Non-Small Cell Lung Cancer, NSCLC, KRAS, NRAS, HRAS-mutated NSCLC, KRAS G12C-mutated Solid Tumors, Lung Cancer, Lung Cancer Stage IV, Advanced Solid Tumor, Cancer, RAS G12D-mutated NSCLC
Conditions
Keywords
NSCLC, KRAS G12C, RAS Mutation, KRAS G12X, Non-Small Cell Lung Cancer, Lung Cancer, Lung Cancer Stage IV, Advanced Solid Tumor, Cancer, RAS G12D
Brief summary
The purpose of this platform study is to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of novel RAS(ON) inhibitors as a monotherapy or combined with Standard(s) of Care (SOC) or with each other. The first four subprotocols include the following: Subprotocol A: RMC-6291 +/- RMC-6236 + SOC Subprotocol B: RMC-6236 + SOC Subprotocol C: RMC-9805 +/- RMC-6236 + SOC Subprotocol D: RMC-9805
Detailed description
The platform study design allows combinations of RAS(ON) inhibitors with other anticancer agents or as a monotherapy to be evaluated in patients with RAS-mutated solid tumors with a focus on NSCLC. This is an open-label platform Phase 1b/2 study to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of novel RAS(ON) inhibitors combined with Standard of Care (SOC), or as a monotherapy and to define the Recommended Phase 2 Dose and Schedule (RP2DS). Enrollment of patients with KRAS or RAS mutations will be specified in each subprotocol. Subprotocol A is an open-label, multicenter, Phase 1b/2 study of RMC-6291, with or without RMC-6236, in combination with pembrolizumab, with or without chemotherapy, in patients with KRAS G12C-mutated advanced solid tumors. Subprotocol B is an open-label, multicenter, Phase1b/2 study of RMC-6236 in combination with pembrolizumab, with or without chemotherapy, in patients with RAS-mutated non-small cell lung cancer (NSCLC) Subprotocol C is an open-label, multicenter, Phase1b/2 study of RMC-9805 with or without RMC-6236, in combination with other anticancer agents, in patients with RAS G12D-mutated non-small cell lung cancer (NSCLC) Subprotocol D is a Phase 2, Open-label, Multicenter Study of Zoldonrasib (RMC-9805) in Previously Treated Patients with RAS G12D-Mutant Non-Small Cell Lung Cancer (NSCLC) Subprotocols A, B, and C consist of two parts: Part 1 - Dose Exploration and Part 2 - Dose Expansion. Subprotocol D consists of only one part.
Interventions
Sponsors
Revolution Medicines, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
All Patients (unless otherwise noted): * ≥ 18 years of age * ECOG PS is 0 to 1 * Adequate organ function as outlined by the study * Received prior standard therapy appropriate for tumor type and stage * Must have pathologically documented, locally advanced or metastatic KRAS G12C-mutated solid tumor malignancy (not amenable to curative surgery) (Subprotocol A) * Must have pathologically documented, locally advanced or metastatic RAS-mutated NSCLC (Subprotocol B) * Must have pathologically documented, locally advanced or metastatic RAS G12D-mutated NSCLC (Subprotocol C and Subprotocol D)
Exclusion criteria
All Patients: * Primary central nervous system (CNS) tumors * Impaired gastrointestinal (GI) function that may significantly alter the absorption of RMC drugs * Major surgery \< 28 days of first dose * Active or history of interstitial lung disease (ILD) or pneumonitis requiring steroids Other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse events | Up to 5 years | Incidence and severity of treatment-emergent Adverse Events (AEs) and serious AEs and clinically significant changes in laboratory values, ECGs and vital signs |
| Dose limiting toxicities | 21 days | Number of participants with dose limiting toxicities |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Drug concentrations over time | Up to 21 weeks | Observed blood concentration of each drug as applicable per subprotocol |
| Cmax | Up to 21 weeks | Maximum observed blood concentration of each drug as applicable per subprotocol |
| Tmax | Up to 21 weeks | Time to reach maximum blood concentration of each drug as applicable per subprotocol |
| AUC | Up to 21 weeks | Area under the concentration-time curve of each drug as applicable per subprotocol |
| ORR | Up to 5 years | Objective Response Rate per RECIST v1.1 |
| DOR | Up to 5 years | Duration of Response per RECIST v1.1 |
Countries
Australia, Denmark, France, Germany, Greece, Italy, Netherlands, South Korea, Spain, Taiwan, United States
Contacts
CONTACTRevolution Medicines
STUDY_DIRECTORRevolution Medicines
Revolution Medicines
Outcome results
None listed