Phase II Trial of Oral Vinorelbine in Children With Recurrent or Progressive Unresectable Low-Grade Glioma

Study Overview
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Brief Summary
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The purpose of this study is to determine whether oral vinorelbine is effective in the treatment of children with progressive or recurrent unresectable low grade glioma.

Detailed Description
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The aim of this study is to determine efficacy of oral vinorelbine in children with progressive or recurrent unresectable low grade glioma, in addition to safety, pharmacokinetic, pharmacogenetic, medical costs and quality of life.

Official Title
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Phase II Trial of Oral Vinorelbine in Children With Recurrent or Progressive Unresectable Low-Grade Glioma

Conditions
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Low-Grade Glioma

Intervention / Treatment
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* Drug: ORAL VINORELBINE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: TUMOR CHARACTERISTICS: Histologically confirmed recurrent or progressive primary Low-Grade Glioma (LGG) defined as follow (WHO classification 2007): optic pathway glioma (OPG), pilocytic astrocytoma (PA), fibrillary or diffuse astrocytoma (DA), oligodendroglioma (OG) or oligoastrocytoma (OA) Patients with OPG do not require biopsy confirmation of disease, if clinical and radiological findings as well as ophthalmological examination are unequivocal Low-Grade Glioma involving the brainstem can be included in case of histological confirmation Tumor has to be considered as non totally resectable PATIENT CHARACTERISTICS: Age 6-18 years old Lansky or Karnofsky status more than 50 % Measurable disease on cerebral and/or spinal MRI, with at least 1 lesion diameter superior to 1 cm Patients with metastatic disease are eligible, but at least 1 lesion must be measurable as previously defined Patients must have received at least 1 prior chemotherapy regimen containing carboplatin Life expectancy of at least 3 months Evidence of adequate organ functions, including: neutrophil count (ANC) ≥ 1500/mm3 , platelet count ≥100 000/mm3 ; serum creatinine < 1.5 x normal for age when the serum creatinine is ≥ 1.5 × the ULN, the glomerular filtration rate (either estimated or formal) must be > 70 mL/min/1.73m2; total bilirubin< 1.5 x normal for age, ASAT and ALAT < 2.5 x normal for age Effective contraception for patients (male and female) with reproductive potential, and for a minimum of 3 months after the end of treatment Negative pregnancy test, if applicable Patients able to swallow capsules Patient affiliated with a health insurance system Written informed consent of patient and/or parents/guardians prior to the study participation. PRIOR OR CONCURRENT THERAPY Prior treatments containing vinca alkaloids like vincristine and/or vinblastine are authorized Patients must have fully recovered from the toxic effects of any prior therapy before entering the study. No organ toxicity superior to grade 2 according to NCI-CTCAE v4.0 An interval of at least 2 months from prior radiotherapy, 6 weeks from nitrosourea chemotherapy, and 4 weeks from other chemotherapy regimen, is required Exclusion Criteria: Inclusion criteria failure Prior treatment with intravenous or oral vinorelbine Known hypersensibility to other vinca-alkaloïdes Digestive pathology affecting absorption in a important way Prior surgical resection of stomach or the small intestine Severe hepatic failure independent from tumoral disease Fructose intolerance Leptomeningeal relapse without any available measurable disease on MRI (for example, leptomeningeal relapse with totally resected primary lesion) Uncontrolled active infection within 2 weeks Pregnancy or breast feeding woman Uncontrolled intercurrent illness or active infection Unsuitable for medical follow-up (geographic, social or mental reasons) Patients requiring long-term oxygen therapy Patients with ANC less than 1500/mm3 Patients vaccinated against yellow fever

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ORAL VINORELBINE<br>Orally vinorelbine 60 mg/m2 D1, 8 and 15 Cycle of 28 days For a maximum of 12 cycles The dose of vinorelbine should be increased to 80 mg/m2 from the 2nd cycle | Drug: ORAL VINORELBINE<br>* Orally vinorelbine 60 mg/m2 D1, 8 and 15 Cycle of 28 days For a maximum of 12 cycles The dose of vinorelbine should be increased to 80 mg/m2 from the 2nd cycle If on D8 and D15, the administration conditions are not met, the administration is canceled and not delayed.<br>* Other names: NAVELBINE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | no progressive disease according to RANO criteria | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Complete, partial and minor responses according to RANO criteria | 6 months | 
| Response rate | Complete, partial and minor responses according to RANO criteria | 12 months | 
| Progression Free Survival PFS | No progressive disease according to RANO criteria | 36 months | 
| Overall Survival OS | Death incidence | 36 months | 
| Growth Modulation Index GMI | GMI defined as PFS2/ PSF1 ratio (PFS2 = PFS since the beginning of study treatment ; PFS1 = PFS observed in previous line of treatment) | 36 months | 
| Adverse events | According to NCI-CTC AE scale v4.0 | 12 months | 
| Modifications of tumor aspects in diffusion and perfusion MRI | Cerebral and/or spinal MRI (morphological and functional) with 2 dimensional assessment of target lesions. | At each tumor assessment, after 3, 6, 9 and 12 cycles of treatment, at the end of study, then every 4 months during the first year post therapy, then every 6 months for 3 years, if no prior progressive disease | 
| Constitutional polymorphisms of cyp3A5, ABCB1 | Single nucleotide polymorphisms (SNPs) will be analyzed by real time PCR and correlated with efficacy and toxicity of vinorelbine | Before the start of treatment | 
| Pharmacokinetic | Plasmatic concentrations measured by LC-MS/MS (liquid chromatography tandem mass spectrometry) ; Area under the curve (AUC), maximal concentration (Cmax), time to Cmax (Tmax). | cycles 1 and 2, prior to the initial dose, 30 min, 1, 1.5, 2, 3, 6, 8, 10 and 26 hours post-dose | 
| Medical costs | Costs of medical care including : hospitalisations, emergency admissions, nursing care at home, medical consultations, diet support... | during all the study (up to 1 year) | 
| Health Utilities Index (HUI) | Health Utilities Index (HUI) | Before the treatment, then at day 1 of 1st cycle, after the 3th, 6th, 9th and the 12th cycles of study treatment, and at the end of study (up to 1 year) |