Condition category
Cancer
Date applied
30/08/2013
Date assigned
04/11/2013
Last edited
03/06/2014
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Contact information

Type

Scientific

Primary contact

Dr Bernadette Brennan

ORCID ID

Contact details

Royal Manchester Children's Hospital
Oxford Road
Manchester
M13 9WL
United Kingdom

Additional identifiers

EudraCT number

2012-002107-17

ClinicalTrials.gov number

Protocol/serial number

N/A

Study information

Scientific title

International randomised controlled trial for the treatment of newly diagnosed Ewing's sarcoma family of tumours (ESFT)

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

NRES Committee North West - Greater Manchester Central, 01/02/2013

Study design

Multi-centre international phase III open-label randomised conrolled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Pediatrics, 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

Phase

Phase III

Drug names

Vincristine, Ifosfamide, Doxorubicin, Etoposide, Actinomycin D, Cyclophosphamide

Primary outcome measures

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 six month period from the end of treatment assessed by MRI scan at the end of treatment and six 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 trial start date

16/09/2013

Overall trial end date

16/09/2018

Reason abandoned

Eligibility

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 type

Patient

Age group

Child

Gender

Both

Target number of participants

600

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. Ewing’s 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

16/09/2013

Recruitment end date

16/09/2018

Locations

Countries of recruitment

France, United Kingdom

Trial participating centre

Royal Manchester Children's Hospital
Manchester
M13 9WL
United Kingdom

Sponsor information

Organisation

University of Birmingham (UK)

Sponsor details

Edgbaston
Birmingham
B15 2TT
United Kingdom

Sponsor type

University/education

Website

Funders

Funder type

Charity

Funder name

Cancer Research UK (UK); C5952/A14745

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes