Navitoclax + Dabrafenib + Trametinib for Melanoma

Recruiting at 52 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anticoagulants, Antiplatelets, Anticonvulsants, others

Disqualifiers: Brain metastasis, Cardiovascular risk, 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

75 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, especially those that affect platelet function, like clopidogrel and ibuprofen, and some herbal supplements. You should also avoid medications that interact with the study drugs, such as certain antibiotics and antifungals. It's important to discuss your current medications with the study team to ensure they don't interfere with the trial.

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

Research shows that the combination of Dabrafenib and Trametinib improves survival and tumor response in patients with advanced melanoma that has a specific BRAF mutation. This combination has been shown to help patients live longer and reduce tumor size compared to other treatments. ^{1 2 3 4 5}

What is known about the safety of the combination of Dabrafenib, Trametinib, and Navitoclax for melanoma?

The combination of Dabrafenib and Trametinib has been studied for safety in melanoma and other conditions, showing common side effects like fever, fatigue, and skin issues, which can be managed effectively. However, specific safety data for the addition of Navitoclax to this combination in melanoma is not provided in the available research. ^{3 6 7 8 9}

How is the drug combination of Navitoclax, Dabrafenib, and Trametinib unique for treating melanoma?

This treatment combines Navitoclax, which targets cancer cell survival, with Dabrafenib and Trametinib, which inhibit specific proteins in the MAPK pathway involved in melanoma growth. This combination is unique because it targets multiple pathways in melanoma cells, potentially improving outcomes for patients with BRAF-mutant melanoma. ^{1 3 4 8 10}

What is the purpose of this trial?

This phase I/II trial studies the side effects and best dose of dabrafenib, trametinib, and navitoclax and to see how well they work in treating patients with BRAF mutant melanoma or solid tumors that has spread from where it first started (primary site) to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Navitoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of tumor cells by blocking Bcl-2, a protein needed for tumor cell survival. Giving navitoclax, dabrafenib, and trametinib may help shrink tumors in patients with melanoma.

Research Team

Ryan J Sullivan

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Eligibility Criteria

Adults with BRAF mutant melanoma that's spread or can't be surgically removed, who have good organ function and no recent significant bleeding or other serious illnesses. They must not have had certain treatments recently, agree to use non-hormonal birth control, and be able to swallow pills. Those with known allergies to the drugs being tested or similar compounds are excluded.

Inclusion Criteria

Your blood clotting tests should be within the normal range.

Your white blood cell count is equal to or greater than 3,000 per microliter.

You must have a certain amount of a type of white blood cell called neutrophils in your blood.

Exclusion Criteria

Patients who are receiving any other investigational agents have received any other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study

I am HIV-positive but not on any HIV medication that would interfere with the study drugs.

I have not taken navitoclax, BRAF, or MEK inhibitors.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Patients receive navitoclax, dabrafenib, and trametinib to determine the maximum tolerated dose and safety profile

28 days per cycle

Regular visits for ECHO/MUGA, MRI/CT, biopsy, and blood sample collection

Phase II Treatment

Randomized treatment with dabrafenib and trametinib, with or without navitoclax, to estimate response rates and compare tumor regression

28 days per cycle

Regular visits for ECHO/MUGA, MRI/CT, biopsy, and blood sample collection

Follow-up

Participants are monitored for safety and effectiveness after treatment

28 days and every 3 months thereafter until disease progression or death

Clinical evaluation visits

Long-term Follow-up

Survival follow-up every 12 months for 3 years

3 years

Treatment Details

Interventions

• Dabrafenib; Trametinib
• Navitoclax

Trial Overview The trial is testing a combination of three drugs: dabrafenib, trametinib, and navitoclax for advanced melanoma with a specific mutation (BRAF V600E/K). It aims to find the best dose and see how well these drugs work together in stopping cancer growth by blocking enzymes and proteins needed by cancer cells.

Participant Groups

Group I: Arm II (dabrafenib, trametinib, and navitoclax) Experimental Treatment 11 Interventions

Patients receive navitoclax PO QD days -7 to -1 of cycle 1 only. Patients also receive dabrafenib PO BID, trametinib PO QD, and navitoclax PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA, MRI or CT, biopsy, and collection of blood samples throughout the trial.

Group II: Arm I (dabrafenib, trametinib) Experimental Treatment 10 Interventions

ARM I: Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA, MRI or CT, biopsy, and collection of blood samples throughout the trial.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

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]

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 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]

Dabrafenib plus trametinib has been approved for treating non-small cell lung cancer (NSCLC) with the BRAF V600E mutation, showing a response rate of approximately 65% and a median progression-free survival of 10-11 months based on clinical trials.

While the combination therapy has a manageable safety profile, it presents unique toxicities such as pyrexia, fatigue, and nausea, which may be unfamiliar to oncologists treating lung cancer, but can be effectively managed using strategies developed from experience in melanoma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Event Management in Patients with BRAF V600E-Mutant Non-Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib. Chalmers, A., Cannon, L., Akerley, W.[2020]

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]

The combination of dabrafenib and trametinib showed promising antitumor activity in Japanese patients with BRAF V600E/K mutant melanoma, with an overall response rate of 83% in both phase 1 and phase 2 of the study involving 12 patients.

The treatment was generally well-tolerated, with common adverse events including fever (75%) and increased liver enzymes (67%), indicating that while effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced cutaneous melanoma. Yamazaki, N., Tsutsumida, A., Takahashi, A., et al.[2018]

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]

References

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

Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. [2023]

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

BRAFi/MEKi in patients with metastatic melanoma: predictive factors of complete response. [2019]

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

Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB-C, BRAFV600 mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial. [2020]

5. United States 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. [2021]

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

Dabrafenib plus trametinib for compassionate use in metastatic melanoma: A STROBE-compliant retrospective observational postauthorization study. [2021]

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

Adverse Event Management in Patients with BRAF V600E-Mutant Non-Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib. [2020]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Treatment related toxicities with combination BRAF and MEK inhibitor therapy in resected stage III melanoma. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced cutaneous melanoma. [2018]

10. 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]