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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how trametinib, a medication that may inhibit tumor growth, can enhance iodine absorption in patients with recurrent or metastatic thyroid cancer. By increasing iodine absorption, iodine I-131 radiation therapy may become more effective. The trial includes different groups: some patients will receive trametinib plus iodine, while others will receive only trametinib. Patients with thyroid cancer unresponsive to traditional treatments and causing new or worsening symptoms might be suitable for this trial. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering patients a chance to explore new treatment options.

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

Research has shown that trametinib is generally safe for people. In previous studies, about 4.3% of patients experienced high fevers, and around 5.1% required hospitalization due to these fevers. Some individuals also faced dehydration related to the fever.

These results come from patients taking trametinib, sometimes alongside other treatments, indicating that trametinib alone might have slightly different side effects. Overall, trametinib has been used safely for other conditions, suggesting it is safe for thyroid cancer trials. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for thyroid cancer?

Trametinib is unique because it targets specific genetic mutations, like RAS and BRAF, which are not addressed by conventional thyroid cancer treatments such as surgery, radioactive iodine, or chemotherapy. Most traditional treatments rely on the thyroid's ability to absorb iodine, but trametinib offers a new mechanism by directly inhibiting the MEK enzyme pathway involved in cancer cell growth. Researchers are excited about trametinib because it offers a targeted approach, potentially benefiting patients whose tumors do not respond to standard iodine-based therapies, providing hope for more personalized and effective interventions.

What evidence suggests that trametinib could be an effective treatment for thyroid cancer?

Research shows that trametinib can help treat thyroid cancer by stopping tumor cells from growing. In this trial, participants will join different cohorts based on their genetic profiles. Studies indicate that combining trametinib with dabrafenib results in tumor shrinkage for about 67% of patients. This combination is particularly effective for patients with certain gene mutations, such as BRAF V600E, which are common in thyroid cancer. Trametinib blocks specific enzymes that cancer cells need to grow, potentially improving iodine treatment for thyroid cancer. Early findings suggest that trametinib alone can be helpful, especially for those with certain genetic profiles, and this trial will further explore its effectiveness in various cohorts. ^{1 6 7 8 9}

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]

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]

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 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. clinicaltrials.gov clinicaltrials.gov/study/NCT03975231

Dabrafenib, Trametinib, and IMRT in Treating Patients With ... Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

2. targetedonc.com targetedonc.com/view/roar-study-update-solidifies-benefit-of-dabrafenib-trametinib-in-braf-v600e-atc

ROAR Study Update Solidifies Benefit of Dabrafenib ... Results from the ROAR study, compared with the historical control, showed an ORR of 15% in patients with ATC 2. The activity of dabrafenib/ ...

3. link.springer.com link.springer.com/article/10.1007/s10147-025-02861-8

A single-center retrospective study of dabrafenib plus ... Dabrafenib plus trametinib combination therapy demonstrated clinical effectiveness in patients with BRAF V600E-positive thyroid cancer, with ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12432571/

Clinical outcomes of dabrafenib plus trametinib in locally ... For these 21 patients, the objective response rate (ORR) was 66.7%, with a disease control rate (DCR) of 85.7%. In the first-line setting, the ORR and DCR were ...

5. 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 ...

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. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9595631/

Dabrafenib Versus Dabrafenib + Trametinib in BRAF- ... DTC, differentiated thyroid cancer. The response and safety data on the 53 patients are reported in this article. At the time of data cutoff for primary ...

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

MEKINIST® (trametinib) tablets, for oral use ... The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to. MEKINIST 2 mg orally, once daily, administered in combination with ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S0923753422000059

Dabrafenib plus trametinib in patients with BRAF V600E ... Dabrafenib plus trametinib notably improved long-term survival and represents a meaningful treatment option for this rare, aggressive cancer.