The trial will enroll competitively up to 41 subjects; male and female, ≥ 18 years, with ECOG PS 0-1 patients with advanced radioactive-iodine refractory differentiated thyroid cancer (DTC) who progressed to previous Tyrosine kinase inhibitors (TKIs), including but not limited to lenvatinib or sunitinib. Patients will have not received previously cabozantinib, selective small-molecule BRAF kinase inhibitors, immune checkpoint inhibitor therapy, or systemic chemotherapy regimens.~The design includes a screening phase in which patient eligibility is addressed, a treatment phase, and a follow-up phase.~Study treatment will begin as soon as possible after signing the informed consent and inclusion will be completed.~All patients will receive cabozantinib at a fixed dose of 60 mg once a day (QD). Patients will continue study treatment until PD (either clinical or radiological), or until unacceptable toxicity, the need for another systemic anticancer treatment, or other reasons for treatment discontinuation.~All patients will undergo periodic tumor assessments by CT or MRI scan every 12 weeks ± 14 days (3 months), and blood monitoring of tumor markers (i.e. thyroglobulin if applicable) every 12 weeks ± 3 days (2 months) from the start of study treatment until progression or patient withdrawal. Further CT/MRI scans could be performed upon suspicion of disease progression according to standard clinical practice and physician criteria. Safety will be assessed at every visit through continuous monitoring of signs and symptoms and periodic laboratory analysis.~The study includes the collection of two blood samples (baseline and after PD; 40 mL at each timepoint) for the determination of cf CHIP-seq (Chromatin immunoprecipitation-sequencing) and patient reported outcomes.
CABOTHYROID is a prospective, exploratory, biomarker-focused, phase II, single-arm, non-randomized, non-blinded, investigator-initiated study of cabozantinib in patients with previously treated advanced radioactive-iodine refractory