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NCT Number: NCT07020221

A Phase 1/2 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.

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Key information

Conditions

Pancreatic Ductal Adenocarcinoma Bronchial Neoplasms Carcinoma, Bronchogenic Carcinoma, Non-Small-Cell Lung Colonic Diseases Colorectal Cancer Colorectal Neoplasms Digestive System Diseases Digestive System Neoplasms Endocrine Gland Neoplasms Endocrine System Diseases G12D Mutated KRAS Gastrointestinal Diseases Gastrointestinal Neoplasms Intestinal Diseases Intestinal Neoplasms Lung Diseases Lung Neoplasms Neoplasm Metastasis Neoplasms Neoplasms by Site Neoplastic Processes Non Small Cell Lung Cancer Pancreatic Diseases Pancreatic Neoplasms Pathologic Processes Pathological Conditions, Signs and Symptoms Rectal Diseases Respiratory Tract Diseases Respiratory Tract Neoplasms Solid Tumor, Adult Thoracic Neoplasms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Peninsula and Southeast Oncology, Frankston, Victoria, Australia

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Key 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.
  • 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.

Treatment and study plan

VS-7375

Drug

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

Cetuximab

Drug

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

Other names: Erbitux

Carboplatin + Pemetrexed + Pembrolizumab

Drug

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

Gemcitabine

Drug

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

Gemcitabine + Nab-paclitaxel

Drug

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

Primary outcomes

  1. Part A: To characterize the safety, tolerability, and AE profile of escalating doses of VS-7375

    Time frame: 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.

  2. Part A: To identify the MTD or MFD

    Time frame: 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).

  3. Part B: To evaluate the preliminary anticancer activity of the optimal VS-7375 regimen

    Time frame: 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), 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

  4. Part C: To characterize the safety, tolerability, and AE profile of VS-7375 in combination regimens.

    Time frame: From enrollment to the end of treatment; an average of 9 months

    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.

  5. Part C: To identify a recommended dose for subsequent studies of combination dosed VS-7375.

    Time frame: Cycle 1 (each cycle is 21 or 28 days)

    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).

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

    Time frame: Up to 2.5 years

    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

Secondary outcomes

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

    Time frame: Up to 2.5 years

    To characterize the PK of VS-7375 as 2L+ monotherapy administered on a daily oral schedule in participants with any KRAS G12D-mutated solid tumor.

    Cmax derived from plasma concentrations of VS-7375.

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

    Time frame: Up to 2.5 years

    To evaluate the preliminary anticancer activity of VS-7375 as 2L+ monotherapy in participants with any KRAS G12D-mutated solid tumor.

    Confirmed ORR, unconfirmed PR and CR rates, DCR, and DOR per RECIST v1.1.

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

    Time frame: Up to 2.5 years

    To characterize the safety, tolerability, and AE profile of the recommended VS-7375 regimens from Part A (VS-7375 monotherapy) and Part C (VS-7375 in combination with other systemic therapies), administered on a daily oral schedule in participants with KRAS G12D-mutated solid tumors.

    Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs, DLTs, and dose interruptions/reductions.

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

    Time frame: Up to 2.5 years

    To continue to evaluate the PK of VS-7375 as monotherapy and in combination with other systemic therapies in participants with KRAS G12D-mutated advanced solid tumors.

    Cmax derived from plasma concentrations of VS-7375.

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

    Time frame: Up to 2.5 years

    To evaluate the impact of VS-7375 on nab-paclitaxel PK in cohort C3.

    Change in nab-paclitaxel exposure in the presence and absence of VS-7375.

Study contacts

Contact information is provided by the study sponsor or research team.

Verastem Call Center

CONTACT

[email protected]

1 781 292 4204

Sponsors and collaborators

Lead sponsor

Verastem, Inc.

Industry

Registry information

Official study title

A Phase 1/2, Open-label Study of VS-7375, a KRAS G12D (ON/OFF) Inhibitor, as Monotherapy and in Combination, in Patients With Advanced KRAS G12D-Mutated Solid Tumors

Important dates

Study start
2025
Primary completion
2028
Study completion
2028
First posted
Jun 13, 2025
Registry last updated
Apr 22, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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