A Study to Evaluate the Safety and Activity of Belvarafenib as a Single Agent and in Combination With Either Cobimetinib or Cobimetinib Plus Nivolumab in Patients With NRAS-mutant Advanced Melanoma.

Melanoma Clinical Trial

Official title:

A Phase Ib, Open-Label, Multicenter Study to Evaluate the Safety, Pharmacokinetics, and Activity of Belvarafenib as a Single Agent and in Combination With Either Cobimetinib or Cobimetinib Plus Nivolumab in Patients With NRAS-Mutant Advanced Melanoma Who Have Received Anti-PD-1/PD-L1 Therapy

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04835805
• Other study ID #: GO42273
• Secondary ID: 2020-003674-41
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: May 13, 2021
• Est. completion date: November 28, 2025

Study information

• Verified date: February 2024
• Source: Genentech, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will evaluate the safety, pharmacokinetics, and activity of belvarafenib as a single agent and in combination with either cobimetinib or cobimetinib plus nivolumab in patients with NRAS-mutant advanced melanoma who have received anti-PD-1/PD-L1 therapy.

Description:

The study will evaluate three treatment regimens in three arms: a belvarafenib monotherapy arm (Belva arm); a belvarafenib plus cobimetinib arm (Belva + Cobi arm) in an initial dose-finding phase followed by an expansion phase and a belvarafenib plus cobimetinib plus nivolumab arm (Belva + Cobi + Nivo arm) in a run-in phase followed by an expansion phase.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 65
• Est. completion date: November 28, 2025
• Est. primary completion date: November 28, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• ECOG Performance Status of 0 or 1
• Histologically confirmed, metastatic (recurrent or de novo Stage IV) or unresectable locally advanced (Stage III) cutaneous melanoma, that has progressed on or after treatment with anti-PD-1 or anti-PD-L1 therapy. Patients may have received up to two lines of systemic cancer therapy. Treatment with anti-PD-1/PD-L1 in the adjuvant setting is acceptable. Patients must have progressed disease at study entry
• Documentation of NRAS mutation-positive within 5 years prior to screening
• Tumor specimen availability
• Adequate hematologic and end-organ function
• Measurable disease per RECIST v1.1

Exclusion Criteria:

• Prior treatment with a pan-RAF inhibitor
• Treatment with systemic immunotherapy agents (e.g., anti-CTLA4, anti-PD(L)1, cytokine therapy, investigational therapy, etc.) within 28 days prior to C1D1
• Symptomatic, untreated, or actively progressing CNS metastases
• History or signs/symptoms of clinically significant cardiovascular disease
• Known clinically significant liver disease
• History of autoimmune disease or immune deficiency
• Prior treatment with a MEK inhibitor (cobimetinib arm)
• History of or evidence of retinal pathology on ophthalmologic examination (cobimetinib arm)
• History of immune-related AE attributed to prior anti-PD(L)1 therapy that resulted in permanent discontinuation of anti-PD(L)1 therapy (nivolumab arm)

Related Conditions & MeSH terms

• Melanoma

Intervention

Drug:
• Belvarafenib
Twice daily (BID), continuous dosing
• Cobimetinib
Once daily (QD) or three times weekly (TIW) for 21 days, 7 days off
• Nivolumab
Once every 4 weeks (Q4W)

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Centre-East Melbourne	Melbourne	Victoria
Australia	Linear Clinical Research Ltd	Nedlands	Western Australia
Australia	Calvary Mater Newcastle	Waratah	New South Wales
Canada	The Sir Mortimer B. Davis General Hospital	Montreal	Quebec
Canada	Ottawa Hospital Regional Cancer Centre	Ottawa	Ontario
Canada	Princess Margaret Hospital; Department of Med Oncology	Toronto	Ontario
Germany	Charité - Universitätsmedizin Berlin	Berlin
Germany	Universitätsklinikum Hamburg-Eppendorf	Hamburg
Germany	Klinikum Mannheim GmbH Universitätsklinikum	Mannheim
Germany	Universitätsklinikum Tübingen	Tübingen
Germany	Universitätsklinikum Würzburg	Würzburg
Korea, Republic of	Asan Medical Center - PPDS	Seoul
Korea, Republic of	Samsung Medical Center - PPDS	Seoul
Norway	Haukeland Universitetssykehus	Bergen
Norway	Oslo universitetssykehus HF	Oslo
United States	University of Colorado Cancer Center	Aurora	Colorado
United States	Johns Hopkins Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland
United States	University of Iowa	Iowa City	Iowa
United States	Tennessee Oncology, PLLC - SCRI - PPDS	Nashville	Tennessee
United States	Memorial Sloan Kettering	New York	New York
United States	Chao Family Comprehensive Cancer Center UCI	Orange	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	California Pacific Medical Center Research Institute	San Francisco	California
United States	UCSF Helen Diller Family CCC	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Genentech, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Germany,  Korea, Republic of,  Norway, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Dose Limiting Toxicity (DLTs)		28 Days from Cycle 1, Day 1
Primary	Percentage of Participants With Adverse Events	Severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0	From Cycle 1, Day 1 Up to 4 Years
Secondary	Objective response rate (ORR) according to RECIST v1.1	Defined as the percentage of participants with a CR or PR on two consecutive occasions >/= 4 weeks apart, as determined by the investigator according to RECIST v1.1	Up to Approximately 4 Years
Secondary	Progression free survival (PFS) according to RECIST v1.1	Defined as the time from the first study treatment to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1	Up to Approximately 4 Years
Secondary	Duration of response (DOR) according to RECIST v1.1	Defined as the time from the first occurrence of a confirmed objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1	Up to Approximately 4 Years
Secondary	Overall survival (OS)	Defined as the time from the first study treatment to death from any cause	Up to Approximately 4 Years
Secondary	Plasma concentration of belvarafenib at specified timepoints		Up to 30 Days After the Final Dose of Study Drug
Secondary	Plasma concentration of cobimetinib at specified timepoints		Up to 30 Days After the Final Dose of Study Drug