Open AccessPhase I study of vinblastine in combination with nilotinib in children, adolescents, and young adults with refractory or recurrent low-grade glioma
Author(s) -
Stéphanie Vairy,
Gwénaël Le Teuff,
Francisco Bautista,
Emilie De Carli,
AnneIsabelle Bertozzi,
Anne Pagnier,
Fanny Fouyssac,
Karsten Nysom,
Isabelle Aerts,
Pierre Leblond,
Frédéric Millot,
Claire Berger,
Sandra Canale,
Angélo Paci,
Vianney Poinsig,
Astrid Chevance,
Monia Ezzalfani,
Dominique Vidaud,
Angela Di Giannatale,
Raquel Hladun-Álvaro,
François Petit,
Gilles Vassal,
Birgit Geoerger,
MarieCécile Le Deley,
Jacques Grill
Publication year - 2020
Publication title -
neuro-oncology advances
Language(s) - English
Resource type - Journals
ISSN - 2632-2498
DOI - 10.1093/noajnl/vdaa075
Subject(s) - medicine , nilotinib , vinblastine , refractory (planetary science) , gastroenterology , progression free survival , hazard ratio , oncology , surgery , confidence interval , chemotherapy , tyrosine kinase , physics , receptor , astrobiology
Background New rescue regimens are needed for pediatric refractory/recurrent low-grade glioma. Nilotinib is a tyrosine kinase inhibitor that has potential synergistic effects with vinblastine on angiogenesis, tumor cell growth, and immunomodulation. Methods This phase I trial aimed to determine the recommended doses of this combination for phase II trials (RP2D) using the dual-agent Bayesian continual reassessment method. Nilotinib was given orally twice daily (BID) in combination with once-weekly vinblastine injections for a maximum of 12 cycles of 28 days (clinicaltrials.gov, NCT01884922). Results Thirty-five pediatric patients were enrolled across 4 dose levels. The median age was 7 years and 10 had neurofibromatosis type 1. Patients had received a median of 3 prior treatment lines and 25% had received more than 4 previous treatment lines. Dose-limiting toxicity (DLT) during cycle 1 was hematologic, dermatologic, and cardiovascular. The RP2D was identified at 3 mg/m 2 weekly for vinblastine with 230 mg/m 2 BID for nilotinib (estimated probability of DLT = 18%; 95% credibility interval, 7–29%). Fifteen patients completed the 12 cycles; 2 stopped therapy prematurely due to toxicity and 18 due to disease progression. Three patients achieved a partial response leading to an objective response rate of 8.8% (95% confidence interval [CI], 1.9–23.7), and the disease control rate was 85.3% (95% CI, 68.9–95.1). The 12-month progression-free survival was 37.1% (95% CI, 23.2–53.67). Conclusions Vinblastine and nilotinib combination was mostly limited by myelosuppression and dermatologic toxicity. The efficacy of the combination at the RP2D is currently evaluated in a randomized phase II trial comparing this regimen to vinblastine alone.