E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Recurrent and refractory Ewing sarcoma |
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E.1.1.1 | Medical condition in easily understood language |
Ewing sarcoma, a type of bone cancer, that has either grown during initial treatment or has grown after the end of treatment. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10015560 |
E.1.2 | Term | Ewing's sarcoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10015564 |
E.1.2 | Term | Ewing's sarcoma recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 27.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10015569 |
E.1.2 | Term | Ewing's tumor recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 27.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058252 |
E.1.2 | Term | Ewing's tumour recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10015764 |
E.1.2 | Term | Extra-osseous Ewing's sarcoma recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10015763 |
E.1.2 | Term | Extra-osseous Ewing's sarcoma NOS |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 27.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10015761 |
E.1.2 | Term | Extra-osseous Ewing's sarcoma metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 27.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10015762 |
E.1.2 | Term | Extra-osseous Ewing's sarcoma non-metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10015570 |
E.1.2 | Term | Ewing's tumour |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 27.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058254 |
E.1.2 | Term | Ewing's tumour localised |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 27.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058253 |
E.1.2 | Term | Ewing's tumour metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10015759 |
E.1.2 | Term | Extra-osseous Ewing's sarcoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 27.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10015566 |
E.1.2 | Term | Ewing's tumor |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 27.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10015567 |
E.1.2 | Term | Ewing's tumor localized |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 27.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10015568 |
E.1.2 | Term | Ewing's tumor metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 27.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10015562 |
E.1.2 | Term | Ewing's sarcoma metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10015563 |
E.1.2 | Term | Ewing's sarcoma NOS |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
In recurrent and refractory Ewing sarcoma, which of the most commonly used chemotherapy regimens is the best to use in future treatment with respect to tumour shrinkage, survival, side effects and acceptability to patients?
In the first stage this will be assessed primarily by measuring tumour shrinkage measured by scans after 4 cycles of chemotherapy. In the second stage effectiveness will be assessed primarily by seeing which regimen is best at stopping tumours from growing.
We will also measure overall survival, side effects, tumour shrinkage after 2 and 6 cycles and at the end of treatment, quality of life and days spent in hospital.
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PET-CT Positron Emission Tomography (PET) CT is not mandatory however centres that use PET to evaluate metastatic disease at baseline should repeat after cycle 4
Quality of Life The Quality of Life analysis in the rEECur trial will not be opened in EU countries for which the questionnaires have not been translated and validated. For that reason the Quality of Life analysis is included in the protocol as a sub-study. However, for UK participants the quality of life analysis is be an integral part of the study. It is incorporated as a section within the main protocol, with the same date and version number as the main protocol.
Biological Studies Biological studies have now been included within the rEECur trial. Providing samples is optional and will require patient consent. The sub study details have been included in version 4.0 of the protocol (29-Feb-2016) The objective of the biological studies is to identify informative prognostic bio-markers for assessment of disease status and response at diagnosis/ prior to cycle 1 and throughout the disease course.
Lenvatinib pharmacokinetics |
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E.3 | Principal 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 ≥ 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. For the IFOS-lenvatinib arm: Adequate liver function , Left ventricular ejection fraction ≥50% at baseline as determined by echocardiography, Normal or adequately controlled blood pressure (BP) |
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E.4 | Principal exclusion criteria |
1. For the IFOS.-lenvatib arm: Significant proteinuria (defined in main protocol eligibility criteria), Arterial Thromboembolism in previous 6 months, Gastrointestinal bleeding or active haemoptysis within previous 3 weeks , Major surgery within previous 3 weeks , Previous treatment with tyrosine kinase inhibitors 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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.
The primary outcome measure of the 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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E.5.2 | Secondary end point(s) |
Progression-free survival (PFS) Overall survival (OS) Quality of Life (QoL) Adverse events and toxicity, defined by NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0 Days spent in hospital Objectine imaging response (OR) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PFS and OS will be assessed at every clinic visit QoL will be assessed at baseline and after 2 and 4 cycles of chemotherapy Adverse events, toxicity and 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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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 93 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
New Zealand |
Switzerland |
Australia |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 13 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 13 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 30 |