A Phase 1/2 Study of VS-7375 in Patients With KRAS G12D-Mutated Solid Tumors
Pancreatic Ductal Adenocarcinoma · Non Small Cell Lung Cancer · Colorectal Cancer · Solid Tumor, Adult · G12D Mutated KRAS
What this study involves
The registry says this study is recruiting. Individual locations may have different availability.
- Study type
- Interventional
- Phase
- Phase 1 / Phase 2
- Age range
- 18 years - Not specified
- Sex eligible
- All sexes
- Healthy volunteers
- Not accepted
- Participants
- 616 Estimated
These are starting points, not an eligibility decision. The research team must review the full requirements.
About the research
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.
Who may be able to participate?
The list below is the sponsor’s full registry wording. It can include conditions, prior treatment, test results and other requirements. A match in search does not mean you qualify.
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 RAS 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, groups and participation
The registry may describe treatments and study duration without a complete visit calendar. Ask the study team for the exact schedule, procedures, risks, costs and alternatives. Keep your usual care plan unless your treating clinician tells you otherwise.
- Assignment
- Not randomized
- Masking
- No masking
VS-7375 Monotherapy Dose Escalation
To characterize the safety and tolerability of escalating doses of VS-7375 as monotherapy and to determine the recommended phase 2 dose (RP2Ds) in patients with advanced solid tumors harboring KRAS G12D mutation.
Drug: VS-7375
VS-7375 Monotherapy Dose Expansion - PDAC
To evaluate the efficacy of VS-7375 at the recommended phase 2 dose (RP2Ds) in patients with metastatic PDAC harboring KRAS G12D-mutation.
Drug: VS-7375
VS-7375 Monotherapy Dose Expansion - NSCLC
To evaluate the efficacy of VS-7375 at the recommended phase 2 dose (RP2Ds) in patients with metastatic NSCLC harboring KRAS G12D-mutation.
Drug: VS-7375
VS-7375 Monotherapy Dose Expansion - Solid Tumors
To evaluate the efficacy of VS-7375 at the recommended phase 2 dose (RP2Ds) in patients with metastatic solid tumors harboring KRAS G12D-mutation.
Drug: VS-7375
VS-7375 + Cetuximab Dose Escalation
To characterize the safety and tolerability of escalating doses of VS-7375 in combination with cetuximab and to determine the recommended phase 2 dose (RP2Ds) in patients with advanced or metastatic PDAC, BTC, CRC harboring KRAS G12D-mutation.
Drug: VS-7375 · Drug: Cetuximab
VS-7375 + Carboplatin/Pemetrexed/Pembrolizumab Dose Escalation
To characterize the safety and tolerability of escalating doses of VS-7375 in combination with carboplatin/pemetrexed/pembrolizumab and to determine the recommended phase 2 dose (RP2Ds) in patients with metastatic NSCLC harboring KRAS G12D-mutation.
Drug: VS-7375 · Drug: Carboplatin + Pemetrexed + Pembrolizumab
VS-7375 + Gemcitabine/Nab-Paclitaxel Dose Escalation
To characterize the safety and tolerability of escalating doses of VS-7375 in combination with gemcitabine/nab-paclitaxel and to determine the recommended phase 2 dose (RP2Ds) in patients with advanced or metastatic PDAC harboring KRAS G12D-mutation.
Drug: VS-7375 · Drug: Gemcitabine + Nab-paclitaxel
VS-7375 + Pembrolizumab Dose Escalation
To characterize the safety and tolerability of escalating doses of VS-7375 in combination with pembrolizumab and to determine the recommended phase 2 dose (RP2Ds) in patients with advanced or metastatic NSCLC harboring KRAS G12D-mutation.
Drug: VS-7375 · Drug: Pembrolizumab
VS-7375 + Defactinib Dose Escalation
To characterize the safety and tolerability of escalating doses of VS-7375 in combination with defactinib and to determine the recommended phase 2 dose (RP2Ds) in patients with advanced or metastatic NSCLC harboring KRAS G12D-mutation.
Drug: VS-7375 · Drug: Defactinib
VS-7375 + Cetuximab Dose Expansion
To evaluate the efficacy of VS-7375 in combination with cetuximab at the recommended phase 2 dose (RP2Ds) in patients with with advanced or metastatic CRC harboring KRAS G12D-mutation.
Drug: VS-7375 · Drug: Cetuximab
VS-7375 + Carboplatin/Pemetrexed/Pembrolizumab Dose Expansion
To evaluate the efficacy of VS-7375 in combination with carboplatin/pemetrexed/pembrolizumab at the recommended phase 2 dose (RP2Ds) in patients with metastatic NSCLC harboring KRAS G12D-mutation.
Drug: VS-7375 · Drug: Carboplatin + Pemetrexed + Pembrolizumab
VS-7375 + Gemcitabine/Nab-Paclitaxel Dose Expansion
To evaluate the efficacy of VS-7375 in combination with gemcitabine/nab-paclitaxel at the recommended phase 2 dose (RP2Ds) in patients with metastatic PDAC harboring KRAS G12D-mutation.
Drug: VS-7375 · Drug: Gemcitabine + Nab-paclitaxel
VS-7375 + Midazolam and Repaglinide Drug-Drug Interaction
To assess the drug-drug interaction of VS-7375 in combination with midazolam and repaglinide in patients with advanced or metastatic PDAC, NSCLC, and CRC harboring a KRAS G12D mutation.
Drug: VS-7375 · Drug: Midazolam · Drug: Repaglinide
VS-7375 Serial Biopsy
To characterize the preliminary anti-cancer activity of VS-7375 in participants with metastatic PDAC who have received 2 or 3 prior therapies, correlated with biopsy-obtained biomarkers.
Drug: VS-7375
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).
Carboplatin + Pemetrexed + Pembrolizumab DRUG
A combination therapy regimen used as a first-line treatment for advanced non-squamous non-small cell lung cancer.
Gemcitabine + Nab-paclitaxel DRUG
A chemotherapy regimen used for the treatment of advanced or metastatic pancreatic ductal adenocarcinoma.
Pembrolizumab DRUG
Immunotherapy used as a first-line treatment for advanced non-squamous non-small cell lung cancer.
Defactinib DRUG
A potent, selective, reversible inhibitor of focal adhesion kinase that also inhibits proline-rich tyrosine kinase-2
Midazolam DRUG
A short-acting benzodiazepine CNS depressant that has sedative, anxiolytic, amnesic, and hypnotic effects.
Repaglinide DRUG
A rapid-acting insulin secretagogue used to lower postprandial blood glucose in patients with type 2 diabetes mellitus.
What researchers are measuring
Outcome measures describe what is being studied. They are not proof that a treatment works.
Primary measures
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 as monotherapy administered on a daily oral schedule in participants with any KRAS G12D-mutated solid tumor who have received 1 to 3 lines of prior systemic therapy.
Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs, and DLTs; and abnormal vital signs, physical examination, ECG parameters, ECOG PS, clinical laboratory results; and dose interruptions/reductions.
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 as monotherapy on a daily oral schedule in participants with any KRAS G12D-mutated solid tumor who have received 1 to 3 lines of prior systemic therapy.
Proportion/number of participants with DLTs during the DLT assessment period (C1D1 through C1D21).
Part B: To evaluate the preliminary anticancer activity of the optimal VS-7375 regimen
Time frame: Up to 2.5 years
To evaluate the efficacy of the optimal VS-7375 regimen identified from Part A in participants with metastatic KRAS G12D-mutated PDAC who have received 1 line of prior systemic therapy (cohort B1), NSCLC who have received 1 or 2 lines of prior systemic therapy (cohort B2), and other solid tumors who have received 1 or 2 lines of prior systemic therapy (cohort B3).
Cohorts B1 and B2:
Confirmed ORR by Investigator assessment per RECIST v1.1 .
Cohort B3:
Confirmed ORR by blinded independent central review (BICR) per RECIST v1.1.
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 adverse event profile of VS-7375 in combination with:
- Cetuximab in participants with advanced/metastatic PDAC after 1 prior systemic therapy, locally advanced/metastatic BTC after 1-2 prior systemic therapies, or metastatic CRC after 1-3 prior systemic therapies (C1)
- Carboplatin, pembrolizumab, and pemetrexed in previously untreated metastatic NSCLC (C2)
- Gemcitabine and nab-paclitaxel in locally advanced/metastatic PDAC after 1 prior systemic therapy (C3)
- Pembrolizumab in locally advanced/metastatic NSCLC after up to 3 prior systemic therapies (C4)
- Defactinib in metastatic PDAC or metastatic CRC (C5)
Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs, DLTs, and dose interruptions/reductions.
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).
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 efficacy of the optimal regimen of VS-7375 identified in Part C:
- In combination with cetuximab in participants with metastatic colorectal adenocarcinoma who have received 1 to 3 prior lines of systemic therapy (cohort D1)
- In combination with carboplatin, pembrolizumab, and pemetrexed in participants with previously untreated metastatic NSCLC (cohort D2)
- In combination with gemcitabine and nab-paclitaxel in participants with previously untreated metastatic PDAC (cohort D3)
Confirmed ORR by Investigator assessment, per RECIST v1.1 .
Part E: To determine the impact of VS-7375 on the PK of midazolam or repaglinide
Time frame: Up to 2.5 years
AUC of midazolam, repaglinide and relative metabolites.
Part E: To determine the impact of VS-7375 on the PK of midazolam or repaglinide
Time frame: 2.5 years
Cmax of midazolam, repaglinide and relative metabolites.
Part E: To characterize the safety, tolerability, and AE profile of VS-7375 administered in combination with CYP3A4 and CYP2C8 substrates
Time frame: 2.5 years
Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs and dose interruptions/reductions.
Part F: Serial biopsy
Time frame: Up to 2.5 years
To characterize the preliminary anti-cancer activity of VS-7375 in participants with metastatic PDAC, correlated with biopsy-obtained biomarkers.
Secondary measures
Part A: To characterize the PK of VS-7375 as monotherapy administered on a daily oral schedule
Time frame: Up to 2.5 years
To characterize the PK of VS-7375 as monotherapy administered on a daily oral schedule in participants with any KRAS G12D-mutated solid tumor.
PK parameters derived from plasma concentrations of VS-7375.
Plasma Pharmacokinetics (PK) of VS-7375, Maximum concentration (Cmax) Plasma Pharmacokinetics (PK) of VS-7375, Area under plasma Concentration (AUC)
Part A: To evaluate the preliminary anticancer activity of VS-7375 as monotherapy
Time frame: Up to 2.5 years
To evaluate the preliminary anticancer activity of VS-7375 as monotherapy in participants with any KRAS G12D-mutated solid tumor.
Confirmed ORR, DCR, and DOR per RECIST v1.1 by Investigator assessments. Tumor response endpoints may also be evaluated using BICR assessments.
Part B and D: To evaluate additional efficacy parameters of the recommended VS-7375 regimens from Part A and Part C
Time frame: Up to 2.5 years
To evaluate additional efficacy parameters 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.
Cohorts B1, B2, D1, D2 and D3:
Confirmed ORR by BICR DOR, BoR, DCR, PFS per RECIST v1.1 and OS.
Cohort B3:
Confirmed ORR by Investigator assessment, DOR, BoR, DCR, PFS per RECIST v1.1 and OS.
Parts B, C, D and F: 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
Cmax of VS-7375
Parts B, C, D and F: 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
AUC of VS-7375
Part C: To evaluate the preliminary anticancer activity of VS-7375 in combination with other systemic therapies
Time frame: Up to 2.5 years
Confirmed ORR per RECIST v1.1 by Investigator assessments. Tumor response endpoints may also be evaluated using BICR assessments.
Part C: To evaluate the preliminary anticancer activity of VS-7375 in combination with other systemic therapies
Time frame: Up to 2.5 years
Confirmed DCR per RECIST v1.1 by Investigator assessments. Tumor response endpoints may also be evaluated using BICR assessments.
Part C: To evaluate the preliminary anticancer activity of VS-7375 in combination with other systemic therapies
Time frame: Up to 2.5 years
Confirmed DOR per RECIST v1.1 by Investigator assessments. Tumor response endpoints may also be evaluated using BICR assessments.
Parts B, and D: To characterize the safety, tolerability, of the recommended VS-7375 regimens from Part A and Part C
Time frame: Up to 2.5 years
To characterize the safety, tolerability, 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, and abnormal vital signs, physical examination, ECG parameters, ECOG PS, clinical laboratory results; and dose interruptions/reductions.
Part C: Cohort C3: To evaluate the impact of VS-7375 on nab-paclitaxel
Time frame: Up to 2.5 years
Cmax of nab-paclitaxel
Part C: Cohort C3: To evaluate the impact of VS-7375 on nab-paclitaxel
Time frame: Up to 2.5 years
AUC of nab-paclitaxel
Review the complete result tables and limitations in the official record.
Open official results ↗Research locations (22)
The overall study status and a local site’s status can differ. Confirm that location’s availability before traveling.
22 locations
Cedars-Sinai Medical CenterLos Angeles, California, United StatesRecruiting
Johns Hopkins UniversityBaltimore, Maryland, United StatesRecruiting
Massachusetts General HospitalBoston, Massachusetts, United StatesRecruiting
University of MichiganAnn Arbor, Michigan, United StatesRecruiting
Washington University School of MedicineSt Louis, Missouri, United StatesRecruiting
Laura & Isaac Perlmutter Cancer Center at NYU LangoneNew York, New York, United StatesRecruiting
Univ of Pennsylvania, Abramson Cancer CenterPhiladelphia, Pennsylvania, United StatesRecruiting
SCRI Oncology PartnersNashville, Tennessee, United StatesRecruiting
MD Anderson Cancer CenterHouston, Texas, United StatesRecruiting
Huntsman Cancer InstituteSalt Lake City, Utah, United StatesRecruiting
University of VirginiaCharlottesville, Virginia, United StatesRecruiting
Virginia Cancer SpecialistsFairfax, Virginia, United StatesRecruiting
Virginia Mason Medical CenterSeattle, Washington, United StatesRecruiting
Macquarie UniversitySydney, New South Wales, AustraliaRecruiting
Peninsula and Southeast OncologyFrankston, Victoria, AustraliaRecruiting
Centre Leon BerardLyon, FranceRecruiting
Centre d'Essais Precoces en Cancerologie de Marseille (CEPCM)Marseille, FranceRecruiting
Institut CurieParis, FranceRecruiting
Vall d'Hebron Instituto de OncologíaBarcelona, SpainRecruiting
START Rioja - Hospital Universitario San PedroLogroño, SpainRecruiting
START Madrid - FJDMadrid, SpainRecruiting
START Madrid CIOCC - Hospital HM SanchinarroMadrid, SpainRecruiting
Study team and timeline
- Lead sponsor
- Verastem, Inc.
- Study start
- Jun 24, 2025 Actual
- Primary completion
- 2028-12 Estimated
- Study completion
- 2028-12 Estimated
- First posted
- Jun 13, 2025 Actual
- Last updated
- Nov 10, 2026 Actual
Official study contacts
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
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Source: ClinicalTrials.gov API v2. Information is submitted by sponsors and investigators. NLM does not approve the safety or science of all listed studies. Registry disclaimer.
Retrieved: Nov 11, 2026 · Last registry update: Nov 10, 2026