A Phase 1/2a Study Of VS-7375 In Patients With KRAS G12D-Mutated Solid Tumors

Study Overview

A Phase 1/2a Study of VS-7375 in Patients With KRAS G12D-Mutated Solid Tumors

This study will assess the safety and efficacy of VS-7375 alone and in combination in patients with advanced solid tumors harboring a KRAS G12D-mutation.

N/A

Pancreatic Ductal Adenocarcinoma
Non Small Cell Lung Cancer
Colorectal Cancer
Solid Tumor, Adult
G12D Mutated KRAS

DRUG: VS-7375
DRUG: Cetuximab

VS-7375-101

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2025-05-26	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2025-07-15
First Submitted that Met QC Criteria 2025-06-04	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2025-07-18
First Posted (ACTUAL) 2025-06-13	Results First Posted N/A	Last Verified 2025-07

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Sequential

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: VS-7375 Dose Escalation To determine the recommended phase 2 dose (RP2D) for VS-7375 in patients with advanced solid tumors harboring a KRAS G12D mutation.	DRUG: VS-7375 VS-7375 is a highly selective oral, non-covalent, small molecule KRAS G12D (ON/OFF) inhibitor. DRUG: Cetuximab Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR).
EXPERIMENTAL: Cetuximab + VS-7375 Dose Escalation To determine the recommended phase 2 dose (RP2D) for cetuximab + VS-7375 in patients with advanced solid tumors harboring a KRAS G12D mutation.	DRUG: VS-7375 VS-7375 is a highly selective oral, non-covalent, small molecule KRAS G12D (ON/OFF) inhibitor. DRUG: Cetuximab Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR).
EXPERIMENTAL: VS-7375 Recommended Phase 2 Dose Expansion To determine the efficacy of VS-7375 at the recommended phase 2 dose (RP2D) in patients with advanced PDAC and NSCLC harboring a KRAS G12D mutation.	DRUG: VS-7375 VS-7375 is a highly selective oral, non-covalent, small molecule KRAS G12D (ON/OFF) inhibitor. DRUG: Cetuximab Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR).
EXPERIMENTAL: Cetuximab + VS-7375 Recommended Phase 2 Dose Expansion To determine the efficacy of cetuximab +VS-7375 at the recommended phase 2 dose (RP2D) in patients with advanced CRC harboring a KRAS G12D mutation.	DRUG: VS-7375 VS-7375 is a highly selective oral, non-covalent, small molecule KRAS G12D (ON/OFF) inhibitor. DRUG: Cetuximab Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR).

Primary Outcome Measures	Measure Description	Time Frame
Part A: To characterize the safety, tolerability, and AE profile of escalating doses of VS-7375	To characterize the safety, tolerability, and AE profile of escalating doses of VS-7375 administered on a daily oral schedule in participants with advanced solid tumors harboring a KRAS G12D mutation. Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs, DLTs, and dose interruptions/reductions.	Up to 2.5 years
Part A: To identify the MTD or MFD	To identify the MTD or MFD using a BOIN design and recommend a dose for subsequent studies of VS-7375 on a daily oral schedule in participants with any KRAS G12D-mutated solid tumor. Proportion/number of participants with DLTs during the DLT assessment period (through C1D21).	Cycle 1 (each cycle is 21 days)
Part B: To evaluate the preliminary anticancer activity of the optimal VS-7375 regimen	To evaluate the preliminary anticancer activity of the optimal VS-7375 regimen identified from Part A in participants with advanced KRAS G12D-mutated PDAC (cohort B1) and NSCLC (cohort B2). Confirmed ORR, PFS rate, unconfirmed PR and CR rates, DCR, DOR, and PFS per RECIST v1.1. Overall Survival	Up to 2.5 years
Part C: To characterize the safety, tolerability, and AE profile of the combination of cetuximab with VS-7375	To characterize the safety, tolerability, and AE profile of the combination of cetuximab with VS-7375 in participants with any solid tumor harboring a KRAS G12D mutation. Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs, DLTs, and dose interruptions/reductions.	From enrollment to the end of treatment; an average of 9 months
Part C: To identify a recommended VS-7375 dose for subsequent studies of VS-7375 in combination with cetuximab.	To identify a recommended VS-7375 dose for subsequent studies of VS-7375 in combination with cetuximab in participants with any solid tumor harboring a KRAS G12D mutation. Proportion/number of participants with DLTs during the DLT assessment period (through C1D21).	Cycle 1 (each cycle is 21 days)
Part D: To determine the preliminary anticancer activity of the optimal cetuximab + VS-7375	To determine the preliminary anticancer activity of the optimal cetuximab + VS-7375 regimen identified from Part C in participants with advanced KRAS G12D mutated CRC. Confirmed ORR, PFS rate, unconfirmed PR and CR rates, DCR, DOR, and PFS per RECIST v1.1. Overall survival	Up to 2.5 years

Secondary Outcome Measures	Measure Description	Time Frame
To characterize the PK of VS-7375 administered on a daily oral schedule	To characterize the PK of VS-7375 administered on a daily oral schedule alone or in combination in participants with any KRAS G12D-mutated solid tumor. Cmax derived from plasma concentrations of VS-7375.	Up to 2.5 years
To characterize the PK of VS-7375 administered on a daily oral schedule	To characterize the PK of VS-7375 administered on a daily oral schedule alone or in combination in participants with any KRAS G12D-mutated solid tumor. AUC derived from plasma concentrations of VS-7375.	Up to 2.5 years

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Name: Verastem Call Center

Phone Number: 1 781 292 4204

Email: clinicaltrials@verastem.com

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Individuals ≥18 years of age.
Agreement to sign and date an informed consent form (ICF) approved by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
Histologic or cytologic evidence of locally advanced unresectable or metastatic solid tumor harboring a KRAS G12D mutation.
Must have received ≥1 prior line of standard systemic therapy for advanced or metastatic disease or experienced cancer progression within 6 months of neoadjuvant or adjuvant therapy.
Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Adequate organ function
Adequate cardiac function
Recovered from all AEs due to previous therapies to Grade ≤1 or baseline.
Agreement to use highly effective contraception

Underwent major surgical procedure as defined by the Investigator, other than for diagnosis, within 4 weeks prior to Cycle 1 Day 1,
Receipt of chemotherapy, targeted therapy, or radiotherapy (excluding palliative radiation) within 4 weeks or 5 half-lives, whichever is shorter, or immunotherapy within 4 weeks prior to Cycle 1 Day 1
Treatment with any investigational drug at least 4 weeks or 5 half-lives, whichever is shorter, prior to Cycle 1 Day 1.
History of treatment with direct and specific KRAS G12D inhibitors.
Symptomatic, untreated, or actively progressing known central nervous system (CNS) metastases.
Inability to swallow oral medications.
Evidence or history of uncontrolled, clinically significant hematological, renal, hepatic, endocrine, pulmonary, gastrointestinal, cardiovascular, psychiatric, coagulation, neurologic, dermatologic, autoimmune, or allergic disease
Individuals who are pregnant or breastfeeding.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications

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