Belvarafenib + Cobimetinib/Nivolumab for Melanoma

Not currently recruiting at 31 trial locations

Overseen By Reference study ID GO42273 whttps://forpatients.roche.com/

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Genentech, Inc.

Must not be taking: Pan-RAF inhibitors, MEK inhibitors

Disqualifiers: CNS metastases, Cardiovascular disease, Liver disease, Autoimmune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

Duration: Up to 4 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatment options for individuals with advanced melanoma, a type of skin cancer, who have a specific NRAS gene mutation. Researchers are testing belvarafenib, a potential new drug, both alone and in combination with other drugs like cobimetinib and nivolumab, to assess their safety and effectiveness. Ideal participants are those whose melanoma has worsened after previous treatments with anti-PD-1 or anti-PD-L1 therapies. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have had certain treatments like systemic immunotherapy within 28 days before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that belvarafenib, when combined with cobimetinib, is generally safe. In past studies, most patients with NRAS-mutant melanoma tolerated it well. Only a few experienced serious side effects, and most reactions were mild or moderate.

For the combination of belvarafenib, cobimetinib, and nivolumab, studies suggest that proper care can usually manage any side effects. This indicates the treatment could be safe for many patients, though individual reactions may vary.

Regarding belvarafenib alone, earlier trials indicated it is generally well-tolerated, with most patients not experiencing severe side effects, suggesting it might be safe to use by itself.

Overall, while these treatments appear promising in terms of safety, experiences can vary. Discuss potential risks and benefits with a healthcare provider before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer new approaches to tackling melanoma. Most treatments for melanoma involve targeted therapies like BRAF inhibitors or immune checkpoint inhibitors. However, Belvarafenib is a novel BRAF inhibitor that may offer improved efficacy due to its unique molecular structure. Additionally, combining Belvarafenib with Cobimetinib, a MEK inhibitor, and Nivolumab, an immune checkpoint inhibitor, could enhance the anti-tumor response by targeting multiple pathways simultaneously. This combination has the potential to overcome resistance seen with monotherapies, offering hope for more durable responses in melanoma patients.

What evidence suggests that this trial's treatments could be effective for melanoma?

Research has shown that using belvarafenib with cobimetinib could be promising for treating NRAS-mutant melanoma, a type of skin cancer. Studies have found that this combination can effectively slow tumor growth by targeting a specific pathway often active in melanoma. In this trial, some participants will receive belvarafenib alone; previous studies showed that 26.3% of patients with this type of melanoma experienced tumor shrinkage. Other participants will receive a combination of belvarafenib with cobimetinib, and some will receive belvarafenib with cobimetinib and nivolumab. Combining belvarafenib with cobimetinib and nivolumab might improve results by also helping the immune system fight the cancer. Overall, these treatments offer hope for those who haven't had success with other therapies. ^{1 3 5 6 7}

Who Is on the Research Team?

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

You have a disease that can be measured using a specific set of guidelines.

My cancer has a documented NRAS mutation within the last 5 years.

I can provide a sample of my tumor for testing.

Exclusion Criteria

You have had a disease that affects your immune system, or your immune system does not work properly.

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

I have a history of serious heart problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive belvarafenib as a single agent or in combination with cobimetinib and/or nivolumab in various phases including dose-finding, run-in, and expansion phases

Up to 4 years

IV infusion every 4 weeks for combination therapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Belvarafenib
• Cobimetinib
• Nivolumab

Trial Overview

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.

How Is the Trial Designed?

Group I: Belvarafenib Plus Cobimetinib Plus Nivolumab Experimental Treatment 1 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 Cobimetinib Experimental Treatment 1 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 Monotherapy Experimental Treatment 1 Intervention

Twice daily (BID), continuous dosing.

Who Is Running the Clinical Trial?

Genentech, Inc.

Lead Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

In the coBRIM study, patients with advanced BRAFV600-mutated melanoma treated with cobimetinib plus vemurafenib (C+V) showed improved health-related quality of life (HRQOL) compared to those receiving placebo plus vemurafenib (P+V), particularly in areas like insomnia and social functioning.

Despite some transient side effects, such as serous retinopathy and fatigue, the overall quality of life was maintained with C+V treatment, indicating its efficacy and safety in improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life impact of cobimetinib in combination with vemurafenib in patients with advanced or metastatic BRAFV600 mutation-positive melanoma. Dréno, B., Ascierto, PA., Atkinson, V., et al.[2019]

The long-term follow-up of the coBRIM study shows that combining cobimetinib with vemurafenib significantly improves overall survival (OS) and progression-free survival (PFS) in patients with advanced melanoma carrying the BRAFV600 mutation, with median OS of 22.5 months compared to 17.4 months for vemurafenib alone.

The safety profile of the combination treatment remains consistent with previous reports, indicating that it is a safe and effective option for patients with this specific type of melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation-Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study. Ascierto, PA., Dréno, B., Larkin, J., et al.[2023]

Recent advances in treating metastatic melanoma have been achieved through targeted therapies using BRAF and MEK inhibitors for patients with the BRAF V600 mutation, with combinations like vemurafenib+cobimetinib and dabrafenib+trametinib showing significant efficacy in clinical trials.

Combination therapies have different toxicity profiles compared to single-agent treatments, necessitating new strategies for prevention, detection, and management of adverse events, as outlined in the tolerance data from pivotal trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Management of toxicities of BRAF inhibitors and MEK inhibitors in advanced melanoma]. Sibaud, V., Baric, L., Cantagrel, A., et al.[2021]

In a real-world study involving 95 patients with metastatic BRAF V600 mutated melanoma, the median overall survival (OS) was significantly higher for patients without brain metastases (21.6 months) compared to those with brain metastases (7.4 months).

The safety profile of cobimetinib/vemurafenib was consistent with previous studies, with high rates of adverse events (83.3% in patients without brain metastases and 87.8% in those with brain metastases), but no new safety concerns were identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness, safety and utilization of cobimetinib and vemurafenib in patients with BRAF V600 mutant melanoma with and without cerebral metastasis under real-world conditions in Germany: the non-interventional study coveNIS. Kähler, KC., Debus, D., Schley, G., et al.[2023]

In the coBRIM trial, patients with BRAF (V600) mutation-positive unresectable or metastatic melanoma who received cobimetinib in combination with vemurafenib experienced significantly longer progression-free survival compared to those treated with vemurafenib alone.

The combination treatment also resulted in a higher overall response rate and prolonged overall survival, while maintaining a manageable safety profile, making it a valuable treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cobimetinib Plus Vemurafenib: A Review in BRAF (V600) Mutation-Positive Unresectable or Metastatic Melanoma. Keating, GM.[2019]

In a study involving 495 patients with advanced BRAF(V600)-mutant melanoma, the combination of cobimetinib and vemurafenib significantly improved median progression-free survival to 12.3 months compared to 7.2 months for the placebo group, indicating a strong efficacy of the treatment.

The combination therapy also resulted in a median overall survival of 22.3 months versus 17.4 months for the placebo group, with a manageable safety profile and no new safety concerns identified during the extended follow-up.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Ascierto, PA., McArthur, GA., Dréno, B., et al.[2022]

The combination of atezolizumab (anti-PD-L1) with BRAF and MEK inhibitors showed a high confirmed objective response rate of 71.8% in patients with BRAFV600-mutated metastatic melanoma, indicating strong anti-tumor activity.

This phase Ib study demonstrated that the triple therapy had manageable toxicity and resulted in a median duration of response of 17.4 months, with 39.3% of patients still responding after nearly 30 months, suggesting long-lasting effects of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Sullivan, RJ., Hamid, O., Gonzalez, R., et al.[2022]

Cobimetinib, when combined with vemurafenib, significantly improves tumor response rates and progression-free survival in metastatic melanoma patients with BRAF V600 mutations compared to vemurafenib alone.

While this combination therapy shows enhanced efficacy, it may also present higher toxicity compared to other treatments like dabrafenib and trametinib, indicating a need for careful management and potential combination with immune therapies for better long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cobimetinib and vemurafenib for the treatment of melanoma. Boespflug, A., Thomas, L.[2019]

In a study of 118 patients with BRAF-mutated metastatic melanoma, both vemurafenib+cobimetinib (V+C) and dabrafenib+trametinib (D+T) showed favorable efficacy, with overall response rates of 76% for V+C and 82% for D+T.

The median overall survival was longer for the V+C group at 18 months compared to 12 months for the D+T group, while both therapies had similar progression-free survival rates of around 8 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[BRAF-MEK inhibitor therapy in melanoma]. Czirbesz, K., Pánczél, G., Baranyai, F., et al.[2022]

Citations

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11144978/

A Belvarafenib Expanded Access Program in Patients with ...

Data were collected from 192 patients with melanoma who underwent NGS between November 2017 and May 2023. Variant call format data were obtained ...

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A phase Ib trial of belvarafenib in combination with ...

Belvarafenib in combination with cobimetinib showed acceptable tolerability and encouraging efficacy in NRASm melanoma, and in those with prior CPI treatment.

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annalsofoncology.org

annalsofoncology.org/article/S0923-7534(21)03280-4/fulltext

529P A phase Ib trial of belvarafenib in combination with ...

Overall 17 out of 118 (14.4%) pts responded. Among 19 pts with NRASm melanoma, 5 (26.3%) pts had a confirmed partial response (cPR) and 8 (42.1%) pts reached ...

4.

asco.org

asco.org/abstracts-presentations/ABSTRACT331645

A phase Ib trial of belvarafenib in combination with ...

Background: Belvarafenib, a potent, selective RAF dimer (type II) inhibitor, exhibits clinical activity in BRAFV600E- and NRAS-mutant (NRASm) melanoma ...

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Abstract 1474: Antitumor activity of belvarafenib in melanoma ...

Belvarafenib significantly increased the overall survival of mice implanted intracranially with BRAF V600E A375SM melanoma cells. Overall, our ...

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clinicaltrials.gov

clinicaltrials.gov/study/NCT04835805

A Study to Evaluate the Safety and Activity of Belvarafenib ...

This study will evaluate the safety, pharmacokinetics, and activity of belvarafenib as a single agent and in combination with either cobimetinib or cobimetinib ...

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genentech-clinicaltrials.com

genentech-clinicaltrials.com/en/trials/cancer/melanoma/a-study-to-evaluate-the-safety-and-activity-of-belvaraf-22554.html

Clinical Trial – Melanoma – Safety, Pharmacokinetics, and...

This study will evaluate the safety, pharmacokinetics, and activity of belvarafenib as a single agent and in combination with either cobimetinib or cobimetinib ...