E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pediatric Solid tumor |
Tumeurs solide de l'enfant |
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E.1.1.1 | Medical condition in easily understood language |
Children and teenagers with refractory/relapsing solid tumors |
Enfants et adolescents atteints de tumeurs solides réfractaire ou en rechute |
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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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065252 |
E.1.2 | Term | Solid tumor |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary Objective: To determine the Maximal Tolerated Dose (MTD) of oral Navelbine® given thrice a week with daily oral propranolol |
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E.2.2 | Secondary objectives of the trial |
- to determine the dose limiting toxicities (DLT) and tolerance of treatment with single agent metronomic navelbine - To determine the toxicity and tolerance of treatment with oral metronomic vinorelbine and daily propranolol - To determine the recommended dose of both drugs To establish PK of oral Navelbine® given 3 times a week during of the first cycle of treatment and and in combination with propranolol during the second cycle. - To evaluate PFS after 2, 4, 6, 12 months in the entire study population and in each cohort during the extension phase - To determine Response Rates at after 2, 4, 6 and 12 months in the entire study population and in each cohort during the extension phase. - To evaluate OS after 6 and 12 months in the entire study population and in each cohort during the extension phase
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Histologically or cytologically confirmed malignant solid tumour and refractory low grade gliomas and desmoids tumours. - Relapsed or refractory tumours after at least one line of treatment (patients can have been previously treated with oral or IV vinorelbine with a weekly schedule) - Measurable targets - Age > 4 years and < 21 years - Lansky Score > 70 or score OMS < 2. - Life expectancy > 6 months. - Adequate haematological function: neutrophil count ≥ 1.0 x 10 9 /L, platelet count ≥ 75 x 10 9 /L - Creatinine< 1.5X normal value for the age or clearance >70 ml/mn/1.73 m2 - Liver function: Bilirubin < 3N and ALAT and ASAT < 4 N). - Other organ toxicity < Grade 2 according to NCI-CTC version 4.0 - No active infection - Able to comply with scheduled follow-up and with management of toxicity - Capable of swallowing capsules and solution - All patients with reproductive potential must practice an effective method of birth control while on study. Female patients aged > 12 years must have a negative pregnancy test within 7 days before study treatment - Associated disease do not prevent patients to be included in the study - Written informed consent from patient, parents or legal guardian. - Able to comply with follow-up - Affiliated with French social health system - Patients must have recovered from the acute toxic effects of all prior therapy before enrolment into the study |
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E.4 | Principal exclusion criteria |
- Absence of a wash out period of: Page 6 of 22 - 21 days in case of previous chemotherapy or targeted therapy (reduced to 2 weeks in case of treatment vincristine or prolonged to 6 weeks in case of treatment with nitrosurea agents) - 6 weeks in case of prior radiotherapy of the target lesions - Peripheral neuropathy > grade 2 - contra-indication to Propranolol (i.e. asthma, bradycardia, hypotention, decreased SF, ECG-anomalies) - Pregnancy or breast feeding - Known allergy to one of the compounds or their solvents |
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E.5 End points |
E.5.1 | Primary end point(s) |
MTD will be evaluated during the first cycle of treatment (28 days) with the NCI-CTC v4.0 scale and defined as followed : · Grade 3 /4 Neutropenia de grade 3 ou 4 with a delay of treatment of 7 days or more. · Grade 3 /4 Thrombocytopenia requiring blood support for 7 days or more. · Grade 3 /4 non hematological toxicity except : Nausea/vomiting despite adequate supportive care, Reversible Grade 3 fever and grade 3 hepatic toxicity Grade 3 bradycardia |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- PK will be performed using liquid chromatography coupled with mass spectometry (LCMS/MS) for Navelbine® and liquid chromatography and UV detection for Hémangiol® - Efficacy: EFS will be evaluated from entry into the study to the date of progression or death (if related to the tumors or toxicity of treatment. Response Rate will be evaluated according to the RECIST criteria or with specific validated criteria for some tumors (i.e.RANO, INCR) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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 |
First association of two authorized drugs in pediaitric refractory/relapsing solid tumors |
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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 | 8 |
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 | 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 | 36 |
E.8.9.1 | In the Member State concerned days | |