Phase 1/2 Study of Avutometinib (VS-6766) + Sotorasib With or Without Defactinib in KRAS G12C NSCLC Patients

NCT05074810 | Active Not Recruiting Phase 1 FDA Drug

• 1 other identifier: VS-6766-203
• Study Type: interventional
• Target: 153
• Locations: 6 countries
• Sites: 35

Brief Summary

This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with sotorasib with or without defactinib in patients with KRAS G12C Non-Small Cell Lung Cancer (NSCLC) in patients who have been exposed to prior G12C inhibitor and those who have not been exposed to prior G12C inhibitor.

Conditions

Non Small Cell Lung Cancer; KRAS Activating Mutation

Keywords

NSCLC; KRAS G12C

Outcome Measures

Primary Outcomes (2)

• Part A: To determine RP2D for avutometinib in combination with sotorasib and the Alt-RP2D for avutometinib in combination with sotorasib and defactinib

  Assessment of Dose-limiting toxicities (DLTs)

  From start of treatment to confirmation of RP2D; 28 days

• Part B: To determine the efficacy of the RP2D and/or Alt-RP2D identified from Part A

  Confirmed overall response rate per RECIST 1.1

  From start of treatment to confirmation of response; 16 weeks

Secondary Outcomes (8)

• Frequency and severity adverse events (AEs) and Serious Adverse Events (SAEs)

  24 months

• Duration of Response (DOR)

  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)

  Greater than or equal to 8 weeks

• Progression Free Survival (PFS)

  24 months

• Overall Survival (OS)

  Up to 5 years

Study Arms (6)

avutometinib (VS-6766)+sotorasib

EXPERIMENTAL

To determine the recommended phase 2 dose (RP2D) for avutometinib (VS 6766) in combination with sotorasib in KRAS G12C inhibitor naïve and exposed patients

Drug: avutometinib and sotorasib

avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor naïve

EXPERIMENTAL

To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients

Drug: avutometinib and sotorasib

avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor exposed

EXPERIMENTAL

To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients

Drug: avutometinib and sotorasib

avutometinib (VS-6766)+sotorasib+defactinib

EXPERIMENTAL

To determine the recommended phase 2 dose (RP2D) for avutometinib (VS-6766) in combination with sotorasib and defactinib in KRAS G12C inhibitor exposed patients

Drug: avutometinib and sotorasib and defactinib

avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor naive

EXPERIMENTAL

To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients

Drug: avutometinib and sotorasib and defactinib

avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor exposed

EXPERIMENTAL

To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients

Drug: avutometinib and sotorasib and defactinib

Interventions

avutometinib and sotorasib DRUG

The RP2D of avutometinib + sotorasib determined in Part A will be used in Part B dose expansion

Also known as: AMG 510, LUMAKRAS™, VS-6766

avutometinib (VS-6766)+sotorasib; avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor exposed; avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor naïve

avutometinib and sotorasib and defactinib DRUG

The RP2D of avutometinib + sotorasib + defactinib determined in Part A will be used in Part B dose expansion

Also known as: AMG 510, LUMAKRAS™, VS-6766, VS-6063

avutometinib (VS-6766)+sotorasib+defactinib; avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor exposed; avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor naive

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female patients ≥ 18 years of age
• Histologic or cytologic evidence of NSCLC
• Known KRAS G12C mutation
• Either exposed or not exposed to a KRAS inhibitor to be included in Part A (avutometinib + sotorasib + defactinib) and not exposed to KRAS inhibitor to be included in Part B (avutometinib + sotorasib + defactinib), Cohort 1
• Received at least 1 dose of a G12C inhibitor to be included in Part B, Cohort 2 (avutometinib + sotorasib + defactinib)
• Must have received appropriate treatment with at least one prior systemic regimen, but no more than 2 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

You may not qualify if:

• Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy
• History of prior malignancy, with the exception of curatively treated malignancies
• Major surgery within 4 weeks, minor surgery within 2 weeks (excluding placement of vascular access)
• History of treatment with a direct and specific inhibitor of MEK
• Exposure to strong CYP3A4 inhibitors or inducers within 14 days prior to the first dose and during the course of therapy
• Symptomatic brain metastases requiring steroids or other local interventions.
• 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 year
• History of rhabdomyolysis
• Concurrent ocular disorders
• Concurrent heart disease or severe obstructive pulmonary disease
• Inability to swallow oral medications
• Female patients that are pregnant or breastfeeding
• Previously treated with sotorasib and were dose reduced due to toxicity

Sponsors & Collaborators

• Verastem, Inc.: lead
• Amgen: collaborator

Study Sites (35)

Rocky Mountain Cancer Center, LLP

Boulder, Colorado, 80303, United States

Location

Georgetown University Medical Center

Washington D.C., District of Columbia, 20007, United States

Location

MedStar Washington Hospital Center, MedStar Georgetown Cancer Institute,

Washington D.C., District of Columbia, 20010, United States

Location

Illinois Cancer Specialists

Arlington Heights, Illinois, 60005, United States

Location

Maryland Oncology & Hematology, P.A.

Rockville, Maryland, 20850, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Henry Ford Health System

Detroit, Michigan, 48202, United States

Location

Minnesota Oncology Hematology, P.A

Woodbury, Minnesota, 55125, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio, 44195, United States

Location

Ohio State University Brain and Spine Hospital

Columbus, Ohio, 43210, United States

Location

Consultants in Medical Oncology & Hematology

Broomall, Pennsylvania, 19008, United States

Location

Alliance Cancer Specialists,

Horsham, Pennsylvania, 19044, United States

Location

Texas Oncology

Austin, Texas, 78731, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Texas Oncology - Fort Worth Cancer Center

Fort Worth, Texas, 76104, United States

Location

Texas Oncology

Longview, Texas, 75601, United States

Location

Oncology and Hematology Associates of Southwest Virginia, Inc., DBA Blue Ridge Cancer Care

Blacksburg, Virginia, 24060, United States

Location

Virginia Cancer Specialists, PC

Fairfax, Virginia, 22031, United States

Location

Northwest Cancer Specialists

Vancouver, Washington, 98684, United States

Location

University Hospital Gent

Ghent, 9000, Belgium

Location

CHU de Liège

Liège, 4000, Belgium

Location

CHRU of Lille

Lille, 59037, France

Location

Hôpital Cochin

Paris, 75014, France

Location

Hôpital Foch

Suresnes, 92150, France

Location

Leids Universitair Medisch Centrum

Leiden, 2333 ZA, Netherlands

Location

Erasmus MC

Rotterdam, 3015 GD, Netherlands

Location

Hospital Teresa Herrera (C.H.U.A.C)

A Coruña, 15006, Spain

Location

Hospital General Universitario Gregorio Marañón

Madrid, 28007, Spain

Location

Hospital Universitario Fundación Jiménez Díaz

Madrid, 28040, Spain

Location

Hospital Universitario Virgen De La Victoria

Málaga, 29010, Spain

Location

Hospital Universitario Virgen de la Macarena

Seville, 41009, Spain

Location

University of Leicester

Leicester, LE2 7LX, United Kingdom

Location

Royal Marsden Hospital

London, SW3 6JJ, United Kingdom

Location

Royal Marsden Hospital

Sutton, SM2 5PT, United Kingdom

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

sotorasib; defactinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• MD Verastem

  Verastem, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 29, 2021
• First Posted: October 12, 2021
• Study Start: April 12, 2022
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): April 1, 2027
• Last Updated: January 12, 2026

Record last verified: 2026-01

Locations

FR (3); ES (5); GB (3); NL (2); BE (2); US (20)