Trametinib + Dabrafenib for Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, CYP2C8 inducers

Disqualifiers: Metastatic melanoma, Papillary thyroid cancer, Colorectal adenocarcinoma, Non-small cell lung cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 5

Duration: Up to 3 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a combination of two drugs, trametinib (a MEK inhibitor) and dabrafenib (a BRAF inhibitor), to determine their effectiveness in shrinking or stopping the growth of cancers with specific genetic changes known as BRAF V600 mutations. These drugs block certain proteins that cancer cells need to grow. Suitable candidates for this trial include individuals with BRAF V600 mutations, excluding those with specific cancers like melanoma or papillary thyroid cancer, who have not previously received similar treatments. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that you stop taking any medications that are strong inhibitors or inducers of certain enzymes (CYP3A or CYP2C8) and herbal remedies like St. John's wort. If you're on these, you may need to stop or switch them before joining the trial.

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

Research shows that using trametinib and dabrafenib together is generally safe for patients with certain types of cancer. Studies have demonstrated that many patients with BRAF V600 mutations have safely used these drugs in combination. Common side effects include fever, tiredness, and nausea, but these can often be managed. Long-term safety data indicate that patients can live longer without their cancer worsening, suggesting the treatment's effectiveness and safety over time. The combination has received FDA approval for treating certain cancers, which often implies it is considered safe for other uses as well. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of trametinib and dabrafenib because it targets cancer cells in a unique way. Unlike many treatments that focus on a single pathway, this combination attacks cancer by inhibiting both BRAF and MEK proteins, which are crucial for cancer cell growth and survival. This dual-targeting approach not only aims to enhance the effectiveness of treatment but also helps to potentially reduce the likelihood of cancer cells developing resistance, offering hope for more durable responses in cancer patients.

What evidence suggests that trametinib and dabrafenib might be effective for cancer with BRAF V600 mutations?

Research has shown that the combination of dabrafenib and trametinib, which participants in this trial will receive, effectively treats cancers with BRAF V600 mutations. This treatment blocks certain proteins that cancer cells need to grow. One study found that 37% of patients were still alive after four years, indicating promising long-term results. The treatment has effectively shrunk tumors or halted their growth in many cases. Overall, this combination targets specific genetic changes, offering a focused approach for certain types of cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Erin R Macrae

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

This trial is for cancer patients with specific genetic changes called BRAF V600 mutations. They must have a normal heart rhythm, controlled blood pressure, and no severe cardiac issues. Those who've had certain antibody therapies or anticoagulants can join if they meet conditions. Excluded are those with metastatic melanoma, papillary thyroid cancer, colorectal adenocarcinoma, non-small cell lung cancer, history of lung disease or pneumonitis, known hypersensitivity to the drugs being tested or their components.

Inclusion Criteria

My blood clotting tests are within normal limits, or I am on blood thinners with stable levels.

My cancer has a specific BRAF mutation.

Patients must have met applicable eligibility criteria in the Master MATCH Protocol prior to registration to treatment subprotocol

Exclusion Criteria

My cancer does not have a history of RAS mutation.

I have never taken dabrafenib or trametinib in the MATCH trial.

I have not taken any BRAF inhibitor medications for my condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive dabrafenib mesylate orally twice daily and trametinib dimethyl sulfoxide once daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 3 years

Tumor assessments at baseline, then every 2 cycles for the first 26 cycles and every 3 cycles thereafter

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 3 years

Every 3 months if less than 2 years from study entry, then every 6 months for year 3

What Are the Treatments Tested in This Trial?

Interventions

• Dabrafenib Mesylate
• Trametinib Dimethyl Sulfoxide

Trial Overview The trial tests Trametinib and Dabrafenib's effectiveness on cancers with BRAF V600 mutations. Trametinib blocks MEK proteins while Dabrafenib targets BRAF proteins involved in cell growth. The goal is to see if these drugs can shrink the cancers or halt their progression.

How Is the Trial Designed?

Group I: Treatment (dabrafenib, trametinib) Experimental Treatment 2 Interventions

Patients receive dabrafenib mesylate PO BID and trametinib dimethyl sulfoxide PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

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 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 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 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]

The combination of BRAF inhibitor dabrafenib and MEK inhibitor trametinib significantly improves outcomes for metastatic melanoma patients compared to single-agent therapies, with a manageable safety profile.

While 98% of patients experience at least one adverse event during combination therapy, these events are mostly mild to moderate and can be effectively managed, highlighting the importance of addressing even minor side effects to maintain patients' quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma. Knispel, S., Zimmer, L., Kanaki, T., et al.[2017]

Trametinib, when combined with dabrafenib, significantly prolongs median survival by about 8 months compared to vemurafenib alone in patients with metastatic or inoperable melanoma, based on a study of 704 patients.

While trametinib can enhance treatment efficacy, it also carries serious adverse effects, including life-threatening conditions like heart failure and gastrointestinal perforation, making it essential for patients to weigh the benefits against the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trametinib (MEKINIST°) Metastatic or inoperable BRAF V600-positive melanoma: a few extra months of life. [2019]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03919071

Study Details | NCT03919071 | Dabrafenib Combined With ... Dabrafenib and trametinib may stop the growth of tumor cells by blocking BRAF and MEK, respectively, which are enzymes that tumor cells need for their growth.

2. clinicaltrials.eu clinicaltrials.eu/trial/long-term-safety-study-of-dabrafenib-mesylate-and-trametinib-dimethyl-sulfoxide-for-patients-benefiting-from-previous-treatment-in-multiple-indications/

Long-Term Safety Study of Dabrafenib Mesylate and ... This study assesses the long-term safety of Dabrafenib Mesylate and Trametinib Dimethyl Sulfoxide in treating various types of cancer, ...

3. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT04439292

Testing Trametinib and Dabrafenib as a Potential Targeted ... This phase II MATCH treatment trial identifies the effects of trametinib and dabrafenib in patients whose cancer has genetic changes called BRAF V600 ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31166680/

Five-Year Outcomes with Dabrafenib plus Trametinib in ... The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several ...

5. ecog-acrin.org ecog-acrin.org/press-release-nci-match-trial-finds-the-combination-of-dabrafenib-and-trametinib-effective/

NCI-MATCH trial finds the combination of dabrafenib and ... Treatment with dabrafenib and trametinib, a drug combination designed to target cancers that harbor certain BRAF gene mutations, was effective in a trial of 35 ...

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. uchicagomedicine.org uchicagomedicine.org/find-a-clinical-trial/clinical-trial/cirb191619

CLINICAL TRIAL / NCT03919071 This phase II trial studies how well the combination of dabrafenib and trametinib works after radiation therapy in children and young adults with high grade ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2019/202806Orig1s002.pdf

Approval Package - accessdata.fda.gov Supportive results came from BRF113220. Part D. The safety data to support the combination of dabrafenib and trametinib are derived from pooled ...