Axitinib and Oral Metronomic Etoposide for Pediatric Children and AYA Refractory/Relapsing Medulloblastoma and Ependymoma

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.