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Trial registered on ANZCTR


Registration number
ACTRN12624000532505
Ethics application status
Approved
Date submitted
14/03/2024
Date registered
29/04/2024
Date last updated
29/04/2024
Date data sharing statement initially provided
29/04/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
International clinical research programme to improve outcomes in newly diagnosed Ewing sarcoma – Trial 1
Scientific title
International clinical research programme to improve outcomes in newly diagnosed Ewing sarcoma – Trial 1 (INTER-EWING-1)
Secondary ID [1] 311410 0
ISRCTN17938906
Secondary ID [2] 311412 0
RG_21-151
Universal Trial Number (UTN)
Trial acronym
INTER-EWING-1
Linked study record
REGO-EWING: Phase Ib study of the combination of regorafenib with conventional chemotherapy for the treatment of newly diagnosed patients with multimetastatic Ewing sarcoma:

REGO-EWING is the dose-finding study for INTER-EWING-1 Randomisation A. The primary objective of this study is to determine the recommended Phase 2 dose (RP2D) of regorafenib in combination
with standard backbone chemotherapy of VDC/IE

ClinicalTrials.gov Identifier: NCT05830084
EudraCT No: 2022-002874-10

Health condition
Health condition(s) or problem(s) studied:
Ewing Sarcoma 332693 0
Condition category
Condition code
Cancer 329403 329403 0 0
Bone
Cancer 329509 329509 0 0
Sarcoma (also see 'Bone') - soft tissue

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study Entry:
INTER-EWING-1 includes a study entry point where all patients with Ewing sarcoma (ES) may give consent for the analysis of their biological samples and/or undergo additional scans, alongside the collection of very basic patient characteristics, a treatment summary, and follow-up data for events.

Treatment questions
Patients may be entered into more than one treatment question following study entry. Separate consent is required for study entry and for each trial question. Newly diagnosed patients should, where possible, be entered into the INTER-EWING-1 study at the time of initial diagnosis prior to receiving any chemotherapy. However, patients may enter the study at any point of the treatment pathway as long as they are eligible.

Screening assessments
A histologically confirmed diagnosis of ES is required for Study Entry.

The majority of screening assessments for subsequent randomisations are standard of care, and will include blood tests, urine tests, physical exam, and scans (e.g. CT, MRI, PET-CT).



Induction chemotherapy for newly diagnosed patients (Randomisation A):
This section will be updated after the recommended phase II dose has been established from the externally sponsored phase Ib study (ClinicalTrials.gov Identifier: NCT05830084, EudraCT No: 2022-002874-10). Patients will be randomised to receive either Vincristine - Doxorubicin - Cyclophosphamide / Ifosfamide - Etoposide (VDC/IE) without regorafenib or VDC/IE with regorafenib.


Randomisation B:
Where a patient is deemed suitable for radiotherapy and is eligible, radiotherapy randomisation should be considered. Radiotherapy may be definitive, pre-operative or post-operative, and is given concurrently with chemotherapy. Pre-operative and definitive radiotherapy will be delivered after cycle 9 of chemotherapy.

Radiotherapy for newly diagnosed disease:
This trial also contains radiotherapy randomisations for patients with newly diagnosed ES.

For patients with non-resectable disease (disease that cannot be removed by surgery) there is the B1 randomisation, in which the patient will be randomised to receive either:
- a standard dose 54Gy, this will usually be given in 30 sessions over 6 weeks, with 1.8 Gy of radiotherapy being given each time they go.
- A higher dose of radiotherapy 64.8Gy, this will usually be given in 36 sessions over 7.2 weeks, with 1.8 Gy of radiotherapy being given each time they go. Sometimes, the higher dose (64.8 Gy) can be given in 30 sessions over 6 weeks. The treating physician will advise if the higher dose will be given over 30 or 36 sessions.

For patients with resectable disease there is the B2 randomisation in which patients will be randomly assigned to either:
- a standard dose of 54Gy, this will usually be given in 30 sessions over 6 weeks
- A lower dose of radiotherapy 45Gy, this will usually be given in 25 sessions over 5 weeks.

All sites and patients participating in the radiotherapy questions will participate in the Radiotherapy Quality Assurance programme, facilitated via the SIOPE QUARTET (Quality and Excellence in Radiotherapy and Imaging for Children and Adolescents with Cancer across Europe in Clinical Trials) initiative. All sites will be required to be approved for radiotherapy delivery via QUARTET, and radiotherapy plans for each individual patient will be uploaded to the online system for approval. There will also be a retrospective Quality Control review of all scans and cross-sectional imaging received as part of the radiotherapy QA review process.



Maintenance Chemotherapy (Randomisation C):
For the majority of patients the treatment of ES includes intensive chemotherapy and either surgery, radiotherapy or a combination of the two.
Currently, once this initial treatment phase finishes, no further treatment is given. However, several other childhood cancers may give patients additional chemotherapy – this is called maintenance chemotherapy. The aim of maintenance chemotherapy is to stop the cancer from returning or to get rid of any traces of cancer that are left over from previous treatment.

Eligible patients can be consented and randomised within 8 weeks of commencing the last cycle of consolidation chemotherapy.


In this part of the INTER-EWING-1 trial, patients will either stop treatment or receive 6 cycles of maintenance chemotherapy. The chemotherapy for this randomisation is vinorelbine and cyclosphosphamide (VnC) and the cycles are each 28 days. Vinorelbine can be given in either an intravenous or oral tablet format. Cyclophosphamide will be given as an oral tablet (oral liquid can be given where licensed formulation is available).

Adherence to the intervention treatment will be monitored via the completion of a patient drug diary.



Imaging sub-studies:
Patients who have a Diffusion Weighted MRI scan at diagnosis may be offered further scans after 3 and then 9 cycles of induction chemotherapy to see whether these additional scans can indicate how well treatment will work in the long term.

The study will also investigate whether whole body-MRI scans are better than FDG-PET scans at measuring how widespread disease is before treatment. Where these scans do not form part of standard care, patients will be asked for consent to have a whole body-MRI scan at diagnosis for research purposes.

This study will also encourage an FDG PET-CT or FDG PET-MRI scan after 3 and then 9 courses of induction chemotherapy to determine prospectively its prognostic value. Should this not be standard of care, the patient will be asked to consent to these optional sub-studies.



QoL sub-study:
All Patients that have enrolled in Study Entry, Randomisation B and Randomisation C arms will be asked to complete Quality of Life questionnaires.



Follow-up:
Following completion of treatment, the frequency of follow-up assessments should be as per local practice.
Intervention code [1] 327850 0
Treatment: Drugs
Intervention code [2] 328195 0
Treatment: Other
Comparator / control treatment
Randomisation A (not currently open until dose has been established): Induction chemotherapy randomisation. VDC/IE as comparator
Randomisation B: B1 (Definitive RT): 54Gy as comparator, B2 (Post-op RT): 45Gy as comparator
Randomisation C: End of standard treatment/no extension as comparator
Control group
Active

Outcomes
Primary outcome [1] 337221 0
1. Event-free survival time (EFS), defined as the time from the date of each randomisation to the date of the first failure event, where failure events are defined as:

1.1. Relapse or progression of existing disease, or recurrence of disease at new sites,
1.2. Death from any cause without disease progression,
1.3. Second malignant neoplasm.

Patients without an event at the time of analysis will be censored at the date when they were last known to be alive and event-free.

All components will be assessed together as a composite primary outcome.
Timepoint [1] 337221 0
Defined as the time from the date of each randomisation to the date of the first failure event
Secondary outcome [1] 433842 0
Overall Survival
Timepoint [1] 433842 0
Overall Survival time is defined as the time from the date of each randomisation to the date of death from any cause. Patients who have not died at the time of analysis will be censored at the date when they were last known to be alive.
Secondary outcome [2] 433843 0
Toxicity
Timepoint [2] 433843 0
Information will be collected from the time of consent and details will be documented and reported from the date of commencement of protocol defined treatment (patients taking part in a randomised trial question) until 30 days after the administration of the last trial treatment in
each randomisation. The 30-day duration period will start again for each randomisation.
Secondary outcome [3] 433851 0
Quality of Life
Timepoint [3] 433851 0
At study entry; prior to radiotherapy and at end of treatment; prior to maintenance therapy and at end of treatment; at 24 months for randomised patients only
Secondary outcome [4] 433852 0
Histological response (if surgery is performed)
Timepoint [4] 433852 0
Observed post-induction chemotherapy surgery of the primary tumour.
Secondary outcome [5] 433853 0
Local failure-free survival time
Timepoint [5] 433853 0
Local failure -free survival time (LFFS) is defined as the time from randomisation to first local failure event. A local failure event is relapse or progression of tumour at the primary tumour site at any time even if there has been a prior/concurrent, regional or distant failure.
Secondary outcome [6] 433854 0
Achievement of local control
Timepoint [6] 433854 0
At the end of treatment
Secondary outcome [7] 433856 0
Acute post radiotherapy toxicity
Timepoint [7] 433856 0
During and up to 120 days after completing radiotherapy
Secondary outcome [8] 433857 0
Late toxicity
Timepoint [8] 433857 0
Occurring from 120 days after completing radiotherapy

Eligibility
Key inclusion criteria
1. Any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or round cell sarcomas which are ‘Ewing’s-like’ but negative for EWSR1-Fli gene rearrangement
2. Age > 2 years
3. Written informed consent from the patient and/or the parent/legal guardian

inclusion criteria for randomisation A will be defined on completion of the externally sponsored phase 1b study (ClinicalTrials.gov Identifier: NCT05830084, EudraCT No: 2022-002874-10). A substantial amendment will be submitted to the relevant competent authority and ethics committee(s) to include these details prior to the opening of Randomisation A.

Radiotherapy Randomisations – B1 and B2
Inclusion Criteria
1. Entered into the INTER-EWING-1 study
2. Received induction/consolidation chemotherapy with a VDC/IE/VC based regimen
3. Patient assessed as medically fit to receive the radiotherapy
4. Documented negative pregnancy test for female patients of childbearing potential
5. Patient agrees to use contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where patient is sexually active
6. Written informed consent from the patient and/or the parent/legal guardian

Randomisation B1 specific Inclusion criteria– Definitive radical radiotherapy dose finding randomisation
1. Patients requiring definitive radical radiotherapy to primary tumour site as sole local therapy following discussion by local multidisciplinary team.
2. Patients who have undergone an R2 resection of the primary tumour (macroscopic residual tumour), requiring definitive radical radiotherapy

Randomisation B2 specific Inclusion criteria– Post-operative radiotherapy dose finding randomisation
1. Patients requiring post-operative radiotherapy following discussion by local multidisciplinary team
according to multidisciplinary team meeting.

Randomisation C – Maintenance chemotherapy randomisation
Inclusion Criteria
1. Entered into the INTER-EWING-1 study
2. Received induction/ consolidation chemotherapy with a VDC/IE/VC based regimen
3. Have responded to induction treatment and not progressed
4. Medically fit to receive treatment
5. Absence of severe vincristine neuropathy – i.e. requiring discontinuation of vincristine treatment
6. Adequate liver function: bilirubin <3 x ULN and ALT or AST < 5 x ULN
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 6 months after last trial treatment (males), where patient is sexually active
9. Written informed consent from the patient and/or the parent/legal guardian
Minimum age
2 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous malignancy

Exclusion criteria for randomisation A will be defined on completion of the externally sponsored phase 1b study (ClinicalTrials.gov Identifier: NCT05830084, EudraCT No: 2022-002874-10). A substantial amendment will be submitted to the relevant competent authority and ethics committee(s) to include these details prior to the opening of Randomisation A.

Exclusion Criteria Radiotherapy Randomisations – B1 and B2
1. Previous radiotherapy to the same site
2. Pregnant or breastfeeding women
3. BuMel high dose chemotherapy within previous 10 weeks

Randomisation B1 specific Exclusion criteria– Definitive radical radiotherapy dose finding randomisation
1. Patients who have had a R1 or R0 surgical resection of their tumour
2. Previous high dose chemotherapy including busulfan when specified dose constraints to critical organs cannot be met (please see INTER-EWING-1 Quartet RTQA guidelines for more details)

Randomisation B2 specific Exclusion criteria– Post-operative radiotherapy dose finding randomisation
1. R2 resection (macroscopic residual tumour)
2. Patients treated by surgery with wide resection (R0 and all tissues involved by the prechemotherapy
tumour volume have been completely resected), good histological response (< 10% viable cells), small tumour volume (< 200 mls at diagnosis), of the limb.

Randomisation C – Maintenance chemotherapy randomisation
Exclusion Criteria
1. Urinary outflow obstruction that cannot be relieved prior to starting treatment
2. Uncontrolled significant inter-current illness or active infection
3. Active inflammation of the urinary bladder (cystitis)
4. Known contraindication or hypersensitivity to any of the treatments or excipients
5. Pregnant or breastfeeding women

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)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised minimisation algorithm
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/04/2024
Actual
Date of last participant enrolment
Anticipated
30/11/2030
Actual
Date of last data collection
Anticipated
30/11/2032
Actual
Sample size
Target
900
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,VIC
Recruitment outside Australia
Country [1] 26102 0
Denmark
State/province [1] 26102 0
Country [2] 26103 0
France
State/province [2] 26103 0
Country [3] 26104 0
Italy
State/province [3] 26104 0
Country [4] 26105 0
Netherlands
State/province [4] 26105 0
Country [5] 26106 0
New Zealand
State/province [5] 26106 0
Country [6] 26108 0
Norway
State/province [6] 26108 0
Country [7] 26109 0
Poland
State/province [7] 26109 0
Country [8] 26110 0
Spain
State/province [8] 26110 0
Country [9] 26111 0
Switzerland
State/province [9] 26111 0
Country [10] 26112 0
United Kingdom
State/province [10] 26112 0

Funding & Sponsors
Funding source category [1] 315672 0
Charities/Societies/Foundations
Name [1] 315672 0
The Australia Organisation for Young People Living with Cancer (Canteen)
Country [1] 315672 0
Australia
Funding source category [2] 316068 0
Government body
Name [2] 316068 0
Australian Department of Health and Aged Care, Medical Research Future Fund (MRFF)
Country [2] 316068 0
Australia
Funding source category [3] 316069 0
Charities/Societies/Foundations
Name [3] 316069 0
The Kid’s Cancer Project
Country [3] 316069 0
Australia
Funding source category [4] 316070 0
Other Collaborative groups
Name [4] 316070 0
Australia and New Zealand Sarcoma Association
Country [4] 316070 0
Australia
Primary sponsor type
University
Name
University of Birmingham
Address
Country
United Kingdom
Secondary sponsor category [1] 317775 0
Other Collaborative groups
Name [1] 317775 0
Australian and New Zealand Children's Haematology Oncology Group
Address [1] 317775 0
Country [1] 317775 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314549 0
Child and Adolescent Health Service Human Research Ethics Committee
Ethics committee address [1] 314549 0
Ethics committee country [1] 314549 0
Australia
Date submitted for ethics approval [1] 314549 0
30/10/2023
Approval date [1] 314549 0
24/11/2023
Ethics approval number [1] 314549 0
Ethics committee name [2] 315194 0
East of England - Cambridge South Research Ethics Committee
Ethics committee address [2] 315194 0
Ethics committee country [2] 315194 0
United Kingdom
Date submitted for ethics approval [2] 315194 0
16/12/2022
Approval date [2] 315194 0
19/07/2023
Ethics approval number [2] 315194 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 131982 0
Dr Marianne Phillips
Address 131982 0
Perth Children's Hospital, 15 Hospital Avenue, Nedlands WA 6009
Country 131982 0
Australia
Phone 131982 0
+61864562222
Fax 131982 0
Email 131982 0
marianne.phillips@health.wa.gov.au
Contact person for public queries
Name 131983 0
Marianne Phillips
Address 131983 0
Perth Children's Hospital, 15 Hospital Avenue, Nedlands WA 6009
Country 131983 0
Australia
Phone 131983 0
+61864562222
Fax 131983 0
Email 131983 0
marianne.phillips@health.wa.gov.au
Contact person for scientific queries
Name 131984 0
Marianne Phillips
Address 131984 0
Perth Children's Hospital, 15 Hospital Avenue, Nedlands WA 6009
Country 131984 0
Australia
Phone 131984 0
+61864562222
Fax 131984 0
Email 131984 0
marianne.phillips@health.wa.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 conferences 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 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.