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.

NCT04835805 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: GO422732020-003674-41
• Study Type: interventional
• Target: 65
• Locations: 5 countries
• Sites: 17

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.

Conditions

Melanoma

Outcome Measures

Primary Outcomes (2)

• Percentage of Participants With Dose Limiting Toxicity (DLTs)

  28 Days from Cycle 1, Day 1

• 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 Outcomes (6)

• Objective response rate (ORR) according to RECIST v1.1

  Up to Approximately 4 Years

• Progression free survival (PFS) according to RECIST v1.1

  Up to Approximately 4 Years

• Duration of response (DOR) according to RECIST v1.1

  Up to Approximately 4 Years

• Overall survival (OS)

  Up to Approximately 4 Years

• Plasma concentration of belvarafenib at specified timepoints

  Up to 30 Days After the Final Dose of Study Drug

Study Arms (3)

Belvarafenib Monotherapy

EXPERIMENTAL

Twice daily (BID), continuous dosing.

Drug: Belvarafenib

Belvarafenib Plus Cobimetinib

EXPERIMENTAL

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.

Drug: Cobimetinib

Belvarafenib Plus Cobimetinib Plus Nivolumab

EXPERIMENTAL

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

Drug: Nivolumab

Interventions

Belvarafenib DRUG

Twice daily (BID), continuous dosing

Belvarafenib Monotherapy

Cobimetinib DRUG

Once daily (QD) or three times weekly (TIW) for 21 days, 7 days off

Belvarafenib Plus Cobimetinib

Nivolumab DRUG

Once every 4 weeks (Q4W)

Belvarafenib Plus Cobimetinib Plus Nivolumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Genentech, Inc.: lead

Study Sites (17)

California Pacific Medical Center Research Institute

San Francisco, California, 94115, United States

Location

UCSF Helen Diller Family CCC

San Francisco, California, 94158, United States

Location

University of Colorado Cancer Center

Aurora, Colorado, 80045, United States

Location

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21231, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Memorial Sloan Kettering

New York, New York, 10021, United States

Location

Calvary Mater Newcastle

Waratah, New South Wales, 2298, Australia

Location

Peter MacCallum Cancer Centre-East Melbourne

Melbourne, Victoria, 3000, Australia

Location

Linear Clinical Research Ltd

Nedlands, Western Australia, 6009, Australia

Location

Ottawa Hospital Regional Cancer Centre

Ottawa, Ontario, K1H 8M2, Canada

Location

Princess Margaret Hospital

Toronto, Ontario, M5G 2M9, Canada

Location

Charité - Universitätsmedizin Berlin

Berlin, 12203, Germany

Location

Universitätsklinikum Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Klinikum Mannheim GmbH Universitätsklinikum

Mannheim, 68167, Germany

Location

Universitatsklinikum Tubingen

Tübingen, 72076, Germany

Location

Universitätsklinikum Würzburg

Würzburg, 97080, Germany

Location

Asan Medical Center - PPDS

Seoul, 05505, South Korea

Location

Related Publications (1)

• Moschos SJ. War against NRAS-Mutant Melanoma Using Targeted Therapies Remains Challenging. Clin Cancer Res. 2022 Jul 15;28(14):2977-2979. doi: 10.1158/1078-0432.CCR-22-1256.

  PMID: 35587446 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

cobimetinib; Nivolumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 6, 2021
• First Posted: April 8, 2021
• Study Start: May 13, 2021
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027
• Last Updated: March 30, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

AU (3); KR (1); DE (5); CA (2); US (6)