This phase II/III trial tests the safety, side effects, and best dose of the drug cabozantinib in combination with standard chemotherapy, and to compare the effect of adding cabozantinib to standard chemotherapy alone in treating patients with newly diagnosed osteosarcoma. Cabozantinib is in a class of medications called kinase inhibitors which block protein signals affecting new blood vessel formation and the ability to activate growth signaling pathways. This may help slow the growth of tumor cells. The drugs used in standard chemotherapy for this trial are methotrexate, doxorubicin, and cisplatin (MAP). Methotrexate stops cells from making DNA and may kill tumor cells. It is a type of antimetabolite. Doxorubicin is in a class of medications called anthracyclines. It works by slowing or stopping the growth of tumor cells in the body. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. Adding cabozantinib to standard chemotherapy may work better in treating newly diagnosed osteosarcoma.
Patients must be < 40 years of age at the time of enrollment.
Patients must have a body surface area of >= 0.8 m² at the time of enrollment.
Patients must have histologic diagnosis (by institutional pathologist) of newly diagnosed high grade osteosarcoma. Primary tumors of all extremity and axial sites are eligible as long as diagnosis of high-grade osteosarcoma is established. Osteosarcoma as a second malignancy is eligible if no prior exposure to systemic chemotherapies.
Feasibility Phase (NOTE: as of Amendment #2B, the feasibility phase has been completed) 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.
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.
Sequential
Bone Scan
Procedure/SurgeryUndergo bone scintography
Cabozantinib S-malate
DrugGiven PO
Cisplatin
DrugGiven IV
Computed Tomography
Procedure/SurgeryUndergo CT
Doxorubicin Hydrochloride
DrugGiven IV
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Methotrexate
DrugGiven IV
Surgical Procedure
Procedure/SurgeryUndergo surgery
X-Ray Imaging
Procedure/SurgeryUndergo X-ray
Occurrence of dose-limiting toxicity (Feasibility)
Only patients with high risk osteosarcoma who have a primary tumor considered resectable at the time of enrollment will be enrolled to this part of the trial. If a feasible dose cannot be established, the study committee will consult with Children's Oncology Group leadership and National Cancer Institute Cancer Therapy Evaluation Program regarding possible modifications of the regimen and subsequent protocol amendment.
Event-free survival (EFS) (Phase II)
The randomization and analysis will be stratified according to risk group. An assessment of the reduction in risk for EFS-event at the designated landmark time will be used to determine whether the trial continues to part 3. If the study proceeds to part 3, patients enrolled to part 2 of the trial will contribute to the primary analyses for part 3 of the study. If the interim criterion for continuation is not obtained, accrual will be closed with the conclusion that cabozantinib does not reduce sufficiently the risk for EFS-event for patients with newly-diagnosed osteosarcoma.
EFS (Phase III)
Will consist of two randomized phase 3 sub-studies ('Phase 3'). One will be conducted in standard risk patients and one will be conducted in high risk patients.
Overall survival
The one-sided logrank test will be the primary statistical methodology for assessing the null statistical hypothesis. The assessment of the reduction in risk of EFS-event will be conducted in standard risk patients and high risk patients separately.
EFS
Will validate whether elevated circulating tumor deoxyribonucleic acid (ctDNA) levels greater than or equal to 5% at the time of diagnosis are associated with increased risk of EFS-event in patients with localized, resectable osteosarcoma.
EFS
Will validate whether elevated ctDNA levels greater than or equal to 5% at the time of diagnosis are associated with increased risk of EFS-event in patients with metastatic, pelvic and unresectable osteosarcoma.
EFS
Will validate whether elevated ctDNA levels greater than or equal to 3% after initiation of therapy and prior to definitive surgery are associated with increased risk of EFS-event in patients with localized, resectable osteosarcoma.
EFS
Will validate whether elevated ctDNA levels greater than or equal to 3% after initiation of therapy and prior to definitive surgery are associated with increased risk of EFS-event in patients with metastatic, pelvic and unresectable osteosarcoma.
EFS
Will determine whether ctDNA at diagnosis and early on-treatment, as a continuous measurement of ctDNA burden, is associated with an increased risk of EFS-event in patients with newly diagnosed osteosarcoma.
EFS
Will evaluate whether the magnitude of change in ctDNA levels from diagnosis to planned surgical procedure is associated with risk of EFS-event in patients with newly diagnosed osteosarcoma.
EFS
Will determine whether ctDNA levels greater than or equal to 3% after planned surgical procedures are associated with increased risk of EFS-event.
EFS
Will describe the presence of specific copy-number alterations, including MYC amplifications, detected in ctDNA and matched diagnostic tumor samples in patients with newly diagnosed osteosarcoma and determine whether frequently occurring copy-number alterations are associated with increased risk of EFS-event.
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