axitinib and oral metronomic etoposide for pediatric children and aya refractory/relapsing medulloblastoma and ependymoma

Conditions: Medulloblastoma; Ependymoma

Summary: it is an open multicentric phase i/ii trial with axitinib (inlyta®) and metronomic delivery of etoposide for children, adolescent and young adults (aya) with refractory/ relapsing solid tumors. it is a two-stage trial: first stage: to determine the maximum tolerated dose (mtd) of the combination of axitinib and oral metronomic etoposide for patient with medulloblastoma or ependymoma second stage: extension cohort evaluating the preliminary efficacy at the recommended dose for the phase ii (rdp2) of the combination. the 2nd stage will start after a meeting of independent data monitoring committee (idmc). two cohorts of 9 patients with ependymoma and medulloblastoma patients treated at first stage won't be included in the second stage.


Eligibility criteria:
inclusion criteria: * histologically proven diagnosis of ependymoma or medulloblastoma * methyloma classification performed or available material for methyloma analysis * confirmed progressive or refractory disease despite standard therapy, or for which no effective standard therapy exists * male and female subjects with \> 4 to ≤ 25 years of age at inclusion * weight \> 20 kg * evaluable target lesion(s) according to rapno * performance status: karnofsky performance status (for patients \>12 years of age) or lansky play score (for patients ≤12 years of age) ≥ 70%. patients who are unable to walk because of paralysis or stable neurological disability, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score * life expectancy ≥ 3 months * no known allergy to any of the compounds in the experimental treatment * able to take oral treatments * adequate organ function: hematologic criteria * peripheral absolute neutrophil count (anc) ≥ 1000/mm3 (unsupported) * platelet count ≥ 100,000/mm3 (unsupported) * hemoglobin ≥ 8.0 g/dl (transfusion is allowed) cardiac function * shortening fraction (sf) \>29% and left ventricular ejection fraction (lvef) ≥50% at baseline, as determined by echocardiography (mandatory only for patients who have received cardiotoxic therapy). renal and hepatic function * serum creatinine \< 1.5 x upper limit of normal (uln) for age * total bilirubin \< 1.5 x uln * alanine aminotransferase (alt)/ aspartate aminotransferase (ast)/ \< 2.5 x uln * able to comply with scheduled follow-up and with management of toxicity. * females of child bearing potential must have a negative serum pregnancy test within 7 days prior to initiation of treatment. * sexually active patients must agree to use adequate and appropriate contraception (in accordance with clinical trials facilitation and coordination group (ctfg) recommendations) while on study drug and for 6 months after stopping the study drug. * patient able to comfortably swallow capsules. * written informed consent from parents/legal representative, patient, and age-appropriate assent before any study-specific screening procedures are conducted according to local, regional or national guidelines. * patient affiliated to a social security regimen or beneficiary of the same according to local requirements. non-inclusion criteria * chemotherapy within 21 days of day 1 from the start of study treatment. this period can be shortened in the case of treatment with vincristine (2 weeks) and extended to 6 weeks in the case of treatment with nitrosureas. the period is set to 5 half-lives in the case of targeted therapies or metronomic chemotherapy. the period is set to 2 weeks after bevacizumab administration. evidence of \> grade 1 recent cns hemorrhage on the baseline mri or scan. * impairment of gastrointestinal (gi) function or gi disease that may significantly alter drug absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome). * clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 12 months of screening). * known active viral hepatitis or known human immunodeficiency virus (hiv) infection or any other uncontrolled infection. * presence of any nci-ctcae v5 grade ≥ 2 treatment-related extra-hematological toxicity with the exception of alopecia, ototoxicity or peripheral neuropathy. * known congenital immunodeficiency. * radiotherapy within the 2 months preceding d1 of the start of study treatment. palliative rt on a non-target lesion is allowed up to 1 weeks before beginning of treatment. * major surgery within 21 days of the first dose. gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery, but for these procedures, a 48 hour interval must be maintained before the first dose of the investigational drug is administered. * bleeding disorder. * clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 12 months of screening). * known hypersensitivity to any study drug or component of the formulation. * absence of effective contraception in patients of childbearing age (see appendix 3) * pregnant or nursing (lactating) females. * patients with galactose intolerance, lactase deficiency or glucose or galactose malabsorption syndrome (rare hereditary diseases). * severe infections requiring parenteral antibiotic therapy. * inability to undergo medical monitoring of the trial for geographic, social or psychological reasons.