First-line Treatment of Ewing Tumours With Primary Extrapulmonary Dissemination in Patients From 2 to 50 Years (CombinaiR3)

NCT03011528 | Completed Phase 2 DMC

• 1 other identifier: IC 2015-13
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 17

Brief Summary

Ewing's sarcoma and related tumours (ESFT) are rare tumours, with a peak incidence in the second decade of life. They start most often from bone, and are characterized by a specific translocation involving the so-called EWS gene. In one patient out of three, the staging procedures detect metastatic tumours at the diagnosis, most commonly in lungs, bones, and bone marrow. ESFT treatment strategy is multidisciplinary, combining primary chemotherapy, a local treatment, and consolidation chemotherapy. The primary metastatic dissemination is the most important prognostic factor, as the survival rate is around 70-75% for localized tumours, in contrast with less than 50% for patients with primary metastatic disease. Among primary metastatic patients, bone involvement and / or bone marrow strike markedly the prognosis of these patients. While the long-term survival of patients with isolated pleural pulmonary metastases is approximately 50%, whereas it is only from 0 to 25% in patients with bone marrow involvement. In 1999, the Intergroup EURO EWING built a new study protocol for patients with Ewing tumours. For the patients with primary extrapulmonary metastatic Ewing tumours (R3 patients), the protocol proposed a heavy induction chemotherapy, in order to propose a consolidation with high dose chemotherapy to a higher rate of patients. The high-dose Busulfan Melphalan chemotherapy (BuMel) was based on Busulfan (600 mg/m²) and Melphalan (140 mg/m²), with autologous peripheral blood stem cell (PBSC) support. Of note, for the full population of patients with metastatic disease, the 3-year EFS rate was 27% (SD 3%), and the OS rate was 34% (SD 4%), with a median follow-up of 3.9 years after diagnosis, and a median survival time of 1.6 years.

Conditions

Ewing Sarcoma Family of Tumors

Outcome Measures

Primary Outcomes (1)

• Anti-tumour effect of the treatment strategy assessed by the number of patients event-free survival (EFS) at 18 months

  EFS is defined as the time from inclusion date to the first documentation of progression, distant disease, second cancer or death (or last news for patients free of event). The event free survival is estimated by Kaplan-Meier method.

  18 months after inclusion of the last patient

Secondary Outcomes (12)

• Anti-tumour effect of the dose-intensified induction chemotherapy assessed by the response rate of patients

  week 19-20 = Response Evaluation 2 (RE2)

• Anti-tumour effect of the dose-intensified induction chemotherapy assessed by the number of patients eligible for consolidation phase

  week 19-20 = RE2

• Overall survival (OS) is assessed by the number of patients still alive at the end of the three years of treatment

  3 years = Response Evaluation End-Of-Treatment (EOT RE)

• 3-years event-free survival (EFS) is assessed by the number of patients without any event at the end of treatment phase

  3 years = EOT RE

• Number of patients with treatment-related adverse events as assessed by CTCAE v4.03

  week 19-20 = RE2 ; week 27-28 = Response Evaluation 3 (RE3); 3 years = EOT RE

Study Arms (4)

VDC - IE x2 & Surgery

OTHER

Patients in Arm A receive * VDC-IE x2: Intensified induction phase: * 4 cycles of VDC (Vincristine Doxorubicine Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "good response" after the 4th treatment, followed by: * 4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association * Consolidation BuMel High dose chemotherapy (Busulfan Melphalan) followed by Peripheral Blood Stem Cell Infusion * Local treatment by surgery of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. Radiotherapy can be added * Maintenance phase * 1st year : VC (Vincristine Cyclophosphamide) association * 2nd year : Cyclophosphamide po 25 mg/m²

Drug: VDC-IE x2; Drug: Consolidation BuMel; Drug: Maintenance; Procedure: Local treatment by surgery; Radiation: Local treatment by radiotherapy

VDC - IE & TEMIRI & Surgery

OTHER

Patients in Arm B receive * VDC-IE \& TEMIRI: Intensified induction phase: * 4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "poor response" after the 4th treatment, followed by: * 4 cycles of TEMIRI (Temozolomide-Irinotecan) association * Local treatment by surgery of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. Radiotherapy can be added * Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion * Maintenance phase * 1st year : VC (Vincristine Cyclophosphamide) association * 2nd year : Cyclophosphamide po 25 mg/m²

Drug: VDC-IE; Drug: TEMIRI; Drug: Consolidation BuMel; Drug: Maintenance; Procedure: Local treatment by surgery; Radiation: Local treatment by radiotherapy

VDC - IE x2 & Radiotherapy

OTHER

Patients in Arm C receive * VDC-IE x2: Intensified induction phase: * 4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "good response" after the 4th treatment, followed by: * 4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association * Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion * Local treatment by radiotherapy of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. * Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion * Maintenance phase * 1st year : VC (Vincristine Cyclophosphamide) association * 2nd year : Cyclophosphamide po 25 mg/m²

Drug: VDC-IE x2; Drug: Consolidation BuMel; Drug: Maintenance; Radiation: Local treatment by radiotherapy

VDC - IE & TEMIRI & Radiotherapy

OTHER

Patients in Arm D receive * VDC-IE \& TEMIRI: Intensified induction phase: * 4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "poor response" after the 4th treatment, followed by: * 4 cycles of TEMIRI (Temozolomide-Irinotecan) association * Local treatment by radiotherapy of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. * Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion * Maintenance phase * 1st year : VC (Vincristine Cyclophosphamide) association * 2nd year : Cyclophosphamide po 25 mg/m²

Drug: VDC-IE; Drug: TEMIRI; Drug: Consolidation BuMel; Drug: Maintenance; Radiation: Local treatment by radiotherapy

Interventions

VDC-IE x2 DRUG

Week 1, 5, 9 and week 13: * Vincristine, IV, D1, 1.5mg/m² * Doxorubicine, IV, D1-D2, 37.5mg/m² * Cyclophosphamide, IV, D1, 1.2g/m² Week 3, 7, 11 and week 15: * Ifosfamide, IV, D15 to D19, 1.8g/m²/d * Etoposide, IV, D15 to D19, 100mg/m²/d

Also known as: Intensified Induction VDC-IE x2

VDC - IE x2 & Radiotherapy; VDC - IE x2 & Surgery

VDC-IE DRUG

Week 1 and week 5: * Vincristine, IV, D1, 1.5mg/m² * Doxorubicine, IV, D1-D2, 37.5mg/m² * Cyclophosphamide, IV, D1, 1.2g/m² Week 3, and week 7: * Ifosfamide, IV, D15 to D19, 1.8g/m²/d * Etoposide, IV, D15 to D19, 100mg/m²/d

Also known as: Intensified Induction VDC-IE

VDC - IE & TEMIRI & Radiotherapy; VDC - IE & TEMIRI & Surgery

TEMIRI DRUG

Week 9, 12, 15 and week 18: * Temozolomide, PO, D1 to D5, 150mg/m²/d * Irinotecan, IV, D1 to D5, 50mg/m²/d

Also known as: Intensified Induction TEMIRI

VDC - IE & TEMIRI & Radiotherapy; VDC - IE & TEMIRI & Surgery

Consolidation BuMel DRUG

After induction phase and local treatment (surgery and/or radiotherapy) and before PBSC: * Busulfan, IV, D-5 to D-2, dosa according to the weight * Melphalan, IV, D-1, 140 mg/m² Peripheral Blood Stem Cell infusion: \- PBSC infusion, D0, at least 3.10\^6 CD34/kg

Also known as: High dose Consolidation chemotherapy

VDC - IE & TEMIRI & Radiotherapy; VDC - IE & TEMIRI & Surgery; VDC - IE x2 & Radiotherapy; VDC - IE x2 & Surgery

Maintenance DRUG

\* 1st year : VC * Vinblastine, IV, 3mg/m², once a week (except during radiotherapy: 1mg/m², 3 times a week) * Cyclophosphamide, PO, 25mg/m² continuously

Also known as: 2 years maintenance

VDC - IE & TEMIRI & Radiotherapy; VDC - IE & TEMIRI & Surgery; VDC - IE x2 & Radiotherapy; VDC - IE x2 & Surgery

Local treatment by surgery PROCEDURE

Surgical excision of whole site of the primary tumour and metastatic sites (outside pulmonary sites) can take place before or after the high dose consolidation chemotherapy. Radiotherapy can be added

Also known as: Surgery of primary tumour/metastatic sites

VDC - IE & TEMIRI & Surgery; VDC - IE x2 & Surgery

Local treatment by radiotherapy RADIATION

Radiotherapy of whole site of the primary tumour and metastatic sites (outside pulmonary sites) can take place before or after the high dose consolidation chemotherapy

Also known as: Radiotherapy of primary tumour/metastatic sites

VDC - IE & TEMIRI & Radiotherapy; VDC - IE & TEMIRI & Surgery; VDC - IE x2 & Radiotherapy; VDC - IE x2 & Surgery

Eligibility Criteria

• Age: 2 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• \- Ewing tumour not previously treated.
• \- Age between 2 and 50 years.
• \- Measurable disease by cross sectional imaging (RECIST 1.1) or evaluable disease with functional metabolic, positron emission tomography scanner (PET SCAN) or other methods (e.g., cytology/histology).
• \- General status compatible with the study treatments (LANSKY score ≥ 50%, or Karnofsky ≥ 50%, or Eastern Cooperative Oncology Group (ECOG) ≤ 2).
• \- Adequate bone marrow function (not applicable in case of bone marrow disease).
• Platelets ≥ 100 x 109 /L
• Absolute Neutrophil Count (ANC) ≥ 1 x 109 /L
• Hemoglobin ≥ 8g /dL.
• \- Adequate liver function :
• Aspartate Aminotransferase (AST) and Alanine Transferase (ALT) ≤ 5 x Upper Limit Normal (ULN)
• Total Bilirubin ≤ 2 Upper Limit Normal (ULN). If total bilirubin \> 2xULN, Bilirubin Conjugated Fraction (BCF) ≤ 2 x ULN
• \- No absolute contra-indication of Busulfan-Melphalan if radiotherapy of the primary tumour is necessary with specific attention to patient with primary spinal tumor.
• \- Adequate cardiac and renal functions:
• Creatinine \< 1.5 of normal for age or clearance \> 60 ml/min/1.73 m²;
• Left Ventricular Ejection Fraction (LVEF) \> 50% and/or shortening fraction \> 28%.

You may not qualify if:

• \- Age below 2 or greater than 50 years.
• \- Ewing tumour localized, or solely with pleural and/or lung metastases.
• \- Concomitant disease, particularly infectious disease, likely to interfere with patient's treatment.
• \- History of cancer, according to investigator's judgment.
• \- Life expectancy \< 2 months.
• \- Patient already included in another clinical trial with an investigational drug.
• \- Pregnant or breastfeeding patient.
• \- Person deprived of liberty or under guardianship.
• \- Patient likely unable to comply with the study medical monitoring for geographical, social or psychological reasons.

Sponsors & Collaborators

• Institut Curie: lead
• UNICANCER: collaborator

Study Sites (17)

Chr Felix Guyon

La Réunion, Saint Denis, 97400, France

Location

Bordeaux Chu

Bordeaux, 33076, France

Location

CHU Grenoble Alpes

Grenoble, 38043, France

Location

LILLE Centre Oscar Lambret

Lille, 59000, France

Location

LYON Centre Léon Bérard

Lyon, 69000, France

Location

Marseille Chu

Marseille, 13000, France

Location

CHRU Montpellier - Hôpital A. de Villeneuve

Montpellier, 34295, France

Location

Nantes Chu

Nantes, 44000, France

Location

PARIS Institut Curie

Paris, 75005, France

Location

PARIS Trousseau

Paris, 75012, France

Location

CHU Hôpital Sud

Rennes, 35056, France

Location

Strasbourg Chu

Strasbourg, 67098, France

Location

Toulouse Chu

Toulouse, 31059, France

Location

TOULOUSE Institut Claudius Regaud

Toulouse, 31059, France

Location

Nancy Chu

Vandœuvre-lès-Nancy, 54511, France

Location

NANCY Institut de Cancérologie de Lorraine

Vandœuvre-lès-Nancy, 54519, France

Location

VILLEJUIF Institut Gustave Roussy

Villejuif, 94805, France

Location

Related Publications (1)

• Laurence V, Jehanno N, Dureau S, Mous L, Claude L, Ballet S, Pierron G, Gaspar N, Brahmi M, Valentin T, Revon-Riviere G, Lervat C, Probert J, Entz-Werle N, Mansuy L, Plantaz D, Rios M, Saumet L, Verite C, Castex MP, Thebaud E, Cassou-Mounat T, Plissonnier AS, Dieppedale J, Delattre O, Legrier ME, Marec-Berard P, Gouin F, Berlanga P, Cordero C, Surdez D, Corradini N. Interest of a sequential multimodal approach for the treatment of newly diagnosed patients with multimetastatic Ewing sarcoma: results of the French prospective CombinaiR3 phase II trial. Br J Cancer. 2025 Nov 17. doi: 10.1038/s41416-025-03263-3. Online ahead of print.

  PMID: 41249450 RESULT

MeSH Terms

Conditions

Neuroectodermal Tumors, Primitive, Peripheral

Interventions

Consolidation Chemotherapy; Maintenance

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Drug Therapy; Therapeutics; Health Care Facilities Workforce and Services

Study Officials

• Valérie LAURENCE, MD

  Institut Curie

  PRINCIPAL INVESTIGATOR

• Nadège CORRADINI, MD

  Institut d'Hématologie et d'Oncologie Pédiatrique

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 6, 2016
• First Posted: January 5, 2017
• Study Start: December 1, 2016
• Primary Completion: August 1, 2022
• Study Completion: November 1, 2023
• Last Updated: November 21, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data requests can be submitted starting 9 months after last article publication and will be made accessible for up to 12 months.
• Access Criteria: Access to trial individual participant data can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a data sharing agreement (DSA).

Locations

FR (17)