E6201 + Dabrafenib for Brain Metastasis from Melanoma

No longer recruiting at 4 trial locations

Overseen By Clinical Trials Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Mayo Clinic

Must be taking: Kinase inhibitors

Must not be taking: Antiretrovirals

Disqualifiers: Uncontrolled infection, Cardiac condition, others

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

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

Compensation: Varies

Number of Visits: 12

Duration: 28 days per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safest and most effective doses of two medications, E6201 and dabrafenib (a BRAF inhibitor), for treating melanoma that has spread to the brain. These drugs block certain proteins that promote cancer cell growth and spread. Suitable candidates for this trial have melanoma with a BRAF V600 mutation that has metastasized to the brain and do not require immediate surgery or radiation. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this potentially groundbreaking therapy.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop your current medications. However, you must have a stable dose of corticosteroids for CNS metastasis for at least 7 days and controlled seizures with stable anti-epileptic treatment for at least 14 days. Bisphosphonates and/or denosumab are allowed. It's best to discuss your specific medications with the trial team.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it allows for stable doses of corticosteroids and anti-epileptic treatments, as well as bisphosphonates and denosumab. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that using E6201 with dabrafenib is effective and generally safe for patients with cancer that has spread to the brain. While side effects occur, they are usually manageable. Some studies administered E6201 on specific days rather than daily, and patients tolerated this schedule well.

Dabrafenib, when combined with trametinib, has already proven effective and generally safe for patients with a specific type of skin cancer that has spread to the brain. Although side effects can vary, this suggests that dabrafenib, even when combined with E6201, might be reasonably safe for similar patients.

In summary, studies have demonstrated positive safety results for these drug combinations, although individual reactions can differ. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of E6201 and dabrafenib for treating brain metastasis from melanoma because of its novel approach. While standard treatments often include surgeries, radiation, or immunotherapies, this duo introduces a targeted strategy. E6201 is a MEK-1/MEKK-1 inhibitor, which blocks specific pathways that cancer cells use to grow, and when paired with dabrafenib, a BRAF inhibitor, it enhances the precision in attacking melanoma cells. This combination not only targets the cancer more directly but also offers potential for improved outcomes with fewer side effects compared to conventional therapies.

What evidence suggests that E6201 and dabrafenib could be effective for brain metastasis from melanoma?

Research shows that dabrafenib, when combined with trametinib, effectively treats patients with BRAF V600-mutated melanoma that has spread to the brain. In real-world situations, this combination has benefited these patients, suggesting potential synergy with another drug, E6201. E6201 blocks enzymes necessary for cancer cell growth. Although direct data on using E6201 with dabrafenib is limited, the success of dabrafenib in treating brain metastases supports its potential when combined with E6201. In this trial, participants will receive E6201 and dabrafenib together, aiming to improve treatment outcomes by more effectively stopping tumor growth than dabrafenib alone. ^{1 3 4 6 7}

Who Is on the Research Team?

Hani Babiker, MD

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

Adults (18+) with stage IV BRAF V600-mutated melanoma that has spread to the brain. They must have at least one brain metastasis, be willing to use contraception, and have certain organ functions within normal limits. Prior immunotherapy is allowed if there's disease progression after treatment. Excluded are those with uncontrolled illnesses, recent heart issues, or who've had extensive prior treatments for metastatic disease.

Inclusion Criteria

You are expected to live for at least 3 more months.

I can take care of myself and perform daily activities.

My hemoglobin level is at least 9 g/dL without needing blood transfusions.

Exclusion Criteria

I still have side effects from my last cancer treatment.

I haven't had a serious heart condition in the last 6 months.

I need immediate treatment to prevent worsening of my brain function.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive MEK-1/MEKK-1 inhibitor E6201 intravenously and dabrafenib orally. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

6 visits (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 6 months for up to 2 years.

Up to 2 years

Every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Dabrafenib
• E6201

Trial Overview The trial tests E6201 combined with dabrafenib on patients with melanoma in the brain due to a specific mutation (BRAF V600). It aims to find the safest dose and see how well these drugs work together compared to when they're used alone.

How Is the Trial Designed?

Group I: Treatment (E6201, dabrafenib) Experimental Treatment 5 Interventions

Patients receive MEK-1/MEKK-1 inhibitor E6201 IV over 2 hours on days 1, 4, 8, 11, 15, and 18, and dabrafenib PO BID on days 1-28. Cycles repeat every 28 days 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?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Dabrafenib demonstrated significant efficacy in treating patients with Val600Glu BRAF-mutant melanoma and brain metastases, with 39.2% of previously untreated patients achieving an overall intracranial response, and 30.8% of those with progressive disease after prior treatment responding as well.

The treatment had an acceptable safety profile, with 22% of patients experiencing grade 3 or worse adverse events, including serious issues like squamous-cell carcinoma and intracranial hemorrhage, indicating that while effective, monitoring for side effects is crucial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Long, GV., Trefzer, U., Davies, MA., et al.[2022]

In a compassionate-use setting involving 271 patients with BRAF V600-mutant unresectable or metastatic melanoma, the combination of dabrafenib and trametinib demonstrated a high overall response rate of 67.3% and a median overall survival of 20.0 months for BRAFi-naive patients.

The treatment was well tolerated with no new safety concerns, showing significant clinical activity even in patients with brain metastases, indicating its effectiveness across different treatment lines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib is effective in the treatment of BRAF V600-mutated metastatic melanoma patients: analysis of patients from the dabrafenib plus trametinib Named Patient Program (DESCRIBE II). Atkinson, V., Sandhu, S., Hospers, G., et al.[2023]

In a large study of 856 patients with advanced BRAF V600-mutant melanoma, the combination of dabrafenib and trametinib showed a median progression-free survival (PFS) of 8.02 months, indicating its efficacy in this patient population.

Factors such as elevated lactate dehydrogenase (LDH), poor Eastern Cooperative Oncology Group Performance Status (ECOG PS), and the presence of brain metastasis were associated with shorter PFS, highlighting the importance of these factors in predicting treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib. Saiag, P., Robert, C., Grob, JJ., et al.[2021]

Dabrafenib, a selective BRAF kinase inhibitor, was found to be safe and well-tolerated in a phase 1 trial involving 184 patients with incurable solid tumors, with a recommended phase 2 dose established at 150 mg twice daily.

The treatment showed significant efficacy, particularly in patients with Val600 BRAF-mutant melanoma, where 69% of patients experienced a response, and notable reductions in brain metastases were observed in 90% of patients with untreated brain lesions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Falchook, GS., Long, GV., Kurzrock, R., et al.[2022]

In a trial involving 24 patients with advanced melanoma and symptomatic brain metastases, vemurafenib was found to be safe, with 23 patients experiencing at least one adverse event, primarily cutaneous squamous cell carcinoma in 17%.

Vemurafenib demonstrated efficacy, achieving a 42% overall partial response rate and significant intracranial tumor regression in 37% of patients, indicating it can lead to meaningful tumor shrinkage and improved patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Dummer, R., Goldinger, SM., Turtschi, CP., et al.[2022]

In the phase 2 COMBI-MB trial involving 125 patients with BRAFV600-mutant melanoma brain metastases, 58% of patients in the asymptomatic cohort (A) achieved an intracranial response, indicating that dabrafenib plus trametinib is effective in this population.

The treatment had a manageable safety profile, with common serious adverse events including pyrexia and decreased ejection fraction, consistent with previous studies in patients without brain metastases, although the median duration of response was relatively short.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Davies, MA., Saiag, P., Robert, C., et al.[2022]

In a phase 3 trial involving 250 patients with BRAF(V600E)-mutated metastatic melanoma, dabrafenib significantly improved median progression-free survival to 5.1 months compared to 2.7 months for dacarbazine, demonstrating its efficacy as a treatment option.

While dabrafenib had a manageable safety profile, with 53% of patients experiencing treatment-related adverse events, it was associated with more skin-related side effects compared to dacarbazine, which had common side effects like nausea and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Hauschild, A., Grob, JJ., Demidov, LV., et al.[2022]

Dabrafenib is a targeted therapy that effectively inhibits V600-mutant BRAF kinase, leading to improved response rates and longer progression-free survival in patients with metastatic melanoma, including those with brain metastases.

While dabrafenib is generally well-tolerated and effective as a standalone treatment, most patients eventually develop resistance, prompting ongoing research into combination therapies to enhance efficacy and combat this resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib. Kainthla, R., Kim, KB., Falchook, GS.[2015]

Citations

1. withpower.com withpower.com/trial/phase-1-metastatic-malignant-neoplasm-in-the-central-nervous-system-5-2022-4bbaf

E6201 + Dabrafenib for Brain Metastasis from Melanoma In combination with trametinib, it has been effective and well-tolerated, with no new safety signals identified. The combination therapy has shown substantial ...

2. jhoponline.com jhoponline.com/melanoma-mminutes/real-world-analysis-finds-that-dabrafenib-trametinib-combination-is-effective-in-patients-with-braf-v600-mutated-melanoma-with-brain-metastases

Real-World Analysis Finds That Dabrafenib/Trametinib ... Real-World Analysis Finds That Dabrafenib/Trametinib Combination Is Effective in Patients with BRAF V600-Mutated Melanoma with Brain Metastases · Metastatic ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12133646/

The safety and efficacy of dabrafenib plus trametinib for ... Our study investigated the safety and effectiveness of combining dabrafenib plus trametinib, as one the most favorable combination therapy of ...

4. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/89/NCT03332589/Prot_SAP_000.pdf

Clinical Study Protocol Phase I This is a Phase 1 study of E6201 for the treatment of CNS metastases in BRAF V600-mutated metastatic melanoma. A total of N = 28 – 34 subjects ...

5. onclive.com onclive.com/view/longterm-and-brain-mets-data-demonstrate-strong-dabrafenibtrametinib-efficacy-in-melanoma

Long-Term and Brain Mets Data Demonstrate Strong ... The response rate increased to 50% for patients with previously untreated melanoma, and one-fifth of patients with untreated disease had IRs to ...

6. mayo.edu mayo.edu/research/clinical-trials/cls-20532385

E6201 Plus Dabrafenib for the Treatment of Metastatic ... The purpose of this study is to determine the overall rate of response of brain metastases in subjects with central nervous system (CNS) metastases.

7. theoncologynurse.com theoncologynurse.com/articles/real-world-analysis-finds-that-dabrafenib-trametinib-combination-is-effective-in-patients-with-braf-v600-mutated-melanoma-with-brain-metastases

Real-World Analysis Finds That Dabrafenib/Trametinib ... Real-world data support a clinical benefit to the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) in patients with BRAF V 600 -mutated ...