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

35 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II MATCH treatment trial identifies the effects of trametinib and dabrafenib in patients whose cancer has genetic changes called BRAF V600 mutations. Dabrafenib may stop the growth of cancer by blocking BRAF proteins which may be needed for cell growth. Trametinib may stop the growth of cancer cells by blocking MEK proteins which, in addition to BRAF proteins, may also be needed for cell growth. Researchers hope to learn if giving trametinib with dabrafenib will shrink this type of cancer or stop its growth.

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 the combination of Trametinib and Dabrafenib safe for humans?

The combination of Trametinib and Dabrafenib is generally considered safe for humans, with most patients experiencing mild to moderate side effects that can be managed with dose adjustments. Common side effects include fever, fatigue, and nausea, but these are usually reversible. There have been rare cases of kidney-related issues, but overall, the treatment is well-tolerated. ^{1 2 3 4 5}

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

The combination of Trametinib and Dabrafenib is unique because it targets melanoma with a specific BRAF V600 mutation, improving survival and response rates compared to using either drug alone or other treatments like vemurafenib. This combination also reduces certain skin-related side effects and is a first-line option for patients willing to accept its significant toxicity for the potential of extended life. ^{2 6 7 8 9}

Research Team

Erin R Macrae

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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 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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma. [2017]

2. 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]

3. Germany pubmed.ncbi.nlm.nih.gov

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

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

Acute granulomatous interstitial nephritis in a patient with metastatic melanoma on targeted therapy with dabrafenib and trametinib-A case report. [2022]

5. 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]

6. France pubmed.ncbi.nlm.nih.gov

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

7. Switzerland pubmed.ncbi.nlm.nih.gov

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

8. France pubmed.ncbi.nlm.nih.gov

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

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

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