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DEFINITIONS
Trial Review
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Trial registered on ANZCTR
Registration number
ACTRN12618001825246
Ethics application status
Approved
Date submitted
26/10/2018
Date registered
9/11/2018
Date last updated
10/05/2024
Date data sharing statement initially provided
9/11/2018
Type of registration
Prospectively registered
Titles & IDs
Public title
rEECur: Chemotherapy for the treatment of recurrent and primary refractory Ewing sarcoma
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Scientific title
International Randomised Controlled Trial of Chemotherapy for the Treatment of Recurrent and Primary Refractory Ewing Sarcoma
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Secondary ID [1]
296438
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RG_13-277
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Secondary ID [2]
296479
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ISRCTN36453794
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Secondary ID [3]
296480
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EudraCT Number: 2014-000259-99
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Ewing Sarcoma
310203
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Condition category
Condition code
Cancer
308947
308947
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0
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Children's - Other
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Cancer
308994
308994
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0
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Bone
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
A comparison of widely used chemotherapy regimens for the treatment of Ewing sarcoma, a type of bone cancer, to see which is most effective and/or has the fewest side effects.
Carboplatin and Etoposide (CE): 6 cycles of 21 days, additional cycles at clinician’s discretion.
IV infusion of Carboplatin 400mg/m2 on day 1, and IV infusion of Etoposide on Days 1, 2, 3
High dose Ifosfamide (IFOS): 4 cycles of 21 days, additional cycles at clinician's discretion.
IV infusion of Ifosfamide 3g/m2 on days 1, 2, 3, 4, 5
High dose Ifosfamide and Lenvatinib (IFOS-L), 4 cycles, of 21 days, additional IFOS cycles at clinician’s discretion. Lenvatinib capsules taken once daily continuously throughout and for up to 2 years in total.
IV infusion of Ifosfamide 3g/m2 on days 1, 2, 3, 4, 5 & 14mg/m2 (oral) starting d1 then daily, continuous
Please note – Gemcitabine and Docetaxel (GD) arm closed in November 2018 and Irinotecan and Temozolomide (IT) arm closed in March 2020.
Please note- Topotecan and Cyclophosphamide (TC) arm was closed in November 2021.
The closed arms:
Gemcitabine and Docetaxel (GD): 6 cycles of 21 days, additional cycles at clinician's discretion.
IV infusion of Gemcitabine 900mg/m2 on days 1, 8.
IV infusion of Docetxal 800mg/m2 on day 8.
Irinotecan and Temozolomide (IT): 6 cycles of 21 days, additional cycles at clinician's discretion.
IV infusion of Irinotecan 50mg/m2 on days 1, 2, 3, 4, 5
Temozolomide 100mg/m2 orally on days 1, 2, 3, 4, 5
Topotecan and Cyclophosphamide (TC): 6 cycles of 21 days, additional cycles at clinician's discretion.
IV Infusion of Topotecan 0.75mg/m2 and Cyclophosphamide 250mg/m2 on day 1, 2, 3, 4, 5
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Intervention code [1]
312762
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Treatment: Drugs
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Comparator / control treatment
Participants will be randomised to one of the available chemotherapy regimens in order to identify the best one for use in future treatment. All chemotherapy regimens are currently used as standard of care treatment options for relapsed/refractory Ewing sarcoma.
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Control group
Active
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Outcomes
Primary outcome [1]
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Event-free survival which is defined as the time from randomisation until the first event (progression, recurrence following response, secondary malignancy or death).
The primary outcome measure will be event free survival. It will be assessed at every clinic visit. The frequency and timing of clinic visits is not specified in the protocol since international practice varies.
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Assessment method [1]
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Timepoint [1]
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The main assessment time point for the phase II study will be at baseline and after 4 cycles of chemotherapy. Additional imaging will be performed after 2 and 6 cycles of chemotherapy.
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Primary outcome [2]
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Phase III: Event-free survival which is defined as the time from randomisation until the first event (progression, recurrence following response, secondary malignancy or death).
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Assessment method [2]
308002
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Timepoint [2]
308002
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The outcome measure of the phase III study will be event free survival. It will be assessed at every clinic visit. The frequency and timing of clinic visits is not specified in the protocol since international practice varies.
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Secondary outcome [1]
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Progression-free survival (PFS)
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Assessment method [1]
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Timepoint [1]
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PFS will be assessed at every clinic visit
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Secondary outcome [2]
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Overall survival (OS)
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Assessment method [2]
353625
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Timepoint [2]
353625
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OS will be assessed at every clinic visit.
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Secondary outcome [3]
353626
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Quality of Life (QoL) QoL sub-study is designed to assess the patient's well-being during chemotherapy using a questionnaire at three specified timepoints (baseline, after 2 and 4 cycles of chemotherapy). PedsQL 4.0 and EORTC-QLQ30 Version 3.0 will be used and presented to patients and parents/guardians as applicable.
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Assessment method [3]
353626
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Timepoint [3]
353626
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QoL will be assessed at baseline and after 2 and 4 cycles of chemotherapy
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Secondary outcome [4]
353627
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Adverse events and toxicity, defined by NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0
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Assessment method [4]
353627
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Timepoint [4]
353627
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Adverse events and toxicity will be assessed prior to the start of the next chemotherapy cycle and after the last chemotherapy cycle for cycles 1-4 (Ifosfamide regimen) and cycles 1-6 (other chemotherapy regimens)
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Secondary outcome [5]
353628
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Days spent in hospital.
The number and proportion of days in hospital will be presented for each arm and overall. Standard statistical tests will be performed to compare the arms.
Sites will provide the numerical value for days spent in hospital during each cycle in the Case Report Form.
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Assessment method [5]
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Timepoint [5]
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Days spent in hospital following each cycle will be assessed prior to the start of the next chemotherapy cycle and after the last chemotherapy cycle for cycles 1-4 (Ifosfamide regimen) and cycles 1-6 (other chemotherapy regimens)
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Secondary outcome [6]
401041
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Objective imaging response according to RECIST 1.1 criteria.
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Assessment method [6]
401041
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Timepoint [6]
401041
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After 2, 4, and 6 cycles for CE, after 2 and 4 cycles for IFOS, and at the end of trial treatment.
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Secondary outcome [7]
401042
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PET-CT tumour response
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Assessment method [7]
401042
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Timepoint [7]
401042
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After 4 cycles
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Eligibility
Key inclusion criteria
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 first or any subsequent line of treatment.
3. Age greater than or equal to 2 years.
4. Eligible for randomisation between at least two open study arms.
5. Patient assessed as medically fit to receive trial treatment
6. Date of planned randomisation within 4 weeks of baseline imaging.
7. Documented negative pregnancy test for female patients of childbearing potential.
8. Patient agrees to use effective contraception during therapy and for 12 months after last trial treatment, where applicable.
9. Written informed consent from the patient and/or parent/legal guardian.
10. Adequate GFR
IFOS-Lenvatinib specific principal inclusion criteria:
1. Adequate liver function
2. Left ventricular ejection fraction greater than or equal to 50% at baseline as determined by echocardiography.
3. Normal or adequately controlled blood pressure (BP)
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Minimum age
2
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
1. Absolute Neutrophil Count (ANC) <1.0 x 10^9/L or platelets <75 x 10^9/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
IFOS-Lenvatinib specific principal exclusion criteria:
1. Significant proteinuria
2. Arterial Thromboembolism in previous 6 months
3. Gastrointestinal bleeding or active haemoptysis within previous 3 weeks
4. Major surgery within previous 3 weeks
5. Previous treatment with tyrosine kinase inhibitors
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2 / Phase 3
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Type of endpoint/s
Efficacy
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Statistical methods / analysis
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Recruitment
Recruitment status
Recruiting
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Date of first participant enrolment
Anticipated
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Actual
25/11/2018
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
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Sample size
Target
600
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Accrual to date
578
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Final
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Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
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Recruitment hospital [1]
12279
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The Chris O’Brien Lifehouse - Camperdown
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Recruitment hospital [2]
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Princess Alexandra Hospital - Woolloongabba
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Recruitment hospital [3]
12281
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Peter MacCallum Cancer Centre - Melbourne
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Recruitment hospital [4]
12283
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The Royal Adelaide Hospital - Adelaide
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Recruitment hospital [5]
12284
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The Children's Hospital at Westmead - Westmead
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Recruitment hospital [6]
12285
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John Hunter Children's Hospital - New Lambton
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Recruitment hospital [7]
12287
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Monash Children’s Hospital - Clayton
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Recruitment hospital [8]
12288
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Perth Children's Hospital - Nedlands
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Recruitment hospital [9]
12290
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Sydney Children's Hospital - Randwick
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Recruitment hospital [10]
12291
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Womens and Childrens Hospital - North Adelaide
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Recruitment hospital [11]
15032
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Queensland Children's Hospital - South Brisbane
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Recruitment hospital [12]
15033
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Sir Charles Gairdner Hospital - Nedlands
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Recruitment postcode(s) [1]
24470
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2050 - Camperdown
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Recruitment postcode(s) [2]
24475
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2145 - Westmead
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Recruitment postcode(s) [3]
24476
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2305 - New Lambton
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Recruitment postcode(s) [4]
24472
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3000 - Melbourne
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Recruitment postcode(s) [5]
24478
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3168 - Clayton
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Recruitment postcode(s) [6]
24471
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4102 - Woolloongabba
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Recruitment postcode(s) [7]
24474
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5000 - Adelaide
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Recruitment postcode(s) [8]
24481
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5006 - North Adelaide
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Recruitment postcode(s) [9]
24479
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6009 - Nedlands
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Recruitment outside Australia
Country [1]
20957
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United Kingdom
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State/province [1]
20957
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Country [2]
20958
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Spain
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State/province [2]
20958
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Country [3]
20959
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Italy
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State/province [3]
20959
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Country [4]
20960
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Norway
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State/province [4]
20960
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Country [5]
20961
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Finland
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State/province [5]
20961
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Country [6]
20962
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Denmark
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State/province [6]
20962
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Country [7]
20963
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Sweden
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State/province [7]
20963
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Country [8]
20964
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France
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State/province [8]
20964
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Country [9]
20965
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Hungary
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State/province [9]
20965
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Country [10]
20966
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Belgium
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State/province [10]
20966
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Country [11]
20967
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Netherlands
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State/province [11]
20967
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Country [12]
20968
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Czech Republic
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State/province [12]
20968
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Country [13]
20969
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Poland
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State/province [13]
20969
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Country [14]
20970
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Germany
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State/province [14]
20970
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Country [15]
20971
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Switzerland
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State/province [15]
20971
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Country [16]
20972
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New Zealand
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State/province [16]
20972
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Funding & Sponsors
Funding source category [1]
301037
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Charities/Societies/Foundations
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Name [1]
301037
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Canteen - Australian Young Cancer Patient Clinical Trials Initiative
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Address [1]
301037
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161 Flemington Road North Melbourne VIC 3051
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Country [1]
301037
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Australia
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Primary sponsor type
University
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Name
University of Birmingham
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Address
Cancer Research Clinical Trials Unit
Vincent Drive
Edgbaston
Birmingham B15 2TT
United Kingdom
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Country
United Kingdom
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Secondary sponsor category [1]
300632
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Other Collaborative groups
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Name [1]
300632
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Australian and New Zealand Children's Haematology Oncology Group
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Address [1]
300632
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Hudson Institute of Medical Research
27-31 Wright Street
Clayton VIC 3168
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Country [1]
300632
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Australia
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Other collaborator category [1]
280411
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Other Collaborative groups
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Name [1]
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Australasian Sarcoma Study Group
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Address [1]
280411
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Peter MacCallum Cancer Centre
Level 1 305 Grattan Street
Melbourne VIC 3000
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Country [1]
280411
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Australia
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
301791
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Hunter New England Human Research Ethics Committee
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Ethics committee address [1]
301791
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Locked Bag No 1 New Lambton NSW 2305
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Ethics committee country [1]
301791
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Australia
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Date submitted for ethics approval [1]
301791
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30/06/2017
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Approval date [1]
301791
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17/01/2018
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Ethics approval number [1]
301791
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HREC/18/HNE/5
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Ethics committee name [2]
301792
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Child and Adolescent Health Service Human Research Ethics Committee
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Ethics committee address [2]
301792
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Perth Children's Hospital 15 Hospital Avenue Nedlands Western Australia 6009
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Ethics committee country [2]
301792
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Australia
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Date submitted for ethics approval [2]
301792
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Approval date [2]
301792
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11/09/2017
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Ethics approval number [2]
301792
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RGS0000000480
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Summary
Brief summary
The purpose of this study is to determine which of the most commonly used chemotherapy used in recurrent and primary refractory Ewing sarcoma is most beneficial. Who is it for? You may be eligible for this study if you are aged 2 years or above and have been diagnosed with relapsed or refractory Ewing sarcoma. Study details: Participants in this trial will be randomly allocated to one of the available treatment groups. These groups include Topotecan and Cyclophosphamide (TC), Carbonplatin and Etoposide (CE) and high dose Ifosfamide (IFOS). Before treatment starts the following routine tests will be performed: Physical check-up including measuring height and weight Blood tests +/- urine tests Assessment of kidney function called a GFR. Scans (which may include CT, PET-CT, MRI, bone scan, x-ray). The doctor will decide which type of scans needed depending on where the tumour is located. A quality of life questionnaire will also be completed before treatment commences. During trial treatment While you are having chemotherapy treatment you will be carefully monitored using the same routine tests that would be used if you were having chemotherapy but were not in the trial. These routine tests will include blood +/- urine tests, scans and GFR. These tests are to ensure that you are fit to continue chemotherapy. In addition if you have had a PET-CT scan before treatment, you will have another PET-CT scan after 4 cycles of chemotherapy. You will be asked to complete two more quality of life questionnaires, one on completion of cycle 2 and one on completion of cycle 4. All treatments in this study are those which are currently used routinely for treatment of Ewing sarcoma. It is hoped that this research will help to determine which of the treatments is most effective in improving overall survival, side effects, tumour shrinkage, quality of life and days spent in hospital.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Dr Martin McCabe
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Address
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The Christie Hospital
Wilmslow Road
Manchester M20 4BX
United Kingdom
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Country
88118
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United Kingdom
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Phone
88118
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+44 0 161 446 3954
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Fax
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Email
88118
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reecur@trials.bham.ac.uk
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Contact person for public queries
Name
88119
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Marianne Phillips
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Address
88119
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Haematology and Oncology
Perth Children's Hospital
15 Hospital Ave
Nedlands Western Australia 6009
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Country
88119
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Australia
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Phone
88119
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+61 8 6456 2222
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Fax
88119
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Email
88119
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anzchog_reecur@anzchog.org
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Contact person for scientific queries
Name
88120
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Marianne Phillips
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Address
88120
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Haematology and Oncology
Perth Children's Hospital
15 Hospital Ave
Nedlands Western Australia 6009
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Country
88120
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Australia
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Phone
88120
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+61 8 6456 2222
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Fax
88120
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Email
88120
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anzchog_reecur@anzchog.org
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
Results will be presented at international conferences and published in journals.
International sponsor (University of Birmingham) will be responsible for the raw data collected during the trial.
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
No additional documents have been identified.
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