Pancreatic Ductal Adenocarcinoma, Non Small Cell Lung Cancer, Colorectal Cancer, Solid Tumor, Adult, G12D Mutated KRAS
Conditions
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, Intrahepatic cholangiocarcinoma, Appendiceal Cancer, Endometrial Cancer, Small bowel Cancer
Brief 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.
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.
A chemotherapy regimen used for the treatment of advanced or metastatic pancreatic ductal adenocarcinoma.
DRUGPembrolizumab
Immunotherapy used as a first-line treatment for advanced non-squamous non-small cell lung cancer.
DRUGDefactinib
A potent, selective, reversible inhibitor of focal adhesion kinase that also inhibits proline-rich tyrosine kinase-2
DRUGMidazolam
A short-acting benzodiazepine CNS depressant that has sedative, anxiolytic, amnesic, and hypnotic effects.
DRUGRepaglinide
A rapid-acting insulin secretagogue used to lower postprandial blood glucose in patients with type 2 diabetes mellitus.
Sponsors
Verastem, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: To characterize the safety, tolerability, and AE profile of escalating doses of VS-7375 | 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. |
| Part A: To identify the MTD or MFD | 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). |
| Part B: To evaluate the preliminary anticancer activity of the optimal VS-7375 regimen | 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. |
| Part C: To characterize the safety, tolerability, and AE profile of VS-7375 in combination regimens. | 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. |
| Part C: To identify a recommended dose for subsequent studies of combination dosed VS-7375. | 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). |
| Part D: To determine the preliminary anticancer activity of the optimal regimen of VS-7375 as identified in Part C | 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 . |
| Part E: To determine the impact of VS-7375 on the PK of midazolam or repaglinide | Up to 2.5 years | AUC of midazolam, repaglinide and relative metabolites. |
| Part E: To characterize the safety, tolerability, and AE profile of VS-7375 administered in combination with CYP3A4 and CYP2C8 substrates | 2.5 years | Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs and dose interruptions/reductions. |
| Part F: Serial biopsy | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: To characterize the PK of VS-7375 as monotherapy administered on a daily oral schedule | 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) |
| Part A: To evaluate the preliminary anticancer activity of VS-7375 as monotherapy | 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. |
| Part B and D: To evaluate additional efficacy parameters of the recommended VS-7375 regimens from Part A and Part C | 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. |
| Parts B, C, D and F: To continue to evaluate the PK of VS-7375 as monotherapy and in combination with other systemic therapies | Up to 2.5 years | Cmax of VS-7375 |
| Part C: To evaluate the preliminary anticancer activity of VS-7375 in combination with other systemic therapies | Up to 2.5 years | Confirmed ORR per RECIST v1.1 by Investigator assessments. Tumor response endpoints may also be evaluated using BICR assessments. |
| Parts B, and D: To characterize the safety, tolerability, of the recommended VS-7375 regimens from Part A and Part C | 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. |
| Part C: Cohort C3: To evaluate the impact of VS-7375 on nab-paclitaxel | Up to 2.5 years | Cmax of nab-paclitaxel |
Countries
Australia, France, Spain, United States
Contacts
CONTACTVerastem Call Center
Outcome results
None listed