Clinical trial NCT05074810: Phase 1/2 Study of Avutometinib (VS-6766) + Sotorasib With or Without Defactinib in KRAS G12C NSCLC Patients
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Non Small Cell Lung Cancer
KRAS Activating Mutation
Keywords: NSCLC
KRAS G12C
Lead sponsor: Verastem, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Amgen
First posted: 2021-10-12
Enrollment: 153
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Part A: To determine RP2D for avutometinib in combination with sotorasib and the Alt-RP2D for avutometinib in combination with sotorasib and defactinib
timeFrame: From start of treatment to confirmation of RP2D; 28 days
measure: Part B: To determine the efficacy of the RP2D and/or Alt-RP2D identified from Part A
timeFrame: From start of treatment to confirmation of response; 16 weeks
Secondary outcomes:
measure: Frequency and severity adverse events (AEs) and Serious Adverse Events (SAEs)
timeFrame: 24 months
measure: Duration of Response (DOR)
timeFrame: 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
measure: Disease Control Rate (DCR)
timeFrame: Greater than or equal to 8 weeks
measure: Progression Free Survival (PFS)
timeFrame: 24 months
measure: Overall Survival (OS)
timeFrame: Up to 5 years
measure: Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites - Tmax
timeFrame: 10 weeks
measure: Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites -AUC
timeFrame: 10 weeks
measure: Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites half-life
timeFrame: 10 weeks
Other outcomes:
Locations:
city: Boulder
country: United States
facility: Rocky Mountain Cancer Center, LLP
state: Colorado
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Washington
country: United States
facility: MedStar Washington Hospital Center, MedStar Georgetown Cancer Institute,
state: District of Columbia
city: Arlington Heights
country: United States
facility: Illinois Cancer Specialists
state: Illinois
city: Rockville
country: United States
facility: Maryland Oncology & Hematology, P.A.
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Woodbury
country: United States
facility: Minnesota Oncology Hematology, P.A
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Brain and Spine Hospital
state: Ohio
city: Broomall
country: United States
facility: Consultants in Medical Oncology & Hematology
state: Pennsylvania
city: Horsham
country: United States
facility: Alliance Cancer Specialists,
state: Pennsylvania
city: Austin
country: United States
facility: Texas Oncology
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Texas Oncology - Fort Worth Cancer Center
state: Texas
city: Longview
country: United States
facility: Texas Oncology
state: Texas
city: Blacksburg
country: United States
facility: Oncology and Hematology Associates of Southwest Virginia, Inc., DBA Blue Ridge Cancer Care
state: Virginia
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Gent
country: Belgium
facility: University Hospital Gent
city: Liège
country: Belgium
facility: CHU de Liège
city: Lille
country: France
facility: CHRU of Lille
city: Paris
country: France
facility: Hôpital Cochin
city: Suresnes
country: France
facility: Hôpital Foch
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: A Coruña
country: Spain
facility: Hospital Teresa Herrera (C.H.U.A.C)
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Málaga
country: Spain
facility: Hospital Universitario Virgen De La Victoria
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen de la Macarena
city: Leicester
country: United Kingdom
facility: University of Leicester
city: London
country: United Kingdom
facility: Royal Marsden Hospital
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital
Study officials:
affiliation: Verastem, Inc.
name: MD Verastem
role: STUDY_DIRECTOR
References: