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

Must not be taking: Antiretrovirals, CYP3A inhibitors

Disqualifiers: CNS metastases, Cardiovascular risks, 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: Unknown

58 Participants Needed

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. ^{1 2 3 4 5}

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. ^{6 7 8 9 10}

Research Team

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.

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.

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 Overview The 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

Group I: Phase I; Phase II Arm 2 (tazemetostat, dabrafenib, trametinib) Experimental Treatment 8 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 Control 3 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.

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF (V600) Mutation. Dhillon, S.[2022]

In a study of 185 patients with advanced melanoma, the combination therapy of dabrafenib and trametinib (CombiDT) showed a significantly lower incidence of serious skin issues, such as cutaneous squamous cell carcinoma, compared to single-agent BRAF inhibitors like dabrafenib and vemurafenib.

While CombiDT therapy resulted in a higher occurrence of folliculitis, it eliminated the risk of other severe skin conditions associated with BRAF inhibitors, highlighting its potential for safer treatment in melanoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma. Carlos, G., Anforth, R., Clements, A., et al.[2022]

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]

In a phase 1 study involving 72 healthy adults, the budesonide/glycopyrronium/formoterol fumarate metered dose inhaler (BGF MDI) demonstrated similar pharmacokinetic profiles to the budesonide/formoterol fumarate metered dose inhaler (BFF MDI), indicating bioequivalence for the active ingredients.

All inhaler treatments were well tolerated, and despite higher systemic exposure to budesonide and formoterol with BGF MDI and BFF MDI compared to the dry powder inhaler (BUD/FORM DPI), there were no significant differences in adverse events, suggesting a comparable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Maes, A., DePetrillo, P., Siddiqui, S., et al.[2020]

In a study involving 14 patients with moderate-to-severe COPD, the use of mometasone furoate (MF) and formoterol fumarate (F) via a metered-dose inhaler (MDI) resulted in lower systemic exposure to MF compared to using a dry-powder inhaler (DPI), indicating a potentially safer option for patients.

The combination of MF and F administered with a spacer showed even lower systemic exposure levels for both drugs compared to using the MDI without a spacer, but these differences were not clinically significant, and all reported side effects were mild to moderate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Kosoglou, T., Hubbell, J., Xuan, F., et al.[2022]

The budesonide/glycopyrronium/formoterol fumarate inhaler (BGF MDI) demonstrated a similar pharmacokinetic profile to the budesonide/formoterol combination, indicating it effectively delivers the medication in a comparable manner, which is crucial for treating COPD.

The study, involving 84 healthy volunteers, showed that BGF MDI had a low rate of adverse events (3.7-17.9%) and no serious adverse events, suggesting it is a safe option for future clinical trials in COPD management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Darken, P., DePetrillo, P., Reisner, C., et al.[2019]

The novel β2 adrenoceptor agonist, sulfone 10b, demonstrated similar potency and selectivity to salmeterol, with a longer duration of action suitable for once-daily dosing, making it a promising candidate for asthma or COPD treatment.

Sulfone 10b showed no genetic toxicity and was metabolized in a way that likely reduces β2 activity of its metabolites, indicating a potentially safer profile compared to existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Procopiou, PA., Barrett, VJ., Biggadike, K., et al.[2014]

In a Phase II study involving 62 patients with chronic obstructive pulmonary disease, BAT/FF 300/100 was found to be non-inferior to placebo in terms of heart rate changes, indicating it does not significantly affect heart rate compared to a placebo.

The treatment was generally well-tolerated, with adverse events occurring in 38% of patients receiving BAT/FF 300/100, similar to 35% in the placebo group, and no new safety concerns were identified during the 6-week study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, controlled, repeat-dose study of batefenterol/fluticasone furoate compared with placebo in the treatment of COPD. Crim, C., Gotfried, M., Spangenthal, S., et al.[2021]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Exposure-response analyses of BRAF- and MEK-inhibitors dabrafenib plus trametinib in melanoma patients. [2023]

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

Dabrafenib and its use in the treatment of metastatic melanoma. [2020]

3. France pubmed.ncbi.nlm.nih.gov

Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF (V600) Mutation. [2022]

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

Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma. [2022]

5. 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]

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

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]

7. New Zealand pubmed.ncbi.nlm.nih.gov

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]

8. England pubmed.ncbi.nlm.nih.gov

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]

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

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]

10. England pubmed.ncbi.nlm.nih.gov

A randomized, controlled, repeat-dose study of batefenterol/fluticasone furoate compared with placebo in the treatment of COPD. [2021]