Study of Avutometinib (VS-6766) + Adagrasib in KRAS G12C NSCLC Patients (RAMP204)

A Phase 1/2 Study of Avutometinib (VS-6766) in Combination With Adagrasib in Patients With KRAS G12C Mutant Non-Small Cell Lung Cancer (NSCLC) (RAMP 204)

This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with adagrasib in patients with G12C Non-Small Cell Lung Cancer (NSCLC) who have been exposed to prior G12C inhibitor and experienced progressive disease.

Study Overview

• Status: Active, not recruiting
• Conditions: Non Small Cell Lung Cancer; Metastatic Cancer; Advanced Cancer; Malignant Neoplasm of Lung; Malignant Neoplastic Disease; KRAS Activating Mutation
• Intervention / Treatment: Drug: avutometinib (VS-6766) and adagrasib

Detailed Description

This is a multicenter, non-randomized, open-label Phase 1/2 study designed to evaluate safety, tolerability and efficacy of avutometinib (VS-6766) in combination with adagrasib in patients with KRAS G12C mutant NSCLC who have been exposed to prior G12C inhibitor and experienced progressive disease.

• Study Type: Interventional
• Enrollment (Estimated): 85
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94158
      • UCSF Thoracic Oncology
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital Anschutz Cancer Pavllion
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 275514
      • University of North Carolina at Chapel Hill
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists, NEXT Oncology
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female subjects ≥ 18 years of age
• Histologic or cytologic evidence of NSCLC
• Known KRAS G12C mutation
• The subject must have received prior therapy with a KRAS G12C inhibitor and experienced progression
• Must have received appropriate treatment with at least one prior systemic regimen, but no more than 3 prior regimens, for Stage 3B-C or 4 NSCLC
• Measurable disease according to RECIST 1.1
• An Eastern Cooperative Group (ECOG) performance status ≤ 1
• Adequate organ function
• Adequate recovery from toxicities related to prior treatments
• Agreement to use highly effective method of contraceptive

Exclusion Criteria:

• Prior chemotherapy, targeted therapies, radiotherapy, immunotherapy or treatment with an investigational agent within 14 days of receipt of study drug (within 6 weeks for nitrosoureas, mitomycin C and chest radiation; within 6 months prior to Cycle 1 Day 1 for chest radiation > 30Gy)
• History of prior malignancy, with the exception of curatively treated malignancies
• Major surgery within 4 weeks (excluding placement of vascular access)
• Exposure to strong CYP3A4 inhibitors or inducers within 14 days prior to the first dose and during the course of therapy
• Exposure to strong inhibitors of breast cancer resistance protein (BCRP) within 14 days prior to the first dose and during the course of therapy
• Symptomatic brain metastases requiring steroids or other local interventions within the 2 weeks prior to initiation of therapy
• Known SARS-Cov2 infection ≤28 days prior to first dose of study therapy
• Known hepatitis B, hepatitis C, or human immunodeficiency virus infection that is active
• Active skin disorder that has required systemic therapy within the past 1 year
• History of rhabdomyolysis or interstitial lung disease
• Concurrent ocular disorders
• Concurrent heart disease or severe obstructive pulmonary disease
• Subjects with the inability to swallow oral medications

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: avutometinib(VS-6766)+adagrasib; To determine the recommended phase 2 dose (RP2D) for VS-6766 in combination with adagrasib in G12C inhibitor exposed patients	Drug: avutometinib (VS-6766) and adagrasib; The RP2D of VS-6766 + adagrasib determined in Part A will be used in Part B dose expansion; Other Names: KRAS G12C Inhibitor, adagrasib, KRAZATI®
Experimental: avutometinib (VS-6766)+adagrasib RP2D; To determine the efficacy of the RP2D identified from Part A in G12C inhibitor exposed patients	Drug: avutometinib (VS-6766) and adagrasib; The RP2D of VS-6766 + adagrasib determined in Part A will be used in Part B dose expansion; Other Names: KRAS G12C Inhibitor, adagrasib, KRAZATI®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the efficacy of the optimal regimen identified from Part A	Confirmed overall response rate per RECIST 1.1	From start of treatment to confirmation of response; 16 weeks
Part A: To determine RP2D for avutometinib(VS-6766) in combination with adagrasib	Assessment of Dose-limiting toxicities (DLTs)	From start of treatment to confirmation of RP2D; 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	From time of first dose of study intervention to death	Up to 5 years
To characterize the safety and toxicity profile:	Incidence of Adverse events (AEs) and Serious Adverse Events (SAEs) assessed by the toxicity grading of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v 5.0); Severity of Adverse events (AEs) and Serious Adverse Events (SAEs) by toxicity grade assessed by the toxicity grading of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v 5.0); Duration of Adverse events (AEs) and Serious Adverse Events (SAEs); Incidence of clinically significant changes in lab parameters; Incidence of abnormal vital signs (including systolic and diastolic blood pressure in mmHg)	24 Months
ECG QT Interval	Corrected ECG QT interval by Fredericia (QTcF)	24 months
Duration of Response (DOR)	Time of first response to PD as assessed per RECIST 1.1	Time from the first documentation of response to first documentation of progressive disease or death due to any cause, greater than or equal to 6 months
Disease Control Rate (DCR)	CR and PR stable disease as assessed per RECIST 1.1	Greater than or equal to 8 weeks
Progression Free Survival (PFS)	From the time of first dose of study intervention to PD or death from any cause	24 months
Clinical Benefit Rate	defined as Complete Response+Partial Response +Stable Disease	≥ 6 months
Plasma Pharmacokinetics (PK) of avutometinib(VS 6766), adagrasib, and relevant metabolites - Tmax	time of Maximum concentration (Tmax)	10 weeks
Plasma Pharmacokinetics (PK) of avutometinib(VS 6766), adagrasib, and relevant metabolites - AUC	Area under plasma Concentration (AUC) 0 to t	10 weeks
Plasma Pharmacokinetics (PK) of avutometinib(VS 6766), adagrasib, and relevant metabolites - Half-life	concentration Half-life (T1/2)	10 weeks

Collaborators and Investigators

• Sponsor: Verastem, Inc.
• Collaborators: Mirati Therapeutics Inc.
• Investigators: Study Director: MD Verastem, Verastem, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2022
• Primary Completion (Estimated): December 24, 2025
• Study Completion (Estimated): January 1, 2026

Study Registration Dates

• First Submitted: May 2, 2022
• First Submitted That Met QC Criteria: May 10, 2022
• First Posted (Actual): May 17, 2022

Study Record Updates

• Last Update Posted (Actual): May 18, 2025
• Last Update Submitted That Met QC Criteria: May 13, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: NSCLC; Non Small Cell Lung Cancer; KRAS G12C; Metastatic Cancer; Adagrasib; Avutometinib (VS-6766)
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplastic Processes; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neoplasms; Lung Neoplasms; Neoplasm Metastasis; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents; Adagrasib
• Other Study ID Numbers: VS-6766-204

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No