This protocol will study treatment for Ewing sarcoma family of tumors (ESFT) and desmoplastic small round cell tumor (DSRCT). Participants with ESFT will be divided into two treatment groups, A or B, based on tumor characteristics.

Group A (standard risk) participants have tumor that is not in the pelvis, has not spread to other parts of the body, and are less than 14 years of age. Because previous clinical trials have shown that standard treatment is very effective for children whose tumors have these characteristics, these participants will receive standard treatment.

Group B (high risk) participants are 14 years of age or older or have tumor in the pelvis, or the tumor has spread to other parts of the body. Participants with DSRCT in the abdomen and/or pelvis or with tumor that cannot be removed by surgery alone or has spread to other parts of the body will be included in Group B. Participants in this group are considered high risk because there is a greater chance of tumor recurring following standard treatments currently in use.

All participants will be followed and evaluated for 10 years following completion of therapy.

PRIMARY OBJECTIVE:

• To estimate the response rate to two initial courses of temsirolimus, temozolomide and irinotecan in previously untreated patients with high-risk Ewing sarcoma family of tumors (ESFT).

SECONDARY OBJECTIVES:

• To estimate the overall survival and progression-free survival in participants with ESFT treated with these approaches.
• To estimate the time to progression in participants with ESFT treated in Group B (high risk).
• To estimate the cumulative incidence of local failure following local control paradigm in this trial.

Group A:

Participants will receive interval compressed (every 2 weeks) alternating courses of chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VDC) and with ifosfamide and etoposide (IE). Doxorubicin will be omitted following a total cumulative dose of 375 mg/m^2. Local control measures (surgery and/or radiation therapy) will be instituted after 6 courses of chemotherapy. Total duration of treatment is approximately 29 weeks.

Group B:

Participants eligible for the window therapy will receive two courses (21 days duration each) of mTOR inhibitor, temsirolimus, in combination with temozolomide and irinotecan. Irinotecan (20 mg/m^2) will be administered IV on a protracted schedule of daily for 5 days, 2 days off, repeated daily x 5 [(qdx5)x2], temozolomide (100 mg/m^2) PO daily x 5 days and temsirolimus 35 mg/m^2 IV weekly on day 1 and 8. Following window treatment (weeks 1 - 6), participants will proceed to induction chemotherapy (weeks 7 - 33) consisting of interval compressed (every 2 weeks) alternating courses of chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VDC) with ifosfamide and etoposide (IE). Doxorubicin will be omitted following a total cumulative dose of 375 mg/m^2. Local control measures (surgery and/or radiation therapy) will be instituted after 6 courses of induction chemotherapy (week 19). Participants whose tumors respond to window therapy will receive temsirolimus, temozolomide and irinotecan at weeks 29 and 31 in place of ifosfamide and etoposide. Following induction therapy, participants will receive six 21-day courses of maintenance therapy consisting of bevacizumab IV on day 1 and daily oral sorafenib and low-dose cyclophosphamide day 1 through day 21.

Inclusion Criteria:

• Group A participants must be <14 years of age at time of diagnosis of histologically proven non-pelvic localized Ewing sarcoma family of tumor (ESFT) involving the bone or soft tissue.

• Group B participants must have newly diagnosed of histologically proven ESFT involving the bone or soft tissue and at least one of the following: metastatic disease (must be biopsy proven), or pelvic primary, or ≥14 years of age at the time of diagnosis.

• OR Group B participants must be newly diagnosed with intra-abdominal, unresectable or metastatic desmoplastic small round cell tumor. Metastatic site must be biopsy proven.

• Age must be ≤25 years.

• Adequate bone marrow function defined as a peripheral absolute neutrophil count (ANC) ≥750/m^3 and platelet count ≥75,000/m^3 (no transfusion within 7 days of study enrollment). Patients with Ewing sarcoma metastatic to the bone marrow are not required to meet bone marrow criteria for study eligibility and are not evaluable for hematologic toxicity.

• Must have adequate renal function based on age.

• Must not have had prior chemotherapy or radiation therapy. Emergent radiotherapy to preserve vital organ function is permitted. Participants who receive emergent radiation will not be eligible for window therapy.

• Must have adequate hepatic function defined as total bilirubin ≤3.0 mg/dL.

• Must have adequate cardiac function defined as shortening fraction ≥28%.

• Females of childbearing potential and males able to father a child must be willing to practice acceptable methods of birth control to prevent pregnancy.

• Additional criteria for Group B participants who will receive upfront window therapy (does not apply to participants who opt out of window therapy):

  • Cytochrome P450 CYP3A4 active agents: Must not be taking any of the following potent CYP3A4 inducers or inhibitors within 1 week prior to study entry: azole antifungals (such as fluconazole, voriconazole, itraconazole, ketoconazole), rifampin, phenytoin, phenobarbitol, carbamazepine, grapefruit juice and St. John's wort.
  • Must have measurable disease.
  • Must not have received emergent radiation therapy.
  • Serum triglyceride level ≤ 300 mg/dL and serum cholesterol ≤ 300 mg/dL.
  • Random or fasting glucose within the upper limits of normal for age. If random glucose is elevated, fasting glucose must be within normal range.
  • SGOT (AST) and SGPT (ALT) ≤3.0 x upper limit of normal for age.

Exclusion Criteria:

• Participant is pregnant or breastfeeding.
• Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.
• Participant has a prior history of malignancy, with the exception of non-melanoma skin cancer. Participants with history of skin cancer must have 5 years elapse since that diagnosis, be in remission, and must not have received chemotherapy, immunotherapy, or radiation therapy.