Phase I study of vinblastine in combination with nilotinib in children, adolescents, and young adults with refractory or recurrent low-grade glioma - Prédicteurs moléculaires et nouvelles cibles en oncologie Accéder directement au contenu
Article Dans Une Revue Neuro-Oncology Advances Année : 2020

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

1 PMNCO - Prédicteurs moléculaires et nouvelles cibles en oncologie
2 IGR - Institut Gustave Roussy
3 CESP - Centre de recherche en épidémiologie et santé des populations
4 Universidad de Salamanca
5 CHU Angers - Centre Hospitalier Universitaire d'Angers
6 Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse]
7 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
8 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
9 Institut Curie [Paris]
10 IHOPe - Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL]
11 CIC 1402 - CIC Poitiers – Centre d'investigation clinique de Poitiers
12 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
13 CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
14 EPICEA [CRESS - U1153 / UMR_A 1125] - Epidemiology of childhood and adolescent cancer | Epidémiologie des cancers de l'enfant et de l'adolescent
15 Pharmacologie
16 RaMo-IT - Radiothérapie Moléculaire et Innovation Thérapeutique
17 SBE - Service de biostatistique et d'épidémiologie
18 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
19 Service de Génétique et Biologie Moléculaires [CHU Cochin]
20 EA 7331 - Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux
21 Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy]
22 AP-HP - Hôpital Antoine Béclère [Clamart]
Karsten Nysom
  • Fonction : Auteur
Vianney Poinsignon
  • Fonction : Auteur

Résumé

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/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.
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hal-04515735 , version 1 (04-06-2024)

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Stephanie Vairy, Gwénaël Le Teuff, Francisco Bautista, Emilie de Carli, Anne-Isabelle Bertozzi, et al.. Phase I study of vinblastine in combination with nilotinib in children, adolescents, and young adults with refractory or recurrent low-grade glioma. Neuro-Oncology Advances, 2020, 2 (1), pp.vdaa075. ⟨10.1093/noajnl/vdaa075⟩. ⟨hal-04515735⟩
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