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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of three drugs to treat melanoma with a specific BRAF V600 mutation. The goal is to determine the safest dosage of the experimental drug XL888 when used with vemurafenib and cobimetinib, ensuring the combination is safe and tolerable. It targets individuals with melanoma that cannot be surgically removed, particularly if it has spread or affects certain lymph nodes. Participants should not have previously tried similar drugs and must have their condition confirmed by a lab test. This trial offers those with advanced melanoma the opportunity to explore new treatment options. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, allowing participants to be among the first to receive this new combination therapy.

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.

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

Research has shown that using vemurafenib and cobimetinib together is generally safe for treating melanoma, a type of skin cancer. Studies have found that this combination is more effective than using either drug alone. Some patients experienced side effects like rash and diarrhea, but these were usually manageable with proper care.

The new part of this trial tests XL888 with vemurafenib and cobimetinib. As a Phase 1 trial, researchers aim to determine the safest dose of XL888 to use with the other drugs. Phase 1 trials typically involve a small number of participants and represent the first step in testing a new treatment in humans.

Since the FDA has already approved vemurafenib and cobimetinib for melanoma, they have a known safety record. This trial will help determine how well XL888 can be integrated into this treatment and identify the optimal dose to minimize side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this triple drug therapy for melanoma because it combines Cobimetinib, Vemurafenib, and XL888 to target the cancer in a unique way. While standard treatments like BRAF inhibitors focus on a single pathway, this combination therapy adds XL888, an HSP90 inhibitor, which helps overcome resistance to existing treatments. By attacking multiple pathways that the cancer cells rely on, this therapy has the potential to be more effective in treating advanced melanoma, offering hope for improved outcomes compared to current options.

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

Research has shown that combining XL888 with vemurafenib and cobimetinib may help treat BRAF V600 mutated melanoma, a type of skin cancer. In this trial, participants will receive escalating doses of XL888 alongside vemurafenib and cobimetinib. Studies have found this combination effective in patients with advanced melanoma. The treatment targets specific pathways that promote cancer growth. Although significant side effects can occur, the goal is to attack cancer cells more effectively. Early results suggest potential benefits, but managing side effects remains important. ^{2 3 6 7 8}

Who Is on the Research Team?

Zeynep Eroglu, M.D.

Principal Investigator

H. Lee Moffitt Cancer Center and Research Institute

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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 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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6195480/

Combined BRAF and HSP90 inhibition in patients with ... XL888 in combination with vemurafenib has clinical activity in patients with advanced BRAFV600-mutant melanoma, with a tolerable side-effect profile. HSP90 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02721459?term=AREA%5BBasicSearch%5D(XL-888)&rank=3

XL888 + Vemurafenib + Cobimetinib for Unresectable ... The main purpose of this study is to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of XL888 when administered ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.9553

Phase I study of vemurafenib (VEM) and cobimetinib (COB) ... Conclusions: VEM/COB plus XL888 had significant toxicity, requiring dose-reductions that may have contributed to the low PFS rate despite high ...

4. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.35029

Combined BRAF, MEK, and heat‐shock protein 90 inhibition ... A phase 1 study of vemurafenib with the HSP90 inhibitor XL888 in patients with advanced melanoma showed activity equivalent to that of BRAF and MEK inhibitors.

5. curemelanoma.org curemelanoma.org/patient-eng/melanoma-treatment/options/vemurafenib-zelboraf-cobimetinib-cotellic

Vemurafenib (Zelboraf) + Cobimetinib (Cotellic) Learn how combining Vemurafenib (Zelboraf) with Cobimetinib (Cotellic) improves melanoma outcomes by targeting BRAF and MEK pathways together.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9401485/

5-Year Outcomes with Cobimetinib plus Vemurafenib in ... In the primary analysis, with a median follow-up of 7.3 months, median progression-free survival (PFS) was 9.9 versus 6.2 months with cobimetinib plus ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10042754/

Long-Term Real-World Outcomes and Safety of ... Combined treatment with BRAFi and/or MEK inhibitors (MEKi) improves outcomes in advanced melanoma patients in comparison with monotherapy.

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000OtherR.pdf

206192Orig1s000 - accessdata.fda.gov COTELLIC is being approved for use in combination with vemurafenib for the treatment of patients with unresectable or metastatic melanoma ...