Dose Escalation of RMC-4630 Monotherapy in Relapsed/Refractory Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of escalating doses of RMC-4630 monotherapy in adult participants with relapsed/refractory solid tumors and to identify the recommended Phase 2 dose (RP2D).

Detailed Description
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This is an open-label, multicenter, Phase 1 study of oral RMC-4630 monotherapy in participants with advanced relapsed or refractory solid tumors. The study will include 2 components: 1) a Dose-Escalation Component for participants with relapsed or refractory solid tumors and 2) a Dose-Expansion Component for participants with relapsed or refractory solid tumors harboring certain specific mutations/rearrangements that result in hyperactivation of the RAS-MAPK pathway. Participants will be treated until disease progression per RECIST v1.1, unacceptable toxicity, or other criteria for withdrawal are met, whichever occurs first.

Official Title
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A Phase 1, Open-Label, Multicenter, Dose-Escalation Study of RMC-4630 Monotherapy in Adult Participants With Relapsed/Refractory Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: RMC-4630


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant (male or female) ≥18 years of age Participants who have advanced solid tumors that have failed, are intolerant to, or are considered ineligible for standard of care anticancer treatments including approved drugs for oncogenic drivers in their tumor type Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Participants in the Dose-Expansion Component must have one of the following genotypic aberrations: KRAS amplifications, KRASG12C (NSCLC), BRAF Class 3, or NF1 LOF (NSCLC and gynecological cancers) mutations Adequate hematologic, hepatic and renal function Participant able to understand and voluntarily sign the informed consent form (ICF) and able to comply with the study visit schedule and other protocol requirements. Participants willing to agree to not father a child/become pregnant and comply with effective contraception criteria Exclusion Criteria: Known or suspected leptomeningeal or brain metastases or spinal cord compression Primary central nervous system (CNS) tumors Clinically significant cardiac disease Active, clinically significant interstitial lung disease or pneumonitis History or current evidence of retinal pigment epithelial detachment (RPED), central serous retinopathy, retinal vein occlusion (RVO), or predisposing factors to RPED or RVO Known HIV infection Active/chronic hepatitis B or C infection Any other unstable or clinically significant concurrent medical condition that would, in the opinion of the investigator, jeopardize the safety of a participant, impact their expected survival through the end of the study participation, and/or impact their ability to comply with the protocol prior/concomitant therapy Females who are pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RMC-4630<br>RMC-4630 for oral administration | Drug: RMC-4630<br>* RMC-4630 for oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs) | Incidence, nature, and severity of treatment-emergent AEs and serious AEs, including incidence and severity of findings in laboratory values and vital signs for RMC-4630 monotherapy | up to 3 years | 
| Number of participants with dose limiting toxicities (DLTs) | Incidence and nature of DLTs with RMC-4630 monotherapy | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | Peak plasma concentration of RMC-4630 | up to 3 years | 
| Tmax | Time to achieve peak plasma concentration of RMC-4630 | up to 3 years | 
| Area Under the Curve (AUC) | Area under the plasma concentration time curve of RMC-4630 | up to 3 years | 
| t1/2 | Elimination half-life of RMC-4630 | up to 3 years | 
| Accumulation Ratio | Ratio of accumulation of RMC-4630 from a single dose to steady state with repeated dosing | up to 3 years | 
| Overall Response Rate (ORR) | Overall response rate of RMC-4630 per RECIST v1.1 | up to 3 years | 
| Duration of Response (DOR) | Duration of response of RMC-4630 per RECIST v1.1 | up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SHP2, PTPN11, NSCLC, EGFR, KRAS G12, BRAF Class 3, NF1 LOF, advanced solid tumor, advanced solid malignancies, melanoma, skin cancer, ovarian cancer, endometrium/uterus cancer, bladder cancer, cervical cancer, Carcinoma, Non-Small-Cell Lung, Neoplasms, Squamous Cell, Carcinoma, Squamous Cell, Esophageal Neoplasms, Carcinoma, Bronchogenic, Bronchial Neoplasms, Lung Neoplasms, Respiratory Tract Neoplasms, Thoracic Neoplasms, Neoplasms by Site, Neoplasms, Lung Diseases, Respiratory Tract Diseases, Neoplasms, Glandular and Epithelial, Gastrointestinal Neoplasms, Digestive System Neoplasms, Head and Neck Neoplasms, Digestive System Diseases, Esophageal Diseases, Gastrointestinal Diseases