Targeted Therapy vs. Chemotherapy for Thyroid Cancer

Recruiting at 113 trial locations

Overseen By Hari A. Deshpande

Age: 18+

Sex: Any

Trial Phase: Phase 3

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 All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 3

Duration: 28-day cycles, up to 5 years

264 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores two treatments for thyroid cancer that resists standard therapies, focusing on patients with the BRAF V600E gene mutation. One group receives cabozantinib, a drug that may slow tumor growth by blocking certain enzymes. The other group receives a combination of dabrafenib and trametinib, which target specific proteins to potentially stop cancer cells from multiplying. The study aims to determine which treatment is safer and more effective. Individuals with differentiated thyroid cancer that hasn't responded to previous treatments and who have the BRAF V600E mutation may be suitable candidates for this trial. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering participants a chance to contribute to groundbreaking research.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that cabozantinib effectively slows tumor growth in thyroid cancer, though it can cause serious side effects. Severe bleeding occurred in about 5% of patients, and around 13% experienced low calcium levels in their blood. These factors are important to consider.

Research on the combination of dabrafenib and trametinib suggests it is generally well-tolerated. Side effects resemble those seen in other cancers treated with these drugs. Common reactions include fever, rash, and chills, affecting about 20% or more of patients.

Both treatments have FDA approval for other uses, providing extensive safety information. However, weighing the potential risks and benefits remains crucial. Always consult a healthcare provider to determine the best option. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for thyroid cancer because they offer targeted approaches that differ from traditional chemotherapy. Cabozantinib is unique because it blocks specific proteins responsible for tumor growth and blood vessel development, potentially leading to more effective tumor suppression. Dabrafenib and trametinib work by targeting specific mutations within cancer cells, known as BRAF mutations, which are not addressed by conventional treatments. These targeted therapies aim to provide more precise and potentially less toxic options compared to the standard chemotherapy, offering hope for improved outcomes in thyroid cancer patients.

What evidence suggests that this trial's treatments could be effective for refractory BRAF V600E-mutated differentiated thyroid cancer?

Research has shown that cabozantinib, which participants may receive in Arm B of this trial, is promising for treating differentiated thyroid cancer. Studies found it slowed disease progression, with patients living about 9.2 months longer without their cancer worsening.

Similarly, the combination of dabrafenib and trametinib, tested in Arm A of this trial, has proven effective. Research found that about 66.7% of patients experienced tumor shrinkage. This combination also helped prevent further cancer spread.

Both treatments target a specific change in cancer cells called the BRAF V600E mutation, which drives cancer growth. Cabozantinib blocks certain enzymes that aid tumor growth, while dabrafenib and trametinib work together to disrupt cancer cell signals. ^{6 7 8 9 10}

Who Is on the Research Team?

Lova Sun

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

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

I have been treated with up to two drugs targeting blood vessel growth in cancer.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Dabrafenib
• Trametinib

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.

How Is the Trial Designed?

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 European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in United States as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39485731/

Real world outcomes of cabozantinib therapy in poorly ... 4/7 (57%) patients had a partial response to cabozantinib, while 2/7 (29%) had stable disease (SD) as their best response. The median time on ...

2. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-cabozantinib-differentiated-thyroid-cancer

FDA approves cabozantinib for differentiated thyroid cancer CABOMETYX significantly reduced the risk of disease progression or death versus placebo (p<0.0001). The median PFS was 11.0 months (95% CI: 7.4, ...

3. ecancer.org ecancer.org/en/news/21906-asco-2022-follow-up-data-further-support-the-superior-efficacy-of-cabozantinib-in-patients-with-progressive-differentiated-thyroid-cancer

ASCO 2022: Follow-up data further support the superior ... Specifically, median progression-free survival (mPFS) in papillary thyroid cancer patients was 9.2 months for cabozantinib compared to 1.9 ...

4. etj.bioscientifica.com etj.bioscientifica.com/view/journals/etj/13/6/ETJ-24-0225.xml

Real world outcomes of cabozantinib therapy in poorly ... Phase I data of high-dose cabozantinib did show impressive efficacy for DTC with a response rate of 53%; however, this dosage led to a dose reduction to 60 mg ...

5. cabometyxhcp.com cabometyxhcp.com/dtc-treatment/monotherapy/efficacy

Efficacy data in 2L DTC CABOMETYX® (cabozantinib) ... CABOMETYX delivered a significant benefit in the primary PFS analysis1. Median PFS was not reached in the primary analysis (n=125, 95% CI: 5.7-NE) vs PFS of ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/208692s012lbl.pdf

cabometyx - accessdata.fda.gov The safety and effectiveness of CABOMETYX for the treatment of differentiated thyroid cancer. (DTC) have been established in pediatric patients aged 12 years ...

7. cabometyxhcp.com cabometyxhcp.com/

CABOMETYX® (cabozantinib) HCP | See Approved Indications Hemorrhage: CABOMETYX can cause severe and fatal hemorrhages. The incidence of Grade 3-5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC ...

8. cabometyx.com cabometyx.com/thyroid-cancer/about-cabometyx

About CABOMETYX® (cabozantinib) a Thyroid Cancer ... In the FIRST AND LATER ANALYSES, people taking CABOMETYX reduced the risk of tumor growth or death by 78% vs placebo. In the later analysis.

9. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35679021/

Cabozantinib for Differentiated Thyroid Cancer The FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or ...

10. ir.exelixis.com ir.exelixis.com/news-releases/news-release-details/exelixis-announces-us-fda-approval-cabometyxr-cabozantinib-3

Exelixis Announces U.S. FDA Approval of CABOMETYX ... Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, ...