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

Non Small Cell Lung Cancer Clinical Trial

— RAMP203  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05074810
• Other study ID #: VS-6766-203
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: April 12, 2022
• Est. completion date: April 2027

Study information

• Verified date: May 2024
• Source: Verastem, Inc.
• Contact: Verastem Call Center
• Phone: 781-292-4204
• Email: clinicaltrials[@]verastem.com
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 153
• Est. completion date: April 2027
• Est. primary completion date: September 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• KRAS Activating Mutation
• Lung Neoplasms
• Non Small Cell Lung Cancer

Intervention

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

Locations

Country	Name	City	State
Belgium	University Hospital Gent	Gent
France	CHRU of Lille	Lille
France	Hôpital Cochin	Paris
France	Hôpital Foch	Suresnes
Netherlands	Leids Universitair Medisch Centrum	Leiden
Netherlands	Erasmus MC	Rotterdam
Spain	Hospital Teresa Herrera (C.H.U.A.C)	A Coruña
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Universitario Fundación Jiménez Díaz	Madrid
Spain	Hospital Universitario Virgen De La Victoria	Málaga
Spain	Hospital Universitario Virgen de la Macarena	Sevilla
United Kingdom	University of Leicester	Leicester
United Kingdom	Royal Marsden Hospital	London
United Kingdom	Royal Marsden Hospital	Sutton
United States	Illinois Cancer Specialists	Arlington Heights	Illinois
United States	Texas Oncology	Austin	Texas
United States	Oncology and Hematology Associates of Southwest Virginia, Inc., DBA Blue Ridge Cancer Care	Blacksburg	Virginia
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Rocky Mountain Cancer Center, LLP	Boulder	Colorado
United States	Consultants in Medical Oncology & Hematology	Broomall	Pennsylvania
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	Ohio State University Brain and Spine Hospital	Columbus	Ohio
United States	Henry Ford Health System	Detroit	Michigan
United States	Virginia Cancer Specialists, PC	Fairfax	Virginia
United States	Texas Oncology - Fort Worth Cancer Center	Fort Worth	Texas
United States	Alliance Cancer Specialists,	Horsham	Pennsylvania
United States	Texas Oncology	Longview	Texas
United States	Maryland Oncology & Hematology, P.A.	Rockville	Maryland
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Georgetown University Medical Center	Washington	District of Columbia
United States	MedStar Washington Hospital Center, MedStar Georgetown Cancer Institute,	Washington	District of Columbia
United States	Minnesota Oncology Hematology, P.A	Woodbury	Minnesota

Sponsors (2)

Lead Sponsor	Collaborator
Verastem, Inc.	Amgen

Countries where clinical trial is conducted

United States,  Belgium,  France,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	Disease Control Rate (DCR)	CR and PR stable disease as assessed per RECIST 1.1	Greater than or equal to 8 weeks
Secondary	Progression Free Survival (PFS)	From the time of first dose of study intervention to PD or death from any cause	24 months
Secondary	Overall Survival (OS)	From time of first dose of study intervention to death	Up to 5 years
Secondary	Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites - Tmax	time of Maximum concentration (Tmax)	10 weeks
Secondary	Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites -AUC	Area under plasma Concentration (AUC) 0 to t	10 weeks
Secondary	Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites half-life	concentration Half-life (T1/2)	10 weeks