Initial testing (stage 1) of AZD6244 (ARRY‐142886) by the pediatric preclinical testing program

Abstract

Background AZD6244 (ARRY‐142886) is a potent small molecule inhibitor of MEK1/2 that is in phase 2 clinical development. Procedures AZD6244 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel (1 nM–10 µM). In vivo AZD6244 was tested at a dose of 100 mg/kg administered orally twice daily 5 days per week for 6 weeks. Subsequently, AZD6244 was evaluated against two juvenile pilocytic astrocytoma (JPA) xenografts using once and twice daily dosing schedules. Phosphorylation of ERK1/2 was used as a surrogate for in vivo inhibition of MEK1/2 was determined by immunoblotting. Results At the highest concentration used in vitro (10 µM) AZD6244 only inhibited growth by 50% in 5 of the 23 cell lines. Against the in vivo tumor panels, AZD6244 induced significant differences in EFS distribution in 10 of 37 (27%) solid tumor models and 0 of 6 acute lymphoblastic leukemia (ALL) models. There were no objective responses. Pharmacodynamic studies indicated at this dose and schedule AZD6244 completely inhibited ERK1/2 phosphorylation. AZD6244 was evaluated against two JPA xenografts, BT‐35 (wild‐type BRAF) and BT‐40 (mutant [V600E] BRAF). BT‐40 xenografts were highly sensitive to AZD6244, whereas BT‐35 xenografts progressed on AZD6244 treatment. Conclusions At the dose and schedule of administration used, AZD6244 as a single agent had limited in vitro and in vivo activity against the PPTP tumor panels despite inhibition of MEK1/2 activity. However, AZD6244 was highly active against BT‐40 JPA xenografts that harbor constitutively activated BRAF, causing complete regressions. Pediatr Blood Cancer. 2010;55:668–677.