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, Uveal melanoma, 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: 2

Duration: Up to 3 years

4 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

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 generally safe for humans?

Trametinib, also known as Mekinist, is generally considered safe for humans, 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 patients need to be monitored closely. ^{1 2 3 4 5}

What makes the drug trametinib unique for treating cancer?

Trametinib is unique because it specifically targets and inhibits MEK1 and MEK2, proteins involved in cancer cell growth, and it can be used alone or in combination with other drugs like dabrafenib for certain types of melanoma. Additionally, it has shown potential in treating KRAS-mutant cancers by affecting immune cells, which is different from many other cancer treatments that primarily target tumor cells directly. ^{3 6 7 8 9}

What is the purpose of this trial?

This phase II MATCH treatment trial identifies the effects of trametinib in patients whose cancer has genetic changes called GNAQ or GNA11 mutations. Trametinib may block proteins called MEK1 and MEK2, which may be needed for cancer cell growth when GNAQ or GNA11 mutations are present. Researchers hope to learn if trametinib will shrink this type of cancer or stop its growth.

Research Team

Jason J Luke

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for patients with various cancers, including solid tumors and blood cancers like lymphoma and multiple myeloma, who have specific genetic changes (GNAQ or GNA11 mutations). They must have met previous MATCH Protocol criteria, have a stable heart condition verified by ECG and echocardiogram/MUGA scan, and not be hypertensive. Those with glioblastoma need confirmed recurrence. People with uveal melanoma, prior MEK inhibitor treatment, lung disease/pneumonitis history, trametinib/DMSO hypersensitivity or risk of retinal vein occlusion are excluded.

Inclusion Criteria

I stopped my monoclonal antibody therapy 8 weeks ago.

My recent ECG showed no major heart issues and my blood pressure is under control.

I have a confirmed case of grade 4 glioblastoma that is getting worse.

Exclusion Criteria

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

I have never had interstitial lung disease or pneumonitis.

I don't have, nor am I at risk of, retinal vein occlusion.

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. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 3 years

Every 2 cycles for the first 26 cycles, then every 3 cycles

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.

Up to 3 years

Treatment Details

Interventions

• Trametinib

Trial Overview The trial tests Trametinib Dimethyl Sulfoxide on patients whose cancer has GNAQ/GNA11 mutations. Trametinib aims to inhibit MEK1/MEK2 proteins that may promote the growth of these genetically mutated cancer cells. The goal is to see if this targeted therapy can shrink the tumors or halt their progression.

Participant Groups

Group I: Treatment (trametinib) Experimental Treatment 1 Intervention

Patients receive trametinib dimethyl sulfoxide PO QD on days 1-28. 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

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]

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 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. France pubmed.ncbi.nlm.nih.gov

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

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

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

3. 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]

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

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

5. 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]

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]