Study of Avutometinib (VS-6766) + Adagrasib in KRAS G12C NSCLC Patients (RAMP204)

• ClinicalTrials.gov Identifier: NCT05375994
• Recruitment Status: Recruiting
• First Posted: May 17, 2022
• Last Update Posted: May 26, 2023
• Sponsor: Verastem, Inc.
• Collaborator: Mirati Therapeutics Inc.
• Information provided by (Responsible Party): Verastem, Inc.

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Non Small Cell Lung Cancer; KRAS Activating Mutation; Advanced Cancer; Metastatic Cancer; Malignant Neoplasm of Lung; Malignant Neoplastic Disease	Drug: avutometinib (VS-6766) and adagrasib	Phase 1; Phase 2

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 85 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: August 1, 2022
• Estimated Primary Completion Date: July 24, 2024
• Estimated Study Completion Date: January 1, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: avutometinib(VS-6766)+adagrasib; To determine the recommended phase 2 dose (RP2D) for VS-6766 in combination with adagrasib in G12C inhibitor exposed patients	Drug: avutometinib (VS-6766) and adagrasib; The RP2D of VS-6766 + adagrasib determined in Part A will be used in Part B dose expansion; Other Name: KRAS G12C Inhibitor, adagrasib, KRAZATI®
Experimental: avutometinib (VS-6766)+adagrasib RP2D; To determine the efficacy of the RP2D identified from Part A in G12C inhibitor exposed patients	Drug: avutometinib (VS-6766) and adagrasib; The RP2D of VS-6766 + adagrasib determined in Part A will be used in Part B dose expansion; Other Name: KRAS G12C Inhibitor, adagrasib, KRAZATI®

Outcome Measures

Primary Outcome Measures :

1. Part A: To determine RP2D for avutometinib(VS-6766) in combination with adagrasib [ Time Frame: From start of treatment to confirmation of RP2D; 28 days ]
   Assessment of Dose-limiting toxicities (DLTs)
2. To determine the efficacy of the optimal regimen identified from Part A [ Time Frame: From start of treatment to confirmation of response; 16 weeks ]
   Confirmed overall response rate per RECIST 1.1

Secondary Outcome Measures :

1. To characterize the safety and toxicity profile: [ Time Frame: 24 Months ]
   • 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)
2. ECG QT Interval [ Time Frame: 24 months ]
   Corrected ECG QT interval by Fredericia (QTcF)
3. Duration of Response (DOR) [ Time Frame: 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
4. Disease Control Rate (DCR) [ Time Frame: Greater than or equal to 8 weeks ]
   CR and PR stable disease as assessed per RECIST 1.1
5. Progression Free Survival (PFS) [ Time Frame: 24 months ]
   From the time of first dose of study intervention to PD or death from any cause
6. Overall Survival (OS) [ Time Frame: Up to 5 years ]
   From time of first dose of study intervention to death
7. Plasma Pharmacokinetics (PK) of avutometinib(VS 6766), adagrasib, and relevant metabolites - Tmax [ Time Frame: 10 weeks ]
   time of Maximum concentration (Tmax)
8. Plasma Pharmacokinetics (PK) of avutometinib(VS 6766), adagrasib, and relevant metabolites - AUC [ Time Frame: 10 weeks ]
   Area under plasma Concentration (AUC) 0 to t
9. Plasma Pharmacokinetics (PK) of avutometinib(VS 6766), adagrasib, and relevant metabolites - Half-life [ Time Frame: 10 weeks ]
   concentration Half-life (T1/2)
10. Clinical Benefit Rate [ Time Frame: ≥ 6 months ]
    defined as Complete Response+Partial Response +Stable Disease

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Verastem Call Center; 1 781 292 4204; clinicaltrials@verastem.com

Locations

United States, California

UCSF Thoracic Oncology; Recruiting

San Francisco, California, United States, 94158

Contact: Bianca Bacaltos 415-885-3526 Bianca.Bacaltos@ucsf.edu

Principal Investigator: Collin Blakely, MD

United States, Colorado

University of Colorado Hospital Anschutz Cancer Pavllion; Recruiting

Aurora, Colorado, United States, 80045

Contact: Halle Kuykendall 720-848-0356 halle.kuykendall@cuanschutz.edu

Principal Investigator: David Camidge, MD

United States, Florida

Mayo Clinic Cancer Center; Not yet recruiting

Jacksonville, Florida, United States, 32224

Contact: Yanyan Lou 855-776-0015 lou.yanyan@mayo.edu

Principal Investigator: YanYan Lou, MD

United States, Minnesota

Mayo Clinic Cancer Center; Not yet recruiting

Rochester, Minnesota, United States, 55905

Contact: Kaushal Parikh 855-776-0015 parikh.kaushal@mayo.edu

Principal Investigator: Kaushal Parikh, MD

United States, New York

Memorial Sloan Kettering Cancer Center; Recruiting

New York, New York, United States, 10065

Principal Investigator: Kathryn Arbour, MD

United States, North Carolina

University of North Carolina at Chapel Hill; Recruiting

Chapel Hill, North Carolina, United States, 275514

Contact: Bryana Roberts 919-966-4432 bryana_roberts@med.unc.edu

Principal Investigator: Jared Weiss, MD

United States, Virginia

Virginia Cancer Specialists, NEXT Oncology; Recruiting

Fairfax, Virginia, United States, 22031

Contact: MaryAnn Poole 703-280-5390 mpoole@nextoncology.com

Principal Investigator: Alexander Spira, MD

United States, Wisconsin

Medical College Wisconsin; Recruiting

Milwaukee, Wisconsin, United States, 53226

Contact: Val Hutsen 414-805-5856 vhutsen@mcw.edu

Principal Investigator: Hui-Zi Chen, MD

Sponsors and Collaborators

Verastem, Inc.

Mirati Therapeutics Inc.

Investigators

• Study Director: MD Verastem; Verastem, Inc.

More Information

• Responsible Party: Verastem, Inc.
• ClinicalTrials.gov Identifier: NCT05375994
• Other Study ID Numbers: VS-6766-204
• First Posted: May 17, 2022
• Last Update Posted: May 26, 2023
• Last Verified: May 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Verastem, Inc.:

NSCLC; KRAS G12C; Non Small Cell Lung Cancer; Metastatic Cancer; Adagrasib; Avutometinib (VS-6766)

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasm Metastasis; Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neoplastic Processes; Pathologic Processes; Adagrasib; Antineoplastic Agents