A Phase I/II, 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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Study 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.
The study is currently evaluating a 1200 mg QD monotherapy dose and a 900 mg QD cetuximab combination cohort.
To evaluate VS-7375 in patients with advanced KRAS G12D-mutated pancreatic, non-small cell lung, colorectal, and other solid tumor cancers.
Part A: VS-7375 Single-Agent Dose Escalation 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. 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. Part B: VS-7375 Single-Agent Dose Expansion To evaluate the efficacy of the optimal VS-7375 2L+ regimen identified from Part A in participants with advanced or metastatic KRAS G12D-mutated PDAC who have received 1 line of prior systemic therapy (cohort B1), NSCLC who have received 1 of 2 lines of prior system therapy (cohort B2), and other solid tumors who have received 1 of 2 lines of prior systemic therapy (cohort B3). Part C: VS-7375 Combination Dose Escalation To characterize the safety, tolerability, and AE profile of VS-7375: • In combination with cetuximab in participants with any advanced or metastatic solid tumor harboring a KRAS G12D mutation who have received 1 to 3 lines of prior systemic therapy (cohort C1) • In combination with carboplatin, pembrolizumab, and pemetrexed in participants with previously untreated metastatic NSCLC (cohort 2) • In combination with gemcitabine and nab-paclitaxel in participants with locally advanced or metastatic PDAC • who have received 1 to 3 lines of prior systemic therapy (cohort C1) To identify a recommended dose for subsequent studies of combination dosed VS-7375. Part D: VS-7375 Combination Dose Expansion To determine the efficacy of the optimal regimen of VS-7375 identified in Part C as: • Monotherapy or in combination with cetuximab in participants with metastatic colorectal adenocarcinoma who have received 1 to 3 lines of prior systemic therapy (cohort C1) • In combination with carboplatin, pembrolizumab, and pemetrexed in participants with previously untreated metastatic NSCLC (cohort D) • In combination with gemcitabine and nab-paclitaxel in participants with previously untreated metastatic PDAC (cohort D3) Part E: DDI To determine the impact of VS-7375 (600 mg QD) on the PK of midazolam (CYP3A4 substrate) or repaglinide (CYP2C8 substrate) in participants with metastatic KRAS G12D-mutated PDAC who have received 2 or 3 prior lines of systemic therapy, NSCLC who have received 3 or 4 prior lines of systemic therapy, colorectal adenocarcinoma who have received 4 prior lines of systemic therapy, or other KRAS G12D-mutated solid tumor who have received 3 or more prior lines of systemic therapy To characterize the safety, tolerability, and AE profile of VS-7375 administered in combination with CYP3A4 and CYP2C8 substrates
- 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
- * 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.
Clinical Study Information for Healthcare Providers
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