Zanzalintinib Plus Cemiplimab for the Treatment of BRAF Wild-Type Anaplastic Thyroid Cancer

Inclusion Criteria: * Male/female participants who are at least 18 years of age on the day of signing informed consent * Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Evaluation of ECOG is to be performed within 7 days prior to the date of allocation/randomization. * Pathologic findings supporting the clinical impression of anaplastic thyroid carcinoma. Diagnosis may include consistent with or suggestive of terminology associated with anaplastic thyroid carcinoma, undifferentiated carcinoma, squamous carcinoma; carcinoma with spindled, giant cell, or epithelial features; poorly differentiated carcinoma with pleomorphism, extensive necrosis with tumor cells present. * Patients deemed to have unresectable locoregional disease (stage IVB) or metastatic disease (stage IVC). Patients who are unwilling to undergo surgery or external beam radiation are also eligible. * Patients with BRAF-wild type ATC will be eligible for this study. Patients with a BRAFV600E mutation who are unable to receive the FDA approved drugs, dabrafenib/trametinib, are also eligible as long as this is documented. * Unless clinically contraindicated, all patients with active neck disease who have not received prior neck radiation will be considered for palliative-dose EBRT to the neck (preferably 14 Gy, but 7 to 30 Gy is acceptable) within one month prior to the initiation of study drugs. All patients eligible for palliative neck EBRT who do not undergo radiation will need to be discussed with the PI for study eligibility. In patients with unstable airway, an intervention to stabilize the airway must be implemented prior to enrollment. * Patients must have adequate organ and marrow function, based upon meeting all the following laboratory criteria within 14 days before first dose of study treatment: * Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L) without granulocyte colonystimulating factor support within 2 weeks of screening laboratory sample collection. * Platelets ≥ 100,000/mm3 (≥ 100 GI/L) without transfusion within 2 weeks of screening laboratory sample collection. * Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without transfusion within 2 weeks prior to screening laboratory sample collection. * International Normalized Ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.2 x upper limit of normal (ULN). * Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x ULN. For subjects with documented bone metastasis ALP ≤ 5 x ULN. For subjects with concurrent liver metastases, AST/ALT ≤ 5 x ULN * Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3 x ULN). * Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40 mL/min (≥ 0.67 mL/sec) using the Cockcroft Gault equation. Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) creatinine. * Capable of understanding and complying with the protocol requirements and must have signed the informed consent document. * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. * Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be \< class II. * 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 for 186 days after the last dose of zanzalintinib or 4 months after the last dose of cemiplimab, whichever is later. 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. * Women of childbearing potential (WOCBP) must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria is met: * Postmenopausal, i.e.no menses in greater than or equal to 12 consecutive months 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 * History of hysterectomy or bilateral salpingo-oophorectomy. * Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy). * History of bilateral tubal ligation or another surgical sterilization procedure. Exclusion Criteria: * Prior treatment with zanzalintinib or any other multikinase inhibitor (e.g. lenvatinib, sorafenib, vandetanib, cabozantinib). * Prior treatment with cemiplimab or any other immune checkpoint inhibitor or immunotherapy (e.g. anti-CTLA4, anti-PD-1, anti-PD-L1, BITEs). * Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks or 5 half-lives before first dose of study treatment, whichever is longer. * Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment * Subjects with clinically relevant ongoing complications from prior radiation therapy that have not completely resolved (eg, radiation esophagitis or other inflammation of the viscera). * 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. * Concomitant anticoagulation with oral anticoagulants (e.g, warfarin, direct thrombin inhibitors) and platelet inhibitors (eg, clopidogrel), except: * Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH). * Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen. Note: Subjects must have discontinued oral anticoagulants (eg, warfarin, direct thrombin inhibitors) within 3 days or 5 half-lives prior to first dose of study treatment, whichever is longer. * Any complementary medications (eg, herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks before first dose of study treatment. * Electrolyte abnormalities that have not been corrected, with the exception of calcium if oral calcium and calcitriol are being titrated. * Free thyroxine (FT4) outside the laboratory normal reference range. Asymptomatic subjects with FT4 abnormalities can be eligible after Principal Investigator approval * Subjects having \> 2+ proteinuria on urine dipstick testing unless a 24-hour urine collection for quantitative assessment indicates that the urine protein is \<1 g/24 hours. * The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: * Unstable of deteriorating cardiovascular disorders: * Congestive heart failure New York Heart Association Class 3 or 4, class 2 or higher, unstable angina pectoris, new-onset angina, serious cardiac arrhythmias (eg, ventricular flutter, ventricular fibrillation, Torsades de pointes). * Uncontrolled hypertension defined as sustained blood pressure (BP) \> 140 mm Hg systolic or \> 90 mm Hg diastolic despite optimal antihypertensive treatment. * Stroke (including transient ischemic attack \[TIA\]), myocardial infarction, or other clinically significant arterial thrombotic and/or ischemic event within 12 months before first dose of study treatment. * Pulmonary embolism (PE) or deep vein thrombosis (DVT) or prior clinically significant venous events within 3 months before first dose of study treatment. Note: Subjects with a diagnosis of DVT within 6 months are allowed if asymptomatic and stable at screening and are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen. Note: Subjects who don't require prior anticoagulation therapy may be eligible but must be discussed and approved by the Principal Investigator. * Prior history of myocarditis. * Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: * Tumors invading the GI-tract from external viscera * Active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or acute pancreatitis * Acute obstruction of the bowel, gastric outlet, or pancreatic or biliary duct within 6 months before first dose unless cause of obstruction is definitively managed and subject is asymptomatic * Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intraabdominal abscess within 6 months before first dose. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose of study treatment. * Known gastric or esophageal varices * Ascites, pleural effusion, or pericardial fluid requiring drainage in last 4 weeks * Clinically significant hematuria, hematemesis, or hemoptysis of \> 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) within 12 weeks before first dose of study treatment. Patients with suspected tracheal or esophageal invasion can be included on a case-by-case basis after a discussion with the principal investigator. The degree of tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe hemorrhage and tracheoesophageal fistula associated with tumor shrinkage/necrosis following zanzalintinib therapy. * Symptomatic cavitating pulmonary lesion(s) or endobronchial disease (asymptomatic or radiated lesions allowed) * Lesions invading major blood vessel including, but not limited to, inferior vena cava, pulmonary artery, or aorta. Note: Subjects with intravascular tumor extension (eg, tumor thrombus in renal vein or inferior V. cava) may be eligible following Principal Investigator approval. * Other clinically significant disorders that would preclude safe study participation. * Active infection requiring systemic treatment. Note: Prophylactic antimicrobial treatments (antibiotics, antimycotic, antiviral) are allowed. * Serious non-healing wound/ulcer/bone fracture. Note: non-healing wounds or ulcers are permitted if due to tumor-associated skin lesions. * Malabsorption syndrome. * Pharmacologically uncompensated, symptomatic hypothyroidism. * Moderate to severe hepatic impairment (Child-Pugh B or C). * Requirement for hemodialysis or peritoneal dialysis. * History of solid organ or allogeneic stem cell transplant. * Uncontrolled infection with HIV, hepatitis B or hepatitis C infection, diagnosis of immunodeficiency, and/or tuberculosis (active or latent). * Participants with known controlled HIV infection (undetectable viral load on HIV RNA PCR) and CD4 count above 350 either spontaneously or on a stable antiviral regimen are eligible. For these participants monitoring will be performed per local standards. * Participants with HBsAg positive who have controlled infection (serum HBV DNA PCR that is below the limit of detection and receiving anti-viral therapy for hepatitis B) are eligible. Participants with controlled infections must undergo periodic monitoring of HBV DNA. Participants must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study medication. * Participants with HBsAg negative but total HBcAb positive are permitted with the following requirements: If serum HBV DNA PCR is above the limit of detection at screening, initiate HBV antiviral therapy before study entry. If serum HBV DNA PCR is below the limit of detection, periodic monitoring of HBsAg must be performed. * Participants who are HCV Ab+ who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are eligible * Note: To be eligible, participants taking CYP inhibitors (eg, zidovudine, ritonavir, cobicistat, didanosine) or CYP3 inducers (efavirenz) must change to a different regimen not including these drugs 7 days prior to initiation of study treatment. Antiretroviral therapies (ART) must have been received for at least 4 weeks prior to the first dose. * Note: CD4+ T cell counts, and viral load are monitored per standard of care by the local health care provider. * Recent major (as defined in Appendix B) or minor surgery. Some patients may be eligible on a case-by-case basis after a discussion with the principal investigator. Complete wound healing from major or minor surgery must have occurred at least prior to first dose of study treatment. * Corrected QT interval calculated by the Fridericia formula (QTcF) \> 480 ms within 14 days per electrocardiogram (ECG) before first dose of study treatment. * History of psychiatric illness likely to interfere with ability to comply with protocol requirements or give informed consent. * Pregnant or lactating females. * Inability to swallow tablets or ingest a suspension either orally or by a nasogastric (NG) or gastrostomy (PEG) tube. * Previously identified allergy or hypersensitivity to components of the study treatment formulations. * Another malignancy that requires active therapy and in the opinion of the Investigator would interfere with monitoring of radiologic assessments of response to Investigational Product, within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, lowgrade tumors deemed cured and not treated with systemic therapy. Incidentally diagnosed prostate cancer is allowed if assessed as stage ≤ T2N0M0 and Gleason score ≤ 6. * Other conditions, which in the opinion of the Investigator, would compromise the safety of the patient or the patient's ability to complete the study. * Any active, known, or suspected autoimmune disease within two years of enrollment. Note: Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. * History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computerized tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted. * Diagnosis of immunodeficiency or is receiving systemic steroid therapy (\> 10 mg daily prednisone equivalent) or any other form of immunosuppressive therapy within 2 weeks prior to first dose of study treatment. Inhaled, intranasal, intraarticular, and topical corticosteroids and mineralocorticoids are allowed. Note: Adrenal replacement steroid doses \> 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease. Transient short-term use of higher doses of systemic corticosteroids (up to 2 days in the week before enrollment) for allergic conditions (eg, contrast allergy) or tumor-related respiratory distress is also allowed. * Administration of a live, attenuated vaccine within 30 days before first dose of study treatment. * Patients taking any of the other prohibited concomitant therapies as detailed in section 5.4.1.