E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Recurrent or refractory ependymoma |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10014967 |
E.1.2 | Term | Ependymoma |
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 |
If 5-fluorouracil, given as a bolus followed by continuous infusion over 2 days, can reduce tumour burden in children and young adults with recurrent/refractory ependymoma. |
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E.2.2 | Secondary objectives of the trial |
If functional MRI can provide objective biomarkers that correlate with clinical outcome. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Patients aged 1-24 years old at the time of informed consent. - Histological confirmation of ependymoma at the time of initial diagnosis. - Relapsed or progressed disease following previous standard treatment including radiotherapy. N.B.: patients suitable for re-irradiation at the time of relapse might still be eligible for the present study. - Stable neurologic examination. - Measurable disease as per RECIST 1.1. - Life expectancy of ≥ 12 weeks. - Performance status as follows: Lansky scale ≥ 50% for patients <12 years; Karnofsky ≥ 50% for patients ≥12 years. - Adequate bone marrow function at the time of eligibility assessment, defined as per full blood count on peripheral blood. - Adequate liver function at the time of eligibility assessment, defined as per routine liver function tests on peripheral blood. - Adequate renal function, defined as per routine parameters on peripheral blood and Glomerular Filtration Rate estimated by Schwartz formula. - Adequate cardiac function at the time of eligibility assessment, defined as per previous history, physical examination, and ECG. - Negative pregnancy test in female patients of childbearing potential. - Males and females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. - Written informed consent/assent prior to enrolment.
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E.4 | Principal exclusion criteria |
- The patient must not have received, at the time of eligibility assessment: o any myelosuppressive chemotherapy within 3 weeks (exceptions: 6 weeks if prior nitrosourea, or 1 week if low dose metronomic chemotherapy); o any biological agent within 2 weeks; o focal radiotherapy within 4 weeks or craniospinal radiotherapy within 3 months; o any investigational therapy within 4 weeks. Investigational therapy is defined as any medicinal product that is not approved in the UK for any indication. - Concomitant use of dehydropyrimidine dehydrogenase (DPD) inhibitors, such as brivudin, sorivudin and analogues within the previous 4 weeks. - Patients who have an uncontrolled infection. - Known active viral hepatitis, including Hepatitis A, B or C, or known diagnosis of human immunodeficiency virus (HIV) infection. Viral testing is not mandatory. - Pregnant or lactating females. - Low probability of treatment compliance. - Other severe, acute or chronic, medical or psychiatric condition, or laboratory abnormality, that may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for the study.
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall response rate, complete (CR) or partial (PR), after 6 cycles of fluorouracil as per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At baseline and after 6 cycles of chemotherapy (i.e. 12 weeks). |
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E.5.2 | Secondary end point(s) |
Evaluate the safety and tolerability of 5-FU 400 mg/m2 bolus followed by 2,400 mg/m2 in continuous intravenous infusion over 48 hours in children and young adults with relapsed/refractory ependymoma who have received previous radiotherapy. Safety will assessed by the incidence and severity of adverse events (AE) and serious adverse events (SAE), changes in laboratory values, assessments of physical examinations, and vital signs. Incidence and severity of adverse events will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Tolerability will be assessed by the incidence of AEs leading to delay or discontinuation of 5-FU.
As exploratory endpoints we will also preliminarily correlate the overall response rate(ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) with the functional imaging phenotype of the pendymomas before administration of 5-FU and after 6 courses of 5-FU. The imaging phenotype will be defined by: o T1 and T2 relaxation times (s-1); o R2*air (s-1); o iAUC60 (mMol/sec), Ktrans (min-1), Ve (no unit), Kep (min-1), Vp (no unit); o ADC (mm2/sec), ADClow (mm2/sec), ADChigh (mm2/sec); o and Magnetisation Transfer Ratio (%). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary endpoints of the study (safety and tolerability) will be evaluated as a continuum throughout the study. The exploratory functional MRI parameters will be collected at baseline and after 6 cycles of 5-FU. |
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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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
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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For the purposes of the Competent Authorities, the end of trial will be 30 days after the last patient has completed treatment. For the purposes of main REC approval, the trial end date will be the final participant’s last visit (final follow-up visit at 5 years). The CI or trial coordinator will notify the Competent Authorities and Ethics Committees of the end of trial as detailed above. The end of study report will be provided within 12 months of the REC end of study date. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
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 | 1 |