Irinotecan and Temozolomide in Combination With Existing High Dose Alkylator Based Chemotherapy for Treatment of Patients With Newly Diagnosed Ewing Sarcoma

Memorial Sloan Kettering Cancer Center (MSK)

Status and phase: Active, not recruiting; Phase 2

Conditions: Newly Diagnosed Ewing Sarcoma

Treatments: Drug: Dexrazoxane; Drug: Mesna; Drug: Irinotecan; Device: Doxorubicin; Drug: G-CSF; Drug: Vincristine; Procedure: Surgery; Drug: Cyclophosphamide; Drug: Etoposide; Radiation: Radiation Therapy*; Drug: Temozolomide; Drug: Ifosfamide

Study type: Interventional

Funder types: Other

Identifiers

NCT01864109

13-068

Details and patient eligibility

About

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.

Enrollment: 83 patients

Sex: All

Ages: 1 to 40 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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83 participants in 2 patient groups

Patients with localized disease

Experimental group

Description:

Patients with localized disease will receive six cycles of the combination as "maintenance" therapy following standard chemotherapy. * Cycles 4-6 will include: * Ifosfamide 2,800 mg/m2/day on days 1-5 * Etoposide 100 mg/m2/day on days 1-5 * Cycle 7 will include : * Cyclophosphamide will be given on days 1 and 2 at a dose of 2,100 mg/m2/day, or for patients \< 10 years of age at a dose of 70 mg/kg/day * Doxorubicin will be given on days 1 and 2 at a dose of 37.5 mg/m2/day * Vincristine will be given on day 1 at a dose of 2 mg/m2 or 0.067 mg/kg (whichever is lower, to a max dose of 2 mg) * Cycles 8-13 will include: * Irinotecan will be given on 10 days over weeks 1 and 2 of a cycle at a dose of 20 mg/m2/day intravenously * Temozolomide will be given daily on the first 5 days of irinotecan administration at a dose of 100 mg/m2/day orally or intravenously

Treatment:

Drug: G-CSF

Drug: Temozolomide

Radiation: Radiation Therapy*

Drug: Ifosfamide

Device: Doxorubicin

Drug: Irinotecan

Drug: Mesna

Drug: Etoposide

Drug: Cyclophosphamide

Drug: Dexrazoxane

Procedure: Surgery

Drug: Vincristine

Patients with metastatic disease

Experimental group

Description:

Patients will get 10 cycles of the combination intercalated between the final 4 cycles of standard chemotherapy. * Cycles 4, 5, 7, 8, 10, 11, 13, 14, 16, and 17 will include: * Irinotecan will be given on 10 days over weeks 1 and 2 of a cycle at a dose of 20 mg/m2/day intravenously * Temozolomide will be given daily on the first 5 days of irinotecan administration at a dose of 100 mg/m2/day orally or intravenously * Cycles 6, 9, and 12 will include: * Ifosfamide 2,800 mg/m2/day on days 1-5 * Etoposide 100 mg/m2/day on days 1-5 * Cycle 15 will include: * Cyclophosphamide will be given on days 1 and 2 at a dose of 2,100 mg/m2/day, or for patients \< 10 years of age at a dose of 70 mg/kg/day * Doxorubicin will be given on days 1 and 2 at a dose of 37.5 mg/m2/day * Vincristine will be given on day 1 at a dose of 2 mg/m2 or 0.067 mg/kg (whichever is lower, to a max dose of 2 mg)

Treatment:

Drug: G-CSF

Drug: Temozolomide

Radiation: Radiation Therapy*

Drug: Ifosfamide

Device: Doxorubicin

Drug: Irinotecan

Drug: Mesna

Drug: Etoposide

Drug: Cyclophosphamide

Drug: Dexrazoxane

Procedure: Surgery

Drug: Vincristine