KRAS Activating Mutation, Non Small Cell Lung Cancer
Conditions
Keywords
NSCLC, KRAS G12C
Brief summary
This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with sotorasib with or without defactinib in patients with KRAS G12C Non-Small Cell Lung Cancer (NSCLC) in patients who have been exposed to prior G12C inhibitor and those who have not been exposed to prior G12C inhibitor.
Detailed description
This is a multicenter, non-randomized, open-label Phase 1/2 study designed to evaluate safety and tolerability and efficacy of avutometinib (VS-6766) in combination with sotorasib with or without defactinib in patients with KRAS G12C mutant NSCLC.
Interventions
DRUGavutometinib and sotorasib
The RP2D of avutometinib + sotorasib determined in Part A will be used in Part B dose expansion
DRUGavutometinib and sotorasib and defactinib
The RP2D of avutometinib + sotorasib + defactinib determined in Part A will be used in Part B dose expansion
Sponsors
Amgen
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
* Male or female patients ≥ 18 years of age * Histologic or cytologic evidence of NSCLC * Known KRAS G12C mutation * Either exposed or not exposed to a KRAS inhibitor to be included in Part A (avutometinib + sotorasib + defactinib) and not exposed to KRAS inhibitor to be included in Part B (avutometinib + sotorasib + defactinib), Cohort 1 * Received at least 1 dose of a G12C inhibitor to be included in Part B, Cohort 2 (avutometinib + sotorasib + defactinib) * Must have received appropriate treatment with at least one prior systemic regimen, but no more than 2 prior regimens, for Stage 3B-C or 4 NSCLC * Measurable disease according to RECIST 1.1 * An Eastern Cooperative Group (ECOG) performance status ≤ 1 * Adequate organ function * Adequate recovery from toxicities related to prior treatments * Agreement to use highly effective method of contraceptive
Exclusion criteria
* Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy * History of prior malignancy, with the exception of curatively treated malignancies * Major surgery within 4 weeks, minor surgery within 2 weeks (excluding placement of vascular access) * History of treatment with a direct and specific inhibitor of MEK * Exposure to strong CYP3A4 inhibitors or inducers within 14 days prior to the first dose and during the course of therapy * Symptomatic brain metastases requiring steroids or other local interventions. * Known SARS-Cov2 infection ≤28 days prior to first dose of study therapy * Known hepatitis B, hepatitis C, or human immunodeficiency virus infection that is active * Active skin disorder that has required systemic therapy within the past year * History of rhabdomyolysis * Concurrent ocular disorders * Concurrent heart disease or severe obstructive pulmonary disease * Inability to swallow oral medications * Female patients that are pregnant or breastfeeding * Previously treated with sotorasib and were dose reduced due to toxicity
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: To determine RP2D for avutometinib in combination with sotorasib and the Alt-RP2D for avutometinib in combination with sotorasib and defactinib | From start of treatment to confirmation of RP2D; 28 days | Assessment of Dose-limiting toxicities (DLTs) |
| Part B: To determine the efficacy of the RP2D and/or Alt-RP2D identified from Part A | From start of treatment to confirmation of response; 16 weeks | Confirmed overall response rate per RECIST 1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | Greater than or equal to 8 weeks | CR and PR stable disease as assessed per RECIST 1.1 |
| Progression Free Survival (PFS) | 24 months | From the time of first dose of study intervention to PD or death from any cause |
| Overall Survival (OS) | Up to 5 years | From time of first dose of study intervention to death |
| Frequency and severity adverse events (AEs) and Serious Adverse Events (SAEs) | 24 months | Count of AE and SAEs by grade, based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grading scale |
| Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites -AUC | 10 weeks | Area under plasma Concentration (AUC) 0 to t |
| Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites half-life | 10 weeks | concentration Half-life (T1/2) |
| Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites - Tmax | 10 weeks | time of Maximum concentration (Tmax) |
| Duration of Response (DOR) | Time from the first documentation of response to first documentation of progressive disease or death due to any cause, greater than or equal to 6 months | Time of first response to PD as assessed per RECIST 1.1 |
Countries
Belgium, France, Netherlands, Spain, United Kingdom, United States
Outcome results
None listed