Testing the Combination of Cabozantinib, Nivolumab, and Ipilimumab (CaboNivoIpi) for Advanced Differentiated Thyroid Cancer

PRIMARY OBJECTIVE: I. To assess the objective response rate, defined as the proportion of patients who have had a partial response (PR) or complete response (CR) within the first 6 months after initiation of therapy with cabozantinib S-malate (XL184 \[cabozantinib\]), nivolumab, and ipilimumab (CaboNivoIpi). SECONDARY OBJECTIVES: I. To assess duration of objective response (DOR), progression-free survival (PFS), and overall survival (OS). II. To assess tolerability and adverse events of CaboNivoIpi in patients with differentiated thyroid cancer (DTC). EXPLORATORY OBJECTIVES: I. To correlate treatment response (Response Evaluation Criteria in Solid Tumors \[RECIST\] version \[v\]1.1) with tumor mutation status. II. To correlate treatment response (RECIST v1.1) with frequency of tumor infiltrating lymphocytes in biopsies taken pre-treatment and after 12 weeks of CaboNivoIpi therapy. III. To evaluate the effect of CaboNivoIpi on T cell receptor (TCR) repertoire and to identify the frequency of shared T cell clones between tumor and peripheral blood. IV. To evaluate the effect of XL184 (cabozantinib) alone and of the CaboNivoIpi combination on peripheral blood mononuclear cells (PBMCs) and to correlate their frequency with treatment response (RECIST v1.1). V. To evaluate the effect of XL184 (cabozantinib) alone and of the CaboNivoIpi combination on myeloid-derived suppressor cells (MDSCs) and to correlate their frequency with treatment response (RECIST v1.1). VI. To correlate treatment response (RECIST v1.1) with programmed cell death protein 1 (PD-1) / programmed cell death-ligand 1 (PD-L1) expression in the primary/metastatic tumor. OUTLINE: Patients receive cabozantinib S-malate orally (PO) once daily (QD) on days -14 to -1 prior to cycle 1, days 1-42 of cycles 1-4 and days 1-28 of subsequent cycles. Patients also receive nivolumab intravenously (IV) over 30 minutes on days 1, 15, and 29 of cycles 1-4 and day 1 of subsequent cycles and ipilimumab IV over 90 minutes on day 1 of cycles 1-4. Treatment repeats every 42 days for cycles 1-4 and every 28 days for subsequent cycles in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) during screening, and blood sample collection throughout the study. After completion of study treatment, patients are followed up at 6 weeks, and then every 12 weeks for up to 2 years.