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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether trametinib (also known as Mekinist) can shrink or halt cancer growth in patients with specific genetic changes called GNAQ or GNA11 mutations. Trametinib may block certain proteins that promote cancer cell growth. The trial seeks patients with these genetic mutations who have not recently received similar treatments. It is suitable for those with recurrent or progressive tumors confirmed by imaging scans. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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

Research has shown that trametinib has been tested for safety both on its own and with other treatments. One study tested trametinib alone and found it generally well-tolerated. Common side effects included skin rash, diarrhea, and tiredness, mostly mild to moderate.

Another study combined trametinib with dabrafenib, providing long-term benefits for some cancer patients. However, this combination also increased the risk of side effects like fever and high blood pressure.

Since this trial is in its second phase, trametinib has already demonstrated a reasonable safety profile in earlier research. The current study focuses on its effectiveness and any additional safety information for specific genetic changes in cancer. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard cancer treatments that often focus on chemotherapy or radiation, trametinib offers a unique approach by specifically targeting the MEK pathway, which is crucial for cancer cell growth. This targeted mechanism can potentially lead to fewer side effects compared to more general treatments. Researchers are excited about trametinib because it offers a more precise method to halt cancer progression, possibly improving patient outcomes and quality of life.

What evidence suggests that trametinib might be an effective treatment for cancer with GNAQ or GNA11 mutations?

Research has shown that trametinib, which participants in this trial will receive, may help treat cancers with specific genetic changes, such as GNAQ or GNA11 mutations. In other studies, trametinib, often used with another drug called dabrafenib, showed promising results. Specifically, about 21% of patients experienced no cancer progression after four years, and 19% after five years. Additionally, 37% of patients were still alive at four years, and 34% at five years. These findings suggest that trametinib could help slow or stop cancer growth in some patients. ^{2 5 6 7 8}

Who Is on the Research Team?

Jason J Luke

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

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 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. 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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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, 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]

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]

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. 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 ...

5. 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 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9818023/

BRAF and MEK Inhibitors and Their Toxicities: A Meta-Analysis Our study provides comprehensive data on treatment-related adverse events of BRAFi and MEKi combination therapies, showing related toxicity profiles.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36375115/

Efficacy and Safety of Trametinib Monotherapy or in ... We describe a phase I/II study establishing pediatric dosing and pharmacokinetics of trametinib with or without dabrafenib, as well as efficacy and safety

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

Updated efficacy and safety data of dabrafenib (D) ... Among 16 pts, overall response rate (ORR) was 69%, and median duration of response (DOR), progression-free survival (PFS), and OS were not reached (NR) due to ...