Study in Localized and Disseminated Ewing Sarcoma (EWING2008)

October 18, 2019 updated by: University Hospital Muenster

Phase 3, Open Label, Multi-centre, Randomised Controlled International Study in Ewing Sarcoma

Ewing Sarcoma

Primary objectives:

Standard Risk R1: in a randomised trial, to examine whether add-on treatment with zoledronic acid in addition to induction and maintenance chemotherapy improves event-free survival in patients with localised Ewing sarcoma and good histological response or with initial tumour volume <200 mL compared to no add-on treatment.

*High Risk R2: in a randomised trial, to examine whether high-dose chemotherapy using busulfan-melphalan with autologous stem cell reinfusion, compared with standard chemotherapy, improves event-free survival in patients with localised Ewing sarcoma and poor histological response or tumour volume ≥200 mL (R2loc). In patients with pulmonary metastases high dose busulfan-melphalan chemotherapy with autologous stem cell reinfusion is randomised versus standard chemotherapy plus whole lung irradiation (R2pulm).

Very High Risk R3: in a randomised trial, to examine whether the addition of high dose chemotherapy using treosulfan-melphalan followed by autologous stem cell reinfusion to eight cycles of standard adjuvant chemotherapy, compared to eight cycles of standard adjuvant chemotherapy alone, improves event-free survival in patients with primary disseminated disease.

*R2 accrual discontinued on December 1st 2015.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

EWING 2008 is a joint protocol of European and North American Ewing sarcoma study groups. The protocol is aimed at optimising treatment and treatment results of patients with Ewing sarcomas. The EWING 2008 protocol is open to all patients diagnosed with Ewing sarcomas, localised or metastatic, who are considered eligible for neoadjuvant chemotherapy. All patients registered will receive induction chemotherapy consisting of six cycles of vincristine, ifosfamide, doxorubicin and etoposide (VIDE). The decision regarding local therapy must be made following the fifth cycle of induction treatment, with a preference for surgical intervention with or without additional radiotherapy. Preoperative radiotherapy may be considered to improve the operability of otherwise inoperable lesions. In patients with localised disease or with pulmonary metastases, local treatment should be performed following the 6th cycle of VIDE chemotherapy, and should be a complete tumour resection, whenever feasible. Post-operative radiotherapy is determined by the completeness of surgery and the histological response to chemotherapy.

Standard Risk R1 Good responders (R1) (< 10% viable tumour cells) with localised disease are allocated to the standard risk arm and will receive a further eight cycles of chemotherapy composed of vincristine, actinomycin D, and cyclophosphamide (VAC) (females) or ifosfamide instead of cyclophosphamide (VAI) (males). They will be randomised to receive add-on treatment with either fenretinide, zoledronic acid, fenretinide plus zoledronic acid, or no add-on treatment.

High Risk R2 *Poor responders (R2) with localised disease will continue to be randomised as in EURO-E.W.I.N.G. 99 to receive either eight cycles of VAI chemotherapy or high dose treatment with busulfan-melphalan (R2loc).

Patients with primary pulmonary metastases are also allocated to continue to be randomised as in EURO-E.W.I.N.G. 99 to receive either eight cycles of VAI chemotherapy or high dose treatment with busulfan-melphalan (R2pulm).

Very High Risk R3 Patients with disseminated disease, i.e. dissemination to bone and/or other sites and possibly additional pulmonary dissemination (R3), receive six cycles of VIDE induction chemotherapy. Patients are then randomised to either continue with eight cycles of vincristine, actinomycin D and cyclophosphamide (VAC) chemotherapy or high dose treosulfan-melphalan (TreoMel) chemotherapy followed by autologous stem cell reinfusion followed thereafter by eight cycles of VAC chemotherapy. Local therapy in R3 patients is following VIDE induction, whenever feasible prior to high dose therapy (HDT). When long periods of immobilisation following surgery are anticipated, e.g pelvic reconstruction, surgery following HDT may be advisable. Depending on clinical response to induction chemotherapy radiotherapy prior to HDT and surgery may be an option to be considered in such patients. Any delay between VIDE and HDT for reasons of e.g. local treatment must be bridged with VAC cycles. The total number of VAC cycles is not to exceed eight cycles.

*R2 accrual discontinued on December 1st 2015.

Study Type

Interventional

Enrollment (Actual)

907

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
      • Essen, Germany, 45147
        • University Hopital Essen, Pediatrics III, Hematology/ Oncology, Sarcoma Centre, International Ewing Sarcoma Study Group, West German Cancer Centre
      • Muenster, Germany, 48149
        • University Children´s Hospital, Pediatric Hematology and Oncology

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

4 years to 50 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Diagnosis: Histologically confirmed Ewing sarcoma of bone or soft tissue.
  • Age and sex: Either sex, age >48 months (for GPOH patients) and <50 years at the date of diagnostic biopsy. Younger or elderly patients may be reported to the appropriate office (see section 1.4) but are not included in this study.
  • Registration: ≤ 45 days after diagnostic biopsy/surgery.
  • Start of chemotherapy: ≤ 45 days after diagnostic biopsy/surgery.
  • Informed consent: Must be signed prior to study entry.
  • Performance status: Lansky or Karnofsky score > 50%, may be modified for handicapped patients.

  • Haematological parameters:

    • Haemoglobin > 8 g/dl (transfusion allowed),
    • Platelets > 80.000/µl (transfusion allowed),
    • WBC > 2000/µl.
  • Cardiac values: LVEF > 40%, SF > 28%.

Exclusion Criteria:

  • More than one cycle of other chemotherapy prior to registration
  • Second malignancy
  • Pregnancy and lactation
  • Concurrent treatment within any other clinical trial, except trials with different endpoints that due to the nature of their endpoints must run parallel to EWING 2008 e.g. trials on antiemetics, antimycotics, antibiotics, strategies for psychosocial support, etc...
  • Any other medical, psychiatric, or social condition incompatible with protocol treatment

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: R1
Standard Risk R1: in a randomised trial, to examine whether add-on treatment with zoledronic acid in addition to induction and maintenance chemotherapy improves event-free survival in patients with localised Ewing sarcoma and good histological response or with initial tumour volume <200 mL compared to no add-on treatment.
Drug: Zoledronic acid

intravenously at 28 day intervals beginning with cycle 6 of VAC/VAI consolidation chemotherapy for a total period of nine months.

Patients < 18 years will receive 0.05 mg/kg BW by IV infusion 30 min-1 h.

Patients >= 18 years will receive a bodyweight-dependent dose:

Patients >40kg receive 4 mg by IV infusion 30 min-1h Patients 20-40 kg receive 2 mg by IV infusion 30 min-1h

Other Names:
  • Zometa
  • Bisphosphonate
Experimental: R2
High Risk R2: in a randomised trial, to examine whether high-dose chemotherapy using busulfan-melphalan with autologous stem cell reinfusion, compared with standard chemotherapy, improves event-free survival in patients with localised Ewing sarcoma and poor histological response or tumour volume ≥200 mL (R2loc). In patients with pulmonary metastases high dose busulfan-melphalan chemotherapy with autologous stem cell reinfusion is randomised versus standard chemotherapy plus whole lung irradiation (R2pulm).
Drug: Busulfan
intravenously, day -6 to d -3 adults: 0.8 mg/kg body weight (BW) children and adolescents: <9 kg= 1mg/kg BW 9 - <16 kg= 1.2 mg/kg BW 16 - 23 kg= 1.1 mg/kg BW >23 - 34 kg= 0.95 mg/kg BW >34 kg = 0.8 mg/kg BW
Other Names:
  • Busilvex
Experimental: R3
Very High Risk R3: in a randomised trial, to examine whether the addition of high dose chemotherapy using treosulfan-melphalan followed by autologous stem cell reinfusion to eight cycles of standard adjuvant chemotherapy, compared to eight cycles of standard adjuvant chemotherapy alone, improves event-free survival in patients with primary disseminated disease.
Drug: Treosulfan
12 g/m² d-5 to d-3

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Event free survival
Time Frame: 9.5 years
9.5 years

Secondary Outcome Measures

Outcome Measure
Time Frame
Overall survival
Time Frame: 9.5 years
9.5 years
Safety and toxicity
Time Frame: permanent
permanent
Quality of life
Time Frame: 9.5 years
9.5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital Muenster

Investigators

  • Principal Investigator: Uta Dirksen, Prof MD, University Hospital, Essen
  • Study Chair: Alan W Craft, Prof Sir MD, Royal Victoria Infirmary
  • Study Chair: Heribert Jürgens, Prof MD, University Hospital Muenster

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2009

Primary Completion (Actual)

March 31, 2019

Study Completion (Actual)

March 31, 2019

Study Registration Dates

First Submitted

September 30, 2009

First Submitted That Met QC Criteria

September 30, 2009

First Posted (Estimate)

October 1, 2009

Study Record Updates

Last Update Posted (Actual)

October 22, 2019

Last Update Submitted That Met QC Criteria

October 18, 2019

Last Verified

October 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 108128
  • 2008-003658-13 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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