This single arm study is designed to demonstrate the feasibility of a radically different approach for an exceptionally high-risk subset of MES with widely metastatic disease (WMES). We incorporate the use of evolutionary principles that apply to species and population dynamics as related to adaptation and extinction to populations of cancer cells that similarly adapt and that we are attempting to make extinct, resulting in a cure for the patient. Such principles include an initial intense first strike to deplete the bulk of the cancer cells, followed by a series of sequential second strikes towards eliminating residual, resistant populations, followed by a prolonged period of maintenance chemotherapy to eliminate any remnant cells, using agents generally regarded to be active against newly diagnosed ES.

Inclusion Criteria:

• Patients must be >1 year of age. There is no upper age limit.
• Patients, in the opinion of the enrolling investigator, must be healthy enough to tolerate protocol therapy.
• Patients must have a new histologic diagnosis of either: widely metastatic Ewing sarcoma or metastatic CIC-rearranged sarcoma.
• Patients must have sufficient tissue submitted (flash frozen tissue, FFPE block, or up to 10 unstained FFPE slides) for correlative testing. This may be from a primary or metastatic site.
• Patients must not have received any prior systemic therapy with the exception that they may have started an initial cycle of vincristine/doxorubicin/cyclophosphamide (VDC) prior to enrollment, i.e. VDC may have been given, but not ifosfamide/etoposide (IE).
• Adequate organ function.
• Males and females of reproductive potential may not participate unless they have agreed to the use of, at minimum, two methods of contraception during and after treatment or abstinence.
• All patients and/or their parents or legal guardians must have the ability to understand and the willingness to sign a written informed consent or assent document.

Exclusion Criteria:

• Patients with localized disease or lung only metastases for Ewing sarcoma or localized disease for CIC-rearranged sarcomas.
• Patients with central nervous system (CNS) tumors (primary or metastatic) are not eligible.
• Patients who are receiving any other investigational agents for their cancer.
• Patients with a history of cancer that was treated with myelosuppressive chemotherapy or radiation therapy.
• Patients must not be receiving any additional medicines being given for the specific purpose of treating cancer.
• Patients are ineligible if they have uncontrolled intercurrent illness.
• Pregnancy or Breast Feeding: Pregnant or breast-feeding women will not be entered on this study, because there is no available information regarding human fetal or teratogenic toxicities. Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to starting protocol therapy.
• Patients who are considered unable to comply with the safety monitoring requirements of the study are not eligible.