AZD1480: A phase I study of a novel JAK2 inhibitor in solid tumors

Background: AZD1480 is a novel agent that inhibits Janus-associated kinases 1 and 2 (JAK1 and JAK2). The primary objec-tive of this phase I study was to investigate the safety and tolerability of AZD1480 when administered as monotherapy to patients with solid tumors. Methods: Thirty-eight patients with advanced malignancies were treated at doses of 10-70 mg once daily (QD) and 20-45 mg b.i.d. Results: Pharmacokinetic (PK) analysis revealed rapid ab-sorption and elimination with minimal accumulation after repeated QD or b.i.d. dosing. Exposure increased in a dose- dependent manner from 10-50 mg. Maximum plasma con-centration (C_max) was attained ~1 hour after dose, and t_1/2 was ~5 hours. Pharmacodynamic analysis of circulating granulocytes demonstrated maximum phosphorylated STAT3 (pSTAT3) inhibition 1-2 hours after dose, coincident with C_max, and greater pSTAT3 inhibition at higher doses. The average pSTAT3 inhibition in granulocytes at the high-est dose tested, 70 mg QD, was 56% (standard deviation: ±21%) at steady-state drug levels. Dose-limiting toxicities (DLTs) consisted of pleiotropic neurologic adverse events (AEs), including dizziness, anxiety, ataxia, memory loss, hal- lucinations, and behavior changes. These AEs were gener-ally reversible with dose reduction or treatment cessation. Conclusions: Whether the DLTs were due to inhibition of JAK-1/2 or to off-target effects is unknown. The unusual DLTs and the lack of clinical activity led to discontinuation of development.