Dose-Escalation/Expansion of RMC-4630 and Cobimetinib in Relapsed/Refractory Solid Tumors and RMC-4630 and Osimertinib in EGFR Positive Locally Advanced/Metastatic NSCLC

• Sponsor: Revolution Medicines, Inc. (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03989115
• Collaborator: Sanofi (Industry)
• Enrollment: 168
• Locations: 24
• Arms: 2
• Anticipated Duration (Months): 33.9
• Patients Per Site: 7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumor	Drug: RMC-4630; Drug: Cobimetinib; Drug: Drug: Osimertinib	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 168 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1b/2, Open-Label, Multicenter Dose-Escalation and Dose-Expansion Study of the Combination of RMC-4630 and Cobimetinib in Adult Participants With Relapsed/Refractory Solid Tumors and a Phase 1b Study of RMC-4630 With Osimertinib in Participants With EGFR Mutation Positive, Locally Advanced or Metastatic NSCLC
• Actual Study Start Date: Jul 2, 2019
• Anticipated Primary Completion Date: Mar 31, 2022
• Anticipated Study Completion Date: Apr 30, 2022

Arms and Interventions

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; Other Names: GDC-0973, XL518
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; Other Names: Tagrisso AZD9291

Outcome Measures

Primary Outcome Measures

1. Number of participants with adverse events (AEs) [up to 3 years]

   Incidence, nature, and severity of treatment-emergent AEs and SAEs, graded according to the NCI CTCAE v5 for the combination of RMC-4360 and cobimetinib or RMC-4360 and osimertinib

2. Number of participants with dose limiting toxicities (DLTs) [28 days]

   Incidence and nature of DLTs for the combination of RMC-4630 and cobimetinib or RMC-4360 and osimertinib

Secondary Outcome Measures

1. Cmax [up to 3 years]

   Peak plasma concentration of RMC-4630 and cobimetinib or RMC-4360 and osimertinib

2. Tmax [up to 3 years]

   Time to achieve peak plasma concentration of RMC-4630 and cobimetinib or RMC-4360 and osimertinib

3. Area Under the Curve (AUC) [up to 3 years]

   Area under the plasma concentration time curve of RMC-4630 and cobimetinib or RMC-4360 and osimertinib

4. t1/2 [up to 3 years]

   Elimination half-life of RMC-4630 and cobimetinib or RMC-4360 and osimertinib

5. Accumulation Ratio [up to 3 years]

   Ratio of accumulation of RMC-4630 and cobimetinib or RMC-4360 and osimertinib from a single dose to steady state with repeated dosing

6. Overall Response Rate (ORR) [up to 3 years]

   Overall response rate of RMC-4630 and cobimetinib or RMC-4360 and osimertinib per RECIST v1.1

7. Duration of Response (DOR) [up to 3 years]

   Duration of response of RMC-4630 and cobimetinib or RMC-4360 and osimertinib per RECIST v1.1

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Honor Health Research Institute	Scottsdale	Arizona	United States	85258
2	City of Hope	Duarte	California	United States	91010
3	UC Irvine - Chao Family Comprehensive Cancer Center	Orange	California	United States	92868
4	UC Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
5	UC San Francisco - Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
6	University of Colorado Cancer Center	Aurora	Colorado	United States	80045
7	Moffitt Cancer Center	Tampa	Florida	United States	33612
8	Winship Cancer Institute, Emory University	Atlanta	Georgia	United States	30322
9	Northwestern University	Chicago	Illinois	United States	60611
10	Johns Hopkins Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland	United States	21287
11	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
12	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
13	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10021
14	Ohio State University	Columbus	Ohio	United States	43210
15	University of Oklahoma - Stephenson Cancer Center	Oklahoma City	Oklahoma	United States	73104
16	Providence Cancer Institute, Franz Clinic	Portland	Oregon	United States	97213
17	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
18	Sarah Cannon Research Institute - Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37203
19	Dell Seton Medical Center at University of Texas	Austin	Texas	United States	78712
20	Virginia Cancer Specialists (Fairfax) - USOR	Fairfax	Virginia	United States	22031
21	University of Wisconsin	Madison	Wisconsin	United States	53792
22	Severance Hospital Yonsei University Health System	Seoul	Seoul Teugbyeolsi	Korea, Republic of	03722
23	Seoul National University Hospital	Seoul		Korea, Republic of	110744
24	Samsung Medical Center - PPDS	Seoul		Korea, Republic of	135-710

Sponsors and Collaborators

• Revolution Medicines, Inc.
• Sanofi

Investigators

• Study Director: Revolution Medicines, Inc., Revolution Medicines, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Revolution Medicines, Inc.
• ClinicalTrials.gov Identifier: NCT03989115
• Other Study ID Numbers: RMC-4630-02
• First Posted: Jun 18, 2019
• Last Update Posted: Sep 1, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Revolution Medicines, Inc.: 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
• Additional relevant MeSH terms: Neoplasms; Osimertinib

Study Results

No Results Posted as of Sep 1, 2021