Triple Drug Therapy for Melanoma

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Antiretrovirals

Disqualifiers: Pregnancy, Brain metastases, Cardiac dysfunction, others

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

Compensation: Varies

Number of Visits: Unknown

26 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have previously taken BRAF, MEK, or HSP90 inhibitors, and certain foods and supplements like St. John's wort and grapefruit juice are prohibited.

What data supports the effectiveness of the drug combination of Cobimetinib, Cotellic, Vemurafenib, Zelboraf, PLX4032, RG7204, PLX4720, RO5185426, and XL888 for melanoma?

Research shows that the combination of cobimetinib (Cotellic) and vemurafenib (Zelboraf) significantly improves survival and tumor response rates in patients with advanced melanoma that have a specific genetic mutation (BRAF V600), compared to using vemurafenib alone. ^{1 2 3 4 5}

Is the triple drug therapy for melanoma safe for humans?

The combination of cobimetinib and vemurafenib, used in treating melanoma, has been generally well tolerated in humans, with common side effects including diarrhea, rash, fatigue, and nausea. Serious side effects were less common but included severe diarrhea and rash, and blurred vision due to reversible fluid in the eye. ^{1 2 4 6 7}

What makes the triple drug therapy for melanoma unique?

The triple drug therapy for melanoma combines cobimetinib, vemurafenib, and XL888, targeting the BRAF V600 mutation in melanoma. This combination is unique because it not only targets the BRAF mutation but also includes a MEK inhibitor (cobimetinib) and a heat shock protein 90 inhibitor (XL888), potentially enhancing the treatment's effectiveness and overcoming resistance seen with other therapies. ^{1 2 4 6 8}

What is the purpose of this trial?

The main purpose of this study is to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of XL888 when administered orally with vemurafenib plus cobimetinib in participants with BRAF V600 mutated melanoma and to evaluate the safety and tolerability of this combination.

Research Team

Zeynep Eroglu, M.D.

Principal Investigator

H. Lee Moffitt Cancer Center and Research Institute

Eligibility Criteria

Adults with unresectable BRAF V600 mutated melanoma can join this trial. They must have a performance status indicating they are relatively active, agree to use contraception, and not be pregnant or nursing. Prior treatments for cancer are okay if side effects have settled, but no past use of BRAF, MEK or HSP90 inhibitors is allowed. Participants need functioning major organs and cannot have untreated brain metastases or certain serious health conditions.

Inclusion Criteria

My melanoma cannot be surgically removed and has a BRAF V600 mutation.

You must have a tumor that can be measured using specific guidelines.

I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

I have not consumed St. John's wort, hyperforin, or grapefruit juice in the last 7 days.

I do not have any severe illnesses or social situations that would stop me from following the study's requirements.

I am HIV-positive and on antiretroviral therapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Escalating doses of XL888 with Vemurafenib plus Cobimetinib are administered to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D)

Up to 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Cobimetinib
• Vemurafenib
• XL888

Trial Overview The study aims to find the highest dose of XL888 that's safe when taken with vemurafenib and cobimetinib in patients with advanced melanoma. It will also assess how well participants tolerate this drug combination.

Participant Groups

Group I: Dose Escalation Experimental Treatment 3 Interventions

Escalating Doses of XL888 with Vemurafenib plus Cobimetinib.

Cobimetinib is already approved in European Union, United States, Canada, Switzerland, Japan for the following indications:

Approved in European Union as Cotellic for:

• Melanoma

Approved in United States as Cotellic for:

• Melanoma

Approved in Canada as Cotellic for:

• Melanoma

Approved in Switzerland as Cotellic for:

• Melanoma

Approved in Japan as Cotellic for:

• Melanoma

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Exelixis

Industry Sponsor

Trials

126

Recruited

20,500+

Michael M. Morrissey

Exelixis

Chief Executive Officer since 2010

PhD in Chemistry from Harvard University, BSc in Chemistry from the University of Wisconsin

Vicki L. Goodman

Exelixis

Chief Medical Officer since 2022

MD

Genentech, Inc.

Industry 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

Findings from Research

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]

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 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]

In a phase 1b study involving 103 patients with advanced BRAFV600 wild-type melanoma who had progressed on anti-PD-1 therapy, the combination of cobimetinib and atezolizumab showed an objective response rate of 14.6% and a disease control rate of 38.8%.

The treatment was associated with significant adverse events, including diarrhea (72.8%), dermatitis acneiform (55.3%), and nausea (50.5%), highlighting the need for careful monitoring of side effects despite the limited efficacy observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of cobimetinib plus atezolizumab in patients with advanced BRAFV600 wild-type melanoma progressing on prior anti-programmed death-1 therapy. Sandhu, S., Atkinson, V., Cao, MG., et al.[2023]

The combination of encorafenib (ENC) and binimetinib (BIN) was found to be cost-effective compared to cobimetinib (COB) and vemurafenib (VEM) only at a very high willingness-to-pay threshold of $573,000 per quality-adjusted life year (QALY).

The combination of dabrafenib (DAB) and trametinib (TRA) was determined to be the most optimal treatment option for BRAF-mutated advanced melanoma, dominating the COB + VEM combination in terms of cost-effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic Evaluation of Three BRAF + MEK Inhibitors for the Treatment of Advanced Unresectable Melanoma With BRAF Mutation From a US Payer Perspective. Halloush, S., Alkhatib, NS., Almutairi, AR., et al.[2023]

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]

Cobimetinib, a MEK1/2 inhibitor, was found to be generally well tolerated in a study involving 97 patients with advanced solid tumors, with the maximum tolerated doses established at 60 mg on a 21/7 schedule and 100 mg on a 14/14 schedule.

The treatment showed promising anti-tumor activity, particularly in melanoma patients with the BRAF(V600E) mutation, resulting in one unconfirmed complete response and six confirmed partial responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors. Rosen, LS., LoRusso, P., Ma, WW., et al.[2019]

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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

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

2. England pubmed.ncbi.nlm.nih.gov

Cobimetinib and vemurafenib for the treatment of melanoma. [2019]

3. England 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. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Phase 1b study of cobimetinib plus atezolizumab in patients with advanced BRAFV600 wild-type melanoma progressing on prior anti-programmed death-1 therapy. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Economic Evaluation of Three BRAF + MEK Inhibitors for the Treatment of Advanced Unresectable Melanoma With BRAF Mutation From a US Payer Perspective. [2023]

6. England 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. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. [2022]