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 2TerminatedNCT06024174

Bristol-Myers Squibb5 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Advanced Solid Tumors

Interventions

BMS-986466DRUG

Specified dose on specified days

AdagrasibDRUG

Specified dose on specified days

CetuximabDRUG

Specified dose on specified days

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (9)

Local Institution - 0047

Los Angeles, California, United States

Local Institution - 0040

Athens, Georgia, United States

Local Institution - 0025

Hackensack, New Jersey, United States

Local Institution - 0008

Morristown, New Jersey, United States

Outcomes

Primary Outcomes

Part 1: Number of Participants With Dose Limiting Toxicity (DLTs)

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

Time frame: Cycle 1 (Each cycle consist of 28 days)

Part 1: Number of Participants With Adverse Events (AEs)

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.

Time frame: From first dose until 100 days after last dose (Up to approximately 5 months)

Part 1: Number of Participants With Serious Adverse Events (SAEs)

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.

Time frame: From first dose until 30 days after last dose (Up to approximately 3 months)

Part 1: Number of Participants With AEs Leading to Discontinuation

Data from ClinicalTrials.gov

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Secondary Outcomes

Part 1: Maximum Observed Plasma Concentration (Cmax)

Blood samples were collected to assess adequate PK profiles. Participants were not enrolled in Part 1a, 1b.

Time frame: Cycle 1 Day 1 (Each cycle consist of 28 days)

Part 1: Time to Maximum Concentration (Tmax)

Blood samples were collected to assess adequate PK profiles. Participants were not enrolled in Part 1a, 1b.

Time frame: Cycle 1 Day 1 (Each cycle consist of 28 days)

Part 1: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-T])

Blood samples were collected to assess adequate PK profiles. Participants were not enrolled in Part 1a, 1b.

Time frame: Cycle 1 Day 1 (Each cycle consist of 28 days)

Part 2-Progression-free Survival (PFS) Assessed by BICR as Per RECIST v1.1

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.

Time frame: From randomization untill disease progression or death, whichever occurs first (up to approximately 5 months)

Part 2- Disease Control Rate (DCR) Assessed by BICR as Per RECIST v1.1

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.

Time frame: From randomization untill disease progression or death, whichever occurs first (up to approximately 5 months)

Part 2- Duration of Response (DOR) Assessed by BICR as Per RECIST v1.1

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.

Time frame: From randomization untill disease progression or death, whichever occurs first (up to approximately 5 months)

Part 2- Time to Response (TTR)

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.

Time frame: From randomization untill disease progression or death, whichever occurs first (up to approximately 5 months)

Part 2- Number of Participants With Adverse Events (AEs)

Time frame: From first dose until 100 days after last dose (Up to approximately 5 months)

Part 2- Number of Participants With Serious Adverse Events (SAEs)

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.

Time frame: From first dose until 100 days after last dose (Up to approximately 5 months)

Part 2- Number of Participants With AEs Leading to Discontinuation

Time frame: From first dose until 100 days after last dose (Up to approximately 5 months)

Part 2- Number of Participants Who Died

Death due to any cause was assessed.

Time frame: From first dose until 100 days after last dose (Up to approximately 5 months)

Part 1a and 1b - Changes From Baseline in Pharmacodynamic Biomarker

Blood samples were collected for assessing pharmacodynamic parameters.

Time frame: Baseline and Cycle 1 Day 1 (Each cycle consist of 28 days)