Zanzalintinib for the Treatment of Advanced Thyroid Cancer Before Surgery

Primary Objectives • To evaluate the efficacy of neoadjuvant zanzalintinib in DTC, non-RET-mutated MTC, and poorly differentiated thyroid cancer (PDTC) by overall objective response rate (overall ORR), defined as the proportion of participants who have a minor response (MR), partial response (PR), or complete response (CR) per RECIST. Participants with locally invasive extrathyroidal and/or extra nodal DTC, non- RET-mutated MTC or PDTC who have high surgical morbidity/complexity based on baseline radiographic assessment (as measured by Thyroid Neck Surgical Morbidity/Complexity Scoring, will be eligible for the study. Hypothesis: Neoadjuvant administration of zanzalintinib will result in acceptable overall ORR (MR+PR+CR rate) for participants with locoregionally advanced DTC and non-RETmutated MTC, ultimately allowing patients to safely undergo complete gross surgical tumor resection with less surgical morbidity. Secondary Objectives * To evaluate the efficacy of neoadjuvant zanzalintinib in DTC, non-RET-mutated MTC or PDTC by objective response rate (ORR) per modified neck RECIST. * To evaluate the safety profile of neoadjuvant zanzalintinib in thyroid cancer. * To evaluate the efficacy of neoadjuvant zanzalintinib on progression-free survival (PFS), including overall PFS and locoregional PFS. * To measure changes in expected and actual thyroid neck surgical morbidity/complexity scoring before and after zanzalintinib treatment. * To evaluate the efficacy of neoadjuvant zanzalintinib by surgical margin status. Exploratory Objectives * To define and measure changes of patient-reported outcomes (PROs) and quality of life (QOL) as measured by MDASI-HN and EQ-5D in participants who receive zanzalintinib treatment. * To evaluate the efficacy of neoadjuvant zanzalintinib by pathologic response. * To evaluate the efficacy of neoadjuvant zanzalintinib by PET metabolic response.