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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called trametinib (also known as Mekinist) to determine if it can shrink or halt the growth of certain cancers. Researchers focus on patients whose cancer has a specific genetic change called a BRAF mutation or fusion. Trametinib blocks proteins that may aid cancer cell growth. Suitable candidates for this trial have cancer with a BRAF mutation and no history of heart issues or certain lung conditions. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of participants.

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 there any evidence suggesting that trametinib is likely to be safe for humans?

Research shows that patients usually tolerate trametinib well, but some side effects require attention. In earlier studies, about 4.3% of patients experienced serious fever (high temperature). Additionally, 5.1% of patients required hospitalization due to fever while taking trametinib.

The FDA has approved trametinib for certain uses, indicating a thorough safety review. However, side effects may still occur. Discuss any concerns with the study team, who can provide detailed information and guidance. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Trametinib is unique because it targets the MEK pathway, which is often involved in cancer cell growth and survival. This is different from many standard cancer treatments, which typically include chemotherapy or targeted therapies that may not specifically inhibit this pathway. Researchers are excited about trametinib because it offers a more precise mechanism of action that could potentially lead to improved outcomes for patients with certain types of cancer. By specifically inhibiting MEK, trametinib could provide a new option for those who do not respond well to existing treatments.

What evidence suggests that trametinib might be an effective treatment for cancer with BRAF mutations?

Research has shown that trametinib, which participants in this trial will receive, may help treat cancers with BRAF mutations. In studies, patients taking trametinib, often alongside another drug, have lived longer. For instance, 37% of patients were still alive after four years, and 34% after five years. Additionally, trametinib has outperformed traditional chemotherapy in some cases. These results suggest that trametinib might slow down or reduce cancer growth in certain patients. ^{6 7 8 9 10}

Who Is on the Research Team?

Douglas B Johnson

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

Citations

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

Five-Year Outcomes with Dabrafenib plus Trametinib in ... The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years.

2. 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 ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e21515

Results of the study GEM1801. | Journal of Clinical Oncology In patients who had a complete response, the 5-year OS rate was 58.3% (95% CI: 31.3-100) while the median overall survival was not reached. In ...

4. curemelanoma.org curemelanoma.org/patient-eng/melanoma-treatment/options/trametinib-mekinis

Trametinib (Mekinist) MEK Inhibitor Therapy for Melanoma Results from a large Phase III clinical trial showed that trametinib provided better outcomes for patients than chemotherapy. However, melanoma experts ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0169500224005725

Real-world efficacy of the dabrafenib-trametinib (D-T) ... The 12-month OS rate in patients receiving D + T as a second-line therapy or beyond (n = 119) was 67.4 %, with a median progression-free survival (mPFS) of 10.4 ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2022/204114s024lbl.pdf

Mekinist - accessdata.fda.gov Grade 3-4 pyrexia occurred in 4.3% of patients, hospitalizations due to pyrexia occurred in 5.1% of patients, pyrexia with complications (dehydration, ...

7. novartis.com novartis.com/us-en/sites/novartis_us/files/mekinist.pdf

MEKINIST® (trametinib) tablets, for oral use ... MEKINIST as a Single Agent. The safety of MEKINIST was evaluated in the METRIC study, a randomized, open-label trial of patients with. BRAF V600E or V600K ...

8. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)50260-5/fulltext

Updated efficacy and safety data of dabrafenib (D) ... 1821PD - Updated efficacy and safety data of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E–mutated anaplastic thyroid cancer (ATC).

9. pro.novartis.com pro.novartis.com/uk-en/medicines/oncology/tafinlar-mekinist/melanoma/safety

Safety profile of TAFINLAR® (dabrafenib) + MEKINIST® ... TAFINLAR® (dabrafenib) and MEKINIST® (trametinib) safety profile in melanoma from clinical studies. For UK healthcare professionals only.

10. mayoclinic.org mayoclinic.org/drugs-supplements/trametinib-oral-route/description/drg-20061171

Trametinib (oral route) - Side effects & dosage Trametinib belongs to the group of medicines, called antineoplastics (cancer medicines). ... Safety and efficacy have not been established. Geriatric.