Zanzalintinib for the Treatment of Advanced Thyroid Cancer Before Surgery

Eligibility Criteria 1. Participants with differentiated thyroid cancer, non-RET-mutated medullary thyroid cancer, or poorly differentiated thyroid cancer who present with locoregionally advanced disease, as defined by extrathyroidal and/or extra nodal extension, or with advanced recurrent/residual invasive/bulky nodal disease will be enrolled in this trial, regardless of whether distant metastases are present or not. 2. At least 18 years of age on the day of signing informed consent. 3. Pathologic findings supporting the clinical impression of papillary thyroid cancer, follicular thyroid cancer, oncocytic thyroid cancer, medullary thyroid carcinoma, and/or poorly differentiated thyroid carcinoma. For patients with Bethesda IV or V FNA's (e.g. follicular neoplasm, follicular lesion, Hürthle cell neoplasm, Hürthle cell lesion), if the radiographic context is conclusive for carcinoma of thyroid origin, including significant extrathyroidal extension with invasion of surrounding structures and PET avidity, patients can be enrolled. 4. Thyroid Neck Group morbidity complexity score of 1 to 4 (moderate, severe, very severe, or unresectable). 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 with no known sudden deterioration 2 weeks prior to the first dose of trial treatment. 6. Recovery to baseline or ≤ Grade 1 severity (CTCAE v5) from adverse events (AEs), including immune-related adverse events (irAEs), related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy (e.g., physiological replacement of mineral corticosteroid). Low-grade or controlled toxicities such as alopecia, ≤ Grade 2 hypomagnesemia, ≤ Grade 2 neuropathy are permitted. 7. Adequate organ and marrow function, based upon meeting all the following laboratory criteria within 28 days before first dose of study treatment: 1. Absolute neutrophil count (ANC)≥ 1500/mm3 (≥1.5 GI/L) without granulocyte colony-stimulating factor support within 2 weeks of screening laboratory sample collection. 2. Platelets ≥ 100,000/mm3 (≥100 GI/L) without transfusion within 2 weeks of screening laboratory sample collection. 3. Hemoglobin ≥9 g/dL (≥90 g/L) without transfusion within 2 weeks prior to screening laboratory sample collection. 4. International Normalized Ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.2 x upper limit of normal (ULN). 5. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x ULN. For subjects with documented bone metastasis ALP ≤5 x ULN. 6. Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert fs disease ≤ 3 x ULN). 7. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40 mL/min ( ≥0.67 mL/sec) using the Cockcroft Gault equation. 8. Urine protein-to-creatinine ratio (UPCR) ≤1 mg/mg ( ≤113.2 mg/mmol) creatinine. 8. Capable of understanding and complying with the protocol requirements and must have signed the informed consent document. 9. For MD Anderson site only, subjects must be willing to undergo tumor biopsy prior to trial treatment, unless in the opinion of the treating physician, a biopsy is not feasible or safe. For all sites, subjects must be willing to ultimately undergo surgery if their tumor becomes surgically resectable. Subjects retain the right to refuse any research interventions. 10. Sexually active fertile subjects and their partners must agree to use highly effective method of contraception (defined in Appendix A) during the course of the study and for the following durations after the last dose of treatment (whichever is later). An additional contraceptive method, such as a barrier method (e.g., condom), is required. In addition, men must agree not to donate sperm and women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods. (1) through 186 days after the last dose of zanzalintinib for women of childbearing potential (WOCBP) or through 96 days after the last dose of zanzalintinib for men. 11. Female subjects of childbearing potential must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria is met: permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman \> 45 years-of-age in the absence of other biological or physiological causes. In addition, females \< 55 years-of-age must have a serum follicle stimulating hormone \[FSH\] level \> 40 mIU/mL to confirm menopause). Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff. Exclusion Criteria: 1. Medullary thyroid cancer participants with germline RET or known somatic RET mutations. 2. Prior treatment with zanzalintinib. 3. Prior treatment with a tyrosine kinase inhibitor. 4. Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment. 5. Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Participants with clinically relevant ongoing complications from prior radiation therapy are not eligible. 6. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment. Note: Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of enrollment. Note: Base of skull lesions without definitive evidence of dural or brain parenchymal involvement are allowed. 7. Concomitant anticoagulation with oral anticoagulants (e.g., war