PRIMARY OBJECTIVE:~I. Assess progression free survival (PFS) of ipilimumab + nivolumab versus (vs.) the cabozantinib + nivolumab + ipilimumab combination in patients with refractory soft tissue sarcoma (STS) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.~SECONDARY OBJECTIVES:~I. Evaluate the response rate (complete response [CR]+partial response [PR]) of ipilimumab + nivolumab vs. the cabozantinib + nivolumab + ipilimumab combination.~II. Evaluate the response rate (CR+PR) of cabozantinib + ipilimumab + nivolumab in (crossover) patients whose disease has progressed on ipilimumab + nivolumab doublet therapy.~III. Assess the number of tumor-infiltrating CD8+ T cells in tumor biopsies before and after treatment.~EXPLORATORY OBJECTIVES:~I. Measure tumor-infiltrating CD3+ T cells and CD68+ macrophages in biopsy specimens.~II. Investigate whether response is associated with genetic aberrations and/or tumor mutational burden.~III. Analyze T cell receptor (TCR) signaling in tumor-infiltrating T cells. IV. Analyze total MET and activated MET (p1235-MET) in biopsy specimens before and after study treatment and evaluate molecular target engagement by cabozantinib (as shown by a lower phosphorylated [p]MET/MET ratio).~OUTLINE: Patients are randomized to 1 of 2 arms.~ARM I: Patients receive nivolumab intravenously (IV) and ipilimumab IV on study. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) scans throughout the trial, tumor biopsies on study, and collection of blood throughout the trial.~ARM II: Patients receive cabozantinib orally (PO), nivolumab IV, and ipilimumab IV on study. Patients also undergo CT or MRI scans throughout the trial, tumor biopsies on study, and collection of blood throughout the trial.~Patients are followed for 30 days after completion of study treatment.
This phase II trial compares the effect of ipilimumab and nivolumab combination with cabozantinib, ipilimumab, and nivolumab combination in treating patients >= 18 years old with soft tissue sarcoma that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib is a chemotherapy drug that works by blocking the formation of new blood vessels in tumors, something tumors need to do to grow. Adding cabozantinib to the combination of ipilimumab and nivolumab may be effective in slowing the growth of soft tissue sarcoma tumors.