Study Of Vinblastine in Combination With Nilotinib in Children, Adolescents and Young Adults
Study Of Vinblastine in Combination With Nilotinib in Children, Adolescents and Young Adults
Multicenter, open label, prospective study including successively a phase I trial and then a
 phase II trial Phase I : Open label, non-randomized, sequential dose escalation of both
 drugs, vinblastine and nilotinib.
Low grade gliomas (LGG) are the most frequent brain tumor type in children. They are often
 chemosensitive. However, more than 50% of these tumors will progress within the first 5 years
 after the start of the treatment and need a second-line therapy (Laithier, JCO 2003). In most
 cases, patients are still young and the risk of side effects from radiation therapy will call
 for another medical treatment. If a tumor does not respond to first-line chemotherapy, the
 prognosis worsens with 25% of deaths within the first 5 years for optic gliomas (de Haas,
 Pediatr Blood Cancer 2009). Vinblastine (Velbe®) is an effective drug for low grade gliomas
 with both antiproliferative and antiangiogenic effects. An update of the Canadian phase II of
 weekly vinblastine (6 mg/m²/week) reported one complete response (CR), three partial
 responses (PR) and 9 minor responses (MR) in the first 31 patients (Bouffet, Abstract in
 Neuro-Oncology 2008). The 1-year progressionfree survival (PFS) rate was 57%. Tolerance of
 the treatment is fair allowing prolonged maintenance therapy as in Langerhans cell
 histiocytosis and anaplastic large cell lymphoma (ALCL). These data encourage proceeding with
 further testing this approach in pediatric low-grade glioma.

 Nilotinib is a tyrosine kinase inhibitor (TKI) known to affect c-Kit, DDR1 and the PDGF
 receptors alpha and beta. PDGF is a growth factor for normal and tumoral astrocytes and
 oligodendrocytes. In addition, PDGF receptors are expressed on pediatric low-grade glioma
 vessels (McLaughlin, J Pediatr Hematol Oncol 2003; Peyrl, Pediatr Blood Cancer 2009). Tumor
 response to this class of TKI has been reported occasionally (Peyrl, Pediatr Blood Cancer
 2009; McLaughlin, J Pediatr Hematol Oncol 2003). When used as monotherapy, this class of TKI
 was well tolerated in children, including those with brain tumors (Wayne, Blood 2008;
 Baruchel, Eur J Cancer 2009; Geoerger, Eur J Cancer 2009). Taking advantage of their
 different antiangiogenic mechanisms, their limited and non-overlapping toxicities,
 vinblastine and nilotinib could play an interesting role in the treatment of pediatric
 low-grade glioma. Nilotinib via PDGFRA and c-kit interactions may also interfere with the
 stroma of the tumor which is a key factor for tumor growth as shown in the NF1 mouse model
 (Daginakatte, Cancer Res 2008; Kim, Neuroscience 2010; Simmons, J Neuropathol Exp Neurol
 2011). Both drugs have also immunostimulating effects especially in dendritic cells, that
 will be explored during treatment in selected patients (Tanaka, Cancer Res 2009; Nishioka
 Immunotherapy 2011) Previous to the phase II assessing the efficacy of the combination
 compared to vinblastine as single agent, nilotinib and vinblastine have to be administered by
 escalating dosages in order to identify the recommended doses of each agent when given in
 combination. This phase I part of the trial is justified by a possible interaction of the two
 drugs that are substrates of cytochrome P450 CYP3A4. Initial/starting dose of nilotinib (115
 mg/m² BID) will be 50% of the recommended dose when used as monotherapy in adults (800
 mg/day: 400 mg BID =230 mg/m2 BID). Initial/starting dose of vinblastine will be 50% of the
 recommended dose when used as monotherapy or in association with other chemotherapeutic drugs
 (i.e. 3 mg/m2 once a week). This justifies obtaining pharmacokinetic data on both drugs when
 used in combination. A phase I trial evaluating nilotinib as single agent in pediatrics in
 hematological malignancies is ongoing, run by the ITCC and the COG group, exploring the
 dose-levels 230 mg/m² to 460 mg/m² BID. The results of this phase I trial, expected by 2012,
 and the data of the current trial will be considered to decide whether a higher dose-level
 for nilotinib can be opened (350 mg/m² BID).
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)