Phase 1/2 Study of Avutometinib (VS-6766) + Sotorasib With or Without Defactinib in KRAS G12C NSCLC Patients (RAMP203)

A Phase 1/2 Study of Avutometinib (VS-6766) in Combination With Sotorasib With or Without Defactinib in Patients With KRAS G12C Mutant Non-Small Cell Lung Cancer (NSCLC)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Non Small Cell Lung Cancer; KRAS Activating Mutation
• Intervention / Treatment: Drug: avutometinib and sotorasib; Drug: avutometinib and sotorasib and defactinib

Detailed Description

This is a multicenter, non-randomized, open-label Phase 1/2 study designed to evaluate safety and tolerability and efficacy of avutometinib (VS-6766) in combination with sotorasib with or without defactinib in patients with KRAS G12C mutant NSCLC.

• Study Type: Interventional
• Enrollment (Estimated): 153
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Ghent, Belgium, 9000
    • University Hospital Gent
  • Liège, Belgium, 4000
    • CHU de Liège
• France
  • Lille, France, 59037
    • CHRU of Lille
  • Paris, France, 75014
    • Hopital Cochin
  • Suresnes, France, 92150
    • Hopital Foch
• Netherlands
  • Leiden, Netherlands, 2333 ZA
    • Leids Universitair Medisch Centrum
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus MC
• Spain
  • A Coruña, Spain, 15006
    • Hospital Teresa Herrera (C.H.U.A.C)
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon
  • Málaga, Spain, 29010
    • Hospital Universitario Virgen de la Victoria
  • Seville, Spain, 41009
    • Hospital Universitario Virgen de la Macarena
• United Kingdom
  • Leicester, United Kingdom, LE2 7LX
    • University of Leicester
  • London, United Kingdom, SW3 6JJ
    • Royal Marsden Hospital
  • Sutton, United Kingdom, SM2 5PT
    • Royal Marsden Hospital
• United States
  • Colorado
    • Boulder, Colorado, United States, 80303
      • Rocky Mountain Cancer Center, LLP
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • Georgetown University Medical Center
    • Washington D.C., District of Columbia, United States, 20010
      • MedStar Washington Hospital Center, MedStar Georgetown Cancer Institute,
  • Illinois
    • Arlington Heights, Illinois, United States, 60005
      • Illinois Cancer Specialists
  • Maryland
    • Rockville, Maryland, United States, 20850
      • Maryland Oncology & Hematology, P.A.
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Minnesota
    • Woodbury, Minnesota, United States, 55125
      • Minnesota Oncology Hematology, P.A
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
    • Columbus, Ohio, United States, 43210
      • Ohio State University Brain and Spine Hospital
  • Pennsylvania
    • Broomall, Pennsylvania, United States, 19008
      • Consultants in Medical Oncology & Hematology
    • Horsham, Pennsylvania, United States, 19044
      • Alliance Cancer Specialists,
  • Texas
    • Austin, Texas, United States, 78731
      • Texas Oncology
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Fort Worth, Texas, United States, 76104
      • Texas Oncology - Fort Worth Cancer Center
    • Longview, Texas, United States, 75601
      • Texas Oncology
  • Virginia
    • Blacksburg, Virginia, United States, 24060
      • Oncology and Hematology Associates of Southwest Virginia, Inc., DBA Blue Ridge Cancer Care
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists, PC
  • Washington
    • Vancouver, Washington, United States, 98684
      • Northwest Cancer Specialists

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 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

Exclusion Criteria:

• 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

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

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: avutometinib (VS-6766)+sotorasib; 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; The RP2D of avutometinib + sotorasib determined in Part A will be used in Part B dose expansion; Other Names: AMG 510; VS-6766; LUMAKRAS™
Experimental: avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor naïve; To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients	Drug: avutometinib and sotorasib; The RP2D of avutometinib + sotorasib determined in Part A will be used in Part B dose expansion; Other Names: AMG 510; VS-6766; LUMAKRAS™
Experimental: avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor exposed; To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients	Drug: avutometinib and sotorasib; The RP2D of avutometinib + sotorasib determined in Part A will be used in Part B dose expansion; Other Names: AMG 510; VS-6766; LUMAKRAS™
Experimental: avutometinib (VS-6766)+sotorasib+defactinib; 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; The RP2D of avutometinib + sotorasib + defactinib determined in Part A will be used in Part B dose expansion; Other Names: AMG 510; VS-6063; VS-6766; LUMAKRAS™
Experimental: avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor naive; To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients	Drug: avutometinib and sotorasib and defactinib; The RP2D of avutometinib + sotorasib + defactinib determined in Part A will be used in Part B dose expansion; Other Names: AMG 510; VS-6063; VS-6766; LUMAKRAS™
Experimental: avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor exposed; To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients	Drug: avutometinib and sotorasib and defactinib; The RP2D of avutometinib + sotorasib + defactinib determined in Part A will be used in Part B dose expansion; Other Names: AMG 510; VS-6063; VS-6766; LUMAKRAS™

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 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
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
Frequency and severity adverse events (AEs) and Serious Adverse Events (SAEs)	Count of AE and SAEs by grade, based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grading scale	24 months
Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites - Tmax	time of Maximum concentration (Tmax)	10 weeks
Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites -AUC	Area under plasma Concentration (AUC) 0 to t	10 weeks
Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites half-life	concentration Half-life (T1/2)	10 weeks

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): April 12, 2022
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: September 29, 2021
• First Submitted That Met QC Criteria: September 29, 2021
• First Posted (Actual): October 12, 2021

Study Record Updates

• Last Update Posted (Estimated): January 12, 2026
• Last Update Submitted That Met QC Criteria: January 8, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: NSCLC; KRAS G12C
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; sotorasib; defactinib
• Other Study ID Numbers: VS-6766-203

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No