| ISRCTN | ISRCTN92192408 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN92192408 |
| EudraCT/CTIS number | 2012-002107-17 |
| Secondary identifying numbers | N/A |
- Submission date
- 30/08/2013
- Registration date
- 04/11/2013
- Last edited
- 16/04/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Plain English Summary
Contact information
Prof Bernadette Brennan
Scientific
Scientific
Royal Manchester Children's Hospital
Oxford Road
Manchester
M13 9WL
United Kingdom
Study information
| Study design | Multi-centre international Phase III open-label randomized controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | International randomised controlled trial for the treatment of newly diagnosed Ewing's sarcoma family of tumours (ESFT) |
| Study acronym | EE2012 |
| Study hypothesis | For randomisation 1 - To compare the Vincristine, Ifosfamide, Doxorubicin, Etoposide (VIDE) strategy [VIDE induction and VAI/VAC (Vincristine, Actinomycin D, Ifosfamide/ Vincristine, Actinomycin D, Cyclophosphamide) consolidation] with the Vincristine, Doxorubicin, Cyclophosphamide/Ifosfamide, Etoposide (VDC/IE) strategy (compressed to VDC/IE induction and IE/VC consolidation). |
| Ethics approval(s) | NRES Committee North West - Greater Manchester Central, 01/02/2013 |
| Condition | Ewing's sarcoma |
| Intervention | Randomisation R1 At trial entry, patients will be randomised to one of the following treatment arms: 1. Arm A (VIDE strategy): VIDE induction; VAI/VAC consolidation Induction chemotherapy: 6 cycles of VIDE Consolidation chemotherapy: 1 cycle of VAI and 7 cycles of VAC or 8 cycles of VAI (unless randomised to Bu-Mel at R2) 2. Arm B (VDC/IE strategy): VDC/IE induction; IE/VC consolidation Induction chemotherapy: 9 cycles of alternating VDC and IE Consolidation chemotherapy: 5 cycles of alternating IE and VC (unless randomised to Bu-Mel at R2) Randomisation R2zol Following induction chemotherapy, patients who fulfil the eligibility criteria for R2zol and consent to take part in the randomisation will receive consolidation chemotherapy as allocated at trial entry and be randomised to receive either: 1. 9 cycles of zoledronic acid following the first cycle of consolidation chemotherapy (either VAI (Arm A) or IE (Arm B)) OR 2. No zoledronic acid Randomisation R2loc Following induction chemotherapy, patients who fulfil the eligibility criteria for R2loc and consent to take part in the randomisation will be randomised to receive either: 1. Consolidation chemotherapy as assigned at R1 either 8 cycles of VAI (Arm A) or 5 cycles of alternating IE and VC (Arm B) OR 2. 1 cycle of VAI (Arm A) or 1 cycle of IE (Arm B), followed by high-dose treatment with busulfan and melphalan Randomisation R2pulm Following induction chemotherapy, patients who fulfil the eligibility criteria for R2pulm and consent to take part in the randomisation will be randomised to receive either: 1. Consolidation chemotherapy as assigned at R1 either 8 cycles of VAI (Arm A) or 5 cycles of alternating IE and VC (Arm B), plus lung irradiation OR 2. 1 cycle of VAI (Arm A) or 1 cycle of IE (Arm B), followed by high-dose treatment with busulfan and melphalan Drug names, frequency of administration and dose; Arm A: VIDE Vincristine (d1; 1.5mg/m2), Ifosfamide (d1, d2,d3; 3g/m2/d), Doxorubicin (d1,d2,d3; 20mg/m2/d), Etoposide (d1,d2,d3; 150mg/m2/d). VAI Vincristine (d1; 1.5mg/m2), Actinomycin D (d1, d2; 0.75mg/m2/d), Ifosfamide (d1,d2; 3g/m2/d) VAC Vincristine(d1; 1.5mg/m2), Actinomycin D (d1, d2; 0.75mg/m2/d), Cyclophosphamide (d1; 1500mg/m2) Arm B: VDC Vincristine(d1; 1.5mg/m2), Doxorubicin (d1, d2; 37.5mg/m2/d), Cyclophosphamide (d1; 1200mg/m2) IE Ifosfamide (d1,d2,d3,d4,d5; 1800mg/m2/d), Etoposide (d1,d2,d3,d4,d5; 100mg/m2/d) VC- Vincristine(d1; 2mg/m2), Cyclophosphamide (d1; 1200mg/m2) Following treatment, patients will be followed up for progression and death until all trial objectives have been met. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Vincristine, ifosfamide, doxorubicin, etoposide, actinomycin D, cyclophosphamide |
| Primary outcome measure | Event-free survival, defined as the time from randomisation to first event, where an event is progression without complete remission, recurrence (following complete remission), diagnosis of secondary malignancy or death. Patients who have not had an event will be censored at their last follow-up date. Patients lost to follow-up without an event will be censored at the date of their last consultation. |
| Secondary outcome measures | 1. Overall survival defined as the time from randomisation to death, irrespective of cause. Surviving patients will be censored at their last follow-up date 2. Adverse events and toxicity - measured by CTCAE 3. Histological response of the primary tumour to induction chemotherapy if surgery is performed as local control - tumours will be graded using the Salzer-Kuntschik scale 4. Achievement of local control at the end of treatment, defined as complete surgical resection following induction chemotherapy, or no measurable disease assessed by end of treatment MRI scan, or no change in measurable residual tumour over a 6-month period from the end of treatment assessed by MRI scan at the end of treatment and 6 months after the end of treatment 5. Growth parameters and jaw osteonecrosis (R2zol only), defined as the change in Standard Deviation height score between baseline, end of treatment and throughout follow-up |
| Overall study start date | 16/09/2013 |
| Overall study end date | 02/01/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Sex | Both |
| Target number of participants | 600 |
| Total final enrolment | 640 |
| Participant inclusion criteria | R1 Inclusion criteria: 1. Histologically confirmed ESFT of bone or soft tissue 2. Localised or pulmonary and/or pleural metastatic disease 3. Age >2 years and <50 years (from second birthday to 49 years and 364 days) at the date of diagnostic biopsy 4. Randomisation ≤45 days after diagnostic biopsy/surgery 5. Patient assessed as medically fit to receive the treatment in either of the R1 treatment arms 6. No prior treatment for ESFT other than surgery 7. Documented negative pregnancy lactation test for female patients of childbearing potential 8. Patient agrees to use contraception during therapy and for 12 months after last trial treatment (females) or 5 months after last trial treatment (males), where applicable 9. Written informed consent from the patient and/or parent/legal guardian R2zol Inclusion criteria: 1. No evidence of metastatic disease 2. Age >5 years (from fifth birthday) at date of randomization 3. Localised tumour of any tumour volume with surgery after chemotherapy alone, and good histological response to induction chemotherapy (<10% viability) OR 4. Localised tumour with initial tumour volume <200ml with resection after chemotherapy and early radiotherapy, and good histological response to induction chemoradiotherapy (<10% viability) OR 5. Localised tumour with initial tumour volume <200ml and surgery at diagnosis OR 6. Localised tumour with initial tumour volume <200ml with resection after chemotherapy alone and extracorporeal irradiation of the primary tumour at surgery OR 7. Localised unresected tumour with initial tumour volume <200ml and at least a partial radiological response to induction chemotherapy (≥50% regression of evaluable soft tissue component) 8. Consolidation chemotherapy as per protocol intended 9. Patient assessed medically fit to receive zoledronic acid if allocated 10. Written informed consent from the patient and/or parent/legal guardian R2loc Inclusion criteria: 1. No evidence of metastatic disease 2. Localised tumour of any tumour volume with surgery after chemotherapy alone, and poor histological response to induction chemotherapy (≥10% viability) OR 3. Localised tumour with initial tumour volume ≥200ml with surgery after chemotherapy and early radiotherapy, irrespective of histological response OR 4. Localised tumour with initial tumour volume ≥200ml and surgery at diagnosis OR 5. Localised tumour with initial tumour volume ≥200ml with extracorporeal irradiation of the primary tumour at surgery, and no progression under induction chemotherapy OR 6. Localised unresected tumour with initial tumour volume <200ml treated by radiation therapy alone as local therapy and with poor radiological response to induction chemotherapy (<50% regression of evaluable soft tissue component) but no progression under induction chemotherapy 7. Consolidation chemotherapy as per protocol intended 8. Patient assessed medically fit to receive the treatment in either of the R2loc treatment arms 9. Written informed consent from the patient and/or parent/legal guardian R2pulm Inclusion criteria: 1. Pulmonary and/or pleural metastatic disease only at diagnosis 2. Partial response of the lung metastatses and no progression of the primary tumour during induction chemotherapy 3. Consolidation chemotherapy as per protocol intended 4. Patient assessed medically fit to receive the treatment in either of the R2pulm treatment arms 5. Written informed consent from the patient and/or the parent/legal guardian |
| Participant exclusion criteria | R1 Exclusion criteria: 1. Extrapulmonary metastatic disease 2. Contra-indication to the treatment in either of the R1 treatment arms 3. Second malignancy 4. Pregnant or breastfeeding women 5. Follow-up not possible due to social, geographic or psychological reasons R2zol Exclusion criteria: 1. History of dental surgery (extraction or jaw surgery) in the 6 months preceding the start of zoledronic acid treatment, or planned dental surgery within the treatment period or within 6 months after the end of treatment 2. Ewings tumour of the maxilla or of the mandible 3. Progression of the primary tumour or appearance of new lesions R2loc Exclusion criteria: 1. Radiotherapy required encompassing spine, a significant volume of digestive tract or lungs (such patients should be discussed during a web conference before randomisation for technique, volume, and dose validation with the national radiotherapy committee) 2. Progression of the primary tumour or appearance of new lesions R2pulm Exclusion criteria: 1. Radiotherapy required encompassing spine, a significant volume of digestive tract or lungs (such patients should be discussed during a web conference before randomisation for technique, volume, and dose validation with the national radiotherapy committee) 2. Progression of the primary tumour or appearance of new lesions |
| Recruitment start date | 20/12/2013 |
| Recruitment end date | 30/04/2019 |
Locations
Countries of recruitment
- England
- France
- United Kingdom
Study participating centre
Royal Manchester Children's Hospital
Manchester
M13 9WL
United Kingdom
M13 9WL
United Kingdom
Sponsor information
University of Birmingham (UK)
University/education
University/education
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
"ROR" |
https://ror.org/03angcq70 |
|---|
Funders
Funder type
Charity
Cancer Research UK (UK); C5952/A14745
No information available
Results and Publications
| Intention to publish date | 01/08/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | 17/01/2020 | 20/01/2020 | Yes | No |
| Results article | 29/10/2022 | 16/12/2022 | Yes | No | |
| Plain English results | 17/03/2023 | No | Yes | ||
| Other publications | Secondary analysis | 20/12/2024 | 20/01/2025 | Yes | No |
Editorial Notes
16/04/2025: The following changes were made to the study record:
1. The overall study end date was changed from 01/04/2025 to 02/01/2025.
2. The intention to publish date was changed from 30/09/2025 to 01/08/2025.
20/01/2025: Publication reference added.
28/11/2024: The following changes were made to the study record:
1. The overall study end date was changed from 01/11/2024 to 01/04/2025.
2. The intention to publish date was changed from 30/04/2025 to 30/09/2025.
12/09/2024: The overall end date was changed from 01/09/2024 to 01/11/2024.
18/04/2024: The overall end date was changed from 30/04/2024 to 01/09/2024.
17/03/2023: Cancer Research UK plain English results link added to outputs table.
16/12/2022: Publication reference added.
15/07/2022: The following changes were made to the trial record:
1. The recruitment start date was corrected from 16/09/2013 to 20/12/2013.
2. The total final enrolment number.
20/01/2020: Publication reference added.
22/10/2018 The following changes were made:
1. The publication and dissemination plan was added.
2. The intention to publish date was added.
3. The participant level data was added.
18/10/2018: The following changes were made:
1. The recruitment end date was changed from 16/09/2018 to 30/04/2019
2. The overall trial end date was changed from 16/09/2018 to 30/04/2024
