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.
- Conditions
- Melanoma
- Interventions
- Registration Number
- NCT04835805
- Lead Sponsor
- Genentech, Inc.
- Brief 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.
- Detailed 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 & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 65
- 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
- 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)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Belvarafenib Monotherapy Belvarafenib Twice daily (BID), continuous dosing. Belvarafenib Plus Cobimetinib Cobimetinib Recommended dose (RD) and schedule of belvarafenib and cobimetinib selected based on the safety data, tolerability, pharmacokinetics, and anti-tumor activity tested in dose-finding phase followed by an expansion phase. Belvarafenib Plus Cobimetinib Plus Nivolumab Nivolumab Recommended dose (RD) and schedule of belvarafenib and cobimetinib plus nivolumab IV infusion every 4 weeks (Q4W) in a run-in phase followed by an expansion phase
- Primary Outcome Measures
Name Time Method Percentage of Participants With Adverse Events From Cycle 1, Day 1 Up to 4 Years Severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0
Percentage of Participants With Dose Limiting Toxicity (DLTs) 28 Days from Cycle 1, Day 1
- Secondary Outcome Measures
Name Time Method Objective response rate (ORR) according to RECIST v1.1 Up to Approximately 4 Years 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
Progression free survival (PFS) according to RECIST v1.1 Up to Approximately 4 Years 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
Duration of response (DOR) according to RECIST v1.1 Up to Approximately 4 Years 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
Overall survival (OS) Up to Approximately 4 Years Defined as the time from the first study treatment to death from any cause
Plasma concentration of belvarafenib at specified timepoints Up to 30 Days After the Final Dose of Study Drug Plasma concentration of cobimetinib at specified timepoints Up to 30 Days After the Final Dose of Study Drug
Trial Locations
- Locations (14)
California Pacific Medical Center Research Institute
🇺🇸San Francisco, California, United States
UCSF Helen Diller Family CCC
🇺🇸San Francisco, California, United States
University of Colorado Cancer Center
🇺🇸Aurora, Colorado, United States
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
🇺🇸Baltimore, Maryland, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Memorial Sloan Kettering
🇺🇸New York, New York, United States
Calvary Mater Newcastle
🇦🇺Waratah, New South Wales, Australia
Peter MacCallum Cancer Centre-East Melbourne
🇦🇺Melbourne, Victoria, Australia
Linear Clinical Research Ltd
🇦🇺Nedlands, Western Australia, Australia
Ottawa Hospital Regional Cancer Centre
🇨🇦Ottawa, Ontario, Canada
Charité - Universitätsmedizin Berlin
🇩🇪Berlin, Germany
Universitätsklinikum Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Universitätsklinikum Tübingen
🇩🇪Tuebingen, Germany
Asan Medical Center - PPDS
🇰🇷Seoul, Korea, Republic of