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

• ClinicalTrials.gov Identifier: NCT02063022
• Recruitment Status: Completed
• First Posted: February 14, 2014
• Last Update Posted: September 19, 2022
• Sponsor: Italian Sarcoma Group
• Information provided by (Responsible Party): Italian Sarcoma Group

Tracking Information

• First Submitted Date: February 21, 2013
• First Posted Date: February 14, 2014
• Last Update Posted Date: September 19, 2022
• Actual Study Start Date: January 22, 2009
• Actual Primary Completion Date: April 14, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 13, 2014)

Event Free Survival (EFS) [ Time Frame: 5 years ]

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 13, 2014)

• Disease Free Survival (DFS) [ Time Frame: expected average 3 years ]
  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 [ Time Frame: expected average 2 years ]
  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) [ Time Frame: expected average 5 years ]
  The OS will be evaluated for the start treatment day to the day of death (for any causes)

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Ewing's Sarcoma

Intervention

• 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:

  • Vincristine
  • Dactinomycin
  • Doxorubicin
  • Ifosfamide
  • Cyclophosphamide
  • Etoposide
  • Busulfan
  • Melphalan
• 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:

  • Vincristine,
  • Doxorubicin
  • Ifosfamide
  • Cyclophosphamide
  • Etoposide
  • Busulfan
  • Melphalan

Study Arms

• 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

  Intervention: Drug: Standard treatment (as per protocol ISG SSG III)
• 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
  Intervention: Drug: Intensified chemotherapy

• 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

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 16, 2022): 278
• Original Estimated Enrollment (submitted: February 13, 2014): 220
• Actual Study Completion Date: April 14, 2022
• Actual Primary Completion Date: April 14, 2022 (Final data collection date for primary outcome measure)

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 40 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT02063022
• Other Study ID Numbers: ISG/AIEOP EW-1
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Italian Sarcoma Group
• Original Responsible Party: Same as current
• Current Study Sponsor: Italian Sarcoma Group
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Roberto Luksch, MD; Italian Sarcoma Group

• PRS Account: Italian Sarcoma Group
• Verification Date: September 2022