Dose-Esc/Exp RMC4630 & Cobi In Relapsed/Refractory Solid Tumors & RMC4630& Osi In EGFR+ Locally Adv/Meta NSCLC

Study Overview

Dose-Esc/Exp RMC4630 & Cobi in Relapsed/Refractory Solid Tumors & RMC4630& Osi in EGFR+ Locally Adv/Meta NSCLC

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) proﬁles of RMC-4630 and cobimetinib in adult participants with relapsed/refractory solid tumors with specific genomic aberrations and to identify the recommended Phase 2 dose (RP2D); and to evaluate the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) proﬁles of RMC-4630 and osimertinib in adult participants with EGFR mutation-positive locally advanced or metastatic NSCLC.

This open-label, phase 1b/2 dose-escalation and dose-expansion study is designed to evaluate the safety and maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of RMC-4630 in combination with cobimetinib in participants with relapsed/refractory solid tumors; and of RMC-4630 in combination with osimertinib in adult participants with EGFR mutation-positive locally advanced or metastatic NSCLC.

Solid Tumor

DRUG: RMC-4630
DRUG: Cobimetinib
DRUG: Drug: Osimertinib

RMC-4630-02

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2019-06-14	Results First Submitted 2023-02-08	Last Update Submitted that met QC Criteria 2023-05-31
First Submitted that Met QC Criteria 2019-06-14	Results First Submitted that Met QC Criteria 2023-05-31	Last Update Posted (ACTUAL) 2023-06-26
First Posted (ACTUAL) 2019-06-18	Results First Posted 2023-06-26	Last Verified 2023-02

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: RMC-4630 and Cobimetinib RMC-4630 and Cobimetinib for oral administration	DRUG: RMC-4630 RMC-4630 for oral administration DRUG: Cobimetinib Cobimetinib for oral administration
EXPERIMENTAL: RMC-4630 and Osimertinib RMC-4630 and Osimertinib for oral administration	DRUG: RMC-4630 RMC-4630 for oral administration DRUG: Drug: Osimertinib Osimertinib for oral administration

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: RMC-4630 and Cobimetinib

RMC-4630 and Cobimetinib for oral administration

DRUG: RMC-4630

RMC-4630 for oral administration

DRUG: Cobimetinib

Cobimetinib for oral administration

EXPERIMENTAL: RMC-4630 and Osimertinib

RMC-4630 and Osimertinib for oral administration

DRUG: RMC-4630

RMC-4630 for oral administration

DRUG: Drug: Osimertinib

Osimertinib for oral administration

Primary Outcome Measures	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs).	An adverse event (AE) was defined as any untoward medical occurrence in a participant, temporally associated with the use of a pharmaceutical / an investigational product, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product(s) was also an AE. All AEs and SAEs will be collected from the start of intervention until the safety visit or EOT visit, whichever is later. The number of safety-evaluable participants who experienced at least one treatment-emergent AE was reported per protocol.	AEs were collected from the start of intervention through 30 days post last day of study drug taken. Participants were monitored/assessed for adverse events for a maximum of 17 months which includes a maximum duration of 16 months on treatment.
Number of Participants With Dose Limiting Toxicities (DLTs)	Any toxicities occurring during the DLT observation period (cycle 1) that were considered R/T study treatment, including GR4 AEs; GR3 febrile neutropenia or hemorrhage; GR3 thrombocytopenia with clinically significant bleeding; GR ≥2 pneumonitis; GR3 hypertension or rash which does not improve or remains uncontrolled for >5 or more days despite maximal supportive care; GR3 non hematologic AEs that remain uncontrolled for >72 hours despite maximal supportive care; Concurrent elevation of AST or ALT >3 × ULN & total bilirubin >2 × ULN or international normalized ratio (INR) >1.5 in the absence of cholestasis and other causes; Grade 3 QTcF prolongation based on a triplicate ECG; Ejection fraction <50% with an absolute decrease of >10% from baseline; Retinal vein occlusion any grade; 50% or less dose intensity of RMC4630 and/or cobimetnib or osimertinib due to study drug related toxicity. Refer to protocol for further details.	Cycle 1: Study Day 1 - Study Day 28 (28 days)

Secondary Outcome Measures	Measure Description	Time Frame
Cmax	Peak plasma concentration of RMC-4630 and cobimetinib or RMC-4630 and osimertinib	0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15
Tmax	Time to achieve peak plasma concentration of RMC-4630 and cobimetinib or RMC-4630 and osimertinib	0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15
Area Under the Curve (AUC)	Area under the plasma concentration time curve of RMC-4630 and cobimetinib or RMC-4630 and osimertinib	0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15
Accumulation Ratio	AUC ratio (C1D15 versus C1D1) of RMC-4630 and cobimetinib or RMC-4630 and osimertinib	0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15
Duration of Response (DOR)	Duration of response of RMC-4630 and cobimetinib or RMC-4630 and osimertinib per RECIST v1.1	Response assessment occurs from the start of intervention until the date of documented disease progression per RECIST 1.1 or the date of subsequent therapy, whichever occurs first.
t1/2	Elimination half-life of RMC-4630 and cobimetinib or RMC-4630 and osimertinib	0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15
Overall Response Rate (ORR)	ORR is defined as the proportion of participants who achieve a CR or PR per RECIST v1.1. ORR and the corresponding 95% two-sided confidence interval were derived.	Response assessment occurs from the start of intervention until the date of documented disease progression per RECIST 1.1 or the date of subsequent therapy, whichever occurs first.

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Age ≥18 years
For RMC-4630 + Cobimetinib only - Participants who have advanced solid tumors that have failed, are intolerant to, or are considered ineligible for standard of care anti-cancer treatments including approved drugs for oncogenic drivers in their tumor type.
For RMC-4630 + Osimertinib only - Locally advanced or metastatic EGFR mutant NSCLC not amenable to curative surgery or radiotherapy
For RMC-4630 + Cobimetinib only - Participants must have one of the following genotypic aberrations: KRAS mutations and amplifications, BRAF Class 3 mutations, or NF1 LOF mutations
For RMC-4630 + Osimertinib only - Evidence of radiological documentation of progression with osimertinib monotherapy or an osimertinib containing regimen. Participants should not be considered a current candidate for 1st generation EGFR TKI's by the investigator.
Eastern Cooperative Oncology Group (ECOG) performance status of ≤1
Adequate hematological, hepatic, and renal function
Capable of giving signed informed consent form (ICF). Willing and able to compile with study requirements and restrictions
Life expectancy >12 weeks
Female of childbearing potential and males with partners of childbearing potential must comply with effective contraception criteria .

Primary central nervous system (CNS) tumors.
Known or suspected leptomeningeal or brain metastases or spinal cord compression.
For RMC-4630 + osimertinib arm only - Known or suspected Small cell, squamous, or pleomorphic lung transformations
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 or 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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sanofi

Investigators

STUDY_DIRECTOR: Revolution Medicines, Inc., Revolution Medicines, Inc.

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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