Testing the Combination of XL184 (Cabozantinib), Nivolumab, and Ipilimumab for Poorly Differentiated Neuroendocrine Tumors

PRIMARY OBJECTIVE: I. To evaluate the overall response rate (ORR) associated with the combination of XL184 (cabozantinib), nivolumab, and ipilimumab in patients with advanced poorly-differentiated neuroendocrine carcinomas (NECs), after the failure of at least one line of prior therapy. SECONDARY OBJECTIVES: I. To evaluate progression-free survival (PFS). II. To measure the safety and tolerability of the combination of XL184 (cabozantinib), nivolumab, and ipilimumab in patients with advanced, poorly-differentiated NECs. III. To evaluate disease control rate (DCR). IV. To measure duration of response (DOR). V. To describe the tumor molecular profile using whole exome sequencing (WES) and correlate it with treatment outcome. VI. To describe the tumor molecular profile using ribonucleic acid (RNA) sequencing (RNAseq) and correlate it with treatment outcome. EXPLORATORY OBJECTIVES: I. To measure the tumor-infiltrating CD8+ T lymphocytes in pre- and on-treatment biopsies. II. To measure tumor-infiltrating myeloid derived suppressor cells (MDSCs) in pre- and on-treatment biopsies. III. To measure tumor-infiltrating tumor-associated macrophages (TAM) in the pre and on-treatment biopsies. IV. To measure the expression of programmed death-ligand 1 (PD-L1) in tumor cells and infiltrating immune cells. OUTLINE: Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-21 of cycles 1-4 and days 1-28 of subsequent cycles, nivolumab intravenously (IV) over 30 minutes on day 1, and ipilimumab IV over 90 minutes on day 1 of cycles 1-4 only. Treatment repeats every 21 for 4 cycles then every 28 days for subsequent cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 4 weeks, and then every 3 months thereafter.