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

Primary Purpose

Ewing's Sarcoma

Status
Completed
Phase
Phase 3
Locations
Italy
Study Type
Interventional
Intervention
Standard treatment (as per protocol ISG SSG III)
Intensified chemotherapy
Sponsored by
Italian Sarcoma Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ewing's Sarcoma focused on measuring Non metastatic Ewing's Sarcoma

Eligibility Criteria

undefined - 40 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Centro di Riferimento Oncologico - Unit of Medical Oncology
  • I.R.C.C. - Unit of Medical Oncology
  • IRCCS materno infantile Burlo Garofolo
  • Azienda Ospedaliero Universitaria Consorziale Policlinico - Bari
  • Istituto Ortopedico Rizzoli
  • A.O. Universitaria Meyer
  • Istituto Giannina Gaslini
  • FONDAZIONE IRCCS Istituto Nazionale dei Tumori
  • Azienda Ospedaliera Universitaria "Federico Ii" .
  • Azienda Ospedaliera di Padova
  • Azienda Ospedaliero Universitaria Pisana
  • Istituto Nazionale Tumori Regina Elena - Unit of Medical Oncology I
  • Ospedale Pediatrico Bambin Gesu'
  • Ospedale Infantile Regina Margherita - Unit of Paediatric Oncoematology

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Standard treatment (as per ISG SSG III protocol)

Intensified treatment

Arm Description

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

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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
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
Overall Survival (OS)
The OS will be evaluated for the start treatment day to the day of death (for any causes)

Full Information

First Posted
February 21, 2013
Last Updated
September 16, 2022
Sponsor
Italian Sarcoma Group
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1. Study Identification

Unique Protocol Identification Number
NCT02063022
Brief Title
Efficacy of Dose Intensification in Patients With Non-metastatic Ewing Sarcoma
Acronym
EW-1
Official Title
Phase III Study on Efficacy of Dose Intensification in Patients With Non-metastatic Ewing Sarcoma.
Study Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Completed
Study Start Date
January 22, 2009 (Actual)
Primary Completion Date
April 14, 2022 (Actual)
Study Completion Date
April 14, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Italian Sarcoma Group

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ewing's Sarcoma
Keywords
Non metastatic Ewing's Sarcoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
278 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Standard treatment (as per ISG SSG III protocol)
Arm Type
Active Comparator
Arm Description
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
Arm Title
Intensified treatment
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Standard treatment (as per protocol ISG SSG III)
Other Intervention Name(s)
Vincristine, Dactinomycin, Doxorubicin, Ifosfamide, Cyclophosphamide, Etoposide, Busulfan, Melphalan
Intervention Description
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)
Intervention Type
Drug
Intervention Name(s)
Intensified chemotherapy
Other Intervention Name(s)
Vincristine,, Doxorubicin, Ifosfamide, Cyclophosphamide, Etoposide, Busulfan, Melphalan
Intervention Description
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)
Primary Outcome Measure Information:
Title
Event Free Survival (EFS)
Description
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
Time Frame
5 years
Secondary Outcome Measure Information:
Title
Disease Free Survival (DFS)
Description
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
Time Frame
expected average 3 years
Title
Metastasis Free Survival
Description
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
Time Frame
expected average 2 years
Title
Overall Survival (OS)
Description
The OS will be evaluated for the start treatment day to the day of death (for any causes)
Time Frame
expected average 5 years

10. Eligibility

Sex
All
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roberto Luksch, MD
Organizational Affiliation
Italian Sarcoma Group
Official's Role
Principal Investigator
Facility Information:
Facility Name
Centro di Riferimento Oncologico - Unit of Medical Oncology
City
Aviano
State/Province
Pordenone
ZIP/Postal Code
33081
Country
Italy
Facility Name
I.R.C.C. - Unit of Medical Oncology
City
Candiolo
State/Province
Torino
ZIP/Postal Code
10060
Country
Italy
Facility Name
IRCCS materno infantile Burlo Garofolo
City
Trieste
State/Province
T
ZIP/Postal Code
34137
Country
Italy
Facility Name
Azienda Ospedaliero Universitaria Consorziale Policlinico - Bari
City
Bari
ZIP/Postal Code
70124
Country
Italy
Facility Name
Istituto Ortopedico Rizzoli
City
Bologna
ZIP/Postal Code
40136
Country
Italy
Facility Name
A.O. Universitaria Meyer
City
Firenze
ZIP/Postal Code
50139
Country
Italy
Facility Name
Istituto Giannina Gaslini
City
Genova
Country
Italy
Facility Name
FONDAZIONE IRCCS Istituto Nazionale dei Tumori
City
Milano
Country
Italy
Facility Name
Azienda Ospedaliera Universitaria "Federico Ii" .
City
Napoli
ZIP/Postal Code
80131
Country
Italy
Facility Name
Azienda Ospedaliera di Padova
City
Padova
Country
Italy
Facility Name
Azienda Ospedaliero Universitaria Pisana
City
Pisa
ZIP/Postal Code
56126
Country
Italy
Facility Name
Istituto Nazionale Tumori Regina Elena - Unit of Medical Oncology I
City
Roma
ZIP/Postal Code
00144
Country
Italy
Facility Name
Ospedale Pediatrico Bambin Gesu'
City
Roma
Country
Italy
Facility Name
Ospedale Infantile Regina Margherita - Unit of Paediatric Oncoematology
City
Torino
ZIP/Postal Code
10126
Country
Italy

12. IPD Sharing Statement

Citations:
Citation
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
Results Reference
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Efficacy of Dose Intensification in Patients With Non-metastatic Ewing Sarcoma

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