Trametinib for Thyroid Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Herbal supplements

Disqualifiers: Other malignancy, Lung disease, Brain metastases, Cardiovascular risk, 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: 4-5 weeks

34 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase II trial studies how well trametinib works in increasing tumoral iodine incorporation in patients with thyroid cancer that has come back or spread to another place in the body. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and may help make treatment with iodine I-131 more effective.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does prohibit the use of certain medications, including other anti-cancer therapies and herbal supplements. It's best to discuss your current medications with the study team to see if any adjustments are needed.

Is Trametinib safe for use in humans?

Trametinib, used in combination with dabrafenib, was generally well tolerated in patients with a specific type of thyroid cancer, with common side effects including fatigue, fever, and nausea. No new safety concerns were identified in the study. ^{1 2 3 4 5}

How is the drug Trametinib unique for treating thyroid cancer?

Trametinib, when combined with dabrafenib, is unique for treating thyroid cancer because it targets specific genetic mutations (BRAF V600E) found in aggressive forms like anaplastic thyroid cancer, offering a new option where traditional treatments often fail. ^{1 6 7 8 9}

What data supports the effectiveness of the drug Trametinib for thyroid cancer?

Research shows that Trametinib, when used alone or with other drugs like pazopanib, can effectively reduce tumor size in thyroid cancer. In particular, it has shown promising results in treating a rare and aggressive form of thyroid cancer called anaplastic thyroid cancer, especially when combined with another drug, dabrafenib. ^{1 2 8 10 11}

Who Is on the Research Team?

Alan L Ho, MD, PhD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with recurrent or metastatic thyroid cancer who have measurable disease, adequate organ function, and a life expectancy over 3 months. They must not be pregnant, agree to use contraception, and be willing to undergo biopsies. Exclusions include other recent cancers (with some exceptions), lung disease, certain heart risks, active infections or severe psychiatric issues.

Inclusion Criteria

My thyroid cancer has been confirmed and is of follicular origin.

I can take care of myself but might not be able to do heavy physical work.

Your disease does not respond to radioactive iodine treatment, as shown in imaging tests.

Exclusion Criteria

I have brain or spinal cord cancer symptoms that are not treated.

I have a history of heart problems.

I have specific eye conditions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive trametinib orally daily for 4 weeks, with iodine I-124 PET/CT scans to assess iodine absorption. If absorption is adequate, iodine I-131 is administered.

4-5 weeks

Multiple visits for PET/CT scans and treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

4 weeks

Follow-up visits for safety assessment

Extension

Patients may continue trametinib at the doctor's discretion if iodine absorption is inadequate

What Are the Treatments Tested in This Trial?

Interventions

• Trametinib

Trial Overview The study tests trametinib's ability to enhance iodine incorporation into tumors in thyroid cancer patients. This could make iodine I-131 treatment more effective. Participants will receive trametinib and undergo imaging studies like CT scans and PET scans along with laboratory biomarker analysis.

How Is the Trial Designed?

Group I: Cohort C (trametinib) Experimental Treatment 3 Interventions

Patients may continue trametinib at the doctor's discretion and do not receive iodine I-131.

Group II: Cohort B (iodine I-124 PET/CT, trametinib, iodine I-131) Experimental Treatment 7 Interventions

Patients without BRAF/RAS gene mutations undergo iodine I-124 PET/CT on day 5 of week 1. Beginning day 6, patients receive trametinib PO daily for 4 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo second iodine I-124 PET/CT on week 5. If I-124 PET/CT shows enough iodine absorption, patients may receive iodine I-131 PO and continue receiving trametinib for another 2 days. If I-124 shows that the thyroid is not absorbing iodine, patients have the option to be assigned to Cohort C.

Group III: Cohort A (iodine I-124 PET/CT, trametinib, iodine I-131) Experimental Treatment 7 Interventions

Patients with RAS gene mutations undergo iodine I-124 PET/CT on day 5 of week 1. Beginning day 6, patients receive trametinib PO daily for 4 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo second iodine I-124 PET/CT on week 5. If I-124 PET/CT shows enough iodine absorption, patients may receive iodine I-131 PO and continue receiving trametinib for another 2 days. If I-124 shows that the thyroid is not absorbing iodine, patients have the option to be assigned to Cohort C.

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 phase II trial involving 16 patients with BRAF V600E-mutated anaplastic thyroid cancer, the combination of dabrafenib and trametinib showed a high overall response rate of 69%, indicating significant efficacy in a cancer type with previously limited treatment options.

The treatment was well tolerated, with common side effects including fatigue, fever, and nausea, and no new safety concerns were identified, marking a promising advancement for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer. Subbiah, V., Kreitman, RJ., Wainberg, ZA., et al.[2022]

Dabrafenib, a BRAF inhibitor, effectively reduced the viability of anaplastic thyroid cancer (ATC) cells with BRAF mutations by inducing cell cycle arrest, while trametinib, a MEK inhibitor, showed variable efficacy across different ATC cell lines.

The study revealed that combining both inhibitors had a cytostatic effect on all tested ATC cells, but resistance mechanisms, such as increased SNAI1 expression, were observed, particularly in cells with specific mutations, indicating the need for tailored treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Growth arrest by activated BRAF and MEK inhibition in human anaplastic thyroid cancer cells. Kurata, K., Onoda, N., Noda, S., et al.[2017]

Lenvatinib, a multitargeted kinase inhibitor, has shown effectiveness in stabilizing progressive metastatic thyroid cancer and may improve overall survival, based on pivotal phase III trials.

While lenvatinib is a promising treatment option, it comes with a side-effect profile similar to other kinase inhibitors, necessitating careful monitoring and management of adverse events to maintain therapy continuity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimal use of lenvatinib in the treatment of advanced thyroid cancer. Takahashi, S., Kiyota, N., Tahara, M.[2023]

In a phase 2 trial involving 53 patients with BRAF-mutated radioactive iodine refractory differentiated thyroid cancer, both dabrafenib monotherapy and the combination of dabrafenib + trametinib showed similar objective response rates, with 42% and 48% respectively, indicating no significant advantage of the combination therapy.

The most common side effects included skin disorders and fever, but there were no treatment-related deaths, suggesting that both treatment options are relatively safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib Versus Dabrafenib + Trametinib in BRAF-Mutated Radioactive Iodine Refractory Differentiated Thyroid Cancer: Results of a Randomized, Phase 2, Open-Label Multicenter Trial. Busaidy, NL., Konda, B., Wei, L., et al.[2023]

In a study of 27 patients with anaplastic thyroid carcinoma (ATC), those treated with the combination of Dabrafenib and Trametinib (DT) had a median overall survival of 475 days, significantly longer than the 156 days for multimodal therapy and 39 days for compassionate care (P < .001).

The DT group also demonstrated a median progression-free survival of 270 days, compared to less than 32 days for BRAF wild type patients, with no severe adverse events reported, indicating a strong safety and efficacy profile for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Target therapy for BRAF mutated anaplastic thyroid cancer: a clinical and molecular study. da Silva, TN., Rodrigues, R., Saramago, A., et al.[2023]

Citations

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

Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer. [2022]

3. Greece pubmed.ncbi.nlm.nih.gov

Growth arrest by activated BRAF and MEK inhibition in human anaplastic thyroid cancer cells. [2017]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Case report: Visibly curative effect of dabrafenib and trametinib on advanced thyroid carcinoma in 2 patients. [2023]

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

Kinase inhibitors in thyroid cancers. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Management of VEGFR-Targeted TKI for Thyroid Cancer. [2021]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Efficacy and safety of vascular endothelial growth factor receptor tyrosine kinase inhibitors in the treatment of advanced thyroid cancer: a meta-analysis of randomized controlled trials. [2020]

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

Optimal use of lenvatinib in the treatment of advanced thyroid cancer. [2023]

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

Dabrafenib Versus Dabrafenib + Trametinib in BRAF-Mutated Radioactive Iodine Refractory Differentiated Thyroid Cancer: Results of a Randomized, Phase 2, Open-Label Multicenter Trial. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Target therapy for BRAF mutated anaplastic thyroid cancer: a clinical and molecular study. [2023]

11. Brazil pubmed.ncbi.nlm.nih.gov

Dramatic clinical response to dabrafenib plus trametinib in anaplastic thyroid carcinoma and the challenges faced during the COVID-19 pandemic. [2023]