Brief Summary

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.

Trial Health

On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment

264

participants targeted

Target at P50-P75 for phase_3

Timeline

50mo left

Started Aug 2024

Longer than P75 for phase_3

Geographic Reach

1 country

301 active sites

Status

recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

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Study Timeline

Key milestones and dates

6.1 years study duration

Study Progress32%

Aug 2024Sep 2030

First Submitted

Initial submission to the registry

May 17, 2024

Completed

1 month until next milestone

First Posted

Study publicly available on registry

June 26, 2024

Completed

2 months until next milestone

Study Start

First participant enrolled

August 22, 2024

Completed

6.1 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

September 30, 2030

Expected

Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

September 30, 2030

Last Updated

June 18, 2026

Status Verified

June 1, 2026

Enrollment Period

6.1 years

First QC Date

May 17, 2024

Last Update Submit

June 16, 2026

Conditions

Refractory Differentiated Thyroid Gland Carcinoma

Outcome Measures

Primary Outcomes (1)

Progression free survival (PFS)
PFS will be compared between the two groups using a stratified log-rank test with one-sided type I error of 0.05. Median PFS and 95% confidence interval (CI) for each treatment arm will be estimated using the Kaplan-Meier method. The stratified hazard ratio and 95% CI will be estimated using a Cox proportional hazard model with treatment group as the independent variable.
From randomization to radiographic progression of disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or death from any cause, up to 5 years

Secondary Outcomes (5)

Objective response
Up to 5 years
Overall survival
From randomization to death from any cause, up to 5 years
Duration of response
From confirmed response (complete response or partial response) to progression among patients who achieve a response, up to 5 years
PFS2 - the time from randomization to progression on subsequent therapy or death from any cause (whichever occurs first)
From randomization to progression on subsequent therapy or death from any cause, up to 5 years
Incidence of adverse events
at 2 weeks, 4 weeks, 8 weeks, 16 weeks, and then every 12 weeks after the 16-week confirmatory scan

Other Outcomes (1)

Patient tolerability
At baseline, 4, 8, 16, and 28 weeks

Study Arms (2)

Arm A (Dabrafenib and trametinib)

ACTIVE COMPARATOR

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.

Procedure: Biospecimen CollectionProcedure: Computed TomographyDrug: DabrafenibProcedure: Magnetic Resonance ImagingOther: Questionnaire AdministrationDrug: Trametinib

Arm B (Cabozantinib)

EXPERIMENTAL

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.

Procedure: Biospecimen CollectionDrug: CabozantinibProcedure: Computed TomographyProcedure: Magnetic Resonance ImagingOther: Questionnaire Administration

Interventions

Biospecimen CollectionPROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Arm A (Dabrafenib and trametinib)Arm B (Cabozantinib)

CabozantinibDRUG

Given PO

Arm B (Cabozantinib)

Computed TomographyPROCEDURE

Undergo CT scan

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, tomography

Arm A (Dabrafenib and trametinib)Arm B (Cabozantinib)

DabrafenibDRUG

Given PO

Also known as: BRAF Inhibitor GSK2118436, GSK-2118436, GSK-2118436A, GSK2118436

Arm A (Dabrafenib and trametinib)

Magnetic Resonance ImagingPROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Arm A (Dabrafenib and trametinib)Arm B (Cabozantinib)

Questionnaire AdministrationOTHER

Ancillary study

Arm A (Dabrafenib and trametinib)Arm B (Cabozantinib)

TrametinibDRUG

Given PO

Also known as: GSK 1120212, GSK-1120212, GSK1120212, JTP-74057, MEK Inhibitor GSK1120212

Arm A (Dabrafenib and trametinib)

Eligibility Criteria

Age18 Years+

Sexall

Healthy VolunteersNo

Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

Patient must be ≥ 18 years of age
Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Patient must have differentiated thyroid cancer (DTC) with BRAF V600E mutation as determined by local testing, including the following subtypes (Note: results of a previous biopsy will be accepted):
Papillary thyroid carcinoma including histological variants of papillary thyroid carcinoma (PTC) such as follicular variant, tall cell, columnar cell, cribriform-morular, solid, oxyphil, Warthin-like, trabecular, tumor with nodular fasciitis-like stroma, Hürthle cell variant of papillary carcinoma, poorly differentiated.
Follicular thyroid carcinoma including histological variants of follicular thyroid carcinoma (FTC) such as Hürthle cell, clear cell, insular, and poorly differentiated
Patient must have been previously treated with or deemed ineligible for treatment with Iodine-131 for DTC, and must be receiving thyroxine suppression therapy
Patient must have had prior treatment with at least one of the following vascular endothelial growth factor receptors (VEGFR)-targeting tyrosine kinase inhibitor (TKI) agents for DTC: lenvatinib or sorafenib.
NOTE: Up to two prior VEGFR-targeting TKI agents are allowed including, but not limited to lenvatinib and sorafenib
Patient must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1·1 on chest CT (computed tomography)/abdominal/pelvis CT/MRI (magnetic resonance imaging) performed within 4 weeks prior to randomization
Patient must have radiographic progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 over any time interval on or after most recent prior systemic treatment
Patient must not have any of the following cardiovascular and thromboembolic disorders or medical conditions:
Congestive heart failure class 3 or 4 as defined by the New York Heart Association, unstable angina pectoris, or serious cardiac arrhythmias.
Uncontrolled hypertension defined as sustained blood pressure \> 150 mm Hg systolic or \> 100 mm Hg diastolic despite optimal antihypertensive treatment.
Stroke, myocardial infarction, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months prior to randomization. Patients with more recent diagnosis of deep venous thrombosis are allowed if stable and treated with therapeutic anticoagulation for at least 6 weeks prior to randomization
Patient must not have any clinically significant hematemesis or haemoptysis of \> 0·5 teaspoon (\> 2·5 mL) of red blood or history of other significant bleeding within 3 months prior to randomization
+34 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

National Cancer Institute (NCI)collaborator
ECOG-ACRIN Cancer Research Grouplead

Study Sites (301)

Anchorage Associates in Radiation Medicine

Anchorage, Alaska, 98508, United States

RECRUITING

Anchorage Radiation Therapy Center

Anchorage, Alaska, 99504, United States

SUSPENDED

Alaska Breast Care and Surgery LLC