Study in Localized and Disseminated Ewing Sarcoma

Ewing's Sarcoma Clinical Trial

— EWING2008  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00987636
• Other study ID #: 108128
• Secondary ID: 2008-003658-13
• Status: Completed
• Phase: Phase 3
• Start date: October 1, 2009
• Est. completion date: March 31, 2019

Study information

• Verified date: October 2019
• Source: University Hospital Muenster
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 907
• Est. completion date: March 31, 2019
• Est. primary completion date: March 31, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 48 Months to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Ewing's Sarcoma
• Sarcoma
• Sarcoma, Ewing

Intervention

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
• 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
• Treosulfan
12 g/m² d-5 to d-3

Locations

Country	Name	City	State
Germany	University Hopital Essen, Pediatrics III, Hematology/ Oncology, Sarcoma Centre, International Ewing Sarcoma Study Group, West German Cancer Centre	Essen
Germany	University Children´s Hospital, Pediatric Hematology and Oncology	Muenster

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital Muenster

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event free survival		9.5 years
Secondary	Overall survival		9.5 years
Secondary	Safety and toxicity		permanent
Secondary	Quality of life		9.5 years

External Links

•   High-Dose Chemotherapy and Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-Risk Ewing Sarcoma: Results of Euro-E.W.I.N.G.99 and Ewing-2008
•   High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma With Pulmonary Metastases: Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING 2008