.
Treated
All participants who have received any amount of study intervention.
Response-evaluable
All participants who receive at least one dose of study intervention, have a 
baseline tumor assessment with measurable disease, and 1 of the following: 1) 
at least 1 evaluable on-treatment tumor assessment, 2) clinical progression, or 
3) death prior to the first on-treatment tumor evaluation.
PK
All participants who received at least one dose of BMS-986315/nivolumab 
and have at least one evaluable serum concentration-time data.
Biomarker
All participants who take at least one dose of study treatment and have at least 
one non-missing biomarker assessment, excluding the disqualified 
assessments.
DLT-evaluable
A participant who received 2 doses of BMS-986315, nivolumab and PDCT 
and completed the DLT observation period, or a participant who experienced a 
DLT after receiving a minimum of a partial dose of BMS-986315.
Immunogenicity
All treated participants who have baseline and at least 1 post-baseline 
preinfusion immunogenicity assessment.
Abbreviations: DLT, dose limiting roxicity; IRT, Interactive Response Technology; PK, pharmacokinetics.
10.4
Statistical Analyses
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. More detailed description of the statistical 
analyses will be described in the statistical analysis plan (SAP). The SAP will describe the 
selection of participants to be included in the analyses and procedures, accounting for missing, 
unused, and spurious data.
A description of the participant population will be included in the clinical study report, including 
subgroups of age, gender, race, and other study-specific populations and demographic 
characteristics.
Participant characteristics and/or demographic data may be pooled across studies for future 
analysis.
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10.4.1
Efficacy Endpoint(s)
The Efficacy Endpoints are shown in Table 10.4.1-1.
Table 10.4.1-1: Efficacy Endpoint(s)
Endpoint
Statistical Analysis Methods
TimHframe
Primary Analysis
ORR by Response 
Evaluation Criteria 
in Solid Tumors 
(RECIST) 1.1 per 
BICR assessment
Objective response rate (ORR) is defined as the number of participants 
who achieve a best overall response (BOR) of confirmed complete 
response (CR) or confirmed partial response (PR), based on BICR
assessments (using RECIST 1.1), divided by the number of all 
randomized participants. BOR is defined as the best response, recorded 
between the date of randomization and the date of first objectively 
documented progression per RECIST 1.1. For participants without 
documented progression or subsequent therapy, all available response 
designations will contribute to the BOR determination. The number and 
percentage of participants in each category of BOR per BICR (complete 
response [CR], partial response [PR], stable disease [SD], progressive 
disease, or unable to determine [UTD]) will be presented, by treatment 
group. 
 
 
Formal statistical testing for the difference of ORR will 
only be performed between Arm B and Arm A. The difference of ORR 
between Arm B and Arm A will be estimated along with its exact two-
sided 90% confidence interval for all randomized subjects using 
Cochran-Mantel-Haenszel (CMH) method of weighting, adjusting for the 
stratification factors. The descriptive summary of differences of ORR 
between Arm A and Arm C or between Arm B and Arm C will be 
provided along with their 2-sided 95 % confidence intervals.
Up to 5 years
Secondary/Exploratory Analysis
PFS by RECIST 1.1 
per BICR 
assessment
PFS is defined as the time between the date of randomization and the first 
date of documented progression, per BICR assessments (using RECIST 
1.1), or death due to any cause, whichever occurs first. Participants who 
did not progress or die will be censored on the date of their last evaluable 
tumor assessment. Participants who did not have any on-study tumor 
assessments and did not die will be censored on their date of 
randomization. The PFS function for each treatment group will be 
estimated using the KM product limit method and will be displayed 
graphically. A two-sided 95% CI for median PFS in each treatment group 
will be computed via the log-log transformation method. PFS rates at 
fixed time points (eg, 3, 6 months, depending on the minimum follow-
up) will be presented along with their associated 95% CIs. These 
estimates will be derived from the Kaplan Meier estimate and 
corresponding CIs will be derived based on Greenwood’s formula for 
variance derivation and the log-log transformation applied on the 
survivor function. Hazard Ratio and its 95% confidence interval for PFS
between the experimental arm and the control arm will be estimated 
using the stratified Cox proportional model.
Up to 5 years
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Table 10.4.1-1: Efficacy Endpoint(s)
Endpoint
Statistical Analysis Methods
TimHframe
DCR by RECIST 
1.1 per BICR 
assessment
Disease control rate (DCR) is defined as the number of participants who 
achieve a BOR of confirmed CR, confirmed PR, or stable disease (SD), 
based on BICR assessments (using RECIST 1.1) divided by the number 
of all randomized participants. Estimates of DCR, along with its exact 
two-sided 95% CI by Clopper and Pearson, will be presented by 
treatment group.
Up to 5 years
DoR by RECIST 
1.1 per BICR 
assessment among 
responders
Duration of response (DoR) is defined as the time between the date of 
first documented response (CR or PR) that is subsequently confirmed, to 
the date of the first objectively documented tumor progression as 
determined by BICR (per RECIST 1.1), or death due to any cause, 
whichever occurs first. Participants who die without a reported prior 
progression will be considered to have an event on the date of their death. 
Participants who neither progress nor die will be censored on the date of 
their last evaluable tumor assessment. DoR will be evaluated for 
responders (confirmed CR or PR) only. DoR will be analyzed using 
similar method as PFS.
Up to 5 years
TTR by RECIST 
1.1 per BICR 
assessment
•
TTR assessed by BICR is defined as the time between the date of 
randomization and the first confirmed documented response (CR or 
PR) per RECIST 1.1 criteria. TTR will be summarized by treatment 
group in all responders using descriptive statistics and frequency 
statistics by time point.
Up to 5 years
Abbreviations: BICR, blinded independent central review; BOR, best overall response; CI, confidence interval; CR, 
complete response; DCR, disease control rate; DoR, duration of response; KM, Kaplan Meier; ORR, objective 
response rate; PD, progressive disease; PFS, progression free survival; PR, partial response, RECIST, Response 
Evaluation Criteria in Solid Tumors; SD, stable disease; UTD, unable to determine; TTR, time to response.
10.4.2
Safety Endpoint(s)
The Safety Endpoints are shown in Table 10.4.2-1
Table 10.4.2-1:
Safety Endpoint(s)
Endpoint
Statistical Analysis Methods
TimeFrame
Primary Secondary and Exploratory Analyses
Safety
Incidence and severity of AEs/SAEs, treatment-related AEs/SAEs, AEs meeting 
protocol-defined DLT criteria, AEs leading to discontinuation, adverse events of 
special interest (AESI), deaths and laboratory abnormalities. Safety analysis will 
be performed in all treated participants. Descriptive statistics of safety will be 
presented using NCI CTCAE v5.0 by treatment group. All on-study AEs, drug-
related AEs, SAEs and drug-related SAEs will be tabulated using worst grade per 
NCI CTCAE v5.0 criteria by system organ class and preferred term. On-study 
laboratory parameters including hematology, chemistry, liver function and renal 
function will be summarized using worst grade per NCI CTCAE v5.0 criteria.
100 days after 
discontinuation of 
study treatment
Abbreviations: AE adverse event; AESI, adverse events of special interest; CTCAE, Common Terminology Criteria 
for Adverse Event; DLT, dose-limiting toxicity; NCI, National Cancer Institute; SAE, serious adverse event; TRAE, 
treatment-related adverse event.
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10.4.3
Other Analyses
PK and biomarker exploratory analyses will be described in the SAP. The population PK analysis 
and pharmacodynamic analyses may also be presented separately from the main CSR.
10.5
Interim Analyses for Part 2
Interim Analysis for Efficacy
. The 
ORR comparison is conducted between Arm B and Arm A. 
 
 
 
 
 
Bayesian optimal interval (BOIN) design 
Part 1 will employ the Bayesian optimal interval (BOIN) to find the maximum tolerated dose 
(MTD). The BOIN design is implemented in a simple way similar to the traditional 3+3 design but 
is more flexible and possesses superior operating characteristics that are comparable to those of 
the more complex model-based designs.
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The target toxicity rate for the MTD is ߶ൌ0.3 and the maximum sample size is 12. As shown in 
Figure 10.5-1, the BOIN design uses the following rule, optimized to minimize the probability of 
incorrect dose assignment, and to guide dose escalation/de-escalation:
•
If the observed DLT rate at the current dose is ൑0.236, escalate the dose to the next higher 
dose level
•
If the observed DLT rate at the current dose is ൐0.359, de-escalate the dose to the next lower 
dose level
•
Otherwise, stay at the current dose.
For the purpose of overdose control, doses ݆and higher levels will be eliminated from further 
examination
 
, where ݌௝is the true DLT rate of dose level ݆, ݆ൌ1,⋯, 2. This posterior probability is 
evaluated based on the beta-binomial model ݕ௝∣݌௝∼binomialሺ݌௝ሻwith ݌௝∼uniformሺ0,1ሻ, 
where ݕ௝is the number of participants experienced DLT at dose level ݆. When the lowest dose is 
eliminated, stop the trial for safety. The above dose escalation/de-escalation and elimination rule 
can be equivalently presented in Table 10.5-2, which will be used to conduct the trial.
Table 10.5-2:
Dose Escalation/Deescalation Rule for the BOIN Design
Number of evaluable participants treated at 
current dose
3*
4*
5*
6
7
8
9
10
11
12
Escalate if # of DLT ≤ 
0
0
1
1
1
1
2
2
2
2
Deescalate if # of DLT ≥ 
2
2
2
3
3
3
4
4
4
5
Eliminate if # of DLT ≥
2
3
3
3
4
4
5
5
5
6
Abbreviations: BOIN, Bayesian Optimal Interval; DLT, dose limiting toxicity.
Note. "# of DLT" is the number of patients with at least 1 DLT. When none of the actions (ie, escalate, de-escalate or 
eliminate) is triggered, stay at the current dose for treating the next cohort of patients. 
* Dose esclation recommendation will occur when 
 participants within a cohort have completed a 
 DLT period or have been sufficiently followed. Dose de-esclation decision may be made as early as  subjects 
have completed the DLT period based on totality of data.
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Figure 10.5-1:
BOIN Design Flow Chart
Abbreviations: DLT, dose limiting toxicity; MTD, maximum tolerated dose.
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11
REFERENCES
1
Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously 
untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer 
(KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. 
Lancet. 
2019;393(10183):1819-1830. doi:10.1016/S0140-6736(18)32409-7.
2
Hellmann M, Paz-Ares I, Caro R et al. Nivolumab plus ipilimumab in advanced non-small cell 
lung cancer. N Engl J Med 2019: 81:2020-2031.
3
Wang Y, Zhao S, Chen J et al. The KEYNOTE-189 trial as a new paradigm making cure a 
reality for metastatic non-squamous non-small cell lung cancer. Transl Lung Cancer Res. 2020; 
9:2184-2187.
4
Paz-Ares L, Vicente D, Tafreshi A et al. A randomized, placebo-controlled trial of 
pembrolizumab plus chemotherapy in patients with metastatic squamous NSCLC: protocol-
specified final analysis of KEYNOTE 407. J Thorac Oncol 2020; 15:1657-1669.
5
Paz-Ares L, Ciuleau TE, Cobo M et al. First-line nivolumab plus ipilimumab combined with 
two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an 
international, randomised, open-label, Phase 3 trial. Lancet Oncol 2021; 22:198-211.
6
Herbst RS, Majem M, Barlesi F et al. COAST: an open-label, Phase II, multidrug platform 
study of durvalumab alone or in combination with oleclumab or monalizumab in patients with 
unresectable, stage III non-small-cell lung cancer. J Clin Oncol 2022; 0:3383-3393.
7
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics [published 
correction appears in CA Cancer J Clin. 2011 Mar-Apr;61(2):134]. CA Cancer J Clin. 
2011;61(2):69-90. doi:10.3322/caac.20107.
8
BMS-986315: Investigator’s Brochure Version 3. Bristol-Myers Squibb Company; 2023 
Document Control No. 930146552.
9
BMS-986315: Study of BMS-986315 Alone and in Combination With Nivolumab or 
Cetuximab in Participants With Advanced Solid Tumors (Study CA047-004). Bristol-Myers 
Squibb Company; study ongoing.
10 BMS-936558: An Open-Label, Randomized Phase 3 Trial of Nivolumab, or Nivolumab plus 
Ipilimumab, or Nivolumab plus platinum doublet chemotherapy versus platinum doublet 
chemotherapy in Subjects with Chemotherapy-Naïve Stage IV or Recurrent Non-Small Cell 
Lung Cancer (NSCLC) (Study CA209227). Bristol-Myers Squibb Company; study ongoing.
11 BMS-986016: A Phase 2 Randomized Study of Relatlimab plus Nivolumab in Combination 
with Chemotherapy vs. Nivolumab in Combination with Chemotherapy as First Line 
Treatment for Participants with Stage IV or Recurrent Non-small Cell Lung Cancer (NSCLC) 
(Study CA224104). Bristol-Myers Squibb Company; study ongoing.
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12 Rizvi NA, Hellmann MD, Brahmer JR, et al. Nivolumab in Combination With Platinum-Based 
Doublet Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. 
J Clin Oncol. 2016;34 :2969-2979. doi:10.1200/JCO.2016.66.9861.
13 United States Food and Drug Administration. Surrogate Endpoint Table 2022 Available from: 
URL:https://www.fda.gov/drugs/development-resources/table-surrogate-endpoints-were-
basis-drug-approval-or-licensure.
14 Blumenthal GM, Karuri SW, Zhang H, et al. Overall response rate, progression-free survival, 
and overall survival with targeted and standard therapies in advanced non-small-cell lung 
cancer: US Food and Drug Administration trial-level and participant-level analyses. J Clin
Oncol. 2015;33(9):1008-1014. doi:10.1200/JCO.2014.59.0489.
15 Goring S, Varol N, Waser N, et al. Correlations between objective response rate and survival-
based endpoints in first-line advanced non-small cell lung Cancer: A systematic review and 
meta-analysis. Lung Cancer. 2022;170:122-132. doi:10.1016/j.lungcan.2022.06.009.
16 Peey-Sei Kok, Won-Hee Yoon, et al. Tumor Response End Points as Surrogates for Overall
Survival in Immune Checkpoint Inhibitor Trials: A Systematic Review and Meta-Analysis. 
JCO Precision Oncology 2021;5;1151-1159.
17 Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-
cell non–small-cell lung cancer. N Engl J Med. 2015;373:123-35.
18 Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous 
non–small-cell lung cancer. N Engl J Med. 2015;373:1627-39.
19 Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or 
monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.
20 Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line 
treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, 
Phase 1, multicohort study. Lancet Oncol. 2017;18:31-41.
21 Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-
cell carcinoma. N Engl J Med. 2015;373:1803-13.
22 Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from 
Phase II and Phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin 
Oncol. 2015;33:1889-94.
23 Schadendorf D, Wolchok JD, Hodi FS, et al. Efficacy and quality of life outcomes in patients 
with advanced melanoma (MEL) who discontinued treatment with nivolumab (NIVO) plus 
ipilimumab (IPI) due to toxicity in a Phase III trial (CheckMate 067). Presented at 2016 Annual 
Meeting of the European Association of Dermato-Oncology; 2016 Aug 31-Sep 3, Vienna, 
Austria.
24 Felp A, Font E, Gettinger SN, Burgio MA, et al. Three-year follow-up from Checkmate 
017/057: nivolumab versus docetaxel in patients with previously treated advanced non-small 
lung cancer (NSCLC). Poster discussion presentation at: European Society of Medical 
Oncology Annual Meeting; 2017 Sep 8-12; Madrid, Spain.
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25 Spigel DR, McLeod M, Hussein MA, et al. Oral presentation at: European Society of Medical 
Oncology Annual Meeting; 2017 Sep 8- 12; Madrid, Spain.
26 Investigator Brochure Nivolumab Bristol Myers Squibb Company 2022, Document Control 
No. 930038243.
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APPENDICES
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APPENDIX 1
LIST OF ABBREVIATIONS
Term
Definition
ADA
anti-drug antibodies 
AE
adverse event
AI_AUC   
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose.    
ALK
ALK receptor tyrosine kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ART
antiretroviral therapy
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC(0-T)  
Area under the serum concentration-time curve from time zero to time of 
last quantifiable concentration  
AUC(TAU)  
Area under the serum concentration-time curve in 1 dosing interval  
AxMP
Auxiliary Medicinal Product
BICR
blinded independent central review
BMI
Body mass index
BMS
Bristol-Myers Squibb Company
BOIN
Bayesian optimal interval
BOR
best overall response
BP
blood pressure
BRAF
B-Raf proto-oncogene
C
Cycle
CD8
cluster of differentiation 8
CI
confidence interval
Cmax
Maximum observed serum concentration  
CONSORT
Consolidated Standards of Reporting Trials
CPK
creatine phosphokinase
CR
complete response
CrCl 
creatinine clearance
CRP
C-reactive protein 
Css-avg   
Average serum concentration over a dosing interval (AUC[TAU]/tau) at 
steady state   
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Term
Definition
CT
computed tomography
Ctau
Serum concentration at the end of a dosing interval  
Ctrough  
Trough observed serum concentrations (this includes pre-dose 
concentrations [C0] and Ctau)  
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor deoxyribonucleic acid
CTLA-4
cytotoxic T lymphocyte–associated antigen 4
D
Day
DCR
disease control rate
DF
Degree of fluctuation or fluctuation index (to be calculated at steady 
state)   
 
DLT
dose-limiting toxicity
DAC
Data Assessment Committee
DNA
deoxyribonucleic acid
DoR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
EOI
end of infusion
ESMO
European Society for Medical Oncology
ER
exposure-response 
FDA
US Food and Drug Administration
FSH
follicle-stimulating hormone
HCV
hepatitis C virus
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Term
Definition
Hgb
Hemoglobin
HIV
human immunodeficiency virus
HLA-E
MHC class I antigen E
HR
hazard ratio
IA
interim analysis
IASLC
International Association for the Study of Lung Cancer classification
IB
Investigator  Brochure
ICF
informed consent form 
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IHC
Immunohistochemistry
IMAE
immune-mediated adverse event.  
IMG
Immunogenicity
IMP
Investigational Medicinal Product
IA
interim analysis
I-O
Immuno-Oncology
IP
Investigational Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITIM
immunoreceptor tyrosine-based inhibitory motif
IV
intravenous(ly)
LAG-3
lymphocyte activation gene 3
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MET
MET proto-oncogene
MHC
major histocompatibility complex
MRI
magnetic resonance imaging
MUGA
multiple gated acquisition scan
MTD
maximum tolerated dose 
NK
natural killer
NKG2A
natural killer group 2 member A
NTRK
neurotrophic tyrosine receptor kinase
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Term
Definition
Non-IMP
Non-investigational Medicinal Product
NQ
non-quantifiable
NSCLC
Non-Small Cell Lung Cancer
NSCLC-SAQ
Non-Small Cell Lung Cancer Symptom Assessment Questionnaire
NSQ 
non-squamous
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PD
Pharmacodynamic(s)
PDCT
platinum doublet chemotherapy
PD-1
programmed cell death 1
PD-L1
programmed death-ligand 1
PET-CT
Positron emission tomography–computed tomography
PFS
progression free survival
PK
pharmacokinetic(s)
PR
partial response
Q3W
every 3 weeks
Q4W
every 4 weeks
QD
daily
RECIST
Response Evaluation Criteria in Solid Tumors
RET
RET proto-oncogene
RNA
ribonucleic acid 
ROS1
ROS proto-oncogene 1
RT-PCR
reverse transcription-polymerase chain reaction 
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SD
stable disease
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Term
Definition
SmPC
summary of product characteristics
SMT
Safety Management Team
SQ
Squamous
T-HALFeff   
Effective elimination half-life 
TIL
tumor-infiltrating lymphocytes 
Tmax  
Time of maximum observed serum concentration  
TMB
tumor mutational burden
TRAE
treatment-related adverse event
TTE
transthoracic echocardiogram
TTR
time to response
ULN
upper limit of normal
US
United States
USPI
US prescribing information
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
REGULATORY AND ETHICAL CONSIDERATIONS
This study will be conducted in accordance with:
•
Consensus ethical principles derived from international guidelines, including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS)
international ethical guidelines
•
Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP)
guidelines
•
Applicable laws, regulations, and requirements
The study will be conducted in compliance with the protocol. The protocol,
any 
revisions/amendments,
and the participant informed consent form (ICF) will receive 
approval/favorable 
opinion 
by 
the 
Institutional 
Review 
Board/Independent 
Ethics 
Committee (IRB/IEC), and regulatory authorities according to applicable regulations prior to 
initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a quality issue (eg, protocol deviation) that is likely to affect, 
to a significant degree, 1 or more of the following: (1) the rights, physical safety, or mental integrity 
of 1 or more participants; (2) the scientific value of the clinical trial (eg, reliability and robustness 
of generated data). Items (1) or (2) can be associated with either GCP regulation(s) or trial 
protocol(s).
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). 
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, Investigator’s Brochure, product labeling information, ICF, 
participant recruitment materials (eg, advertisements), and any other written information to be 
provided to participants.
The investigator, Sponsor, or designee should provide the IRB/IEC with reports, updates, and other 
information (eg, expedited safety reports, amendments, administrative letters) annually, or more 
frequently, in accordance with regulatory requirements or institution procedures.
The investigator is responsible for providing oversight of the conduct of the study at the site and 
adherence to requirements of the following where applicable:
•
ICH guidelines
•
United States (US) Code of Federal Regulations, Title 21, Part 50 (21CFR50)
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•
European Regulation 536/2014 for clinical studies
•
European Medical Device Regulation 2017/745 for clinical device research 
•
the IRB/IEC
•
all other applicable local regulations
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and, if 
applicable, by the local Health Authority), except where necessary to eliminate an immediate 
hazard(s) to study participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s), the deviation or change will be submitted as soon 
as possible to the following:
•
IRB/IEC
•
Regulatory authority(ies), if applicable according to local regulations (per national 
requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and, if applicable, by the local Health Authority must be sent to Bristol-Myers 
Squibb Company (BMS).
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the ICF 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 participants 
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 participants prior to enrollment.
FINANCIAL DISCLOSURE
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information, in accordance with regulations, to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate Health Authorities. Investigators 
are responsible for providing information on financial interests during the study and for 1 year 
after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that participants are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. 
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The Sponsor or designee will provide the investigator with an appropriate sample ICF, which will 
include all elements required by the ICH GCP, and applicable regulatory requirements. The sample 
ICF will adhere to the ethical principles that have their origin in the Declaration of Helsinki.
The investigator or his/her representative must:
•
Obtain IRB/IEC written approval/favorable opinion of the written ICF and any other 
information to be provided to the participant prior to the beginning of the study and after any 
revisions are completed for new information.
•
Provide a copy of the ICF and written information about the study in the language in which 
the participant is proficient prior to clinical study participation. The language must be 
nontechnical and easily understood. 
•
Explain the nature of the study to the participant and answer all questions regarding the study.
•
Inform the participant that his/her participation is voluntary. The participant will be required 
to sign a statement of informed consent that meets the requirements of 21 CFR Part 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.
•
Allow time necessary for the participant to inquire about the details of the study.
•
Obtain an ICF signed and personally dated by the participant and by the person who conducted 
the informed consent discussion. 
•
Include a statement in the participant’s medical record that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.
•
Re-consent the participant to the most current version of the ICF(s) during his/her participation.
•
Revise the ICF whenever important new information becomes available that is relevant to the 
participant’s consent. The investigator, or a person designated by the investigator, should fully 
inform the participant of all pertinent aspects of the study and of any new information relevant 
to the participant’s willingness to continue participation in the study. This communication 
should be documented. 
The confidentiality of records that could identify participants must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the participant’s signed 
ICF, and, in the US, the participant’s signed HIPAA authorization.
The ICF must also include a statement that BMS and local and foreign regulatory authorities have 
direct access to participant records. 
The rights, safety, and well-being of the study participants are the most important considerations 
and should prevail over interests of science and society.
BMS COMMITMENT TO DIVERSITY IN CLINICAL TRIALS
The mission of BMS is to transform patients’ lives through science by discovering, developing, 
and delivering innovative medicines that help them prevail over serious diseases. 
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BMS is committed to doing its part to ensure that patients have a fair and just opportunity to 
achieve optimal health outcomes.
BMS is working to improve the recruitment of a diverse participant population with the goal that 
the clinical trial becomes more reflective of the real-world population and the people impacted by 
the diseases studied.
RECRUITMENT AND INFORMED CONSENT PROCEDURES
Potential participants may be identified by the recruiting investigational team (called “site”) within 
the affiliated clinic/hospital, and/or group practice, through their own chart/database review, using
the inclusion/exclusion criteria defined by the protocol. Potential participants may also be referred
to the site by medical doctors from surrounding hospitals/practices or directly contact one of the 
investigative “sites” following study and site identification through a public registry, such as 
clinicaltrials.gov or euclinicaltrials.eu. The investigator has access to the participant’s medical file,
so, the medical data will remain confidential without the sponsor having access to them. 
Recruitment material will also be utilized as an additional tool to recruit participants per local 
regulations and requirements.
The principal investigator or sub-investigator, or a qualified designee of the investigator’s research 
team will approach potential participants to discuss the option of participating in the clinical trial 
and the consent process.  Informed consent will be obtained by the principal investigator or a 
qualified delegate on the principal investigator’s research team from each participant prior to 
enrollment into the study. The participant will be provided the opportunity to read the information 
sheet and consent form and have all their questions and concerns addressed before giving consent 
in writing.
DATA PROTECTION, DATA PRIVACY, AND DATA SECURITY
BMS collects and processes personal data of study participants, patients, health care providers,
and researchers for biopharmaceutical research and development to advance innovative, high-
quality medicines that address the medical needs of patients. BMS ensures the privacy, protection,
and confidentiality of such personal data to comply with applicable laws. To achieve these goals, 
BMS has internal policies that indicate measures and controls for processing personal data. BMS 
adheres to these standards to ensure that collection and processing of personal data are limited and 
proportionate to the purpose for which BMS collects such personal data. This purpose is clearly 
and unambiguously notified to the individual at the time of collection of personal data. In the true 
spirit of science, BMS is dedicated to sharing clinical trial information and data with participants, 
medical/research communities, the media, policy makers, and the general public. This is done in a 
manner that safeguards participant privacy and informed consent while respecting the integrity of 
national regulatory systems. Clinical trial data, health-related research, and pharmacovigilance 
activities on key-coded health data transferred by BMS across national borders is done in 
compliance with the relevant data protection laws in the country and GCP requirements.
BMS protects Personal Information with adequate and appropriate security controls as indicated 
under the data protection laws. To align with the recommended security standards, BMS has 
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adopted internal security standards and policies to protect personal data at every stage of 
its processing.
To supplement these standards, BMS enters into Clinical Trial Agreements (CTAgs) with 
confidentiality obligations to ensure proper handling and protection of personal data by third 
parties accessing and handling personal data.
BMS takes unauthorized access and disclosure of Personal Information very seriously. BMS has 
adopted the security standards that include National Institute of Standards and Technology 
Cybersecurity Framework for studies in the US. BMS aligns with these standards to continuously 
assess and improve its ability to protect, detect, and respond to cyber attacks and other 
unauthorized attempts to access personal data. These standards also aid in mitigating possible 
adverse effects. Furthermore, BMS Information Technology has defined 6 principles to protect our 
digital resources and information: 
1)
Responsibilities of IT Personnel
2) Securing the BMS Digital Infrastructure
3) Identity and Access Management
4) External Partner Connections
5) Cyber Threat Detection and Response
6) Internal Cyber Incident Investigation
SOURCE DOCUMENTS
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the electronic Case Report Form (eCRF) that are 
transcribed from source documents must be consistent with the source documents or the 
discrepancies must be explained. 
•
The investigator may need to request previous medical records or transfer records depending 
on the study. Also, current medical records must be available.
•
Definition of what constitutes source data and its origin can be found in the source data location 
list/map or equivalent document.
The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original, and attributable, whether the data are handwritten 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 records/electronic health 
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records, adverse event (AE) tracking/reporting, protocol-required assessments, and/or drug 
accountability records.
When paper records from such systems are used in place of an 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. 
STUDY INTERVENTION RECORDS
Records for study intervention (whether supplied by BMS, its vendors, or the site) must 
substantiate study intervention integrity and traceability from receipt, preparation, administration, 
and through destruction or return. Records must be made available for review at the request of 
BMS/designee or a Health Authority.
If
Then
Supplied by BMS (or its 
vendors)
Records or logs must comply with applicable regulations and 
guidelines and should include the following:
•
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 participant, 
including unique participant identifiers
•
amount transferred to another area/site for dispensing or 
storage
•
non-study disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for 
bioavailability/bioequivalence/biocomparability, if applicable 
•
dates and initials of person responsible for Investigational 
Product dispensing/accountability per the Delegation of 
Authority Form
Sourced by site and not 
supplied by BMS or its 
vendors 
(examples 
include 
Investigational 
Product sourced from the 
site’s 
stock 
or 
commercial supply or a 
specialty pharmacy)
The investigator or designee accepts responsibility for documenting 
traceability and study intervention integrity in accordance with 
requirements applicable under law and the standard operating 
procedures/standards of the sourcing pharmacy
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BMS or its designee will provide forms to facilitate inventory control if the investigational site 
does not have an established system that meets these requirements.
CASE REPORT FORMS
The terms “participant” and “subject” refer to a person who has consented to participate in the 
clinical research study. Typically, the term “participant” is used in the protocol and the term 
“subject” is used in the Case Report Form (CRF).
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 test result 
abnormalities that are reported or identified during the study.
For sites using the Sponsor or designee electronic data capture (EDC) tool, eCRFs will be prepared 
for all data collection fields except for fields specific to serious adverse events (SAEs) and 
pregnancy, which will be reported on the electronic SAE form and Pregnancy Surveillance Form, 
respectively. If the electronic SAE form is not available, a paper SAE form can be used.
The confidentiality of records that could identify participants 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 and SAE/pregnancy CRFs must be promptly reviewed, signed, and dated by 
the investigator or qualified physician who is a sub-investigator and who is delegated this task on 
the Delegation of Authority Form. Sub-investigators in Japan may not be delegated the CRF 
approval task. For eCRFs, review and approval/signature are completed electronically through the 
BMS EDC tool. The investigator must retain a copy of the CRFs, including records of the changes 
and corrections.
Each individual electronically signing eCRFs must meet Sponsor or designee training 
requirements and must only access the BMS EDC tool using the unique user account provided by 
the Sponsor or designee. User accounts are not to be shared or reassigned to other individuals.
MONITORING
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of non-compliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan.
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 
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with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable.
Certain CRF pages and/or electronic files may serve as source documents.
In addition, the study may be evaluated by the Sponsor or designee internal auditors and 
government inspectors who must be allowed access to CRFs, source documents, other study files, 
and study facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities 
and promptly forward copies of inspection reports to the Sponsor or designee. 
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or its designee, whichever is longer. 
The investigator (or head of the study site in Japan) must contact BMS prior to destroying any 
records associated with the study.
BMS or its designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed-upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or its designee. 
Records collected throughout the study will be stored in the BMS clinical data management system 
for a duration of the life of the product plus 25 years.
RETURN OF STUDY INTERVENTION
For this study, study interventions (those supplied by BMS or a vendor or sourced by the 
investigator), such as partially used study intervention containers, vials, and syringes, may be 
destroyed on site. 
If
Then
Study interventions supplied by 
BMS (including its vendors)
Any unused study interventions supplied by BMS can only 
be destroyed after being inspected and reconciled by the 
responsible Study Monitor,
unless study intervention
containers must be immediately destroyed as required for 
safety or to meet local regulations (eg, cytotoxic or biologic
agents).
Partially used study interventions and/or empty containers 
may 
be 
destroyed 
after 
proper reconciliation 
and 
documentation. However, unused Investigational Medicinal 
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If
Then
Product must be reconciled by the site monitor/clinical 
research associate prior to destruction.
If study interventions will be returned, the return will be 
arranged by the responsible study monitor.
Study interventions sourced by 
site, not supplied by BMS (or its 
vendors; eg, study interventions 
sourced from the site’s stock or 
commercial 
supply 
or 
a 
specialty pharmacy)
It is the investigator’s or designee’s responsibility to dispose 
of all containers according to the institutional guidelines 
and procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal of study interventions, 
provided that procedures for proper disposal have been established according to applicable federal, 
state, local, and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. The following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
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 (eg, 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 
Study Monitor to review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met, the responsible Study Monitor will make arrangements 
for return of study interventions provided by BMS (or its vendors). Destruction of non-study 
interventions sourced by the site, not supplied by BMS, is solely the responsibility of the 
investigator or designee.
STUDY AND SITE CLOSURE
The Sponsor/designee reserves the right to close the study site or to terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study-site closure visit has been performed.
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The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or investigator may include, but are 
not limited to, the following:
For study termination:
•
Discontinuation of further study intervention development
For site termination:
•
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local Health Authorities, the Sponsor’s procedures, or GCP guidelines
•
Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by 
the investigator
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should ensure 
appropriate participant therapy and/or follow-up.
DISSEMINATION OF CLINICAL STUDY DATA
To benefit potential study participants, patients, health care providers, and researchers and to help 
BMS honor its commitments to study participants, BMS will make information about clinical 
research studies and a summary of their results available to the public per regulatory and BMS 
requirements. BMS will post study information on local, national, or regional databases in 
compliance with national and international standards for disclosure. BMS may also voluntarily 
disclose information to applicable databases.
CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the Clinical Study Report (CSR). 
For each CSR related to this protocol, the following criteria will be used to select the Signatory 
Investigator:
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator 
•
Study Steering Committee chair or designee
•
Participant recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (eg, among top quartile of enrollers from a specified region or country)
•
Other criteria (as determined by the study team)
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In the European Union (EU), the summary of results and summary for laypersons will be submitted 
within 1 year of the end of trial in EU/European Economic Area and third countries.
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to the Sponsor or designee. 
Any publications or abstracts arising from this study must adhere to the publication requirements 
set forth in the Clinical Trial Agreement (CTAg) governing [study site or investigator] 
participation in the study. These requirements include, but are not limited to, submitting proposed 
publications to the Sponsor or designee at the earliest practicable time prior to submission or 
presentation and otherwise within the period set forth in the CTAg.
Scientific publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
Principal Investigator, sub-investigator, or any other member of the study staff without the prior 
written consent of the Sponsor.
Authorship of publications at the Sponsor is aligned with the criteria of the International 
Committee of Medical Journal Editors (ICMJE; www.icmje.org). Authorship selection is based on 
significant contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE 
criteria for authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable participants with quality data), analysis, or interpretation of data for the 
work (eg, problem solving, advice, evaluation, insights, and conclusion)
2) Drafting the work or revising it critically for important intellectual content
3) Final approval of the version to be published
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved
Those who make the most significant contributions, as defined above, will be considered by the 
Sponsor for authorship of the primary publication. Sub-investigators will generally not be 
considered for authorship in the primary publication. Geographic representation will also be 
considered.
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. 
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition occurring in a clinical investigation participant after signing of 
informed consent, whether or not considered related to the study intervention.
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
test result), symptom, or disease temporally associated with the study intervention.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, electrocardiograms, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal laboratory test 
results or other safety assessment findings 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 
the condition 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), should not be reported as an AE/serious adverse event (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).
DEFINITION OF SAE
If an event is not an AE per the definition above, then it cannot be an SAE, even if serious 
conditions are met.
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SERIOUS ADVERSE EVENTS
A serious adverse event (SAE) is defined as any untoward medical occurrence that, at 
any dose:
Results in death.
Is life threatening (defined as an event in which the participant 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).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
•
A visit to the emergency department or other hospital department < 24 hours that does not 
result in admission (unless considered an important medical or life-threatening event).
•
Elective surgery that was planned prior to signing consent.
•
Admissions 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 enrollment 
in the study. Appropriate documentation is required in these cases.
•
Admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason).
•
Admission for administration of anticancer therapy in the absence of any other 
SAEs (applies to oncology protocols).
Results in persistent or significant disability/incapacity.
Is a congenital anomaly/birth defect.
Is an important medical event (defined as a medical event[s] that may not be immediately life
threatening or results in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above). Examples 
of such events include, but are not limited to, intensive treatment in an emergency department 
or at home for allergic bronchospasm and 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 9.2.7: Potential Drug-induced Liver Injury of the protocol for the 
definition of a potential DILI.) 
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Pregnancy and DILI must follow the same transmission timing and processes to BMS as those 
used for SAEs. (See Section 9.2.5: Pregnancy of the protocol for reporting pregnancies.)
EVALUATING AES AND SAES
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 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 the 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 the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study using National Cancer Institute Common Terminology Criteria for Adverse Events NCI-
CTCAE v.5.0.
An event is defined as “serious” when it meets at least 1 of the pre-defined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. 
(Note: Follow-up SAE reports must include the same investigator term[s] initially reported.) 
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If an ongoing SAE changes in its intensity or relationship to study intervention or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or the designee) using the same procedure used for transmitting the initial SAE report.
All AEs/SAEs must be followed to resolution or stabilization.
REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study intervention, and pregnancies must be reported 
to BMS (or the designee) promptly and not to exceed 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the electronic Case Report 
Form (eCRF).
−
The paper SAE Report Form is intended only as a back-up option when the electronic 
data capture system is unavailable/not functioning for transmission of the eCRF to BMS 
(or the designee).
♦In this case, the paper form is transmitted via email or confirmed fax transmission.
♦When paper forms are used, the original paper forms are to remain on site.
•
Pregnancies must be recorded on paper Pregnancy Surveillance Forms and transmitted via 
email or confirmed fax transmission.
SAE Email Address: 
SAE Fax Number: Will be provided by local site monitor.
SAE Telephone Contact (required for SAE and pregnancy reporting): Will be provided by 
local site monitor.
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND
METHODS OF CONTRACEPTION
Appendix 4 provides general information and definitions related to Women of Childbearing 
Potential (WOCBP) and methods of contraception that can be applied to most clinical trials. For 
information specific to this study regarding acceptable contraception requirements for female and 
male participants, refer to Section 6.1: Inclusion Criteria of the protocol. Only the contraception 
methods as described in Section 6.1: Inclusion Criteria of the protocol are acceptable for this study.
DEFINITIONS
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Pre-menopausal 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.
•
Post-menopausal female
−
A post-menopausal state is defined as 12 months of amenorrhea in a woman over the age 
of 45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle-stimulating hormone (FSH) level 
> 40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period to obtain a physiologic FSH level. The 
duration of the washout period is a function of the type of HRT used. Suggested guidelines for the 
duration of the washout periods for HRT types are presented below. Investigators should use their 
judgment in checking serum FSH levels. 
•
1-week minimum for vaginal hormonal products (rings, creams, gels)
•
4-week minimum for transdermal products
•
8-week minimum for oral products
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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.
End of Relevant Systemic Exposure
End of relevant systemic exposure is the time point at which the study intervention (Investigational 
Medicinal Product [IP/IMP] and other study interventions ie, Non-IMP/AxMP required for study)
or any active major metabolites have decreased to a concentration that is no longer considered 
relevant for human teratogenicity or fetotoxicity. This should be evaluated in context of safety 
margins from the no-observed-adverse-effect level or the time required for 5 half-lives of the study 
intervention to pass.
METHODS OF CONTRACEPTION
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of < 1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation. (This method of contraception can only be used 
by WOCBP participants in studies in which hormonal contraception is permitted by the 
study protocol.)b
−
Oral (birth control pills)
−
Intravaginal (rings)
−
Transdermal
•
Combined (estrogen- and progestogen-containing) hormonal contraception must begin at 
least 30 days prior to initiation of study therapy.
•
Progestogen-only hormonal contraception associated with inhibition of ovulation. (This
method of contraception can only be used by WOCBP participants in studies in which 
hormonal contraception is permitted by the study protocol.)b
−
Oral
−
Injectable
•
Progestogen-only hormonal contraception must begin at least 30 days prior to initiation of 
study therapy.
Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation. (This method of contraception can only be used by WOCBP 
participants in studies in which hormonal contraception is permitted by the study protocol.)b
•
Intrauterine device.
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•
Intrauterine system (IUS). (This method of contraception can only be used by WOCBP 
participants in studies in which hormonal contraception is permitted by the study 
protocol.)b,c
•
Bilateral tubal occlusion.
•
Vasectomized partner.
Having a vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used.
A vasectomy is a highly effective contraception method provided that the participant is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.
Male participants will be required to always use a latex or other synthetic condom during any 
sexual activity (eg, vaginal, anal, oral) with WOCBP, even if the participants have undergone a 
successful vasectomy or if their partner is pregnant or breastfeeding.
•
Sexual abstinence.
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
•
Continuous abstinence must begin at least 30 days prior to initiation of study therapy.
•
It is not necessary to use any other method of contraception when complete abstinence 
is elected.
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2 of the protocol.
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participant chooses to forego complete abstinence.
•
Periodic abstinence (including, but not limited to, calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactation amenorrhea 
method (LAM) are not acceptable methods of contraception for this study.
NOTES: 
a Typical use failure rates may differ from failure rates when contraceptive methods are used 
consistently and correctly. Use should be consistent with local regulations regarding the use 
of contraceptive methods for participants in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study intervention, which 
may reduce the efficacy of the contraceptive method. Hormonal contraception is permissible 
only when there is sufficient evidence that the Investigational Medicinal Product and other 
study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous. In this case, 
alternative methods of contraception should be utilized. For information specific to this study
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regarding permissibility of hormonal contraception, refer to Section 6.1: Inclusion Criteria
and Section 7.7.1: Prohibited and/or Restricted Treatments of the protocol.
c IUSs are acceptable methods of contraception in the absence of definitive drug interaction 
studies when hormone exposures from intrauterine devices do not alter contraception 
effectiveness. For information specific to this study regarding permissibility of hormonal 
contraception, refer to Section 6.1: Inclusion Criteria and Section 7.7.1: Prohibited and/or 
Restricted Treatments of the protocol.
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of > 1% per year when used consistently and correctly.
•
Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously.
•
Diaphragm with spermicide.
•
Cervical cap with spermicide.
•
Vaginal sponge with spermicide.
•
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 in which hormonal contraception is prohibited.)
Unacceptable Methods of Contraception
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods).
•
Withdrawal (coitus interruptus).
•
Spermicide only.
•
LAM.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of pregnancy information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5: Pregnancy of the protocol and Appendix 3.
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APPENDIX 5
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS 
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about 
more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
Reference: Oken MM, Creech RH, et al. Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. 
Am J Clin Oncol 1982; 5: 649-655.
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APPENDIX 6
IMAE MANAGEMENT ALGORITHMS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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APPENDIX 7
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline with BMS modifications.1
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
•
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or ൒2x slice thickness if 
greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm).
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/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other lesions are considered non-measurable, 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, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
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Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions
•
Bone scan, PET scan and plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
•
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
above.
•
Blastic bone lesions are non-measurable.
1.4
Baseline Documentation Of ‘Target’ And ‘Non-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 (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Note: A maximum of two lesions can be selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum of 
two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
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 above, 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.
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’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
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2
RESPONSE CRITERIA
2.1
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.
•
Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed 
as either fully resolved or too small to measure (due to missing or poor quality images), and the 
sum of diameters of the remaining measured target lesions (if any) has not increased sufficiently 
to meet Progressive Disease as defined above. 
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (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. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm).
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. 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 
as the reference diameter. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
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small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
2.1.1.3
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. Similarly, 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’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group 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)
•
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, 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 qualify for unequivocal progression status. Pleural effusions, pericardial 
effusions and ascites will not be followed as target or non-target lesions and will not contribute to 
response or progression. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely rare.
2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
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disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, 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 lymphangitic disease from localized to widespread, or may be 
described as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial.
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, 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 patient’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.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). 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 patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued 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. While FDG-PET 
response assessments need additional study, it is sometimes reasonable to incorporate the use 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:
1) 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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2) 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 abnormal 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.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmation and censoring rules regarding subsequent therapy. The patient’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. Furthermore, depending on the nature of the study 
and the protocol requirements, it may also require confirmatory measurement.
2.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response
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
1 CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = 
inevaluable.
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Table 2.3.2-2:
Time Point Response
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
≥4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in 
Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment or randomization date.
For example, if the first scheduled follow-up imaging visit is Week 6 (± 7 days) for a particular 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study).  If the subject is not on-study 
for at least this amount of time, any tumor assessment indicating stable disease before this time 
period will have a Best Response of NE unless PD is identified.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
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Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
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, and NE = inevaluable.
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 patient 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.
2.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with an intervening NE or PR (eg, 
CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of a 
previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRs for confirmation.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
REFERENCES
1
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47.
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