PHASE I-II STUDY OF VINBLASTINE IN COMBINATION WITH NILOTINIB IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH REFRACTORY OR RECURRENT LOW-GRADE GLIOMA
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).
Interventional
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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.
Assessed over the first 28-day cycle
Yes
Jacques GRILL, MD
Study Chair
Gustave Roussy, Cancer Campus, Grand Paris
France: Agence Nationale de Sécurité du Médicament et des produits de santé
2012-003005-10 Phase I
NCT01884922
May 2013
May 2019
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