Study in Localized and Disseminated Ewing Sarcoma

NCT00987636 | Completed Phase 3 DMC

• 2 other identifiers: 1081282008-003658-13
• Study Type: interventional
• Target: 907
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Ewing's Sarcoma

Keywords

Ewing Sarcoma; localized; disseminated; metastases; bone; soft tissue

Outcome Measures

Primary Outcomes (1)

• Event free survival

  9.5 years

Secondary Outcomes (3)

• Overall survival

  9.5 years

• Safety and toxicity

  permanent

• Quality of life

  9.5 years

Study Arms (3)

R1

EXPERIMENTAL

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

R2

EXPERIMENTAL

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

R3

EXPERIMENTAL

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

Interventions

Zoledronic acid DRUG

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

Also known as: Zometa, Bisphosphonate

R1

Busulfan DRUG

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

Also known as: Busilvex

R2

Treosulfan DRUG

12 g/m² d-5 to d-3

R3

Eligibility Criteria

• Age: 48 Months - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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%.

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital Muenster: lead

Study Sites (2)

University Hopital Essen, Pediatrics III, Hematology/ Oncology, Sarcoma Centre, International Ewing Sarcoma Study Group, West German Cancer Centre

Essen, 45147, Germany

Location

University Children´s Hospital, Pediatric Hematology and Oncology

Münster, 48149, Germany

Location

Related Publications (5)

• Stork T, Ranft A, Aigner C, Jurgens H, Ladenstein RL, Timmermann B, Van den Berg H, Dirksen U, Collaud S. Primary Mediastinal Ewing's Sarcoma: Post Hoc Analysis from Two International Multicenter Prospective Randomized Trials. Cancers (Basel). 2025 Jan 2;17(1):118. doi: 10.3390/cancers17010118.

  PMID: 39796745 DERIVED

• Rechl V, Ranft A, Bhadri V, Brichard B, Collaud S, Cyprova S, Eich H, Ek T, Gelderblom H, Hardes J, Haveman LM, Hartmann W, Hauser P, Heesen P, Jurgens H, Kanerva J, Kuhne T, Raciborska A, Rascon J, Streitburger A, Uhlenbruch Y, Timmermann B, Kersting J, Pham MT, Dirksen U. Factors Influencing the Outcome of Patients with Primary Ewing Sarcoma of the Sacrum. Sarcoma. 2024 Mar 16;2024:4751914. doi: 10.1155/2024/4751914. eCollection 2024.

  PMID: 38524902 DERIVED

• Koch R, Gelderblom H, Haveman L, Brichard B, Jurgens H, Cyprova S, van den Berg H, Hassenpflug W, Raciborska A, Ek T, Baumhoer D, Egerer G, Eich HT, Renard M, Hauser P, Burdach S, Bovee J, Bonar F, Reichardt P, Kruseova J, Hardes J, Kuhne T, Kessler T, Collaud S, Bernkopf M, Butterfass-Bahloul T, Dhooge C, Bauer S, Kiss J, Paulussen M, Hong A, Ranft A, Timmermann B, Rascon J, Vieth V, Kanerva J, Faldum A, Metzler M, Hartmann W, Hjorth L, Bhadri V, Dirksen U. High-Dose Treosulfan and Melphalan as Consolidation Therapy Versus Standard Therapy for High-Risk (Metastatic) Ewing Sarcoma. J Clin Oncol. 2022 Jul 20;40(21):2307-2320. doi: 10.1200/JCO.21.01942. Epub 2022 Apr 15.

  PMID: 35427190 DERIVED

• Dirksen U, Brennan B, Le Deley MC, Cozic N, van den Berg H, Bhadri V, Brichard B, Claude L, Craft A, Amler S, Gaspar N, Gelderblom H, Goldsby R, Gorlick R, Grier HE, Guinbretiere JM, Hauser P, Hjorth L, Janeway K, Juergens H, Judson I, Krailo M, Kruseova J, Kuehne T, Ladenstein R, Lervat C, Lessnick SL, Lewis I, Linassier C, Marec-Berard P, Marina N, Morland B, Pacquement H, Paulussen M, Randall RL, Ranft A, Le Teuff G, Wheatley K, Whelan J, Womer R, Oberlin O, Hawkins DS; Euro-E.W.I.N.G. 99 and Ewing 2008 Investigators. 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. J Clin Oncol. 2019 Dec 1;37(34):3192-3202. doi: 10.1200/JCO.19.00915. Epub 2019 Sep 25.

  PMID: 31553693 DERIVED

• van den Berg H, Paulussen M, Le Teuff G, Judson I, Gelderblom H, Dirksen U, Brennan B, Whelan J, Ladenstein RL, Marec-Berard P, Kruseova J, Hjorth L, Kuhne T, Brichard B, Wheatley K, Craft A, Juergens H, Gaspar N, Le Deley MC; Euro-EWING99 Group. Impact of gender on efficacy and acute toxicity of alkylating agent -based chemotherapy in Ewing sarcoma: secondary analysis of the Euro-Ewing99-R1 trial. Eur J Cancer. 2015 Nov;51(16):2453-64. doi: 10.1016/j.ejca.2015.06.123. Epub 2015 Aug 10.

  PMID: 26271204 DERIVED

MeSH Terms

Conditions

Sarcoma, Ewing; Neoplasm Metastasis

Interventions

Zoledronic Acid; Diphosphonates; Busulfan; treosulfan

Condition Hierarchy (Ancestors)

Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Butylene Glycols; Glycols; Alcohols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• Uta Dirksen, Prof MD

  University Hospital, Essen

  PRINCIPAL INVESTIGATOR

• Alan W Craft, Prof Sir MD

  Royal Victoria Infirmary

  STUDY CHAIR

• Heribert Jürgens, Prof MD

  University Hospital Muenster

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 30, 2009
• First Posted: October 1, 2009
• Study Start: October 1, 2009
• Primary Completion: March 31, 2019
• Study Completion: March 31, 2019
• Last Updated: October 22, 2019

Record last verified: 2019-10

Locations

DE (2)