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).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
35
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.
Medical University of Vienna
Vienna, Austria
Rigshospitalet
Copenhagen, Denmark
Gustave Roussy
Villejuif, Val De Marne, France
University Hospital of Padua
Padua, Italy
Safety Assessment - Dose-Limiting Toxicity (DLT)
Dose-Limiting Toxicity (DLT), assessed over the first 28-day cycle, defined as * Grade \> 3 neutropenia (\<1 x 109/L) for more than 7 days; * Grade \> 2 thrombopenia (\<75 x 109/L) or thrombocytopenia requiring transfusions for more than 7 days. * Grade 3 or grade 4 non-hematological toxicity, excluding grade 3 nausea, vomiting, fever, and hepatic toxicity that is rapidly reversible (i.e. returns to \< 2.5 x ULN within 2 weeks after study drug discontinuation), and symptoms that are related to tumor progression.
Time frame: Assessed over the first 28-day cycle
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Erasmus MC/Sophia Children's Hospital
Rotterdam, Netherlands
Fundació Sant Joan de Déu
Barcelona, Spain
Swiss Pediatric Oncology Group
Bern, Switzerland
Cancer Research UK Clinical Trials Unit School of Cancer Sciences University of Birmingham
Edgbaston, Birmingham, United Kingdom