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

NCT03989115 | Completed Phase 1 Results FDA Drug

• 1 other identifier: RMC-4630-02
• Study Type: interventional
• Target: 113
• Locations: 2 countries
• Sites: 24

Brief Summary

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.

Conditions

Solid Tumor

Keywords

SHP2; PTPN11; NSCLC; KRAS G12; BRAF Class 3; NF1 LOF; KRAS amplification; KRAS mutations; advanced solid tumor; advanced solid malignancies; bladder cancer; carcinoma, non-small-cell lung; neoplasm, 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; gastrointestinal cancer; colorectal cancer; skin cancer; ovarian cancer; pancreatic cancer; endometrium/uterus cancer; cervical cancer

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (7)

• Cmax

  0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15

• Tmax

  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)

  0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15

• Accumulation Ratio

  0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15

• Duration of Response (DOR)

  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.

Study Arms (2)

RMC-4630 and Cobimetinib

EXPERIMENTAL

RMC-4630 and Cobimetinib for oral administration

Drug: RMC-4630; Drug: Cobimetinib

RMC-4630 and Osimertinib

EXPERIMENTAL

RMC-4630 and Osimertinib for oral administration

Drug: RMC-4630; Drug: Drug: Osimertinib

Interventions

RMC-4630 DRUG

RMC-4630 for oral administration

RMC-4630 and Cobimetinib; RMC-4630 and Osimertinib

Cobimetinib DRUG

Cobimetinib for oral administration

Also known as: GDC-0973, XL518

RMC-4630 and Cobimetinib

Drug: Osimertinib DRUG

Osimertinib for oral administration

Also known as: Tagrisso, AZD9291

RMC-4630 and Osimertinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 .

You may not qualify if:

• 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

Sponsors & Collaborators

• Revolution Medicines, Inc.: lead
• Sanofi: collaborator

Study Sites (24)

Honor Health Research Institute

Scottsdale, Arizona, 85258, United States

Location

City of Hope

Duarte, California, 91010, United States

Location

UC Irvine - Chao Family Comprehensive Cancer Center

Orange, California, 92868, United States

Location

UC Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

Location

UC San Francisco - Helen Diller Family Comprehensive Cancer Center

San Francisco, California, 94115, United States

Location

University of Colorado Cancer Center

Aurora, Colorado, 80045, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Winship Cancer Institute, Emory University

Atlanta, Georgia, 30322, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21287, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10021, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

University of Oklahoma - Stephenson Cancer Center

Oklahoma City, Oklahoma, 73104, United States

Location

Providence Cancer Institute, Franz Clinic

Portland, Oregon, 97213, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

Sarah Cannon Research Institute - Tennessee Oncology, PLLC

Nashville, Tennessee, 37203, United States

Location

Dell Seton Medical Center at University of Texas

Austin, Texas, 78712, United States

Location

Virginia Cancer Specialists (Fairfax) - USOR

Fairfax, Virginia, 22031, United States

Location

University of Wisconsin

Madison, Wisconsin, 53792, United States

Location

Severance Hospital Yonsei University Health System

Seoul, Seoul Teugbyeolsi, 03722, South Korea

Location

Seoul National University Hospital

Seoul, 110744, South Korea

Location

Samsung Medical Center - PPDS

Seoul, 135-710, South Korea

Location

MeSH Terms

Conditions

Noonan Syndrome; Urinary Bladder Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasms, Squamous Cell; Carcinoma, Squamous Cell; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Gastrointestinal Neoplasms; Colorectal Neoplasms; Skin Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Uterine Neoplasms; Uterine Cervical Neoplasms

Interventions

cobimetinib; osimertinib

Condition Hierarchy (Ancestors)

Craniofacial Abnormalities; Musculoskeletal Abnormalities; Musculoskeletal Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases; Carcinoma, Bronchogenic; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Carcinoma; Bronchial Diseases; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Skin Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Genital Neoplasms, Female; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Pancreatic Diseases; Uterine Diseases; Uterine Cervical Diseases

Results Point of Contact

• Title: Vice-President Clinical Operations
• Organization: Revolution Medicines

RMC-4630-02@revmed.com

650-779-2300

Study Officials

• Revolution Medicines, Inc.

  Revolution Medicines, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a dose escalation study followed by dose expansion.

Study Record Dates

• First Submitted: June 14, 2019
• First Posted: June 18, 2019
• Study Start: July 2, 2019
• Primary Completion: February 8, 2022
• Study Completion: February 8, 2022
• Last Updated: June 26, 2023
• Results First Posted: June 26, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (21); KR (3)