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Non Small Cell Lung CancerPhase 1/2RAMP203NCT05074810

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

A Phase 1/2 study testing avutometinib and sotorasib and avutometinib and sotorasib and defactinib in people with Non Small Cell Lung Cancer and KRAS Activating Mutation, run by Verastem, Inc. at 35 sites in 6 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
avutometinib and sotorasib and avutometinib and sotorasib and defactinib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
153 participants
Where
35 sitesin 6 countries
Study dates
12 Apr 2022to Apr 2027
Phase
Phase 1/2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 11Show fewer
  • 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

Who cannot join

  • 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.
Show all 15Show fewer
  • 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

Trial locations and contacts

35 sites in 6 countries.

35 sites in 6 countries

United States20 sites

  • Illinois Cancer Specialists

    Arlington Heights, Illinois, 60005

  • Texas Oncology

    Austin, Texas, 78731

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

    Blacksburg, Virginia, 24060

  • Dana Farber Cancer Institute

    Boston, Massachusetts, 02215

  • Rocky Mountain Cancer Center, LLP

    Boulder, Colorado, 80303

  • Consultants in Medical Oncology & Hematology

    Broomall, Pennsylvania, 19008

  • Cleveland Clinic Taussig Cancer Center

    Cleveland, Ohio, 44195

  • Ohio State University Brain and Spine Hospital

    Columbus, Ohio, 43210

  • University of Texas Southwestern Medical Center

    Dallas, Texas, 75390

  • Henry Ford Health System

    Detroit, Michigan, 48202

  • Virginia Cancer Specialists, PC

    Fairfax, Virginia, 22031

  • Texas Oncology - Fort Worth Cancer Center

    Fort Worth, Texas, 76104

  • Alliance Cancer Specialists,

    Horsham, Pennsylvania, 19044

  • Texas Oncology

    Longview, Texas, 75601

  • Maryland Oncology & Hematology, P.A.

    Rockville, Maryland, 20850

  • Washington University School of Medicine

    St Louis, Missouri, 63110

  • Northwest Cancer Specialists

    Vancouver, Washington, 98684

  • Georgetown University Medical Center

    Washington D.C., District of Columbia, 20007

  • MedStar Washington Hospital Center, MedStar Georgetown Cancer Institute,

    Washington D.C., District of Columbia, 20010

  • Minnesota Oncology Hematology, P.A

    Woodbury, Minnesota, 55125

Other trials in United States

Spain5 sites

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

    A Coruña, 15006

  • Hospital General Universitario Gregorio Marañón

    Madrid, 28007

  • Hospital Universitario Fundación Jiménez Díaz

    Madrid, 28040

  • Hospital Universitario Virgen De La Victoria

    Málaga, 29010

  • Hospital Universitario Virgen de la Macarena

    Seville, 41009

Other trials in Spain

France3 sites

  • CHRU of Lille

    Lille, 59037

  • Hôpital Cochin

    Paris, 75014

  • Hôpital Foch

    Suresnes, 92150

Other trials in France

United Kingdom3 sites

  • University of Leicester

    Leicester, LE2 7LX

  • Royal Marsden Hospital

    London, SW3 6JJ

  • Royal Marsden Hospital

    Sutton, SM2 5PT

Other trials in United Kingdom

Belgium2 sites

  • University Hospital Gent

    Ghent, 9000

  • CHU de Liège

    Liège, 4000

Other trials in Belgium

Netherlands2 sites

  • Leids Universitair Medisch Centrum

    Leiden, 2333 ZA

  • Erasmus MC

    Rotterdam, 3015 GD

Other trials in Netherlands

About this study

Official title: 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.

Read the 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.

Being tested
avutometinib and sotorasib, avutometinib and sotorasib and defactinib
Keywords
NSCLC, KRAS G12C
Medical subject headings
Carcinoma, Non-Small-Cell Lung

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • avutometinib and sotorasibDrug

    Also called AMG 510, LUMAKRAS™, VS-6766

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

  • avutometinib and sotorasib and defactinibDrug

    Also called AMG 510, LUMAKRAS™, VS-6766, VS-6063

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

Study groups in NCT05074810
Study groupRoleWhat they receive
avutometinib (VS-6766)+sotorasibExperimentalTo determine the recommended phase 2 dose (RP2D) for avutometinib (VS 6766) in combination with sotorasib in KRAS G12C inhibitor naïve and exposed patients
Receives: Drug: avutometinib and sotorasib
avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor naïveExperimentalTo determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients
Receives: Drug: avutometinib and sotorasib
avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor exposedExperimentalTo determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients
Receives: Drug: avutometinib and sotorasib
avutometinib (VS-6766)+sotorasib+defactinibExperimentalTo determine the recommended phase 2 dose (RP2D) for avutometinib (VS-6766) in combination with sotorasib and defactinib in KRAS G12C inhibitor exposed patients
Receives: Drug: avutometinib and sotorasib and defactinib
avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor naiveExperimentalTo determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients
Receives: Drug: avutometinib and sotorasib and defactinib
avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor exposedExperimentalTo determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients
Receives: Drug: avutometinib and sotorasib and defactinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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)

    Measured: From start of treatment to confirmation of RP2D; 28 days

  2. 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

    Measured: From start of treatment to confirmation of response; 16 weeks

Secondary outcomes (8)

  1. 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

    Measured: 24 months

  2. Duration of Response (DOR)

    Time of first response to PD as assessed per RECIST 1.1

    Measured: 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

  3. Disease Control Rate (DCR)

    CR and PR stable disease as assessed per RECIST 1.1

    Measured: Greater than or equal to 8 weeks

  4. Progression Free Survival (PFS)

    From the time of first dose of study intervention to PD or death from any cause

    Measured: 24 months

  5. Overall Survival (OS)

    From time of first dose of study intervention to death

    Measured: Up to 5 years

  6. Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites - Tmax

    time of Maximum concentration (Tmax)

    Measured: 10 weeks

  7. Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites -AUC

    Area under plasma Concentration (AUC) 0 to t

    Measured: 10 weeks

  8. Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites half-life

    concentration Half-life (T1/2)

    Measured: 10 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Oct 2021
  2. Study start12 Apr 2022
  3. Primary completionJun 2026 (estimated)
  4. Study completionApr 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
153 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05074810
Sponsor's protocol ID
VS-6766-203
Acronym
RAMP203
Status last verified
Jan 2026
First submitted
29 Sep 2021
Last updated
12 Jan 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Coma S, Musteanu M, Malvezzi CC, Jamieson RR, Patrucco E, Mira A, Dilly J, Li Z, Fernandez-Rodriguez A, Lopez-Garcia A, Aguirre AJ, Barbacid M, Ambrogio C, Pachter JA. FAK inhibitor and RAF/MEK clamp avutometinib enhance KRAS G12C inhibitor efficacy in preclinical models of non-small cell lung cancer. Sci Transl Med. 2026 Sep 30;18(869):eaea4608. doi: 10.1126/scitranslmed.aea4608. Epub 2026 Sep 30.

    PubMed 42814800

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing avutometinib and sotorasib and avutometinib and sotorasib and defactinib in people with Non Small Cell Lung Cancer and KRAS Activating Mutation, run by Verastem, Inc. at 35 sites in 6 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 12 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 35 sites in United States, Spain, France, United Kingdom, Belgium and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05074810, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Jan 2026.

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