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.

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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.

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

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)

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT04835805
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 1
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Genentech, Inc.
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Clinical Trials
Principal Investigator Affiliation	Hoffmann-La Roche
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Industry
Overall Status	Active, not recruiting
Countries	Australia, Canada, Germany, South Korea, United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Melanoma

Additional Details

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.

Arms & Interventions

Arms

Experimental: Belvarafenib Monotherapy

Twice daily (BID), continuous dosing.

Experimental: Belvarafenib Plus 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.

Experimental: Belvarafenib Plus Cobimetinib Plus 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

Interventions

Drug: - Belvarafenib

Twice daily (BID), continuous dosing

Drug: - Cobimetinib

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

Drug: - Nivolumab

Once every 4 weeks (Q4W)

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

San Francisco 5391959, California 5332921

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California Pacific Medical Center Research Institute

San Francisco 5391959, California 5332921, 94115

UCSF Helen Diller Family CCC, San Francisco 5391959, California 5332921

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UCSF Helen Diller Family CCC

San Francisco 5391959, California 5332921, 94158

University of Colorado Cancer Center, Aurora 5412347, Colorado 5417618

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University of Colorado Cancer Center

Aurora 5412347, Colorado 5417618, 80045

Baltimore 4347778, Maryland 4361885

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Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Baltimore 4347778, Maryland 4361885, 21231

Washington University School of Medicine, St Louis 4407066, Missouri 4398678

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Washington University School of Medicine

St Louis 4407066, Missouri 4398678, 63110

Memorial Sloan Kettering, New York 5128581, New York 5128638

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Memorial Sloan Kettering

New York 5128581, New York 5128638, 10021

International Sites

Calvary Mater Newcastle, Waratah 10103871, New South Wales 2155400, Australia

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Calvary Mater Newcastle

Waratah 10103871, New South Wales 2155400, 2298

Melbourne 2158177, Victoria 2145234, Australia

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Peter MacCallum Cancer Centre-East Melbourne

Melbourne 2158177, Victoria 2145234, 3000

Linear Clinical Research Ltd, Nedlands 2064874, Western Australia 2058645, Australia

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Linear Clinical Research Ltd

Nedlands 2064874, Western Australia 2058645, 6009

Ottawa Hospital Regional Cancer Centre, Ottawa 6094817, Ontario 6093943, Canada

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Ottawa Hospital Regional Cancer Centre

Ottawa 6094817, Ontario 6093943, K1H 8M2

Princess Margaret Hospital, Toronto 6167865, Ontario 6093943, Canada

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Princess Margaret Hospital

Toronto 6167865, Ontario 6093943, M5G 2M9

Charité - Universitätsmedizin Berlin, Berlin 2950159, Germany

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Charité - Universitätsmedizin Berlin

Berlin 2950159, , 12203

Universitätsklinikum Hamburg-Eppendorf, Hamburg 2911298, Germany

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Universitätsklinikum Hamburg-Eppendorf

Hamburg 2911298, , 20246

Mannheim 2873891, Germany

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Klinikum Mannheim GmbH Universitätsklinikum

Mannheim 2873891, , 68167

Universitatsklinikum Tubingen, Tübingen 2820860, Germany

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Universitatsklinikum Tubingen

Tübingen 2820860, , 72076

Asan Medical Center - PPDS, Seoul 1835848, South Korea

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Asan Medical Center - PPDS

Seoul 1835848, , 05505

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