• Patients must be < 40 years of age at the time of enrollment.
• Patients must have a body surface area of >= 0.8 m^2 at the time of enrollment.
• Patients must have histologic diagnosis (by institutional pathologist) of newlydiagnosed high grade osteosarcoma. Primary tumors of all extremity and axial sites aregible as long as diagnosis of high-grade osteosarcoma is established. Osteosarcomad malignancy is eligible if no prior exposure to systemic chemotherapies.
• Feasibility Phase:

    Patients must have metastatic disease and a resectable primary tumor. Designation of a
    primary tumor as resectable will be determined at the time of diagnosis by the
    institutional multidisciplinary team.
    For this study, metastatic disease is defined as one or more of the following:
     - Lesions which are discontinuous from the primary tumor, are not regional lymph nodes,
       and do not share a bone or body cavity with the primary tumor. Skip lesions in the
       same bone as the primary tumor do not constitute metastatic disease. Skip lesions in
       an adjacent bone are considered bone metastases.
     - Lung metastases: defined as biopsy-proven metastasis or the presence of one or more
       pulmonary lesions >= 5 mm, OR multiple pulmonary lesions >= 3 mm or greater in size.
     - Bone metastases: Areas suspicious for bone metastasis based on fludeoxyglucose F-18
       (18F-FDG)-positron emission tomography (PET) scan (or whole body technetium-99 bone
       scan if 18F-FDG-PET is unavailable at the treating institution) require confirmatory
       biopsy or supportive anatomic imaging of at least one suspicious site with either
       magnetic resonance imaging (MRI) or computed tomography (CT) (whole body
       18F-FDG-PET/CT or 18F-FDG-PET/MR scans are acceptable).
        - Efficacy Phases (Phase 2/3)
    Patients with both localized and metastatic disease are eligible for the efficacy phase,
    regardless of resectability. Patients will be enrolled to two separate cohorts:
     - Cohort 1 (Standard Risk): Patients with non-pelvic primary osteosarcoma deemed to be
       resectable at the time of diagnosis by the institutional multidisciplinary team,
       without evidence of metastatic lesions.
     - Cohort 2 (High-Risk): Patients with a primary pelvic tumor, a primary tumor designated
       as unresectable by the institutional multidisciplinary team, AND/OR radiographic
       evidence of metastatic lesions.
        - A serum creatinine based on age/gender as follows (within 7 days prior to
         enrollment unless otherwise indicated):
     - (Age: Maximum Serum Creatinine [mg/dL]; Gender)
        - 1 month to < 6 months: 0.4 (male); 0.4 (female)
        - 6 months to < 1 year: 0.5 (male); 0.5 (female)
        - 1 to < 2 years: 0.6 (male); 0.6 (female)
        - 2 to < 6 years: 0.8 (male); 0.8 (female)
        - 6 to < 10 years: 1 (male); 1 (female)
        - 10 to < 13 years: 1.2 (male); 1.2 (female)
        - 13 to < 16 years: 1.5 (male); 1.4 (female)
        - >= 16 years: 1.7 (male); 1.4 (female)
     - OR - a 24 hour urine creatinine clearance >= 70 mL/min/1.73 m^2
     - OR - a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2. GFR must be performed
       using direct measurement with a nuclear blood sampling method OR direct small molecule
       clearance method (iothalamate or other molecule per institutional standard).
        - Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates
         are not acceptable for determining eligibility.
          - Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days
            prior to enrollment unless otherwise indicated)
          - Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase
            [ALT]) =< 135 U/L (within 7 days prior to enrollment unless otherwise
            indicated)
     - Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value
       of 45 U/L
        - No history of congenital prolonged corrected QT (QTc) syndrome, New York Heart
         Association (NYHA) Class III or IV congestive heart failure, unstable angina
         pectoris, serious cardiac arrhythmias or
     - Shortening fraction of >= 27%, or
     - Ejection fraction of >= 50%, or
     - Corrected QT interval by Fridericia (QTcF) < 480 msec on electrocardiogram. Patients
       with Grade 1 prolonged QTc (450-480 msec) at time of study enrollment should have
       correctable causes of prolonged QTc addressed if possible (i.e., electrolytes,
       medications).
        - Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to
         enrollment unless otherwise indicated)
        - Platelet count >= 100,000/uL (transfusion independent, defined as not receiving
         platelet transfusions within a 7-day period prior to enrollment) (within 7 days
         prior to enrollment unless otherwise indicated)
        - Hemoglobin >= 8.0 g/dL (within 7 days prior to enrollment unless otherwise
         indicated)
        - International normalized ratio (INR) =< 1.5 (within 7 days prior to enrollment
         unless otherwise indicated)
        - Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
         therapy with undetectable viral load within 6 months are eligible as long as they
         are NOT receiving anti-retroviral agents that are strong inhibitors or inducers
         of CYP3A4, CYP2D6, and/or MRP2 transporter protein.
        - All patients and/or their parents or legal guardians must sign a written informed
         consent.
        - All institutional, Food and Drug Administration (FDA), and National Cancer
         Institute (NCI) requirements for human studies must be met.
    Exclusion Criteria:
     - Patients who have received previous systemic therapy for osteosarcoma or a prior
       oncologic diagnosis.
     - Patients who have central nervous system metastases.
     - Patients with central cavitating pulmonary lesions invading or encasing any major
       blood vessels in the lung.
     - Patients who are unable to swallow tablets. Tablets cannot be crushed or chewed.
     - Patients with gastrointestinal disorders including active disorders associated with a
       high risk of perforation or fistula formation. Specifically, no clinically significant
       gastrointestinal (GI) bleeding, GI perforation, bowel obstruction, intra-abdominal
       abscess or fistula for 6 months prior to enrollment, no hemoptysis or other signs of
       pulmonary hemorrhage for 3 months prior to enrollment.
     - Patients with active bleeding or bleeding diathesis. No clinically significant
       hematuria, hematemesis, or hemoptysis or other history of significant bleeding within
       3 months prior to enrollment.
     - Patients with uncompensated or symptomatic hypothyroidism. Patients who have
       hypothyroidism controlled with thyroid replacement hormone are eligible.
     - Patients with moderate to severe hepatic impairment (Child-Pugh B or C).
     - Patients who have had primary tumor resection or attempted curative resection of
       metastases prior to enrollment.
     - Patients who have undergone other major surgical procedure (eg, laparotomy) within 14
       days prior to enrollment. Thoracoscopic procedures for diagnostic purposes (biopsy of
       lung nodule) and central access such as port-a-cath placement are allowed.
     - Patients with a history of serious or non-healing wound or bone fracture (pathologic
       fracture of primary tumor is not considered exclusion).
     - Patients with any medical or surgical conditions that would interfere with
       gastrointestinal absorption of cabozantinib.
     - Patients with previously identify allergy or hypersensitivity to components of the
       study treatment formulations.
     - Patients who are receiving any other investigational agent not defined within this
       protocol are not eligible.
     - Patients who in the opinion of the investigator may not be able to comply with the
       safety monitoring requirements of the study are not eligible.
     - Patients who received enzyme-inducing anticonvulsants within 14 days prior to
       enrollment.
     - Patients with a prior history of hypertension (> 95th percentile for age, height, and
       gender for patients < 18 years and > 140/90 mmHg for patients >= 18 years requiring
       medication for blood pressure control.
     - Patients who are receiving drugs that prolong QTc.
     - Patients receiving anticoagulation with oral coumarin agents (eg warfarin), direct
       thrombin inhibitors (eg dabigatran), direct factor Xa inhibitor betrixaban, or
       platelet inhibitors (eg, clopidogrel). Low dose aspirin for cardioprotection (per
       local applicable guidelines) and low dose, low molecular weight heparins (LMWH) are
       permitted. Anticoagulation with therapeutic doses of LMWH and direct factor Xa
       inhibitors rivaroxaban or apixaban are allowed in subjects who are on a stable dose
       for at least 6 weeks before the first dose of study treatment, and who have had no
       complications from a thromboembolic event or the anticoagulation regimen.
     - Patients receiving strong CYP3A4 inducers or strong CYP3A4 inhibitors.
     - Female patients who are pregnant since fetal toxicities and teratogenic effects have
       been noted for several of the study drugs. A pregnancy test is required for female
       patients of childbearing potential.
     - Lactating females who plan to breastfeed their infants.
     - Sexually active patients of reproductive potential who have not agreed to use an
       effective contraceptive method for the duration of protocol therapy.