Efficacy of Dose Intensification in Patients With Non-metastatic Ewing Sarcoma

Study Overview
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Brief Summary
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Controlled, randomized phase III study, with the intent of optimizing the treatment of not metastatic Ewing Sarcoma. The patients will be randomized into 2 arms: standard treatment vs intensive treatment. Both arms will receive an induction treatment followed by surgery (wherever is possible) and/or radiotherapy. The maintenance treatment will be different on the basis of the response to the induction treatment (good or poor)

Detailed Description
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Eligible patients with non metastatic Ewing's Sarcoma will be randomized into 2 different arms: standard treatment arm A (based on the ISG/SSG III protocol) or into the experimental arm B(chemotherapy with dose intensification and shorter length of treatment). Both arm will receive an induction treatment with higher dose intensity of doxorubicin and ifosfamide in Arm B. After the induction treatment all the patient will undergo to local treatment (surgery and/or radiotherapy)that will be followed by a maintenance therapy. The maintenance therapy will be different for both arms and, within each arm, on the basis of the response (histologically evaluated) of the pre-local treatment therapy. Maintenance for Arm A: Poor responders will undergo to stem cells apheresis and their reinfusion after treatment with high doses of Busulfan and Melphalan 25 weeks. Good responders will receive a 6 drugs maintenance treatment for 37 weeks (as per standard ISG/SSG III protocol) Maintenance for Arm B: Poor responders will undergo to stem cells apheresis and their reinfusion after an intensified treatment with high doses of Busulfan and Melphalan (25 weeks). Good responders will receive a maintenance treatment for 25 weeks The primary aim of the study is to assess the Event Free Survival (EFS) that is expected to be similar in both arms The secondary objectives are: To assess if the induction treatment in Arm B is able to increase the percentage of good responders compared to those who receive standard treatment. To assess the toxicity and the Quality of Life related to the chemotherapy treatment

Official Title
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Phase III Study on Efficacy of Dose Intensification in Patients With Non-metastatic Ewing Sarcoma.

Conditions
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Ewing's Sarcoma

Intervention / Treatment
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* Drug: Standard treatment (as per protocol ISG SSG III)
* Drug: Intensified chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Ewing Sarcoma or PNET diagnosis centrally confirmed Age ≤ 40 years Absence of evident metastasis or lung met < 0.5 cm Presence of skip metastasis in the bone compartment of the primary tumor is to be considered as local disease and not metastatic. Adeguate bone marrow, hepatic and renal function Left Ventricular Ejection Fraction > 50% No primary Ewing Sarcoma treatments (both chemotherapy and/or radiotherapy) Voluntarily signed an informed consent form Radiological and histological documentation available for central review. Exclusion Criteria Presence of lung or extra-pulmonary lesions Bone Marrow involvement In case of chest disease: presence of plural effusion Elapsed time between histological diagnosis and chemotherapy start, more than 4 weeks Any medical contraindication to the use of the study drugs Any psychological or social conditions that can compromise the protocol compliance and/or follow-up Previous malignancies (excluded in situ cervix carcinoma)

Ages Eligible for Study
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Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard treatment (as per ISG SSG III protocol)<br>Standard treatment for non metastatic Ewing's Sarcoma (as defined by the ISG/SSG III protocol). It is based on a 6 drugs pre-local treatment (Vincristin, dactinomycin, cyclophosphamide,ifosfamide,etoposide and doxorubicin) followed by local treatment (surgery and/or radiotherapy)and by a maintenance treatment based on induction response | Drug: Standard treatment (as per protocol ISG SSG III)<br>* Induction treatment with: 4 cycle of Vincristine (9mg/,2), Dactinomycin (6mg/m2), Doxorubicin (160mg/m2), Cyclophosphamide (2.4g/m2), Ifosfamide (18g/M2) and Etoposide (450mg/m2) given every 3 weeks Maintenance treatment for poor responder (25 weeks): Vincristine (12mg/m2), Dactinomycin (1.5mg/m2), Doxorubicin (320mg/m2), Ifosfamide (27g/m2), Cyclophosphamide (8.8g/m2), Etoposide (1.5g/m2) and peripheral Cells Steam Transplant after Busulfan and Melphalan treatment Maintenance treatment (37 week) for good responder: Vincristine (18mg/m2), Dactinomycin (6mg/m2), Doxorubicin (400mg/m2), Ifosfamide (72g/m2), Cyclosphosphamide(6g/m2), Etoposide (1.8 g/m2)<br>* Other names: Melphalan;|
| Experimental: Intensified treatment<br>Dose intense treatment for non metastatic Ewing's Sarcoma It is based on a 3 drug pre-local treatment (Vincristin, ifosfamide and doxorubicin)followed by local treatment (surgery and/or radiotherapy)and by a maintenance treatment based on induction response | Drug: Intensified chemotherapy<br>* Induction treatment with: 4 cycle of Vincristine (10.5 mg/m2), Doxorubicin (320 mg/m2) and Ifosfamide (36 mg/m2) given every 3 weeks Maintenance treatment for poor responder (25 weeks): Vincristine (12mg/m2), Doxorubicin (400mg/m2), Ifosfamide (63g/m2), Cyclophosphamide (4g/m2), Etoposide (1.5g/m2) and Cells Steam Transplant after Busulfan and Melphalan treatment Maintenance treatment (25 week) for good responder: Vincristine (12mg/m2), Doxorubicin (400mg/m2), Ifosfamide (72g/m2), Etoposide (1.8g/m2)<br>* Other names: Melphalan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival (EFS) | The EFS (event defined as Progressive Disease , onset of local relapse and/or metastasis, death due to chemotherapy toxicity or for other causes) will be calculated from the first treatment day up to the event onset or to last follow-up | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival (DFS) | The DFS will be calculated from the day that the patient will be free from disease (surgery date and/or radiotherapy completion) up to the date of progression disease or last follow-up | expected average 3 years | 
| Metastasis Free Survival | The Metastasis free Survival will be evaluated from the time of disease free (surgery performed and/or radiotherapy completed) to the onset of distance metastasis or last follow-up | expected average 2 years | 
| Overall Survival (OS) | The OS will be evaluated for the start treatment day to the day of death (for any causes) | expected average 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non metastatic Ewing's Sarcoma