Navitoclax + Dabrafenib + Trametinib for Melanoma

Not currently recruiting at 56 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of a combination of three drugs—dabrafenib, trametinib, and navitoclax—for treating melanoma with a specific BRAF mutation that has spread or cannot be surgically removed. Dabrafenib and trametinib block certain enzymes to halt tumor growth, while navitoclax targets a protein that aids tumor cell survival. The trial seeks to determine the optimal doses and monitor side effects. Individuals with BRAF-mutant melanoma or similar tumors that cannot be removed might be suitable candidates, particularly if other treatments have proven ineffective. As a Phase 1, Phase 2 trial, this research focuses on understanding the treatment's effects in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking advancements in melanoma treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using dabrafenib and trametinib together is generally safe. Long-term studies have found this combination to be effective and usually well-tolerated by patients with certain types of melanoma. Common side effects include fever, tiredness, and skin problems, but these are typically manageable.

For navitoclax, which is being added to this combination in the trial, less information is available. However, early research from other studies suggests it can cause side effects like low blood platelets, affecting blood clotting. Therefore, close monitoring of patients is important.

In summary, while dabrafenib and trametinib have a strong safety record, the safety of navitoclax is still under study, especially when used with the other two drugs. Participants will be monitored carefully for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine existing melanoma therapies with a new player, navitoclax, which could enhance their effectiveness. Unlike the standard treatments dabrafenib and trametinib, which target specific mutations in cancer cells, navitoclax works by inhibiting proteins that help cancer cells avoid death, potentially leading to more effective tumor shrinkage. This combination approach aims to tackle melanoma more aggressively and may offer hope for improved outcomes compared to current options.

What evidence suggests that this trial's treatments could be effective for melanoma?

Research shows that using the drugs dabrafenib and trametinib together can help patients with BRAF-mutant melanoma, a type of skin cancer. One study found that about one-third of patients experienced long-term benefits from this combination. In this trial, some participants will receive only dabrafenib and trametinib, while others will also receive navitoclax. Studies have shown that adding navitoclax leads to even better results, with patients experiencing an average tumor shrinkage of 68.8%. Another study found that the 2-year survival rate was higher for those taking all three drugs—74% compared to 57% for just dabrafenib and trametinib. These treatments block certain proteins to stop cancer cells from growing, offering hope for people with advanced melanoma. ^{2 4 6 7 8}

Who Is on the Research Team?

Ryan J Sullivan

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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]

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 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]

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]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa1904059

Five-Year Outcomes with Dabrafenib plus Trametinib in ... First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10526829/

COMBI-r: A Prospective, Non-Interventional Study of ... Most patients (n = 300, 63.6%) received dabrafenib plus trametinib as first-line therapy; 172 (36.4%) patients were treated in later therapy lines. Patients ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.22.01763

Mutant Melanoma: The DREAMseq Trial—ECOG-ACRIN ... One hundred patients had died, of which 62 had dabrafenib/trametinib as initial therapy. The 2-year OS rate was 71.8% (95% CI, 62.5 to 79.1) for ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0959804917309978

Three-year pooled analysis of factors associated with ... These results demonstrate that durable responses lasting ≥3 years are possible in subsets of patients with BRAF-mutant melanoma receiving D + T.

5. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2517401

Clinical, Molecular, and Immune Analysis of Dabrafenib ... Combined treatment with dabrafenib and trametinib (CombiDT) achieves clinical responses in only about 15% of patients with BRAF inhibitor (BRAFi)-refractory ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5834102/

long-term survival and safety analysis of a phase 3 study These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and ...

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

The safety and efficacy of dabrafenib plus trametinib for ... In a phase 2 study, dabrafenib was beneficial in 39.2% of patients with metastatic brain melanoma who had never received medication before, as ...

8. nature.com nature.com/articles/s41598-025-07467-8

A post-marketing surveillance study of dabrafenib and ... This post marketing surveillance study investigated the safety and effectiveness of dabrafenib and trametinib in Japan between March 2018 and August 2023.