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

NCT07020221 | Recruiting Phase 1 FDA Drug

• 1 other identifier: VS-7375-101
• Study Type: interventional
• Target: 295
• Locations: 2 countries
• Sites: 14

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.

Conditions

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

Keywords

KRAS G12D mutation; Solid tumors; Non Small Cell Lung Cancer; Lung Cancer; Colorectal Cancer; Metastatic Cancer; Pancreatic Cancer; Pancreatic Ductal Adenocarcinoma; NSCLC; CRC; PDAC; Pancreatic Neoplasms; Colorectal Neoplasms; Lung Neoplasms; Gastrointestinal Neoplasms; KRAS; RAS

Outcome Measures

Primary Outcomes (6)

• 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), NSCLC (cohort B2), and other solid tumors (cohort B3). 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 VS-7375 in combination regimens.

  To characterize the safety, tolerability, and AE profile of VS-7375 in the following combination regimens in participants with any solid tumor harboring a KRAS G12D mutation. * 2L+ therapy in combination with cetuximab in participants with any advanced or metastatic solid tumor harboring a KRAS G12D mutation * 1L therapy in combination with carboplatin, pembrolizumab, and pemetrexed in participants with previously untreated metastatic NSCLC * 2L+ therapy in combination with gemcitabine and nab-paclitaxel in participants with metastatic PDAC * 1L therapy in combination with gemcitabine in participants aged 75 years or older with previously untreated metastatic PDAC. 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 dose for subsequent studies of combination dosed VS-7375.

  To identify a recommended dose for subsequent studies of combination dosed VS-7375. Proportion/number of participants with DLTs during the DLT assessment period (through end of Cycle 1).

  Cycle 1 (each cycle is 21 or 28 days)

• Part D: To determine the preliminary anticancer activity of the optimal regimen of VS-7375 as identified in Part C

  To determine the preliminary anticancer activity of the optimal regimen of VS-7375 as identified in Part C as: * 2L+ therapy in combination with cetuximab in participants with metastatic colorectal adenocarcinoma * 1L therapy in combination with carboplatin, pembrolizumab, and pemetrexed in participants with previously untreated metastatic NSCLC * 2L+ therapy in combination with gemcitabine and nab-paclitaxel in participants with metastatic PDAC * 1L therapy in combination with gemcitabine in participants aged 75 years or older with previously untreated metastatic PDAC. 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 Outcomes (5)

• Part A: To characterize the PK of VS-7375 as 2L+ monotherapy administered on a daily oral schedule

  Up to 2.5 years

• Part A: To evaluate the preliminary anticancer activity of VS-73753 as 2L+ monotherapy

  Up to 2.5 years

• Parts B and D: To characterize the safety, tolerability, and AE profile of the recommended VS-7375 regimens from Part A and Part C

  Up to 2.5 years

• Parts B, C, and D: To continue to evaluate the PK of VS-7375 as monotherapy and in combination with other systemic therapies

  Up to 2.5 years

• Part C: Cohort C3: To evaluate the impact of VS-7375 on nab-paclitaxel PK

  Up to 2.5 years

Study Arms (10)

VS-7375 Dose Escalation

EXPERIMENTAL

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

Cetuximab + VS-7375 Dose Escalation

EXPERIMENTAL

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; Drug: Cetuximab

VS-7375 Recommended Phase 2 Dose Expansion

EXPERIMENTAL

To determine the efficacy of VS-7375 at the recommended phase 2 dose (RP2D) in patients with advanced PDAC, NSCLC, or solid tumors harboring a KRAS G12D mutation.

Drug: VS-7375

Cetuximab + VS-7375 Recommended Phase 2 Dose Expansion

EXPERIMENTAL

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; Drug: Cetuximab

VS-7375 + Carboplatin/Pemetrexed/Pembrolizumab Dose Escalation

EXPERIMENTAL

To determine the recommended phase 2 dose (RP2D) for VS-7375 in combination with carboplatin/pemetrexed/pembrolizumab in patients with advanced 1L NSCLC harboring a KRAS G12D mutation.

Drug: VS-7375; Drug: Carboplatin + Pemetrexed + Pembrolizumab

VS-7375 + Carboplatin/Pemetrexed/Pembrolizumab Dose Expansion

EXPERIMENTAL

To determine the efficacy of VS-7375 in combination with carboplatin/pemetrexed/pembrolizumab at the RP2D in patients with advanced 1L NSCLC harboring a KRAS G12D mutation.

Drug: VS-7375; Drug: Carboplatin + Pemetrexed + Pembrolizumab

VS-7375 + Gemcitabine/Nab-Paclitaxel Dose Escalation

EXPERIMENTAL

To determine the recommended phase 2 dose (RP2D) for VS-7375 in combination with gemcitabine/nab-paclitaxel in patients with advanced PDAC harboring a KRAS G12D mutation.

Drug: VS-7375; Drug: Gemcitabine + Nab-paclitaxel

VS-7375 + Gemcitabine/Nab-Paclitaxel Dose Expansion

EXPERIMENTAL

To determine the efficacy of VS-7375 in combination with gemcitabine/nab-paclitaxel at the RP2D in patients with advanced PDAC harboring a KRAS G12D mutation.

Drug: VS-7375; Drug: Gemcitabine + Nab-paclitaxel

VS-7375 + Gemcitabine Dose Escalation

EXPERIMENTAL

To determine the RP2D for VS-7375 in combination with gemcitabine in patients 75 years or older with advanced PDAC harboring a KRAS G12D mutation.

Drug: VS-7375; Drug: Gemcitabine

VS-7375 + Gemcitabine Dose Expansion

EXPERIMENTAL

The determine the efficacy of VS-7375 in combination with gemcitabine at the RP2D in patients 75 years or older with advanced PDAC harboring a KRAS G12D mutation.

Drug: VS-7375; Drug: Gemcitabine

Interventions

VS-7375 DRUG

VS-7375 is a highly selective oral, non-covalent, small molecule KRAS G12D (ON/OFF) inhibitor.

Cetuximab + VS-7375 Dose Escalation; Cetuximab + VS-7375 Recommended Phase 2 Dose Expansion; VS-7375 + Carboplatin/Pemetrexed/Pembrolizumab Dose Escalation; VS-7375 + Carboplatin/Pemetrexed/Pembrolizumab Dose Expansion; VS-7375 + Gemcitabine Dose Escalation; VS-7375 + Gemcitabine Dose Expansion; VS-7375 + Gemcitabine/Nab-Paclitaxel Dose Escalation; VS-7375 + Gemcitabine/Nab-Paclitaxel Dose Expansion; VS-7375 Dose Escalation; VS-7375 Recommended Phase 2 Dose Expansion

Cetuximab DRUG

Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR).

Also known as: Erbitux

Cetuximab + VS-7375 Dose Escalation; Cetuximab + VS-7375 Recommended Phase 2 Dose Expansion

Carboplatin + Pemetrexed + Pembrolizumab DRUG

A combination therapy regimen used as a first-line treatment for advanced non-squamous non-small cell lung cancer.

VS-7375 + Carboplatin/Pemetrexed/Pembrolizumab Dose Escalation; VS-7375 + Carboplatin/Pemetrexed/Pembrolizumab Dose Expansion

Gemcitabine DRUG

A chemotherapy used for the treatment of several types of cancer including advanced or metastatic pancreatic ductal adenocarcinoma.

VS-7375 + Gemcitabine Dose Escalation; VS-7375 + Gemcitabine Dose Expansion

Gemcitabine + Nab-paclitaxel DRUG

A chemotherapy regimen used for the treatment of advanced or metastatic pancreatic ductal adenocarcinoma.

VS-7375 + Gemcitabine/Nab-Paclitaxel Dose Escalation; VS-7375 + Gemcitabine/Nab-Paclitaxel Dose Expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Verastem, Inc.: lead

Study Sites (14)

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

RECRUITING

Johns Hopkins University

Baltimore, Maryland, 21287, United States

RECRUITING

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

RECRUITING

University of Michigan

Ann Arbor, Michigan, 48109, United States

RECRUITING

Washington University School of Medicine

St Louis, Missouri, 63110, United States

RECRUITING

Laura & Isaac Perlmutter Cancer Center at NYU Langone

New York, New York, 10016, United States

RECRUITING

Univ of Pennsylvania, Abramson Cancer Center

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

SCRI Oncology Partners

Nashville, Tennessee, 37203, United States

RECRUITING

MD Anderson Cancer Center

Houston, Texas, 77030, United States

RECRUITING

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

RECRUITING

University of Virginia

Charlottesville, Virginia, 22908, United States

RECRUITING

Virginia Cancer Specialists

Fairfax, Virginia, 22031, United States

RECRUITING

Virginia Mason Medical Center

Seattle, Washington, 98101, United States

RECRUITING

Peninsula and Southeast Oncology

Frankston, Victoria, 3199, Australia

RECRUITING

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Lung Neoplasms; Neoplasm Metastasis; Pancreatic Neoplasms; Gastrointestinal Neoplasms

Interventions

Cetuximab; Carboplatin; Pemetrexed; pembrolizumab; Gemcitabine; 130-nm albumin-bound paclitaxel

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Intestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Endocrine Gland Neoplasms; Pancreatic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Coordination Complexes; Organic Chemicals; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Dicarboxylic; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Central Study Contacts

Verastem Call Center

CONTACT

1 781 292 4204; clinicaltrials@verastem.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 26, 2025
• First Posted: June 13, 2025
• Study Start: June 24, 2025
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: April 22, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (13); AU (1)