Phase I study of vinblastine in combination with nilotinib in children, adolescents, and young adults with refractory or recurrent low-grade glioma. Issue 1 (9th June 2020)

• Record Type: Journal Article
• Authors: Vairy, Stephanie; Le Teuff, Gwénaël; Bautista, Francisco; De Carli, Emilie; Bertozzi, Anne-Isabelle; Pagnier, Anne; Fouyssac, Fanny; Nysom, Karsten; Aerts, Isabelle; Leblond, Pierre; Millot, Frederic; Berger, Claire; Canale, Sandra; Paci, Angelo; Poinsignon, Vianney; Chevance, Aurelie; Ezzalfani, Monia; Vidaud, Dominique; Di Giannatale, Angela; Hladun-Alvaro, Raquel; Petit, Francois M; Vassal, Gilles; Geoerger, Birgit; Le Deley, Marie-Cécile; Grill, Jacques
• Is Part Of: Neuro-oncology advances. Volume 2:Issue 1(2020)
• Publication Date: 2020-06-09
• Subjects: Gilbert disease -- neurofibromatosis type 1 -- pharmacogenomics -- pharmacokinetics -- pilocytic astrocytoma; 616.99481
• DOI: 10.1093/noajnl/vdaa075
• Languages: English
• ISSNs: 2632-2498

Abstract

Abstract: 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.