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Phase I study of vinblastine in combination with nilotinib in children, adolescents, and young adults with refractory or recurrent low-grade glioma

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  • Stephanie Vairy
  • Gwénaël Le Teuff
  • Francisco Bautista
  • Emilie De Carli
  • Anne-Isabelle Bertozzi
  • Anne Pagnier
  • Fanny Fouyssac
  • Karsten Nysom
  • Isabelle Aerts
  • Pierre Leblond
  • Frederic Millot
  • Claire Berger
  • Sandra Canale
  • Angelo Paci
  • Vianney Poinsignon
  • Aurelie Chevance
  • Monia Ezzalfani
  • Dominique Vidaud
  • Angela Di Giannatale
  • Raquel Hladun-Alvaro
  • Francois M Petit
  • Gilles Vassal
  • Birgit Geoerger
  • Marie-Cécile Le Deley
  • Jacques Grill
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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 (, 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/m2 weekly for vinblastine with 230 mg/m2 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.

TidsskriftNeuro-Oncology Advances
Udgave nummer1
Sider (fra-til)vdaa075
StatusUdgivet - 16 jul. 2020

Bibliografisk note

© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

ID: 61992113