Testing Ipilimumab and Nivolumab Combination With or Without Cabozantinib in People >= 18 Years Old With Advanced Soft Tissue Sarcoma

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed metastatic STS,specifically undifferentiated pleomorphic sarcoma (UPS), extraskeletal myxoidchondrosarcoma (EMC), liposarcoma (LPS) or non-uterine leiomyosarcoma (LMS) that arelocally advanced and surgically unresectable

• Patients must have measurable disease, defined as at least one lesion that can beaccurately measured in at least one dimension (longest diameter to be recorded fornon-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chestx-ray or as >= 10 mm (>= 1 cm) with CT scan, MRI, or calipers by clinical exam.Disease will be measured by RECISTv1.1

• Patients with prior treatment with MET or VEGFR inhibitors are allowed. However,prior cabozantinib-treated patients will not be allowed. Prior ipilimumab incombination with nivolumab-treated patients will not be allowed

• Age >= 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Absolute neutrophil count >= 1,000/mcL

• Platelets >= 75,000/mcL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN

• Creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 50mL/min/1.73 m^2

• Serum albumin >= 2.8g/dL

• Lipase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis

• Urine protein/creatinine ratio (UPCR) =< 1 mg/mg

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand have undetectable HCV viral load 12 or more weeks after treatment completion.For patients with HCV infection who are currently on treatment, they are eligible ifthey have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression >= 1month after treatment of the brain metastases. Patients with new or progressivebrain metastases (active brain metastases) or leptomeningeal disease are eligible ifthe treating physician determines that immediate CNS specific treatment is notrequired and is unlikely to be required during the first 2 cycles of therapy

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• Patients must be willing to provide blood specimens and undergo biopsies forresearch purposes

• Patients with baseline blood pressure (BP) lower than 140 mmHg (systolic) and 90mmHg (diastolic). Patients on > 2 anti-hypertensive agents will be excluded

• Human immunodeficiency virus (HIV)-infected patients on effective combinationantiretroviral therapy are eligible as long as HIV is well-controlled and there isundetectable viral load within 6 months. For these patients, an HIV viral load testmust be completed within 28 days prior to enrollment

• The effects of nivolumab, ipilimumab, and cabozantinib on the developing human fetusare unknown. For this reason and because other therapeutic agents used in this trialare known to be teratogenic, women of child-bearing potential (WOCBP) and men mustagree to use adequate contraception (hormonal or barrier method of birth control;abstinence) prior to study entry and for the duration of study participation. WOCBP (defined as any female who has experienced menarche and who has not undergonesurgical sterilization [hysterectomy or bilateral oophorectomy] or who is notpostmenopausal) should use an adequate method to avoid pregnancy for 5 months afterthe last dose of investigational drug. Women of childbearing potential must have anegative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalentunits of human chorionic gonadotropin [HCG]) at the time of enrollment and within 8days prior to each cycle. Women must not be breastfeeding

• Men who are sexually active with women of child-bearing potential (WOCBP) must useany contraceptive method with a failure rate of less than 1% per year. Men receivingcabozantinib and who are sexually active with WOCBP will be instructed to adhere tocontraception for a period of 5 months after the last dose of investigationalproduct. Women who are not of childbearing potential (i.e., who are postmenopausalor surgically sterile) as well as azoospermic men do not require contraception

• Ability to understand and the willingness to sign a written informed consentdocument

Exclusion Criteria:

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia, stablehyperthyroidism on replacement therapy, type-1 diabetes, well-controlled on insulin,and non-clinically significant toxicities at the discretion of the study PrincipalInvestigator

• Patients who are receiving any other investigational agents

• Eligibility of subjects receiving any medications or substances known to affect orwith the potential to affect the activity of cabozantinib will be determinedfollowing review of their cases by the Principal Investigator. Patients who aretaking enzyme-inducing anticonvulsant agents are not eligible

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to cabozantinib, nivolumab, or ipilimumab

• Patients receiving any medications or substances that are strong inhibitors orinducers of CYP3A4 are ineligible. Strong CYP3A4 inducers (e.g., phenytoin,carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's Wort)are not allowed for this study. Because the lists of these agents are constantlychanging, frequently updated lists available athttp://medicine.iupui.edu/clinpharm/ddis/table.asp or other reliable resources willbe consulted. Patients who need to come off CYP3A4 inhibitors/inducers should adhereto a washout period of at least 5 times the half-life of the CYP3A4 inhibitors and 14 days of CYP3A4 inducers

• Patients with any other significant condition(s) that would make this protocolunreasonably hazardous are ineligible. Patients with uncontrolled intercurrentillness or clinical evidence of an active infection at the time of enrollment areineligible

• Pregnant women are excluded from this study because cabozantinib is a receptorkinase inhibitor agent with the potential for teratogenic or abortifacient effects.Because there is an unknown but potential risk for adverse events in nursing infantssecondary to treatment of the mother with cabozantinib in combination with nivolumaband ipilimumab, breastfeeding should be discontinued if the mother is treated withcabozantinib. These potential risks may also apply to other immunotherapeutic agents (ipilimumab and nivolumab) used in this study

• Patients with any of the following within 12 weeks prior to the first dose ofcabozantinib: gastrointestinal bleeding, hemoptysis or pulmonary hemorrhage,radiographic evidence of cavitating pulmonary lesion(s), evidence of tumor invasionof the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel,rectum, or anus), or any evidence of endotracheal or endobronchial tumor orencasement of any major blood vessels are ineligible

• The patient is unable to swallow tablets

• The patient has a corrected QT interval calculated by the Fridericia formula (QTcF) >= 470 ms within 28 days before enrollment

• Patients with a requirement for steroid or immunosuppressive treatment should beexcluded if they have a condition requiring systemic treatment with eithercorticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressivemedications within 14 days of study drug administration. Inhaled or topical steroidsand adrenal replacement doses > 10 mg daily prednisone equivalents are permitted inthe absence of active autoimmune disease