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

NCT07020221
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Phase
Phase 1/Phase 2
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Recruitment status
Recruiting
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Participants
616
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Lead sponsor
Verastem, Inc.
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Start date
2025-06-24
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Number of sites
20
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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.
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Short title
A Phase 1/2 Study of VS-7375 in Patients With KRAS G12D-Mutated Solid Tumors
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Official 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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Control arm
Open label
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Registry reports results
No
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Listing at source
Listed
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Recruitment status
Recruiting
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Phase
Phase 1/Phase 2
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Study type
Interventional
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Completion date
2028-12-01
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First posted
2025-06-13
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Registry last updated
2026-10-23
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Primary completion date
2028-12-01
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Start date
2025-06-24
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Participants
616
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Participant count basis
Estimated
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Planned participants
616
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Protocol amendments
3
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Number of sites
20
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Data monitoring committee
No
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Registry sponsor category
Industry
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Lead sponsor
Verastem, Inc.
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Source registry
ClinicalTrials.gov
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Registry ID
NCT07020221
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ClinicalTrials.gov ID
NCT07020221
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Registry record
Open registry record
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Allocation
Not randomised
Model
Sequential
Purpose
Treatment
Masking
No masking
Sources for study design
clinicaltrials.gov

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

    Timeframe: 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.

  2. Part A: To identify the MTD or MFD

    Timeframe: 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).

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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

    Timeframe: 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 .

  7. Part E: To determine the impact of VS-7375 on the PK of midazolam or repaglinide

    Timeframe: Up to 2.5 years

    AUC of midazolam, repaglinide and relative metabolites.

  8. Part E: To determine the impact of VS-7375 on the PK of midazolam or repaglinide

    Timeframe: 2.5 years

    Cmax of midazolam, repaglinide and relative metabolites.

  9. Part E: To characterize the safety, tolerability, and AE profile of VS-7375 administered in combination with CYP3A4 and CYP2C8 substrates

    Timeframe: 2.5 years

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

  10. Part F: Serial biopsy

    Timeframe: 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.

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

    Timeframe: 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)

  2. Part A: To evaluate the preliminary anticancer activity of VS-7375 as monotherapy

    Timeframe: 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.

  3. Part B and D: To evaluate additional efficacy parameters of the recommended VS-7375 regimens from Part A and Part C

    Timeframe: 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.

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

    Timeframe: Up to 2.5 years

    Cmax of VS-7375

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

    Timeframe: Up to 2.5 years

    AUC of VS-7375

  6. Part C: To evaluate the preliminary anticancer activity of VS-7375 in combination with other systemic therapies

    Timeframe: Up to 2.5 years

    Confirmed ORR per RECIST v1.1 by Investigator assessments. Tumor response endpoints may also be evaluated using BICR assessments.

  7. Part C: To evaluate the preliminary anticancer activity of VS-7375 in combination with other systemic therapies

    Timeframe: Up to 2.5 years

    Confirmed DCR per RECIST v1.1 by Investigator assessments. Tumor response endpoints may also be evaluated using BICR assessments.

  8. Part C: To evaluate the preliminary anticancer activity of VS-7375 in combination with other systemic therapies

    Timeframe: Up to 2.5 years

    Confirmed DOR per RECIST v1.1 by Investigator assessments. Tumor response endpoints may also be evaluated using BICR assessments.

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

    Timeframe: 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.

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

    Timeframe: Up to 2.5 years

    Cmax of nab-paclitaxel

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

    Timeframe: Up to 2.5 years

    AUC of nab-paclitaxel

Sources for outcomes
clinicaltrials.gov

Sex
All
Age groups
Adults, Older adults
Minimum age
18 Years
Healthy 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 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.
Sources for eligibility
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  • Cedars-Sinai Medical CenterLos Angeles, United StatesRecruiting
  • Johns Hopkins UniversityBaltimore, United StatesRecruiting
  • Massachusetts General HospitalBoston, United StatesRecruiting
  • University of MichiganAnn Arbor, United StatesRecruiting
  • Washington University School of MedicineSt Louis, United StatesRecruiting
  • Laura & Isaac Perlmutter Cancer Center at NYU LangoneNew York, United StatesRecruiting
  • Univ of Pennsylvania, Abramson Cancer CenterPhiladelphia, United StatesRecruiting
  • SCRI Oncology PartnersNashville, United StatesRecruiting
  • MD Anderson Cancer CenterHouston, United StatesRecruiting
  • Huntsman Cancer InstituteSalt Lake City, United StatesRecruiting
  • University of VirginiaCharlottesville, United StatesRecruiting
  • Virginia Cancer SpecialistsFairfax, United StatesRecruiting
  • Virginia Mason Medical CenterSeattle, United StatesRecruiting
  • Macquarie UniversitySydney, AustraliaRecruiting
  • Peninsula and Southeast OncologyFrankston, AustraliaRecruiting
  • Centre Leon BerardLyon, FranceRecruiting
  • Centre d'Essais Precoces en Cancerologie de Marseille (CEPCM)Marseille, FranceRecruiting
  • Institut CurieParis, FranceRecruiting
  • START Madrid - FJDMadrid, SpainRecruiting
  • START Madrid CIOCC - Hospital HM SanchinarroMadrid, SpainRecruiting
Sources for sites
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Related records

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