Phase 1/2 Open-label Study of BMS-986466 in Combination With Adagrasib With or Without Cetuximab in Participants With KRAS G12C-mutant Advanced Solid Tumors
Phase: PHASE1
Conditions: Advanced Solid Tumors
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
Phase 1/2 Open-label Study of BMS-986466 in Combination with Adagrasib with or without 
Cetuximab in Participants with KRAS G12C-mutant Advanced Solid Tumors 
 
NCT Number: NCT06024174 
Document Date (Date in which document was last revised): 07 Jul 2023 
 
 
 

Page:
1
Protocol Number:
CA1260015
Date:
16-May-2023
Revised Date
07-Jul-2023
CLINICAL PROTOCOL CA1260015
Phase 1/2 Open-label Study of BMS-986466 in Combination with Adagrasib with or without 
Cetuximab in Participants with KRAS G12C-mutant Advanced Solid Tumors 
Compound: BMS-986466 (BBP-398, IACS-15509)
Brief Title:
A Study of BMS-986466 with Adagrasib with or without Cetuximab in Participants with KRAS 
G12C-mutant Solid Tumors
Protocol Amendment 01
Medical Monitor Name and Contact Information:
Clinical Trial Physician – Medical Monitor
Bristol-Myers Squibb Company
Parque Tecnológico Cartuja 93
C/ Isaac Newton 4
41092 Sevilla, Spain
Phone:
email: 
24-hour 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
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Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
Protocol Amendment No.: 01
Date: 07-Jul-2023
2
REGULATORY AGENCY IDENTIFIER NUMBER(S)
IND: 164519
EU CT Number: 2023-505070-15-00
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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BMS-986466 (BBP-398)
SHP2 inhibitor
Protocol Amendment No.: 01
Date: 07-Jul-2023
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Changes
Protocol 
Amendment 01
07-Jul-2023
The purpose of this protocol amendment is to elaborate on the 
inclusion criteria for participants harboring actionable mutations, 
 
 to 
include the criterion of having received an approved targeted therapy 
for that particular mutation, if any, to be considered eligible to 
participate in this study. 
Administrative 
Letter 01
22-May-2023
The purpose of this Administrative Letter is to correct a typographical 
error in Table 2-1: Cycle 1 Day 15 (changed to Day 18) and Day 22 
(deleted). Updates were made to align with Table 2-3. 
Original Protocol
16-May-2023
Not applicable.
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CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 01:
The purpose of this protocol amendment is to elaborate on the inclusion criteria for participants
harboring actionable mutations, 
 
 to include the criterion of having received an approved targeted therapy for that particular 
mutation, if any, to be considered eligible to participate in this study.
This amendment also incorporates changes from the approved Administrative Letter 01, which are 
detailed in the Document History, but not listed in the Summary of Key Changes below. 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 01
Section 
Number & 
Title
Description of Change
Brief Rationale
Table 2-1: 
Procedural 
Outline (Part 1 
DDI Cohort 
Only; 
CA1260015)
Deleted footnote “h” “Other targetable 
mutations, including ALK, ROS1, RET, 
NTRK, MET amplification, MET exon 14 
skipping mutations, and other non-KRAS 
mutations, should be
documented if 
available.” As a result of the deletion, 
footnote “h” was updated to “g” for the 
“Participants with PDAC and BTC: 
EGFR, GFFR2, IDH1, BRAF non-
V600X, and Other Mutations.”
To address redundancy of footnote “h” with “g”
Section 6.1: 
Inclusion Criteria
Added 
inclusion 
criterion 
2)d)iii) 
regarding 
participants 
with 
known 
actionable mutations.
 to clarify prior 
treatments with targeted therapies for tumors 
with actionable mutations.
All
Minor formatting and typographical 
corrections
Minor, therefore, have not been summarized
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Date: 07-Jul-2023
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 01: ............................ 
 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 01 ......................... 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 PROTOCOL SUMMARY ......................................................................................... 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.1 Study Rationale ................................................................................................. 
 
3.2 Background ....................................................................................................... 
 
3.2.1 BMS-986466 Mechanism of Action ......................................................... 
 
3.2.1.1 BMS-986466 Nonclinical Pharmacology ....................................... 
 
3.2.1.2 BMS-986466 Nonclinical Pharmacokinetics .................................. 
 
3.2.1.3 BMS-986466 Nonclinical Toxicology ............................................. 
 
3.2.1.4 BMS-986466 Clinical Pharmacology ............................................. 
 
3.2.1.5 BMS-986466 Clinical Safety ........................................................... 
 
3.2.1.6 BMS-986466 Clinical Efficacy ....................................................... 
 
3.2.2 Adagrasib ................................................................................................. 
 
3.2.3 Cetuximab ................................................................................................ 
 
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 Part 1: DDI Cohort and Dose Escalation ............................................... 
 
5.1.2 Part 2: Randomized Dose Expansion ...................................................... 
 
5.1.2.1 Part 2A: 2L KRAS G12C-mutant (G12C Inhibitor-treatment Naïve) 
NSCLC .................................................................................................. 
 
5.1.2.2 Part 2B: 2L KRAS G12C-mutant (G12C Inhibitor-treatment Naïve) 
CRC ....................................................................................................... 
 
5.1.3 Screening.................................................................................................. 
 
5.1.4 Treatment Period ..................................................................................... 
 
5.1.5 Follow-up Period ..................................................................................... 
 
5.1.6 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 DDI Cohort ........................................................................ 
 
5.4.2 Rationale for Dose Escalation Design ..................................................... 
 
5.4.3 Rationale for SHP2 and EGFR Inhibitors in Combination with KRAS 
G12C Inhibitors .......................................................................................... 
 
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5.4.4 Rationale for Adagrasib and Adagrasib Plus Cetuximab as Comparator
..................................................................................................................... 
 
5.5 Justification for Dose ........................................................................................ 
 
5.5.1 Choice of Target Exposures for BMS-986466 Based on Study NAV-1001
..................................................................................................................... 
 
5.5.2 Justification for the Choice of BMS-986466 10 mg Single Dose in 
Combination with Adagrasib 400 mg BID in Part 1A DDI Cohort ........... 
 
5.5.3 Dose Selection Strategy for BMS-986466 in Parts 1A and 1B ................ 
 
5.5.4 Justification for the Choice of Adagrasib 400 mg BID in Combination 
with BMS-986466........................................................................................ 
 
5.5.5 Justification for the Choice of Adagrasib 600 mg BID with or without 
Cetuximab as a Comparator ....................................................................... 
 
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 ........................................................................................ 
 
6.3.1 Meals and Dietary Restrictions ............................................................... 
 
6.3.2 Caffeine, Alcohol, and Tobacco ............................................................... 
 
6.3.3 Activity ..................................................................................................... 
 
6.4 Screen Failures .................................................................................................. 
 
6.4.1 Re-testing During Screening .................................................................... 
 
7 STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ....................... 
 
7.1 Study Interventions Administered .................................................................... 
 
7.1.1 BMS-986466 and Adagrasib Administration ........................................... 
 
7.1.2 Cetuximab Administration ....................................................................... 
 
7.2 Assignment to Study Intervention .................................................................... 
 
7.3 Blinding............................................................................................................. 
 
7.4 Dosage Modification ......................................................................................... 
 
7.4.1 Dose-limiting Toxicities ........................................................................... 
 
7.4.1.1 Non-hematological Toxicity ............................................................ 
 
7.4.1.2 Hematological Toxicity ................................................................... 
 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
 
7.6 Study Intervention Compliance ........................................................................ 
 
7.7 Concomitant Therapy........................................................................................ 
 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
 
7.7.2 Imaging Restrictions and Precautions ..................................................... 
 
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 Post-study Intervention Study Follow-up................................................. 
 
8.2 Discontinuation From the Study ....................................................................... 
 
8.2.1 Individual Discontinuation Criteria ........................................................ 
 
8.3 Lost to Follow-up .............................................................................................. 
 
8.4 Study Stopping Criteria..................................................................................... 
 
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9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
9.1 Efficacy Assessments ........................................................................................ 
 
9.1.1 Efficacy Assessment for the Study ............................................................ 
 
9.1.2 Imaging Assessment for the Study............................................................ 
 
9.1.2.1 Imaging Schedule ............................................................................ 
 
9.1.2.2 Methods of Measurement ................................................................ 
 
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 ..................................................... 
 
9.2.7 Potential Drug-induced Liver Injury ....................................................... 
 
9.2.8 Other Safety Considerations .................................................................... 
 
9.3 Overdose ........................................................................................................... 
 
9.4 Safety ................................................................................................................ 
 
9.4.1 Physical Examinations and Measurements ............................................. 
 
9.4.2 Vital Signs and Oxygen Saturation .......................................................... 
 
9.4.3 Electrocardiograms ................................................................................. 
 
9.4.4 2-D Echocardiogram/MUGA................................................................... 
 
9.4.5 Clinical Safety Laboratory Assessments .................................................. 
 
9.4.6 Suicidal Risk Monitoring ......................................................................... 
 
9.5 Pharmacokinetics .............................................................................................. 
 
9.5.1 Pharmacokinetic Sampling Instructions and Collection Windows .......... 
 
9.5.1.1 Pharmacokinetic Sample Collection Windows ............................... 
 
9.5.2 Pharmacokinetic Sample Analyses .......................................................... 
 
9.6 Immunogenicity Assessments ........................................................................... 
 
9.7 Biomarkers ........................................................................................................ 
 
9.7.1 Germline Genetics ................................................................................... 
 
9.7.2 Participant Selection Biomarkers ............................................................ 
 
9.7.3 Blood Samples for Exploratory Biomarkers ............................................ 
 
9.7.4 Tumor Samples for Exploratory Biomarkers ........................................... 
 
9.7.5 Other Biomarkers..................................................................................... 
 
9.8 Optional Future Research ................................................................................. 
 
9.9 Other Assessments ............................................................................................ 
 
9.10 Healthcare Resource Utilization ..................................................................... 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
 
10.1 Statistical Hypotheses ..................................................................................... 
 
10.2 Sample Size Determination ............................................................................. 
 
10.3 Analysis Sets ................................................................................................... 
 
10.4 Statistical Analyses ......................................................................................... 
 
10.4.1 General Considerations ......................................................................... 
 
10.4.2 Primary Endpoint(s) .............................................................................. 
 
10.4.3 Secondary Endpoint(s) ........................................................................... 
 
10.4.4 Exploratory Endpoint(s) ........................................................................ 
 
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10.4.5 Other Safety Analyses ............................................................................ 
 
10.4.5.1 Continuous Safety Monitoring ...................................................... 
 
10.4.6 Other Analyses ....................................................................................... 
 
10.5 Interim Analyses ............................................................................................. 
 
11 REFERENCES ........................................................................................................ 
 
12 APPENDICES ......................................................................................................... 
 
APPENDIX 1 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 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS ........................ 
 
APPENDIX 7 TITE-BOIN DECISION TABLE ......................................................... 
 
APPENDIX 8 MEDICATIONS ASSOCIATED WITH QT PROLONGATION ....... 
 
 
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CA1260015
SHP2 inhibitor
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Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
1
PROTOCOL SUMMARY
Protocol Title
Phase 1/2 Open-label Study of BMS-986466 in Combination with Adagrasib with or without 
Cetuximab in Participants with KRAS G12C-mutant Advanced Solid Tumors 
Brief Title
A Study of BMS-986466 with Adagrasib with or without Cetuximab in Participants with KRAS 
G12C-mutant Solid Tumors
Study 
Intervention
BMS-986466 in combination with adagrasib in participants with KRAS G12C-mutant non-small 
cell lung cancer, pancreatic duct adenocarcinoma, and biliary tract cancer, and BMS-986466 in 
combination with adagrasib with or without cetuximab in participants with KRAS G12C-mutant 
colorectal cancer.
Background 
and Rationale
BMS-986466 is a potent, selective, orally active allosteric inhibitor of SHP2, a ubiquitously 
expressed scaffolding protein and tyrosine phosphatase that transduces signaling from multiple 
RTKs to activate the small GTPase, RAS, and MAPK signaling pathway and can 
dephosphorylate and deactivate several negative regulators of the RAS/MAPK pathway. 
Adagrasib is a potent, orally available, small molecule, covalent inhibitor of KRAS G12C 
 
 
 
 Since SHP2 is a central node in downstream RTK activation, BMS-986466 may be 
beneficial as a component of combination therapy in cancers driven by constitutive MAPK
pathway mutations to maximize the therapeutic potential of adagrasib with or without cetuximab. 
Objectives and 
Endpoints
Objectives
Endpoints
Primary

To characterize the safety and 
tolerability; to establish the MTD, if 
reached; to evaluate the MAD if MTD is 
not reached; and to identify dose level(s) 
for expansion of:

Part 1A: BMS-986466 administered 
in combination with adagrasib to 
participants with KRAS 
G12C-mutant NSCLC, CRC, PDAC, 
and BTC

Part 1B: BMS-986466 administered 
in combination with adagrasib with
cetuximab to participants with KRAS 
G12C-mutant CRC

Incidence of DLTs, AEs, SAEs, AEs 
leading to discontinuation, and deaths

To evaluate anti-tumor activity:

Part 2A: BMS-986466 in 
combination with adagrasib vs 
adagrasib in participants with KRAS 
G12C-mutant (G12Ci
treatment-naïve) NSCLC 

Part 2B: BMS-986466 in 
combination with adagrasib with or 
without cetuximab vs adagrasib with
cetuximab in participants with KRAS 
G12C-mutant (G12Ci
treatment-naïve) CRC

ORR per RECIST v1.1 by BICR
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Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
Secondary

Parts 1 and 2: To characterize the PK 
profile of BMS-986466 following first 
dose and at steady state in combination 
with adagrasib with or without cetuximab 

Summary measures of BMS-986466 PK 
parameters in plasma including Cmax, 
Tmax, and AUC(0-T), from 
concentration-time data 

To evaluate the preliminary efficacy of:

Part 2A: BMS-986466 in 
combination with adagrasib vs 
adagrasib in participants with KRAS 
G12C-mutant (G12Ci treatment-
naïve) NSCLC 

Part 2B: BMS-986466 in 
combination with adagrasib with or 
without cetuximab vs adagrasib with
cetuximab in participants with KRAS 
G12C-mutant (G12Ci treatment-
naïve) CRC

PFS, DCR, DOR, and TTR per 
RECIST v1.1 by BICR

To assess the safety and tolerability of:

Part 2A: BMS-986446 in 
combination with adagrasib in 
participants with KRAS G12C-
mutant (G12Ci treatment -naïve) 
NSCLC 

Part 2B: BMS-986446 in 
combination with adagrasib with or 
without cetuximab in participants 
with KRAS G12C-mutant (G12Ci 
treatment-naïve) CRC

Incidence of AEs, SAEs, AEs leading to 
discontinuation, and deaths

To assess the PD profile of BMS-986466 

Summary measures of target engagement 
such as, but not limited to, pERK.
Overall Design
This is a Phase 1/2 multi-center, open-label study of BMS-986466 in combination with adagrasib 
in participants with KRAS G12C-mutant NSCLC, PDAC, BTC, and BMS-986466 in 
combination with adagrasib with or without cetuximab in KRAS G12C-mutant CRC.
Part 1 (DDI Cohort and Dose Escalation): The potential DDI between BMS-986466 and 
adagrasib will be evaluated. A minimum of 6 PK-evaluable participants will be treated with a 
single dose of BMS-986466 10 mg PO on C1D1 followed by continuous dosing of adagrasib 
400 mg BID starting on 
 and another single dose of BMS-986466 10 mg on 
. Starting 
on C3D1, participants will be treated daily with the combination of BMS-986466 10 mg QD and 
adagrasib 400 mg BID. The PK evaluation from the DDI cohort will inform the subsequent dose 
levels of BMS-986466 in combination with adagrasib.
Based on the data from this DDI cohort, dose levels will be evaluated to achieve exposures 
approximately comparable to or less than BMS-986466 
 and 
 mg QD monotherapy 
from Study NAV-1001 in combination with adagrasib (Part 1A) or adagrasib plus cetuximab 
(Part 1B).
Part 2 (Randomized Dose Expansion): A randomized, open-label dose expansion with 
comparator cohorts to assess preliminary efficacy, optimal dose level(s), safety, and tolerability 
of BMS-986466 in combination with adagrasib with or without cetuximab. The doses to be 
administered in Parts 2A and 2B will not exceed doses determined to be tolerable from Parts 1A 
and 1B of the study, respectively.
Number of 
Participants
A total of approximately 410 evaluable participants will be treated in this study. A minimum of 
6 PK-evaluable participants will be treated in Part 1 DDI cohort. In Parts 1A and 1B (excluding 
the DDI cohort), approximately 3 to 9 DLT-evaluable participants will be tested per dose level 
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Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
up to approximately 54 participants. In Parts 2A and 2B, approximately 150 and 
200 response-evaluable participants will be treated, respectively.
Study 
Population
Key Inclusion 
Criteria
Part 1:

Participants must have histologically documented, locally advanced and 
unresectable, or metastatic NSCLC, PDAC, BTC (DDI, Part 1A), or CRC 
(DDI, Parts 1A and 1B) with KRAS G12C mutation, whether naïve to 
KRAS G12C inhibitor treatment or not. 

For NSCLC and CRC: Participants must have a documented KRAS 
G12C mutation from a NYS-approved or FDA-approved/cleared or CE-
marked test or, when such result is not available, positive KRAS G12C 
mutation status should be confirmed by a central laboratory(Guardant360 
CDx) in liquid biopsy samples collected at the time of screening.

For PDAC and BTC: Participants must have a documented KRAS G12C 
mutation from an NYS-approved, FDA-approved/cleared, or CE-marked 
test and liquid biopsy samples collected only for retrospective testing.

Have progression or are intolerant or have disease recurrence on or after 
available standard of care treatments.
Part 2:

Participants must have histologically documented, locally advanced and 
unresectable, or metastatic KRAS G12C-mutant NSCLC (Part 2A) or 
CRC (Part 2B), naïve to treatment with KRAS G12C inhibitor. 

Participants must have a documented KRAS G12C mutation from a
NYS-approved or FDA-approved/cleared or CE-marked test or, when 
such result is not available, positive KRAS G12C mutation status should 
be confirmed by a central laboratory (Guardant360 CDx) in liquid biopsy 
and/or tumor samples collected at the time of screening or from archival 
biopsies (less than 1 year old).

Have progression or disease recurrence or are intolerant after at least 
1 prior line of systemic therapy.
Key Exclusion 
Criteria

Have tumors harboring known activating mutations in BRAF V600X, 
PTPN11 (SHP2), or KRAS Q61X. 

Uncontrolled or significant cardiovascular disease.

Interstitial lung disease or pneumonitis (previous Grade 1 or 2 immuno-
mediated pneumonitis is permitted if completely resolved).
Study 
Intervention 
Administration 
and Duration
In the DDI cohort, a single dose of BMS-986466 10 mg PO will be given on C1D1 and 
 
with continuous dosing of adagrasib 400 mg BID starting on 
. Starting on C3D1, 
participants will be treated daily with the combination of BMS-986466 10 mg QD and adagrasib 
400 mg BID. Based on the data from this DDI cohort, dose levels will be evaluated to achieve 
exposures approximately comparable to or less than BMS-986466 
 mg QD 
monotherapy from Study NAV-1001 in combination with adagrasib (Part 1A) or adagrasib plus 
cetuximab (Part 1B). Decisions for dose escalation and to continue enrollment according to the 
outlined study protocol will be made by the Sponsor in collaboration with the investigators, and 
take into consideration all available safety, PK, and PD data.
Part 2 is a randomized, open-label dose expansion with comparator cohorts to assess preliminary 
efficacy, safety, and tolerability of optimal dose level(s) of BMS-986466 in combination with 
adagrasib with or without cetuximab. The doses to be administered in Parts 2A and 2B will not 
exceed doses determined to be tolerable from Parts 1A and 1B of the study, respectively. 
The treatment period will last approximately 2 years or until confirmed disease progression, 
unacceptable AE, withdrawal by participant, or death. In the follow-up period, safety and survival 
follow-up will occur concurrently. The safety follow-up period is 30 days (± 7 days) after the 
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CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
EOT visit. Survival follow-up every 3 months (± 15 days) for all parts will begin at EOT and last 
for a period of 2 years, or until death, lost to follow-up, withdrawal of consent, conclusion of the 
study, or study termination, whichever comes first. The survival follow-up visits can be 
conducted in person or via telephone.
Statistical 
Methods
Decisions to dose escalate or de-escalate in the dose escalation Parts 1A and 1B will be guided 
by the TITE-BOIN method, where ≥ 3 participants are treated per dose cohort. 
 
 
The primary endpoint for Part 1 is to assess safety based on incidence of AEs, SAEs, AEs leading 
to discontinuation, and deaths. In addition, the selected tolerable dose levels of BMS-986466 in 
combination with adagrasib (Part 1A) and BMS-986466 in combination with adagrasib and 
cetuximab (Part 1B) will be determined using the DLT rate within the 28-day window among 
DLT-evaluable participants in Parts 1A and 1B. The incidence of DLTs will be calculated and 
compared to the actions recommended by the TITE-BOIN design to guide the dose 
escalation/stay/de-escalation decision for the BMS-986466 plus adagrasib treatment and for the 
BMS-986466 plus adagrasib plus cetuximab treatment.
The primary endpoint for Part 2 is ORR of BMS-986466 plus adagrasib compared to adagrasib 
control (Part 2A), and ORR of BMS-986466 in combination with adagrasib plus cetuximab 
compared to adagrasib plus cetuximab control (Part 2B), in the randomized population. Bayesian 
continuous safety monitoring framework will be utilized to monitor toxicity and detect safety 
signals affecting conduct of the study. ORR is defined as the proportion of participants who 
achieve a best response of CR or PR using the RECIST v1.1 criteria.
Data 
Monitoring or 
Other 
Committee
Bristol-Myers Squibb Company (BMS) has developed a multi-layered process to ensure safety 
monitoring through close collaboration of study site investigators, the BMS study team, and the 
BMS Worldwide Patient Safety (WWPS)-led Safety Management Team (SMT), and this will be 
employed in this study.
Abbreviations: AE, adverse event; AUC (0-T), area under the concentration-time curve from time zero to time of last 
quantifiable concentration; BICR, Blinded Independent Central Review; BID, twice daily; BMS, Bristol-Myers 
Squibb Company; BRAF, proto-oncogene B-Raf; C, cycle; CE, conformité européenne; Cmax, maximum (or peak) 
concentration; CR, complete response; CRC, colorectal cancer; D, day; DCR, disease control rate; DDI, drug-drug 
interaction; DLT, dose-limiting toxicity; DOR, duration of response; EOT, end of treatment; FDA, Food and Drug 
Administration; G12Ci, G12C inhibitor; KRAS, Kirsten rat sarcoma viral oncogene; MAD, maximum administered 
dose; MAPK, mitogen-activated protein kinase; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer; 
NYS, New York State; ORR, overall response rate; PD, pharmacodynamic; pERK, phosphorylation of extracellular 
signal-regulated kinase; PFS, progression-free survival; PK, pharmacokinetic; PO, orally; PR, partial response; QD, 
once daily; RECIST, Response Evaluation Criteria in Solid Tumors; RTK, receptor tyrosine kinase; SAE, serious 
adverse event; SHP2, Src homology-2 phosphatase; SMT, Safety Management Team; TITE-BOIN, time-to-event 
Bayesian optimal interval; Tmax, time at which maximum concentration (Cmax) occurs; TTR, time to response; 
WWPS, Worldwide Patient Safety.
Brief Summary:
The purpose of this study is to find a safe, tolerable, and efficacious dose of BMS-986466 when 
given orally, in combination with adagrasib with or without cetuximab in participants with 
advanced KRAS G12C-mutant non-small cell lung cancer, pancreatic duct adenocarcinoma, 
biliary tract cancer, or colorectal cancer. The safety and tolerability will be assessed by the
incidence of DLTs, AEs, SAEs, AEs leading to discontinuation, and deaths, whereas the efficacy 
will be assessed by ORR per RECIST v1.1 by BICR.
Study Duration: Approximately 4 years.
Study Intervention Duration: Approximately 2 years or until progression. 
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Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
Study Visit Frequency: Approximately every 2 weeks (more frequent in first 2 cycles).
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CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Procedural Outline (Part 1 DDI Cohort Only; CA1260015)
Procedurea,b
Screening
Cycle 1
(1 Cycle = 28 Days)
Cycle 2
Cycle 3+
EOTc
Follow-up
Visit
D1
D2
D3
D4
D9
D10
D12
D18
D1
D15
D1
D15
FU1
Survival FU (Q3M)
Visit Window
(Days)
(-28 to -1)
± 2
± 2
± 3
± 3
± 2
(± 7)
(± 15)
Eligibility Assessments
Informed Consent
X
Inclusion/ 
Exclusion Criteria
X
Medical History
X
Safety Assessments (Section 9.4)
Physical 
Examination 
(Section 9.4.1)
X
X
X
X
X
X
Targeted PE 
X
X
X
X
X
X
X
X
X
Physical 
Measurements
(Height, Weight, 
and BMI)
X
Body Weight
X
X
X
X
Vital Signs and 
Oxygen 
Saturation 
(Section 9.4.2)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance 
Status (ECOG; 
Appendix 5)
X
X
X
X
X
X
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Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
Table 2-1:
Procedural Outline (Part 1 DDI Cohort Only; CA1260015)
Procedurea,b
Screening
Cycle 1
(1 Cycle = 28 Days)
Cycle 2
Cycle 3+
EOTc
Follow-up
Visit
D1
D2
D3
D4
D9
D10
D12
D18
D1
D15
D1
D15
FU1
Survival FU (Q3M)
Visit Window
(Days)
(-28 to -1)
± 2
± 2
± 3
± 3
± 2
(± 7)
(± 15)
Prior/Concomitant
Medication Use
(Section 7.7.1)
Prior 
medication 
including 
previous 
cancer 
treatment
Continuously throughout the study.
Subsequent cancer treatment
Single 12-lead 
ECG 
(Section 9.4.3)
X
X
X
Triplicate ECGd
(Section 9.4.3)
X
X
X
2-D 
ECHO/MUGA 
(Section 9.4.4)
X
X
Odd 
cycles 
X
Laboratory Tests 
Clinical 
Laboratory 
Assessments 
(Table 9.4.5-1)
X
X
X
X
X
X
X
X
X
X
Urinalysis 
(Table 9.4.5-1)
X
X
X
X
X
X
Pregnancy 
Testing (WOCBP 
only)e
X
X
X
X
X
X
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Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
Table 2-1:
Procedural Outline (Part 1 DDI Cohort Only; CA1260015)
Procedurea,b
Screening
Cycle 1
(1 Cycle = 28 Days)
Cycle 2
Cycle 3+
EOTc
Follow-up
Visit
D1
D2
D3
D4
D9
D10
D12
D18
D1
D15
D1
D15
FU1
Survival FU (Q3M)
Visit Window
(Days)
(-28 to -1)
± 2
± 2
± 3
± 3
± 2
(± 7)
(± 15)
FSH (for 
post-menopausal 
women under 
55 years of age)
X
Serology 
(HBV, 
HCV, HIV; see 
Table 9.4.5-1)
X
KRAS G12C 
Mutation Statusf
X
Participants with 
NSCLC: PD-L1 
(TPS), STK11, 
and Other Known 
Mutation Statusg
If 
available 
Participants with 
CRC: MSI, 
MMR, and TMB 
Status
If 
available 
Participants with 
PDAC and BTC:
EGFR, FGFR2, 
IDH1, BRAF 
non-V600X, and 
Other Mutationsg
If 
available
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Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
Table 2-1:
Procedural Outline (Part 1 DDI Cohort Only; CA1260015)
Procedurea,b
Screening
Cycle 1
(1 Cycle = 28 Days)
Cycle 2
Cycle 3+
EOTc
Follow-up
Visit
D1
D2
D3
D4
D9
D10
D12
D18
D1
D15
D1
D15
FU1
Survival FU (Q3M)
Visit Window
(Days)
(-28 to -1)
± 2
± 2
± 3
± 3
± 2
(± 7)
(± 15)
PK Assessments (Section 9.5)
PK Collectionsd
See Table 2-3.
Biomarker Assessments (Section 9.7)
Biomarker 
Sample Collection
See Section 9.7 and Table 2-6.
Fresh Tumor 
Biopsy (Table 2-
6)
Optional
Op-
tional
Op-
tional
Archival Tumor 
Biopsy 
Required, if 
available
AE Reporting (Section 9.2)
Monitor for 
Serious and Non-
serious AEs
Continuously throughout the study from the time of consent until 30 days post discontinuation of study 
intervention (Section 9.2).
Disease/Efficacy Assessment (Section 9.1)
Body Imaging 
(Section 9.1.2)
X
Contrast-enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all other 
known and/or suspected sites of disease should occur every 8 weeks (± 7 days) starting 
from date of first dose for the first 48 weeks, then every 12 weeks (± 7 days) until 
disease progression or discontinuation of all study intervention, whichever occurs later.
X
See Section 9.1.2
Brain Imaging 
(Section 9.1.2)
X
NSCLC -
Mandatory
Participants with a brain metastasis at baseline should have surveillance MRIs (without 
and with contrast) per standard of care (approximately every 12 weeks [± 7 days] or 
sooner if clinically indicated. CT of the brain without and with contrast can be 
performed if MRI is contraindicated.
X
See Section 9.1.2
Optional 
for all other 
indications 
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Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
Table 2-1:
Procedural Outline (Part 1 DDI Cohort Only; CA1260015)
Procedurea,b
Screening
Cycle 1
(1 Cycle = 28 Days)
Cycle 2
Cycle 3+
EOTc
Follow-up
Visit
D1
D2
D3
D4
D9
D10
D12
D18
D1
D15
D1
D15
FU1
Survival FU (Q3M)
Visit Window
(Days)
(-28 to -1)
± 2
± 2
± 3
± 3
± 2
(± 7)
(± 15)
Assessment of 
Participant 
Survival Status
(Section 5.1.5)
X
X
Study Intervention (Section 7.1)
Contact IRT 
(Section 7.2)
X
X
Dispense 
BMS-986466
10 mg
X
X
X
Dispense 
Adagrasib 
400 mgh
X
X
Study 
Intervention 
Compliance
X
X
X
X
X
X
Abbreviations: AE, adverse event; ALK, anaplastic lymphoma kinase; BMI, body mass index; BRAF, proto-oncogene B-Raf; BTC, biliary tract cancer; C, cycle; 
CE, conformité européenne; CRC, colorectal cancer; CT, computed tomography; D, day; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern
Cooperative Oncology Group; eCRF, electronic Case Report Form; EGFR, epidermal growth factor receptor; EOT, end of treatment; FDA, Food and Drug 
Administration; FGFR2, fibroblast growth factor receptor 2; FSH, follicle-stimulating hormone; FU, follow-up; HBV, hepatitis B virus; hCG, human chorionic 
gonadotrophin; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IDH1, isocitrate dehydrogenase 1; IRT, Interactive Response Technology; IU, 
international units; KRAS, Kirsten rat sarcoma viral oncogene; M, month; MET, mesenchymal to epithelial transition; MMR, mismatch repair; MRI, magnetic 
resonance imaging; MSI, microsatellite instability; MUGA, multigated acquisition; NSCLC, non-small cell lung cancer; NTRK, neurotrophic tyrosine receptor 
kinase; NYS, New York State; PDAC, pancreatic duct adenocarcinoma; PD-L1, programed death ligand 1; PE, physical examination; PK, pharmacokinetic; Q3M, 
every 3 months; RET, rearranged during transfection; ROS1, ROS proto-oncogene 1; STK11, serine/threonine kinase 11; TMB, tumor mutational burden; TPS,
tumor proportion score; WOCBP, women of childbearing potential. 
Protocol Amendment No.: 01
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Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
a If all components of study intervention are delayed, the procedures scheduled for that same time point should be delayed to coincide with when the time point’s 
dosing actually occurs (except tumor imaging assessments).
b 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.
c EOT is defined as the visit where the decision is made to discontinue the participant from treatment. Evaluations will be made prior to study discharge for the 
participants who are permanently discontinued.
d See Table 2-3 for exact PK and triplicate ECG time points.
e Serum or urine pregnancy test (minimum sensitivity equivalent units 25 IU/L or equivalent units of hCG) to be done at screening visit and repeated within 
24 hours prior to the start of study intervention. WOCBP must have a negative pregnancy test within 24 hours prior to the start of study intervention and results 
also must be evaluated prior to study intervention administration. If pregnancy test is taken within 24 hours of dosing (C1D1), a further pregnancy test is not 
required. An extension up to 72 hours prior to the start of study intervention is permissible in situations where results cannot be obtained within standard 24-hour 
window.
f Participants must have a documented KRAS G12C mutation from an NYS-approved, FDA-approved/cleared or CE-marked test or, when such result is not 
available, positive KRAS G12C mutation status should be confirmed by a central laboratory in liquid biopsy samples collected at the time of screening. 
g Other targetable mutations, including EGFR, ALK, ROS1, RET, NTRK, MET amplification, MET exon 14 skipping mutations, and non-KRAS G12C, should 
be documented if available.
h Dispense adagrasib every 42 days (± 3 days).
Protocol Amendment No.: 01
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Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
Table 2-2:
Procedural Outline (All Parts Excluding Part 1 DDI Cohort; CA1260015)
Procedurea,b
Screening
Cycle 1
(1 Cycle = 28 Days)
Cycle 2
Cycle 3+
EOTc
Follow-up
Visit
D1
D2
D15
D1
D2d
D15
D1
D15
FU1
Survival 
FU
(Q3M)
Visit Window (Days)
(-28 to -1)
± 2
± 2
±3
± 3
± 2
(± 7)
(± 15)
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
Medical History
X
Safety Assessments (Section 9.4)
Physical Examination
X
X
X
X
X
X
Targeted PE 
X
X
X
X
X
Physical Measurements
(Height, Weight, and BMI)
X
Body Weight
X
X
X
X
Vital Signs and Oxygen 
Saturation
X
X
X
X
X
X
X
X
X
X
X
Performance Status (ECOG; 
Appendix 5)
X
X
X
X
X
X
Prior/Concomitant Medication 
Use
Prior medication 
including previous 
cancer treatment
Continuous throughout the study.
Subsequent 
cancer treatment
Single 12-lead ECGe
X
X
X
X
Triplicate ECG (Part 1A and 1B
only)
X
X
2-D ECHO/MUGAf
X
X
Odd 
cyclesf
X
Protocol Amendment No.: 01
Date: 07-Jul-2023
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Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
Table 2-2:
Procedural Outline (All Parts Excluding Part 1 DDI Cohort; CA1260015)
Procedurea,b
Screening
Cycle 1
(1 Cycle = 28 Days)
Cycle 2
Cycle 3+
EOTc
Follow-up
Visit
D1
D2
D15
D1
D2d
D15
D1
D15
FU1
Survival 
FU
(Q3M)
Visit Window (Days)
(-28 to -1)
± 2
± 2
±3
± 3
± 2
(± 7)
(± 15)
Laboratory Tests
Clinical Laboratory Assessments
(Table 9.4.5-1)
X
X
X
X
X
X
X
X
X
Urinalysis (Table 9.4.5-1)
X
X
X
X
X
X
Pregnancy Testing 
(WOCBP only)g
X
X
X
X
X
X
FSH (for post-menopausal
women only)
X
Serology (HBV, HCV, HIV)
(Table 9.4.5-1)
X
KRAS G12C Mutation Statush
X
Participants with NSCLC: 
PD-L1 (TPS), STK11, and Other 
Mutation Statusi
If available
Participants with CRC: MSI, 
MMR, and TMB Status
If available
Participants with PDAC and 
BTC (Part 1A only): EGFR,
FGFR2, IDH1, BRAF 
non-V600X, and Other 
Mutationsi
If available
PK Assessments (Section 9.5)
PK Collections
See Table 2-4 for Parts 1A and 1B and Table 2-5 for Parts 2A and 2B.
Protocol Amendment No.: 01
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Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
Table 2-2:
Procedural Outline (All Parts Excluding Part 1 DDI Cohort; CA1260015)
Procedurea,b
Screening
Cycle 1
(1 Cycle = 28 Days)
Cycle 2
Cycle 3+
EOTc
Follow-up
Visit
D1
D2
D15
D1
D2d
D15
D1
D15
FU1
Survival 
FU
(Q3M)
Visit Window (Days)
(-28 to -1)
± 2
± 2
±3
± 3
± 2
(± 7)
(± 15)
Biomarker Assessments (Section 9.7)
Biomarker Sample Collection 
See Section 9.7 and Table 2-7.
Fresh Tumor Biopsy (Parts 1A 
and 1B)
Optional
Op-
tional
Op-
tional
Fresh Tumor Biopsy (Part 2)
(Section 9.7.4)
X
X
Op-
tional
Archival Tumor Biopsy 
Required if 
available
AE Reporting
Monitor for Serious and Non-
serious AEs
Continuously throughout the study from the time of consent until 30 days post discontinuation of study 
intervention (see Section 9.2).
Disease/Efficacy Assessment (Section 9.1)
Body Imaging 
(Section 9.1.2)
X
Contrast-enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all 
other known and/or suspected sites of disease should occur every 8 weeks
(± 7 days) starting from date of first dose for the first 48 weeks, then every 
12 weeks (± 7 days) until disease progression or discontinuation of all study 
intervention, whichever occurs later.
X
Brain Imaging 
(Section 9.1.2)
X
NSCLC -
Mandatory 
Participants with brain metastasis at baseline should have surveillance MRIs 
(without and with contrast) per standard of care (approximately every 
12 weeks) (± 7 days) or sooner if clinically indicated. CT of the brain without 
and with contrast can be performed if MRI is contraindicated.
X
Optional for all 
other indications
Assessment of Participant 
Survival Status (Section 5.1.5)
X
X
Protocol Amendment No.: 01
Date: 07-Jul-2023
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1.0
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Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
Table 2-2:
Procedural Outline (All Parts Excluding Part 1 DDI Cohort; CA1260015)
Procedurea,b
Screening
Cycle 1
(1 Cycle = 28 Days)
Cycle 2
Cycle 3+
EOTc
Follow-up
Visit
D1
D2
D15
D1
D2d
D15
D1
D15
FU1
Survival 
FU
(Q3M)
Visit Window (Days)
(-28 to -1)
± 2
± 2
±3
± 3
± 2
(± 7)
(± 15)
Study Intervention (Section 7.1)
Contact IRT (Randomization for 
Parts 2A and 2B only)
X
X
Dispense BMS-986466
X
X
X
Dispense Adagrasib 600 mgj
X
X
X
Dispense Adagrasib 400 mgk
X
Xk
Cetuximab (Parts 1B and 2B 
only)l
X
X
X
X
X
X
Study Intervention Compliance
X
X
X
X
X
X
Abbreviations: AE, adverse event; ALK, anaplastic lymphoma kinase; BMI, body mass index; BRAF, proto-oncogene B-Raf; BTC, biliary tract cancer; C, cycle; 
CE, conformité européenne; CRC, colorectal cancer; CT, computed tomography; D, day; ECG, electrocardiogram; DDI, drug-drug interaction; ECHO, 
echocardiogram; ECOG, Eastern Cooperative Oncology Group; eCRF, electronic Case Report Form; EGFR, epidermal growth factor receptor (her-1); EOT, end 
of treatment; FDA, Food and Drug Administration; FGFR2, fibroblast growth factor receptor 2; FSH, follicle-stimulating hormone; FU, follow-up; HBV, hepatitis 
B virus; hCG, human chorionic gonadotrophin; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IDH1, isocitrate dehydrogenase 1; IRT, Interactive 
Response Technology; KRAS, Kirsten rat sarcoma viral oncogene; M, month; MET, mesenchymal to epithelial transition; MMR, mismatch repair; MRI, magnetic 
resonance imaging; MSI, microsatellite instability; MUGA, multigated acquisition; NSCLC, non-small cell lung cancer; NTRK, neurotrophic tyrosine receptor 
kinase; NYS, New York State; PDAC, pancreatic duct adenocarcinoma; PD-L1, programed death ligand 1; PE, physical examination; PK, pharmacokinetic; Q3M, 
every 3 months; RET, rearranged during transfection; ROS1, ROS proto-oncogene 1; TPS, tumor proportion score; WOCBP, women of childbearing potential. 
a If all components of study intervention are delayed, the procedures scheduled for that same time point should be delayed to coincide with when the time point’s 
dosing actually occurs (except radiographic tumor assessments).
b 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.
c EOT is defined as the visit where the decision is made to discontinue the participant from treatment. Evaluations will be made prior to study discharge for the 
participants who are permanently discontinued.
Protocol Amendment No.: 01
Date: 07-Jul-2023
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930204199
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v

Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
d C2D2 visit applicable for Parts 1A and 1B only.
e In Part 1: Single 12-lead ECG not required if triplicate ECG obtained (eg, Part 1 C1D1 and C2D1). See Table 2-4 for triplicate ECG time points on assigned 
day. Part 2: 12-lead ECGs as clinically indicated.
f For Part 2, 2-D echocardiogram or MUGA every odd cycle if clinically indicated.
g Serum or urine pregnancy test (minimum sensitivity equivalent units 25 IU/L or equivalent units of hCG) to be done at screening visit and repeated within 
24 hours prior to first dose of study intervention. WOCBP must have a negative pregnancy test within 24 hours prior to the start of study intervention and results 
also must be evaluated prior to study intervention administration. If pregnancy test is taken within 24 hours of dosing (C1D1), a further pregnancy test is not 
required. An extension up to 72 hours prior to the start of study intervention is permissible in situations where results cannot be obtained within standard 24-hour 
window.
h NSCLC and CRC: Participants must have a documented KRAS G12C mutation from an NYS-approved, FDA-approved/cleared, or CE-marked test or, when 
such result is not available, positive KRAS G12C mutation status should be confirmed by a central laboratory (Guardant360 CDx) in liquid biopsy samples 
collected at the time of screening (for parts 1A and 1B) and in liquid biopsy and/or tumor samples (only for parts 2A and 2B) collected at the time of the screening 
or from archival biopsies (less than 1 year old). PDAC and BTC: Participants must have a documented KRAS G12C mutation from NYS-approved, 
FDA-approved/cleared or CE-marked test and liquid biopsy samples collected only for retrospective testing.
i
Other targetable mutations, including EGFR, ALK, ROS1, RET, NTRK, MET amplification, MET exon 14 skipping mutations, FGFR2, IDH1, BRAF including 
BRAF non-V600X and other non-KRAS G12C mutations, should be documented if available.
j
Dispense adagrasib 600 mg every 28 days (± 2 days).
k Dispense adagrasib 400 mg every 42 days (± 3 days).
l
Given intravenous biweekly. If weekly cetuximab dosing is implemented, additional visits on Days 8 and 22 will be required. In addition to cetuximab 
administration, relevant targeted PE, vital signs, and oxygen saturation should be done.
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SHP2 inhibitor
Table 2-3:
Pharmacokinetic Sampling Schedule for BMS-986466 (Part 1 DDI 
Cohort; CA1260015)
Study Day of Sample 
Collection
(1 Cycle = 28 Days)
Event
Time Relative to 
BMS-986466 
Dose and/or 
Adagrasib Dose
(hr:min)
BMS-986466
PK Plasma 
Sample
Adagrasib
PK Plasma
Sample
Triplicate
ECGsa
Cycle 1 Day 1
Predoseb
0:00
X
X
Cycle 1 Day 1
X
Cycle 1 Day 1
X
Cycle 1 Day 1
X
Cycle 1 Day 2
24:00
X
Cycle 1 Day 3
48:00
X
Predoseb
0:00
X
X
X
X
X
X
Predoseb
0:00
X
X
X
X
X
X
X
X
X
X
X
Cycle 1 Day 10c
Predoseb
0:00
X
X
Cycle 1 Day 12c
Predoseb
0:00
X
Cycle 1 Day 18c
Predoseb
0:00
X
Cycle 2 Day 1c
Predoseb
0:00
X
Cycle 3 Day 1c
Predoseb
0:00
X
Abbreviations: DDI, drug-drug interaction; ECG, electrocardiogram; hr, hour(s); min, minutes; PK, pharmacokinetic.
Note: For more information, see Section 9.5.1.
 
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a All triplicate ECGs should be recorded 5 minutes apart on the Sponsor-provided ECG machine and results should 
be transmitted electronically to the central laboratory.
b
 If it is known that a dose is 
going to be delayed, then collect the pre-dose sample just prior to delayed dose. However, if a pre-dose sample is 
collected but the dose is subsequently delayed, do not collect additional pre-dose sample.
c
onward sample collections are relative to the adagrasib dose.
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Table 2-4:
Pharmacokinetic Sampling Schedule for BMS-986466, Adagrasib 
along with Triplicate ECG (Dose Escalation Parts 1A and 1B; 
CA1260015)
Study Day of
Sample Collection
(1 Cycle = 
28 Days)
Event
Time Relative 
to BMS-986466 
Dose (hr:min)
BMS-986466 PK 
Plasma Sample
Adagrasib PK 
Plasma Sample
Triplicate ECGsa
Cycle 1 Day 1
Predoseb
0:00
X
X
X
Cycle 1 Day 1
X
X
X
Cycle 1 Day 1
X
X
X
Cycle 1 Day 1
X
X
Cycle 1 Day 2
Predoseb
0:00
X
X
Cycle 1 Day 15
Predoseb
0:00
X
X
Cycle 2 Day 1
Predoseb
0:00
X
X
X
Cycle 2 Day 1
X
X
X
Cycle 2 Day 1
X
X
X
Cycle 2 Day 1
X
X
Cycle 2 Day 2
Predoseb
0:00
X
X
Cycle 2 Day 15
Predoseb
0:00
X
X
Cycle 3 Day 1
Predoseb
0:00
X
X
Abbreviations: ECG, electrocardiogram; hr, hour(s); min, minutes; PK, pharmacokinetic.
Note: For more information regarding PK collection sample windows, see Section 9.5.1.
 
a All triplicate ECGs should be recorded 5 minutes apart on the Sponsor-provided ECG machine and results should 
be transmitted electronically to the central laboratory.
b
 If it is known that a dose is 
going to be delayed, then collect the pre-dose sample just prior to delayed dose. However, if a pre-dose sample is 
collected but the dose is subsequently delayed, do not collect additional pre-dose sample.
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Table 2-5:
Pharmacokinetic Sampling Schedule for BMS-986466, Adagrasib 
(Dose Expansion Parts 2A and 2B; CA1260015)
Study Day of 
Sample Collection
(1 Cycle = 28 Days)
Event
Time Relative to 
BMS-986466 Dose 
(hr:min)
BMS-986466 PK 
Plasma Sample
Adagrasib PK Plasma 
Sample
Cycle 1 Day 1
Predosea
0:00
X
X
Cycle 1 Day 1
X
X
Cycle 2 Day 1
Predosea
0:00
X
X
Cycle 2 Day 1
X
X
Cycle 3 Day 1
Predosea
0:00
X
X
Abbreviations: hr, hour(s); min, minutes; PK, pharmacokinetic.
Note: For more information, see Section 9.5.1.
 
a
 If it is known that a dose is 
going to be delayed, then collect the pre-dose sample just prior to delayed dose. However, if a pre-dose sample is 
collected but the dose is subsequently delayed, do not collect additional pre-dose sample.
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Table 2-6:
Biomarker Sampling Schedule (Part 1 DDI Cohort Only; 
CA1260015)
Study Day of 
Sample 
Collection
(1 Cycle = 28 
Days)
Event
Time 
Relative 
to BMS-
986466
Dose 
(hr:min)
Tumor
for 
IHC, 
RNA 
Seq
Whole 
Blood
for
pERKa
Whole 
Blood 
for 
Myeloid/
Immune 
Panel
Whole 
Blood 
for
ctDN
A
NGS
Plasma
for
Soluble 
PD
Markers
Whole 
Blood for
DNA 
Sequencing
Screening
(Day -28 to -1)
Baseline
Xb
X
X
Cycle 1 Day 1
Predosec
0:00
X
X
Predosec
0:00
X
X
X
X
Predosec
0:00
X
Cycle 2 Day 1
Predosec
0:00
X
X
X
Cycle 2 Day 1
Xb
Cycle 3 Day 1
Predosec
0:00
X
X
X
Cycle 4 Day 1
Predosec
0:00
X
X
Cycle 5 Day 1
Predosec
0:00
X
X
Cycle 6 Day 1
Predosec
0:00
X
X
EOT 
Xb
X
X
X
Abbreviations: ctDNA, circulating tumor deoxyribonucleic acid; DDI, drug-drug interaction; DNA, deoxyribonucleic 
acid; EOT, end of treatment; hr, hour(s); IHC, immunohistochemistry; min, minutes; NGS, next-generation 
sequencing; PD, pharmacodynamic; pERK, phosphorylation of extracellular signal-regulated kinase; RNA, 
ribonucleic acid; Seq, sequencing.
a Whole blood pERK assay for Part 1 dose-escalation only (including DDI and non-DDI).
b Optional (tumor biopsies can be collected irrespective of study intervention administration). Visit window (± 7 
days).
c Collect predose applicable for blood samples (within 2 hours prior to dosing of BMS-986466).
 
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Table 2-7:
Biomarker Sampling Schedule (All Parts Excluding Part 1 DDI 
Cohort; CA1260015)
Study Day of 
Sample 
Collection
(1 Cycle = 
28 Days)
Event
Time 
Relative to 
BMS-986466
Dose 
(hr:min)
Tumor 
for 
IHC, 
RNA 
Seq
Whole 
Blood 
for 
pERKa
Whole 
Blood 
for 
Myeloid/
Immune 
Panel
Whole
Blood 
for 
ctDNA 
NGS
Plasma
for 
Soluble 
PD 
Markers
Whole 
Blood 
for 
DNA 
Seq
Screening
(Day -28 to -1)
Baseline
Xb
X
X
Cycle 1 Day 1
Predosec
0:00
X
X
X
Cycle 1 Day 1
Xa,
Cycle 1 Day 1
Xa,
Cycle 1 Day 1
Xa,
Cycle 1 Day 2
Predosec
0:00
X
Cycle 2 Day 1
Predosec
0:00
X
Xc
Xc
Xc
Cycle 2 Day 1
Xb
Cycle 2 Day 1
Xa,
Cycle 2 Day 1
Xa,
Cycle 2 Day 1
Xa,
Cycle 2 Day 2
Predosec
0:00
Xa
Cycle 3 Day 1
Predosec
0:00
X
X
X
Cycle 4 Day 1
Predosec
0:00
X
X
Cycle 5 Day 1
Predosec
0:00
X
X
Cycle 6 Day 1
Predosec
0:00
X
X
EOT upon 
Progression
Xe
X
X
X
Abbreviations: ctDNA, circulating tumor deoxyribonucleic acid; DDI; drug-drug-interaction; DNA, deoxyribonucleic 
acid; EOT, end of treatment; hr, hour(s); IHC, immunohistochemistry; min, minutes; NGS, next-generation 
sequencing; PD, pharmacodynamic; pERK, phosphorylation of extracellular signal-regulated kinase; RNA, 
ribonucleic acid; Seq, sequencing.
a Whole blood pERK assay for Parts 1A and 1B (dose escalation).
b Optional (tumor biopsies can be collected irrespective of study intervention administration for Parts 1A and 1B).
Visit window (± 7 days).
c Collect predose (within 2 hours prior to dosing of BMS-986466).
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e Optional.
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3
INTRODUCTION
CA1260015 is a Phase 1/2 study of BMS-986466 in combination with adagrasib in participants 
with Kirsten rat sarcoma virus glycine 12 to cysteine (KRAS G12C)-mutated non-small cell lung 
cancer (NSCLC), pancreatic duct adenocarcinoma (PDAC), and biliary tract cancer (BTC) and 
BMS-986466 in combination with adagrasib with or without cetuximab in participants with KRAS 
G12C-mutant colorectal cancer (CRC). Adagrasib (MRTX849) is an oral inhibitor of RAS GTPase 
family indicated for treatment of adult patients with KRAS G12C-mutant locally advanced or 
metastatic NSCLC and is also being tested for KRAS G12C-mutant CRC. BMS-986466 (also
known as BBP-398; IACS-15509) is an oral, allosteric inhibitor of Src homology-2 phosphatase 
(SHP2), a tyrosine phosphatase that plays a key role in the receptor tyrosine kinase (RTK)-
mediated mitogen-activated protein kinase (MAPK) signal transduction pathway.1 In preclinical 
models, SHP2 inhibition potentiates the activity of KRAS inhibitors and suppresses RTK-driven 
resistance observed with KRAS G12C inhibitors. This study will evaluate the safety and 
tolerability; establish the maximum tolerated dose (MTD) if reached; identify dose level(s) for 
expansion; and evaluate the preliminary efficacy of BMS-986466 in combination with adagrasib 
in participants with 2L+ KRAS G12C-mutant NSCLC and BMS-986466 in combination with 
adagrasib with or without cetuximab in participants with 2L+ KRAS G12C-mutant CRC.
3.1
Study Rationale
KRAS is one of the most commonly mutated oncogenes with KRAS G12C mutations comprising 
approximately 14% of NSCLC, 3% of CRC, 1.5% in PDAC2, with a lower prevalence in other 
cancers.3 Targeted therapies to KRAS G12C mutations have successfully been developed and 2
inhibitors of RAS GTPase family, sotorasib and adagrasib, were granted accelerated approval by 
the United States (US) Food and Drug Administration (FDA) in adult patients with KRAS G12C-
mutant NSCLC who have received at least 1 prior systemic therapy. Additionally, both sotorasib 
and adagrasib have demonstrated clinical benefit in KRAS G12C-mutant CRC with objective 
response rate (ORR) of 9.7% and 19%, respectively.4,5 Despite this transformational breakthrough, 
a considerable proportion of patients do not respond or do not have durable responses with KRAS 
G12C monotherapy; thus, an unmet need remains in patients with KRAS G12C-mutant tumors. 
Resistance to KRAS inhibitors has been demonstrated in both nonclinical and clinical studies and 
is frequently driven by compensatory activation or upregulation of other components of the 
pathway, including RTKs.6,7 Recent studies have shown that inhibition of SHP2 suppresses 
MAPK pathway activation and inhibits the growth of tumors that harbor oncogenic KRAS 
mutations. In addition, SHP2 inhibition can potentiate the activity of KRAS inhibitors in 
nonclinical tumor models.8,9 These data suggest that inhibition of SHP2 has the potential to inhibit 
the growth of tumors that harbor certain oncogenic RAS mutations (eg, KRAS G12C), including 
tumors in which adaptive resistance to therapeutic inhibitors of these pathways has developed. 
Importantly, the observation that epidermal growth factor receptor (EGFR) blockade in 
combination with KRAS G12C inhibitors, namely adagrasib and sotorasib, increases the ORR
relative to KRAS G12Ci monotherapy in CRC provides clinical validation of RTK-driven 
resistance.4,5, 10 In addition, preclinical data demonstrate SHP2 inhibition more effectively 
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suppresses RTK-driven resistance than EGFR blockade, providing further rationale for exploring 
the combination of KRAS G12C and SHP2 inhibitors in the clinic.11
 
 
 
The proposed CA1260015 is a Phase 1/2 open-label study evaluating the combination of 
BMS-986466 with adagrasib in KRAS G12C-mutant NSCLC and BMS-986466 in combination 
with adagrasib with or without cetuximab in KRAS G12C-mutant CRC. The objective is to 
evaluate safety and tolerability, establish the MTD if reached, identify dose level(s) of both 
combinations for dose expansion.
3.2
Background
3.2.1
BMS-986466 Mechanism of Action
BMS-986466 is a potent, selective, orally active allosteric inhibitor of SHP2, a ubiquitously 
expressed scaffolding protein and tyrosine phosphatase that plays a key regulatory role in both 
tumor and immune cell signaling. SHP2 transduces signaling from multiple RTKs to activate the 
small guanosine triphosphatase (GTPase), RAS, and MAPK signaling pathway and can 
dephosphorylate and deactivate several negative regulators of the RAS/MAPK pathway.
A detailed description of the chemistry, pharmacology, and safety of BMS-986466 is provided in 
the Investigator’s Brochure (IB).12
3.2.1.1
BMS-986466 Nonclinical Pharmacology
 
 
 
 
 
 
 
 Furthermore, the combination of KRAS G12C and SHP2 inhibitors 
demonstrated superior efficacy than the combination of KRAS G12C inhibitor and EGFR 
blockade in CRC xenograft models.11
 
 
 
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3.2.1.2
BMS-986466 Nonclinical Pharmacokinetics
In pre-clinical studies, BMS-986466 exhibited low plasma clearance, moderate to high volume of 
distribution at steady-state (Vss) and moderate terminal half-lives across species, and it was well 
absorbed with time to maximum plasma drug concentration (Tmax) of 
 post dose. 
The results of a cytochrome P450 (CYP) reaction phenotyping study suggest that in vitro 
metabolism of BMS-986466 is mainly mediated by 
. In vitro studies suggest
BMS-986466 did not notably inhibit the major human CYP isoforms nor did it induce 
, 
, or 
 in human hepatocytes; it is a substrate of 
, and an inhibitor of 
 
.
3.2.1.3
BMS-986466 Nonclinical Toxicology
Although single and repeat-dose nonclinical toxicology studies with BMS-986466 in rats and dogs 
were overall well tolerated at doses equivalent to the lower doses proposed for this study, the 
studies suggest potential toxicities that may be observed with oral administration of BMS-986466 
to humans, including diarrhea, vomiting, lymphopenia, and liver toxicity with increased 
transaminases. The inhibitory concentration 50 (IC50; > 100 µM) in the in vitro hERG assay and 
no test article-related effects in the cardiovascular and central nervous system (CNS) parameters 
in the in vivo studies indicate low risk for adverse pharmacological effects on the CNS and 
cardiovascular systems. In rats, increased thickness of the physis and increased trabecular bone in
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the metaphyseal region of tibia and femur, mineralization in several organs correlating with 
changes in serum calcium and phosphorus, as well as degenerative changes in the ovaries (corpus 
lutea) were observed. In dogs, reductions in circulating red cell and leukocyte parameters, bone 
marrow atrophy, depletion of splenic white pulp, and thymic atrophy (reflected by the hematologic 
changes) were observed.12
3.2.1.4
BMS-986466 Clinical Pharmacology
Based on BMS-986466 monotherapy data from Study NAV-1001, BMS-986466 exposure 
increases dose proportionally over the range of 80 to 550 mg once daily (QD) with low inter-
participant variability. BMS-986466 is rapidly absorbed, with time to maximum plasma drug 
concentration (Tmax) values in the range of 
 post oral dose. The estimated half-life 
is determined to be approximately 
. Accumulation ratio of AUC is approximately 
 
over the dose range of 80 to 
 mg QD.
To further assess clinical drug-drug interaction (DDI) potential of BMS-986466, a physiologically 
based pharmacokinetic (PBPK) model was developed based on BMS-986466 in vitro 
metabolism/transporter data and preliminary clinical PK data from the dose escalation phase of 
NAV-1001. 
 
 
 
 
 
 
 
3.2.1.5
BMS-986466 Clinical Safety
In NAV-1001, as of 13-Aug-2022, a total of 31 participants have been treated with monotherapy 
of BMS-986466 at 6 dose levels: 80 mg (n = 1), 150 mg (n = 3), 
 mg (n = 3), 400 mg (n = 5), 
550 mg (n = 13), and 
mg (n = 6). Nineteen participants across all dose levels completed the 
dose-limiting toxicity (DLT) assessment period of at least 21 days, and 16 participants 
discontinued treatment early due to disease progression. No DLTs were reported.12
Twenty-eight (90.3%) participants reported adverse events (AEs). Four (12.9%) participants 
reported Grade 3 treatment-related AEs (TRAEs): diarrhea, platelet count decreased, and aspartate 
aminotransferase (AST) increased (n = 1 each, possibly related) and edema peripheral (n = 1, 
related). All TRAEs occurred in the 550 mg dose level, except AST increased that occurred at the 
150 mg dose level. No Grade 4 or 5 AEs were considered related to treatment. Eleven (35.5%) 
participants reported SAEs, and none were deemed related to treatment. 
Five participants reported AEs that led to study drug discontinuation: Grade 3 edema peripheral 
(n = 1, related); Grade 2 ejection fraction decreased (n = 1, possibly related); Grade 1 temperature 
intolerance (n = 1, possibly related); Grade 4 acute respiratory failure (n = 1, unlikely related); and 
Grade 3 deep vein thrombosis (n = 1, not related). Excluding the Grade 2 ejection fraction 
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decreased at BMS-986466
 mg daily, all other AEs leading to discontinuation occurred at the 
BMS-986466 550 mg QD dose. Overall, no relevant safety findings impacting the benefit/risk of 
BMS-986466 have been reported. For detailed safety listings by dose level in Study NAV-1001, 
refer to Tables 8 and 9 in Section 5.3.1 of the BMS-986466 IB.12
3.2.1.6
BMS-986466 Clinical Efficacy
Based on preliminary observations and pharmacodynamic (PD) data from Study NAV-1001,
, there has been no evidence of clinical 
response as of Apr-2023. The best overall response reported is stable disease.
3.2.2
Adagrasib
Adagrasib is a potent, orally available, small molecule, covalent inhibitor of KRAS G12C that 
irreversibly and selectively binds KRAS G12C in its inactive, GDP-bound state. Adagrasib has 
favorable pharmacokinetic (PK) properties, including a long half-life (23 hours), dose dependence, 
and CNS penetration. Adagrasib acts as a strong CYP3A4 inhibitor when dosed at 400 mg twice 
daily (BID) and at 600 mg BID and increases midazolam’s (a sensitive CYP3A substrate) AUC 
by 20- and 30-fold, respectively.14
In clinical trials, adagrasib has demonstrated clinical benefit in participants with KRAS 
G12C-mutant NSCLC, CRC, PDAC, and BTC treated with adagrasib 600 mg BID (ORR 43%,
19%, 33%, and 42%15 respectively) and participants with KRAS G12C-mutant CRC treated with 
adagrasib 600 mg BID plus cetuximab (ORR 46%). Overall, adagrasib has demonstrated to be safe 
and tolerable as monotherapy14 and in combination with cetuximab.5, 16 The most common 
(≥25%) adverse reactions for adagrasib monotherapy were nausea, diarrhea, vomiting, fatigue, 
musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, and decreased appetite. 
The most common Grade 3 or 4 (≥ 2%) laboratory abnormalities were decreased lymphocytes, 
decreased hemoglobin, increased alanine aminotransferase (ALT), increased AST, hypokalemia, 
hyponatremia, increased lipase, decreased leukocytes, decreased neutrophils, and increased 
alkaline phosphatase (ALP). Adagrasib was granted accelerated approval for the treatment of adult 
patients with KRAS G12C-mutant, locally advanced or metastatic NSCLC, who have received at 
least 1 prior systemic therapy. See Section 5.4.4 and the adagrasib United States Prescribing 
Information (USPI)14 for additional information.
3.2.3
Cetuximab
Cetuximab is an EGFR antagonist indicated for treatment of KRAS wild-type, EGFR-expressing, 
metastatic CRC.17 It is not indicated for the treatment of RAS-mutant CRC or when the results of 
the RAS mutation tests are unknown.18
Refer to the USPI/SmPC for additional information.17,19
3.3
Benefit/Risk Assessment
Since SHP2 is a central node in downstream RTK activation, SHP2 inhibitors may be beneficial 
as a component of combination therapy in cancers driven by constitutive MAPK pathway 
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mutations to maximize the therapeutic potential of RTK, RAS, and other MAPK pathway 
inhibitors, which often have limited efficacy as single agents due to activation of feedback loops 
that enhance upstream signaling and lead to extracellular signal-regulated kinase (ERK) 
reactivation. Hence it is hypothesized that addition of BMS-986466 to KRAS G12C targeted 
therapy may improve efficacy. This hypothesis is supported by data demonstrating that 
compensatory bypass signaling feedback activation of either upstream or downstream mediators 
of the RTK/MAPK pathway reduce effectiveness of KRAS G12Ci both preclinically and 
clinically.9,20,21,22,23,24,25 BMS-986466 has not been administered in combination with adagrasib 
or cetuximab to humans. Therefore, nonclinical toxicology, in vitro and in vivo safety 
pharmacology, and in vitro genotoxicity studies with the individual components alone (not 
combination toxicology studies) will be utilized to guide the initial benefit/risk assessment for this 
clinical trial.
More detailed information about the known and expected benefits and risks and reasonably 
anticipated AEs of BMS-986466 may be found in the IB.12 Additional information regarding 
adagrasib and cetuximab are presented in their product labels, including results from other clinical 
studies and, hence, is not being reported here.
The study has been designed with study visits that allow for close monitoring of participants’ safety
throughout the clinical trial (see Section 2), and participants are encouraged to contact the
investigator if an intercurrent illness develops between study visits. Testing for coronavirus disease 
2019 (COVID-19) to inform decisions about clinical care during the study should follow local
standard practice. Non-live COVID-19 vaccination is considered a simple concomitant medication 
within the study. However, the efficacy and safety of non-live vaccines (including non-live 
COVID-19 vaccines) in participants receiving BMS-986466 with adagrasib with or without 
cetuximab is unknown.
3.3.1
Risk Assessment
Although the study may not provide clinical benefit to the enrolled participants, BMS-986466 is 
a novel therapeutic agent that has the potential to significantly improve outcomes in a similar 
population of patients once an optimal human dose and schedule is identified, supporting its 
evaluation in clinical studies. Other notable risks include AEs and the potential for DDIs since 
BMS-986466 is a substrate of CYP3A4 while adagrasib is a strong CYP3A4 inhibitor. Dosing 
modifications for AEs are outlined in Section 7.4.
An assessment of potential risks associated with study interventions and trial procedures is 
presented in Table 3.3.1-1.
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Table 3.3.1-1:
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s)
Drug-drug Interaction
Adagrasib USPI14 and 
BMS-986466 IB12

Start with a DDI cohort to validate predicted 
clinical drug interaction prior to the 
combination escalation.

Exclude participants that require medications 
that will change the exposure of adagrasib or 
BMS-986466, including 
 modulators.

Intensive PK sampling during Part 1 DDI 
cohort and dose escalation to allow adequate 
DDI assessment.

Inclusion of comprehensive list of strong and 
moderate 
 inhibitors, CYP2C8, 
, 
 inhibitors that must be avoided or taken 
with caution (see Section 7.7.1).

Inclusion of list of substrates of 
,
,
2C9, 2D6,
, and 
 that must be 
taken with caution.
GI Toxicities:

Nausea/Vomiting

Diarrhea
Adagrasib USPI14,
BMS-986466 IB12, and 
Cetuximab SmPc19

A sentinel participant approach with a 7-day 
observation period for each new dose level (see 
Section 5.1.1).

Routine scheduled clinical laboratory 
monitoring throughout treatment of 
hematologic, hepatic, and metabolic parameters 
for early detection of abnormalities.

Dose modification per Section 7.4 and Table 
7.4-3.
LVEF Reduction
Adagrasib USPI14 and 
BMS-986466 IB12

Routine scheduled 2-D ECHO/MUGA
throughout treatment for early detection of
abnormalities.

BNP and troponin included in routine safety 
laboratory evaluations.
QTc Prolongation
Adagrasib USPI14

A sentinel participant approach with a 7-day 
observation period for each new dose level.

Triplicate and 12-lead ECGs performed at 
selected times throughout the study.

Avoid drugs with a known potential to prolong 
the QTc.

Inclusion of list of drugs known to prolong
QTc (refer to Appendix 8).

Dose modification per Section 7.4 and Table 
7.4-3.
Liver Toxicity
Adagrasib USPI14 and 
BMS-986466 IB12

Routine scheduled clinical laboratory 
monitoring throughout treatment of hepatic, 
and metabolic parameters for early detection of 
abnormalities.
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Table 3.3.1-1:
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy

Close monitoring during the study for 
mitigation of drug-induced liver injury.

Dose modification per Section 7.4 and Table 
7.4-3.
Interstitial Lung
Disease/Pneumonitis
Adagrasib USPI14,
cetuximab
USPI17/SmPC19, and
BMS-986466 IB12

Vital signs and oxygen saturation at each visit.

Exclude participants with previous interstitial
lung disease or pneumonitis (previous Grade 1 
or 2 immuno-mediated pneumonitis is permitted 
if completely resolved) (see Section 6.2).

Dose modification per Section 7.4 and Table 
7.4-3.
Renal Impairment
Adagrasib USPI14

Routine scheduled clinical laboratory 
monitoring throughout treatment of renal 
function and urinalysis.
Hematologic Effects
Adagrasib USPI14 and 
BMS-986466 IB12

Routine scheduled clinical laboratory 
monitoring throughout treatment.

Dose modification per Section 7.4 and Table 
7.4-3.
Hypomagnesemia
Cetuximab USPI17

Routine scheduled clinical chemistry laboratory
monitoring throughout treatment.

Dose modification per Section 7.4 and Table 
7.4-3.
Infertility
Adagrasib USPI14 and 
BMS-986466 IB12

Pregnancy and family planning counselling.
Study Procedures
Tumor Biopsy (eg, pain, 
infection)
Not applicable

Per institutional protocol/investigator’s
discretion.
Phlebotomy (eg, pain,
ecchymosis, bleeding,
syncope)
Not applicable

Per institutional protocol/investigator’s
discretion.
Other
Allergy to Contrast Agent (eg,
hives, anaphylaxis)
Not applicable

Prophylaxis and/or treatment per institutional 
protocol/investigator’s discretion.
Abbreviations:
; BNP, b-type natriuretic protein; CYP, cytochrome P450; 
DDI, drug-to-drug 
interaction; 
ECG, 
electrocardiogram;
ECHO, 
echocardiogram; 
GI, 
gastrointestinal; 
IB, Investigator’s Brochure; LVEF, left ventricle ejection fraction; MUGA, multigated acquisition; 
 
; PK, pharmacokinetic; SmPC, summary of product characteristics; USPI, United States Prescribing 
Information.
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3.3.2
Benefit Assessment
This is a clinical trial evaluating the safety and efficacy of BMS-986466 in combination with 
adagrasib with or without cetuximab in human participants with advanced KRAS G12C-mutant 
NSCLC and CRC. Although benefits might be hypothesized based on mechanism of action and/or 
preclinical observations, actual clinical benefits to patients with advanced cancer have not been 
established.
3.3.3
Overall Benefit/Risk Conclusion
Considering the measures taken to minimize risk to participants in this study, the potential risks 
identified in association with BMS-986466 in combination with adagrasib with or without 
cetuximab are justified by the anticipated benefits that may be afforded to participants with 
advanced KRAS G12C-mutant NSCLC and CRC.
The Sponsor will evaluate the benefit/risk profile of the study on an ongoing basis. This evaluation 
will be based on all available data, with particular attention to (i) AEs or other safety trends in this 
or any other clinical study of BMS-986466 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.
If an important and urgent safety concern is identified, enrollment may be halted and appropriate 
measures will be taken, including interactions with appropriate Health Authorities.
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary

To characterize the safety and tolerability; to establish 
the MTD, if reached; to evaluate the MAD if MTD is 
not reached; and to identify dose level(s) for expansion 
of:

Part 1A: BMS-986466 administered in 
combination with adagrasib to participants with 
KRAS G12C-mutant NSCLC, CRC, PDAC, and 
BTC

Part 1B: BMS-986466 administered in 
combination with adagrasib with cetuximab to 
participants with KRAS G12C-mutant CRC

Incidence of DLTs, AEs, SAEs, AEs leading 
to discontinuation, and deaths

To evaluate anti-tumor activity:

Part 2A: BMS-986466 in combination with 
adagrasib vs adagrasib in participants with KRAS 
G12C-mutant (G12Ci treatment-naïve) NSCLC 

Part 2B: BMS-986466 in combination with 
adagrasib with or without cetuximab vs adagrasib 
with cetuximab in participants with KRAS 
G12C-mutant (G12Ci treatment-naïve) CRC

ORR per RECIST v1.1 by BICR
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Secondary

Parts 1 and 2: To characterize the PK profile of 
BMS-986466 following first dose and at steady state in 
combination with adagrasib with or without cetuximab 

Summary measures of BMS-986466 PK 
parameters in plasma including Cmax, Tmax, 
and AUC(0-T), from concentration-time data 

To evaluate the preliminary efficacy of:

Part 2A: BMS-986466 in combination with 
adagrasib vs adagrasib in participants with KRAS 
G12C-mutant (G12Ci treatment-naïve) NSCLC 

Part 2B: BMS-986466 in combination with 
adagrasib with or without cetuximab vs adagrasib 
with cetuximab in participants with KRAS 
G12C-mutant (G12Ci treatment-naïve) CRC

PFS, DCR, DOR, and TTR per RECIST v1.1 
by BICR

To assess the safety and tolerability of:

Part 2A: BMS-986446 in combination with 
adagrasib in participants with KRAS G12C-mutant
(G12Ci treatment-naïve) NSCLC 

Part 2B: BMS-986446 in combination with 
adagrasib with or without cetuximab in 
participants with KRAS G12C-mutant (G12Ci 
treatment-naïve) CRC

Incidence of AEs, SAEs, AEs leading to 
discontinuation, and deaths

To assess the PD profile of BMS-986466 

Summary measures of target engagement such 
as, but not limited to, pERK.
Exploratory

Part 1 DDI : To determine the magnitude of drug 
interaction 
between 
BMS-986466 
(victim) 
and 
adagrasib

Geometric mean ratio of BMS-986466 AUC(0-
T) and Cmax in the presence and absence of 
adagrasib

Part 2A: To assess the OS in KRAS G12C-mutant
(G12Ci treatment-naïve) NSCLC participants treated 
with BMS-986466 in combination with adagrasib 

Part 2B: To assess the OS in KRAS G12C-mutant
(G12Ci treatment-naïve) CRC participants treated with 
BMS-986466 in combination with adagrasib with or 
without cetuximab

OS

To explore the associations between BMS-986466 PK, 
safety, efficacy, and clinical biomarkers

Association measures between BMS-986466 
PK levels and select outcomes and biomarkers 
of interest

To explore the pharmacodynamic activity of 
BMS-986466 administered in combination with 
adagrasib with or without cetuximab via assessment of 
translational biomarkers

Summary measures of change (or percentage
change) from baseline in intratumoral and 
peripheral biomarkers of immune activation 
and their association with anti-tumor activity

To explore potential associations between antitumor 
activity and select biomarker measures in the tumor 
and peripheral blood prior to treatment

Summary measures of anti-tumor activity by 
pretreatment level of biomarkers of interest

To characterize adagrasib PK when co-administered
with cetuximab

Summary measures of adagrasib PK 
parameters in plasma.
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SHP2 inhibitor
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints

To explore the dose and exposure-related effects of 
BMS-986466 in combination with adagrasib with or 
without cetuximab on QTc interval.

Concentration QTc analysis

To explore potential associations between image-based 
features and antitumor activity

Summary of measures of image-based feature 
changes, including but not limited to 
heterogeneity, shape and/or volume
Abbreviations: AE, adverse event; AUC(0-T), area under the concentration-time curve from time zero to time of last 
quantifiable concentration; BICR, Blinded Independent Central Review; Cmax, maximum observed concentration; 
CRC, colorectal cancer; DLT, dose-limiting toxicity; DCR, disease control rate; DOR, duration of response; G12Ci, 
G12C inhibitor; KRAS, Kirsten rat sarcoma viral oncogene; MAD, maximum administered dose; MTD, maximum 
tolerated dose; NSCL, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PD, 
pharmacodynamic; pERK, phosphorylation of extracellular signal-regulated kinase; PFS, progression-free survival; 
PK, pharmacokinetic; RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious adverse event; Tmax, 
time of maximum observed plasma concentration; TTR, time to response.
5
STUDY DESIGN
5.1
Overall Design
This is a Phase 1/2 multi-center, open-label study of BMS-986466 in combination with adagrasib 
in participants with KRAS G12C-mutant NSCLC, PDAC, and BTC and BMS-986466 in 
combination with adagrasib with or without cetuximab in KRAS G12C-mutant CRC. 
The study is composed of 2 parts: the first part, Part 1 (Phase 1) includes DDI cohort and dose 
escalation (Parts 1A and 1B); whereas the second part, Part 2 (Phase 2) includes randomized dose
expansion with comparator cohort (Parts 2A and 2B).
The study design schema is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schema
Abbreviations: 2L+, second-line therapy or later; BID, twice daily; BTC, biliary tract cancer; C, cycle; CRC, colorectal 
cancer; D, day; DDI, drug-drug interaction; DL, dose level; G12Ci, G12C inhibitor; IV, intravenous; KRAS, Kirsten
rat sarcoma viral oncogene; MTD, maximum tolerated dose; N/n, number of participants; NSCLC, non-small cell lung 
cancer; PDAC, pancreatic duct adenocarcinoma; Q2W, every 2 weeks; QD, once daily; R, randomization; R/R, 
relapsed and refractory to all available therapies.
a Part 1 DDI cohort: BMS-986466 10 mg single dose on C1D1 
 and adagrasib 400 mg BID starting on 
. Combination BMS-986466 10 mg QD and adagrasib 400 mg BID starting C3D1.
b BMS-986466 dosing is dependent on DDI cohort to achieve exposures comparable to BMS-986466 
, and 
mg QD monotherapy from Study NAV-1001. BMS-986466 will be given in combination with adagrasib 
400 mg BID with or without cetuximab 500 mg/m2 IV Q2W. Alternate dose levels and/or schedules of 
BMS-986466 (not to exceed exposures of the MTD), adagrasib (not to exceed 600 mg BID) with or without
cetuximab (not to exceed 500 mg/m2 Q2W) may be modified, or intermediate dose levels may be added. 
c Approximately 3 dose levels of BMS-986466 in combination with adagrasib will be evaluated not to exceed 
exposures of the maximum tolerable dose level evaluated in Part 1A.
d Approximately 3 dose levels of BMS-986466 will be evaluated in combination with adagrasib 400 mg BID with
cetuximab 500 mg/m2 Q2W not to exceed exposures of the MTD evaluated in Part 1B.
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5.1.1
Part 1: DDI Cohort and Dose Escalation

Part 1 will begin with evaluation of the DDI followed by Part 1A, dose escalation of 
BMS-986466 in combination with adagrasib in KRAS G12C-mutant NSCLC, PDAC, BTC,
and CRC.

Part 1B will evaluate the dose escalation of BMS-986466 in combination with adagrasib plus 
cetuximab in KRAS G12C-mutant CRC.
In the first part (DDI cohort), the potential DDI between BMS-986466 and adagrasib will be 
evaluated. A minimum of 6 PK-evaluable participants will be treated with a single dose of 
BMS-986466 10 mg PO on C1D1 followed by continuous dosing of adagrasib 400 mg BID starting 
on 
 and another single dose of BMS-986466 10 mg on 
. Starting on C3D1, participants 
will be treated daily with the combination of BMS-986466 10 mg QD and adagrasib 400 mg BID. 
PK samples will be collected as per Table 2-3. Based on the data from this DDI cohort, dose levels 
will be evaluated to achieve exposures approximately comparable to or less than BMS-986466 
 mg QD monotherapy from Study NAV-1001 in combination with adagrasib 
(Part 1A) or adagrasib plus cetuximab (Part 1B). The PK evaluation from the DDI cohort will 
assess the geometric mean ratio between AUC(INF), AUC(0-T), and Cmax of BMS-986466 with 
and without adagrasib and the results will inform the subsequent dose levels of BMS-986466 in 
combination with adagrasib 400 mg. 
Decisions to dose escalate or de-escalate in the dose escalation Parts 1A and 1B will be guided by 
the time-to-event Bayesian optimal interval (TITE-BOIN) method,26 where 
 
(refer to Appendix 7 TITE-BOIN design). 
 
 Excluding the 
DDI cohort, after the first participant per dose level is treated, there will be a 7-day observation 
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period before treating additional participants at the same dose level. Part 1A will identify a safe 
dose range of BMS-986466, based on which DL1A and DL2A to be tested further in Part 2A. Part 
1B will begin in parallel once the first dose level for BMS-986466 plus adagrasib combination is 
declared safe in Part 1A. The dose of BMS-986466 tested in Part 1B will not exceed the MTD
explored in Part 1A.
In Parts 1A and 1B, decisions for dose escalation and to continue enrollment according to the 
outlined study protocol will be made by the Sponsor in collaboration with the investigators, and 
take into consideration all available safety, PK, and pharmacodynamic (PD) data. Based on the 
safety data, planned dose levels and/or schedules of BMS-986466 (not to exceed the MTD), 
adagrasib (not to exceed the approved dose of 600 mg BID) and/or cetuximab (not to exceed the 
approved dose of 500 mg/m2 every 2 weeks [Q2W]) may be modified, or intermediate dose levels 
may be added after discussion and agreement between the Sponsor and the investigators. The 
Sponsor has the option to expand the DDI cohort and/or any dose level previously established to 
be tolerable to obtain additional data. The implementation of various dose levels and/or schedules 
based on evolving PBPK data in the dose escalation and dose expansion may be done using dose 
clarification memo/protocol clarification letters as appropriate as per local regulations. 
All participating sites may not be able to enroll in DDI and/or dose escalation cohorts in Part 1 due 
to their time of onboarding/activation, challenges around PK samples stability and sample 
management logistics.
5.1.2
Part 2: Randomized Dose Expansion
Part 2 is a randomized, open-label dose expansion with comparator cohorts to assess preliminary 
efficacy, safety, and tolerability of optimal dose level(s) of BMS-986466 in combination with 
adagrasib with or without cetuximab. The doses to be administered in Parts 2A and 2B will not 
exceed doses determined to be tolerable from Parts 1A and 1B of the study, respectively.

Part 2A will evaluate BMS-986466 in combination with adagrasib in KRAS G12C-mutant
(G12C inhibitor treatment-naïve) NSCLC participants. 

Part 2B will evaluate BMS-986466 in combination with adagrasib with or without cetuximab 
in KRAS G12C-mutant (G12C inhibitor treatment-naïve) CRC participants.
5.1.2.1
Part 2A: 2L KRAS G12C-mutant (G12C Inhibitor-treatment Naïve) 
NSCLC
Part 2A will begin after Part 1A identifies up to 2 safe dose levels, DL1A and DL2A, of 
BMS-986466 to be tested in combination with adagrasib. The doses of BMS-986466 and adagrasib
will not exceed the MTD in Part 1A. Participants with 2L+ KRAS G12C-mutant (G12C 
inhibitor-treatment naïve) NSCLC will be randomized (1:1:1) to receive either: 

BMS-986466 DL1A with adagrasib

BMS-986466 DL2A with adagrasib

Adagrasib 600 mg BID
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5.1.2.2
Part 2B: 2L KRAS G12C-mutant (G12C Inhibitor-treatment Naïve) CRC
Part 2B will begin after Part 1B identifies up to 2 safe dose levels, DL1B and DL2B, of BMS-986466 
to be tested in combination with adagrasib plus cetuximab. The dose selected for BMS-986466 in 
combination with adagrasib without cetuximab, herein referred to as DLA, will be based on the 
totality of the available data from Parts 1A and 2A (not to exceed the MTD from Part 1A). Up to 
2 dose levels of BMS-986466 may be tested in combination with adagrasib with cetuximab (not 
to exceed the MTD in Part 1B.) A comparator cohort of adagrasib plus cetuximab will also be 
tested. Participants with 2L+ KRAS G12C-mutant (G12C inhibitor-treatment naïve) CRC will be 
randomized (1:1:1:1) to receive either:

BMS-986466 DLA with adagrasib

BMS-986466 DL1B with adagrasib plus cetuximab

BMS-986466 DL2B with adagrasib plus cetuximab

Adagrasib 600 mg BID with cetuximab
5.1.3
Screening
The screening period will be up to 28 days and begins by establishing the participant’s initial 
eligibility after signing the informed consent form. Participants will be enrolled using Interactive 
Response Technology (IRT). Participants must start treatment within 3 days of treatment 
assignment (Part 1) or randomization (Part 2). The screening assessments are shown in Table 2-1
and Table 2-2.
If a participant exceeds the 28-day screening period due to a study-related procedure (eg, 
scheduling of a tumor biopsy or waiting for a study-related laboratory value), the participant must
be reconsented, but does not require a new participant identification number. In this situation, the 
Medical Monitor should be notified, and the fewest number of procedures from the initial 
screening should be repeated to qualify the participant, while maintaining participant safety and 
eligibility.
See Section 6.4.1 for re-screening procedures and requirements.
5.1.4
Treatment Period
The treatment period will last approximately 2 years or until confirmed disease progression, 
unacceptable AE, withdrawal by participant, or death. Participants with clinical benefit after
2 years of treatment are eligible to continue treatment after discussion with the Medical Monitor.
See Section 7.8 for continued access to study intervention after the end of study. Cycles are 28 days 
and the DLT evaluation period is 1 cycle (28 days).
On-treatment monitoring will include planned clinic visits with standard safety monitoring
including cardiovascular monitoring, blood draws for laboratory testing, PK, and biomarkers
(Part 1: Table 2-1, Part 2: Table 2-2). Imaging for tumor assessment will occur every 8 weeks
(Q8W) during the first 48 weeks of treatment followed by every 12 weeks (Q12W) until disease 
progression or study discontinuation, whichever occurs later. All participants will be supplied with
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a mechanism to capture daily symptoms, if any, and the intake of BMS-986466 and adagrasib
(with or without food).
5.1.5
Follow-up Period
The follow-up period includes a safety follow-up and a survival follow-up, which occur in parallel
after the end of treatment (EOT) visit. EOT is defined as the visit where the decision is made to 
discontinue the participant from treatment. Evaluations will be made prior to study discharge for 
the participants who are permanently discontinued. For participants who complete all scheduled 
cycles of therapy, the EOT visit will be the same as the last scheduled and completed on-treatment 
visit (eg, C26D1) and the start of the safety follow-up period. For participants who do not complete 
all scheduled cycles of therapy, the EOT visit will be the most recent on treatment visit (with all
available safety and response data); it does not need to be repeated and will be considered as the 
start of the safety follow-up period.
In the follow-up period, safety and survival follow-up will occur concurrently. The safety follow-
up period is 30 days (± 7 days) after the EOT visit. Survival follow-up every 3 months (± 15 days)
for all parts will begin at EOT and last for a period of 2 years, or until death, lost to follow-up, 
withdrawal of consent, conclusion of the study, or study termination, whichever comes first. The 
survival follow-up visits can be conducted in person or via telephone.
5.1.6
Data Monitoring Committee and Other Committees
Bristol-Myers Squibb Company (BMS) has developed a multi-layered process to ensure safety 
monitoring through close collaboration of study site investigators, the BMS study team, and the 
BMS Worldwide Patient Safety (WWPS)-led Safety Management Team (SMT), and this will be 
employed in this study. BMS WWPS is an internal group that operates independently from the 
clinical team to monitor safety across all BMS protocols and analyze all data in an unblinded 
fashion. Within BMS, an SMT is established for investigational therapies under clinical 
development, and a member of WWPS chairs this team. In addition, signal detection is performed 
at least quarterly and ad hoc throughout the study by the SMT composed, at a minimum, of the 
WWPS Medical Safety Assessment Physician (Chair of the SMT), the Medical Monitor, Global 
Regulatory Lead, and Pharmacovigilance Scientist, all of whom analyze the data in an unblinded 
fashion. A Data Monitoring Committee will not be used in the study.
Since this is an open-label study, WWPS, the Medical Monitor, and the investigators will have 
access to all data necessary for safety evaluation and continuous safety monitoring as described in 
Section 10.4.1. 
Dose escalation decisions and decisions to continue enrollment according to the outlined study 
protocol will be made by the Sponsor in collaboration with the investigators, Medical Monitor, 
medical safety physician, and other appropriate members and take into consideration all available 
safety, PK, and PD data at convened Scientific Review Committee (SRC).
5.2
Number of Participants
A total of approximately 410 evaluable participants will be treated in this study as described below.

A minimum of 6 PK-evaluable participants will be treated in Part 1 DDI cohort. 
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
In Parts 1A and 1B (excluding the DDI cohort), approximately 3 to 9 DLT-evaluable 
participants will be treated per dose level up to approximately 54 participants. 

In Parts 2A and 2B, approximately 150 and 200 response-evaluable participants will be treated,
respectively.
5.3
End of Study Definition
The start of the study is defined as the first participant’s first visit.
The primary completion date is defined as the date on which the last data point is collected for the 
study’s last primary endpoint (outcome). For this study, the last primary outcome for the primary 
endpoints, defined as follows:
For Part 1: When the dose level(s) for expansion for Part 2 have been selected.
For Part 2: The primary completion date will be the date when the data of the last participant for 
primary analysis has been collected.
End of study is defined as the last participant’s last visit.
Participants are considered to have completed the study if they have completed all periods of the 
study, including last visit.
5.4
Scientific Rationale for Study Design
BMS-986466 is a potent, selective, orally active allosteric inhibitor of SHP2 that plays a key 
regulatory role in both tumor and immune cell signaling.
 
 
 
SHP2 being a central node in the MAPK pathway, adding a SHP2 
inhibitor with KRAS G12C inhibitor may help to overcome the resistance to KRAS inhibitors by 
inhibiting the feedback activity, potentially improving antitumor activity and overall response in
participants with KRAS G12C-mutant solid tumors who fail to respond to KRAS inhibitors or in 
participants naïve to KRAS inhibitors, as explained in Section 5.4.3.
 
 
. This combination study is designed to thoroughly
evaluate safety, PK, and peripheral blood and tumor PD of BMS-986466 in combination with 
adagrasib, with or without cetuximab in KRAS G12C-mutant solid tumors.
In Part 1, the DDI evaluation will guide the dosing and schedule selection for combination testing 
in dose escalation with the objective of identifying dose(s) and schedule(s) that provide
maximal target engagement in the peripheral blood/tumor, while remaining safe and well
tolerable.
Part 2 is focused on evaluating safety and efficacy of BMS-986466 in combination with adagrasib 
and with or without cetuximab in randomized dose expansion with comparators. Given the 
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growing knowledge about KRAS inhibitors and the evolving landscape of KRAS G12C inhibitor
monotherapy versus combination efficacy4 evaluation of these regimens in this study will provide 
important safety and PD insights on 2 targeted, rational combination approaches that can be 
employed within a variety of tumor indications. 
5.4.1
Rationale for DDI Cohort
Adagrasib is a strong, time dependent CYP3A4 inhibitor, and BMS-986466 is a CYP3A4 
substrate. In Part 1, the DDI cohort will identify a safe starting dose for BMS-986466 in 
combination with adagrasib by measuring the magnitude of potential DDI between BMS-986466 
and adagrasib. This cohort is designed to compare single dose BMS-986466 PK with and without 
concomitant administration of adagrasib (see Section 5.5.2). Based on the magnitude of observed
DDI, the starting dose of BMS-986466 in the dose escalation in combination with adagrasib 
400 mg BID (Part 1A) will be adjusted to match the approximate exposure comparable to or less 
than the exposure of BMS-986466 achieved at 
 mg QD when administrated as a 
single agent (see Section 5.5).
5.4.2
Rationale for Dose Escalation Design
The TITE-BOIN design is used to guide escalation decisions and the MTD selection in Part 1. 
Unlike many existing Phase 1 designs, which require suspending the accrual after treating each 
cohort of participants, the TITE-BOIN design allows the option for real-time dose assignment 
decisions for new participants while some enrolled participants’ toxicities data are still pending. 
This may shorten the trial duration and reduce the logistic difficulties caused by repeatedly 
suspending accrual. The TITE-BOIN works by predicting the DLT outcome for participants whose 
DLT data are pending based on their follow-up time. It 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 more complex model-based designs, such as the time-to-event continual 
reassessment method (TITE-CRM). Parts 1A and 1B will evaluate the primary study objective 
(see Table 4-1).
5.4.3
Rationale for SHP2 and EGFR Inhibitors in Combination with KRAS 
G12C Inhibitors
RAS pathway inhibitors often have limited efficacy as single agents due to the activation of 
feedback loops that enhance upstream signaling and lead to ERK reactivation. Since SHP2 is a 
central node in downstream RTK activation, SHP2 inhibitors may also be beneficial as a 
component of combination therapy to maximize the therapeutic potential of RAS pathway 
inhibitors. Recent preclinical studies, including those with BMS-986466, have shown that SHP2 
inhibition can potentiate the activity of approved KRAS G12C inhibitors in nonclinical cell line 
and tumor models by inhibiting feedback activation.7,8,27 Additionally, SHP2 inhibition also 
decreases RTK-driven SOS1-dependent GTP loading of RAS, which leads to elevated RAS-GDP 
levels and therefore, may enhance the efficacy of adagrasib, as it binds irreversibly to the inactive 
guanosine diphosphate (GDP)-bound form of mutant KRAS G12C but not to the active 
GTP-bound form.11
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Using EGFR inhibitors to improve efficacy with KRAS G12C inhibitors has been demonstrated 
in preclinical models and in clinical studies. In Study KRYSTAL-1 (NCT03785249), adagrasib in 
combination with cetuximab had an ORR of 46% compared to 19% with adagrasib monotherapy.5
This was recapitulated in a pre-clinical model of KRAS G12C-mutant CRC in which the addition 
of a SHP2 inhibitor to a KRAS G12C inhibitor was superior to the combination of an EGFR 
inhibitor plus KRAS G12C inhibitor and both combinations were superior to KRAS G12C 
inhibitor monotherapy.22 Thus, preclinical and clinical data provide the rationale for SHP2 and 
EGFR inhibitors to be used in combination with KRAS G12C inhibitors.
5.4.4
Rationale for Adagrasib and Adagrasib Plus Cetuximab as Comparator
KRYSTAL-1 is a registrational Phase 2 study evaluating adagrasib 600 mg BID in participants 
with 2L+ KRAS G12C-mutant NSCLC.10 Of 112 response-evaluable participants, 48 (43%) 
participants had an objective response with 1 participant having a complete response and the 
remaining 47 participants having a partial response. The mPFS is 6.5 months (95% confidence 
interval [CI] 4.7-8.4) and OS is 12.6 months (95% CI 9.2-19.2).
Also in KRYSTAL-1, participants with 2L+ KRAS G12C-mutant CRC were treated with 
adagrasib 600 mg BID (n = 45) or adagrasib 600 mg BID plus cetuximab (n = 28).5 The ORR for 
adagrasib monotherapy was 19% and there was additional benefit in the combination with 
cetuximab (ORR = 46%). KRYSTAL-10 (NCT04793958) is an ongoing Phase 3 study 
investigating adagrasib 600 mg BID with cetuximab 500 mg/m2 versus chemotherapy in 
participants with 2L KRAS G12C-mutant CRC.28 In the same Phase 2 KRYSTAL-1 study, 
21 PDAC and 12 BTC participants treated with adagrasib monotherapy with two median prior 
lines of therapy showed an ORR of 33% and 42%, respectively.29
These results have led to the recent accelerated FDA approval of adagrasib for the treatment of 
2L+ KRAS G12C-mutant NSCLC14 and breakthrough therapy designation for adagrasib plus 
cetuximab for the treatment of 2L+ KRAS G12C-mutant CRC.4
Based on the above data, adagrasib with or without cetuximab is considered to be a safe and 
efficacious comparator that will permit evaluation of the contribution of BMS-986466.
5.5
Justification for Dose
5.5.1
Choice of Target Exposures for BMS-986466 Based on Study NAV-1001
Based on the FIH NAV-1001 study results, in which participants received oral BMS-986466 
monotherapy from 80 to 550 mg QD, BMS-986466 
 mg QD was considered to be a safe and 
well tolerated dose 
.
Following oral QD dosing, BMS-986466 exhibited dose-proportional exposure increases up to 
550 mg QD with low interparticipant variability based on 358 PK samples available from 
32 participants from Study NAV-1001. 
 
 
 
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. Although no DLTs were observed at the 550 mg 
QD dose level, given the observed AEs, including a Grade 3 thrombocytopenia, (leading to 2 dose 
reductions out of 4 DLT-evaluable participants; refer to the IB for additional information12), the 
550 mg QD dose level is not considered to be well tolerated 
 
observed at this dose level. In comparison, BMS-986466
 mg QD is considered to be safe and 
well tolerated with predicted exposure to be 79% above the biologically effective AUCss, as 
compared to 19% above the biological effective AUCss (derived from mice xenograft tumor 
growth inhibition) at 400 mg QD and 119% at 550 mg QD, respectively.
5.5.2
Justification for the Choice of BMS-986466 10 mg Single Dose in 
Combination with Adagrasib 400 mg BID in Part 1A DDI Cohort
BMS-986466 metabolism is primarily mediated by CYP3A4. Also, notably it does not inhibit the 
major human CYP isoforms, nor does it induce CYP1A2, 2B6, or 3A4 in human hepatocytes.
Thus, the main drug interaction risk for BMS-986466 is being a victim and can have its clearance 
modified by inhibitors or inducers of CYP3A4. On the other hand, adagrasib is a strong, time 
dependent CYP3A4 inhibitor; at 400 and 600 mg BID dose, it increases midazolam AUC by 20-
and 30-fold, respectively.14 As a result, the dose of BMS-986466 may need to be adjusted carefully
when used in combination with adagrasib to adequately address the drug interaction potential.
To evaluate the potential DDI between adagrasib and BMS-986466, in Part 1A the first cohort 
(DDI cohort) is planned. This cohort will evaluate BMS-986466 10 mg single dose (considered as 
DL1 for study) on C1D1, followed by continuous dosing of adagrasib 400 mg BID starting 
 
and another single dose of BMS-986466 10 mg on 
 
. Participants will not
start continuous dosing of BMS-986466 in combination with adagrasib 400 mg BID until C3D1,
assuming the DDI evaluation is supportive of acceptable safety exposure.
Despite PBPK modeling predictions suggesting that adagrasib 400 mg BID is expected to increase 
BMS-986466 exposure by
, for participant safety, the proposed strategy is 
more conservative. The selected single dose of 10 mg of BMS-986466 in the DDI cohort is 20-fold 
lower (suggested by USPI for the adagrasib-midazolam DDI) than the dose of
mg QD (2 dose 
levels lower than the dose of
 mg QD, 
is approximately 10 mg). Therefore, 
BMS-986466 10 mg single dose in combination with adagrasib is expected to achieve an exposure
of less than BMS-986466 
 mg QD monotherapy. Based on the acceptable safety observations 
at BMS-986466 
 mg QD, and at 
 mg QD, a single dose of 10 mg BMS-986466 is not 
expected to increase the toxicity of adagrasib. 
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Given the preliminary observed half-life of approximately 
 for BMS-986466 and the drug 
interaction with adagrasib, which prolongs the BMS-986466 half-life, PK samples will be 
collected 
-BMS-986466 dose when administered as a single agent and up to 
 when a single dose of BMS-986466 is administered with continuous dose of adagrasib in 
order to adequately capture the terminal phase of the PK profile.
5.5.3
Dose Selection Strategy for BMS-986466 in Parts 1A and 1B
For Parts 1A and 1B, the dosing regimen for BMS-986466 will be adjusted based on the results of 
DDI evaluation from the DDI cohort, in order to match the exposure achieved in BMS-986466 
monotherapy at 
 mg QD dose. To address the potential overlapping 
toxicity between BMS-986466 and adagrasib, the starting dose for the combination will be selected 
to match the approximate exposure comparable to or less than the exposure of 
mg QD, rather 
than 
 mg QD, even though BMS-986466 at the dose of 
 mg QD was considered to be safe 
and well tolerated, and 
 in the monotherapy setting.
Further, to optimize the BMS-986466 dosing regimen in the combination setting, dose-escalation 
will be performed to escalate the dose up to the level achieving approximate exposure comparable 
to or less than the exposure of 
 mg QD. The dose-escalation decision will be based on the safety 
observation at the previous dose level, PBPK, and population PK modeling, and simulation will 
be adopted to support dose selection and optimization.
5.5.4
Justification for the Choice of Adagrasib 400 mg BID in Combination 
with BMS-986466
Although the USPI recommended dose for adagrasib is 600 mg BID, due to the safety 
observations, including 79% Grade 3 or greater treatment-emergent adverse events (TEAEs), 82% 
of TEAEs leading to dose reduction or interruption, and 13% TEAEs leading to dose 
discontinuation, a Post Marketing Requirement was issued to “compare the safety of adagrasib 
600 mg BID versus an alternative daily dosage.”14,30 Based on the safety profile of adagrasib and 
potential overlapping toxicities for adagrasib and BMS-986466, adagrasib 400 mg BID will be 
used in combination with BMS-986466. 
Adagrasib 400 mg BID is expected to be a biologically active dose. Based on nonclinical human 
xenograft models, anti-tumor efficacy is expected at human exposure over the range of 596 to 
1,544 ng/mL Cavg (derived most sensitive and least sensitive cell lines). Adagrasib 400 mg BID is 
expected to achieve Cavg,ss of 1,764 ng/mL and Cmin,ss of 1,804 ng/mL (versus Cavg,ss of 
2,633 ng/mL and Cmin,ss of 2,693 at 600 mg BID, given the observed dose proportionality),31
which is roughly beyond the upper bound threshold (1,544 ng/mL) identified from the nonclinical 
model. Also, efficacy has been observed in participants who received 400 mg BID (preliminary 
ORR rate = 67% [4/6, all PRs] versus overall ORR [42.9%] at 600 mg BID).31
In concordance with the selection of adagrasib 400 mg BID dose for combination escalation, the 
400 mg BID dose will also be selected for DDI cohort in order to provide direct evidence 
supporting DDI evaluation at adagrasib 400 mg BID.
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In the event that BMS-986466 at the tested dose levels in combination with adagrasib 400 mg BID 
has manageable safety profile, the Sponsor may test BMS-986466 in combination with alternative 
doses of adagrasib not to exceed the approved dose of 600 mg BID.
5.5.5
Justification for the Choice of Adagrasib 600 mg BID with or without
Cetuximab as a Comparator
When used as a comparator, either as monotherapy or in combination with cetuximab, adagrasib 
600 mg BID will be administered. Adagrasib 600 mg BID is an approved monotherapy dose that
was granted accelerated approval by the FDA in 2L+ KRAS G12C-mutant NSCLC. The FDA 
granted Breakthrough Therapy Designation to adagrasib in combination with cetuximab for KRAS 
G12C-mutant CRC, and the registrational Phase 3 study KRYSTAL-10 includes a combination of 
adagrasib (600 mg BID) with cetuximab (500 mg/m2 Q2W) as an investigational arm.28 Hence,
the comparator cohorts will use these regimens in Part 2 (see Section 5.4.4 for additional 
information).
5.6
Rationale for Exploratory Biomarker Research
Biomarker samples may also be used for research to develop methods, assays, prognostics, and/or 
diagnostics and to explore relationships between participant molecular and cellular data versus
participant clinical response and/or resistance to therapy.
Genetic variation may affect a participant’s response to study intervention, susceptibility to
disease, and severity and progression of disease. Variable response to study intervention may be 
due to genetic determinants that affect intervention absorption, distribution, metabolism, and 
excretion; mechanism of action of the intervention; disease etiology; and/or molecular subtype of 
the disease being treated. 
DNA samples will be used for research related to the study intervention(s) and/or disease/condition 
under study and related conditions. The samples may also be used to develop tests/assays, 
including diagnostic tests related to the study intervention(s) and/or the disease/condition under 
study and related conditions. Genetic research may consist of the analysis of 1 or more candidate 
genes or the analysis of genetic markers throughout the genome or analysis of the entire genome. 
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. 
The research may involve genetic tests using deoxyribonucleic acid (DNA) or ribonucleic acid 
(RNA); this may consist of the analysis of 1 or more candidate genes or the analysis of genetic 
markers throughout the genome or analysis of the entire genome. Analysis of samples for future 
research may also involve the use of other clinical data collected as part of this study. Such future 
research may also lead to the development of new diagnostic tests. The participant’s decision to 
consent to this optional future research will not affect his/her ability to participate in the main 
study.
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6
STUDY POPULATION
The target study population consists of participants with KRAS G12C-mutant advanced solid 
tumors, including NSCLC, PDAC, BTC, and CRC, who have met the following inclusion criteria 
and no exclusion criteria. Approximately 410 participants will be enrolled across various parts of 
the study. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
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 18 years and above 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 ICF must be 
obtained before performing any protocol-related procedures that are not part of normal 
patient care. Participants under legal protection who require a legally authorized 
representative (LAR) are prohibited from consenting.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study.
2) Type of Participant and Target Disease Characteristics
a) Measurable disease per RECIST v1.1.
b) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at 
screening and confirmed prior to randomization. 
c) Participants must have a life expectancy of at least 3 months at the time of first dose
according to the investigator’s judgement.
d) All participants with KRAS G12C-mutant NSCLC:
i)
Should have documented status for PD-L1 (tumor proportion score [TPS]), 
serine/threonine kinase 11 [STK11], KRAS non-G12C mutations, epidermal growth 
factor receptor (EGFR) including exon 20 insertion mutations, anaplastic lymphoma 
kinase (ALK) rearrangements, ROS proto-oncogene 1 (ROS1) rearrangements, 
rearranged during transfection (RET) rearrangements, neurotrophic tropomyosin-
receptor kinase (NTRK) gene fusions, mesenchymal to epithelial transition (MET)
amplification, MET exon 14 skipping, or proto-oncogene B-Raf (BRAF) non-V600X
mutations, if known.
ii) Should have received prior treatment with platinum-based doublet chemotherapy and 
anti PD-(L)1.
iii) Harboring other known actionable mutations (eg, EGFR, ALK, and ROS1) should have 
received prior treatment with an approved targeted therapy (as available per 
country/region standard-of-care practices).
e) All participants with KRAS G12C-mutant CRC:
i)
Should have documented status for microsatellite instability (MSI), mismatch repair 
(MMR), and tumor mutational burden (TMB), if known.
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ii) Should have received prior systemic therapy, including prior treatment with 
fluoropyrimidine, oxaliplatin and/or irinotecan-based chemotherapy, and vascular 
endothelial growth factor (VEGF)-targeted antibodies. Participants with microsatellite
instability (MSI)-high CRC should have received approved immune checkpoint 
inhibitor therapy.
f)
All participants with KRAS G12C-mutant PDAC or BTC:
i)
Should have documented status for EGFR, fibroblast growth factor receptor 2 
(FGFR2), isocitrate dehydrogenase 1 (IDH1), BRAF non-V600X, and other mutations,
if available.
g) For Participants in Part 1:
i)
Participants in Part 1 DDI and 1A: must have histologically documented, locally 
advanced and unresectable, or metastatic NSCLC, PDAC, BTC, or CRC with KRAS
G12C mutation, whether naïve to KRAS G12C inhibitor treatment or not.
ii) Participants in Part 1B must have histologically documented, locally advanced and 
unresectable, or metastatic CRC with KRAS G12C mutation, whether naïve to KRAS 
G12C inhibitor treatment or not.
iii) For NSCLC and CRC: Participants must have a documented KRAS G12C mutation 
from an New York State (NYS)-approved, FDA-approved/cleared, or conformité 
européenne (CE)-marked test or, when such result is not available, positive KRAS 
G12C mutation status should be confirmed by a central laboratory (Guardant360 CDx)
in liquid biopsy samples collected at the time of screening.
iv) For PDAC and BTC: Participants must have a documented KRAS G12C mutation from 
an NYS-approved, FDA-approved/cleared or CE-marked test and liquid biopsy 
samples collected only for retrospective testing.
v)
Have progression or are intolerant or have disease recurrence on or after available 
standard of care treatments
h) For Participants in Part 2 Dose Expansion:
i)
Participants must have a documented KRAS G12C mutation from an NYS-approved,
FDA-approved/cleared or CE-marked test or, when such result is not available, positive 
KRAS G12C mutation status should be confirmed by a central laboratory (Guardant360 
CDx) in liquid biopsy and/or tumor samples collected at the time of screening or from 
archival biopsies (less than 1 year old).
ii) Have tumor lesions that can be biopsied at acceptable risk and must consent to undergo 
pre-treatment and on treatment biopsy collection. See Section 9.7 for additional 
information.
i)
Participants in Part 2A:
i)
Must have histologically documented, locally advanced and unresectable or metastatic 
KRAS G12C-mutant NSCLC, naïve to treatment with KRAS G12C inhibitor.
ii) Must have progression or disease recurrence or are intolerant after at least 1 prior line 
of systemic therapy, which must include platinum-based doublet chemotherapy and
anti-PD-(L)1 therapy.
j)
Participants in Part 2B:
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i)
Must have histologically documented, locally advanced and unresectable, or metastatic 
KRAS G12C-mutant CRC, naïve to treatment with KRAS G12C inhibitor.
ii) Must have progression or disease recurrence or are intolerant after at least 1 prior line 
of systemic therapy.
3) Age of Participant
a) Participant must be age ≥ 18 years or local age of majority at the time of consent.
4) Reproductive Status

Investigators shall counsel women of childbearing potential (WOCBP) participants (as defined 
in Appendix 4), and male participants who are sexually active with WOCBP, on the importance 
of pregnancy prevention, the implications of an unexpected pregnancy, and the potential of
infertility or fetal toxicity occurring due to transmission of study intervention, 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 contraceptive
methods.
a) Female Participants:
i)
Female participants, who are not of childbearing potential, must have documented 
proof. Note: Documentation can be obtained from the site personnel’s review of the 
participant’s medical records or medical examination of medical history interview.
(1) Women who are not of childbearing potential (as defined in Appendix 4) are 
exempt from contraceptive requirements.
ii) WOCBP must have a negative highly sensitive urine or serum human chorionic 
gonadotropin (serum HCG) pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of human chorionic gonadotropin) within 24 hours prior to the start of study 
intervention.
(1) 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.
(2) Additional requirements for pregnancy testing during and after study intervention 
are in Section 2 Schedule of Activities.
(3) The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to potentially decrease the risk for inclusion of a woman with 
an undetected pregnancy.
iii) WOCBP and male participants who are sexually active with WOCBP must agree to 
follow instructions for method(s) of contraception as described below and included in 
the ICF.
(1) Hormonal contraceptive agents are prohibited during this study because of an 
anticipated drug-drug interaction which could cause unintended 
high 
concentrations of hormonal contraception drugs and possibly lead to adverse effects
(see Section 7.7.1). WOCBP are not permitted to use hormonal contraceptives as a 
method of contraception (as described in Appendix 4).
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iv) 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 non-hormonal contraceptive method that is highly 
effective (with a failure rate of < 1% per year), preferably, with user independent 
methods, as described in Appendix 4, during the intervention period and for at least 
2 months after the last dose of BMS-986466, 1 week after the last dose of adagrasib 
and 2 months after the last dose of cetuximab, whichever is longest and agrees not 
to donate eggs (ova, oocytes) for the purpose of reproduction for the same period.
b) 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.
i)
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.
ii) 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 participant 
has undergone a successful vasectomy or if the partner is pregnant or breastfeeding. 
Male participants should continue to use a condom during the intervention period and 
for at least 2 months after the last dose of BMS-986466, 1 week after the last dose of 
adagrasib and 2 months after the last dose of cetuximab, whichever is longest.
iii) Female partners of male participants should be advised to use a highly effective method
of contraception during the intervention period and for at least 2 months after the last 
dose of BMS-986466, 1 week after the last dose of adagrasib and 2 months after the 
last dose of cetuximab, whichever is longest, after the last dose of study intervention 
for the male participant.
iv) Male participants with a pregnant or breastfeeding partner must agree to remain 
abstinent from sexual activity or use a male condom during any sexual activity 
(eg, vaginal, anal, oral), even if the participant has undergone a successful vasectomy, 
during the intervention period and for at least 2 months after the last dose of 
BMS-986466, 1 week after the last dose of adagrasib and 2 months after the last dose 
of cetuximab, whichever is longest.
v) Male participants must refrain from donating sperm during the intervention period and 
for at least 2 months after the last dose of BMS-986466, 1 week after the last dose of 
adagrasib and 2 months after the last dose of cetuximab, whichever is longest.
vi) Breastfeeding partners of male participants should be advised to consult their health
care provider about using appropriate highly effective contraception during the time 
the male participant is required to use condoms. Female partners of male participants 
are permitted to use hormonal contraception.
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6.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1) Medical Conditions
a) Have tumors harboring known activating mutations in BRAF V600X, protein tyrosine 
phosphatase non-receptor type 1 (PTPN11 [SHP2]), or KRAS Q61X.
b) Any major surgery within 4 weeks of first dose of study intervention. Participants must 
have recovered from the effects of major surgery or significant traumatic injury at least 
14 days before the first dose of study intervention.
c) Any gastrointestinal disease or surgery that could impact the absorption of the study 
intervention.
d) Inability to administer and/or tolerate oral medication.
e) Have untreated brain metastases. Participants who have had brain metastases resected or 
have received radiation therapy ending at least 4 weeks prior to C1D1 are eligible if they 
meet all of the following criteria prior to first dose of study medication: 
i)
Residual neurological symptoms related to the CNS treatment Grade ≤2; 
ii) On a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent) for at least 
2 weeks prior to C1D1; and 
iii) Follow-up contrast-enhanced magnetic resonance imaging (MRI) within 4 weeks prior 
to C1D1 shows no new lesions appearing.
f)
Participants with leptomeningeal metastases (carcinomatous meningitis).
g) Concurrent malignancy (present during screening) requiring treatment or history of prior 
malignancy active within 2 years prior to treatment (ie, participants with a history of prior 
malignancy are eligible if treatment was completed at least 2 years before randomization 
and the participant has no evidence of disease). Participants with history of prior early stage 
basal/squamous cell skin cancer or non-invasive or in situ cancers that have undergone 
definitive treatment at any time are also eligible.
h) Uncontrolled or significant cardiovascular disease including, but not limited to, any of the 
following:
i)
Myocardial infarction or stroke/transient ischemic attack within the past 12 months.
ii) Unstable or poorly controlled angina pectoris or symptomatic peripheral vascular 
disease including Prinzmetal variant of angina pectoris.
iii) History of aortic aneurysm.
iv) Any history of clinically significant arrhythmias (such as sustained ventricular 
tachycardia, ventricular fibrillation, or torsades de pointes), individual or family history 
of long QT syndrome.
v) History of other clinically significant heart disease (eg, cardiomyopathy, congestive 
heart failure with New York Heart Association functional classification III to IV, 
pericarditis, or significant pericardial effusion).
vi) History of left ventricular ejection fraction (LVEF) < 50% within the previous 
12 months before starting the study intervention.
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vii)QT interval corrected for heart rate using Fridericia’s formula (QTcF) prolongation 
> 470 msec (for women) and > 450 msec (for men), except for right bundle branch 
block.
viii)
Complete left bundle branch block, bifascicular block, or other clinically significant 
abnormal ECG finding at screening.
ix) Clinically symptomatic bradycardia or sick sinus syndrome.
i)
Interstitial lung disease or pneumonitis (previous Grade 1 or 2 immuno-mediated 
pneumonitis is permitted if completely resolved)
j)
History of allogenic bone marrow transplant.
k) On dialysis.
l)
Any significant acute or chronic medical illness, active uncontrolled infection, or organ 
system dysfunction, such as ascites, coagulopathy, or encephalopathy or other reasons that,
in the investigator’s opinion, could compromise the participants’ safety or interfere with or 
compromise the integrity of study outcomes.
m) Any other sound medical, psychiatric, and/or social reason as determined by the 
investigator.
2) Reproductive Status
a) Women who are breastfeeding or pregnant.
3) Prior/Concomitant Therapy
a) Inability to comply with restrictions and prohibited treatments as listed in Section 7.7: 
Concomitant Therapy.
b) Have previously received a SHP2 inhibitor (eg, TNO-155, RMC-4630, RLY-1971, 
JAB-3068, JAB-3312, or PF-07284892).
c) For Part 2 only: Have previously received a KRAS G12C inhibitor (eg, sotorasib, 
adagrasib, or other investigational agents).
d) Systemic anticancer therapies or biological therapies (including programmed cell death 
protein 1 [PD-1], PD-L1, or CTLA-4 antibodies) within 4 weeks or 5 half-lives (whichever 
is shorter) prior to the first administration of study intervention.
e) Have participated in an interventional clinical study within last 4 weeks OR, if applicable, 
be within 5 times the half-life period of the investigational study intervention, whichever 
is lesser, prior to the first administration of the study intervention.
f)
Participants with unresectable locally advanced NSCLC who are eligible for curative intent 
therapy with chemoradiation.
g) Prior focal palliative radiotherapy must have been completed at least 2 weeks before the 
first dose of study intervention. Participants must have recovered (ie, Grade ≤ 1 or at 
baseline) from radiation-related toxicities prior to first study intervention.
h) Use of known strong or moderate inducers or inhibitors of CYP3A4, CYP2C8 (including 
herbal supplements or food products containing grapefruit juice, star fruit, or Seville 
oranges) within 14 days or 5 half-lives (whichever is longer) of start of treatment or 
expected to require such medicines during the study.
i)
Use of known P-gp and BCRP inhibitors within 14 days or 5 half-lives (whichever is 
longer) of start of treatment or expected to require such medicines during the study.
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j)
Use of known CYP3A4 sensitive substrates within 14 days or 5 half-lives of the drug or its 
major active metabolite(s), whichever is longer, prior to start of treatment or expected to 
require chronic use of such medicines during the study.
k) Use of known CYP2C9, CYP2D6, CYP2B6, MATE-1/-2K, and P-gp sensitive substrates,
where minimal concentration changes may lead to serious adverse reactions, within 
14 days or 5 half-lives of the drug or its major active metabolite(s), whichever is longer, 
prior to the start of the treatment, or if expected to require chronic use of such medicines 
during the study.
l)
Acid-reducing agents, such as proton pump inhibitors (PPIs) or H2 receptor antagonists,
within 14 days or 5 half-lives, whichever is longer, prior to the first administration of the 
study intervention.
m) Medications that prolong QT interval.
4) Physical and Laboratory Test Findings
a) White blood cells < 2,000/μL
b) Absolute neutrophil count < 1,500/μL
c) Platelets < 100,000/μL
d) Hemoglobin < 9 g/dL
e) Creatinine clearance < 60 mL/min (measured using Cockcroft-Gault formula).
f)
Total bilirubin > 1.5× ULN (except participants with Gilbert syndrome who must have a 
total bilirubin level of < 3.0× ULN).
g) AST/ALT: > 2.5× ULN.
h) Electrolyte abnormalities must be corrected prior to study intervention (calcium, 
potassium, sodium, magnesium, phosphate).
i)
Any positive test result for hepatitis B virus (HBV) indicating presence of virus, eg, 
hepatitis B surface antigen (HBsAg, Australia antigen) positive. Note: Participants with 
positive HBV antibody and an undetectable viral load are eligible to enroll.
j)
Any positive test result for hepatitis C virus (HCV) indicating presence of active viral 
replication (detectable HCV RNA). Note: Participants with positive HCV antibody and an 
undetectable HCV RNA are eligible to enroll.
k) Any positive test result for HIV indicating presence of active viral replication and/or 
receiving treatment for HIV. Note: Participants with positive HIV antibody and an 
undetectable viral load that do not require treatment are eligible to enroll.
5) Allergies and Adverse Drug Reactions
a) History of allergy to adagrasib, and/or BMS-986466 active or inactive ingredients of drug 
or related compounds.
b) For Parts 1B and 2B: History of allergy to cetuximab active or inactive ingredients of drug 
or related compounds. 
c) History of any significant drug allergy (such as anaphylaxis or hepatotoxicity).
6) 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 
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imprisoned may be included or permitted to continue as a participant. Strict conditions 
apply, and Sponsor approval is required.)
b) Participation in another interventional clinical trial concurrent with this study.
6.3
Lifestyle Restrictions
6.3.1
Meals and Dietary Restrictions
Refrain from consumption of Seville oranges, grapefruit, or grapefruit juice, pomelos, exotic citrus 
fruits, grapefruit hybrids, or fruit juices from 7 days before the start of study intervention until after 
the final dose.
6.3.2
Caffeine, Alcohol, and Tobacco
In general, participants should avoid use of alcohol and tobacco while on treatment.
6.3.3
Activity
Not applicable.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently entered 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 
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.
Re-testing of laboratory parameters and/or other assessments in any single screening period will 
be permitted (in addition to any parameters that require a confirmatory value).
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.
Re-testing is limited to these specific laboratory parameters and/or assessments:

The fewest number of procedures from the initial screening should be repeated to qualify the 
participant, while maintaining participant safety and eligibility 
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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 Investigational Product (IP), also known as an Investigational Medicinal Product (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
The time of dose administration will be called “0” hour.
Restrictions related to food and fluid intake are described in Section 6.3.1. See Section 5.1.4 for 
the treatment period duration.
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 
Sourcinga
Packaging 
and Labeling
Current/
Former 
Name(s) or 
Alias(es)
Drug/
BMS-986466/
Capsules
10 mg/
mg/
mg 
IMP, Open-
label
Provided 
centrally by the 
Sponsor or 
locally by the 
study site, 
subsidiary, or 
designee
Study 
intervention 
will be 
provided in 
bottles. Each 
bottle will be 
labeled as 
required per 
country 
requirement.
BBP-398/ 
IACS-15509
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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 
Sourcinga
Packaging 
and Labeling
Current/
Former 
Name(s) or 
Alias(es)
Drug/Adagrasib/
Tablets
200 mg per tablet
IMP, Open-
label
Provided 
centrally by the 
Sponsor or 
locally by the 
study site, 
subsidiary, or 
designee
Study 
intervention 
will be 
provided in 
bottles. Each 
bottle will be 
labeled as 
required per 
country 
requirement.
MRTX849, 
KRAZATI®
Drug/Cetuximab/
Vials
5 mg/mL
(100-mL vial)
IMP, Open-
label
Provided 
centrally by the 
Sponsor or 
locally by the 
study site, 
subsidiary, or 
designee
Study 
intervention 
will be 
provided in 
vials. Each 
vial will be 
labeled as 
required per 
country 
requirement.
Erbitux®
Abbreviations: AxMP, Auxiliary Medicinal Product; IMP, Investigational Medicinal Product; SmPC, summary of 
product characteristics.
a These products may be obtained by 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 SmPC.
Table 7.1-2:
Study Arm(s)
Arm Title/
Arm Type
Intervention Description/
Dosage Levels
Route of 
Administration
BMS-986466
DDI cohort: single dose of 10 mg on C1D1 
. 
Regular administration starting C3D1.
All other cohorts: starting on Day 1 of each cycle, dose TBD 
Oral
Adagrasib
DDI cohort: 400 mg BID starting 
Other cohorts: starting on Day 1 of each cycle, 400 mg BID or 600 mg BID
Oral
Cetuximab
(Parts 1B and
2B only)
Initial and subsequent doses: 500 mg/m2 infused over 120 minutes once 
every 2 weeks.
IV
Abbreviations: BID, twice a day; C, cycle; D, day; DDI, drug-drug interaction; IV, intravenously; TBD, to be 
determined.
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7.1.1
BMS-986466 and Adagrasib Administration
Participants will take BMS-986466 and adagrasib orally. When given together, the morning doses 
of BMS-986466 and adagrasib should be taken together regardless of food intake at approximately 
the same time each day with a cup of water. Participants should swallow the BMS-986466 and/or 
adagrasib whole and not chew them. If vomiting occurs after dosing, the doses should not be 
replaced.14
For scheduled clinic visit days for PK assessments, BMS-986466 and/or adagrasib will be 
administered to the participant in the clinical facility, regardless of food intake. Water is allowed 
ad libitum.
If a dose of BMS-986466 is missed, the participant will take the next regular dose at the scheduled 
time. If a dose of adagrasib is inadvertently missed, the dose should be skipped if > 4 hours have 
elapsed since the expected dosing time.14
Intra-participant dose reductions of BMS-986466 and adagrasib will be permitted under 
circumstances as described in Table 7.4-1. Doses of BMS-986466 and/or adagrasib may be 
interrupted, delayed, or discontinued depending on how well the participant tolerates the treatment. 
7.1.2
Cetuximab Administration
Cetuximab will be given as per package insert (500 mg/m2 intravenously [IV] infused over 
120 minutes once every 2 weeks [Q2W]). Participants will be premedicated with a histamine (H)
1 antagonist IV 30 to 60 minutes prior to the initial dose, and premedication for subsequent doses 
may be necessary if clinically indicated. Participants should be monitored for at least 1 hour 
following infusion. Intra-participant dose reductions of cetuximab will be permitted under 
circumstances as described in Table 7.4-4. Doses of cetuximab may be interrupted, delayed, or 
discontinued depending on how well the participant tolerates the treatment. See Table 7.4-4 for 
additional information.
 
 
7.2
Assignment to Study Intervention
All participants will be centrally assigned to treatment using IRT. Before the study is initiated, 
each user will receive log-in information and directions on how to access the IRT. Study 
intervention will be dispensed at the study visits listed in the Schedule of Activities (Section 2).
Enrolled participants, including those not dosed, will be assigned sequential participant numbers 
starting with 
. Those enrolled participants meeting 
inclusion and exclusion criteria will be eligible to be dosed. The investigative site will utilize the 
Interactive Response Technology (IRT) to centrally assign (Parts 1, 1A, 1B) or randomize (Parts
2A, 2B) the participant within 3 days of Cycle 1 Day 1.
7.3
Blinding
This is an open-label study with randomization in Part 2. Blinding procedures are not applicable
and access to treatment assignment information is unrestricted to any Sponsor team, site, or 
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participant. The specific treatment to be taken by a participant will be assigned using IRT. The site 
will contact the IRT prior to the start of study intervention administration for each participant. The 
site will record the treatment assignment on the applicable Case Report Form (CRF), if required.
7.4
Dosage Modification
Participants will be monitored for AEs during all phases of the study. Participants experiencing
Grade ≥3 TRAEs that do not qualify as DLT events will hold study intervention until symptoms
improve to Grade ≤ 1 or return to baseline. The decision to proceed to the next dose level of 
BMS-986466 (either an increase or a decrease) will be made by the investigators and the Sponsor 
based on safety, tolerability, and preliminary PK and PD data obtained in at least 3 participants at 
the prior dose level. The dosing schedule may also be adjusted to expand a dosing cohort to further 
evaluate safety, PK, and/or PD findings at a given dose level or to add cohorts. This protocol allows 
some alteration from the currently outlined dosing schedule, but the dose will not exceed the 
maximum exposure of BMS-986466 comparable to the AUC/Cmax from the dose deemed 
acceptable from Study NAV-1001, or the approved dose for adagrasib or cetuximab. The study 
procedures for these additional participant(s)/cohort(s) will be the same as those described for 
other study participants/cohorts.
Dose delays/omissions/interruptions may occur for a single agent or multiple agents, depending 
on the assessment by the investigator. If it is unclear if a single agent is causing the toxicity or 
reason for delays/omissions/interruption, all agents should be withheld until resolution of toxicity 
to baseline or Grade ≤ 1.
In case of an AE relationship assignment to 1 study intervention, dose modifications for that 
intervention alone are allowed. For AEs attributable to both adagrasib and BMS-986466 requiring 
a dose modification, the dose of adagrasib may be reduced without the dose reduction of 
BMS-986466, as reduced adagrasib exposure will also decrease BMS-986466 exposure. For each 
participant, a maximum of 2 dose reductions of BMS-986466 will be allowed. Dose reduction for 
BMS-986466 means treatment at the next lower, previously tested dose level. If a dose reduction 
is required below the lowest BMS-986466 dose that was previously tested, the dose should be 
selected after the discussion with the Medical Monitor.
Adagrasib 600 mg BID starting dose (approved dose) may be reduced 2 dose levels to a minimum
of 600 mg QD for AEs or laboratory abnormalities, as per the package insert.14 Adagrasib at 
400 mg BID starting dose may be reduced only 1 dose level, as summarized in Table 7.4-1.
Cetuximab may be reduced 2 dose levels to a minimum of 
 mg/m2 for AEs or laboratory 
abnormalities. Dose reductions beyond the second dose reduction are not allowed for cetuximab.
Recommended dose modifications for cetuximab based on the occurrence of cetuximab TRAEs 
are summarized in Table 7.4-2.

If criteria for discontinuation of the cetuximab are met, adagrasib and BMS-986466 may 
continue until the criteria for treatment discontinuation are met. 

If criteria for discontinuation of the BMS-986466 are met, adagrasib and cetuximab (if 
applicable) may continue until the criteria for treatment discontinuation are met. 
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
If criteria for discontinuation of the adagrasib are met, all study interventions should be 
discontinued.
All dose modifications and missed doses/dosing holidays due to AE will be captured in the 
electronic data capture (EDC) and also in participant-supplied pill diaries/mechanism used to track 
the compliance with the dosing regimen.
In case a dose reduction/modification is necessary, the study intervention will be administered as 
follows in Table 7.4-3 and Table 7.4-4.
Table 7.4-1:
Recommended Adagrasib Dose Reductions
Starting Adagrasib Dose
First Dose Reduction 
Second Dose Reduction 
600 mg BID (approved dose)
400 mg BID 
600 mg QD
400 mg BID
600 mg QD
Not applicable
Abbreviations: BID, twice daily; QD, once daily.
Table 7.4-2:
Recommended Cetuximab Dose Reductions
Starting Cetuximab Dose
First Dose Reduction 
Second Dose Reduction 
500 mg/m2 Q2W
 mg/m2
 mg/m2
Abbreviation: Q2W, every 2 weeks.
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Table 7.4-3:
BMS-986466 and Adagrasib Dose Modifications
Adverse Reaction
Severity
Dosage Modification
Nausea or Vomiting, Despite 
Appropriate Supportive Care 
(Including Anti-emetic 
Therapy)
Grade 3 or 4

Withhold adagrasib and BMS-986466 until recovery to Grade ≤1 or return 
to baseline.

Resume adagrasib at the next lower dose level and BMS-986466 at pre-
interruption dose.
Diarrhea, Despite Appropriate 
Supportive Care (Including 
Anti-diarrheal Therapy)
Grade 3 or 4

Withhold adagrasib and BMS-986466 until recovery to Grade ≤1 or return 
to baseline.

Resume adagrasib at the next lower dose level and BMS-986466 at pre-
interruption dose.
Hepatotoxicity
Grade 2 AST or ALT

Decrease adagrasib to next lower dose level.
Grade 3 or 4 AST or ALT

Withhold adagrasib and BMS-986466 until recovery to Grade ≤ 1 or return 
to baseline.

Resume adagrasib at the next lower dose level.

If first Grade 3 occurrence, resume BMS-986466 at pre interruption dose if 
recovery to Grade ≤ 1 or baseline occurs within 14 days. Otherwise, resume 
BMS-986466 at next lower dose level.
AST or ALT > 3× ULN with total 
bilirubin > 2× ULN in the absence of 
alternative causes

Permanently discontinue from study intervention.
QTc Interval Prolongation
QTc absolute value greater than 500 ms 
or with an increase greater than 60 ms 
from baseline

Withhold adagrasib and BMS-986466 until QTc interval resolves to less than 
481 ms or returns to baseline.

Resume adagrasib at the next lower dose level and BMS-986466 at pre-
interruption dose.
Torsade de Pointes
Torsade de Pointes, polymorphic 
ventricular tachycardia, or signs or 
symptoms of serious or life-threatening 
arrhythmia

Permanently discontinue from study intervention.
Interstitial Lung Disease/ 
Pneumonitis
Any grade

Withhold adagrasib and BMS-986466 if ILD/pneumonitis is suspected.

Permanently discontinue study intervention
if ILD/pneumonitis is 
confirmed.
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Table 7.4-3:
BMS-986466 and Adagrasib Dose Modifications
Adverse Reaction
Severity
Dosage Modification
Other Adverse Reactions
Grade 3 or 4

Withhold adagrasib and BMS-986466 until recovery to Grade ≤ 1 or return 
to baseline.

Resume adagrasib at the next lower dose level.

If first Grade 3 occurrence, resume BMS-986466 at pre-interruption dose if 
recovery to Grade ≤ 1 or baseline occurs within 14 days. Otherwise, resume 
BMS-986466 at next lower dose level.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ILD, interstitial lung disease; ULN, upper limit of normal.
Table 7.4-4:
Cetuximab Recommended Dosage Modifications 
Adverse Reaction
Severity
Dosage Modification
Rash
Grade 1 or 2
Maintain dose level; consider initiating appropriate therapy (such as 
antihistamines, topical corticosteroids, and low-dose systemic corticosteroids).
Grade 3, despite therapy
Hold cetuximab until resolved to Grade ≤2, then: 

If resolved in ≤7 days (or ≤14 days for acneiform rash), then maintain dose 
level.

If not resolved in ≤7 days despite appropriate skin toxicity therapy (or 
≤14 days for acneiform rash), then permanently discontinue cetuximab.
Grade 3 recurrent
Hold cetuximab until resolved to Grade ≤ 2, then: 

If resolved in ≤7 days (or ≤14 days for acneiform rash), then decrease 1 dose 
level.

If not resolved in ≤7 days despite appropriate skin toxicity therapy (or 
≤14 days for acneiform rash), then permanently discontinue cetuximab.

Permanently discontinue cetuximab after the third recurrence (upon the 
fourth occurrence).
Grade 4, despite skin toxicity therapy
Permanently discontinue cetuximab.
Hypomagnesemia
Hypomagnesemia has been seen with cetuximab. Should hypomagnesemia 
occur, magnesium supplementation should be provided. No dose adjustment is 
required; however, continue careful monitoring.
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Table 7.4-4:
Cetuximab Recommended Dosage Modifications 
Adverse Reaction
Severity
Dosage Modification
Infusion Reaction
(If an infusion reaction occurs 
while cetuximab is being 
infused, the infusion should be 
stopped immediately, and the 
participant should be 
evaluated)
Grade 1 or 2 
Restart and complete the disrupted infusion at the discretion of the investigator. 
The infusion must be restarted at a reduced rate. Additional pre-medications 
such as antihistamines or low-dose systemic corticosteroids may be 
administered when the infusion is restarted per institutional standards. All 
subsequent infusions must also be administered at the reduced rate.
Grade 3 or 4
Permanently discontinue cetuximab.
Pulmonary Toxicity
Grade 2 or worsening pulmonary 
symptoms
Cetuximab therapy should be stopped, and symptoms investigated. Cetuximab 
therapy may resume when symptoms resolve to Grade ≤1.
Grade 3 cough, dyspnea, hypoxia, 
pneumonitis, or pulmonary infiltrates
Hold cetuximab until interstitial lung disease is ruled out. Permanently 
discontinue cetuximab if interstitial lung disease is confirmed.
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7.4.1
Dose-limiting Toxicities
The DLT evaluation period is 1 cycle (28 days) for Part 1 dose escalation. All participants who 
receive at least 1 dose of BMS-986466 will be evaluable for safety. Participants in Part 1A will be 
considered DLT evaluable if they complete ≥ 75% of all planned doses of BMS-986466 and 
adagrasib without experiencing a DLT or experience a DLT after receiving at least 1 dose of 
BMS-986466 and adagrasib. Participants in Part 1B must complete ≥ 75% of all planned doses of 
BMS-986466 and adagrasib and have received at least 2 doses of cetuximab without experiencing 
a DLT or experience a DLT after receiving at least 1 dose of BMS-986466, adagrasib, and 
cetuximab. Participants with suspected DLTs may have study intervention delayed (at the treating 
investigator’s discretion) until the relatedness is defined. Participants who do not meet the DLT
evaluation criteria may be replaced during the dose escalation part.
AEs that meet the following criteria will be DLTs, except for those that are clearly and 
incontrovertibly due to disease progression or extraneous causes (see Sections 7.4.1.1 and 7.4.1.2).
7.4.1.1
Non-hematological Toxicity

Any Grade ≥ 3 non-hematological toxicity. Exceptions will be made for the following:

Grade 3 nausea, diarrhea, or vomiting that resolves to baseline or Grade 1 within 72 hours 
after holding study intervention and implementing optimal medical management.

Grade 3 fatigue lasting for less than 7 days.

Grade 3 increases in amylase or lipase that are not associated with clinical symptoms or 
radiographic manifestations of pancreatitis.

Grade 3 rash that reduces to Grade ≤ 1 within 14 days.

Grade 3 or higher electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and resolve spontaneously or are responding to supplementation/appropriate 
management within 72 hours.

AST/ALT > 3× and ≤ 5× ULN or total bilirubin > 1.5× and ≤ 3× ULN if the baseline was 
normal; AST/ALT > 3× and ≤ 5× baseline or total bilirubin > 1.5× and ≤ 3× baseline if the 
baseline was abnormal.

Any AST/ALT > 5× ULN or total bilirubin > 3× ULN irrespective of baseline values; any case 
that meets Hy’s Law criteria (either ALT or AST > 3× ULN AND total bilirubin > 2× ULN).
7.4.1.2
Hematological Toxicity

Grade 4 anemia

Grade 4 neutropenia of > 7 days duration

Grade 4 thrombocytopenia

Grade 3 thrombocytopenia with clinically significant bleeding

Febrile neutropenia
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7.5
Preparation/Handling/Storage/Accountability
The IP/IMP/Non-IMP/AxMP must be stored in a secure area according to local regulations. It is 
the responsibility of the investigator, or designee where permitted, to ensure that IP/IMP/Non-
IMP/AxMP is only dispensed to study participants. The IP/IMP/Non-IMP/AxMP must be 
dispensed only from official study sites by authorized personnel according to local regulations.
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).

The investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention.

Only participants enrolled in the study may receive study intervention, and only authorized site 
staff may supply, prepare, or administer study intervention. 

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).

Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual.
For study interventions not provided by the Sponsor and obtained commercially by the site, storage 
should be in accordance with the product label.
7.6
Study Intervention Compliance
Study intervention compliance will be monitored periodically by drug accountability (review of 
dosing diary). Drug accountability should be reviewed by the study site staff at each visit to 
confirm treatment compliance. Study site staff should discuss discrepancies with the participant at 
each on-treatment study visit. 
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
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 

When participants self-administer BMS-986466 and adagrasib at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed (by review of dosing 
diaries, direct questioning, counting returned tablets/capsules, etc) during the site visits and 
documented in the source documents and relevant dosing diaries. Deviation(s) from the 
prescribed dosage regimen should be recorded in the CRF.

A record of the quantity of BMS-986466 and adagrasib dispensed to and administered by each 
participant must be maintained and reconciled with study intervention and compliance records. 
Intervention start and stop dates, including dates for intervention delays and/or dose reductions,
will also be recorded in the CRF.

For Parts 1B and 2B: 

For cetuximab compliance: IV cetuximab will be administered in the outpatient setting
during biweekly visits, the compliance with study intervention will be assessed by source 
documentation and relevant forms. Deviation(s) from the prescribed dosage regimen 
should be recorded in the CRF.
7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
The following medications and treatments are prohibited during the study (unless used to treat a 
drug-related AE). For a comprehensive and up to date list of substrates, inhibitors, and inducers, 
refer to the FDA website.32

Concomitant use of strong/moderate inhibitors of CYP3A4 or strong/moderate inducers of 
CYP3A4 is prohibited. Concurrent use of strong/moderate inhibitors or inducers of CYP3A4 
may affect the systemic exposure of BMS-986466.

Seville oranges, grapefruit, or grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids, 
or fruit juices, cannabinoid (CBD) can inhibit CYP3A4 and should not be consumed while on 
study.

Concomitant use of BCRP inhibitors should be avoided. Participants that receive them should 
be closely monitored for safety events. 

Avoid concomitant use with sensitive CYP3A4 substrates.

Avoid concomitant use with sensitive CYP2C9, CYP2D6, CYP2B6, P-gp, and MATE-1/-2K
substrates where minimal concentration change may lead to serious adverse reactions.

Participants who require concomitant use of QT modulating drugs for pre-existing conditions 
will be excluded. Adagrasib treatment should be held for participants who require a QT 
modulatory drug during the treatment period for the management of AEs. 

Any concurrent systemic anti-neoplastic therapy (ie, chemotherapy, hormonal therapy,
immunotherapy, or standard or investigational agents for treatment of malignancy).

Avoid acid-reducing agents, such as proton pump inhibitors (PPIs) or H2 receptor antagonists.
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
Any non-palliative radiation therapy. Radiation therapy administered with palliative intent (ie,
for pain, bleeding, spinal cord compression, brain metastasis, new or impending pathologic
fracture, superior vena-cava syndrome, or obstruction) is permitted.

Any complementary medications (eg, herbal supplements such as St. John’s wort or traditional 
Chinese medicines) intended to treat the disease under study. Such medications are permitted 
if they are used as supportive care and are not known modulators of CYP3A4.
7.7.2
Imaging Restrictions and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes 
(eg, allergy history, diabetic history, 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 [eGFR] < 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.
7.8
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 Sponsor-supplied study intervention for a maximum treatment duration as specified in 
Section 7.1. If the study intervention is not available as an approved and available treatment, study 
intervention will be provided via an extension of the study, a rollover study requiring approval by 
the responsible Health Authority and Ethics Committee, or through another mechanism at the 
discretion of the Sponsor.
The Sponsor reserves the right to terminate access to Sponsor-supplied study intervention if any 
of the following occur: a) the study is terminated due to safety concerns; b) the development of 
BMS-986466 is terminated for other reasons, including, but not limited to, lack of efficacy and/or 
not meeting the study objectives; or c) the participant can obtain medication from a government-
sponsored or other health program. In all cases, the Sponsor will follow local regulations.
8
DISCONTINUATION CRITERIA
Discontinuation of the study at specific sites or of the entire study is detailed in Appendix 2.
8.1
Discontinuation of Study Intervention
Participants MUST discontinue IP/IMP (and Non-IMP/AxMP at the discretion of the investigator) 
for any of the following reasons:
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
Participant’s request to stop study intervention. Participants who request to discontinue study 
intervention will remain in the study and should 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 that, 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.

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.)

Start of anticancer therapy other than as outlined in this protocol (palliative radiation is allowed 
after discussion with the Medical Monitor).

Documented and confirmed disease progression as defined by RECIST v1.1 (refer to 
Appendix 6 and Section 8.1.1).

Clinical deterioration while receiving active study therapy that, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
participant.

Any TRAE that meets the criteria for permanent discontinuation of all study intervention, as 
outlined in Table 7.4-1.

Inability to comply with protocol.

Discretion of the investigator.

Pregnancy
Study intervention must be permanently discontinued per criteria in Section 7.4. Discontinue
BMS-986466 and/or adagrasib and/or cetuximab for any AE, laboratory abnormality, or
intercurrent illness that, in the judgment of the investigator, presents a substantial clinical
risk to the participant with continued dosing of study intervention.
Any event that leads to delay in BMS-986466 dosing lasting > 4 weeks from the previous dose 
requires discontinuation of study drug, with the following exceptions:

Dosing delays lasting > 4 weeks from the previous dose that occur for non-drug-related reasons 
may be allowed if approved by the Medical Monitor.
Refer to Section 2: Schedule of Activities for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed.
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 
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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
Post-study Intervention Study Follow-up
In this study, safety and efficacy are key endpoints. 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.
8.2
Discontinuation From the Study

Participants should notify the investigator of the decision to withdraw consent from future 
follow-up.

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 
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 Section 2 Schedule of Activities. 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.
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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 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.

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.

If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
8.4
Study Stopping Criteria

Systematic review of SAEs experienced through the duration of therapy will serve as a key 
basis for pausing or prematurely stopping the study. Review of these SAEs, and any decision 
to stop enrollment or terminate the study, will be determined by the Sponsor in collaboration 
with the investigators regarding possible study continuation, adjustment of the dose/schedule, 
health authority consultation, and study termination.

During Part 1, stopping rules based on TITE-BOIN will be used to continuously monitor for 
excess toxicity, defined as the occurrence of AEs during any cycle that would fulfill the DLT 
criteria (refer to Appendix 7).

During Part 2, continuous safety monitoring will be applied, based on the Bayesian framework. 
If at any time during the treatment and safety follow-up periods, it reaches the pre-specified 
threshold of toxicity, then, taking into account all available safety information, additional 
evaluation will be conducted to allow a complete by treatment arm safety assessment and 
benefit/risk evaluation.
(see Section 10.4.5 for 
additional information).

The Sponsor and investigators will convene regularly to review all the available safety, PK, 
PD, and efficacy data and in the event of any of the following occurrences:

Unanticipated SAEs that are related to study intervention are reported.

Death attributable to study intervention is reported.
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
The Sponsor or IRB/IEC decides that participant safety may be compromised by 
continuing the study.

Decisions to stop the enrollment or terminate the study will be communicated promptly to 
investigators, to the IRBs/IECs, Institutional Biosafety Committees, if applicable, and to the 
appropriate regulatory authorities.
9
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and timing are summarized in Section 2: Schedule of Activities. 

Protocol waivers or exemptions are not allowed.

All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine whether the participant should continue or discontinue 
treatment.

Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before initiation of study intervention/randomization. 
The investigator will maintain a screening log to record details of all participants screened and 
to confirm eligibility or record reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, complete 
blood count) and obtained before signing of informed consent may be utilized for screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has been 
performed within the time frame defined in the Schedule of Activities.

Evaluate participants immediately to rule out cardiac toxicity if the participants show signs of 
QTc prolongation (eg, palpitations, dizziness).

Some of the assessments referred to in this section may not be captured as data in the electronic 
CRF (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.

Perform additional measures, including non-study required laboratory tests, 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.

Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
9.1
Efficacy Assessments
9.1.1
Efficacy Assessment for the Study
Screening, on treatment and follow-up images should be acquired as outlined in Table 2-1 and 
Table 2-2 and as defined in Section 8.1. For participants continuing past that period, imaging will 
continue as defined in Table 2-2. Any additional imaging that may demonstrate tumor response or 
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progression (including scans performed at unscheduled time points and/or at an outside institution) 
should be collected for tumor assessment and be submitted to the central imaging vendor (for 
Part 2 only). Imaging should continue until disease progression or discontinuation of all study 
intervention, whichever occurs later.
Efficacy assessments for the anti-tumor activity of BMS-986466 in combination with adagrasib 
and with or without cetuximab will be based on tumor measurements using RECIST v1.1 with 
computed tomography (CT) and/or MRI, as appropriate, at baseline, and during the treatment 
period.
Only data for the procedures and assessments specified in this protocol should be submitted to the 
Sponsor or designee on a CRF. Additional procedures and assessments may be performed as part 
of standard of care. However, data for these assessments should remain in the participant’s medical 
record and should not be provided to the Sponsor or designee, unless specifically requested from 
the Sponsor or designee.
9.1.2
Imaging Assessment for the Study
All images will be submitted to a central imaging vendor and recorded in the EDC. For Part 2, the 
images will also be read by a blinded independent central review (BICR). 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. 
Any additional CT/MR images performed either at unscheduled time points and/or at an outside 
institution that may demonstrate tumor response or progression per RECIST v1.1 should be 
recorded in the EDC and submitted to the central imaging vendor. X-rays and bone scans that
clearly demonstrate interval progression of disease, for example most commonly as unequivocal 
lesions that are unmistakably new since the prior CT/MRI, should also be submitted to central 
imaging vendor.
Tumor assessments should continue on the protocol-defined imaging schedule regardless of dosing 
delays or discontinuation. Changes in tumor measurements and responses will be assessed by the 
same investigator or designee using RECIST v1.1 criteria. Investigators will report the number 
and size of new lesions that appear while on the study. The time point of tumor assessments will 
be reported on the eCRF based on the investigator’s assessment using RECIST v1.1 criteria (refer 
to Appendix 6 for specifics of RECIST v1.1 criteria to be used in this study). Assessments of 
partial response and complete response must be confirmed at least 4 weeks (28 days) after the
initial response. A best overall response (BOR) of stable disease (SD) requires a minimum of 
49 days on study from date of first dose to the date of the first imaging assessment.
Refer to Section 2.3.3 in Appendix 6 for determination of BOR.
9.1.2.1
Imaging Schedule
Screening Procedural Outline
Body Imaging: Contrast-enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all other 
known and/or suspected sites of disease, within 28 days prior to date of first dose.
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Brain Imaging:
MRI of the brain (without and with contrast) is mandatory for all NSCLC 
participants. MRI of the brain is required for CRC participants with known or suspected brain 
metastases at the time of screening, within 28 days prior to date of first dose. CT of the brain 
(without and with contrast) can be performed if MRI is contraindicated.
On-treatment Procedural Outline
Body Imaging: Contrast-enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all other 
known and/or suspected sites of disease, should occur Q8W (7 days) starting from date of first 
dose for the first 48 weeks, then Q12W (7 days) until disease progression or discontinuation of 
all study intervention, whichever occurs later. If pregnancy is the reason for study intervention 
discontinuation, no imaging is performed.
Brain Imaging: Participants with a brain metastasis at baseline should have surveillance MRIs 
(without and with contrast) per standard of care (approximately Q12W [± 7days]) or sooner if 
clinically indicated. CT of the brain without and with contrast can be performed if MRI is 
contraindicated.
Long-term Follow-up Procedural Outline
Body Imaging: Contrast-enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all other 
known and/or suspected sites of disease should occur Q8W starting from date of first dose 
(7 days) for the first 48 weeks, then Q12W (7 days) until disease progression or discontinuation 
of all study intervention, whichever occurs later, for up to 2 years from the date of EOT.
Brain Imaging: Participants with a history of brain metastasis should have surveillance MRIs 
(without and with contrast) per standard of care (approximately Q12W) or sooner if clinically 
indicated. Participants without a history of brain metastasis should undergo brain MRI when 
clinically indicated CT of the brain without and with contrast can be performed if MRI is
contraindicated.
9.1.2.2
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. In case of a contraindication for either contrast agent or MRI (eg,
incompatible pacemaker), it is strongly recommended to use the following guidance: 
If a participant has a contraindication for CT IV 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 IV 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. 
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Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
Participants will be followed for all SAEs and all AEs (SAEs and non-serious AEs) associated 
with confirmed or suspected SARS-CoV-2 infection until resolution, the condition stabilizes, the 
event is otherwise explained, the event is deemed irreversible, the participant is lost to follow-up, 
or for suspected cases, until SARS-CoV-2 infection is ruled-out.
9.2.1
Period and Frequency for Collecting AE and SAE Information
All AEs and SAEs must be collected from the time of signing the informed consent form, including 
those thought to be associated with protocol-specified procedures and until 30 days following 
discontinuation of dosing or the last scheduled visit as noted in the Schedule of Activities 
(Section 2). However, SAEs that are considered to be related to study drug have an indefinite
timeframe during which they must be reported.
The investigator must report any SAE that occurs after these periods and that is believed to be 
related to a study intervention or protocol-specified procedure (eg, a follow-up skin biopsy).

All SAEs will be recorded and reported to the Sponsor or designee, promptly and not to exceed
24 hours of awareness of the event , 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.
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.
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SHP2 inhibitor
All SAEs 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: Lost to 
Follow-up).
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 participant is pregnant or 
may have been pregnant at the time of study intervention exposure, including at least 2 months 
after the last dose of BMS-986466, 1 week after the last dose of adagrasib, and 2 months after the 
last dose of cetuximab, whichever is longest after study intervention administration, 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. Pregnancy reporting must follow the same transmission timing and 
processes to BMS as those used for SAEs, in accordance with 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, including at least 2 months after the last dose of BMS-986466, 1 week after 
the last dose of adagrasib, and 2 months after the last dose of cetuximab, whichever is longest after 
study intervention administration, 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 
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SHP2 inhibitor
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 during and for at least
2 months after the last dose of BMS-986466, 1 week after the last dose of adagrasib, and 2 months 
after the last dose of cetuximab, whichever is longest after study intervention administration, the 
information should be reported to the Sponsor or designee, even if the male participant has 
undergone a successful vasectomy.
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 versus low hemoglobin value).
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: Adverse Events and Appendix 3 for reporting details).
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
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SHP2 inhibitor
The key responsibilities for investigators during potential drug-induced liver injury (p-DILI)
assessment include (i) early detection, medical evaluation (including the exclusion of other 
potential causes), and rapid laboratory confirmation of liver-related abnormalities; and (ii) Sponsor 
notification of p-DILI cases via SAE forms. Following the gathering and assessment of relevant 
clinical information, Sponsor is responsible for (i) timely evaluation and triaging of p-DILI cases; 
(ii) expedited reporting of p-DILI cases; and (iii) expanded review of p-DILI cases including a 
detailed assessment of all available clinical information, investigations, and biochemical data.
Investigators are expected to monitor ongoing routine and ad hoc hepatic laboratory test results to 
rapidly determine whether a participant meets p-DILI criteria. They are expected to promptly 
notify the Sponsor of all p-DILI cases. p-DILI cases may be identified by abnormal liver 
biochemistry values, whether or not they are accompanied by liver-related signs and/or symptoms. 
In both cases, expedited confirmation with repeat laboratory testing should occur within 3 business 
days using a hepatic laboratory panel (ALT, AST, total bilirubin, ALP). Any participant with an 
abnormal hepatic laboratory panel that meets p-DILI criteria is a candidate for study intervention
discontinuation. Any confirmed p-DILI events must be reported (along with a description of the 
clinical findings) to the Sponsor as an SAE within 24 hours of confirmation.
An extensive clinical history, examination, and appropriate investigations should be obtained to 
exclude cholestatic and other apparent causes that may explain the observed abnormalities in liver 
function and/or hepatic signs and symptoms. Other apparent causes include, non-exhaustively and 
by way of example only, the following: infectious diseases (such as active hepatitis A, B, and C), 
congenital diseases (such as Gilbert’s syndrome), neoplastic diseases, autoimmune diseases (such 
as primary biliary cirrhosis), and the use of concomitant hepatotoxic medications (such as 
antibiotics, the oral contraceptive pill, and herbal medicines). All investigations to exclude 
potential causes of liver function abnormalities or hepatic signs and/or symptoms should be guided 
by relevant factors such as the participant’s age, gender, clinical history, and signs and symptoms.
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.
9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. Overdoses that meet the regulatory 
definition of an SAE will be reported as SAEs (see Appendix 3).
In the event of an overdose, the investigator should:

Contact the Medical Monitor immediately.

Closely monitor the participant for AEs/SAEs and laboratory test result abnormalities.

Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
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SHP2 inhibitor
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
9.4
Safety
Planned time points for all safety assessments are listed in Section 2: Schedule of Activities.
Safety assessments will be based on reported AEs and the measurement results of vital signs, 
ECGs, physical examinations, and clinical laboratory tests. AEs will be coded using the most 
current version of Medical Dictionary for Regulatory Activities and the incidence of observed AEs 
will be tabulated and reviewed for potential significance and clinical importance. AEs will be 
tabulated by system organ class, preferred term, and treatment and reviewed for potential 
significance and clinical importance. Clinical laboratory results will also be listed and tabulated.
AEs will be assessed continuously during the study and for a minimum of 30 days after the last 
dose of study intervention including BMS-986466, adagrasib, and/or cetuximab. Local laboratory 
will perform the clinical laboratory tests and will provide reference ranges for these tests. Both 
AEs and laboratory tests will be graded using the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0.
9.4.1
Physical Examinations and Measurements
Refer to Section 2: Schedule of Activities. If the screening physical examination is performed 
within 72 hours prior to dosing on Day 1, then a single examination may count as both the 
screening and pre-dose evaluation. If there are any new or worsening clinically significant changes 
since the last examination, report changes on the appropriate non-serious or serious AE CRF page.
At screening, Day 1 of each cycle, EOT, and Follow-up Visit 1, the physical examination should 
be comprehensive. For subsequent visits, the targeted physical examinations should be symptom
directed as clinically indicated. Investigators should pay special attention to clinical signs related 
to previous serious illnesses. Any treatment-emergent abnormal findings will be recorded as AEs.
9.4.2
Vital Signs and Oxygen Saturation
Refer to Section 2: Schedule of Activities. Includes 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. Obtain oxygen saturation by pulse 
oximetry at rest in room air.
9.4.3
Electrocardiograms
Refer to Section 2: Schedule of Activities for timing of ECG assessments for safety in Table 2-1
and Table 2-2. The investigators will review the 12-lead ECGs throughout the study. The corrected 
QTc will be applied to each ECG reading.
Refer to the schedule of specific ECG collections to analyze the effect of BMS-986466 on the QTc 
interval in Table 2-1 and Table 2-2 in Parts 1 and 2.
In Part 1, triplicate ECGs collected 5 minutes apart (using the ECG machine supplied by the 
Sponsor and results should be transmitted electronically to the central laboratory) as follows:
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SHP2 inhibitor

Part 1 DDI cohort: On C1D1 
 at approximately 30 min before BMS-986466 dosing,
and
 at approximately 30 minutes before BMS-986466 dosing, and after the 
 
 post-dose PK sample 

Parts 1A (excluding DDI Cohort) and 1B: On C1D1 at approximately 30 minutes before 
BMS-986466 dosing and C1D1 and C2D1 after the 
post-dose PK sample 
For all of Part 2, a single 12-lead ECG will be collected as outlined in Table 2-4 and Table 2-5. 
On C2D1 a single 12-lead ECG (using site ECG machine or supplied by the Sponsor, if requested) 
will be performed at approximately 30 minutes before BMS-986466 dosing and after the 
 
 post-dose PK sample.
All ECGs should be recorded after the participant has been supine for at least 5 minutes. All other 
time points require a single 12-lead ECG reading collected for safety purposes, and site ECG 
machines should be used. Additional ECG monitoring as clinically indicated.
9.4.4
2-D Echocardiogram/MUGA
In Parts 1 DDI, 1A, and 1B, 2-D echocardiograms or MUGA are required at screening, C2D1, 
C3D1 then every odd cycle (eg, C5D1, C7D1, etc), and at EOT. In Parts 2A and 2B, 2-D 
echocardiograms or MUGA are required at screening, C2D1, and every odd cycle (C3, C5, C7,
etc) if clinically indicated.
9.4.5
Clinical Safety Laboratory Assessments

Investigators must document their review of each laboratory safety report.

A local laboratory will perform the analyses and will provide reference ranges for these tests.

Results of clinical laboratory tests performed on Day -1 must be available prior to dosing.

The laboratory tests that will be performed for study participants are shown in Section 2 and
Table 9.4.5-1.

Results of all laboratory tests required by this protocol must be provided to the Sponsor, 
recorded either on the laboratory pages of the CRF or by another mechanism as agreed upon
between the investigator and the Sponsor (eg, provided electronically). If the units of a test 
result differ from those printed on the CRF, the recorded laboratory values must specify the 
correct units.

Any abnormal laboratory test result considered clinically significant by the investigator must 
be recorded on the appropriate AE page of the CRF.
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SHP2 inhibitor
Table 9.4.5-1:
Clinical Laboratory Assessments
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Screening only: Prothrombin time, activated partial thromboplastin time, and international normalized ratio
Chemistry
Aspartate aminotransferase (AST/SGOT)
Alanine aminotransferase (ALT/SGPT)
Total bilirubin
Direct bilirubin (reflex, if total bilirubin is abnormal)
Alkaline phosphatase
Lactate dehydrogenase 
Creatinine
Blood urea nitrogen 
Uric acid
Gamma-glutamyl transferase (reflex, if liver function is 
abnormal)
BNP
Troponin
Blood glucose (fasting at screening only)
Total protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Magnesium
Creatine kinase
Creatinine clearance (at screening)
Amylase
Lipase
Screening only: TSH, free T3, free T4
Urinalysis
Protein
Glucose
Blood
Leukocyte esterase
Specific gravity
pH
Microscopic examination of the sediment if blood, protein, or leukocytes esterase are positive on the dipstick
Serology (Screening only)
Hepatitis B/C, HIV-1, and HIV-2 antibodies. Measure viral load for participants with positive serology for either 
of the virus.
Other Analyses
Pregnancy test (WOCBP only: screening, predose, EOT).
Follicle-stimulating hormone (screening only; for post-menopausal women only) use as applicable
Abbreviations: ALT, alanine aminotransaminase; AST, aspartate transaminase; BNP, b-type natriuretic protein; EOT, 
end of treatment; HIV, human immunodeficiency virus; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, 
serum glutamic pyruvic transaminase; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone; 
WOCBP, women of childbearing potential.
9.4.6
Suicidal Risk Monitoring
Not applicable.
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CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
9.5
Pharmacokinetics
PK of BMS-986466 will be derived from plasma concentration versus time. The PK of adagrasib 
may be assessed if data permits. The PK parameters to be assessed, if feasible, include the 
following:
Cmax
Maximum observed plasma concentration
Tmax
Time of maximum observed plasma concentration
AUC(0-T)
Area under the plasma concentration-time curve from time zero to time of last 
quantifiable concentration
AUC(INF)
Area under the plasma concentration-time curve from time zero extrapolated to infinite 
time (single dosing only)
Ctrough
Trough-observed plasma concentration (multiple dosing only)
AUC(TAU)
Area under the concentration-time curve in 1 dosing interval (multiple dosing only)
Cavg
Average plasma concentration derived by AUC(0-t) being divided by time t 
AI_Cmax
Cmax accumulation index (multiple dosing only)
AI_AUC
AUC accumulation index (multiple dosing only)
Individual participant PK parameter values will be derived by non-compartmental methods by a 
validated PK analysis program. Actual times will be used for the analyses. See Table 2-3, Table 
2-4, and Table 2-5 in Section 2: Schedule of Activities for the PK sampling schedule.
PK data from this study may be combined with PK data from other studies to characterize the PK 
using population PK and PBPK analysis and to assess exposure-response relationships for efficacy 
and safety. Results of this analysis will be reported separately (see Section 10.4 Statistical 
Analyses for additional details).
9.5.1
Pharmacokinetic Sampling Instructions and Collection Windows
Refer to Table 2-3, Table 2-4, and Table 2-5 in Section 2: Schedule of Activities for the PK 
sampling schedule.
All on-treatment time points are intended to align with days on which study intervention is 
administered. If it is known that a dose will be delayed, then the pre-dose sample, if appropriate, 
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 pre-dose sample should not be collected. For 
participants receiving cetuximab in Parts 1B and 2B, 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.
Detailed instructions for PK blood collection, labeling, processing, storage, and shipping will be 
provided to the site in the laboratory/procedure manual.
9.5.1.1
Pharmacokinetic Sample Collection Windows
It is expected that every effort will be made to collect PK samples at the times indicated in 
the protocol. The following time windows serve as a guideline for PK sample collections:

 
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SHP2 inhibitor

9.5.2
Pharmacokinetic Sample Analyses
Treatment assignments will be released to the bioanalytical laboratory to minimize unnecessary 
analysis and/or re-analysis of PK/anti-drug antibody (ADA) study samples.
Concentration analyses for BMS-986466 and adagrasib will be performed by validated 
bioanalytical method(s).
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 AEs, 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 (including, but not limited to, cross-
validation, ADA/PK selectivity, cut point, etc). 
9.6
Immunogenicity Assessments
No immunogenicity will be assessed in this study. Based on cetuximab USPI,17 the incidence of 
anti-cetuximab binding antibodies in 105 participants (from Studies I4E-MC-JXBA, I4E-MC-
JXBB, and I4E-MC-JXBD) with at least 1 post-baseline blood sample (≥4 weeks post first 
cetuximab administration) was < 5%. Small molecule drugs such as BMS-986466 and adagrasib 
are not expected to change the immunogenicity profile of cetuximab.
9.7
Biomarkers
Peripheral blood and tumor tissue samples will be collected in this study at baseline and several 
on-treatment time points to identify PD markers associated with response and/or resistance to 
therapy. Additional biomarkers related to mechanism of action of BMS-986466 will be explored. 
The PD changes between baseline and on-treatment measures will also be monitored and evaluated 
for associations with PK data and select AEs. Peripheral blood and tumor samples will be collected 
at the times indicated in Table 2-6 and Table 2-7 for biomarker assessments. If biomarker samples 
are collected but study intervention is not administered, samples will be retained. Further details 
of blood and tumor tissue collection and processing will be provided to the site in the laboratory 
manual.
Other samples may be used for research to develop methods, assays, prognostics, and/or 
companion diagnostics related to BMS-986466 treatment.
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9.7.1
Germline Genetics
For the purpose of normal germline reference comparison for tumor DNA sequencing, blood
samples for DNA isolation and sequencing will be collected from all participants unless prohibited 
by local law/regulation or if not approved by the IRB/IEC. In these cases, the DNA collection may 
be presented to participants as an optional collection. See Table 2-6 and Table 2-7 in Section 2:
Schedule of Activities for the biomarker sampling schedule.
Collection and shipment information for these samples is in the laboratory/procedure manual. The 
Sponsor will store the DNA samples in a secure storage space with adequate measures to protect 
confidentiality. The samples may be retained for up to 20 years beyond the end of the study, unless 
prohibited by local law/regulation or IRB/IEC, to understand genetic mechanisms of response 
and/or the disease/condition under study and related conditions.
9.7.2
Participant Selection Biomarkers
For NSCLC and CRC enrollment: Participants must have a documented KRAS G12C mutation 
from an NYS-approved, FDA-approved/cleared, or CE-marked test or, when such result is not 
available, positive KRAS G12C mutation status should be confirmed by a central laboratory 
(Guardant360 CDx) in liquid biopsy samples collected at the time of screening (for parts 1 DDI, 
1A and 1B) and in liquid biopsy and/or tumor samples (only for parts 2A and 2B) collected at the 
time of the screening or from archival biopsies (less than 1 year old). 
For PDAC and BTC enrollment: Participants must have a documented KRAS G12C mutation from
an NYS approved, FDA approved/cleared or CE-marked test and liquid biopsy samples collected 
only for retrospective testing. Participants must have no other activating mutations in BRAF 
V600X, PTPN11 (SHP2), or KRAS Q61X.
9.7.3
Blood Samples for Exploratory Biomarkers
Whole blood will be collected during dose escalation prior to treatment and at various time points 
on treatment in order to evaluate PD of pathway modulation. 
 
 The pre-dose sample 
 levels are compared to the on-treatment sample 
 levels to determine 
 
 in normal blood cells. Both pre-treatment and on-treatment whole blood, plasma, and/or 
serum sample collections will also be utilized for 
 
 to evaluate various surrogate tumor and/or immune PD effects. Finally, blood 
samples will be collected at screening and on-treatment time points (see Table 2-6 and Table 2-7)
for circulating tumor DNA sequencing in order to follow various DNA mutations (ie), as they 
relate to clinical response and resistance.
9.7.4
Tumor Samples for Exploratory Biomarkers
Mandatory fresh tumor biopsies will be collected during Part 2 dose expansion (optional for 
Part 1), at screening and C2D1 (± 7 days), in order to evaluate PD of pathway modulation, immune 
response, and other changes in tumor cells. See Table 2-6 and Table 2-7 regarding the requirements 
for mandatory versus optional biopsy collections. A formalin-fixed, paraffin-embedded (FFPE) 
tissue block of tumor tissue from a core biopsy, punch biopsy, excisional or incisional biopsy, or 
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surgical specimen obtained during screening or within 3 months before the start of the screening 
period, with no intervening systemic anti-cancer treatment between time of acquisition and 
enrollment, must be sent to the central laboratory prior to randomization, except if the biopsy was 
attempted but was not completed due to safety concerns. Fine needle aspirates or other cytology 
samples are not acceptable. A repeat biopsy at screening from the same or an alternative site will 
be required if clinically feasible (at the discretion of the investigator), and the initial attempt was 
unsuccessful in obtaining adequate tissue for biomarker analysis. Only 1 repeat attempt may be
performed at each time point, if clinically feasible. An unsuccessful fresh tumor biopsy at 
screening will not exclude participants from receiving or continuing the study intervention. Bone 
lesions are unacceptable sites for biopsy. Tumor biopsy material will be utilized for 
immunohistochemical analysis as well as DNA and/or RNA sequencing to determine the PD 
effects of drug on tumor cells and to determine potential resistance biomarkers. Please notify the
Medical Monitor if on-treatment biopsy may pose unacceptable clinical risk or if tumor at the
time of on-treatment biopsy is not accessible for sampling. Institutional guidelines for the safe
performance of biopsies should be followed. The screening and on-treatment biopsies will follow
the same guidance methodology for sample collections, processing, and submission provided in 
the laboratory manual.
Archived tumor specimens in the form of blocks or sectioned slides obtained within 1 year of 
screening should be submitted prior to study intervention, if available.
Based on the data and upon discussion with the investigator and Sponsor, biopsies may become 
optional for all parts of the study.
This protocol will involve storage of residual samples including blood and tissue for up to 20 years 
for additional research.
9.7.5
Other Biomarkers
Not applicable.
9.8
Optional Future Research
This protocol will include both additional sample collection and residual sample storage for 
optional future research. The following additional samples will be collected from participants for 
this research as specified in Section 2: Schedule of Activities:

Blood/tumor for DNA
Samples kept for future research will be stored at 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 25 years 
after the end of the study or the maximum period allowed by applicable law.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
will be securely held by the investigator at the clinical site, so there is no direct ability for a 
researcher to connect a sample to a specific individual.
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Further details of sample collection and processing will be provided to the site in the 
laboratory/procedure manual.
9.9
Other Assessments
Not applicable.
9.10
Healthcare Resource Utilization
Health economics/medical resource utilization and health economics parameters will not be 
evaluated in this study.
10
STATISTICAL CONSIDERATIONS
10.1
Statistical Hypotheses
It is expected that the ORR of participants with KRAS G12C mutation randomized to 
BMS-986466 plus adagrasib will be improved as compared to the ORR in participants receiving 
adagrasib monotherapy in NSCLC, while the ORR of BMS-986466 plus adagrasib and cetuximab 
will be improved as compared to the ORR in participants receiving adagrasib with cetuximab in 
CRC.
10.2
Sample Size Determination
Part 1 (DDI cohort): A minimum of 6 PK-evaluable participants in the DDI cohort. 
Part 1A (Dose Escalation): A total of up to approximately 27 DLT-evaluable participants will be 
enrolled. At least 3 participants will be accrued in each dose.
Part 1B (Dose Escalation): A total of up to approximately 27 DLT-evaluable participants will be 
enrolled. At least 3 participants will be accrued in each dose.
Part 2A (Dose Expansion): A sample size of approximately 150 response-evaluable participants 
will be randomized to 3 treatment arms in the ratio of 1:1:1, which allows for 80% power 
 
 
Part 2B (Dose Expansion): A sample size of approximately 200 response-evaluable participants 
will be randomized to 4 treatment arms in the ratio of 1:1:1:1, which allows for 80% power to 
 
10.3
Analysis Sets
For the purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who signed the informed consent form and obtained a participant
number.
Treated 
All participants who received at least 1 dose of study intervention. 
Randomized
All participants who were randomized using IRT.
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Population
Description
Response-evaluable
All participants who received at least 1 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
3) Death prior to the first on-treatment tumor evaluation
DLT-evaluable
Participants in Part 1A will be considered DLT evaluable if they complete ≥ 75% of all 
planned doses of BMS-986466 and adagrasib without experiencing a DLT or experience 
a DLT after receiving at least 1 dose of BMS-986466 and adagrasib. Participants in Part 
1B must complete ≥ 75% of all planned doses of BMS-986466 and adagrasib and have 
received at least 2 doses of cetuximab without experiencing a DLT or experience a DLT 
after receiving at least 1 dose of BMS-986466, adagrasib, and cetuximab.
PK
All participants who received at least 1 dose of BMS-986466 and/or adagrasib and had 
any available concentration-time data.
PK-evaluable 
Subset of the PK population. 
All participants in the PK population with adequate PK profiles.
Biomarker
All treated participants with available biomarker data.
Abbreviation: AUC(0-T), area under the concentration-time curve from time zero to time of last quantifiable 
concentration; Cmax, maximum observed concentration; DDI, drug-drug interaction; DLT, dose-limiting toxicity; 
IRT, Interactive Response Technology; PK, pharmacokinetic.
10.4
Statistical Analyses
The statistical analysis plan (SAP) will be finalized prior to database lock, and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints, including 
primary and key secondary endpoints.
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. 
Unless otherwise specified, all analyses will be performed separately by study part.
10.4.1
General Considerations
The analysis of safety will be based on all treated population. The efficacy analysis (Parts 2A and 
2B) will be based on all randomized population. Further details will be provided in the SAP.
10.4.2
Primary Endpoint(s)
The primary endpoint for Part 1 is to assess safety based on incidence of AEs, SAEs, AEs leading 
to discontinuation, and deaths. In addition, the selected tolerable dose levels of BMS-986466 in 
combination with adagrasib (Part 1A) and BMS-986466 in combination with adagrasib and 
cetuximab (Part 1B) will be determined using the DLT rate within the 28-day window among 
DLT-evaluable participants in Parts 1A and 1B. The incidence of DLTs will be calculated and 
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compared to the actions recommended by the TITE-BOIN design to guide the dose 
escalation/stay/de-escalation decision for the BMS-986466 plus adagrasib treatment and for the 
BMS-986466 plus adagrasib plus cetuximab treatment (refer to Appendix 7).
The primary endpoint for Part 2 is ORR of BMS-986466 plus adagrasib compared to adagrasib 
control (Part 2A), and ORR of BMS-986466 in combination with adagrasib plus cetuximab 
compared to adagrasib plus cetuximab control (Part 2B), in the randomized population. Bayesian 
continuous safety monitoring framework will be utilized to monitor toxicity and detect safety 
signals affecting conduct of the study. ORR is defined as the proportion of participants who 
achieve a best response of CR or PR using the RECIST v1.1 criteria.
The primary endpoints and analyses are shown in Table 10.4.2-1.
Table 10.4.2-1:
Primary Endpoints
Primary Endpoint
Description of Analysis
Time Frame
Incidence of DLTs, AEs, SAEs, 
AEs leading to discontinuation, and 
deaths
DLT rate by dose level, frequency 
distribution of treated participants 
with AE using the worst 
CTCAE v5.0 grade. Participants 
will only be counted (1) once at the 
preferred term level; (2) once at the 
system organ class level; and (3) 
once in the “total participant” row 
at their worst CTCAE grade, 
regardless of system organ class or 
PT.

For DLTs, up to 28 days

For AEs, up to approximately 
2 years
ORR assessed by BICR is defined 
as the proportion of participants 
who achieve a best response of CR 
or PR using the RECIST v1.1 
criteria
The ORR and its corresponding 
95% exact CI will be calculated by 
Clopper-Pearson method for each 
arm, based on BICR by 
RECIST v1.1.
The ORR difference will also be 
estimated by 95% CI, and p-value.
Up to approximately 4 years
Abbreviations: AE, adverse event; BICR, Blinded Independent Central Review; CI, confidence interval; CR, complete 
response; CTCAE, Common Terminology Criteria for Adverse Events; DLT, dose-limiting toxicity; ORR, overall
response rate; PR, partial response; PT, preferred term; RECIST, Response Evaluation Criteria in Solid Tumors; SAE, 
serious adverse event.
Efficacy analysis will be performed with one-sided alpha level of 0.1 to evaluate if the ORR of 
BMS-986466 plus adagrasib is superior to that of adagrasib (Part 2A), and if the ORR of 
BMS-986466 plus adagrasib plus cetuximab is superior to that of adagrasib plus cetuximab 
(Part 2B).
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Table 10.4.2-2:
Summary of the Attributes of the Main Estimand for the Primary 
Objective
Estimand Attribute
Definition
Treatment

Part 1A: BMS-986466 and adagrasib

Part 1B: BMS-986466, adagrasib and cetuximab
Population
DLT evaluable
Variable
DLT
Intercurrent Events
Event
Strategy
Description (or 
Rationale)
Discontinuation 
from study without 
DLT prior to end of 
DLT assessment 
period
Principal stratum strategy
DLT will only be 
reported among DLT 
evaluable participants 
during the DLT evaluable 
period
Population-level 
Summary
Proportion of participants with DLTs per dose level per part
Treatment

Part 1A: BMS-986466 and adagrasib

Part 1B: BMS-986466, adagrasib, and cetuximab
Population
Eligible participants who receive at least 1 dose of study medication
Variable
Incidence of AEs, SAEs, AEs leading to discontinuation, and death
Intercurrent Events
Event
Strategy
Description (or 
Rationale)
All intercurrent 
events, eg, 
discontinuation of 
treatment
Treatment policy strategy
AEs, SAEs, AEs leading 
to discontinuation, and 
death will be reported 
regardless of the 
intercurrent events
Population-level 
Summary
Proportion of participants with events per dose level per part
Treatment

Part 2A: BMS-986466 and adagrasib

Part 2B: BMS-986466, adagrasib, and cetuximab
Population
All randomized participants
Variable
BOR per RECIST v1.1 by BICR
Intercurrent Events
Event
Strategy
Description (or 
Rationale)
New anticancer 
therapy prior to any 
progression
While on treatment policy 
strategy
BOR will be analyzed 
before the start of the new 
anticancer therapy.
Dropout or death 
without disease 
assessment
Composite strategy
Dropout or death without 
disease assessment will 
be considered as non-
responder
Population-level 
Summary
Proportion of participants with best overall response of any CR or PR per BICR for 
ORR (with 2-sided 95% Clopper-Pearson CI)
Abbreviations: AE, adverse event; BICR, Blinded Independent Central Review; BOR, best overall response; CI, 
confidence interval; CR, complete response; DLT, dose-limiting toxicity; ORR, overall response rate; PR, partial 
response; RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious adverse event.
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10.4.3
Secondary Endpoint(s)
The secondary endpoints (Parts 1 and 2) and statistical analysis methods are described in Table 
10.4.3-1.
The effect of each treatment will be estimated based on the additional efficacy endpoints using 
point estimates and 95% CI. Details of censoring rules for the time-to-event endpoints will be 
provided in the study SAP. 
Table 10.4.3-1:
Secondary Endpoints
Secondary Endpoint
Description
Time Frame
BMS-986466 Geometric Mean 
Ratio of AUC(0-T) and Cmax
To determine the magnitude of drug 
interaction between BMS-986466 
(victim) and adagrasib
Up to approximately 60 days 
BMS-986466 PK parameters in 
plasma: Cmax, Tmax, AUC(0-T),
AUC(INF), AUC(TAU), Cavg, 
Ctrough, AI_Cmax, AI_AUC, as 
appropriate, from
concentration-time data
Summary measures will be 
tabulated for BMS-986466 PK 
parameters, if feasible, and 
wherever applicable, by treatment 
and dosing regimen. Summary 
statistics for plasma BMS-986466
Ctrough will also be tabulated by 
treatment, study day, and time. 
Up to approximately 60 days 
PFS is defined as the time between 
the first dose of
treatment/randomization and the 
date of first documented tumor 
progression, based on BICR (per 
RECIST v1.1) or death due to any 
cause, whichever occurs first. 
The PFS curve will be estimated 
using the Kaplan-Meier product-
limit method. A 2-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 will be 
presented along with their 
associated 95% CIs.
Up to approximately 4 years 
Incidence of AEs, SAEs, AEs 
leading to discontinuation, and 
deaths 
Frequency distribution of treated 
participants with AE using the 
worst CTCAE v5.0 grade. 
Participants will only be counted 
(1) once at the preferred term level;
(2) once at the system organ class 
level; and (3) once in the ‘total 
participant’ row at their worst 
CTCAE grade, regardless of system 
organ class or PT.
Up to approximately 2 years
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 v1.1 criteria or death due 
to any cause, whichever occurs 
first.
Median DOR and its corresponding 
95% CI will be estimated using 
Kaplan-Meier method.
Up to approximately 4 years
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Table 10.4.3-1:
Secondary Endpoints
Secondary Endpoint
Description
Time Frame
DCR is defined as the number of 
treated/randomized participants 
who achieve a primary BOR of 
confirmed CR, confirmed PR, or 
SD (and/or SD > 6 months), based 
on BICR assessments (using 
RECIST v1.1) divided by the 
number of all treated/randomized 
participants.
The DCR and its corresponding 
95% exact CI will be calculated by 
Clopper-Pearson method for each 
arm, based on BICR by 
RECIST v1.1.
Up to approximately 4 years
TTR assessed by BICR is defined 
as the time between the first dose of 
treatment/randomization to the date 
of the first confirmed documented 
response (CR or PR) per 
RECIST v1.1 criteria.
Descriptive statistics and 
summaries will be presented for 
TTR.
Up to approximately 4 years
Summary measures of target 
engagement, such as, but not 
limited to, pERK.
Descriptive statistics of pERK

Up to approximately 10 days in 
the DDI cohort 

Up to approximately 30 days in 
the non-DDI cohort
Abbreviations: AE, adverse event; AI_AUC; area under the plasma concentration-time curve accumulation index; 
AI_Cmax, Cmax accumulation index; AUC(0-T), area under the concentration-time curve from time zero to time of 
last quantifiable concentration; AUC(INF), area under the plasma concentration-time curve from time zero 
extrapolated to the infinite time; AUC(TAU), area under the concentration-time curve within a dosing interval; BICR, 
Blinded Independent Central Review; BOR, best overall response; CI, confidence interval; Cmax, maximum observed 
concentration; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; Ctrough, trough 
observed plasma or serum concentration; DCR, disease control rate; DOR, duration of response; pERK, 
phosphorylation of extracellular signal-regulated kinase; PFS, progression-free survival; PK, pharmacokinetic; PR, 
partial response; PT, preferred term; RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious adverse 
event; SD, stable disease; Tmax, time of maximum observed plasma concentration; TTR, time to response.
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Table 10.4.3-2:
Summary of the Attributes of the Main Estimand for the Key 
Secondary Objective
Estimand Attribute
Definition
Treatment

DDI cohort

Part 1A: BMS-986466 and adagrasib 

Part 1B: BMS-986466, adagrasib, and cetuximab
Population
Eligible participants who received at least 1 dose of BMS-986466 and/or adagrasib 
and had any available concentration-time data and have adequate PK profiles or have 
at least 1 evaluable PK parameter.
Variable
BMS-986466 PK parameters 
Intercurrent Events
Event
Strategy
Description (or 
Rationale)
All intercurrent 
events, eg, 
discontinuation of 
treatment
Treatment policy strategy
The PK results will be 
reported regardless of the 
intercurrent events
Population-level 
Summary
Summary measures will be tabulated for BMS-986466 PK parameters, if feasible, and 
wherever applicable, by treatment and dosing regimen. Summary statistics for plasma 
BMS-986466 Ctrough will also be tabulated by treatment, study day, and time. For 
the DDI cohort, geometric mean and geometric mean ratio will be reported.
Treatment

Part 2A: BMS-986466 and adagrasib

Part 2B: BMS-986466, adagrasib, and cetuximab
Population
All randomized participants
Variable
PFS per RECIST v1.1 by BICR
Intercurrent Events
Event
Strategy
Description (or 
Rationale)
New anticancer 
therapy prior to any 
progression
Treatment strategy
The endpoints will be 
analyzed regardless of the 
start of the new 
anticancer therapy
Population-level 
Summary

Kaplan-Meier estimated HR, median survival time and landmark survival rate of 
PFS
Treatment

Part 2A: BMS-986466 and adagrasib

Part 2B: BMS-986466, adagrasib and cetuximab
Population
Eligible participants who receive at least 1 dose of study intervention
Variable
Incidence of AEs, SAEs, AEs leading to discontinuation, and death
Intercurrent Events
Event
Strategy
Description (or 
Rationale)
All intercurrent 
events, eg, 
discontinuation of 
treatment
Treatment policy strategy
AEs, SAEs, AE leading 
to discontinuation, and 
death will be reported
regardless of the 
intercurrent events
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Table 10.4.3-2:
Summary of the Attributes of the Main Estimand for the Key 
Secondary Objective
Estimand Attribute
Definition
Population-level 
Summary
Proportion of participants with events per dose level per part
Abbreviations: AE, adverse event; BICR, Blinded Independent Central Review; DDI, drug-drug interaction; HR, 
hazard ratio; PFS, progression-free survival; PK, pharmacokinetic; RECIST, Response Evaluation Criteria in Solid 
Tumors; SAE, serious adverse event.
10.4.4
Exploratory Endpoint(s)
Exploratory PK, biomarker, and efficacy analyses will be described in the SAP, finalized before 
final database lock. Unless specified otherwise, all safety analyses will be performed on all treated 
participants.
10.4.5
Other Safety Analyses
10.4.5.1
Continuous Safety Monitoring
A Bayesian continuous monitoring framework will be utilized in the randomized part of the study 
to monitor for toxicity and detect safety signals that may lead to changes in study conduct.
Incidence rates of TRAEs of Grade 3 and above as assessed by the investigator during treatment 
and safety follow up period will be evaluated in reference to 
 of Grade 3 
and above, which is close to the incidence rate observed in adagrasib and cetuximab studies.10
For safety data for each arm in Part 2A and Part 2B, the Bayesian safety monitoring boundaries 
are established using a noninformative prior, Beta (0.5, 0.5). The posterior distribution is 
Beta(0.5+n, 0.5+[m-n]), where n and m are the number of TRAEs observed out of the total number 
of evaluable participants. 
 
 This criterion is not binding; If anytime during the treatment and safety 
follow-up period, it reaches the pre-specified threshold of toxicity, then, taking into account all 
available safety information, additional evaluation will be conducted to allow a complete by 
treatment arm safety assessment and risk benefit evaluation.
 
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10.4.6
Other Analyses
PBPK modeling will be performed by integrating in vitro DDI information for BMS-986466 and 
adagrasib and PK data obtained from DDI cohorts. PBPK modeling will serve as supportive 
evidence informing dose selection for dose escalation cohorts.
The BMS-986466 concentration data obtained in this study may be combined with data from other 
studies in the clinical development program to develop a population PK model. The population 
PK model will be used to evaluate the impact of intrinsic and extrinsic covariates on the PK of 
BMS-986466. In addition, exposure-response analyses with selected efficacy and safety endpoints 
may be conducted. Population PK modeling and simulation and exposure response analysis will 
be used to support dose selection and optimization. Results of population PK and exposure-
response analyses may be reported separately.
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10.5
Interim Analyses
In both Parts 2A and 2B, interim analyses (including integrated PK/PD, dose-response, and 
exposure-response analysis) will be conducted after approximately the first 60 and 80 response-
evaluable participants, respectively, to support dose selection for expansion in each indication. The 
data from interim analysis may be reviewed by the study team, SRC, and SMT to plan for further 
development of the BMS-986466 program. Based on post-interim analysis of the data, including 
safety, PK, PD, and efficacy, the Sponsor may stop enrollment in any cohort. Enrollment may 
continue during the interim analysis. Additional details of the interim analyses will be provided in 
the SAP. 
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11
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Matozaki T, Murata J, Saito Y, et al. Protein tyrosine phosphatase SHP-2: a proto-oncogene 
product that promotes Ras activation. Cancer Sci 2009;100:1786-93.
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Lee JK, Sivakumar S, Schrock AB, et al. Comprehensive pan-cancer genomic landscape of 
KRAS altered cancers and real-world outcomes in solid tumors. NPJ Precis Oncol 2022;6:91.
3
Kim D, Xue JY, Lito P. Targeting KRAS(G12C): from inhibitory mechanism to modulation 
of antitumor effects in patients. Cell 2020;850-9.
4
Yaeger R, Weiss J, Pelster MS, et al. Adagrasib with or without cetuximab in colorectal 
cancer with mutated KRAS G12C. N Engl J Med 2023;388:44-54.
5
Kuboki Y, Yaeger R, Fakih MG, et al. Sotorasib in combination with panitumumab in
refractory KRAS G12C-mutated colorectal cancer: safety and efficacy for phase Ib full
expansion cohort. Ann Oncol 2022;33(Suppl_7):S136-96.
6
Mainardi S, Mulero-Sanchez A, Prahallad A, et al. SHP2 is required for growth of KRAS-
mutant non-small-cell lung cancer in vivo. Nat Med 2018;24:961-7.
7
Ruess DA, Heynen GJ, Ciecielski KJ, et al. Mutant KRAS-driven cancers depend on 
PTPN11/SHP2 phosphatase. Nat Med 2018;24:954-60.
8
Fedele C, Ran H, Diskin B, et al. SHP2 inhibition prevents adaptive resistance to MEK 
inhibitors in multiple cancer models. Cancer Discov 2018;8:1237-49.
9
Ryan MB, de la Cruz FF, Phat S, et al. Vertical pathway inhibition overcomes adaptive 
feedback resistance to KRASG12C inhibition. Clin Cancer Res 2020;26:1633-43.
10 Janne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in non-small-cell lung cancer harboring a 
KRASG12C mutation. N Engl J Med 2022;387:120-31.
11 Ryan MB, Coker O, Sorokin A, et al. KRASG12C-independent feedback activation of wild-
type RAS constrains KRASG12C inhibitor efficacy. Cell Rep 2022;39:110993.
12 BBP-398 (Formerly known as IACS-15509) Investigator’s Brochure, Version 9. Navire 
Pharma Inc. 2022. 
 
14 KRAZATI (adagrasib) Tablets, for Oral Use. US Prescribing Information. Mirati Therapeutics, 
Inc.; 2022. 
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15 Mirati Therapeutics. Press Releases; Journal of Clinical Oncology Publishes Rapid 
Communication Featuring Updated Clinical Data for Adagrasib as a Targeted Treatment for 
KRASG12C-Mutated Advanced Solid Tumors [cited 2023 May 01]. Available from: URL: 
https://ir.mirati.com/press-releases/press-release-details/2023/Journal-of-Clinical-Oncology-
Publishes-Rapid-Communication-Featuring-Updated-Clinical-Data-for-Adagrasib-as-a-
Targeted-Treatment-for-KRASG12C-Mutated-Advanced-Solid-Tumors/default.aspx
16 Kerr DL, Haderk F, Bivona TG. Allosteric SHP2 inhibitors in cancer: targeting the intersection 
of RAS, resistance, and the immune microenvironment. Curr Opin Chem Biol 2021;62:1-12.
17 ERBITUX (cetuximab) Injection, for Intravenous Use. US Prescribing Information. Eli Lilly 
and 
Company; 
2021. 
Available 
from: 
URL: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125084s277s280lbl.pdf.
18 Allegra CJ, Rumble BR, Hamilton SR, et al. Extended RAS gene mutation testing in metastatic 
colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal 
antibody therapy: American Society of Clinical Oncology provisional clinical opinion update 
2015. J Clin Oncol 2016;34:179-85.
19 Erbitux Annex 1 Summary of Product Characteristics. Merck Serono Ltd. 2022.
20 Awad MM, Liu S, Rybkin II, et al. Acquired resistance to KRASG12C inhibition in cancer. N 
Engl J Med 2021;384:2382-93.
21 Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-
tumour immunity. Nature 2019;575:217-23.
22 Hallin J, Engstrom LD, Hargis L, et al. The KRASG12C inhibitor MRTX849 provides insight 
toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. 
Cancer Discov 2020;10:54-71.
23 Misale S, Fatherree JP, Cortez E, et al. KRAS G12C NSCLC models are sensitive to direct 
targeting of KRAS in combination with PI3K inhibition. Clin Cancer Res 2019;25:796-807.
24 Tanaka N, Lin JJ, Li C, et al. Clinical acquired resistance to KRASG12C inhibition through a 
novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK 
reactivation. Cancer Discov 2021;11:1913-22.
25 Xue JY, Zhao Y, Aronowitz J, et al. Rapid non-uniform adaptation to conformation-specific 
KRAS(G12C) inhibition. Nature 2020;577:421-5.
26 Yuan Y, Lin R, Li D, et al. Time-to-event Bayesian optimal interval design to accelerate Phase 
I trials. Clin Cancer Res 2018;24:4921-30.
27 Fedele C, Li S, Teng KW, et al. SHP2 inhibition diminishes KRASG12C cycling and promotes 
tumor microenvironment remodeling. J Exp Med 2021;218:e20201414.
28 NIH U.S. National Library of Medicine. ClinicalTrials.gov; Phase 3 Study of MRTX849 with 
cetuximab vs chemotherapy in patients with advanced colorectal cancer with KRAS G12C 
mutation 
(KRYSTAL-10) 
[cited 
2023 
Apr 
23]. 
Available 
from: 
URL: 
https://clinicaltrials.gov/ct2/show/NCT04793958. 
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29 Mirati Therapeutics. Press Releases; Journal of Clinical Oncology Publishes Rapid 
Communication Featuring Updated Clinical Data for Adagrasib as a Targeted Treatment for 
KRASG12C-Mutated Advanced Solid Tumors [cited 2023 May 01]. Available from: URL: 
https://ir.mirati.com/press-releases/press-release-details/2023/Journal-of-Clinical-Oncology-
Publishes-Rapid-Communication-Featuring-Updated-Clinical-Data-for-Adagrasib-as-a-
Targeted-Treatment-for-KRASG12C-Mutated-Advanced-Solid-Tumors/default.aspx.
30 U.S. Food & Drug Administration. Drugs@FDA: FDA-Approved Drugs; New Drug 
Application: 216340; Company: MIRATI THERAPS [cited 2023 Mar 27]. Available from: 
URL: 
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplN
o=216340. 
31 Ou SI, Janne PA, Leal TA, et al. First-in-human phase I/IB dose-finding study of adagrasib 
(MRTX849) in patients with advanced KRASG12C solid tumors (KRYSTAL-1). J Clin Oncol 
2022;40:2530-8.
32 U.S. Food & Drug Administration. Drug Development and Drug Interactions Table of 
Substrates, Inhibitors, and Inducers [cited 2023 Mar 29]. Available from: URL: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers#table3-3/.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS
Term
Definition
2L
second-line therapy
2L+
second-line therapy or later 
ADA
anti-drug antibody 
AE
adverse event 
AI_AUC
area under the plasma concentration-time curve accumulation index
AI_Cmax
Cmax accumulation index
ALK
anaplastic lymphoma kinase 
ALP
alkaline phosphatase 
ALT
alanine aminotransaminase 
AST
aspartate transaminase 
AUC
area under the concentration vs time curve 
AUC(0-T)
area under the concentration-time curve from time zero to time of last 
quantifiable concentration 
AUC(INF)
area under the plasma concentration-time curve from time zero 
extrapolated to the infinite time 
AUC(TAU)
area under the concentration-time curve within a dosing interval 
AUCss
area under the concentration-time curve at steady-state 
AxMP
auxiliary medicinal product 
BCRP
breast cancer resistance protein 
BICR
Blinded Independent Central Review 
BID
twice daily dose 
BMI
body mass index 
BMS
Bristol-Myers Squibb Company
BNP
b-type natriuretic protein 
BOR
best overall response
BRAF
proto-oncogene B-Raf
BTC
biliary tract cancer
C
cycle
Cavg
average concentration 
CE
conformité européenne
CI
confidence interval 
Cmax
maximum (or peak) concentration 
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Term
Definition
Cmin
minimum observed concentration 
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials 
CRC
colorectal carcinoma 
CRF
Case Report Form 
CRO
contract research organization
CSR
clinical study report 
CT
computed tomography 
CTCAE
Common Terminology Criteria Adverse Events 
ctDNA
circulating tumor deoxyribonucleic acid
Ctrough
trough observed plasma or serum concentration 
CYP
cytochrome P450
D
day
DCR
disease control rate
DDI
drug-drug interaction 
DILI
drug-induced liver injury 
DL
dose level
DLT
dose-limiting toxicity 
DNA
deoxyribonucleic acid 
DOR
duration of response 
ECG
electrocardiogram
ECHO
echocardiogram 
ECOG
Eastern Cooperative Oncology Group 
eCRF
electronic Case Report Form
EDC
electronic data capture
EGFR
epidermal growth factor receptor (her-1) 
EOI
end of infusion 
EOT
end of treatment 
ERK
extracellular signal-regulated kinase 
EU
European Union 
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database 
FDA
Food and Drug Administration 
FFPE
formalin-fixed, paraffin-embedded 
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Term
Definition
FIH
first-in-human 
FSH
follicle-stimulating hormone
FU
follow-up
 
GTP
glutamyl transferase 
GTPase
guanosine triphosphatase 
HBsAg
hepatitis B surface antigen 
HBV
hepatitis B virus
HCG
human chorionic gonadotropin 
HCV
hepatitis C virus 
HIV
human immunodeficiency virus 
HR
hazard ratio
IAC
ileocecal/ascending colon 
IB
Investigator’s Brochure 
ICF
informed consent 
IDH1
isocitrate dehydrogenase 1
IEC
Independent Ethics Committee 
IHC
immunohistochemistry
ILD
interstitial lung disease 
IMP
investigational medicinal product 
IP
investigational product 
IRB
Institutional Review Board 
IRT
Interactive Response Technology 
IU
international unit
IV
intravenous(ly)
KRAS
Kirsten rat sarcoma viral oncogene 
LDH
lactate dehydrogenase 
log
logarithm 
LVEF
left ventricular ejection fraction 
MAD
maximum administered dose
MAPK
mitogen-activated protein kinase 
MATE
multidrug and toxin extrusion 
MATE1
multidrug and toxin extrusion protein 1 
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Term
Definition
MET
mesenchymal to epithelial transition
MMR
mismatch repair 
mPFS
median progression-free survival 
MRI
magnetic resonance imaging 
MSI
microsatellite instability 
MTD
maximum tolerated dose 
MUGA
multigated acquisition 
N/n
number of participants 
NA
not applicable 
NSCLC
non-small cell lung cancer 
NTRK
neurotrophic tyrosine receptor kinase
NYS
New York State
 
ORR
objective response rate 
OS
overall survival 
PDAC
pancreatic duct adenocarcinoma
pERK
phosphorylation of extracellular signal-related kinase 
p-DILI
potential drug-induced liver injury
P-gp
p-glycoprotein 
PBMC
peripheral blood mononuclear cell 
PBPK
physiologically based pharmacokinetics 
PD
pharmacodynamics
PD-1
programmed cell death protein 1
PD-L1
programmed death–ligand 1 
PE
physical examination 
pERK
phosphorylation of extracellular signal-regulated kinase
PET
positron emission tomography
PFS
progression-free survival 
PID
patient identification number 
PK
pharmacokinetic 
PPI
proton pump inhibitor 
PR
partial response 
PS
performance status 
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Term
Definition
PT
preferred term 
PTPN11
protein tyrosine phosphatase non-receptor type 1
Q3M
every 3 months
QD
once daily
QT
Q and T waves
QT interval
time between the start of the Q wave and the end of the T wave 
QTc
QT interval corrected for heath rate 
QTcF
QT interval corrected using Fridericia’s method 
QXW
every X week(s) 
R
randomization
R/R
relapsed and refractory
RECIST
Response Evaluation Criteria in Solid Tumors 
RET
rearranged during transfection
RNA
ribonucleic acid 
ROS1
ROS proto-oncogene 1
RTK
receptor tyrosine kinase 
SAE
serious adverse event
SAP
statistical analysis plan 
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SD
stable disease
SGOT
serum glutamic-oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SHP2
Src homology-2 phosphatase
SmPC
summary of product characteristics 
SMT
Safety Management Team 
SRC
Scientific Review Committee
STK11
serine/threonine kinase 11
SUSAR
suspected unexpected serious adverse reaction 
T3
triiodothyronine
T4
thyroxine
TBD
to be determined 
TEAE
treatment-emergent adverse event
TITE-BOIN
time-to-event Bayesian optimal interval
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Term
Definition
TITE-CRM
time-to-event continual reassessment method 
Tmax
time at which maximum concentration (cmax) occurs 
TMB
tumor mutational burden 
TPS
tumor proportion score 
TRAE
treatment-related adverse event 
TSH
thyroid-stimulating hormone 
TTR
time to response 
ULN
upper limit of normal 
US
United States 
USPI
United States Prescribing Information
VEGF
vascular endothelial growth factor
Vss
volume of distribution at steady state 
WOCBP
women of childbearing potential 
WWPS
Worldwide Patient Safety 
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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 Union (EU) Directive 2001/20/EC

European Regulation 536/2014 for clinical studies (if applicable)

European Medical Device Regulation 2017/745 for clinical device research (if applicable)

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 STRATEGY
A patient engagement and recruitment program will be developed and implemented to assist sites 
with patient recruitment efforts. Tactics will support patient education and awareness, and HCP 
outreach. This program will also include solutions to address anticipated recruitment challenges.
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 
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 cyberattacks 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
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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 
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.
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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
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.
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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. 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 
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.
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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 
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.
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
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.
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 
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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.
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 the EU/European Economic Area and third countries.
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)
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 
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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 v 5.0
(NCI CTCAE v 5.0).
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.) 
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.
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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 contraceptive 
methods 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:

Hysterectomy

Bilateral salpingectomy

Bilateral oophorectomy

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
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal.
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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 contraceptive methods.
The use of hormonal contraception is prohibited in the protocol by female participants
because of a possible drug-drug interaction which could increase the concentration of 
hormones in the body and expose these female participants to additional risk.
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 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.
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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
Eastern Cooperative Oncology Group (ECOG) Performance Status
Grade
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 housework, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982;Dec;5(6):649-55. PMID: 7165009.
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APPENDIX 6
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 
< 10mm 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.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
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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 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
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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 (< 10mm 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 
disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
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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.
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 
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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: Patients With Target (± Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations: 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: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Abbreviations: 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
Abbreviations: 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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APPENDIX 7
TITE-BOIN DECISION TABLE
To assign a dose to the next cohort of patients, count the number of treated patients (# Patients), 
the number of patients who experienced dose-limiting toxicity (# DLTs observed), and the number 
of pending patients (“# Pending patients”) and their standardized total follow-up time (STFT) at 
the current dose, and then make the dose escalation/de-escalation decision according to the rule 
displayed in Table 1.
Please also note the following when using Table 1:
1) “Yes & Eliminate” means de-escalating to the next lower dose and eliminating the current 
and higher doses from the trial to prevent treating any future patients at these doses because 
they are overly toxic. When the lowest dose is eliminated, stop the trial for safety. In this 
case, no dose should be selected as the MTD.
2) If the current dose is the lowest dose and the decision table indicates dose de-escalation but 
no elimination, treat the new patients at the lowest dose.
3) If the current dose is the highest dose and the rule indicates dose escalation, treat the new 
patients at the highest dose.
4) For patient safety, if at the current dose, more than 50% of the patients’ DLT outcomes are 
pending, suspend the accrual to wait for more data to become available. This rule corresponds 
to “Suspend” in Table 1.
5) Dose escalation will stop if the maximum number of treated patients at the current dose level 
has been reached.
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APPENDIX 8
MEDICATIONS ASSOCIATED WITH QT PROLONGATION
The list below is not meant to be all inclusive. Please consult individual drug labels for further 
information.
Table 1:
Medications Associated with QT Prolongation
Generic Name
Brand Names (Partial List)
Drug Class
Therapeutic Use
Sevoflurane
Ultane, Sojourn
Anesthetic, general
Anesthesia
Propofol
Diprivan, Propoven
Anesthetic, general
Anesthesia
Bepridil
Vascor
Antianginal
Angina Pectoris (heart 
pain)
Ibutilide
Corvert
Antiarrhythmic
Arrhythmia
Dronedarone
Multaq
Antiarrhythmic
Arrhythmia
Sotalol
Betapace, Sotalex, Sotacor, 
Sotalol-AF
Antiarrhythmic
Arrhythmia
Quinidine
Quinaglute, Duraquin, Quinact, 
Quinidex, Cin-Quin, Quinora
Antiarrhythmic
Arrhythmia
Procainamide
Pronestyl, Procan
Antiarrhythmic
Arrhythmia
Flecainide
Tambocor, Almarytm, Apocard, 
Ecrinal, Flécaine
Antiarrhythmic
Arrhythmia
Disopyramide
Norpace
Antiarrhythmic
Arrhythmia
Dofetilide
Tikosyn
Antiarrhythmic
Arrhythmia
Amiodarone
Cordarone, Pacerone, Nexterone
Antiarrhythmic
Arrhythmia
Hydroquinidine 
(Dihydroquinidine)
(Only on Non US Market)
Serecor
Antiarrhythmic
Arrhythmia
Nifekalant
(Only on Non US Market)
Shinbit
Antiarrhythmic
Arrhythmia
Levofloxacin
Levaquin, Tavanic
Antibiotic
Bacterial infection
Moxifloxacin
Avelox, Avalox, Avelon
Antibiotic
Bacterial infection
Clarithromycin
Biaxin, Prevpac
Antibiotic
Bacterial infection
Roxithromycin
(Only on Non US Market)
Rulide, Xthrocin, Roxl-150, 
Roxo, Surlid, Rulide, Biaxsig, 
Roxar, Roximycinv, Roxomycin, 
Rulid, Tirabicin, Coroxin
Antibiotic
Bacterial infection
Azithromycin
Zithromax, Zmax
Antibiotic
Bacterial infection
Ciprofloxacin
Cipro, Cipro-XR, Neofloxin
Antibiotic
Bacterial infection
Erythromycin
E.E.S., Robimycin, EMycin, 
Erymax, Ery-Tab, Eryc Ranbaxy, 
Erypar, Eryped, Erythrocin 
Stearate Filmtab, Erythrocot, E-
Base, Erythroped, Ilosone, MY-E, 
Pediamycin, Abboticin, 
Abboticin-ES, Erycin, PCE 
Antibiotic
Bacterial infection, 
increase GI motility
Protocol Amendment No.: 01
Date: 07-Jul-2023
144
2.0
Approved
930204199
2.0
v
Approved
1.0
v

Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
Table 1:
Medications Associated with QT Prolongation
Generic Name
Brand Names (Partial List)
Drug Class
Therapeutic Use
Dispertab, Stiemycine, Acnasol, 
Tiloryth
Arsenic trioxide
Trisenox
Anti-cancer
Cancer (leukemia)
Vandetanib
Caprelsa
Anti-cancer
Cancer (thyroid)
Oxaliplatin
Eloxatin
Anti-cancer
Cancer
Aclarubicin
(Only on Non US Market)
Aclacin, Aclacinomycine, 
Aclacinon, Aclaplastin, Jaclacin
Anti-cancer
Cancer
Escitalopram
Cipralex, Lexapro, Nexito, 
Anxiset-E, Exodus, Esto, 
Seroplex, Elicea, Lexamil, 
Lexam, Entact, Losita, Reposil, 
Animaxen, Esitalo, Lexamil
Antidepressant, 
SSRI
Depression (major), 
anxiety disorders
Citalopram
Celexa, Cipramil
Antidepressant, 
SSRI
Depression
Domperidone
(Only on Non US Market)
Motilium, Motillium, Motinorm 
Costi, Nomit
Antiemetic
Nausea, vomiting
Ondansetron
Zofran, Anset, Ondemet, Zuplenz, 
Emetron, Ondavell, Emeset, 
Ondisolv, Setronax
Antiemetic
Nausea, vomiting
Fluconazole
Diflucan, Trican
Antifungal
Fungal infection
Pentamidine
Pentam
Antifungal
Fungal infection 
(Pneumocystis
pneumonia)
Chloroquine
Aralen
Antimalarial
Malaria
Halofantrine
(Only on Non US Market)
Halfan
Antimalarial
Malaria
Hydroxychloroquine
Plaquenil, Quineprox
Antimalarial, Anti-
inflammatory
Malaria, SLE, 
rheumatoid arthritis
Meglumine antimoniate
(Only on Non US Market)
Glucantime
Antiparasitic
Leishmaniasis
Haloperidol
Haldol, Aloperidin, Bioperidolo, 
Brotopon, Dozic, Duraperidol, 
Einalon S, Eukystol, Halosten, 
Keselan, Linton, Peluces, 
Serenace, Serenase, Sigaperidol
Antipsychotic
Schizophrenia, agitation
Thioridazine
Mellaril, Novoridazine, Thioril
Antipsychotic
Schizophrenia
Pimozide
Orap
Antipsychotic
Tourette's Disorder
Levomepromazine 
(Methotrimeprazine)
(Only on Non US Market)
Nosinan, Nozinan, Levoprome
Antipsychotic
Schizophrenia
Levosulpiride
(Only on Non US Market)
Lesuride, Levazeo, Enliva
Antipsychotic
Schizophrenia
Protocol Amendment No.: 01
Date: 07-Jul-2023
145
2.0
Approved
930204199
2.0
v
Approved
1.0
v

Clinical Protocol
CA1260015
BMS-986466 (BBP-398)
SHP2 inhibitor
Table 1:
Medications Associated with QT Prolongation
Generic Name
Brand Names (Partial List)
Drug Class
Therapeutic Use
Chlorprothixene
(Only on Non US Market)
Truxal
Antipsychotic
Schizophrenia
Droperidol
Inapsine, Droleptan, Dridol, 
Xomolix
Antipsychotic / 
Antiemetic
Anesthesia (adjunct), 
nausea
Chlorpromazine
Thorazine, Largactil, Megaphen
Antipsychotic / 
Antiemetic
Nausea, Schizophrenia, 
many others
Sertindole
(Only on Non US Market)
Serdolect, Serlect
Antipsychotic, 
atypical
Schizophrenia, anxiety
Sulpiride
(Only on Non US Market)
Dogmatil, Dolmatil, Eglonyl, 
Espiride, Modal, Sulpor
Antipsychotic, 
atypical
Schizophrenia
Sultopride
(Only on Non US Market)
Barnetil, Barnotil, Topral
Antipsychotic, 
atypical
Schizophrenia
Donepezil
Aricept
Cholinesterase 
inhibitor
Dementia (Alzheimer's 
Disease)
Cocaine
Cocaine
Local anesthetic
Anesthesia (topical)
Terodiline
(Only on Non US Market)
Micturin, Mictrol
Muscle relaxant
Bladder spasm
Methadone
Dolophine, Symoron, Amidone, 
Methadose, Physeptone, 
Heptadon
Opioid agonist
Narcotic dependence, 
pain
Anagrelide
Agrylin, Xagrid
Phosphodiesterase 3 
inhibitor
Thrombocythemia
Cilostazol
Pletal
Phosphodiesterase 3 
inhibitor
Intermittent 
claudication
Ibogaine
(Only on Non US Market)
Psychedelic
Narcotic addiction, 
unproven
Cesium Chloride
Energy Catalyst
toxin
Alternative therapy 
cancer
Terlipressin
(Only on Non US Market)
Teripress, Glypressin, Terlipin, 
Remestyp, Tresil, Teriss
Vasoconstrictor
Septic shock
Papaverine HCl (Intra-
coronary)
Vasodilator, 
Coronary
Diagnostic adjunct
Source: CredibleMeds. https://crediblemeds.org, accessed 04-Oct-2021.
Marketed drugs only.
Known QTc risk only.
Protocol Amendment No.: 01
Date: 07-Jul-2023
146
2.0
Approved
930204199
2.0
v
Approved
1.0
v