RecruitingInterventionalPhase 1/Phase 2

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

NCT ID: NCT07020221Sponsor: Verastem, Inc.Last updated: 2026-04-22

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.

Arms & interventions

DrugVS-7375
VS-7375 is a highly selective oral, non-covalent, small molecule KRAS G12D (ON/OFF) inhibitor.
DrugCetuximab
Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR).
DrugCarboplatin + Pemetrexed + Pembrolizumab
A combination therapy regimen used as a first-line treatment for advanced non-squamous non-small cell lung cancer.
DrugGemcitabine
A chemotherapy used for the treatment of several types of cancer including advanced or metastatic pancreatic ductal adenocarcinoma.
DrugGemcitabine + Nab-paclitaxel
A chemotherapy regimen used for the treatment of advanced or metastatic pancreatic ductal adenocarcinoma.

Outcome measures

Primary

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.
Time frame: 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).
Time frame: 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
Time frame: 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.
Time frame: 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).
Time frame: 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
Time frame: Up to 2.5 years

Secondary

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
Part A: To evaluate the preliminary anticancer activity of VS-73753 as 2L+ monotherapy
Time frame: 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
Time frame: 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
Time frame: Up to 2.5 years
Part C: Cohort C3: To evaluate the impact of VS-7375 on nab-paclitaxel PK
Time frame: Up to 2.5 years

Eligibility criteria

Sex: AllAge: 18 Years and olderHealthy volunteers: No

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.