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

NCT ID: NCT03011528

Last Updated: 2025-11-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 45 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-12-31
• Study Completion Date: 2023-11-30

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.

Detailed Description

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. The gene rearrangement results in the production of a transcription factor, in the majority EWS-FLI1 transcription.

In one patient out of three, the staging procedures detect metastatic tumours at the diagnosis; metastases involve most commonly lungs, bones, and bone marrow.

Therefore, in addition to local imaging, the initial extension assessment of any Ewing tumour includes at least a chest CT scan, and a bone marrow extensive evaluation, comprising bone marrow punctures into several different sectors, bone marrow biopsies, and a bone imaging evaluation. The FDG-PET scan is more sensible than bone scan and conventional imaging as MRI in detection of bone metastases. It is more and more widely used in the bone metastasis search in Ewing tumours and seems useful to complement the search of extra-osseous metastases (outside the lungs), including that of bone marrow metastases. The full-body MRI is still under evaluation for the disease extension evaluation.

ESFT treatment strategy is multidisciplinary, combining primary chemotherapy, a local treatment, and consolidation chemotherapy. The local treatment may combine surgery and / or radiotherapy, according to the tumour site and size, and to the tumour response. ESFT chemotherapy is based on alkylating agents (ifosfamide and / or cyclophosphamide), etoposide, anthracyclines, vincristine, and actinomycin.

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, localized or metastatic and below 50 years of age. 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 BuMel chemotherapy was based on Busulfan (600 mg/m²) and Melphalan (140 mg/m²), with autologous peripheral blood stem cell (PBSC) support.

The study enrolled 281 patients with primary dissemination and skeletal metastases, with or without bone marrow involvement and with or without additional pulmonary metastases or metastases to other sites. In contrast to the distribution in the entire group of patients with Ewing tumours, the primary site in this subgroup was extremity in only 31% patients, pelvis/abdomen in 45%, and axial/other in 24% patients. The overall survival at 3 years was 28% (SD 4%) in the group with primary tumour in the abdomen or pelvis, versus 39% (SD 6%) for each of the two other groups. 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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

VDC - IE x2 & Surgery

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

Group Type: OTHER

VDC-IE x2

Intervention Type: 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

Consolidation BuMel

Intervention Type: 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

Maintenance

Intervention Type: 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

Local treatment by surgery

Intervention Type: 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

Local treatment by radiotherapy

Intervention Type: 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

VDC - IE & TEMIRI & Surgery

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

Group Type: OTHER

VDC-IE

Intervention Type: 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

TEMIRI

Intervention Type: DRUG

Week 9, 12, 15 and week 18:

• Temozolomide, PO, D1 to D5, 150mg/m²/d
• Irinotecan, IV, D1 to D5, 50mg/m²/d

Consolidation BuMel

Intervention Type: 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

Maintenance

Intervention Type: 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

Local treatment by surgery

Intervention Type: 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

Local treatment by radiotherapy

Intervention Type: 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

VDC - IE x2 & Radiotherapy

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

Group Type: OTHER

VDC-IE x2

Intervention Type: 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

Consolidation BuMel

Intervention Type: 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

Maintenance

Intervention Type: 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

Local treatment by radiotherapy

Intervention Type: 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

VDC - IE & TEMIRI & Radiotherapy

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

Group Type: OTHER

VDC-IE

Intervention Type: 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

TEMIRI

Intervention Type: DRUG

Week 9, 12, 15 and week 18:

• Temozolomide, PO, D1 to D5, 150mg/m²/d
• Irinotecan, IV, D1 to D5, 50mg/m²/d

Consolidation BuMel

Intervention Type: 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

Maintenance

Intervention Type: 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

Local treatment by radiotherapy

Intervention Type: 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

Interventions

VDC-IE x2

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

Intervention Type: DRUG

VDC-IE

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

Intervention Type: DRUG

TEMIRI

Week 9, 12, 15 and week 18:

• Temozolomide, PO, D1 to D5, 150mg/m²/d
• Irinotecan, IV, D1 to D5, 50mg/m²/d

Intervention Type: DRUG

Consolidation BuMel

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

Intervention Type: DRUG

Maintenance

• 1st year : VC

• Vinblastine, IV, 3mg/m², once a week (except during radiotherapy: 1mg/m², 3 times a week)
• Cyclophosphamide, PO, 25mg/m² continuously

Intervention Type: DRUG

Local treatment by surgery

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

Intervention Type: PROCEDURE

Local treatment by radiotherapy

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

Intervention Type: RADIATION

Other Intervention Names

Intensified Induction VDC-IE x2; Intensified Induction VDC-IE; Intensified Induction TEMIRI; High dose Consolidation chemotherapy; 2 years maintenance; Surgery of primary tumour/metastatic sites; Radiotherapy of primary tumour/metastatic sites

Eligibility Criteria

Inclusion Criteria

1. - Ewing tumour histologically or cytologically confirmed, harboring a specific transcript, and with extrapulmonary metastases (including nodal extension) - histology and FISH results must be consistent, specific transcript can be obtained after inclusions.

2. - Ewing tumour not previously treated.

3. - Age between 2 and 50 years.

4. - 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).

5. - General status compatible with the study treatments (LANSKY score ≥ 50%, or Karnofsky ≥ 50%, or Eastern Cooperative Oncology Group (ECOG) ≤ 2).

6. - 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.

7. - 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

8. - No absolute contra-indication of Busulfan-Melphalan if radiotherapy of the primary tumour is necessary with specific attention to patient with primary spinal tumor.

9. - 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%.

10. - No underlying disease contra-indicating the study treatments.

11. - Patient likely compliant with the recommended study medical monitoring during and after treatments.

12. - Patients of childbearing potential must agree to use adequate contraception for the duration of study treatments and up to 12 months for women and 6 months for men following completion of therapy.

13. - Females of childbearing potential must have a negative serum β-human chorionic gonadotropin (HCG) pregnancy test within 10 days prior study inclusion, and/or urine pregnancy test within 48 hours before the first administration of the study treatment.

14. - Patients covered by a health insurance system.

15. - Patient, or patient's legal representative, informed and having signed the informed consent.

Exclusion Criteria

1. - Age below 2 or greater than 50 years.

2. - Ewing tumour localized, or solely with pleural and/or lung metastases.

3. - Concomitant disease, particularly infectious disease, likely to interfere with patient's treatment.

4. - History of cancer, according to investigator's judgment.

5. - Life expectancy < 2 months.

6. - Patient already included in another clinical trial with an investigational drug.

7. - Pregnant or breastfeeding patient.

8. - Person deprived of liberty or under guardianship.

9. - Patient likely unable to comply with the study medical monitoring for geographical, social or psychological reasons.

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

UNICANCER

OTHER

Sponsor Role: collaborator

Institut Curie

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Valérie LAURENCE, MD

Role: PRINCIPAL_INVESTIGATOR

Institut Curie

Nadège CORRADINI, MD

Role: PRINCIPAL_INVESTIGATOR

Institut d'Hématologie et d'Oncologie Pédiatrique

Locations

Chr Felix Guyon

La Réunion, Saint Denis, France

Bordeaux Chu

Bordeaux, , France

CHU Grenoble Alpes

Grenoble, , France

LILLE Centre Oscar Lambret

Lille, , France

LYON Centre Léon Bérard

Lyon, , France

Marseille Chu

Marseille, , France

CHRU Montpellier - Hôpital A. de Villeneuve

Montpellier, , France

Nantes Chu

Nantes, , France

PARIS Institut Curie

Paris, , France

PARIS Trousseau

Paris, , France

CHU Hôpital Sud

Rennes, , France

Strasbourg Chu

Strasbourg, , France

Toulouse Chu

Toulouse, , France

TOULOUSE Institut Claudius Regaud

Toulouse, , France

Nancy Chu

Vandœuvre-lès-Nancy, , France

NANCY Institut de Cancérologie de Lorraine

Vandœuvre-lès-Nancy, , France

VILLEJUIF Institut Gustave Roussy

Villejuif, , France

Countries

France

References

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.

Reference Type: RESULT

PMID: 41249450 (View on PubMed)

Other Identifiers

IC 2015-13

Identifier Type: -

Identifier Source: org_study_id