Abstract LB-318: Pediatric Preclinical Testing Program (PPTP) evaluation of the JAK inhibitor AZD1480

Abstract

Abstract Background: AZD1480 is a potent, competitive small molecule inhibitor of JAK1/2 kinase that has entered clinical evaluation. JAK inhibition is of particular pediatric interest given the activating JAK1/2 mutations observed in a subset of pediatric ALL cases. The activity of AZD1480 was evaluated against the PPTP's in vitro and in vivo panels. Methods: AZD1480 (provided by AstraZeneca) was tested in vitro at concentrations from 1.0 nM to 10.0 µM. It was evaluated against solid tumor xenografts at 60 mg/kg administered by oral gavage daily x 5 for 3 weeks, with a total treatment and observation period of 6 weeks. For the ALL panel (using NOD-SCID mice), the maximum tolerated dose was lower, and a twice daily schedule was utilized: 10 mg/kg BID (with a single daily dose of 15 mg/kg on weekends). Standard PPTP measures of in vivo antitumor activity were employed to assess response to AZD1480. Results: The median relative IC50 (rIC50) for AZD1480 against the PPTP cell lines was 1.5 µM, with a range from 0.3 µM to 5.9 µM. AZD1480 induced significant differences in EFS distribution compared to control in 25 of 27 (93%) evaluable solid tumor xenografts. AZD1480 induced tumor growth inhibition meeting criteria for intermediate or high EFS T/C activity in 11 of 26 (42%) solid tumor xenografts evaluable for this measure. Both Wilms tumor xenografts tested showed EFS T/C > 2, as did 2 of 4 GBM xenografts and 2 of 4 neuroblastoma xenografts. An objective response was observed for 1 solid tumor xenograft, a Wilms tumor xenograft KT-10 that achieved a maintained complete response (MCR). Many solid tumor xenografts show phospho-STAT3 expression, but this marker showed no discernible relationship with response to AZD1480. For the ALL panel, 5 JAK mutated xenografts (3 JAK2 and 2 JAK1) were selected for testing to determine whether AZD1480 shows high activity in models in which the JAK-STAT pathway is activated by mutation. Additionally, 4 non-JAK mutated xenografts were evaluated. Models with JAK mutations show phospho-STAT5 as evidence of JAK-STAT signaling. However, the only ALL xenograft with EFS T/C > 2 was a JAK2 mutant (R867Q) xenograft, TGT-20, and no models showed objective responses (PR or CR). Conclusions: AZD1480 showed tumor growth inhibitory activity against most of the solid tumor xenografts, and induced an objective response (an MCR) in a single Wilms tumor xenograft. Genomic sequencing is being undertaken to determine whether this xenograft has a genomic alteration(s) in a JAK family kinase or another kinase that may explain its favorable response. No objective responses were noted for the ALL panel, even among xenografts with JAK mutations. Our results suggest that inhibition of JAK signaling alone may not be sufficient for clinical activity against JAK-mutated ALL. (Supported by NCI NO1CM42216) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-318. doi:1538-7445.AM2012-LB-318