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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.

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ClinicalTrials.gov Identifier: NCT04835805
Recruitment Status : Active, not recruiting
First Posted : April 8, 2021
Last Update Posted : February 20, 2024
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.

Study Description
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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.

Condition or disease Intervention/treatment Phase
Melanoma Drug: Belvarafenib Drug: Cobimetinib Drug: Nivolumab Phase 1

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 65 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 13, 2021
Estimated Primary Completion Date : November 28, 2025
Estimated Study Completion Date : November 28, 2025

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arms and Interventions
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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)


Outcome Measures
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Primary Outcome Measures :
  1. Percentage of Participants With Dose Limiting Toxicity (DLTs) [ Time Frame: 28 Days from Cycle 1, Day 1 ]
  2. Percentage of Participants With Adverse Events [ Time Frame: From Cycle 1, Day 1 Up to 4 Years ]
    Severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0


Secondary Outcome Measures :
  1. Objective response rate (ORR) according to RECIST v1.1 [ Time Frame: 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

  2. Progression free survival (PFS) according to RECIST v1.1 [ Time Frame: 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

  3. Duration of response (DOR) according to RECIST v1.1 [ Time Frame: 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

  4. Overall survival (OS) [ Time Frame: Up to Approximately 4 Years ]
    Defined as the time from the first study treatment to death from any cause

  5. Plasma concentration of belvarafenib at specified timepoints [ Time Frame: Up to 30 Days After the Final Dose of Study Drug ]
  6. Plasma concentration of cobimetinib at specified timepoints [ Time Frame: Up to 30 Days After the Final Dose of Study Drug ]

Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04835805


Locations
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Sponsors and Collaborators
Genentech, Inc.
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT04835805    
Other Study ID Numbers: GO42273
2020-003674-41 ( EudraCT Number )
First Posted: April 8, 2021    Key Record Dates
Last Update Posted: February 20, 2024
Last Verified: February 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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).

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Melanoma
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
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action