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.

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Melanoma
• Intervention / Treatment: Drug: Belvarafenib; Drug: Nivolumab; Drug: Cobimetinib

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.

• Study Type: Interventional
• Enrollment (Actual): 65
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Waratah, New South Wales, Australia, 2298
      • Calvary Mater Newcastle
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Centre-East Melbourne
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Linear Clinical Research Ltd
• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8M2
      • Ottawa Hospital Regional Cancer Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital; Department of Med Oncology
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • The Sir Mortimer B. Davis General Hospital
• Germany
  • Berlin, Germany, 10117
    • Charité - Universitätsmedizin Berlin
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg-Eppendorf
  • Mannheim, Germany, 68167
    • Klinikum Mannheim GmbH Universitätsklinikum
  • Tübingen, Germany, 72076
    • Universitätsklinikum Tübingen
  • Würzburg, Germany, 97080
    • Universitätsklinikum Würzburg
• Korea, Republic of
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center - PPDS
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center - PPDS
• Norway
  • Bergen, Norway, 5053
    • Haukeland Universitetssykehus
  • Oslo, Norway, 0379
    • Oslo Universitetssykehus HF
• United States
  • California
    • Orange, California, United States, 92868
      • Chao Family Comprehensive Cancer Center UCI
    • San Francisco, California, United States, 94158
      • UCSF Helen Diller Family CCC
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center Research Institute
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Cancer Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering
  • Tennessee
    • Nashville, Tennessee, United States, 37203-1625
      • Tennessee Oncology, PLLC - SCRI - PPDS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Belvarafenib Monotherapy; Twice daily (BID), continuous dosing.	Drug: Belvarafenib; 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.	Drug: Cobimetinib; Once daily (QD) or three times weekly (TIW) for 21 days, 7 days off
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	Drug: Nivolumab; Once every 4 weeks (Q4W)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
Overall survival (OS)	Defined as the time from the first study treatment to death from any cause	Up to Approximately 4 Years
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

Collaborators and Investigators

• Sponsor: Genentech, Inc.
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2021
• Primary Completion (Estimated): November 28, 2025
• Study Completion (Estimated): November 28, 2025

Study Registration Dates

• First Submitted: April 6, 2021
• First Submitted That Met QC Criteria: April 6, 2021
• First Posted (Actual): April 8, 2021

Study Record Updates

• Last Update Posted (Actual): February 20, 2024
• Last Update Submitted That Met QC Criteria: February 16, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: GO42273; 2020-003674-41 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No