Study of Avutometinib (VS-6766) + Adagrasib in KRAS G12C NSCLC Patients

Non Small Cell Lung Cancer Clinical Trial

— RAMP204  

Official title:

A Phase 1/2 Study of Avutometinib (VS-6766) in Combination With Adagrasib in Patients With KRAS G12C Mutant Non-Small Cell Lung Cancer (NSCLC) (RAMP 204)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05375994
• Other study ID #: VS-6766-204
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: August 1, 2022
• Est. completion date: January 1, 2025

Study information

• Verified date: July 2023
• Source: Verastem, Inc.
• Contact: Verastem Call Center
• Phone: 1 781 292 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 adagrasib in patients with G12C Non-Small Cell Lung Cancer (NSCLC) who have been exposed to prior G12C inhibitor and experienced progressive disease.

Description:

This is a multicenter, non-randomized, open-label Phase 1/2 study designed to evaluate safety, tolerability and efficacy of avutometinib (VS-6766) in combination with adagrasib in patients with KRAS G12C mutant NSCLC who have been exposed to prior G12C inhibitor and experienced progressive disease.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 85
• Est. completion date: January 1, 2025
• Est. primary completion date: July 24, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male or female subjects = 18 years of age

• Histologic or cytologic evidence of NSCLC

• Known KRAS G12C mutation

• The subject must have received prior therapy with a KRAS G12C inhibitor and experienced progression

• Must have received appropriate treatment with at least one prior systemic regimen, but no more than 3 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:

• Prior chemotherapy, targeted therapies, radiotherapy, immunotherapy or treatment with an investigational agent within 14 days of receipt of study drug (within 6 weeks for nitrosoureas, mitomycin C and chest radiation; within 6 months prior to Cycle 1 Day 1 for chest radiation > 30Gy)

• History of prior malignancy, with the exception of curatively treated malignancies

• Major surgery within 4 weeks (excluding placement of vascular access)

• Exposure to strong CYP3A4 inhibitors or inducers within 14 days prior to the first dose and during the course of therapy

• Exposure to strong inhibitors of breast cancer resistance protein (BCRP) within 14 days prior to the first dose and during the course of therapy

• Symptomatic brain metastases requiring steroids or other local interventions within the 2 weeks prior to initiation of therapy

• 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 1 year

• History of rhabdomyolysis or interstitial lung disease

• Concurrent ocular disorders

• Concurrent heart disease or severe obstructive pulmonary disease

• Subjects with the inability to swallow oral medications

Related Conditions & MeSH terms

• Advanced Cancer
• Carcinoma, Non-Small-Cell Lung
• KRAS Activating Mutation
• Lung Neoplasms
• Malignant Neoplasm of Lung
• Malignant Neoplastic Disease
• Metastatic Cancer
• Neoplasm Metastasis
• Neoplasms
• Non Small Cell Lung Cancer

Intervention

Drug:
• avutometinib (VS-6766) and adagrasib
The RP2D of VS-6766 + adagrasib determined in Part A will be used in Part B dose expansion

Locations

Country	Name	City	State
United States	University of Colorado Hospital Anschutz Cancer Pavllion	Aurora	Colorado
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Virginia Cancer Specialists, NEXT Oncology	Fairfax	Virginia
United States	Mayo Clinic Cancer Center	Jacksonville	Florida
United States	Medical College Wisconsin	Milwaukee	Wisconsin
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	UCSF Thoracic Oncology	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
Verastem, Inc.	Mirati Therapeutics Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part A: To determine RP2D for avutometinib(VS-6766) in combination with adagrasib	Assessment of Dose-limiting toxicities (DLTs)	From start of treatment to confirmation of RP2D; 28 days
Primary	To determine the efficacy of the optimal regimen identified from Part A	Confirmed overall response rate per RECIST 1.1	From start of treatment to confirmation of response; 16 weeks
Secondary	To characterize the safety and toxicity profile:	Incidence of Adverse events (AEs) and Serious Adverse Events (SAEs) assessed by the toxicity grading of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v 5.0); Severity of Adverse events (AEs) and Serious Adverse Events (SAEs) by toxicity grade assessed by the toxicity grading of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v 5.0); Duration of Adverse events (AEs) and Serious Adverse Events (SAEs); Incidence of clinically significant changes in lab parameters; Incidence of abnormal vital signs (including systolic and diastolic blood pressure in mmHg)	24 Months
Secondary	ECG QT Interval	Corrected ECG QT interval by Fredericia (QTcF)	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(VS 6766), adagrasib, and relevant metabolites - Tmax	time of Maximum concentration (Tmax)	10 weeks
Secondary	Plasma Pharmacokinetics (PK) of avutometinib(VS 6766), adagrasib, and relevant metabolites - AUC	Area under plasma Concentration (AUC) 0 to t	10 weeks
Secondary	Plasma Pharmacokinetics (PK) of avutometinib(VS 6766), adagrasib, and relevant metabolites - Half-life	concentration Half-life (T1/2)	10 weeks
Secondary	Clinical Benefit Rate	defined as Complete Response+Partial Response +Stable Disease	= 6 months