Dabrafenib + Trametinib Before and After Surgery for Melanoma

Overseen By Rodabe Amaria, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Chemotherapy, Immunotherapy, Biologics, others

Disqualifiers: Uncontrolled diabetes, Hypertension, Heart failure, 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: 4

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two medications, dabrafenib (a BRAF inhibitor) and trametinib, used before and after surgery to treat melanoma, a specific type of skin cancer. It targets melanoma with a particular BRAF gene mutation, aiming to shrink tumors before surgery and eliminate any remaining cancer cells afterward. Suitable participants have melanoma confirmed as stage IIIB or IIIC and possess a BRAF mutation. As a Phase 2 trial, it measures the treatment's effectiveness in an initial, smaller group, providing an opportunity to contribute to important research.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions that you cannot use certain prohibited medications during the study. It's best to discuss your current medications with the trial team to see if any are prohibited.

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

Research has shown that using dabrafenib and trametinib together is generally safe. In one study, less than 5% of patients experienced serious side effects, such as fever and other treatment-related reactions. Another study found that long-term use of these drugs helped patients with melanoma, a type of skin cancer, live longer. However, some patients developed new cases of basal cell carcinoma, another type of skin cancer, though this was uncommon. Overall, the treatment is considered well-tolerated, with most side effects being manageable. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for melanoma?

Dabrafenib and trametinib are unique because they specifically target mutations in the BRAF gene, which are common in melanoma patients. Unlike traditional chemotherapy, which attacks all rapidly dividing cells, these drugs focus on disrupting the cancer's growth pathways, potentially leading to fewer side effects. Researchers are excited about this combination because it can be used both before and after surgery, aiming to shrink tumors initially and then prevent recurrence, offering a more comprehensive approach to treating melanoma.

What evidence suggests that dabrafenib and trametinib might be an effective treatment for melanoma?

Research has shown that using the drugs dabrafenib and trametinib together can effectively treat melanoma with a specific change in the BRAF gene. Studies have found that this drug combination can shrink melanoma tumors and slow their growth. In this trial, participants will receive dabrafenib and trametinib before surgery to potentially reduce tumor size, which may improve surgical outcomes. After surgery, participants will continue with dabrafenib and trametinib to assess long-term benefits. Previous studies revealed that about one-third of patients with melanoma that cannot be surgically removed or has spread experienced long-term benefits, with a five-year survival rate of about 34%. ^{2 4 6 7 8}

Who Is on the Research Team?

Rodabe N. Amaria

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with stage IIIB-C melanoma that can be removed by surgery and have a BRAF V600 mutation. Participants must be fit for surgery, not on current cancer treatments, able to consent, and meet specific health criteria including blood counts. Women of childbearing potential and men must agree to use contraception.

Inclusion Criteria

The surgical team has approved me as fit for surgery.

Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

My melanoma has a BRAF mutation (V600E or V600K).

Exclusion Criteria

I do not have stomach or intestine problems that affect how drugs work in my body.

Pregnant or lactating female

I have not taken any cancer treatment or experimental drugs in the last 28 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive dabrafenib and trametinib orally for 8 weeks before surgery

8 weeks

Regular visits for monitoring and assessment

Surgery

Participants undergo surgery to remove the tumor

1 week

1 visit (in-person)

Adjuvant Treatment

Participants receive dabrafenib and trametinib orally for 44 weeks after surgery

44 weeks

Regular visits for monitoring and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Dabrafenib
• Therapeutic Conventional Surgery
• Trametinib

Trial Overview The study tests the effects of dabrafenib and trametinib before and after surgery in shrinking tumors and eliminating remaining cancer cells. It's a phase II trial where all participants receive both drugs; there are no comparison groups.

How Is the Trial Designed?

Group I: Treatment (dabrafenib, trametinib, surgery) Experimental Treatment 4 Interventions

Patients receive dabrafenib PO BID and trametinib PO QD for 8 weeks. After completion of 8 weeks of dabrafenib and trametinib, patients undergo surgery. Approximately 1 week after surgery, patients receive dabrafenib PO BID and trametinib PO QD for 44 additional weeks 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

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]

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 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 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]

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]

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 phase II trial involving 21 patients with unresectable locally advanced melanoma, neoadjuvant treatment with dabrafenib and trametinib enabled radical surgical resection in 86% of participants, with 81% achieving complete (R0) resection.

The median recurrence-free survival for patients who underwent surgery was 9.9 months, indicating that this combination therapy is a promising option for patients with previously inoperable melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Cytoreductive Treatment With BRAF/MEK Inhibition of Prior Unresectable Regionally Advanced Melanoma to Allow Complete Surgical Resection, REDUCTOR: A Prospective, Single-arm, Open-label Phase II Trial. Blankenstein, SA., Rohaan, MW., Klop, WMC., et al.[2021]

The combination of dabrafenib and trametinib significantly improves progression-free survival and overall survival in patients with unresectable or metastatic melanoma with a BRAF (V600E/K) mutation, compared to monotherapy with dabrafenib or vemurafenib, based on results from two large phase III studies.

This combination therapy is well-tolerated, showing no increase in overall toxicity compared to monotherapy, and results in fewer skin-related adverse events, likely due to reduced activation of the MAPK pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF (V600) Mutation. Dhillon, S.[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]

In a real-world study of 20 patients with resected stage III BRAF-mutant melanoma, 90% experienced treatment-related toxicities requiring at least one interruption, highlighting the need for careful monitoring during therapy.

The most common adverse events included recurrent fever and chills (85%) and liver abnormalities (50%), with 65% of patients permanently discontinuing treatment due to these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment related toxicities with combination BRAF and MEK inhibitor therapy in resected stage III melanoma. Homan, M., Warrier, G., Lao, CD., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31166680/

Five-Year Outcomes with Dabrafenib plus Trametinib in ... The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several ...

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

Dabrafenib (Tafinlar) + Trametinib (Mekinist) Slowing the growth or spread of melanoma; Shrinking melanoma tumors; Helping patients live longer. Results from two Phase III clinical trials in 2014 showed ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0923753424001418

Five-year analysis of neoadjuvant dabrafenib and ... Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma.

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa1904059

Five-Year Outcomes with Dabrafenib plus Trametinib in ... First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e21515

Results of the study GEM1801. | Journal of Clinical Oncology Response to treatment also showed correlation with OS (3-years OS rate: 57.1% vs 23% vs 46.9% vs 26.8% for CR, PR, SD and PD, respectively; p < ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5834102/

long-term survival and safety analysis of a phase 3 study These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and ...

7. nejm.org nejm.org/doi/full/10.1056/NEJMoa2404139

Final Results for Adjuvant Dabrafenib plus Trametinib in ... The analysis of overall survival showed that the risk of death was 20% lower with combination therapy than with placebo, but the benefit was not ...

8. gsk.com gsk.com/en-gb/media/press-releases/trametinib-mekinist-and-dabrafenib-tafinlar-combination-demonstrated-overall-survival-benefit-compared-to-vemurafenib/

Trametinib (Mekinist™) and dabrafenib (Tafinlar ... The incidence of basal cell carcinoma was 9% (5/55) in patients receiving the combination compared to 2% (1/53) in patients receiving Tafinlar as a single agent ...