First-line Treatment of Ewing Tumours With Primary Extrapulmonary Dissemination in Patients From 2 to 50 Years (CombinaiR3)
CombinaiR3 - First-line Treatment of Ewing Tumours With Primary Extrapulmonary Dissemination in Patients From 2 to 50 Years
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.
Study Overview
Status
Conditions
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
-
Bordeaux, France, 33076
- Bordeaux CHU
-
Grenoble, France, 38043
- Chu Grenoble Alpes
-
Lille, France, 59000
- LILLE Centre Oscar Lambret
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Lyon, France, 69000
- LYON Centre Léon Bérard
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Marseille, France, 13000
- Marseille Chu
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Montpellier, France, 34295
- CHRU Montpellier - Hôpital A. de Villeneuve
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Nantes, France, 44000
- Nantes CHU
-
Paris, France, 75005
- PARIS Institut Curie
-
Paris, France, 75012
- PARIS Trousseau
-
Rennes, France, 35056
- Chu Hopital Sud
-
Strasbourg, France, 67098
- Strasbourg Chu
-
Toulouse, France, 31059
- Toulouse Chu
-
Toulouse, France, 31059
- TOULOUSE Institut Claudius Regaud
-
Vandoeuvre les Nancy, France, 54519
- NANCY Institut de Cancérologie de Lorraine
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Vandoeuvre-les-Nancy, France, 54511
- Nancy CHU
-
Villejuif, France, 94805
- VILLEJUIF Institut Gustave Roussy
-
-
Saint Denis
-
La Réunion, Saint Denis, France, 97400
- Chr Felix Guyon
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- - 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.
- - 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%.
- - No underlying disease contra-indicating the study treatments.
- - Patient likely compliant with the recommended study medical monitoring during and after treatments.
- - 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.
- - 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.
- - Patients covered by a health insurance system.
- - Patient, or patient's legal representative, informed and having signed the informed consent.
Exclusion Criteria:
- - 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Other: VDC - IE x2 & Surgery
Patients in Arm A receive
|
Week 1, 5, 9 and week 13:
Week 3, 7, 11 and week 15:
Other Names:
After induction phase and local treatment (surgery and/or radiotherapy) and before PBSC:
Peripheral Blood Stem Cell infusion: - PBSC infusion, D0, at least 3.10^6 CD34/kg
Other Names:
* 1st year : VC
Other Names:
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
Other Names:
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
Other Names:
|
|
Other: VDC - IE & TEMIRI & Surgery
Patients in Arm B receive
|
After induction phase and local treatment (surgery and/or radiotherapy) and before PBSC:
Peripheral Blood Stem Cell infusion: - PBSC infusion, D0, at least 3.10^6 CD34/kg
Other Names:
* 1st year : VC
Other Names:
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
Other Names:
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
Other Names:
Week 1 and week 5:
Week 3, and week 7:
Other Names:
Week 9, 12, 15 and week 18:
Other Names:
|
|
Other: VDC - IE x2 & Radiotherapy
Patients in Arm C receive
|
Week 1, 5, 9 and week 13:
Week 3, 7, 11 and week 15:
Other Names:
After induction phase and local treatment (surgery and/or radiotherapy) and before PBSC:
Peripheral Blood Stem Cell infusion: - PBSC infusion, D0, at least 3.10^6 CD34/kg
Other Names:
* 1st year : VC
Other Names:
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
Other Names:
|
|
Other: VDC - IE & TEMIRI & Radiotherapy
Patients in Arm D receive
|
After induction phase and local treatment (surgery and/or radiotherapy) and before PBSC:
Peripheral Blood Stem Cell infusion: - PBSC infusion, D0, at least 3.10^6 CD34/kg
Other Names:
* 1st year : VC
Other Names:
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
Other Names:
Week 1 and week 5:
Week 3, and week 7:
Other Names:
Week 9, 12, 15 and week 18:
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Anti-tumour effect of the treatment strategy assessed by the number of patients event-free survival (EFS) at 18 months
Time Frame: 18 months after inclusion of the last patient
|
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 Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Anti-tumour effect of the dose-intensified induction chemotherapy assessed by the response rate of patients
Time Frame: week 19-20 = Response Evaluation 2 (RE2)
|
Number of patients with complete response (CR) / partial response (PR) eligible for consolidation phase
|
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
Time Frame: week 19-20 = RE2
|
Number of patients eligible for consolidation phase have good response after induction 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
Time Frame: 3 years = Response Evaluation End-Of-Treatment (EOT RE)
|
The overall survival (OS) is estimated by Kaplan-Meier method.
|
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
Time Frame: 3 years = EOT RE
|
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.
|
3 years = EOT RE
|
|
Number of patients with treatment-related adverse events as assessed by CTCAE v4.03
Time Frame: week 19-20 = RE2 ; week 27-28 = Response Evaluation 3 (RE3); 3 years = EOT RE
|
Number of patients with treatment-related adverse events using the NCI CTCAE version 4.03 to graduate the severity of adverse events
|
week 19-20 = RE2 ; week 27-28 = Response Evaluation 3 (RE3); 3 years = EOT RE
|
|
Number of patients with treatment-related toxicities on laboratory data as assessed by CTCAE v4.03 of the different phases of treatment
Time Frame: week 19-20 = RE2 ; week 27-28 = RE3; 3 years = EOT RE
|
Number of patients with treatment-related toxicities on laboratory data using the NCI CTCAE version 4.03 to graduate the severity of toxicities
|
week 19-20 = RE2 ; week 27-28 = RE3; 3 years = EOT RE
|
|
18F-FDG PET evaluation efficacy assessed by primary tumour uptake
Time Frame: study inclusion, after week 8 (RE1), after week18-19 (if VDC-IE) or week19-20 (if TEMIRI)=RE2, after local treatment ≤week30 (RE3), from week31 (=RE4), 3 years = EOT RE
|
Efficacy assessed by primary tumour uptake (Standardized Uptake Value max at 18F-FDG PET)
|
study inclusion, after week 8 (RE1), after week18-19 (if VDC-IE) or week19-20 (if TEMIRI)=RE2, after local treatment ≤week30 (RE3), from week31 (=RE4), 3 years = EOT RE
|
|
18F-FDG PET evaluation efficacy assessed by metabolic tumour volume (MTV)
Time Frame: study inclusion, after week 8 (RE1), after week18-19 (if VDC-IE) or week19-20 (if TEMIRI)=RE2, after local treatment ≤week30 (RE3), from week31 (=RE4), 3 years = EOT RE
|
Efficacy assessed by metabolic tumour volume (MTV at 18F-FDG PET)
|
study inclusion, after week 8 (RE1), after week18-19 (if VDC-IE) or week19-20 (if TEMIRI)=RE2, after local treatment ≤week30 (RE3), from week31 (=RE4), 3 years = EOT RE
|
|
Percentage of circulating tumour cells in blood and bone marrow to correlate with patient outcome (EFS). Ancillary study
Time Frame: study inclusion, and/or during Procedure=surgery (if done) either after week 19-20=RE2 or after PBSC infusion=RE4
|
sample collected : primary tumour and metastatic site (if possible)
|
study inclusion, and/or during Procedure=surgery (if done) either after week 19-20=RE2 or after PBSC infusion=RE4
|
|
Percentage of circulating tumour cells in blood and bone marrow to correlate with patient outcome (EFS). Ancillary study
Time Frame: study inclusion, at each evaluation time (RE1=week8 to Response Evaluation before maintenance therapy (RE5=<week38)), every 3 months during 2 years maintenance therapy, at End of Treatment
|
sample collected : blood
|
study inclusion, at each evaluation time (RE1=week8 to Response Evaluation before maintenance therapy (RE5=<week38)), every 3 months during 2 years maintenance therapy, at End of Treatment
|
|
Percentage of circulating tumour cells in blood and bone marrow to correlate with patient outcome (EFS). Ancillary study
Time Frame: at diagnosis (before treatment), at 1st evaluation time (RE1=wk8 if bone marrow involvement at diagnosis), at RE2=week19-20 (or RE3=<week30), after PBSC infusion=RE4 or RE5=< week38 (if bone marrow involvement at diagnosis), at End of Treatment
|
sample collected : bone marrow
|
at diagnosis (before treatment), at 1st evaluation time (RE1=wk8 if bone marrow involvement at diagnosis), at RE2=week19-20 (or RE3=<week30), after PBSC infusion=RE4 or RE5=< week38 (if bone marrow involvement at diagnosis), at End of Treatment
|
|
Comparison of transcriptomic profiles between those of primary disease and those of bone marrow metastases to determine if they are the same or not. Ancillary study
Time Frame: study inclusion
|
Investigation whether the cells from metastatic material harbour a unique transcriptomic signature compared to primary tumour cells : quantification of EWS-ETS transcript and EWS-ETS gene using Polymerase Chain Reaction (PCR) methods to determine the genomic EWS-ETS translocation loci
|
study inclusion
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Valérie LAURENCE, MD, Institut Curie
- Principal Investigator: Nadège CORRADINI, MD, Institut D'Hematologie Et D'Oncologie Pediatrique
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- IC 2015-13 CombinaiR3
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
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