Targeted Therapy vs. Chemotherapy for Thyroid Cancer

Recruiting at 110 trial locations

Overseen By Hari A. Deshpande

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: ECOG-ACRIN Cancer Research Group

Must be taking: Thyroxine, VEGFR-targeting TKIs

Must not be taking: Oral anticoagulants

Disqualifiers: Cardiovascular disorders, GI disorders, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase III trial compares the effect of cabozantinib versus combination dabrafenib and trametinib for the treatment of patients with differentiated thyroid cancer that does not respond to treatment (refractory) and which expresses a BRAF V600E mutation. Cabozantinib is in a class of medications called receptor tyrosine kinase inhibitors. It binds to and blocks the action of several enzymes which are often over-expressed in a variety of tumor cell types. This may help stop or slow the growth of tumor cells and blood vessels the tumor needs to survive. Dabrafenib is an enzyme inhibitor that binds to and inhibits the activity of a protein called B-raf, which may inhibit the proliferation of tumor cells which contain a mutated BRAF gene. Trametinib is also an enzyme inhibitor. It binds to and inhibits the activity of proteins called MEK 1 and 2, which play a key role in activating pathways that regulate cell growth. This may inhibit the growth of tumor cells mediated by these pathways. The usual approach for patients with thyroid cancer is targeted therapy with dabrafenib and trametinib. This trial may help researchers decide which treatment option (cabozantinib alone or dabrafenib in combination with trametinib) is safer and/or more effective in treating patients with refractory BRAF V600E-mutated differentiated thyroid cancer.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not be on certain anticoagulants (blood thinners) or platelet inhibitors, except for low-dose aspirin or specific anticoagulation treatments that meet certain conditions. It's best to discuss your current medications with the trial team.

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

Research shows that the combination of Dabrafenib and Trametinib is effective in treating BRAF V600E-mutated anaplastic thyroid cancer, with a high response rate of 69% and good survival outcomes. This combination has shown significant clinical activity and is well tolerated, representing a meaningful advance for this aggressive cancer type. ^{1 2 3 4 5}

Is targeted therapy for thyroid cancer safe?

The targeted therapies, including cabozantinib, dabrafenib, and trametinib, have been studied for thyroid cancer and other conditions. Common side effects include fatigue, fever, nausea, and skin issues, but no new safety concerns were found in recent studies. ^{2 3 4 6 7}

How is the drug Cabozantinib, Dabrafenib, and Trametinib different from other thyroid cancer treatments?

This drug combination is unique because it targets specific genetic mutations (BRAF mutations) in thyroid cancer, offering a more personalized treatment approach compared to traditional chemotherapy. Cabozantinib is also approved for cases where other targeted therapies have failed, providing an option for advanced thyroid cancer that has progressed. ^{2 3 5 7 8}

Research Team

Lova Sun

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

Adults with differentiated thyroid cancer that's unresponsive to treatment and has a BRAF V600E mutation. They must have tried or be ineligible for Iodine-131 therapy, taken certain tyrosine kinase inhibitors, and show measurable disease progression. Excludes those with severe heart issues or arrhythmias.

Inclusion Criteria

I do not have severe heart failure, unstable chest pain, or serious irregular heartbeats.

I am 18 years old or older.

I am able to get out of my bed or chair and move around.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive either cabozantinib or a combination of dabrafenib and trametinib orally on a 28-day cycle, with regular CT scans, blood sample collection, and possible MRIs.

28-day cycles, up to 5 years

Regular visits for CT scans and blood collection

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-ups every 3 months for 2 years, then every 6 months up to 5 years.

5 years

Every 3 months for 2 years, then every 6 months

Treatment Details

Interventions

• Cabozantinib (Receptor Tyrosine Kinase Inhibitor)
• Dabrafenib (Enzyme Inhibitor)
• Trametinib (Enzyme Inhibitor)

Trial Overview The trial compares cabozantinib (a receptor tyrosine kinase inhibitor) against dabrafenib plus trametinib (both enzyme inhibitors) in treating refractory BRAF V600E-mutated thyroid cancer. It aims to determine which treatment is safer/more effective.

Participant Groups

Group I: Arm B (Cabozantinib) Experimental Treatment 5 Interventions

Patients receive cabozantinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, blood sample collection and may undergo MRI throughout the study.

Group II: Arm A (Dabrafenib and trametinib) Active Control 6 Interventions

Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, blood sample collection and may undergo MRI throughout the study.

Cabozantinib is already approved in Canada, Japan for the following indications:

Approved in Canada as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Japan as Cabometyx for:

• Renal cell carcinoma

Who Is Running the Clinical Trial?

ECOG-ACRIN Cancer Research Group

Lead Sponsor

Trials

122

Recruited

160,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

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 phase II trial involving 24 patients with radioactive iodine refractory metastatic differentiated thyroid cancer, dabrafenib and trametinib treatment led to a partial response in 38% of patients at 6 months, indicating its efficacy in restoring iodine uptake in BRAF p.V600E-mutated cases.

The treatment was associated with a high rate of adverse events (96%), although only 10 patients experienced severe (grade 3-4) adverse effects, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory BRAF p.V600E-Mutated Differentiated Thyroid Cancer. Leboulleux, S., Do Cao, C., Zerdoud, S., et al.[2023]

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 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]

Cabozantinib (Cabometyx) has been approved by the FDA for treating locally advanced or metastatic differentiated thyroid cancer (DTC) in patients aged 12 and older who are RAI-refractory and have progressed after prior VEGFR-targeted therapy, marking a significant advancement in treatment options for this patient group.

In a clinical trial with 258 participants, cabozantinib demonstrated a median progression-free survival of 11.0 months compared to just 1.9 months for the placebo group, indicating its efficacy in prolonging survival without disease progression, although the overall response rate did not meet the study's endpoint.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Cabozantinib for Differentiated Thyroid Cancer. Duke, ES., Barone, AK., Chatterjee, S., et al.[2023]

Cabozantinib (Cabometyx) has received approval for the treatment of locally advanced or metastatic differentiated thyroid cancer that has not responded to previous therapies targeting vascular endothelial growth factor receptors.

This approval highlights Cabozantinib's efficacy in addressing a specific type of thyroid cancer that has progressed after other treatments, providing a new option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Indication for Cabozantinib. Aschenbrenner, DS.[2023]

In a study of 36 patients with BRAF V600E-mutant anaplastic thyroid cancer, the combination of dabrafenib and trametinib showed a significant overall response rate of 56%, with three patients achieving complete responses.

The treatment demonstrated manageable safety, with no new adverse effects identified, and improved median progression-free survival of 6.7 months and overall survival of 14.5 months, indicating it is a promising option for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study. Subbiah, V., Kreitman, RJ., Wainberg, ZA., et al.[2022]

References

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

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

2. 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]

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

A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory BRAF p.V600E-Mutated Differentiated Thyroid Cancer. [2023]

4. 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]

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

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

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

FDA Approval Summary: Cabozantinib for Differentiated Thyroid Cancer. [2023]

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

New Indication for Cabozantinib. [2023]

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

Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study. [2022]