A Phase 2 Trial of Zanzalintinib in Advanced/Metastatic Bone Sarcomas (ZAMBONE)

Inclusion Criteria: • Patients ≥ 18 years old with pathologically confirmed unresectable locally advanced or metastatic bone sarcoma in one of the following categories: Cohort A - Osteosarcoma, Cohort B - Ewing sarcoma, Cohort C - Chondrosarcoma (conventional, grades 2-3), Cohort D - Other primary sarcoma of bone including but not limited to dedifferentiated chondrosarcoma, undifferentiated pleomorphic sarcoma (UPS) of bone, chordoma, and non-Ewing's round cell sarcomas of bone. chondrosarcoma, undifferentiated pleomorphic sarcoma (UPS) of bone, chordoma, and non-Ewing's round cell sarcomas of bone. * Patients with conventional chondrosarcoma (Cohort C) must demonstrate evidence of disease progression by RECIST 1.1 within 12 weeks of trial enrollment * Patients must have relapsed or become refractory to conventional therapy, receiving at least 1 prior line of systemic therapy unless no standard of care exists. * Patients may have received no more than 2 prior lines of systemic therapy in the advanced/metastatic setting. * Multi-agent and/or alternating neoadjuvant/adjuvant standard of care chemotherapy will be counted as 1 line of systemic therapy if given for metastatic disease. Otherwise, neoadjuvant/adjuvant chemotherapy for localized disease does not apply towards the limitation regarding prior lines of systemic therapy. * Patients must have a performance status corresponding to ECOG scores of 0, 1 or 2 (Karnofsky ≥60%). * Weight \>/= 40 kg. * Patients must have measurable disease per RECIST v1.1 * Prior radiation will be allowed assuming there is measurable disease based upon RECIST 1.1 and at least 21 days from the completion of all radiation prior to initiation of study treatment. (Note: Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation) * Hematological function, as follows: * Absolute neutrophil count (ANC) ≥ 1500/mm3 (growth factor/G-CSF permitted) * Platelet count ≥ 100,000/mm3 * Hemoglobin \> 9 g/dL. * INR ≤ 1.5 and activated partial thromboplastin time (aPTT) \< 1.2 x upper limit of normal (ULN), except subjects on anticoagulation. * Renal function as follows: calculated creatinine clearance ≥ 40 mL/min (≥ 0.67 mL/sec) using the Cockcroft Gault equation. * Hepatic function as follows: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 x ULN and total bilirubin ≤ 1.5 x ULN (for subjects with Gilberts's disease ≤ 3 x ULN), serum albumin ≥ 2. * All patients must agree to consent and co-enroll on MD Anderson MOSAIC protocol to allow for sample collection and correlative studies * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. * Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. * Patients with a prior malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. * Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. * 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 is met: permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman \> 45 years-of-age in the absence of other biological or physiological causes. In addition, females \< 55 years-of-age must have a serum follicle stimulating hormone \[FSH\] level \> 40 mIU/mL to confirm menopause). Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff. * Sexually active fertile subjects and their partners must agree to use highly effective method of contraception (hormonal or barrier method of birth control, intrauterine device, tubal ligation or hysterectomy, subject/partner post vasectomy, implantable or injectable contraceptives, condoms, or abstinence) prior to study entry and for the duration of study participation. (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114). This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following: * Postmenopausal (no menses in greater than or equal to 12 consecutive months). * History of hysterectomy or bilateral salpingo-oophorectomy. * Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy). * History of bilateral tubal ligation or another surgical sterilization procedure. In addition, men must agree not to donate sperm through 96 days after the last dose of zanzalintinib and women (WOCBP) must agree not to donate effs (ova, oocyte) for the purpose of reproduction for at least 186 days after the last dose of zanalintinib. • Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Prior treatment with zanzalintinib. * Patients with primary soft tissue sarcoma with metastasis to bone. o Patients with hist