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

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

• Ages 18 years and older
• All sexes
• No healthy volunteers
• Adult, Older adult

Trial locations and contacts

20 sites in 4 countries. Contact the study team or a site near you to ask about taking part.

About this study

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

Conditions

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

Being tested

VS-7375, Cetuximab, Carboplatin + Pemetrexed + Pembrolizumab, Gemcitabine + Nab-paclitaxel, Pembrolizumab

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, Biliary Tract Cancer, BTC, Biliary Tract Neoplasms

Medical subject headings

Carcinoma, Non-Small-Cell Lung, Colorectal Neoplasms, Lung Neoplasms, Neoplasm Metastasis, Pancreatic Neoplasms, Gastrointestinal Neoplasms, Biliary Tract Neoplasms, Cholangiocarcinoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

• VS-7375Drug

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

• CetuximabDrug

  Also called Erbitux

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

• Carboplatin + Pemetrexed + PembrolizumabDrug

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

• Gemcitabine + Nab-paclitaxelDrug

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

• PembrolizumabDrug

  Immunotherapy used as a first-line treatment for advanced non-squamous non-small cell lung cancer.

• DefactinibDrug

  A potent, selective, reversible inhibitor of focal adhesion kinase that also inhibits proline-rich tyrosine kinase-2

• MidazolamDrug

  A short-acting benzodiazepine CNS depressant that has sedative, anxiolytic, amnesic, and hypnotic effects.

• RepaglinideDrug

  A rapid-acting insulin secretagogue used to lower postprandial blood glucose in patients with type 2 diabetes mellitus.

What is being measured

The primary outcome is the main question the study is designed to answer.

1. 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 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.

   Measured: Up to 2.5 years

2. 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 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).

   Measured: Cycle 1 (each cycle is 21 days)

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

   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.

   Measured: Up to 2.5 years

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

   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.

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

5. 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).

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

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

   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 .

   Measured: Up to 2.5 years

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

   AUC of midazolam, repaglinide and relative metabolites.

   Measured: Up to 2.5 years

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

   Cmax of midazolam, repaglinide and relative metabolites.

   Measured: 2.5 years

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

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

   Measured: 2.5 years

10. Part F: Serial biopsy

    To characterize the preliminary anti-cancer activity of VS-7375 in participants with metastatic PDAC, correlated with biopsy-obtained biomarkers.

    Measured: Up to 2.5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1. First posted13 Jun 2025
2. Study start24 Jun 2025
3. Primary completionDec 2028 (estimated)
4. Study completionDec 2028 (estimated)

Resources

• Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
• Other trials for Pancreatic Ductal AdenocarcinomaStudies of the same condition, open and under way.
• What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.