title: AZD1480: a phase I study of a novel JAK2 inhibitor in solid tumors.
abstract: BACKGROUND
  AZD1480 is a novel agent that inhibits Janus-associated kinases 1 and 2 (JAK1 and JAK2). The primary objective 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 absorption 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 concentration (Cmax) was attained ∼1 hour after dose, and t1/2 was ∼5 hours. Pharmacodynamic analysis of circulating granulocytes demonstrated maximum phosphorylated STAT3 (pSTAT3) inhibition 1-2 hours after dose, coincident with Cmax, and greater pSTAT3 inhibition at higher doses. The average pSTAT3 inhibition in granulocytes at the highest 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, hallucinations, and behavior changes. These AEs were generally 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.
authors.affiliation: Fox Chase Cancer Center, Temple Health, Philadelphia, Pennsylvania 19111, USA. elizabeth.plimack@fccc.edu
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Plimack
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Lorusso
authors.forename: Patricia
authors.initials: P
authors.lastname: McCoon
authors.forename: Weifeng
authors.initials: W
authors.lastname: Tang
authors.forename: Annetta D
authors.initials: AD
authors.lastname: Krebs
authors.forename: Gregory
authors.initials: G
authors.lastname: Curt
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
mesh_terms: D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D015398:Signal Transduction
chemical_list: C545606:AZD 1480; D011720:Pyrazoles; D011743:Pyrimidines; C507924:JAK2 protein, human; D053614:Janus Kinase 2