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

Ewing Sarcoma Family of Tumors Clinical Trial

— CombinaiR3  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03011528
• Other study ID #: IC 2015-13 CombinaiR3
• Status: Completed
• Phase: Phase 2
• Start date: December 2016
• Est. completion date: November 2023

Study information

• Verified date: December 2023
• Source: Institut Curie
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: November 2023
• Est. primary completion date: August 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 50 Years

Eligibility

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 ß-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.

Related Conditions & MeSH terms

• Ewing Sarcoma Family of Tumors
• Sarcoma, Ewing

Intervention

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

Procedure:
• 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

Radiation:
• 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

Locations

Country	Name	City	State
France	Bordeaux Chu	Bordeaux
France	CHU Grenoble Alpes	Grenoble
France	Chr Felix Guyon	La Réunion	Saint Denis
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 Institut de Cancérologie de Lorraine	Vandoeuvre les Nancy
France	Nancy Chu	Vandoeuvre-les-Nancy
France	VILLEJUIF Institut Gustave Roussy	Villejuif

Sponsors (2)

Lead Sponsor	Collaborator
Institut Curie	UNICANCER

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Anti-tumour effect of the dose-intensified induction chemotherapy assessed by the response rate of patients	Number of patients with complete response (CR) / partial response (PR) eligible for consolidation phase	week 19-20 = Response Evaluation 2 (RE2)
Secondary	Anti-tumour effect of the dose-intensified induction chemotherapy assessed by the number of patients eligible for consolidation phase	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).	week 19-20 = RE2
Secondary	Overall survival (OS) is assessed by the number of patients still alive at the end of the three years of treatment	The overall survival (OS) is estimated by Kaplan-Meier method.	3 years = Response Evaluation End-Of-Treatment (EOT RE)
Secondary	3-years event-free survival (EFS) is assessed by the number of patients without any event at the end of treatment phase	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
Secondary	Number of patients with treatment-related adverse events as assessed by CTCAE v4.03	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
Secondary	Number of patients with treatment-related toxicities on laboratory data as assessed by CTCAE v4.03 of the different phases of treatment	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
Secondary	18F-FDG PET evaluation efficacy assessed by primary tumour uptake	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
Secondary	18F-FDG PET evaluation efficacy assessed by metabolic tumour volume (MTV)	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
Secondary	Percentage of circulating tumour cells in blood and bone marrow to correlate with patient outcome (EFS). Ancillary study	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
Secondary	Percentage of circulating tumour cells in blood and bone marrow to correlate with patient outcome (EFS). Ancillary study	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
Secondary	Percentage of circulating tumour cells in blood and bone marrow to correlate with patient outcome (EFS). Ancillary study	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
Secondary	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	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