What side effects are associated with this type of intervention?

Common treatments for melanoma, particularly those involving RAF kinase inhibitors like Belvarafenib, often include combination therapies with MEK inhibitors (e.g., cobimetinib) and immune checkpoint inhibitors (e.g., nivolumab). Known side effects of these treatments can include diarrhea, hypertension, decreased appetite, and various immune-related adverse events such as skin rash, colitis, and hepatitis. Ocular side effects are also notable, with symptoms like uveitis and retinopathy being reported. These side effects can vary in severity and may require management strategies to mitigate their impact on patients.

What prior FDA approvals exist?

The FDA has approved several treatments for melanoma that target similar pathways to Belvarafenib, a RAF kinase inhibitor. Notably, vemurafenib and dabrafenib are BRAF inhibitors approved for BRAF-mutant melanoma. Additionally, combination therapies such as dabrafenib with trametinib (a MEK inhibitor) have been approved to enhance efficacy. Immunotherapies like pembrolizumab and nivolumab, which target PD-1, have also been approved for melanoma, often used in combination with kinase inhibitors to improve outcomes.

What other types of research exist?

Promising alternatives to Belvarafenib for melanoma patients include: 1) Dabrafenib and Trametinib combination therapy, which targets BRAF V600 mutations and has shown efficacy in various cancers including melanoma. 2) Nivolumab and Ipilimumab combination, which are immune checkpoint inhibitors that have demonstrated significant improvements in survival for advanced melanoma. 3) Pembrolizumab, another immune checkpoint inhibitor, which has been effective as monotherapy or in combination with other agents. These alternatives offer different mechanisms of action and have shown promising results in clinical settings.

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MAPK Inhibitor

Belvarafenib + Cobimetinib/Nivolumab for Melanoma

Phase 1

Waitlist Available

Research Sponsored by Genentech, Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Tumor specimen availability

ECOG Performance Status of 0 or 1

Must not have

Treatment with systemic immunotherapy agents (e.g., anti-CTLA4, anti-PD(L)1, cytokine therapy, investigational therapy, etc.) within 28 days prior to C1D1

History or signs/symptoms of clinically significant cardiovascular disease

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to approximately 4 years

Awards & highlights

No Placebo-Only Group

Summary

This trial tests belvarafenib alone and in combination with other drugs for advanced melanoma patients who haven't responded to previous treatments. The drugs aim to stop cancer growth or help the immune system fight the cancer.

Who is the study for?

This trial is for adults with advanced melanoma that has an NRAS mutation and worsened after anti-PD-1/PD-L1 therapy. They can have had up to two cancer treatments before, but not certain drugs like pan-RAF inhibitors or MEK inhibitors (for cobimetinib arm). No serious liver disease, untreated brain metastases, significant heart issues, autoimmune diseases, or immune deficiencies are allowed.

What is being tested?

The study tests the safety and effectiveness of belvarafenib alone and combined with cobimetinib or both cobimetinib and nivolumab in treating advanced melanoma with NRAS mutations. Participants will be assessed for how their bodies handle the drugs (pharmacokinetics) and how well their tumors respond.

What are the potential side effects?

Possible side effects include skin reactions from belvarafenib; vision changes from cobimetinib; fatigue, digestive issues, skin problems from nivolumab; as well as general risks like infection due to immune system effects.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I can provide a sample of my tumor for testing.

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I am fully active or can carry out light work.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I haven't had immunotherapy or similar treatments in the last 28 days.

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I have a history of serious heart problems.

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I stopped taking anti-PD(L)1 therapy due to a severe side effect.

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I have been treated with a pan-RAF inhibitor before.

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I have previously been treated with a MEK inhibitor.

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I have a significant liver condition.

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I have brain metastases that are causing symptoms or getting worse.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to approximately 4 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to approximately 4 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to approximately 4 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Percentage of Participants With Adverse Events

Secondary study objectives

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

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

Overall survival (OS)

+1 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

3Treatment groups

Experimental Treatment

Group I: Belvarafenib Plus Cobimetinib Plus NivolumabExperimental Treatment1 Intervention

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

Group II: Belvarafenib Plus CobimetinibExperimental Treatment1 Intervention

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.

Group III: Belvarafenib MonotherapyExperimental Treatment1 Intervention

Twice daily (BID), continuous dosing.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Cobimetinib

2017

Completed Phase 3

~3300

Nivolumab

2015

Completed Phase 3

~4010

0 / 9Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Melanoma treatments often target specific molecular pathways involved in tumor growth and immune evasion. RAF kinase inhibitors like Belvarafenib block the RAF/MEK/ERK signaling pathway, which is frequently mutated in melanoma, thereby inhibiting tumor cell proliferation. Immune checkpoint inhibitors, such as nivolumab and ipilimumab, enhance the body's immune response against melanoma cells by blocking proteins that suppress immune activity. Combination therapies, which may include RAF inhibitors with MEK inhibitors or immune checkpoint inhibitors, aim to overcome resistance and improve efficacy. Understanding these mechanisms is crucial for melanoma patients as it helps tailor treatments to their specific genetic mutations and improve outcomes.

Is combination therapy the next step to overcome resistance and reduce toxicities in melanoma?