Plain English Summary
Trial website
Additional identifiers
EudraCT number
2014-000259-99
ClinicalTrials.gov number
Protocol/serial number
vn 5.0 vd 03-Jun-2016
Study information
Scientific title
rEECur: an international randomised controlled trial of chemotherapy for the treatment of recurrent and primary refractory Ewing sarcoma
Acronym
rEECur
Study hypothesis
To compare four chemotherapy regimens: topotecan and cyclophosphamide (TC); irinotecan and temozolomide (IT); gemcitabine and docetaxel (GD) and high-dose ifosfamide (IFOS) in relapsed Ewing sarcoma with respect to efficacy, toxicity and acceptability to patients.
Ethics approval
NRES Committee North West - Greater Manchester Central, 29/08/2014, 14/NW/1110.
Study design
Multi-Arm, Multi-Stage (MAMS), randomised phase II/III, open-label multicentre international 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
Paediatrics, Recurrent/refractory Ewing sarcoma
Intervention
At trial entry patients will be randomised to one of four chemotherapy regimens:
1. Topotecan and Cyclophosphamide (TC)
6 cycles of TC. Additional cycles may be given at the discretion of the treating clinician.
2. Irinotecan and Temozolomide (IT)
6 cycles of IT. Additional cycles may be given at the discretion of the treating clinician.
3. Gemcitabine and Docetaxel (GD)
6 cycles of GD. Additional cycles may be given at the discretion of the treating clinician.
4. High-dose Ifosfamide (IFOS)
4 cycles of IFOS.
Clinicians are encouraged to use local disease control measures where possible after four cycles of chemotherapy. Stem cell harvesting may be carried out in patients for whom high-dose therapy is planned but the first four chemotherapy cycles must be given according to the randomised regimen. Patients randomised to receive TC, IT or GD who have not progressed on treatment may continue to receive the randomised regimen for more than six cycles at the discretion of the treating physician. Myeloablative therapy may be given at the discretion of the treating physician after six cycles of TC, IT or GD, or after four cycles of IFOS.
Intervention type
Drug
Phase
Phase II/III
Drug names
Topotecan, cyclophosphamide, irinotecan, temozolomide, gemcitabine, docetaxel and ifosfamide (IFOS)
Primary outcome measure
Phase II: Objective Response Rate (ORR) will be measured by cross-sectional imaging according to RECIST criteria
Phase III: Progression-Free Survival (PFS) is defined as the time from randomisation until first event (progression, recurrence following response or death without progression or recurrence). Second malignancy is not classified as an event for progression-free survival. For those patients who do not experience event during the course of the trial, progression-free survival times will be censored at the date of their last available trial assessment.
Secondary outcome measures
1. 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. OS will only be analysed for the first randomisation for each patient (re-randomisations will not be considered). Analysis methods will be as per PFS.
2. Adverse events and toxicity: Safety data will be summarised by arm for all treated patients using appropriate tabulations and descriptive statistics. Exploratory standard statistical tests will be performed to compare the arms.
3. Quality of Life (QoL) will be assessed at the following time points: baseline, following chemotherapy cycle 2, following chemotherapy cycle 4 using ≥18 years: EORTC QLQ-C30 , <18 years: PedsQL™ Generic Core Scales and Multidimensional Fatigue Score
4. Days spent in hospital while on trial treatment or due to trial treatment. The number (range) and proportion (with confidence intervals) of days in hospital will be presented for each arm and overall. Exploratory standard statistical tests will be performed to compare the arms.
Overall trial start date
31/03/2014
Overall trial end date
28/02/2030
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
Participant inclusion criteria as of 14/12/2018:
1. Histologically confirmed ES.
2. Disease progression (during or after completion of first line treatment) or any subsequent recurrence OR Refractory disease, defined by progression during first line treatment or within 12 weeks of its completion. Disease progression will be based on RECIST criteria. The appearance of new bone lesions on bone scan will require confirmation with cross-sectional imaging.
3. Soft tissue disease component evaluable by cross-sectional imaging (RECIST). Patients with bone disease without a measurable soft tissue component or bone marrow disease only will be eligible for the study but will not contribute to the phase II primary outcome measure.
4. Age ≥4 years and <50 years.
5. Patient assessed as medically fit to receive cytotoxic chemotherapy.
6. Documented negative pregnancy test for female patients of childbearing potential.
7. Patient agrees to use effective contraception during therapy and for 12 months after last trial treatment, where applicable.
8. Written informed consent from the patient and/or parent/legal guardian.
Previous participant inclusion criteria:
1. Histologically confirmed Ewing sarcoma
2. Disease recurrence after completion of first-line treatment
3. Refractory disease, defined by progression during first-line treatment or within 12 weeks of its completion
4. Soft tissue disease component evaluable by cross-sectional imaging. Patients with bone disease without a measurable soft tissue component or bone marrow disease only will be eligible for the study but will not contribute to the phase II primary outcome measure.
5. Age 2-50 years
6. Patient assessed as medically fit to receive cytotoxic chemotherapy
7. Documented negative pregnancy 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 the parent/legal guardian
Participant type
Patient
Age group
Mixed
Gender
Both
Target number of participants
275 for phase II; 400 for phase III
Participant exclusion criteria
Participant exclusion criteria as of 14/12/2018:
1. Bone marrow infiltration resulting in Absolute Neutrophil Count (ANC) <1.0 x 109/L or platelets <75 x 109/L.
2. Cytotoxic chemotherapy or other investigational medicinal product (IMP) within previous two weeks.
3. Myeloablative therapy within previous eight weeks.
4. Radiotherapy to target lesion within previous six weeks.
5. Pregnant or breastfeeding women.
6. Follow-up not possible due to social, geographic or psychological reasons.
7. Previous randomisation into the rEECur trial
Additional criteria for specific arms:
1. Patients with a contraindication to any IMP may be entered into the study but may not be randomised to receive an arm that contains a contraindicated IMP. They will be eligible for trial entry as long as they can be randomised between a minimum of two study arms.
2. Patients who are unable to receive one or more IMPs due to local or national funding arrangements will be eligible for trial entry as long as they can be randomised between a minimum of two study arms.
3. Patients and investigators may decline randomisation to one or more trial regimens but will be eligible for trial entry as long as they can be randomised between a minimum of two study arms.
4. Patients who have previously received one of the trial regimens off-trial may not be randomised to receive that chemotherapy regimen again. However, patients who have received cyclophosphamide during first line therapy may be randomised to receive the TC arm and patients who have had ifosfamide during first line therapy may receive the ifosfamide arm if they do not have pre-existing renal or other toxicity that would necessitate in rEECur a dose modification. There is no requirement for a minimum time between receiving first line ifosfamide and entry to rEECur.
Previous participant exclusion criteria:
1. Conventional dose cytotoxic chemotherapy or other investigational medicinal product (IMP) within previous four weeks
2. Myeloablative dose chemotherapy within previous 8 weeks
3. Radiotherapy to target lesions within previous 6 weeks
4. Pregnant or breastfeeding women
5. Follow-up not possible due to social, geographic or psychological reasons
Additional criteria for specific arms:
1. Patients who have previously received one of the randomised regimens may not be randomised to receive that chemotherapy regimen again
2. Patients with a contraindication to any IMP may be entered into the study but may not be randomised to receive an arm that contains a contraindicated IMP
3. Patients who have received cyclophosphamide during first-line therapy may be randomised to receive the TC arm
4. Patients who have had ifosfamide during first-line therapy may be randomised to receive the IFOS arm if they do not have pre-existing renal or other toxicity that would necessitate a dose modification. There is no requirement for a minimum time between receiving first-line ifosfamide and randomisation to IFOS as part of the rEECur trial.
Recruitment start date
01/12/2014
Recruitment end date
28/02/2025
Locations
Countries of recruitment
Australia, Belgium, Czech Republic, Denmark, Finland, France, Germany, Hungary, Italy, Netherlands, New Zealand, Norway, Poland, Spain, Sweden, Switzerland, United Kingdom
Trial participating centre
Christie Hospital
Manchester
M20 4BX
United Kingdom
Trial participating centre
Addenbrooke's Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Trial participating centre
Alder Hey Children's Hospital
Eaton Road
Liverpool
L12 2AP
United Kingdom
Trial participating centre
Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom
Trial participating centre
Birmingham Children's Hospital
Steelhouse Lane
Birmingham
B4 6NH
United Kingdom
Trial participating centre
Bristol Royal Hospital for Children
Upper Maudlin Street
Bristol
BS2 8BJ
United Kingdom
Trial participating centre
Churchill Hospital
Old Road
Oxford
OX3 7LE
United Kingdom
Trial participating centre
Clatterbridge Cancer Centre
Clatterbridge Road
Birkenhead
CH63 4JY
United Kingdom
Trial participating centre
Freeman Hospital
Freeman Road,
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
Trial participating centre
John Radcliffe Hospital
Headley Way,
Headington
Oxford
OX3 9DU
United Kingdom
Trial participating centre
Leeds General Infirmary
Great George Street
Leeds
LS1 3EX
United Kingdom
Trial participating centre
Leicester Royal Infirmary
Infirmary Square
Leicester
LE1 5WW
United Kingdom
Trial participating centre
Noah's Ark Children's Hospital for Wales
Heath Park Way
Cardiff
CF14 4XW
United Kingdom
Trial participating centre
Nottingham City Hospital
Hucknall Road
Nottingham
NG5 1PB
United Kingdom
Trial participating centre
Queen's Medical Centre
Derby Road
Nottingham
NG7 2UH
United Kingdom
Trial participating centre
Royal Aberdeen Children's Hospital
Westburn Road
Aberdeen
AB25 2ZG
United Kingdom
Trial participating centre
Royal Belfast Hospital for Sick Children
180 Falls Road
Belfast
BT12 6BE
United Kingdom
Trial participating centre
Royal Hospital for Children Glasgow
1345 Govan Road
Glasgow
G51 4TF
United Kingdom
Trial participating centre
Royal Hospital for Sick Children Edinburgh
9 Sciennes Road
Edinburgh
EH9 1LF
United Kingdom
Trial participating centre
Royal Manchester Childrens Hospital
Oxford Road
Manchester
M13 9WL
United Kingdom
Trial participating centre
Royal Marsden Hospital London
203 Fulham Road
London
SW3 6JJ
United Kingdom
Trial participating centre
Royal Marsden Hospital Sutton
Downs Road
Sutton
SM2 5PT
United Kingdom
Trial participating centre
Royal Victoria Infirmary
Queen Victoria Road
Newcastle upon Tyne
NE1 4LP
United Kingdom
Trial participating centre
Sheffield Children's Hospital
The Mount,
Glossop Road
Sheffield
S10 3FL
United Kingdom
Trial participating centre
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom
Trial participating centre
St James's University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom
Trial participating centre
The Queen Elizabeth Hospital
Mindelsohn Way
Birmingham
B15 2TH
United Kingdom
Trial participating centre
University College London Hospital
235 Euston Road
London
NW1 2BU
United Kingdom
Trial participating centre
Weston Park Hospital
Whitham Road
Sheffield
S10 2SJ
United Kingdom
Trial participating centre
Hospital Universitari Vall D'hebron
119-129
Barcelona
08035
Spain
Trial participating centre
Istituto Ortopedico Rizzoli
Via Giulio Cesare Pupilli, 1
Bologna
40136
Italy
Trial participating centre
Helsinki Children's Hospital
Stenbäckinkatu 11
Helsinki
00290
Finland
Trial participating centre
Oslo University Hospital
Sognsvannsveien 20
Oslo
0372
Norway
Trial participating centre
University Hospital Rigshospitalet
Blegdamsvej 9
København
2100
Denmark
Trial participating centre
Institut Gustave Roussy
114 Rue Edouard Vaillant
Villejuif
94800
France
Trial participating centre
Semmelweiss Universitat Ii
Üllői út 26
Budapest
1085
Hungary
Trial participating centre
U.Z Leuven- Campus Gasthuisberg
Herestraat 49
Leuven
3000
Belgium
Trial participating centre
Maria Sklodowska-curie Memorial Cancer Center and Institute of Oncology
Wawelska 15 B
Warszawa
00-001
Poland
Trial participating centre
University Hospital Motol
V Úvalu 84
Praha
150 06
Czech Republic
Trial participating centre
Leiden University Medical Centre
Albinusdreef 2
Leiden
2333 ZA
Netherlands
Trial participating centre
Princess Margaret Hospital
Roberts Road,
Subiaco
Perth
6008
Australia
Trial participating centre
Starship Children’s Hospital
2 Park Road,
Grafton
Auckland
1023
New Zealand
Trial participating centre
Universitäts Kinderspital beider Basel
Spitalstrasse 33
Basel
4056
Switzerland
Funders
Funder type
Government
Funder name
Seventh Framework Programme
Alternative name(s)
EC Seventh Framework Programme, European Commission Seventh Framework Programme, EU Seventh Framework Programme, European Union Seventh Framework Programme, FP7
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
Results and Publications
Publication and dissemination plan
Planned publication in a high-impact peer-reviewed journal with intention of publishing one year post planned interim analyses.
IPD sharing statement: the datasets generated during and/or analysed during the current study are not expected to be made available as the majority of countries the study is open in do not permit this on a regulatory level.
Intention to publish date
28/02/2031
Participant level data
Not expected to be available
Basic results (scientific)
Publication list