Cabozantinib With Ifosfamide in Relapsed/Refractory Sarcomas

Inclusion Criteria: 1. Histologic diagnosis of any sarcoma, including bone and soft tissue sarcomas. Biopsy from current relapse/progression is highly preferred, though will accept tissue from prior relapse/progression or initial diagnosis with approval from the study Principal Investigator or designee. 2. Disease that has progressed on or relapsed after upfront initial therapy, which must have included traditional chemotherapy. 3. Evaluable or Measurable disease, according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1), within 21 days of enrollment. 4. Age, within the following parameters by cohort: 1. Phase I dose-finding cohort: age 12 to 40 years at the time of enrollment. 2. Phase I dose-confirmation cohort: age 5 to \< 12 years at the time of enrollment. 5. Body surface area (BSA): \> 0.35 m2. 6. Performance status: Lansky play (\< 16 years of age) or Karnofsky (\> 16 years of age) of ≥ 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories \< 2. 7. Prior toxicity: recovery to baseline or grade \< 1, as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v5.0), from all acute toxicities, unless adverse events (AE) are clinically non-significant (i.e. alopecia) or controlled on supportive care (i.e. nausea/vomiting, hypothyroidism). 8. Able to swallow tablets whole. 9. Hematopoietic function: 1. Absolute neutrophil count \> 1,000/uL (without hematopoietic growth factor within the time frame noted below). 2. Hemoglobin \> 8 g/dL (without transfusion in the last 7 days). 3. Platelets \> 100,000/uL (without transfusion in the last 7 days). 10. Renal function: 1. Normal renal function determined by one of the following means (even if others are outside of normal range): 1) serum creatinine \< 1.5 x upper limit of normal (ULN) for age; 2) cystatin C within normal limits; 3) nuclear medicine glomerular filtration rate (GFR) within normal limits, or 4) calculated creatinine clearance of \> 70 mL/min/1.73 m2 (≥ 1.17mL/sec) 2. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-hour urine protein ≤ 1 g. 11. Hepatic function: 1. Total bilirubin \< 1.5 x ULN (for subjects with Gilbert's disease \< 3.0 x ULN). 2. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x ULN (ALP ≤ 5 x ULN is allowed with documented bone metastases). For the purpose of this study, the ULN for ALT is defined as 45 IU/L. 3. Serum albumin \> 2.8 g/dL. 4. Prothrombin time (PT) and partial thromboplastin time (PTT) \< 1.3 x ULN. 12. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (i.e. barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment. 13. Female subjects of childbearing potential must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria are met: 1. Pre-pubertal by tanner staging, defined as Tanner stage 1 or 2. 2. Documented permanent sterilization (i.e. hysterectomy, bilateral salpingectomy, or bilateral oophorectomy). Documentation of permanent sterilization or postmenopausal status may include review of medical records, medical examinations, or medical history interview by study site. Exclusion Criteria: 1. Radiographic evidence of tumor invading major blood vessels, or endotracheal or endobronchial tumor. 2. Radiographic evidence of tumor invading the gastrointestinal tract, including esophagus, stomach, small or large bowel, rectum, or anus. 3. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy or surgery (including radiosurgery) and stable for at least 4 weeks prior to enrollment after radiotherapy or major surgery (i.e. removal or biopsy of brain metastasis). Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of enrollment. 4. Prior progression/relapse with cabozantinib. Prior therapy with cabozantinib without progression/relapse and prior use of other multi-tyrosine kinase inhibitors is allowed. 5. Prior therapy with high-dose ifosfamide (\> 10 g/m2/cycle) at any point. 6. Any small molecule inhibitor therapy within 5 half-lives of the drug or 14 days, whichever is shorter, before enrollment. 7. Myelosuppressive chemotherapy within 14 days before enrollment. 8. Autologous bone marrow transplant (auto-BMT) within 42 days before enrollment. 9. Immunotherapy, including chimeric antigen receptor T-cells (CAR-T), within 21 days before enrollment. 10. Small port radiation therapy within 14 days before enrollment. Substantial bone marrow radiation (i.e. \> 50% of the pelvis) or craniospinal radiation within 4 weeks before enrollment. Subjects with any clinically relevant ongoing complications from prior radiation therapy should not be treated with cabozantinib until these complications have resolved. 11. Major surgery (i.e. abdominal surgery; excluding intracranial surgery as noted above) within 14 days before enrollment. Minor surgeries (including mediport or tunneled catheter placement; excluding needle biopsy for tumor sampling or peripherally inserted central catheter placement) within 10 days before enrollment. Subjects must have documented complete wound healing from major surgery or minor surgery before enrollment. 12. Hematopoietic growth factors within 7 days (for short-acting growth factor) or 14 days (for long-acting growth factor) before enrollment. 13. Previously identified allergy or hypersensitivity to components of the study treatment formulations. See Table 10 in Section 9.1.4 for components of cabozantinib. 14. History of clinically significant hemorrhagic cystitis, defined as grade \> 3 non-infectious cystitis, associated with antineoplastic agents. 15. Any medi