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

February 20, 2024 updated by: Verastem, Inc.

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

Recruiting

Conditions

Intervention / Treatment

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

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Belgium
      • Gent, Belgium, 9000
        • Recruiting
        • University Hospital Gent
        • Principal Investigator:
          • Veerle Surmont
  • Netherlands
      • Leiden, Netherlands, 2333 ZA
        • Not yet recruiting
        • Leids Universitair Medisch Centrum
        • Principal Investigator:
          • Laurie Steinbusch
  • United Kingdom
      • London, United Kingdom, SW3 6JJ
        • Recruiting
        • Royal Marsden Hospital
        • Principal Investigator:
          • Anna Minchom, MD
      • Sutton, United Kingdom, SM2 5PT
        • Recruiting
        • Royal Marsden Hospital
        • Principal Investigator:
          • Anna Minchom, MD
  • United States
    • Colorado
      • Boulder, Colorado, United States, 80303
        • Recruiting
        • Rocky Mountain Cancer Center, LLP
        • Contact:
        • Principal Investigator:
          • David Andorsky, MD
    • District of Columbia
      • Washington, District of Columbia, United States, 20007
        • Recruiting
        • Georgetown University Medical Center
        • Contact:
        • Principal Investigator:
          • Joshua Reuss, MD
    • Illinois
      • Arlington Heights, Illinois, United States, 60005
        • Recruiting
        • Illinois Cancer Specialists
        • Contact:
        • Principal Investigator:
          • Rajat Malhotra, MD
    • Maryland
      • Rockville, Maryland, United States, 20850
        • Recruiting
        • Maryland Oncology & Hematology, P.A.
        • Contact:
        • Principal Investigator:
          • Nicholas Farrell, MD
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Recruiting
        • Dana Farber Cancer Institute
        • Principal Investigator:
          • Mark Awad, MD
        • Contact:
          • Dana Farber Cancer Institute
          • Phone Number: 877-338-7425
    • Michigan
      • Detroit, Michigan, United States, 48202
        • Recruiting
        • Henry Ford Health System
        • Principal Investigator:
          • Shirish Gadgeel, MD
        • Contact:
    • Minnesota
      • Woodbury, Minnesota, United States, 55125
        • Recruiting
        • Minnesota Oncology Hematology, P.A
        • Contact:
        • Principal Investigator:
          • Girum Lemma, MD
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Recruiting
        • Washington University School of Medicine
        • Principal Investigator:
          • Ramaswamy Govindan, MD
        • Contact:
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • Recruiting
        • Cleveland Clinic Taussig Cancer Center
        • Principal Investigator:
          • Alex Adjei, MD
        • Contact:
      • Columbus, Ohio, United States, 43210
        • Recruiting
        • Ohio State University Brain and Spine Hospital
        • Principal Investigator:
          • Asrar AlAhmadi, MD
        • Contact:
    • Pennsylvania
      • Broomall, Pennsylvania, United States, 19008
        • Recruiting
        • Consultants in Medical Oncology & Hematology
        • Contact:
        • Principal Investigator:
          • John Sprandio, MD
    • Texas
      • Austin, Texas, United States, 78731
        • Recruiting
        • Texas Oncology
        • Principal Investigator:
          • Jeffrey Yorio, MD
        • Contact:
      • Longview, Texas, United States, 75601
    • Virginia
      • Blacksburg, Virginia, United States, 24060
        • Recruiting
        • Oncology and Hematology Associates of Southwest Virginia, Inc., DBA Blue Ridge Cancer Care
        • Contact:
        • Principal Investigator:
          • Jerome Goldschmidt, MD
      • Fairfax, Virginia, United States, 22031
        • Recruiting
        • Virginia Cancer Specialists, PC
        • Contact:
        • Principal Investigator:
          • Alexander Spira, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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
  • Have not received a KRAS inhibitor to be included in Part A (avutometinib + sotorasib) and Part B (avutometinib + sotorasib + defactinib), Cohort 1
  • Received at least 1 dose of a G12C inhibitor to be included in Part A (avutometinib + sotorasib + defactinib) and Part B, Cohort 2
  • 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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

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
Time Frame: From start of treatment to confirmation of RP2D; 28 days
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
Time Frame: From start of treatment to confirmation of response; 16 weeks
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)
Time Frame: Up to 5 years
From time of first dose of study intervention to death
Up to 5 years
Duration of Response (DOR)
Time Frame: 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
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)
Time Frame: Greater than or equal to 8 weeks
CR and PR stable disease as assessed per RECIST 1.1
Greater than or equal to 8 weeks
Progression Free Survival (PFS)
Time Frame: 24 months
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)
Time Frame: 24 months
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 Frame: 10 weeks
time of Maximum concentration (Tmax)
10 weeks
Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites -AUC
Time Frame: 10 weeks
Area under plasma Concentration (AUC) 0 to t
10 weeks
Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites half-life
Time Frame: 10 weeks
concentration Half-life (T1/2)
10 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Verastem, Inc.

Collaborators

Amgen

Investigators

  • Study Director: MD Verastem, Verastem, Inc.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 12, 2022

Primary Completion (Estimated)

September 1, 2025

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)

February 22, 2024

Last Update Submitted That Met QC Criteria

February 20, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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