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 | 18.0 |
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 | 18.0 |
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 | 18.0 |
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 | 18.0 |
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 | 18.0 |
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 | 18.0 |
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 | 18.0 |
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 | 18.0 |
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 | 18.0 |
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 | 18.0 |
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 | 18.0 |
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 | 18.0 |
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 | 18.0 |
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 | 18.0 |
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 | 18.0 |
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 | 18.0 |
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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
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.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The objectives of the study are to compare four chemotherapy regimens in recurrent/refractory ES: cyclophosphamide & topotecan, irinotecan & temozolomide, gemcitabine & docetaxel, and high dose ifosfamide, in order to identify the best one for use as a backbone in future treatment with respect to efficacy (imaging response and survival), toxicity and acceptability to patients. |
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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. |
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E.3 | Principal 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 ≥4 years and <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, where applicable.
8. Written informed consent from the patient and/or legal guardian.
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E.4 | Principal exclusion criteria |
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 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase II: Objective response as measured by RECIST criteria
Phase III: Event-free survival |
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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
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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
Imaging response
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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)
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.
imaging: cycle 2, cycle 6 + End of trial |
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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 | No |
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) | No |
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 | Yes |
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 | 4 |
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 | 18 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 76 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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 | 10 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 28 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 28 |