E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Different pediatric cancers such as malignant glioma and also relapsed or refractory neuroblastoma, rhabdomyosarcoma, medulloblastoma, and Ewing sarcoma, for which treatment with the cytotoxic temozolomide is recommended as per treatment guidelines. |
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E.1.1.1 | Medical condition in easily understood language |
Different pediatric cancers for which treatment with the anticancer temozolomide is recommended as per treatment guidelines |
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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 | SOC |
E.1.2 | Classification code | 10029104 |
E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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 | 10018337 |
E.1.2 | Term | Glioblastoma multiforme |
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 | 10029260 |
E.1.2 | Term | Neuroblastoma |
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 | 10039022 |
E.1.2 | Term | Rhabdomyosarcoma |
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 | 10027107 |
E.1.2 | Term | Medulloblastoma |
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 |
Evaluate pharmacokinetic parameters of the oral suspension of temozolomide in the paediatric population aged 1 year and over |
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E.2.2 | Secondary objectives of the trial |
Evaluate the safety of the oral suspension of temozolomide, Evaluate the acceptability of the oral suspension of temozolomide. Describe the activity of the oral suspension of temozolomide over the course of a 6-month-treatment period (complete or partial response, disease progression, stable disease) according to the standard follow up exams and tests recommended for each indication
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Paediatric patients in need of temozolomide (all indications with 5-day treatment per 21- or 28-day cycle). • Male and female patients aged 1 to less than 18 years • Patients who have signed the informed consent or for which one, both parents or legal guardian (depending on local legislation) have signed the informed consent. • Patients having records of coverage by a health insurance • Life expectancy ≥ 3 months • Adequate haematological function: o haemoglobin ≥ 80 g/L (transfusion support authorized) o neutrophil count ≥ 1.0 x 10e9 cells/L o platelet count ≥ 100 x 10e9 cells/L (without transfusion support) o in case of bone marrow involvement: neutrophils ≥ 0.5 x 10e9 cells/L and platelets ≥75 x 10e9 cells/L • Adequate renal function: o Creatine clearance ≥ 60 mL/min.1.73m² according to the Schwartz formula [1] or its modified form [2] • Adequate hepatic function: o bilirubin ≤1.5 x ULN o AST and ALT ≤ 2.5 x ULN (AST, ALT 5xULN in case of liver metastases) • Lansky Score ≥ 70% |
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E.4 | Principal exclusion criteria |
• Patients who are co-administrated at day one with sodium valproate as it decreases the clearance of temozolomide • Patients with (naso)gastric tube administration of temozolomide during first cycle of treatment • Patients already enrolled in studies investigating temozolomide or other investigational new drugs • A post-menarche female with a positive blood/urine pregnancy test at inclusion • Known contraindication or hypersensitivity to temozolomide or any chemically close substance
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint: Investigated PK parameters will be TMZ apparent clearance (CL/F), distribution volume (V/F) and absorption rate constant (Ka). These PK parameters will be used to derive key estimates of exposure such as TMZ area under the curve between 2 intakes (AUC0-t) and, if feasible, maximum concentration (Cmax) for each included subject and elimination half-life (t1/2), and the total AUC0-∞. Population PK parameters will be estimated by a population analysis performed with NONMEM (7.4). Individual Bayesian estimates of the PK parameters will be used to calculate individual AUC24, Cmax, and t1/2. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
A total of 6 blood samples of 1 ml will be drawn per patient in a single daytime hospitalisation. Blood samples will be collected in prechilled K2-EDTA tubes prior to Kimozo administration and at 0.10-0.20 (6-12 min), 0.33-0.66 (20-40 min), 0.75-1.5 (45-90 min), 2.0-3.0 and 6.0-8.0 hours post-dose. The administered dose and exact time for each sample will be recorded. Should a patient be naïve to any prior treatment with TMZ, the pre-treatment sample is not necessary. |
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E.5.2 | Secondary end point(s) |
Secondary endpoints: • Acceptability The acceptability of the oral suspension of temozolomide will be scored with a standardized assessment tool: CAST - ClinSearch Acceptability Score Test. This tool measures 9 observational drivers of medicine acceptability. • Safety All Safety events will be collected throughout the study, including buccal tolerance • Activity The clinical activity of the oral suspension of temozolomide during the compassionate use period will be described according to the standard follow-up exams and tests (i.e. complete or partial response, disease progression, stable disease) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints: • Acceptability A paper diary will be filled-in to assess palatability/acceptability of the oral suspension of temozolomide. • Safety Safety events recorded by the caregiver in the patient diary will be medically controlled on a monthly basis by the principal investigator. Safety follow-up during the 1st cycle : 21 or 28 days, including buccal tolerance at day 5 and until day 21 or 28 Safety follow-up during the compassionate-use period for 5 potential additional treatment cycles. • Activity The clinical activity during the compassionate use period will be assessed when planned for the standard follow-up exams and tests |
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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 | No |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
population pharmacokinetic study |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 | 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 | |
E.8.9.1 | In the Member State concerned months | 18 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 18 |