E6201 + Dabrafenib for Brain Metastasis from Melanoma

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

25 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I tests the safety, side effects, and best dose of E6201 in combination with dabrafenib in treating patients with BRAF V600 mutated melanoma that has spread to the central nervous system (central nervous system metastases). E6201 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Dabrafenib is used in patients whose cancer has a mutated (changed) form of a gene called BRAF. It is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals tumor cells to multiply. This helps stop the spread of tumor cells. Giving E6201 and dabrafenib together may work better in treating patients with BRAF V600 mutated melanoma that has spread to the central nervous system than either drug alone.

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.

What data supports the idea that E6201 + Dabrafenib for Brain Metastasis from Melanoma is an effective drug?

The available research shows that dabrafenib, when used in combination with other drugs like trametinib, has improved outcomes for patients with melanoma that has spread to the brain. Specifically, studies have shown that dabrafenib can improve response rates and extend the time patients live without the disease getting worse. While the research does not specifically mention E6201, the combination of dabrafenib with other drugs has been effective, suggesting potential benefits when combined with E6201 as well. ^{1 2 3 4 5}

What data supports the effectiveness of the drug combination E6201 and Dabrafenib for treating brain metastasis from melanoma?

Research shows that Dabrafenib, a drug targeting a specific mutation in melanoma, has improved response rates and survival in patients with brain metastases from melanoma. It is often used in combination with other drugs to enhance effectiveness and overcome resistance. ^{1 2 3 4 5}

What safety data is available for the treatment of E6201 + Dabrafenib for brain metastasis from melanoma?

Dabrafenib, a BRAF inhibitor, has been studied extensively in patients with BRAF V600-mutated metastatic melanoma, including those with brain metastases. Clinical trials have shown that dabrafenib has a well-tolerated safety profile, with manageable toxicity. In combination with trametinib, it has been effective and well-tolerated, with no new safety signals identified. The combination therapy has shown substantial clinical activity and a manageable safety profile in patients with brain metastases. However, specific safety data for the combination of E6201 and Dabrafenib is not detailed in the provided research. ^{1 2 5 6 7}

Is the combination of E6201 and Dabrafenib safe for treating brain metastasis from melanoma?

Dabrafenib, used alone or with other drugs, has been shown to have a manageable safety profile in patients with melanoma, including those with brain metastases. It is generally well tolerated with few drug interactions, although resistance can develop over time. No new safety concerns were identified when dabrafenib was combined with trametinib in patients with BRAF V600-mutated melanoma. ^{1 2 5 6 7}

Is the drug Dabrafenib a promising treatment for brain metastasis from melanoma?

Yes, Dabrafenib is a promising drug for treating brain metastasis from melanoma. It targets a specific mutation in the BRAF gene, which is common in aggressive tumors like melanoma. Clinical trials have shown that Dabrafenib improves response rates and helps patients live longer without the disease getting worse. It is effective on its own and even more so when combined with other treatments. ^{1 2 3 5 8}

What makes the drug combination of E6201 and Dabrafenib unique for treating brain metastasis from melanoma?

The combination of E6201 and Dabrafenib is unique because Dabrafenib specifically targets the BRAF V600 mutation, which is common in aggressive melanoma, including those with brain metastases. This combination aims to improve response rates and overcome resistance that often develops with Dabrafenib alone. ^{1 2 3 5 8}

Research Team

Hani Babiker, MD

Principal Investigator

Mayo Clinic

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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 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]

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]

References

1. England 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. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. [2022]

3. England 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. [2021]

4. England 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. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

Dabrafenib. [2015]

6. England 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). [2023]

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

Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. [2022]

8. England 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. [2022]