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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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

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

Detailed 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. 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 contras
Sponsor: Institut Curie

Current Primary Outcome: 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.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • 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
  • 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 :

    • 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).
  • 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 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.
  • 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
  • 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
  • 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)
  • 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)
  • 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)
  • 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
  • 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
  • Same as current

    Information By: Institut Curie

    Dates:
    Date Received: December 6, 2016
    Date Started: December 2016
    Date Completion: December 2022
    Last Updated: March 23, 2017
    Last Verified: March 2017