A Study of BMS-986466 With Adagrasib With or Without Cetuximab in Participants With Kirsten Rat Sarcoma Virus Glycine 12 to Cysteine (KRAS G12C)-Mutant Solid Tumors

Phase 1

Terminated

Conditions: Advanced Solid Tumors

Interventions: Drug: BMS-986466
Drug: Adagrasib
Drug: Cetuximab

Registration Number: NCT06024174

Lead Sponsor: Bristol-Myers Squibb

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 (NSCLC), pancreatic duct adenocarcinoma (PDAC), biliary tract cancer (BTC), or colorectal cancer (CRC).

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 5

Inclusion Criteria

Key Inclusion Criteria:

Part 1:

Individuals with a confirmed diagnosis of advanced KRAS G12C mutant NSCLC, CRC, PDAC and BTC that has spread to other parts of the body and cannot be removed surgically, may or may not have received previous treatment with KRAS G12C inhibitors.
For NSCLC and CRC: Individuals must have a documented KRAS G12C mutation status from NYS 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 in blood sample collected at the time of screening.
For PDAC and BTC: Participants must have a documented KRAS G12Cmutation from NYS or FDA-approved/cleared, or CE-marked test and blood samples will be collected only for retrospective testing.
Are relapsed or refractory to available standard of care treatments.

Part 2:

Individuals with a confirmed diagnosis of advanced KRAS G12C-mutant NSCLC (Part 2A) or CRC (Part 2B) that has spread to other parts of the body and cannot be removed surgically and have not received previous treatment with KRAS inhibitors.
Individuals must have a documented KRAS G12C mutation from FDA or NYS 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 blood sample and /or tumor samples collected at the time of screening or from archival biopsies (less than 1 year old).
Have failed or disease recurrence or are not able to tolerate after at least 1 pervious line of therapy.

Key

Exclusion Criteria

Have tumors with known BARF V600X, PTPN11 or KRASQ61X mutations.
Have or any significant heart disease or condition.
Receiving any medications that are substrate of CYP3A4 or inducers and/ or inhibitors

Note: Other protocol-defined inclusion/exclusion criteria apply.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part 1: DDI Cohort	BMS-986466	-
Part 1: Dose Escalation	BMS-986466	-
Part 2: Dose Expansion	BMS-986466	-
Part 1: Dose Escalation	Cetuximab	-
Part 2: Dose Expansion	Cetuximab	-
Part 1: DDI Cohort	Adagrasib	-
Part 1: Dose Escalation	Adagrasib	-
Part 2: Dose Expansion	Adagrasib	-

Primary Outcome Measures

Name	Time	Method
Part 1: Number of Participants With Dose Limiting Toxicity (DLTs)	Cycle 1 (Each cycle consist of 28 days)	A DLT was defined as: * Death not related to disease progression * Grade (Gr) 4 (Life-threatening) neurotoxicity * Gr 3 (Severe) neurotoxicity of greater than 7 days * Gr 3 neurotoxicity does not revert to baseline within 28 days of the start date of the Grade 3 event * Seizures of grade that do not resolve within 7 days * Gr 4 cytokine release syndrome (CRS) that does not resolve to less than or equal to Gr 3 within 3 days * Gr 3 CRS that does not resolve to less than or equal to Grade 2 within 7 days * Any increase in aspartate aminotransferase (AST) or ALT \\\> 3 Ã- ULN and concurrent increase in total bilirubin \\\> 2 Ã- ULN that is unrelated to CRS and has no other probable reason to explain the combination of increases * Any other Gr 3 or 4 event deemed unexpected by the Investigator and considered a DLT upon evaluation by the safety review committee
Part 1: Number of Participants With Adverse Events (AEs)	From first dose until 100 days after last dose (Up to approximately 5 months)	An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment.
Part 1: Number of Participants With Serious Adverse Events (SAEs)	From first dose until 30 days after last dose (Up to approximately 3 months)	A SAE is defined as any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability or permanent damage, is a congenital anomaly/birth defect, is an important medical event.
Part 1: Number of Participants With AEs Leading to Discontinuation	From first dose until 30 days after last dose (Up to approximately 3 months)	An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatmen
Part 1: Number of Participants Who Died	From first dose until 100 days after last dose (Up to approximately 5 months)	Death due to any cause was assessed.
Part 2 Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1	From randomization untill disease progression or death, whichever occurs first (up to approximately 5 months)	Objective Response Rate (ORR) is defined as the percentage of participants with a confirmed Best overall response of Complete Response (CR) or Partial Response (PR) by RECIST v1.1. 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.

Secondary Outcome Measures

Name	Time	Method
Part 1: Maximum Observed Plasma Concentration (Cmax)	Cycle 1 Day 1 (Each cycle consist of 28 days)	Blood samples were collected to assess adequate PK profiles. Participants were not enrolled in Part 1a, 1b.
Part 1: Time to Maximum Concentration (Tmax)	Cycle 1 Day 1 (Each cycle consist of 28 days)	Blood samples were collected to assess adequate PK profiles. Participants were not enrolled in Part 1a, 1b.
Part 1: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-T])	Cycle 1 Day 1 (Each cycle consist of 28 days)	Blood samples were collected to assess adequate PK profiles. Participants were not enrolled in Part 1a, 1b.
Part 2-Progression-free Survival (PFS) Assessed by BICR as Per RECIST v1.1	From randomization untill disease progression or death, whichever occurs first (up to approximately 5 months)	Progression-Free Survival then (PFS) is defined as the time between the date of randomization and the date of first documented disease progression, based on Investigator assessments (per RECIST v1.1), or death due to any cause, whichever occurs first Calculated using Kaplan-Meier estimates. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum during the 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.
Part 2- Disease Control Rate (DCR) Assessed by BICR as Per RECIST v1.1	From randomization untill disease progression or death, whichever occurs first (up to approximately 5 months)	Disease Control Rate (DCR) (as per Recists v1.1) is defined as the number of randomized participants who achieve a BOR of confirmed CR, confirmed PR, or stable disease (SD), based on BICR assessments divided by the number of all randomized participants.
Part 2- Duration of Response (DOR) Assessed by BICR as Per RECIST v1.1	From randomization untill disease progression or death, whichever occurs first (up to approximately 5 months)	Duration of objective response (DoR) is defined as the time between the date of first confirmed response (CR or PR) to the date of the first documented tumor progression (per RECIST 1.1) per BICR assessment, or death due to any cause, whichever occurs first. 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 during the 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.
Part 2- Time to Response (TTR)	From randomization untill disease progression or death, whichever occurs first (up to approximately 5 months)	Time to response (TTR) is defined as the time, in months, from randomization to the first objective documentation of PR or better assessed per BICR. 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 during the 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. 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.
Part 2- Number of Participants With Adverse Events (AEs)	From first dose until 100 days after last dose (Up to approximately 5 months)	An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment.
Part 2- Number of Participants With Serious Adverse Events (SAEs)	From first dose until 100 days after last dose (Up to approximately 5 months)	A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability or permanent damage, is a congenital anomaly/birth defect, is an important medical event.
Part 2- Number of Participants With AEs Leading to Discontinuation	From first dose until 100 days after last dose (Up to approximately 5 months)	An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment.
Part 2- Number of Participants Who Died	From first dose until 100 days after last dose (Up to approximately 5 months)	Death due to any cause was assessed.
Part 1a and 1b - Changes From Baseline in Pharmacodynamic Biomarker	Baseline and Cycle 1 Day 1 (Each cycle consist of 28 days)	Blood samples were collected for assessing pharmacodynamic parameters.

Trial Locations

Locations (9): Local Institution - 0047
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Los Angeles, California, United States
Local Institution - 0040
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Athens, Georgia, United States
Local Institution - 0025
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Hackensack, New Jersey, United States
Local Institution - 0008
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Morristown, New Jersey, United States
Local Institution - 0053
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Westmead, New South Wales, Australia
Local Institution - 0083
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Helsinki, Finland
Local Institution - 0020
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Lille, France
Local Institution - 0082
🇮🇱
Petah Tikva, HaMerkaz, Israel
Local Institution - 0081
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Tel Aviv, Tell Abīb, Israel
Local Institution - 0047
🇺🇸Los Angeles, California, United States