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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Plazo: 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.

Plazo: 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).

Plazo: 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.

Plazo: 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.

Plazo: 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).

Plazo: 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 .

Plazo: Up to 2.5 years

AUC of midazolam, repaglinide and relative metabolites.

Plazo: 2.5 years

Cmax of midazolam, repaglinide and relative metabolites.

Plazo: 2.5 years

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

Plazo: 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.

Plazo: 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)

Plazo: 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.

Plazo: 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.

Plazo: Up to 2.5 years

Cmax of VS-7375

Plazo: Up to 2.5 years

AUC of VS-7375

Plazo: Up to 2.5 years

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

Plazo: Up to 2.5 years

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

Plazo: Up to 2.5 years

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

Plazo: 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.

Plazo: Up to 2.5 years

Cmax of nab-paclitaxel

Plazo: Up to 2.5 years

AUC of nab-paclitaxel

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