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

• ClinicalTrials.gov Identifier: NCT03989115
• Recruitment Status: Recruiting
• First Posted: June 18, 2019
• Last Update Posted: October 19, 2020
• Sponsor: Revolution Medicines, Inc.
• Collaborator: Sanofi
• Information provided by (Responsible Party): Revolution Medicines, Inc.

Tracking Information

• First Submitted Date: June 14, 2019
• First Posted Date: June 18, 2019
• Last Update Posted Date: October 19, 2020
• Actual Study Start Date: July 3, 2019
• Estimated Primary Completion Date: March 31, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 15, 2020)

• Number of participants with adverse events (AEs) [ Time Frame: 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
• Number of participants with dose limiting toxicities (DLTs) [ Time Frame: 28 days ]
  Incidence and nature of DLTs for the combination of RMC-4630 and cobimetinib or RMC-4360 and osimertinib

Original Primary Outcome Measures (submitted: June 14, 2019)

• Number of participants with adverse events (AEs) [ Time Frame: 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
• Number of participants with dose limiting toxicities (DLTs) [ Time Frame: 28 days ]
  Incidence and nature of DLTs for the combination of RMC-4630 and cobimetinib

Current Secondary Outcome Measures (submitted: September 15, 2020)

• Cmax [ Time Frame: up to 3 years ]
  Peak plasma concentration of RMC-4630 and cobimetinib or RMC-4360 and osimertinib
• Tmax [ Time Frame: up to 3 years ]
  Time to achieve peak plasma concentration of RMC-4630 and cobimetinib or RMC-4360 and osimertinib
• Area Under the Curve (AUC) [ Time Frame: up to 3 years ]
  Area under the plasma concentration time curve of RMC-4630 and cobimetinib or RMC-4360 and osimertinib
• t1/2 [ Time Frame: up to 3 years ]
  Elimination half-life of RMC-4630 and cobimetinib or RMC-4360 and osimertinib
• Accumulation Ratio [ Time Frame: 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
• Overall Response Rate (ORR) [ Time Frame: up to 3 years ]
  Overall response rate of RMC-4630 and cobimetinib or RMC-4360 and osimertinib per RECIST v1.1
• Duration of Response (DOR) [ Time Frame: up to 3 years ]
  Duration of response of RMC-4630 and cobimetinib or RMC-4360 and osimertinib per RECIST v1.1

Original Secondary Outcome Measures (submitted: June 14, 2019)

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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Solid Tumor

Intervention

• Drug: RMC-4630
  RMC-4630 for oral administration
• Drug: Cobimetinib
  Cobimetinib for oral administration
  Other Name: GDC-0973, XL518
• Drug: Drug: Osimertinib
  Osimertinib for oral administration
  Other Names:

  • Tagrisso
  • AZD9291

Study Arms

• Experimental: RMC-4630 and Cobimetinib
  RMC-4630 and Cobimetinib for oral administration
  Interventions:

  • Drug: RMC-4630
  • Drug: Cobimetinib
• Experimental: RMC-4630 and Osimertinib
  RMC-4630 and Osimertinib for oral administration
  Interventions:

  • Drug: RMC-4630
  • Drug: Drug: Osimertinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 15, 2020): 168
• Original Estimated Enrollment (submitted: June 14, 2019): 144
• Estimated Study Completion Date: April 30, 2022
• Estimated Primary Completion Date: March 31, 2022 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Revolution Medicines, Inc.; (650) 779-2300; CT-Inquiries@RevMed.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03989115
• Other Study ID Numbers: RMC-4630-02
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Revolution Medicines, Inc.
• Study Sponsor: Revolution Medicines, Inc.
• Collaborators: Sanofi

Investigators

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

• PRS Account: Revolution Medicines, Inc.
• Verification Date: October 2020