A Phase II Study of Alisertib in Children with Recurrent/Refractory Solid Tumors or Leukemia: Children's Oncology Group Phase I and Pilot Consortium (ADVL0921)

摘要: Purpose: Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centrosome spindle maturation. Alisertib (MLN8237) is a potent selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed neuroblastoma, acute lymphoblastic leukemia, sarcoma xenografts. We conducted phase 2 trial of alisertib patients with refractory or recurrent solid tumors leukemias (NCT01154816). Patients Methods: (80 mg/m2/dose) administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation polymorphisms the AURK gene drug metabolizing enzymes (UGT1A1*28), plasma pharmacokinetic studies (PK) were performed. Using 2-stage design, enrolled to 12 disease strata (10 tumor leukemia). Response assessed after cycle 1, then other cycle. Results: total 139 children adolescents (median age, 10 years) enrolled, 137 evaluable response. Five objective responses (2 complete 3 partial responses). The most frequent toxicity myelosuppression. median trough concentration on day 4 1.3 μmol/L, exceeding 1 μmol/L target 67% patients. No correlations between PG PK observed. Conclusions: Despite xenograft models cogent pharmacokinetic-pharmacodynamic relationships adults, response rate receiving single-agent less than 5%.