Initial Testing (Stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program

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 mu M) In vivo AZD6244 was tested at a close 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 mu M) AZD6244 only inhibited growth by 50% in 5 of the 23 cell lines Against the in vivo tumor panels, AZD6244 induced significant differences in FFS 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 close and schedule AZD6244 completely inhibited ERK1/2 phosphorylation AZD6244 was evaluated against two IPA 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 close 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 (C) 2010 Wiley-Liss, Inc