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NCT00987636 · CITED IN SOURCE DOCUMENTS

Study in Localized and Disseminated Ewing Sarcoma

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE3
Status at capture
COMPLETED
Registry last update
2019-10-22

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part
eligibility Criteria
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
healthy Volunteers
false
maximum Age
50 Years
minimum Age
48 Months
sex
ALL
std Ages
  1. CHILD
  2. ADULT
Treatment arms and interventions
arm Groups
  1. description
    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.
    intervention Names
    1. Drug: Zoledronic acid
    label
    R1
    type
    EXPERIMENTAL
  2. description
    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).
    intervention Names
    1. Drug: Busulfan
    label
    R2
    type
    EXPERIMENTAL
  3. description
    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.
    intervention Names
    1. Drug: Treosulfan
    label
    R3
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. R1
    description
    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
    name
    Zoledronic acid
    other Names
    1. Zometa
    2. Bisphosphonate
    type
    DRUG
  2. arm Group Labels
    1. R2
    description
    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
    name
    Busulfan
    other Names
    1. Busilvex
    type
    DRUG
  3. arm Group Labels
    1. R3
    description
    12 g/m² d-5 to d-3
    name
    Treosulfan
    type
    DRUG
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
907
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. measure
    Event free survival
    time Frame
    9.5 years
secondary Outcomes
  1. measure
    Overall survival
    time Frame
    9.5 years
  2. measure
    Safety and toxicity
    time Frame
    permanent
  3. measure
    Quality of life
    time Frame
    9.5 years
Full study description
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.
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.
Source references
references
  1. citation
    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
    type
    DERIVED
  2. citation
    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
    type
    DERIVED
  3. citation
    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
    type
    DERIVED
  4. citation
    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
    type
    DERIVED
  5. citation
    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
    type
    DERIVED
Source notices and limitations
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        3">63</a>] </p><p id="_2526" tabindex="-1">ctDNA was separately assayed by digital-droplet PCR in 102 patients who were treated in the <a href="/clinicaltrials/NCT00987636">EWING2008 (NCT00987636)</a> trial.[<a href="#cit/section_1.64">64</a>] Pretreatment ctDNA copy numbers correlated with EFS and OS. A reduction in ctDNA levels
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        526" tabindex="-1">ctDNA was separately assayed by digital-droplet PCR in 102 patients who were treated in the <a href="/clinicaltrials/NCT00987636">EWING2008 (NCT00987636)</a> trial.[<a href="#cit/section_1.64">64</a>] Pretreatment ctDNA copy numbers correlated with EFS and OS. A reduction in ctDNA levels below the detection lim
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        <strong>High-dose chemotherapy with stem cell support. </strong> <div class="pdq-content-list"><ul id="_2404"><li><a href="/clinicaltrials/NCT00987636">Ewing 2008R3 (NCT00987636)</a> was the first phase III, open-label, multicenter, randomized controlled trial conducted for newly diagnosed patients with disse
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        e chemotherapy with stem cell support. </strong> <div class="pdq-content-list"><ul id="_2404"><li><a href="/clinicaltrials/NCT00987636">Ewing 2008R3 (NCT00987636)</a> was the first phase III, open-label, multicenter, randomized controlled trial conducted for newly diagnosed patients with disseminated Ewing sarcoma who h
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      Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment (PDQ®)–Health Professional Version
      source update dates
      1. context
        Updated: November 27, 2024
        datetime
        2024-11-27T12:00:00Z
        display
        November 27, 2024

    Preserved source evidence · Not medical advice