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
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.
DRUGGemcitabine
A chemotherapy used for the treatment of several types of cancer including advanced or metastatic pancreatic ductal adenocarcinoma.
A chemotherapy regimen used for the treatment of advanced or metastatic pancreatic ductal adenocarcinoma.
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 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.
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 administered on a daily oral schedule in participants with advanced solid tumors harboring a KRAS G12D mutation. Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs, DLTs, 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 on a daily oral schedule in participants with any KRAS G12D-mutated solid tumor. Proportion/number of participants with DLTs during the DLT assessment period (through C1D21). |
| Part B: To evaluate the preliminary anticancer activity of the optimal VS-7375 regimen | Up to 2.5 years | To evaluate the preliminary anticancer activity of the optimal VS-7375 regimen identified from Part A in participants with advanced KRAS G12D-mutated PDAC (cohort B1), NSCLC (cohort B2), and other solid tumors (cohort B3). Confirmed ORR, PFS rate, unconfirmed PR and CR rates, DCR, DOR, and PFS per RECIST v1.1. Overall Survival |
| 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 AE profile of VS-7375 in the following combination regimens in participants with any solid tumor harboring a KRAS G12D mutation. * 2L+ therapy in combination with cetuximab in participants with any advanced or metastatic solid tumor harboring a KRAS G12D mutation * 1L therapy in combination with carboplatin, pembrolizumab, and pemetrexed in participants with previously untreated metastatic NSCLC * 2L+ therapy in combination with gemcitabine and nab-paclitaxel in participants with metastatic PDAC * 1L therapy in combination with gemcitabine in participants aged 75 years or older with previously untreated metastatic PDAC. 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 preliminary anticancer activity of the optimal regimen of VS-7375 as identified in Part C as: * 2L+ therapy in combination with cetuximab in participants with metastatic colorectal adenocarcinoma * 1L therapy in combination with carboplatin, pembrolizumab, and pemetrexed in participants with previously untreated metastatic NSCLC * 2L+ therapy in combination with gemcitabine and nab-paclitaxel in participants with metastatic PDAC * 1L therapy in combination with gemcitabine in participants aged 75 years or older with previously untreated metastatic PDAC. Confirmed ORR, PFS rate, unconfirmed PR and CR rates, DCR, DOR, and PFS per RECIST v1.1. Overall survival |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: To characterize the PK of VS-7375 as 2L+ monotherapy administered on a daily oral schedule | Up to 2.5 years | To characterize the PK of VS-7375 as 2L+ monotherapy administered on a daily oral schedule in participants with any KRAS G12D-mutated solid tumor. Cmax derived from plasma concentrations of VS-7375. |
| Part A: To evaluate the preliminary anticancer activity of VS-73753 as 2L+ monotherapy | Up to 2.5 years | To evaluate the preliminary anticancer activity of VS-7375 as 2L+ monotherapy in participants with any KRAS G12D-mutated solid tumor. Confirmed ORR, unconfirmed PR and CR rates, DCR, and DOR per RECIST v1.1. |
| Parts B and D: To characterize the safety, tolerability, and AE profile of the recommended VS-7375 regimens from Part A and Part C | Up to 2.5 years | To characterize the safety, tolerability, and AE profile 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, DLTs, and dose interruptions/reductions. |
| Parts B, C, and D: To continue to evaluate the PK of VS-7375 as monotherapy and in combination with other systemic therapies | Up to 2.5 years | To continue to evaluate the PK of VS-7375 as monotherapy and in combination with other systemic therapies in participants with KRAS G12D-mutated advanced solid tumors. Cmax derived from plasma concentrations of VS-7375. |
| Part C: Cohort C3: To evaluate the impact of VS-7375 on nab-paclitaxel PK | Up to 2.5 years | To evaluate the impact of VS-7375 on nab-paclitaxel PK in cohort C3. Change in nab-paclitaxel exposure in the presence and absence of VS-7375. |
Countries
Australia, United States
Contacts
CONTACTVerastem Call Center
Outcome results
None listed