Trametinib for Cancer With NF1 Genetic Changes

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: 5

Duration: Up to 3 years

50 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 stop the growth of cancers with an NF1 genetic change. Trametinib blocks certain proteins that cancer cells with this mutation might need to grow. The trial seeks participants with cancer that has this specific NF1 mutation and has not responded to previous treatments. Those with heart rhythm issues or uncontrolled high blood pressure are not eligible. Participants should also not have lung disease or a history of eye vein problems. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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 trametinib is generally safe for patients with certain NF1-related tumors. In studies, patients taking trametinib experienced some side effects, but these were usually manageable. For instance, one study found that trametinib helped shrink tumors in patients with NF1-related tumors, with side effects considered acceptable.

Another study with adults who had NF1-related tumors showed that 47% of patients saw some improvement after 12 treatment cycles, meaning nearly half of the patients experienced benefits. While side effects can occur, trametinib is generally well-tolerated, especially for those with specific genetic changes related to NF1.

Trametinib is not a new drug; it has undergone extensive study and is already approved for other conditions, confirming its safety. However, participants should discuss any concerns with their healthcare provider before joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Trametinib is unique because it specifically targets and inhibits a protein called MEK1/2, which is part of a signaling pathway often overactive in cancers with NF1 genetic changes. Unlike traditional chemotherapy, which can affect both cancerous and healthy cells, trametinib's targeted approach aims to interfere directly with the cancer cells' growth signals. This precision could potentially lead to fewer side effects and improved outcomes for patients with these genetic changes, making researchers hopeful about its effectiveness.

What evidence suggests that trametinib might be an effective treatment for cancer with NF1 mutation?

Research has shown that trametinib, which participants in this trial will receive, may help treat tumors with NF1 mutations, changes in certain genes. One study found that about 47% of patients with these tumors experienced tumor shrinkage, known as a partial response, after treatment. Another review found that trametinib could effectively slow tumor growth in similar cases. It works by blocking specific proteins, MEK1 and MEK2, which often promote cancer cell growth when an NF1 mutation is present. These findings suggest that trametinib might be useful in managing tumors with these genetic changes. ^{1 2 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 cancer patients with a specific genetic change called NF1 mutation. They must have normal heart function, controlled blood pressure, and no history of severe lung disease or eye problems. Those who've had certain monoclonal antibody therapies or MEK inhibitors are excluded.

Inclusion Criteria

My cancer has a specific genetic change related to NF-1.

Criterion: You need to have had an ECG and an echocardiogram or nuclear study recently to make sure your heart is healthy. You also can't have certain heart conditions or high blood pressure that can't be controlled with medication. If you've had certain antibody treatments in the past, you need to wait a while before starting this treatment. If you have glioblastoma, it needs to be confirmed that your cancer has come back. All tests for assessing your disease must use special imaging techniques.

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 never had interstitial lung disease or pneumonitis.

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 dimethyl sulfoxide 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 thereafter

Follow-up

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

Up to 3 years

Every 3 months for the first 2 years, then every 6 months for year 3

What Are the Treatments Tested in This Trial?

Interventions

• Trametinib

Trial Overview Researchers are testing Trametinib to see if it can shrink tumors or halt their growth in cancers with the NF1 mutation. Trametinib targets proteins that may be essential for the growth of these cancer cells.

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

In a study involving 32 patients with solid tumors and lymphomas harboring non-V600 BRAF mutations, the MEK inhibitor trametinib showed limited efficacy, with only 1 patient (3%) achieving a partial response and a clinical benefit rate of 34%.

The median progression-free survival was 1.8 months and overall survival was 5.7 months, indicating that trametinib did not meet its primary endpoint of demonstrating significant clinical activity in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trametinib Activity in Patients with Solid Tumors and Lymphomas Harboring BRAF Non-V600 Mutations or Fusions: Results from NCI-MATCH (EAY131). Johnson, DB., Zhao, F., Noel, M., et al.[2023]

The combination of trametinib and afuresertib was poorly tolerated at the starting dose, leading to dose-limiting toxicities, but an intermittent dosing schedule showed better tolerability, suggesting a potential for safer administration.

Among 20 patients with advanced solid tumors, the study reported one partial response and four cases of stable disease, indicating some efficacy, but the overall response rate was low, warranting further investigation into alternative dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Tolcher, AW., Patnaik, A., Papadopoulos, KP., et al.[2015]

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]

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]

In a phase 2 study with a minimum of 5-year follow-up, the combination of dabrafenib and trametinib showed a high overall response rate of 68.4% in pretreated patients and 63.9% in treatment-naive patients with BRAF V600E-mutant metastatic NSCLC, indicating strong efficacy.

The therapy demonstrated a manageable safety profile, with pyrexia being the most common side effect (56%), and provided substantial overall survival benefits, with median overall survival of 18.2 months for pretreated patients and 17.3 months for treatment-naive patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis. Planchard, D., Besse, B., Groen, HJM., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11371073/

Efficacy of Trametinib in Neurofibromatosis Type 1 ... In conclusion, in this case report, a patient with NF1-associated GISTs treated with trametinib experienced tumor shrinkage with acceptable ...

2. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1002/ana.78010

Trametinib in Adults with Neurofibromatosis Type 1‐ ... In this phase 2 trial with trametinib, we found a partial response rate of 47% at cycle 12 in adults with NF1-related symptomatic PNs and the ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9415905/

Efficacy and Safety of Trametinib in Neurofibromatosis Type 1 ... The results yielded in this systematic review and meta-analysis showed that trametinib significantly controlled the tumor progression of NF1- ...

4. ascopubs.org ascopubs.org/doi/10.1200/PO.22.00421

Trametinib in Patients With NF1-, GNAQ-, or GNA11-Mutant ... Preclinical data indicate that MEK inhibitors may be effective therapies for tumors harboring Neurofibromatosis 1 (NF1) or GNA11/Q alterations.

5. frontiersin.org frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1481284/full

Case Report: Trametinib in the treatment of patients with ... It showed promising results in patients with unresectable plexiform neurofibromas and low-grade glioma in neurofibromatosis type 1 (5). However, the efficacy ...

6. ascopubs.org ascopubs.org/doi/10.1200/PO.23.00649

Efficacy of Trametinib in Neurofibromatosis Type 1– ... In conclusion, in this case report, a patient with NF1-associated GISTs treated with trametinib experienced tumor shrinkage with acceptable ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S3050461925000140

Mirdametinib approval for neurofibromatosis type 1 with ... This approval was based on results from a trial of 50 pediatric patients, which showed an overall response rate of 66%. The trial also showed clinically ...

8. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/s12885-023-10996-y

Treatment decisions and the use of MEK inhibitors for children ... In a phase I/II trial, most children (approximately 70%) achieved reduction in tumor volume accompanied by improvements in patient-reported ...