PRIMARY OBJECTIVES:~I. To determine if event-free survival (EFS) in patients with newly diagnosed metastatic Ewing sarcoma treated with multiagent chemotherapy is improved with the addition of ganitumab (AMG 479).~SECONDARY OBJECTIVES:~I. To describe the toxicity of the addition of ganitumab to multimodality therapy for patients with newly diagnosed metastatic Ewing sarcoma.~II. To compare overall survival in patients with newly diagnosed metastatic Ewing sarcoma treated with multiagent chemotherapy with and without the addition of ganitumab.~EXPLORATORY OBJECTIVES:~I. To compare bone marrow response rates in patients with newly diagnosed metastatic Ewing sarcoma treated with multiagent chemotherapy with and without the addition of ganitumab.~II. To describe the toxicity of 6 months of ganitumab monotherapy as maintenance therapy following multimodality therapy in patients with newly diagnosed metastatic Ewing sarcoma.~III. To describe trough levels of ganitumab in a cohort of patients with Ewing sarcoma < 21 years of age treated with 18 mg/kg.~IV. To describe the feasibility of and local failure rates following hypofractionated stereotactic body radiotherapy (SBRT) directed at bone metastases in patients with newly diagnosed metastatic Ewing sarcoma.~V. To determine if EFS, overall survival, bone marrow response rates, and toxicity differ based on serum markers of the insulin-like growth factor 1 (IGF-1) pathway in patients with newly diagnosed metastatic Ewing sarcoma treated with interval compressed chemotherapy with and without the addition of ganitumab.~VI. To determine if EFS, overall survival, and bone marrow response rates differ based on protein, deoxyribose nucleic acid (DNA), and ribonucleic acid (RNA) marker in patients with newly diagnosed metastatic Ewing sarcoma treated with interval compressed chemotherapy with and without the addition of ganitumab.~VII. To evaluate bone marrow micrometastatic disease and tumor cell surface IGF-1R expression at diagnosis and after 3 and 6 cycles of study therapy in patients with newly diagnosed metastatic Ewing sarcoma.~VIII. To determine if the presence of germline polymorphisms in EGFR correlate with response to multiagent therapy with and without ganitumab.~IX. To investigate the ability of fludeoxyglucose F 18-positron emission tomography (FDG-PET) to augment conventional response assessment of primary Ewing sarcoma tumors by magnetic resonance imaging (MRI).~X. To explore FDG-PET response at the primary tumor as a prognostic marker and as a predictive biomarker of clinical activity of IGF-1R inhibition in patients with newly diagnosed metastatic Ewing sarcoma.~XI. To collect data on institutional testing for Ewing sarcoma breakpoint region 1 (EWSR1) translocation status in patients enrolling on study.~XII. To explore the capacity of plasma cell-free DNA analysis to detect tumor-specific genetic changes at initial diagnosis and after initiation of protocol therapy.~XIII. To collect a population of bone marrow metastatic tumor cells by flow cytometry for genomic profiling.~OUTLINE: Patients are randomized to 1 of 2 treatment regimens. (As of 3/20/2019, the study is closed to accrual and patients in Regimen B no longer receive ganitumab.)~REGIMEN A (vincristine sulfate, doxorubicin hydrochloride and cyclophosphamide [VDC] and ifosfamide and etoposide phosphate [IE]):~INDUCTION THERAPY: Patients receive vincristine sulfate intravenously (IV) over 1 minute on day 1, doxorubicin hydrochloride IV over 1-15 minutes on days 1 and 2, and cyclophosphamide IV over 30-60 minutes on day 1 of weeks 1, 5, and 9, and ifosfamide IV over 1 hour on days 1 to 5 and etoposide phosphate IV over 1-2 hours on days 1 to 5 of weeks 3, 7, and 11.~LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy.~CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV over 1 minute on day 1 of weeks 1, 7, 9, and 13; doxorubicin hydrochloride IV over 1-15 minutes on days 1 and 2 of weeks 1 and 7, cyclophosphamide IV over 30-60 minutes on day 1 of weeks 1, 7, 9, and 13, ifosfamide IV over 1 hour on days 1 to 5 of weeks 3, 5, 11, and 15, and etoposide phosphate IV over 1-2 hours on days 1 to 5 of weeks 3, 5, 11, and 15.~METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or external beam radiation therapy (EBRT).~REGIMEN B (VDC/IE + ganitumab):~INDUCTION THERAPY: Patients receive Induction therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11.~LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy.~CONSOLIDATION THERAPY: Patients receive Consolidation therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 7, 9, 11, 13, and 15.~METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or EBRT.~MAINTENANCE: Patients receive ganitumab IV over 30-60 minutes or 60-120 minutes every 3 weeks for 8 cycles.~After completion of study treatment, patients are followed for 10 years.
This randomized phase III trial studies how well combination chemotherapy with or without ganitumab works in treating patients with newly diagnosed Ewing sarcoma that has spread to other parts of the body. Treatment with drugs that block the IGF-1R pathway, such as ganitumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether adding ganitumab to combination chemotherapy is more effective in treating patients with newly diagnosed metastatic Ewing sarcoma.