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

Trial Summary

What is the purpose of this trial?

This trial tests trametinib, an oral medication, in patients with advanced cancers having an NF1 mutation. Trametinib works by blocking proteins that help cancer cells grow, aiming to stop or slow down the cancer. Trametinib is approved for treating certain types of advanced cancers.

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.

What data supports the effectiveness of the drug Trametinib for cancer with NF1 genetic changes?

Trametinib has shown effectiveness in treating various cancers with specific genetic mutations, such as BRAF mutations, by inhibiting the MEK pathway, which is involved in cancer cell growth. It has been effective in combination with other drugs for certain lung and thyroid cancers, suggesting potential benefits for other cancers with similar genetic changes. ^{1 2 3 4 5}

Is trametinib generally safe for humans?

Trametinib, also known as Mekinist, has been studied in adults with solid tumors, and the safety results align with its known safety profile. No serious or non-serious adverse events led to stopping the drug in these studies, suggesting it is generally safe for human use. ^{2 6 7 8 9}

How is the drug trametinib unique for treating cancer with NF1 genetic changes?

Trametinib is unique because it targets the MEK pathway, which is often overactive in cancers with NF1 genetic changes, leading to excessive cell growth. This drug is particularly effective in cases where traditional treatments may not work, as it specifically inhibits a part of the signaling pathway that is crucial for the growth of these cancer cells. ^{2 3 10 11 12}

Research Team

Jason J Luke

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

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

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

Treatment Details

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.

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

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]

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]

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 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]

References

1. Greece pubmed.ncbi.nlm.nih.gov

Trametinib with and without pazopanib has potent preclinical activity in thyroid cancer. [2021]

2. United States 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). [2023]

3. United States 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. [2022]

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

BRAF V600E/V600K Mutations versus Nonstandard Alterations: Prognostic Implications and Therapeutic Outcomes. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Therapeutic potential of trametinib to inhibit the mutagenesis by inactivating the protein kinase pathway in non-small cell lung cancer. [2020]

6. 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]

7. Germany pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics and exposure-response of trametinib, a MEK inhibitor, in patients with BRAF V600 mutation-positive melanoma. [2016]

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

Trametinib in metastatic melanoma. [2016]

9. Germany 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. [2015]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy of Dabrafenib and Trametinib in a Patient with Squamous-Cell Carcinoma, with Mutation p.D594G in BRAF and p.R461* in NF1 Genes-A Case Report with Literature Review. [2023]

11. 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]

12. France pubmed.ncbi.nlm.nih.gov

Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF (V600) Mutation. [2022]