Study Of Vinblastine in Combination With Nilotinib in Children, Adolescents and Young Adults (VINILO)

This is an interventional treatment trial for Refractory Low-grade Gliomas focused on measuring Children, adolescents, young adults Read More

Inclusion Criteria:

1. Written informed consent signed by the patient, or parents or legal representative and assent of the minor child.
2. Age: 6 months to < 21 years of age at time of study entry
3. Histologically confirmed low-grade glioma in non-NF1 patients (no further biopsy is needed at study entry). For patients with NF1 and optic pathway glioma, no biopsy is required to confirm the radiological diagnosis of the low grade glioma.
4. Relapse or refractory tumor after at least one first-line therapy, not taking into account surgery only.
5. Evaluable Disease on morphologic MRI
6. Karnofsky performance status score >=70% for patients >12 years of age, or Lansky score >=70% for patients <=12 years of age, including patients with motor paresis due to disease.
7. Administration of stable dose of steroids for at least one week
8. Life expectancy >= 3 months.

9. Adequate organ function:

   • Adequate hematopoietic function: neutrophils ³1.0 x 109/L, platelets ³100 x 109/L; hemoglobin ³8 g/dL
   • Adequate renal function: serum creatinine < 1.5 x ULN for age In others cases where serum creatinine >1.5 ULN according to age, Glomerular filtration rate or creatinine clearance has to be >70 mL/min/1.73 m2 or >70% of the expected value
   • Adequate electrolytes levels: potassium, magnesium, phosphor, total calcium Lower Limit of Normal (LLN)
   • Adequate hepatic function: total bilirubin <=1.5 x ULN; AST and ALT <=2.5 x ULN.
   • Absence of peripheral neuropathy >= grade 2 (Common Toxicity Criteria Adverse Event, NCI CTCAE v4.0)
   • Adequate cardiac function:

   Shortening Fraction (SF) >= 28% (35% for children <3 years) and Left Ventricular Ejection Fraction (LVEF) >= 50% at baseline, as determined by echocardiography

   Absence of QTc prolongation (QTc > 450 msec on baseline ECG, using the QTcF formula) or other clinically significant ventricular or atrial arrhythmia

10. Wash-out period of at least

    • 3 weeks in case of preliminary chemotherapy,
    • 6 weeks in case of nitrosourea-containing chemotherapy,
    • 2 weeks in the case of treatment with vincristine only
    • 6 weeks in case of radiation therapy
11. Possibility of receiving the therapeutic schedule as indicated in the protocol
12. Patients with reproductive potential must use effective contraception during their treatment and for up to 90 days after the last dose. Females with reproductive potential must have a negative pregnancy test <= 7 days before starting Nilotinib and/or Vinblastine.
13. Patients already treated with one of the two drugs can be enrolled in the trial provided that rechallenging them with the same drug could be considered acceptable

Exclusion Criteria:

1. Concomitant anti-tumor treatment
2. Not recovered to <Grade 2 from the acute toxic effects of all prior chemotherapy, immunotherapy or radiotherapy
3. Known intolerance or hypersensitivity to Vinblastine
4. Existence of another severe systemic disease
5. Uncontrolled infections not responsive to antibiotics, antiviral medicines, or antifungal medicines,
6. Any concurrent illness which in the opinion of the investigator may interfere with the treatment and evaluation of the patient
7. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of nilotinib.
8. Simultaneous treatment with strong cytochromes P450 CYP3A4 inhibitors (e.g. antiepileptic drugs, see complete list in the Appendix 5).
9. Simultaneous treatment with antiarrythmic drugs and other drugs known to prolong QT interval (cloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, cisapride and pimozide). A list of QT prolonging compounds can be found at http://www.azcert.org/medical-pros/druglists/drug-lists.cfm (Appendix 6)

10. Impaired cardiac function including any one of the following:

    • Clinically significant resting brachycardia (<50 beats per minute).
    • QTc > 450 msec on baseline ECG. If QTc >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc.
    • Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension).
    • History of or presence of clinically significant ventricular or atrial tachyarrhythmias (including congenital long QT syndrome or a known family history of congenital long QT syndrome)