58 Participants Needed

Tazemetostat + Dabrafenib + Trametinib for Melanoma

Recruiting at 18 trial locations
Age: 18+
Sex: Any
Trial Phase: Phase 1 & 2
Sponsor: National Cancer Institute (NCI)
Must be taking: BRAF/MEK inhibitors
No Placebo GroupAll trial participants will receive the active study treatment (no placebo)
Breakthrough TherapyThis drug has been fast-tracked for approval by the FDA given its high promise

Trial Summary

What is the purpose of this trial?

This phase I/II trial investigates the best dose, possible benefits and/or side effects of tazemetostat in combination with dabrafenib and trametinib in treating patients with melanoma that has a specific mutation in the BRAF gene (BRAFV600) and that has spread from where it first started (primary site) to other places in the body (metastatic). Tazemetostat, dabrafenib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving tazemetostat in combination with dabrafenib and trametinib may stabilize BRAFV600 mutated melanoma.

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

The trial does not specify if you need to stop taking your current medications, but it does exclude those using certain medications that strongly affect specific enzymes. It's best to discuss your current medications with the trial team to see if they might interfere with the study.

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

Research shows that the combination of Dabrafenib and Trametinib is effective for treating melanoma with a specific BRAF mutation, improving survival rates and response compared to using Dabrafenib alone. This combination also has fewer skin-related side effects than using a BRAF inhibitor alone.12345

What makes the drug combination of Tazemetostat, Dabrafenib, and Trametinib unique for treating melanoma?

This drug combination is unique because it combines Tazemetostat, which targets a specific protein involved in cancer cell growth, with Dabrafenib and Trametinib, which are known to inhibit pathways that help melanoma cells survive and multiply. This multi-targeted approach may offer a more comprehensive treatment strategy compared to using each drug alone.678910

Research Team

TM

Tanner M Johanns

Principal Investigator

Yale University Cancer Center LAO

Eligibility Criteria

Adults with BRAFV600 mutated metastatic melanoma that has worsened despite treatment can join this trial. They must have had prior anti-PD-1 therapy, be able to perform daily activities (ECOG <=2), and have organs functioning well. Pregnant women, those with certain psychiatric or medical conditions, or a history of specific cancers are excluded.

Inclusion Criteria

My melanoma is BRAF V600E/K mutation positive.
My blood clotting tests are within normal limits.
My cancer progressed despite being on BRAF/MEK inhibitors.
See 21 more

Exclusion Criteria

I have had interstitial lung disease or pneumonitis.
I have brain melanoma that hasn't been treated or is getting worse, but no spinal issues.
You have a history of certain heart problems like prolonged QT interval, recent heart attacks or procedures, severe heart failure, abnormal heart valves, uncontrolled arrhythmias, or certain high blood pressure that can't be controlled with medication.
See 21 more

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase I

Dose-escalation trial of tazemetostat in combination with dabrafenib and trametinib for BRAF/MEK inhibitor-resistant metastatic melanoma

Up to 30 days per cycle
Regular visits for CT scan, MRI, and other assessments

Treatment Phase II

Randomized trial of tazemetostat alone or in combination with dabrafenib and trametinib, with crossover option after progression

28 days per cycle, up to 3 years
Regular visits for CT scan, MRI, and other assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days post-treatment, then annually

Treatment Details

Interventions

  • Dabrafenib Mesylate
  • Tazemetostat Hydrobromide
  • Trametinib Dimethyl Sulfoxide
Trial OverviewThe trial is testing Tazemetostat combined with Dabrafenib and Trametinib to see if it's safe and effective for advanced melanoma after the usual treatments fail. It includes finding the right dose and understanding how these drugs might control tumor growth by blocking enzymes.
Participant Groups
2Treatment groups
Experimental Treatment
Active Control
Group I: Phase I; Phase II Arm 2 (tazemetostat, dabrafenib, trametinib)Experimental Treatment8 Interventions
Patients receive tazemetostat PO BID, dabrafenib PO BID, and trametinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy, CT scan, MRI, and MUGA or ECHO throughout the study.
Group II: Phase II, Arm 1 (tazemetostat)Active Control3 Interventions
Patients receive tazemetostat PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan and MRI throughout the study. At the time of progression, patients may crossover to Arm 2 after completion of radiation therapy.

Find a Clinic Near You

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials
14,080
Recruited
41,180,000+

Findings from Research

In a study of 140 melanoma patients, higher levels of trametinib (Cmin ≥ 15.6 ng/mL) were associated with significantly longer overall survival (22.8 months vs. 12.6 months), suggesting that monitoring trametinib levels could improve treatment outcomes.
Dabrafenib exposure did not correlate with patient survival, and neither drug exposure was linked to significant toxicities, indicating that while trametinib levels are crucial for efficacy, safety remains a concern with dose adjustments.
Exposure-response analyses of BRAF- and MEK-inhibitors dabrafenib plus trametinib in melanoma patients.Groenland, SL., Janssen, JM., Nijenhuis, CM., et al.[2023]
Dabrafenib, a targeted therapy for melanoma with BRAF mutations, shows high response rates and improved overall and progression-free survival compared to traditional chemotherapy.
When combined with trametinib, a MEK inhibitor, dabrafenib enhances treatment responses and clinical efficacy, while its toxicity profile is manageable and distinct from that of chemotherapy.
Dabrafenib and its use in the treatment of metastatic melanoma.Bowyer, S., Lee, R., Fusi, A., et al.[2020]
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.
Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF (V600) Mutation.Dhillon, S.[2022]

References

Exposure-response analyses of BRAF- and MEK-inhibitors dabrafenib plus trametinib in melanoma patients. [2023]
Dabrafenib and its use in the treatment of metastatic melanoma. [2020]
Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF (V600) Mutation. [2022]
Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma. [2022]
Economic Evaluation of Three BRAF + MEK Inhibitors for the Treatment of Advanced Unresectable Melanoma With BRAF Mutation From a US Payer Perspective. [2023]
Pharmacokinetics of Co-Suspension Delivery Technology Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate (BGF MDI) and Budesonide/Formoterol Fumarate Dihydrate (BFF MDI) Fixed-Dose Combinations Compared With an Active Control: A Phase 1, Randomized, Single-Dose, Crossover Study in Healthy Adults. [2020]
Comparison of the systemic bioavailability of mometasone furoate after oral inhalation from a mometasone furoate/formoterol fumarate metered-dose inhaler versus a mometasone furoate dry-powder inhaler in patients with chronic obstructive pulmonary disease. [2022]
The pharmacokinetics of three doses of budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler compared with active controls: A Phase I randomized, single-dose, crossover study in healthy adults. [2019]
Discovery of a rapidly metabolized, long-acting β(2) adrenergic receptor agonist with a short onset time incorporating a sulfone group suitable for once-daily dosing. [2014]
A randomized, controlled, repeat-dose study of batefenterol/fluticasone furoate compared with placebo in the treatment of COPD. [2021]