Phase 1/2 Study of Avutometinib (VS-6766) + Sotorasib With or Without Defactinib in KRAS G12C NSCLC Patients
- Conditions
- KRAS Activating MutationNon Small Cell Lung Cancer
- Interventions
- Registration Number
- NCT05074810
- Lead Sponsor
- Verastem, Inc.
- 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.
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 153
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description avutometinib (VS-6766)+sotorasib+defactinib avutometinib and sotorasib and 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 avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor naïve avutometinib and sotorasib To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor naive avutometinib and sotorasib and defactinib To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients avutometinib (VS-6766)+sotorasib avutometinib and 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 avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor exposed avutometinib and sotorasib and defactinib To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor exposed avutometinib and sotorasib To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients
- Primary Outcome Measures
Name Time Method Part B: To determine the efficacy of the RP2D and/or Alt-RP2D identified from Part A From start of treatment to confirmation of response; 16 weeks Confirmed overall response rate per RECIST 1.1
Part A: To determine RP2D for avutometinib in combination with sotorasib and the Alt-RP2D for avutometinib in combination with sotorasib and defactinib From start of treatment to confirmation of RP2D; 28 days Assessment of Dose-limiting toxicities (DLTs)
- Secondary Outcome Measures
Name Time Method Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites half-life 10 weeks concentration Half-life (T1/2)
Frequency and severity adverse events (AEs) and Serious Adverse Events (SAEs) 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
Progression Free Survival (PFS) 24 months From the time of first dose of study intervention to PD or death from any cause
Overall Survival (OS) Up to 5 years From time of first dose of study intervention to death
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 Time of first response to PD as assessed per RECIST 1.1
Disease Control Rate (DCR) Greater than or equal to 8 weeks CR and PR stable disease as assessed per RECIST 1.1
Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites - Tmax 10 weeks time of Maximum concentration (Tmax)
Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites -AUC 10 weeks Area under plasma Concentration (AUC) 0 to t
Trial Locations
- Locations (32)
Hôpital Foch
🇫🇷Suresnes, France
Rocky Mountain Cancer Center, LLP
🇺🇸Boulder, Colorado, 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
Illinois Cancer Specialists
🇺🇸Arlington Heights, Illinois, United States
Maryland Oncology & Hematology, P.A.
🇺🇸Rockville, Maryland, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Henry Ford Health System
🇺🇸Detroit, Michigan, United States
Minnesota Oncology Hematology, P.A
🇺🇸Woodbury, Minnesota, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Cleveland Clinic Taussig Cancer Center
🇺🇸Cleveland, Ohio, United States
Ohio State University Brain and Spine Hospital
🇺🇸Columbus, Ohio, United States
Consultants in Medical Oncology & Hematology
🇺🇸Broomall, Pennsylvania, United States
Alliance Cancer Specialists,
🇺🇸Horsham, Pennsylvania, United States
Texas Oncology
🇺🇸Longview, Texas, United States
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Texas Oncology - Fort Worth Cancer Center
🇺🇸Fort Worth, Texas, United States
Oncology and Hematology Associates of Southwest Virginia, Inc., DBA Blue Ridge Cancer Care
🇺🇸Blacksburg, Virginia, United States
Virginia Cancer Specialists, PC
🇺🇸Fairfax, Virginia, United States
University Hospital Gent
🇧🇪Gent, Belgium
CHU de Liège
🇧🇪Liège, Belgium
CHRU of Lille
🇫🇷Lille, France
Hôpital Cochin
🇫🇷Paris, France
Leids Universitair Medisch Centrum
🇳🇱Leiden, Netherlands
Erasmus MC
🇳🇱Rotterdam, Netherlands
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, Spain
University of Leicester
🇬🇧Leicester, United Kingdom
Royal Marsden Hospital
🇬🇧Sutton, United Kingdom