Clinical trial NCT03989115: Dose-Esc/Exp RMC4630 & Cobi in Relapsed/Refractory Solid Tumors & RMC4630& Osi in EGFR+ Locally Adv/Meta NSCLC
Official title: Ph1b/2 Open-Label,Multicenter Dose-Esc & Dose-Exp Study of Combo RMC4630 & Cobimetinib in Participants w/Relapsed/Refractory Solid Tumors & Ph1b Study of RMC4630 w/Osimertinib in Participants w/EGFR Mutation+,Locally Adv or Meta NSCLC
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
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
Lead sponsor: Revolution Medicines, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Sanofi
First posted: 2019-06-18
Enrollment: 113
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a dose escalation study followed by dose expansion.
Primary purpose: TREATMENT

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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* 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 .

Exclusion 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

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs).
timeFrame: 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.
measure: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Cycle 1: Study Day 1 - Study Day 28 (28 days)
Secondary outcomes:
measure: Cmax
timeFrame: 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15
measure: Tmax
timeFrame: 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15
measure: Area Under the Curve (AUC)
timeFrame: 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15
measure: Accumulation Ratio
timeFrame: 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15
measure: Duration of Response (DOR)
timeFrame: 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.
measure: t1/2
timeFrame: 0, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle1 Day 1 and Cycle 1 Day 15
measure: Overall Response Rate (ORR)
timeFrame: 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.
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Honor Health Research Institute
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Orange
country: United States
facility: UC Irvine - Chao Family Comprehensive Cancer Center
state: California
city: Sacramento
country: United States
facility: UC Davis Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: UC San Francisco - Helen Diller Family Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute, Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma - Stephenson Cancer Center
state: Oklahoma
city: Portland
country: United States
facility: Providence Cancer Institute, Franz Clinic
state: Oregon
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute - Tennessee Oncology, PLLC
state: Tennessee
city: Austin
country: United States
facility: Dell Seton Medical Center at University of Texas
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists (Fairfax) - USOR
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center - PPDS
Study officials:
affiliation: Revolution Medicines, Inc.
name: Revolution Medicines, Inc.
role: STUDY_DIRECTOR
References: