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

52 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination Dabrafenib and Trametinib for advanced melanoma?

Research shows that the combination of Dabrafenib and Trametinib is more effective and safer than using a BRAF inhibitor alone for treating metastatic melanoma, leading to improved survival rates and better outcomes for patients with BRAF mutations. ^{1 2 3 4 5}

Is the combination of dabrafenib and trametinib safe for humans?

The combination of dabrafenib and trametinib is generally considered safe, with most patients experiencing mild to moderate side effects that can be managed with dose adjustments. However, some serious side effects like heart issues and high fever can occur, so it's important to monitor and manage these during treatment. ^{2 5 6 7 8}

How is the drug combination of Dabrafenib, Encorafenib, Nivolumab, and Trametinib unique for treating advanced melanoma?

This drug combination is unique because it combines BRAF and MEK inhibitors (Dabrafenib, Encorafenib, and Trametinib) with an immune checkpoint inhibitor (Nivolumab), potentially addressing both tumor growth and immune system activation, which may improve outcomes in patients with advanced melanoma. ^{4 9 10 11 12}

What is the purpose of this trial?

This phase II trial studies the side effects and how well nivolumab with trametinib and dabrafenib, or encorafenib and binimetinib work in treating patients with BRAF-mutated stage III-IV melanoma that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as nivolumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Trametinib, dabrafenib, encorafenib, and binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known if nivolumab with trametinib and dabrafenib, or encorafenib and binimetinib may work better in treating patients with BRAF-mutated melanoma.

Research Team

Hussein A. Tawbi

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

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

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

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

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]

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]

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]

References

1. United States 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. [2017]

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

Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. [2022]

3. England pubmed.ncbi.nlm.nih.gov

BRAFi/MEKi in patients with metastatic melanoma: predictive factors of complete response. [2019]

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

Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. [2023]

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

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

6. Japan 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. [2022]

7. England pubmed.ncbi.nlm.nih.gov

The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma. [2017]

8. France pubmed.ncbi.nlm.nih.gov

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

9. Switzerland pubmed.ncbi.nlm.nih.gov

COMBI-r: A Prospective, Non-Interventional Study of Dabrafenib Plus Trametinib in Unselected Patients with Unresectable or Metastatic BRAF V600-Mutant Melanoma. [2023]

10. 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]

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

Clinical, Molecular, and Immune Analysis of Dabrafenib-Trametinib Combination Treatment for BRAF Inhibitor-Refractory Metastatic Melanoma: A Phase 2 Clinical Trial. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Combination dabrafenib and trametinib in the management of advanced melanoma with BRAFV600 mutations. [2018]