Study Of Vinblastine in Combination With Nilotinib in Children, Adolescents and Young Adults
Condition: Refractory Low-grade Gliomas; Recurrent Low-grade Gliomas
MeSH terms: Glioma
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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).
    

Intervention name(s): Nilotinib; Vinblastine
Intervention type(s): Drug; Drug
Intervention description(s): Tasigna®(nilotinib):: 50 mg, 150 mg and 200 mg capsules. Tasigna® capsules contain lactose monohydrate, crospovidone, poloxamer, colloidal silicon dioxide and magnesium. Orally; the capsules should be swallowed as a whole with water. No food should be consumed for 2 hours before the dose is taken and for at least one hour thereafter. For patients who are unable to swallow capsules, the content of each capsule may be dispersed in one teaspoon of apple sauce or compote or nonfat plain yogurt and should be taken immediately. Not more than one teaspoon of apple sauce / yogourt, and no food other than apple sauce or nonfat plain yogurt must be used.; Vinblastine: 3 to 6 mg/m2 once weekly in a 15-minute infusion, on Days 1, 8, 15 and 22 of each cycle.
Each 28-day cycle is repeated on Day 29/Day 1. No intra-patient doseescalation is permitted. Dose allocation will be centrally defined, based on toxicity observed in patients previously evaluated. Every new patient will be treated at the best current recommended dose, i.e. the dose associated with an estimated level of toxicity that is judged acceptable (20% DLT). At least two patients fully observed with no DLT are requested at a given dose level before dose escalation.
Other intervention name(s): Tasigna®
Intervention MeSH terms: Vinblastine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Children; adolescents; young adults