Efficacy of Dose Intensification in Patients With Non-metastatic Ewing Sarcoma (EW-1)

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

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)

Study Overview

• Status: Completed
• Conditions: Ewing's Sarcoma
• Intervention / Treatment: Drug: Standard treatment (as per protocol ISG SSG III); Drug: Intensified chemotherapy

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 278
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Bari, Italy, 70124
    • Azienda Ospedaliero Universitaria Consorziale Policlinico - Bari
  • Bologna, Italy, 40136
    • Istituto Ortopedico Rizzoli
  • Firenze, Italy, 50139
    • A.O. Universitaria Meyer
  • Genova, Italy
    • Istituto Giannina Gaslini
  • Milano, Italy
    • Fondazione Irccs Istituto Nazionale Dei Tumori
  • Napoli, Italy, 80131
    • Azienda Ospedaliera Universitaria "Federico Ii" .
  • Padova, Italy
    • Azienda Ospedaliera di Padova
  • Pisa, Italy, 56126
    • Azienda Ospedaliero Universitaria Pisana
  • Roma, Italy
    • Ospedale Pediatrico Bambin Gesu'
  • Roma, Italy, 00144
    • Istituto Nazionale Tumori Regina Elena - Unit of Medical Oncology I
  • Torino, Italy, 10126
    • Ospedale Infantile Regina Margherita - Unit of Paediatric Oncoematology
  • Pordenone
    • Aviano, Pordenone, Italy, 33081
      • Centro di Riferimento Oncologico - Unit of Medical Oncology
  • T
    • Trieste, T, Italy, 34137
      • IRCCS Materno Infantile Burlo Garofolo
  • Torino
    • Candiolo, Torino, Italy, 10060
      • I.R.C.C. - Unit of Medical Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 40 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard treatment (as per ISG SSG III protocol); 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); 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); Other Names: Cyclophosphamide; Doxorubicin; Etoposide; Melphalan; Vincristine; Busulfan; Ifosfamide; Dactinomycin
Experimental: Intensified treatment; 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; 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); Other Names: Cyclophosphamide; Doxorubicin; Etoposide; Melphalan; Busulfan; Ifosfamide; Vincristine,

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Italian Sarcoma Group
• Investigators: Principal Investigator: Roberto Luksch, MD, Italian Sarcoma Group

Publications and helpful links

General Publications

• S. Ferrari, T. Alvegard, R. Luksch, A. Tienghi, K. S. Hall, G. Bernini, A. Brach del Prever, P. Picci, G. Bacci, S. Smeland Non-metastatic Ewing's family tumors: High-dose chemotherapy with stem cell rescue in poor responder patients. Preliminary results of the Italian/Scandinavian ISG/SSG III protocol. J Clini Oncol, 2007 ASCO Annual Meeting Proceedings Vol 25 (June 20 Suppl), 2007: 10014

Study record dates

Study Major Dates

• Study Start (Actual): January 22, 2009
• Primary Completion (Actual): April 14, 2022
• Study Completion (Actual): April 14, 2022

Study Registration Dates

• First Submitted: February 21, 2013
• First Submitted That Met QC Criteria: February 13, 2014
• First Posted (Estimate): February 14, 2014

Study Record Updates

• Last Update Posted (Actual): September 19, 2022
• Last Update Submitted That Met QC Criteria: September 16, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Non metastatic Ewing's Sarcoma
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Sarcoma, Ewing; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Antibiotics, Antineoplastic; Cyclophosphamide; Etoposide; Etoposide phosphate; Ifosfamide; Isophosphamide mustard; Melphalan; Doxorubicin; Liposomal doxorubicin; Vincristine; Busulfan; Dactinomycin
• Other Study ID Numbers: ISG/AIEOP EW-1