Clinical Trials /

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

NCT03011528

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. 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.

Related Conditions:
  • Ewing Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: First-line Treatment of Ewing Tumours With Primary Extrapulmonary Dissemination in Patients From 2 to 50 Years
  • Official Title: CombinaiR3 - First-line Treatment of Ewing Tumours With Primary Extrapulmonary Dissemination in Patients From 2 to 50 Years

Clinical Trial IDs

  • ORG STUDY ID: IC 2015-13 CombinaiR3
  • NCT ID: NCT03011528

Conditions

  • Ewing Sarcoma Family of Tumors

Interventions

DrugSynonymsArms
VDC-IE x2Intensified Induction VDC-IE x2VDC - IE x2 & Surgery
VDC-IEIntensified Induction VDC-IEVDC - IE & TEMIRI & Surgery
TEMIRIIntensified Induction TEMIRIVDC - IE & TEMIRI & Surgery
Consolidation BuMelHigh dose Consolidation chemotherapyVDC - IE x2 & Surgery
Maintenance2 years maintenanceVDC - IE x2 & Surgery

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
VDC - IE x2 & SurgeryOtherPatients 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 : VCC (Vincristine Cyclophosphamide Celecoxib) association 2nd year : Cyclophosphamide po 25 mg/m²
  • VDC-IE x2
  • Consolidation BuMel
  • Maintenance
VDC - IE & TEMIRI & SurgeryOtherPatients 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 : VCC (Vincristine Cyclophosphamide Celecoxib) association 2nd year : Cyclophosphamide po 25 mg/m²
  • VDC-IE
  • TEMIRI
  • Consolidation BuMel
  • Maintenance
VDC - IE x2 & RadiotherapyOtherPatients 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 : VCC (Vincristine Cyclophosphamide Celecoxib) association 2nd year : Cyclophosphamide po 25 mg/m²
  • VDC-IE x2
  • Consolidation BuMel
  • Maintenance
VDC - IE & TEMIRI & RadiotherapyOtherPatients 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 : VCC (Vincristine Cyclophosphamide Celecoxib) association 2nd year : Cyclophosphamide po 25 mg/m²
  • VDC-IE
  • TEMIRI
  • Consolidation BuMel
  • Maintenance

Eligibility Criteria

        Inclusion Criteria:

          1. - Ewing tumour histologically or cytologically confirmed, harboring a specific
             transcript, and with extrapulmonary metastases.

          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)

               -  Bilirubin conjugated fraction (BCF) ≤ 2 x Upper Limit Normal (ULN)

          8. - No absolute contra-indication of Busulfan-Melphalan if radiotherapy of the primary
             tumour is necessary.

          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. - Primary tumour localized to the spine.

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

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

          6. - Life expectancy < 2 months.

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

          8. - Pregnant or breastfeeding patient.

          9. - Person deprived of liberty or under guardianship.

         10. - Patient likely unable to comply with the study medical monitoring for geographical,
             social or psychological reasons.
      
Maximum Eligible Age:50 Years
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description:Number of patients with complete response (CR) / partial response (PR) eligible for consolidation phase
Measure: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
Safety Issue:
Description:Number of patients eligible for consolidation phase have good response after induction phase : complete remission on primary tumour and on metastatic sites or very good disease response defined by: complete or partial response according to RECIST 1.1 criteria on primary lesion complete or very good partial response (> 90 %) in case of RECIST 1.1 criteria on metastatic sites AND complete metabolic response in case of metastatic visceral and/or bone/bone marrow lesions, or very good partial response according to investigator's judgment AND in case of bone marrow involvement, bone marrow free of disease on at least one biopsy and two punctures at different sites at RE1 (evaluation after 4 cycles VDC-IE), RE2 (evaluation after 2x4 cycles VDC-IE or 4 cycles VDC-IE+4 cycles TEMIRI), or at the latest RE3 evaluation (evaluation after local treatment).
Measure: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)
Safety Issue:
Description:The overall survival (OS) is estimated by Kaplan-Meier method.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:Number of patients with treatment-related adverse events using the NCI CTCAE version 4.03 to graduate the severity of adverse events
Measure: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
Safety Issue:
Description:Number of patients with treatment-related toxicities on laboratory data using the NCI CTCAE version 4.03 to graduate the severity of toxicities
Measure: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
Safety Issue:
Description:Efficacy assessed by primary tumour uptake (Standardized Uptake Value max at 18F-FDG PET)
Measure: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
Safety Issue:
Description:Efficacy assessed by metabolic tumour volume (MTV at 18F-FDG PET)
Measure: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
Safety Issue:
Description:sample collected : primary tumour and metastatic site (if possible)
Measure: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
Safety Issue:
Description:sample collected : blood
Measure: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
Safety Issue:
Description:sample collected : bone marrow
Measure: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
Safety Issue:
Description: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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Institut Curie

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