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. 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. 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. 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. Tumor response to this class of TKI has been reported occasionally . When used as
monotherapy, this class of TKI was well tolerated in children, including those with brain
tumors. 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. Both drugs have also immunostimulating effects especially in
dendritic cells, that will be explored during treatment in selected patients. 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
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Progression Free Survival (PFS)
PFS computed as the time interval between the date of study entry and the date of tumor progression or death (whatever the cause of death). The progression will be defined either radiologically (>25% increase in two-dimension measurements or appearance of new lesions compared to the baseline or to the best response after initiation of therapy) or clinically by new symptoms related to tumor progression (significant decrease of visual acuity, new or worsening neurological deficit). Hydrocephaly is not considered as progression per se.
assessed up from randomization to tumor progression or death whatever the cause assessed up to 24 months
No
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 II
NCT01887522
May 2013
May 2019
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