Chemotherapy for the treatment of recurrent and primary refractory Ewing sarcoma
| ISRCTN | ISRCTN36453794 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN36453794 |
| EudraCT/CTIS number | 2014-000259-99 |
| IRAS number | 149572 |
| Secondary identifying numbers | vn 8.0 vd 11-Apr-2024 |
- Submission date
- 09/01/2014
- Registration date
- 14/02/2014
- Last edited
- 10/01/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Record updated in last year
Plain English Summary
Contact information
Prof Martin McCabe
Scientific
Scientific
rEECur Trial Office
Cancer Research UK Clinical Trials Unit (CRCTU)
Institute of Cancer and Genomic Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
| Phone | +44 (0) 121 415 9877 |
|---|---|
| reecur@trials.bham.ac.uk |
Study information
| 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 |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| Scientific title | rEECur: an international randomised controlled trial of chemotherapy for the treatment of recurrent and primary refractory Ewing sarcoma |
| Study acronym | rEECur |
| Study hypothesis | Current study hypothesis as of 10/01/2025: To identify the optimum systemic anticancer regimen for recurrent and refractory Ewing sarcoma based on the balance between efficacy and toxicity. Previous 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(s) | NRES Committee North West - Greater Manchester Central, 29/08/2014, 14/NW/1110. |
| Condition | Paediatrics, Recurrent/refractory Ewing sarcoma |
| Intervention | Current intervention as of 10/01/2025: At trial entry, patients will be randomised to one of the available chemotherapy regimens: 1. High dose Ifosfamide (IFOS): 4 cycles of 21 days, additional cycles at clinician's discretion. 2. High dose Ifosfamide and Lenvatinib (IFOS-L): 4 cycles of 21 days, additional IFOS cycles at clinician’s discretion. Lenvatinib capsules are taken once daily continuously throughout and for up to 2 years in total. Local disease control measures are encouraged where possible. However, these should be delayed if possible until the completion of protocol-defined treatment (4 cycles of IFOS) or completion of 4 IFOS cycles for patients on IFOS-L. Stem cell harvesting may be carried out in patients for whom high-dose therapy is planned. However, if an alternative chemotherapy regimen is planned for stem cell mobilisation, it should be delayed if possible until completion of protocol-defined treatment, (i.e after completion of IFOS-L or, 6 cycles of CE or, 4 cycles of IFOS) or as a minimum must be delayed until after the response assessment following cycle 4. Patients who continue to receive Lenvatinib (see section 7.2.3.5) should not receive chemotherapy other than ifosfamide at the protocol-defined dose. If these are planned, lenvatinib must be permanently discontinued prior to treatment. Myeloablative therapy may be given at the discretion of the treating physician after 6 cycles of CE or after 4 cycles of IFOS. High-dose therapy may not be given simultaneously with lenvatinib. If high-dose therapy is planned, lenvatinib must be permanently discontinued beforehand. Previous intervention: At trial entry patients will be randomised to one of four chemotherapy regimens: 1. Topotecan and cyclophosphamide (TC): 6 cycles. Additional cycles may be given at the discretion of the treating clinician. 2. Irinotecan and temozolomide (IT): 6 cycles. Additional cycles may be given at the discretion of the treating clinician. 3. Gemcitabine and docetaxel (GD): 6 cycles. Additional cycles may be given at the discretion of the treating clinician. 4. High-dose Ifosfamide (IFOS): 4 cycles. 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase II/III |
| Drug / device / biological / vaccine name(s) | Ifosfamide, lenvatinib |
| Primary outcome measure | Current primary outcome measure as of 10/01/2025: Event-free survival time (EFS) Previous 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 the 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 events during the trial, progression-free survival times will be censored at the date of their last available trial assessment. |
| Secondary outcome measures | Current secondary outcome measure as of 10/01/2025: 1. Objective imaging response (OR) according to RECIST 1.1 criteria after 2 and 4 cycles of IFOS and IFOS-L, and at the end of trial treatment for all arms 2. Progression-free survival time (PFS) 3. Overall survival time (OS) 4. Toxicity, defined by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.0 5. PET-CT response after 4 cycles (this sub-study is now closed and being analysed) 6. Quality of life (QoL) 7. Days spent in hospital Previous secondary outcome measure: 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 hthe ospital 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 study start date | 31/03/2014 |
| Overall study end date | 30/09/2031 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 2 Years |
| Sex | Both |
| Target number of participants | 275 for phase II; 400 for phase III |
| Participant inclusion criteria | Current participant inclusion criteria (since 03-May-2023) as of 10/01/2025: 1. Histologically confirmed Ewing or Ewing-like sarcoma of the bone or soft tissues. Histological confirmation either at initial diagnosis or disease progression. 2. Radiological evidence of disease progression during or after completion of the first or any subsequent line of treatment. 3. Age ≥ 2 years*. 4. Eligible for randomisation between at least two open study arms. 5. Adequate renal function is defined as GFR ≥60 ml/min/1.73m2. If GFR is calculated and is <90 ml/min/1.73m2, an isotopic GFR should be performed to confirm adequate renal function. 6. Patient assessed as medically fit to receive trial treatment 7. Date of planned randomisation within 4 weeks of baseline imaging. 8. Documented negative pregnancy test for female patients of childbearing potential. 9. Patient agrees to use effective contraception during therapy and for 12 months after the last trial treatment, where applicable. 10. Written informed consent from the patient and/or parent/legal guardian. * Trial sites in Austria will only recruit patients aged ≥2 years<30 years due to the conditional approval issued by their ethics committee. Additional criteria for the CE arm (This treatment arm has been closed to recruitment since 15-Aug-2024. Therefore, this criterion no longer applies): Carboplatin is contraindicated in patients with actively bleeding tumours. Therefore, patients with actively bleeding tumours are not eligible for CE randomisation. Additional criteria for the IFOS-L arm: 1. Adequate liver function: bilirubin <3 x ULN and ALT or AST < 5 x ULN 2. Left ventricular ejection fraction ≥50% at baseline as determined by echocardiography. 2. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as: a. BP <95th percentile for sex, age, and height. Subjects >18 years of age should have BP ≤150/90 mm Hg at screening. 3. Urine dipstick <2+ for proteinuria. If ≥2+ proteinuria on dipstick, a spot urine protein:creatinine ratio test must be < CTCAE grade 2 Proteinuria. Previous 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 exclusion criteria | Current participant exclusion criteria (since 03-May-2023) as of 10/01/2025: 1. 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 the previous two weeks. 3. Myeloablative therapy within the previous eight weeks. 4. Radiotherapy to target lesion within the previous six weeks. 5. Pregnant or breastfeeding women. 6. Pre-existing medical condition that would necessitate a dose modification during cycle 1 as described in section 7. 7. Any central neurotoxicity with previous ifosfamide treatment 8. Clinical evidence of nephrotic syndrome 9. Follow-up is not possible due to social, geographic or psychological reasons. 10. Previous randomisation into the rEECur trial 11. Patients with a contraindication or hypersensitivity to any IMP may not be randomised to receive an arm that contains the contraindicated IMP. 12. Patients who have previously received one of the trial regimens off-trial may not be randomised to receive that regimen again. Patients who have had ifosfamide during first-line therapy may receive the IFOS or IFOS-L arm. There is no requirement for a minimum time between receiving first-line ifosfamide and entry to rEECur. Additional exclusion criteria for the IFOS-L arm: 1. Clinically significant ECG abnormality, including a marked baseline prolonged QT or QTc interval (eg, a repeated demonstration of a QTc interval >480 msec). 2. History of aneurysm 3. Arterial Thromboembolism in previous 6 months 4. Gastrointestinal or non-gastrointestinal fistula. 5. Gastrointestinal bleeding or active haemoptysis within the previous 3 weeks 6. Major surgery within the previous 3 weeks 7. Previous treatment with tyrosine kinase inhibitors 8. Radiographic evidence of intratumoral cavitation, encasement, or invasion of a major blood vessel, or proximity to major blood vessels with the potential risk of severe haemorrhage associated with tumor shrinkage/necrosis after lenvatinib therapy. Previous 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 | 30/09/2025 |
Locations
Countries of recruitment
- Australia
- Belgium
- Czech Republic
- Denmark
- England
- Finland
- France
- Germany
- Hungary
- Italy
- Netherlands
- New Zealand
- Northern Ireland
- Norway
- Poland
- Scotland
- Spain
- Sweden
- Switzerland
- United Kingdom
- Wales
Study participating centres
Christie Hospital
Manchester
M20 4BX
United Kingdom
M20 4BX
United Kingdom
Addenbrooke's Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Cambridge
CB2 0QQ
United Kingdom
Alder Hey Children's Hospital
Eaton Road
Liverpool
L12 2AP
United Kingdom
Liverpool
L12 2AP
United Kingdom
Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom
Glasgow
G12 0YN
United Kingdom
Birmingham Children's Hospital
Steelhouse Lane
Birmingham
B4 6NH
United Kingdom
Birmingham
B4 6NH
United Kingdom
Bristol Royal Hospital for Children
Upper Maudlin Street
Bristol
BS2 8BJ
United Kingdom
Bristol
BS2 8BJ
United Kingdom
Churchill Hospital
Old Road
Oxford
OX3 7LE
United Kingdom
Oxford
OX3 7LE
United Kingdom
Clatterbridge Cancer Centre
Clatterbridge Road
Birkenhead
CH63 4JY
United Kingdom
Birkenhead
CH63 4JY
United Kingdom
Freeman Hospital
Freeman Road
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
John Radcliffe Hospital
Headley Way
Headington
Oxford
OX3 9DU
United Kingdom
Headington
Oxford
OX3 9DU
United Kingdom
Leeds General Infirmary
Great George Street
Leeds
LS1 3EX
United Kingdom
Leeds
LS1 3EX
United Kingdom
Leicester Royal Infirmary
Infirmary Square
Leicester
LE1 5WW
United Kingdom
Leicester
LE1 5WW
United Kingdom
Noah's Ark Children's Hospital for Wales
Heath Park Way
Cardiff
CF14 4XW
United Kingdom
Cardiff
CF14 4XW
United Kingdom
Nottingham City Hospital
Hucknall Road
Nottingham
NG5 1PB
United Kingdom
Nottingham
NG5 1PB
United Kingdom
Queen's Medical Centre
Derby Road
Nottingham
NG7 2UH
United Kingdom
Nottingham
NG7 2UH
United Kingdom
Royal Aberdeen Children's Hospital
Westburn Road
Aberdeen
AB25 2ZG
United Kingdom
Aberdeen
AB25 2ZG
United Kingdom
Royal Belfast Hospital for Sick Children
180 Falls Road
Belfast
BT12 6BE
United Kingdom
Belfast
BT12 6BE
United Kingdom
Royal Hospital for Children Glasgow
1345 Govan Road
Glasgow
G51 4TF
United Kingdom
Glasgow
G51 4TF
United Kingdom
Royal Hospital for Sick Children Edinburgh
9 Sciennes Road
Edinburgh
EH9 1LF
United Kingdom
Edinburgh
EH9 1LF
United Kingdom
Royal Manchester Childrens Hospital
Oxford Road
Manchester
M13 9WL
United Kingdom
Manchester
M13 9WL
United Kingdom
Royal Marsden Hospital London
203 Fulham Road
London
SW3 6JJ
United Kingdom
London
SW3 6JJ
United Kingdom
Royal Marsden Hospital Sutton
Downs Road
Sutton
SM2 5PT
United Kingdom
Sutton
SM2 5PT
United Kingdom
Royal Victoria Infirmary
Queen Victoria Road
Newcastle upon Tyne
NE1 4LP
United Kingdom
Newcastle upon Tyne
NE1 4LP
United Kingdom
Sheffield Children's Hospital
The Mount
Glossop Road
Sheffield
S10 3FL
United Kingdom
Glossop Road
Sheffield
S10 3FL
United Kingdom
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom
Southampton
SO16 6YD
United Kingdom
St James's University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom
Leeds
LS9 7TF
United Kingdom
The Queen Elizabeth Hospital
Mindelsohn Way
Birmingham
B15 2TH
United Kingdom
Birmingham
B15 2TH
United Kingdom
University College London Hospital
235 Euston Road
London
NW1 2BU
United Kingdom
London
NW1 2BU
United Kingdom
Weston Park Hospital
Whitham Road
Sheffield
S10 2SJ
United Kingdom
Sheffield
S10 2SJ
United Kingdom
Hospital Universitari Vall D'hebron
119-129
Barcelona
08035
Spain
Barcelona
08035
Spain
Istituto Ortopedico Rizzoli
Via Giulio Cesare Pupilli, 1
Bologna
40136
Italy
Bologna
40136
Italy
Helsinki Children's Hospital
Stenbäckinkatu 11
Helsinki
00290
Finland
Helsinki
00290
Finland
Oslo University Hospital
Sognsvannsveien 20
Oslo
0372
Norway
Oslo
0372
Norway
University Hospital Rigshospitalet
Blegdamsvej 9
København
2100
Denmark
København
2100
Denmark
Institut Gustave Roussy
114 Rue Edouard Vaillant
Villejuif
94800
France
Villejuif
94800
France
Semmelweiss Universitat Ii
Üllői út 26
Budapest
1085
Hungary
Budapest
1085
Hungary
U.Z Leuven- Campus Gasthuisberg
Herestraat 49
Leuven
3000
Belgium
Leuven
3000
Belgium
Maria Sklodowska-curie Memorial Cancer Center and Institute of Oncology
Wawelska 15 B
Warszawa
00-001
Poland
Warszawa
00-001
Poland
University Hospital Motol
V Úvalu 84
Praha
150 06
Czech Republic
Praha
150 06
Czech Republic
Leiden University Medical Centre
Albinusdreef 2
Leiden
2333 ZA
Netherlands
Leiden
2333 ZA
Netherlands
Princess Margaret Hospital
Roberts Road
Subiaco
Perth
6008
Australia
Subiaco
Perth
6008
Australia
Starship Children’s Hospital
2 Park Road
Grafton
Auckland
1023
New Zealand
Grafton
Auckland
1023
New Zealand
Universitäts Kinderspital beider Basel
Spitalstrasse 33
Basel
4056
Switzerland
Basel
4056
Switzerland
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
Government
Seventh Framework Programme
Government organisation / National government
Government organisation / National government
- Alternative name(s)
- EC Seventh Framework Programme, European Commission Seventh Framework Programme, EU Seventh Framework Programme, European Union Seventh Framework Programme, FP7
Results and Publications
| Intention to publish date | 28/02/2031 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not expected to be made available |
| 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 plan | 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. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
10/01/2025: The following changes were made:
1. IRAS number added.
2. The study hypothesis and intervention were amended.
3. Drug names Topotecan, cyclophosphamide, irinotecan, temozolomide, gemcitabine, and docetaxel were removed.
4. The primary and secondary outcome measures were amended.
5. The overall study end date was changed from 28/02/2030 to 30/09/2031.
6. The participant inclusion and exclusion criteria were amended.
7. The lower age limit (number) was changed from 4.0 to 2.0. and the upper age limit of 50 years was removed.
8. The recruitment end date was changed from 28/02/2025 to 30/09/2025.
14/06/2024: Study website added.
12/06/2020: The scientific contact details have been changed.
10/01/2019: The trial participating centres were updated.
21/12/2018: The following changes were made:
1. The overall trial end date was changed from 28/02/2025 to 28/02/2030.
2. The publication and dissemination plan was added.
3. The intention to publish date was added.
4. The participant level data was added.
14/12/2018: The following changes were made to the trial record:
1. The EudraCT number was added.
2. The protocol/serial number was changed from vn 0.4, vd 06-Jan-2014 to vn 5.0 vd 03-Jun-2016.
3. The ethics approval was added.
4. The overall trial end date was changed from 31/03/2019 to 28/02/2025.
5. The participant inclusion criteria was updated.
6. The target number of participants was changed from 275 for phase II; 390 for phase III to 275 for phase II; 400 for phase III.
7. The participant exclusion criteria was updated.
8. The recruitment end date was changed from 30/09/2018 to 28/02/2025.
9. The countries of recruitment were updated.
