Therapeutic Trial for Patients With Ewing Sarcoma Family of Tumor and Desmoplastic Small Round Cell Tumors

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.