The purpose of this study is to find out what effects, good and/or bad, the combination of irinotecan and temozolomide has on Ewing sarcoma.

Irinotecan and temozolomide are chemotherapy drugs that are used very often to treat pediatric patients at MSKCC. The investigators have used these two drugs for many years to treat patients with Ewing sarcoma whose cancer has relapsed.

For patients with newly diagnosed Ewing sarcoma the current standard of care at MSKCC is a five drug chemotherapy regimen in combination with surgery and/or radiation therapy. This standard regimen is called the EFT regimen. . Some patients with Ewing sarcoma do not have their cancer cured by the chemotherapy and surgery/radiation therapy.

This study adds the chemotherapy drugs called irinotecan and temozolomide to the standard EFT regimen. The investigators are trying to improve the success of standard therapy by adding these drugs. The use of irinotecan and temozolomide in this study is experimental because they have not been used before in patients with newly diagnosed Ewing sarcoma. However the investigators have found these drugs to be effective in patients with relapsed Ewing sarcoma. It is not known if adding these two drugs will improve the outcomes of patients treated for Ewing sarcoma.

Inclusion Criteria:

• Age greater than or equal to one year and less than or equal to 40 years at the time of diagnosis
• Newly diagnosed, previously untreated patients with histologically or molecularly confirmed Ewing sarcoma
• Adequate hematologic function:
• Absolute neutrophil count ≥ 1,000/K/mcl
• Platelet count ≥ 100,000/Kmcl
• Adequate renal function:
• Normal creatinine for age (See table below) OR
• Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 Age(Years) Maximum Serum Creatinine (mg/dL) ≤ 5 0.8 6 to ≤ 10 1 11 to ≤ 15 1.2 ≥ 16 1.5

Adequate hepatic function:

• Total bilirubin ≤ 1.5 x the ULN
• AST ≤ 2.5 x the ULN [in the absence of hepatic involvement of tumor. Patients with hepatic involvement are considered eligibile for study]
• ALT ≤ 2.5 x the ULN [in the absence of hepatic involvement of tumor. Patients with hepatic involvement are considered eligibile for study]

Normal cardiac function:

• Shortening fraction ≥ 28% by echocardiogram OR
• Left ventricular ejection fraction (LVEF) ≥ 50% on technetium- 99m pertechnetate radionuclide cineangiography (MUGA) or echocardiogram
• Patients must consent to an indwelling central venous catheter.
• Sexually active patients of reproductive potential must be willing to use an effective method of contraception.

Exclusion Criteria:

• Prior chemotherapy or radiotherapy (other than limited, emergent radiotherapy for treatment of eg. spinal cord compromise or threatened airway)
• Pregnant or breastfeeding females