Trametinib for Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: MEK inhibitors

Disqualifiers: Interstitial lung disease, pneumonitis, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle, ongoing until disease progression or unacceptable toxicity

35 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests trametinib, an oral medication taken regularly, in patients with advanced cancers having BRAF mutations. Trametinib works by blocking proteins that help cancer cells grow. Researchers aim to see if it can shrink these cancers or stop their growth.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you have previously received monoclonal antibody therapy, you must have stopped it for at least 8 weeks before starting trametinib.

Is trametinib safe for human use?

Trametinib, also known as Mekinist, is generally considered safe for human use, but it can cause side effects. Common side effects include mild to moderate issues like skin reactions, diarrhea, and vomiting, which are usually manageable. However, it can also cause serious side effects like heart problems, blood clots, and lung issues, so it's important to be monitored by a healthcare provider while on this medication. ^{1 2 3 4 5}

What makes the drug trametinib unique compared to other cancer treatments?

Trametinib is unique because it specifically targets and inhibits MEK1 and MEK2 proteins, which are involved in cell growth and proliferation, making it effective for certain cancers with specific genetic mutations like BRAF V600E/V600K. Additionally, it has shown potential in enhancing immune responses against tumors by reducing certain immune-suppressing cells, which is a novel mechanism compared to other treatments. ^{1 6 7 8 9}

Research Team

Douglas B Johnson

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for cancer patients with specific BRAF genetic changes who've met prior MATCH Protocol criteria. They need a normal heart rhythm, controlled blood pressure, and adequate heart function shown by recent tests. Those treated with monoclonal antibodies must have stopped them 8+ weeks before starting trametinib.

Inclusion Criteria

My cancer has a specific BRAF mutation not V600, or a BRAF fusion.

My heart is healthy based on recent tests, and I haven't had certain antibody therapies in the last 8 weeks.

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

Exclusion Criteria

I am not allergic to trametinib, similar drugs, or DMSO.

I have not taken any MEK inhibitor medications.

I don't have, nor am I at risk for, a blocked vein in my eye.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive trametinib orally once daily on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle, ongoing until disease progression or unacceptable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 3 months if less than 2 years from study entry, and then every 6 months for year 3 from study entry.

Up to 3 years post registration

Treatment Details

Interventions

• Trametinib

Trial Overview The study is testing Trametinib's effectiveness on cancers with BRAF mutations. It aims to see if the drug, which blocks certain proteins (MEK1/2) needed by these cancer cells, can shrink or halt their growth.

Participant Groups

Group I: Treatment (trametinib) Experimental Treatment 1 Intervention

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

Trametinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Mekinist for:

• Melanoma
• Non-small cell lung cancer

Approved in United States as Mekinist for:

• Melanoma
• Non-small cell lung cancer
• Thyroid cancer

Approved in Canada as Mekinist for:

• Melanoma
• Non-small cell lung cancer

Approved in Japan as Mekinist for:

• Melanoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

The pediatric oral solution of trametinib showed improved bioavailability compared to the tablet formulation, with significant increases in key pharmacokinetic measures such as Cmax and AUC, indicating it may be more effective in delivering the drug to patients.

The safety profile of the trametinib pediatric oral solution was consistent with existing data, with no serious adverse events leading to withdrawal from the study, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors. Cox, DS., Allred, A., Zhou, Y., et al.[2018]

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]

A systematic review of 16 clinical trials involving cancer patients showed that MEK inhibitors (trametinib, selumetinib, and cobimetinib) significantly increase the risk of gastrointestinal toxicities, including stomatitis (2.03 times more likely), diarrhea (1.92 times), and vomiting (1.35 times) compared to control groups.

The study highlights the importance for clinicians to monitor patients regularly for these side effects, as the risk was consistent across different types of MEK inhibitors and treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of selected gastrointestinal toxicities in cancer patients treated with MEK inhibitors: a comparative systematic review and meta-analysis. Abdel-Rahman, O., ElHalawani, H., Ahmed, H., et al.[2022]

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]

Trametinib, a MEK inhibitor, is effective for treating metastatic melanoma with BRAF V600E and V600K mutations, but it is associated with significant skin-related side effects.

In a case study of a 66-year-old man, the severity of skin reactions increased when trametinib was used alone compared to when it was combined with a BRAF inhibitor, highlighting the need for careful management of these adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Xanthogranulomatous reaction to trametinib for metastatic malignant melanoma. Min, MS., Yao, J., Chee, N., et al.[2019]

Trametinib is an effective oral MEK inhibitor specifically targeting MEK1 and MEK2, approved in the US for treating unresectable or metastatic malignant melanoma with specific BRAF mutations, demonstrating its antineoplastic activity.

The drug is currently undergoing extensive clinical development for various cancers, including phase III trials in combination with dabrafenib for melanoma and phase II trials for pancreatic cancer and non-small cell lung cancer, indicating its potential for broader therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trametinib: first global approval. Wright, CJ., McCormack, PL.[2023]

Trametinib, when used alone, was found to be tolerable in Japanese patients with advanced solid tumors, with a maximum tolerated dose not reached up to 3.0 mg daily and some patients showing stable disease or partial response.

However, combining trametinib with gemcitabine resulted in serious safety concerns, including interstitial lung disease in 3 out of 5 patients, highlighting a higher risk associated with this combination therapy compared to trametinib alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I/Ib study of trametinib (GSK1120212) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors. Kasuga, A., Nakagawa, K., Nagashima, F., et al.[2022]

References

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

Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors. [2018]

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

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

3. England pubmed.ncbi.nlm.nih.gov

Risk of selected gastrointestinal toxicities in cancer patients treated with MEK inhibitors: a comparative systematic review and meta-analysis. [2022]

4. France pubmed.ncbi.nlm.nih.gov

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

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

Xanthogranulomatous reaction to trametinib for metastatic malignant melanoma. [2019]

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

Trametinib: first global approval. [2023]

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

A phase I/Ib study of trametinib (GSK1120212) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors. [2022]

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

A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)†. [2022]

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

Trametinib Drives T-cell-Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis. [2021]