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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
9/11/2018
Date data sharing statement initially provided
9/11/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
rEECur: Chemotherapy for the treatment of recurrent and primary refractory Ewing sarcom
Scientific title
International Randomised Controlled Trial of Chemotherapy for the Treatment of Recurrent and Primary Refractory Ewing Sarcoma
Secondary ID [1] 296438 0
RG_13-277
Secondary ID [2] 296479 0
ISRCTN36453794
Secondary ID [3] 296480 0
EudraCT Number: 2014-000259-99
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ewing Sarcoma 310203 0
Condition category
Condition code
Cancer 308947 308947 0 0
Children's - Other
Cancer 308994 308994 0 0
Bone

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A comparison of four 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.
The study will be analysed in two phases (Phase II/Phase III) with the least effective treatment regimens being dropped after the 1st interim analysis/2nd interim analysis.

Topotecan and Cyclophosphamide (TC): 6 cycles of 21 days, additional cycles at clinician's discretion.
IV Infusoion of Topotecan 0.75mg/m2 and Cyclophosphamide 250mg/m2 on day 1, 2, 3, 4, 5

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

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.

High dose Ifosfamide (IFOS): 4 cycles of 21 days.
IV infusion of Ifosfamide 3g/m2 on days 1, 2, 3, 4, 5.
Intervention code [1] 312762 0
Treatment: Drugs
Comparator / control treatment
Participants will be randomised to one of four chemotherapy regimens in order to identify the best one for use in future treatment. All four arms are currently used as standard of care treatment options for relapsed/refractory Ewings Sarcoma and will therefore be part of a four way comparison.
Control group
Active

Outcomes
Primary outcome [1] 307906 0
Phase II: Objective response as measured by RECIST criteria after four cycles of trial treatment.
Timepoint [1] 307906 0
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.

Primary outcome [2] 308002 0
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).
Timepoint [2] 308002 0
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.
Secondary outcome [1] 353296 0
Progression-free survival (PFS)



Timepoint [1] 353296 0
PFS will be assessed at every clinic visit

Secondary outcome [2] 353625 0
Overall survival (OS)
Timepoint [2] 353625 0
OS will be assessed at every clinic visit.
Secondary outcome [3] 353626 0
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 Version 3.o will be used and presented to patients and parents/guardians as applicable.
Timepoint [3] 353626 0
QoL will be assessed at baseline and after 2 and 4 cycles of chemotherapy
Secondary outcome [4] 353627 0
Adverse events and toxicity, defined by NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0
Timepoint [4] 353627 0
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)
Secondary outcome [5] 353628 0
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.
Timepoint [5] 353628 0
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)

Eligibility
Key inclusion criteria
1. Histologically confirmed Ewing sarcoma.
2. Disease recurrence or progression after completion of first line treatment OR
Refractory disease, defined by progression during first line treatment or within 12 weeks of its completion. Disease progression will be based on Response Evaluation Criteria In Solid Tumors (RECIST). 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. 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 greater than or equal to 4 years and less than or equal to 50 years.
5. Patient assessed as medically fit to receive cytotoxic chemotherapy.
6. Documented negative pregnancy test fr female patients of childbearing potential.
7. Patient agrees to use effective contraception during therapy and for 12 months. after last trial treatment (females) or 5 months after last trial treatment (males), where applicable.
8. Written informed consent from the patient and/or legal guardian.
Minimum age
4 Years
Maximum age
50 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1.Bone marrow infiltration resulting in absolute neutrophil count (ANC) less than 1.0 x 109/l or platelets less than 75 x 109/l
2.Cytotoxic chemotherapy or other investigational medicinal product (IMP) within previosu 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 12279 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [2] 12280 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [3] 12281 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [4] 12282 0
Prince of Wales Hospital - Randwick
Recruitment hospital [5] 12283 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [6] 12284 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [7] 12285 0
John Hunter Children's Hospital - New Lambton
Recruitment hospital [8] 12286 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment hospital [9] 12287 0
Monash Children’s Hospital - Clayton
Recruitment hospital [10] 12288 0
Perth Children's Hospital - Nedlands
Recruitment hospital [11] 12289 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [12] 12290 0
Sydney Children's Hospital - Randwick
Recruitment hospital [13] 12291 0
Womens and Childrens Hospital - North Adelaide
Recruitment postcode(s) [1] 24470 0
2050 - Camperdown
Recruitment postcode(s) [2] 24471 0
4102 - Woolloongabba
Recruitment postcode(s) [3] 24472 0
3000 - Melbourne
Recruitment postcode(s) [4] 24473 0
2031 - Randwick
Recruitment postcode(s) [5] 24474 0
5000 - Adelaide
Recruitment postcode(s) [6] 24475 0
2145 - Westmead
Recruitment postcode(s) [7] 24476 0
2305 - New Lambton
Recruitment postcode(s) [8] 24477 0
4101 - South Brisbane
Recruitment postcode(s) [9] 24478 0
3168 - Clayton
Recruitment postcode(s) [10] 24479 0
6009 - Nedlands
Recruitment postcode(s) [11] 24480 0
3052 - Parkville
Recruitment postcode(s) [12] 24481 0
5006 - North Adelaide
Recruitment outside Australia
Country [1] 20957 0
United Kingdom
State/province [1] 20957 0
Country [2] 20958 0
Spain
State/province [2] 20958 0
Country [3] 20959 0
Italy
State/province [3] 20959 0
Country [4] 20960 0
Norway
State/province [4] 20960 0
Country [5] 20961 0
Finland
State/province [5] 20961 0
Country [6] 20962 0
Denmark
State/province [6] 20962 0
Country [7] 20963 0
Sweden
State/province [7] 20963 0
Country [8] 20964 0
France
State/province [8] 20964 0
Country [9] 20965 0
Hungary
State/province [9] 20965 0
Country [10] 20966 0
Belgium
State/province [10] 20966 0
Country [11] 20967 0
Netherlands
State/province [11] 20967 0
Country [12] 20968 0
Czech Republic
State/province [12] 20968 0
Country [13] 20969 0
Poland
State/province [13] 20969 0
Country [14] 20970 0
Germany
State/province [14] 20970 0
Country [15] 20971 0
Switzerland
State/province [15] 20971 0
Country [16] 20972 0
New Zealand
State/province [16] 20972 0

Funding & Sponsors
Funding source category [1] 301037 0
Charities/Societies/Foundations
Name [1] 301037 0
Canteen - Australian Young Cancer Patient Clinical Trials Initiative
Address [1] 301037 0
161 Flemington Road North Melbourne VIC 3051
Country [1] 301037 0
Australia
Primary sponsor type
University
Name
University of Birmingham
Address
Cancer Research Clinical Trials Unit
Vincent Drive
Edgbaston
Birmingham B15 2TT
United Kingdom
Country
Australia
Secondary sponsor category [1] 300632 0
Other Collaborative groups
Name [1] 300632 0
Australian and New Zealand Children's Haematology Oncology Group
Address [1] 300632 0
Hudson Institute of Medical Research
27-31 Wright Street
Clayton VIC 3168
Country [1] 300632 0
Australia
Other collaborator category [1] 280411 0
Other Collaborative groups
Name [1] 280411 0
Australasian Sarcoma Study Group
Address [1] 280411 0
Peter MacCallum Cancer Centre
Level 1 305 Grattan Street
Melbourne VIC 3000
Country [1] 280411 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301791 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 301791 0
Locked Bag No 1
New Lambton NSW 2305
Ethics committee country [1] 301791 0
Australia
Date submitted for ethics approval [1] 301791 0
30/06/2017
Approval date [1] 301791 0
17/01/2018
Ethics approval number [1] 301791 0
HREC/18/HNE/5
Ethics committee name [2] 301792 0
Child and Adolescent Health Service Human Research Ethics Committee
Ethics committee address [2] 301792 0
Perth Children's Hospital
15 Hospital Avenue
Nedlands Western Australia 6009
Ethics committee country [2] 301792 0
Australia
Date submitted for ethics approval [2] 301792 0
Approval date [2] 301792 0
11/09/2017
Ethics approval number [2] 301792 0
RGS0000000480

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’s Sarcoma is most beneficial.

Who is it for?
You may be eligible for this study if you are aged 4-50 years old and have been diagnosed with relapsed or refractory Ewing sarcoma.

Study details
Participants in this trial will be randomly allocated to one of four different treatment groups. These groups include:
Before treatment starts the following routine tests will be performed :
Physical check-up including measuring height and weight
Blood tests +/- urine tests
Assessment of your child’s kidneys 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 require completion 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 four of these treatments are those which are currently used in 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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88118 0
Dr Martin McCabe
Address 88118 0
The Christie Hospital
Wilmslow Road
Manchester M20 4BX
United Kingdom
Country 88118 0
United Kingdom
Phone 88118 0
+44 0 161 446 3954
Fax 88118 0
Email 88118 0
reecur@trials.bham.ac.uk
Contact person for public queries
Name 88119 0
A/Prof Marianne Phillips
Address 88119 0
Haematology and Oncology
Perth Children's Hospital
15 Hospital Ave
Nedlands Western Australia 6009
Country 88119 0
Australia
Phone 88119 0
+61 8 6456 2222
Fax 88119 0
Email 88119 0
SCHN-REECUR@health.nsw.gov.au
Contact person for scientific queries
Name 88120 0
A/Prof Marianne Phillips
Address 88120 0
Haematology and Oncology
Perth Children's Hospital
15 Hospital Ave
Nedlands Western Australia 6009
Country 88120 0
Australia
Phone 88120 0
+61 8 6456 2222
Fax 88120 0
Email 88120 0
SCHN-REECUR@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Results will be presented at international conference and published in journals.

International sponsor (University of Birmingham) will be responsible for the raw data collected during the trial.
What supporting documents are/will be available?
No other documents available
Summary results
No Results