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

Phase 1

Recruiting

• Conditions: Pancreatic Ductal Adenocarcinoma; Non Small Cell Lung Cancer; Colorectal Cancer; Solid Tumor, Adult; G12D Mutated KRAS
• Interventions: Drug: VS-7375; Drug: Cetuximab

• Registration Number: NCT07020221
• Lead Sponsor: Verastem, Inc.

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2025-05-26
• Status Verified: 2025-06
• Study Start: 2025-06
• Study First Submitted QC: 2025-06-04
• Study First Posted: 2025-06-13
• Last Update Submitted: 2025-06-13
• Last Update Posted: 2025-06-18
• Primary Completion: 2028-09
• Study Completion: 2028-09

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 130

Inclusion Criteria

• 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

Key

Exclusion Criteria

• 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
VS-7375 Dose Escalation	VS-7375	To determine the recommended phase 2 dose (RP2D) for VS-7375 in patients with advanced solid tumors harboring a KRAS G12D mutation.
Cetuximab + VS-7375 Dose Escalation	VS-7375	To determine the recommended phase 2 dose (RP2D) for cetuximab + VS-7375 in patients with advanced solid tumors harboring a KRAS G12D mutation.
Cetuximab + VS-7375 Dose Escalation	Cetuximab	To determine the recommended phase 2 dose (RP2D) for cetuximab + VS-7375 in patients with advanced solid tumors harboring a KRAS G12D mutation.
VS-7375 Recommended Phase 2 Dose Expansion	VS-7375	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.
Cetuximab + VS-7375 Recommended Phase 2 Dose Expansion	VS-7375	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.
Cetuximab + VS-7375 Recommended Phase 2 Dose Expansion	Cetuximab	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.

Primary Outcome Measures

Name	Time	Method
Part A: To characterize the safety, tolerability, and AE profile of escalating doses of VS-7375	Up to 2.5 years	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.
Part B: To evaluate the preliminary anticancer activity of the optimal VS-7375 regimen	Up to 2.5 years	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
Part C: To characterize the safety, tolerability, and AE profile of the combination of cetuximab with VS-7375	From enrollment to the end of treatment; an average of 9 months	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.
Part C: To identify a recommended VS-7375 dose for subsequent studies of VS-7375 in combination with cetuximab.	Cycle 1 (each cycle is 21 days)	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).
Part D: To determine the preliminary anticancer activity of the optimal cetuximab + VS-7375	Up to 2.5 years	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
Part A: To identify the MTD or MFD	Cycle 1 (each cycle is 21 days)	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).

Secondary Outcome Measures

Name	Time	Method
To characterize the PK of VS-7375 administered on a daily oral schedule	Up to 2.5 years	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.

Trial Locations

Locations (3)

SCRI Oncology Partners; 🇺🇸 Nashville, Tennessee, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Virginia Mason Medical Center; 🇺🇸 Seattle, Washington, United States