Design and Objectives
EURO EWING 2012 (EE2012) is an international, multicentre, phase III, open-label randomised controlled trial. There are two randomisations: patients are randomised, at entry (Randomisation 1; R1) and then following local control therapy (Randomisation 2; R2). The trial schema is shown in figure 1.
The objective of the induction/consolidation chemotherapy R1 is to compare:
VIDE as induction chemotherapy and VAI/VAC /BuMel as consolidation chemotherapy (Arm A) with VDC/IE induction and IE/VC or VAI/BuMel consolidation chemotherapy (Arm B) as first line treatment in all patients with ESFT, with respect to clinical outcome and toxicity.
The objective of the zoledronic acid randomisation (R2) is to determine whether the addition of zoledronic acid to the consolidation chemotherapy assigned at R1 is associated with improved clinical outcome in patients in the EE2012 trial.
The third objective is, through the biological studies embedded in EE2012, to identify informative prognostic biomarkers for assessment of disease status and response at diagnosis and throughout the disease course. Whether they are predictive of response to therapy and may be used to improve stratification of patients and whether they might predict those patients that may not tolerate a particular therapy will also be explored.
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Figure 1: Trial Schema
Outcome measures
The primary outcome measure is EFS. EFS is defined as the time from randomisation to first event, where an event is progression without complete remission, recurrence (following complete or partial remission), second malignancy or death. Patients who do not have an event by the end of the follow up period will be censored at their last follow-up date, and patients lost to follow-up without an event will be censored at the date of their last consultation.
The secondary outcome measures are:
· Overall Survival (OS) is defined as the time from randomisation to death, irrespective of the cause. Surviving patients will be censored at their last follow-up date,
· Adverse events and toxicity, defined by NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0,
· Histological response of the primary tumour to induction chemotherapy if surgery is performed as local control defined as the percentage of viable tumour cells in the resected primary tumour specimen,
· Response of the primary tumour, regional lymph nodes and/or metastases using the change in the volume of the primary tumour, the number of lung and/or pleural and other metastases, and /or the diameter of the largest node (or group if not separate),
· Achievement of local control at the end of treatment as defined by either complete surgical resection following induction chemotherapy, no measurable disease as assessed by end of treatment MRI or CT scan or no increase in measurable residual tumour over a six month period from the end of treatment,
· Growth parameters and jaw/ear osteonecrosis (R2 only) will be assessed using patient’s height measured at baseline, treatment and throughout follow up for all patients who enter the second randomisation and who are less than 18 years of age at entry. Whether jaw and ear osteonecrosis occurred will be recorded at the end of or during treatment for all patients who were randomised to R2.
Recruitment and randomisation
All eligible patients with ESFT at participating centres are invited to take part in the trial. EEC partner organisations act as national coordinating centres (NCC) and identify participating centres within their country/countries. The University of Birmingham is the Coordinating Sponsor and also undertakes the responsibilities of NCC in the UK. One hundred and ten participating centres are taking part across 10 countries (Belgium, Czech Republic, Denmark, France, Hungary, Ireland, Netherlands, Spain, Switzerland and United Kingdom). Patients enter the trial via R1 and, if following induction chemotherapy they fulfil the R2 eligibility criteria, are then asked to participate in R2.
Patients are eligible if all of the trial inclusion criteria are met and none of the exclusion criteria apply. The eligibility criteria originally excluded patients with extrapulmonary metastatic disease, but this was amended in September 2016 (the exact date of implementation in each country varies as it was dependent upon gaining country specific regulatory approvals). The current eligibility criteria for R1 and R2 are shown in table 1.
Table 1: Inclusion and exclusion criteria
For each randomisation, patients are allocated in a 1:1 ratio to the two arms. Randomisation is performed by staff at participating centres online using randomisation function of the electronic remote data capture system (eRDC) designed and maintained by the Coordinating Sponsor.
The R1 randomisation is stratified by age at randomisation (<14 years; ≥14 years), sex, disease type (absence of metastases or involvement of lymph nodes only; lung or pleural metastases only; other metastases), volume of tumour at diagnosis (<200ml; ≥200ml) and country (UK, France or other) to ensure that there is a balance between treatments within the strata defined by these key prognostic factors.
The R2 randomisation is stratified by allocated treatment in R1, age at R1 randomisation (<14 years; ≥14 years), sex, disease status (localised disease or regional lymph node involvement of lymph nodes only at diagnosis and good risk after induction, localised disease or regional lymph node involvement only at diagnosis and of lymph nodes only poor risk after induction, lung or pleural metastases at diagnosis, other metastasis at diagnosis), and country (UK, France or other).
Trial Treatment.
Randomisation R1; At trial entry patients are randomised to one of the following treatment arms:
- Arm A (VIDE strategy): VIDE induction; VAI/VAC/BuMel consolidation
Induction chemotherapy: 6 cycles of VIDE
Consolidation chemotherapy: 1 cycle of VAI plus 7 cycles of VAC
(good risk localised disease)- R2 VAC
OR
1 cycle VAI plus one cycle of BuMel (poor risk localised disease without contraindication to BuMel)
OR
8 cycles of VAI (poor risk localised disease with contraindication to BuMel, and/or regional lymph node(s) involvement and/or metastatic disease) - R2 VAI
OR
- Arm B (VDC/IE strategy): VDC/IE induction; IE/VC/VAI/BuMel consolidation
Induction chemotherapy: 9 cycles of alternating VDC and IE
Consolidation chemotherapy: 5 cycles of alternating IE and VC
- R2 IE/VC (good risk localised disease, and/or regional lymph node(s) involvement and/or metastatic disease, or poor risk localised disease with contraindication to BuMel
OR
1 cycle VAI plus BuMel (poor risk localised disease without contraindication to BuMel)
Randomisation R2; Following induction chemotherapy, patients who fulfil the eligibility criteria for R2 and consent to take part in the randomisation will receive consolidation chemotherapy as allocated at trial entry and be randomised to receive either:
- 9 cycles of zoledronic acid following the first cycle of consolidation chemotherapy
OR
A summary of the enrolment, interventions and the main assessments is shown in figure 2, and a SPIRIT checklist is supplied as supplementary file 1. The full schedule of treatments is provided in supplementary table 1.
Figure 2: Summary schedule of enrolment, interventions, and assessments.
Local treatment of surgery and/or radiotherapy follows VIDE or VDC/IE induction chemotherapy, and whenever feasible, surgery proceeds after cycle 6 of VIDE (Arm A) or cycle 9 VDC/IE (Arm B) on haematological recovery. Decisions on treatment of the primary tumour are individualised as is necessary in this disease. Consolidation chemotherapy is administered according to treatment arm randomised to and whether the patient has regional lymph node involvement or metastatic disease, or risk group - localised disease (good risk or poor risk). The definition localised poor risk and good risk is based on presence or absence of a combination of factors, whether there is; resection at diagnosis, tumour volume ≥200ml, pre-operative radiotherapy, histological response (≥10% viable tumour), unresectable tumour treated with radiotherapy alone, and volume <200ml with poor radiological response.
Peripheral blood stem cell (PBSC) mobilisation and harvesting is recommended after VIDE/VDC/IE chemotherapy if defined as poor risk localised disease. PBSC mobilisation and harvesting should be performed according to institutional guidelines. BuMel treatment is contraindicated for patients where radiotherapy is required to the central axial sites (spine, sacrum, pelvis) or when lung or bowel are within the radiotherapy treatment fields (the protocol includes specific criteria regarding doses). Radiotherapy is recommended to be given concurrently with consolidation chemotherapy to the primary site. In patients with pulmonary and/or pleural metastatic disease whole lung radiotherapy is recommended to be given on completion of consolidation chemotherapy. Radiotherapy to bony metastases may be given either during consolidation or at the end. At the end of treatment patients who received radiotherapy only as local control and who had residual disease pre-radiotherapy, an end of treatment MRI or CT scan should be performed. If the end of treatment scan shows residual disease, another scan should be performed six months after the end of treatment. After treatment, patients will be followed up with clinical evaluation and scanning for a minimum of 5 years, or until disease progression or death if sooner. Patient data is collected on the eRDC using a series of case report forms (CRFS), and follow-up forms are requested annually following the completion of treatment in order to track patient’s status.
Patients are also asked to optionally consent to additional biological studies. Participation involves donating blood samples at multiple time points throughout the trial, and agreeing to any remaining bone marrow and diagnostic tumour biopsy tissue taken as routine practise being used for research purposes.
Statistical considerations
The target is to recruit a minimum of 600 patients to R1. The R2 target is a minimum of 300 patients. An analysis of R2 will also be done in conjunction with the German Ewing 2008 trial which will have a similar or greater number of patients, giving a total of about 600 patients (it is estimated 300 will come from EE2012 and 300 from Ewing 2008). It is anticipated that it will take at least 5 years to reach the accrual targets. Patients will be followed up for progression and death until all trial objectives have been met. The first main analysis will be performed once all patients have a minimum of 2 years follow-up. For each randomisation, the main analyses will be intention-to-treat (ITT) with all patients analysed in the arm to which allocated at randomisation.
Due to the rarity of ESFT, and a restricted ability to randomise sufficient numbers of patients for a conventional design (with 2-sided alpha=0.05, power=80%), a Bayesian approach has been taken to the analysis of R1 which makes no prior assumptions that one chemotherapy arm is likely to be better than the other. This design will be reported in detail elsewhere.
For R2 conventional statistical analyses will be performed: Kaplan-Meier life tables will be constructed for time-to-event data (with date of randomisation as reference time point) and arms will be compared by means of the logrank test; continuous variables will be compared across arms by means of t-tests or Wilcoxon tests as appropriate. Multivariable analysis using Cox regression will be used to adjust for baseline co-variates as appropriate. Heterogeneity of the treatment effect according to these factors will be evaluated. As well as by individual trial, analyses of the zoledronic acid randomisation will be performed on the total data set for both trials combined (with stratification by trial).