A Phase 2 Study of Alisertib in Children with Recurrent/Refractory Solid Tumors or Leukemia: Children's Oncology Group Phase 1 and Pilot Consortium ADVL0921)
Mené sur 139 enfants et adolescents (âge médian : 10 ans) atteints d'une leucémie aiguë ou d'une tumeur solide récidivante ou réfractaire, cet essai de phase II analyse les caractéristiques pharmacocinétiques de l'alisertib puis évalue son efficacité, du point de vue du taux de réponse objective, et sa toxicité
Background: Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centrosome and spindle maturation. Alisertib (MLN8237) is a potent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816). Procedures: Alisertib (80 mg/m2/dose) was administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A1*28), and plasma pharmacokinetic studies (PK) were performed. Using a two-stage design, patients were enrolled to 12 disease strata (10 solid tumor and 2 acute leukemia). Response was assessed after cycle 1, then every other cycle. Results: A total of 139 children and adolescents (median age 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 µM, exceeding the 1 µM target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed. Conclusion: Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single agent alisertib was less than 5%.