Drug Combinations for Advanced Melanoma

Overseen By Hussein A Tawbi

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Corticosteroids, Antiretrovirals

Disqualifiers: Autoimmune disease, HIV, Hepatitis, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 58

Duration: Up to 3 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a combination of drugs can more effectively treat advanced melanoma, a type of skin cancer that has spread or cannot be surgically removed. The study targets patients with melanoma that has a specific BRAF mutation, testing whether combining nivolumab (an immunotherapy drug) with other drugs like dabrafenib (a BRAF inhibitor) can halt cancer cell growth. Different treatment groups will try various drug combinations. Participants should have BRAF-mutated melanoma and have experienced cancer spread or growth despite previous treatments. As a Phase 2 trial, this research measures how well the treatment works in an initial, smaller group of people.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on certain treatments like corticosteroids or immunosuppressive medications, you may need to adjust or stop them before starting the trial. It's best to discuss your specific medications with the trial team.

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

Research has shown that combining nivolumab with dabrafenib and trametinib is generally safe for patients with advanced melanoma. Studies have found that this combination can improve survival rates over two years. While some side effects may occur, they are usually manageable. Patients using these drugs demonstrated better survival outcomes, indicating that the treatment can be safe and effective.

Research also suggests that the combination of nivolumab with encorafenib and binimetinib is safe. The 18-month survival rates for patients using this combination are encouraging. Again, side effects can occur, but they are often controlled with proper care.

Studies on the combination of nivolumab and trametinib indicate that this treatment is generally well-tolerated. Evidence suggests better overall survival rates for those starting with this immunotherapy. Any side effects are typically manageable.

Each of these combinations offers a different way to slow tumor growth. While any treatment can have side effects, studies show they are often manageable, making these treatments a viable option for many patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for advanced melanoma because they combine targeted therapies with immunotherapy to potentially enhance effectiveness. Unlike standard treatments that often focus on one pathway, these combinations involve drugs like dabrafenib and encorafenib, which target specific mutations in the BRAF gene, alongside nivolumab, an immunotherapy that helps the immune system recognize and attack cancer cells. Another distinctive feature is the inclusion of trametinib and binimetinib, which inhibit the MEK pathway, potentially preventing cancer cell growth. This multi-faceted approach could offer more comprehensive control of the disease compared to existing options.

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

Research has shown that using nivolumab with dabrafenib and trametinib, which participants in Arm A of this trial may receive, can help treat advanced melanoma. Studies have found that dabrafenib and trametinib work better together than when used alone for this type of cancer. Nivolumab, an immunotherapy drug, might help the immune system fight cancer more effectively. Early findings suggest that combining nivolumab with encorafenib and binimetinib, as studied in Arm C of this trial, could help patients with BRAF-mutated melanoma by delaying the cancer's progression. Overall, these drug combinations are being studied for their potential to better control the growth and spread of melanoma. ^{2 3 5 6 7}

Who Is on the Research Team?

Hussein A. Tawbi

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with stage III-IV melanoma that's spread or can't be surgically removed, specifically those with a BRAF V600 mutation. It includes patients who've had prior treatments except for BRAFi/MEKi and requires stable brain metastases if present. Participants must have good organ function, not need high steroid doses, and agree to contraception.

Inclusion Criteria

Your hemoglobin level is higher than 9.0 grams per deciliter within one week before you join the study.

I've had treatments for melanoma but not with BRAFi or MEKi. Any side effects from previous treatments are minimal.

Your liver enzymes (AST/ALT) should not be more than three times the normal level.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive nivolumab, dabrafenib, and trametinib or encorafenib and binimetinib in cycles of 28 days for up to 3 years

Up to 3 years

Every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

3 years

30 days post-treatment, then every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Dabrafenib
• Encorafenib
• Laboratory Biomarker Analysis
• Nivolumab
• Pharmacological Study
• Trametinib

Trial Overview The study tests how well nivolumab (an immunotherapy drug) works with trametinib and dabrafenib or encorafenib and binimetinib (targeted therapies) in treating advanced melanoma. The goal is to see which combination better inhibits tumor growth by blocking enzymes needed for cell growth.

How Is the Trial Designed?

Group I: Arm C (NEB) Experimental Treatment 5 Interventions

Patients receive nivolumab IV over 30 minutes on day 1 and 15, encorafenib PO QD on days 1-28, and binimetinib PO BID on days 1-28. Cycles repeats every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity.

Group II: Arm B (NT, closed to accrual) Experimental Treatment 4 Interventions

Patients receive nivolumab IV over 30 minutes on day 1 and 15, and trametinib PO QD on days 1-28. Cycles repeats every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity.

Group III: Arm A (NDT, CLOSED) Experimental Treatment 5 Interventions

Patients receive nivolumab IV over 30 minutes on day 1, dabrafenib PO BID on days 1-28, and trametinib PO QD on days 1-28. Cycles repeats every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity.

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

Approved in European Union as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation
• Adjuvant treatment of melanoma with a BRAF V600 mutation

Approved in United States as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600E mutation
• Adjuvant treatment of melanoma with a BRAF V600E or V600K mutation
• Metastatic non-small cell lung cancer with a BRAF V600E mutation

Approved in Canada as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation
• Adjuvant treatment of melanoma with a BRAF V600 mutation

Approved in Japan as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 78 BRAF inhibitor-naive patients with BRAF V600 mutation-positive metastatic melanoma treated with dabrafenib and trametinib, the median overall survival was over 2 years, with 72% of patients alive at 1 year and 47% at 3 years.

Approximately 20% of patients were progression-free at 3 years, with better outcomes associated with having fewer than three organ metastases and lower baseline lactate dehydrogenase levels, suggesting these factors may help predict durable responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. Long, GV., Weber, JS., Infante, JR., et al.[2022]

In a study involving 112 Japanese patients with unresectable and metastatic melanoma, the combination therapy of dabrafenib and trametinib showed a significant objective response rate of 55.45%, indicating its efficacy in treating BRAF V600 mutation-positive melanoma.

The safety profile of the combination therapy was consistent with previous trials, with 75% of patients experiencing adverse drug reactions, the most common being pyrexia and hepatic function abnormalities, but no new safety concerns were identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interim analysis for post-marketing surveillance of dabrafenib and trametinib combination therapy in Japanese patients with unresectable and metastatic melanoma with BRAF V600 mutation. Teshima, Y., Kizaki, M., Kurihara, R., et al.[2022]

Dabrafenib and trametinib, both targeting the MAPK pathway, have shown significant efficacy in treating BRAF-mutant metastatic melanoma, with dabrafenib achieving a 59% objective response rate and improved progression-free survival compared to traditional chemotherapy.

The combination of dabrafenib and trametinib resulted in higher response rates and longer median progression-free survival than dabrafenib alone, while also presenting less cutaneous toxicity, making it a promising treatment option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma. Menzies, AM., Long, GV.[2022]

Combination therapy with dabrafenib and trametinib for BRAF-mutated metastatic melanoma showed a high overall response rate, with 64.6% of patients achieving a partial response and 6.2% achieving a complete response, indicating its efficacy in treating this condition.

The treatment was found to be relatively safe, with only 8.3% of patients experiencing severe adverse events, and 62.5% of patients remained on treatment, suggesting good tolerability in a real-life clinical setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined therapy with dabrafenib and trametinib in BRAF-mutated metastatic melanoma in a real-life setting: the INT Milan experience. Cavalieri, S., Di Guardo, L., Cimminiello, C., et al.[2017]

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 of 66 patients with metastatic BRAF-mutated melanoma treated with dabrafenib and trametinib, 15 patients achieved a complete response (CR), indicating a significant survival benefit from this treatment.

The likelihood of achieving a complete response was higher in patients with smaller lesions (39.3% CR rate) compared to those with larger lesions (10.5% CR rate), suggesting that lesion size and the number of metastatic sites are important factors in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BRAFi/MEKi in patients with metastatic melanoma: predictive factors of complete response. Ribero, S., Malavenda, O., Fava, P., et al.[2019]

Trametinib, when combined with dabrafenib, significantly prolongs median survival by about 8 months compared to vemurafenib alone in patients with metastatic or inoperable melanoma, based on a study of 704 patients.

While trametinib can enhance treatment efficacy, it also carries serious adverse effects, including life-threatening conditions like heart failure and gastrointestinal perforation, making it essential for patients to weigh the benefits against the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trametinib (MEKINIST°) Metastatic or inoperable BRAF V600-positive melanoma: a few extra months of life. [2019]

In a phase 3 trial involving 870 patients with resected stage III melanoma and BRAF V600 mutations, the combination of dabrafenib and trametinib significantly improved relapse-free survival, with a 3-year rate of 58% compared to 39% for the placebo group.

The combination therapy also showed a higher overall survival rate of 86% versus 77% in the placebo group, indicating its efficacy without introducing new safety concerns, as the safety profile was consistent with previous studies in metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. Long, GV., Hauschild, A., Santinami, M., et al.[2023]

The combination of BRAF inhibitor dabrafenib and MEK inhibitor trametinib significantly improves outcomes for metastatic melanoma patients compared to single-agent therapies, with a manageable safety profile.

While 98% of patients experience at least one adverse event during combination therapy, these events are mostly mild to moderate and can be effectively managed, highlighting the importance of addressing even minor side effects to maintain patients' quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma. Knispel, S., Zimmer, L., Kanaki, T., et al.[2017]

Citations

1. cancer.gov cancer.gov/news-events/cancer-currents-blog/2021/advanced-melanoma-braf-immunotherapy-first

Immunotherapy Combination for BRAF+ Melanoma - NCI Both drug combinations have been found to be effective in people with advanced melanoma. But for the estimated 50% of people whose melanomas ...

2. curemelanoma.org curemelanoma.org/patient-eng/melanoma-treatment/options/dabrafenib-tafinlar-trametinib-mekinist

Dabrafenib (Tafinlar) + Trametinib (Mekinist) Through clinical trials, cancer researchers have found that combining dabrafenib and trametinib can treat advanced melanoma more effectively than either ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11361351/

Real-world use and outcomes of targeted therapy ... These results inform on prescription preferences and clinical outcomes for BRAFV600-mutated melanoma patients in the first-line adjuvant setting.

4. aimatmelanoma.org aimatmelanoma.org/results-prove-immunotherapy-should-be-the-initial-treatment-for-braf-mutant-tumors/

Results Prove Immunotherapy Should be the Initial ... After two years of treatment, 88.8% of patients who received immunotherapy first were free from brain and central nervous system or CNS ...

5. cancernetwork.com cancernetwork.com/view/nivolumab-ipilimumab---dabrafenib-and-trametinib-improved-survival-for-braf-metastatic-melanoma

Nivolumab/Ipilimumab +/- Dabrafenib and Trametinib ... The combination of nivolumab and ipilimumab followed by treatment with dabrafenib and trametinib, if necessary, resulted in greater overall survival at 2 years.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4075957/

New developments in the treatment of metastatic melanoma Treatment with dabrafenib plus trametinib is emerging as an efficacious option in the management of BRAF-mutant advanced melanoma.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02224781

Study Details | NCT02224781 | Dabrafenib and Trametinib ... This phase III trial studies how well initial treatment with ipilimumab and nivolumab followed by dabrafenib and trametinib works and compares it to initial ...