PMID- 23847256
OWN - NLM
STAT- MEDLINE
DCOM- 20140317
LR  - 20211021
IS  - 1549-490X (Electronic)
IS  - 1083-7159 (Print)
IS  - 1083-7159 (Linking)
VI  - 18
IP  - 7
DP  - 2013
TI  - AZD1480: a phase I study of a novel JAK2 inhibitor in solid tumors.
PG  - 819-20
LID - 10.1634/theoncologist.2013-0198 [doi]
AB  - 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  approximately 1 hour after dose, and t1/2 was  approximately 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.
FAU - Plimack, Elizabeth R
AU  - Plimack ER
AD  - Fox Chase Cancer Center, Temple Health, Philadelphia, Pennsylvania 19111, USA. 
      elizabeth.plimack@fccc.edu
FAU - Lorusso, Patricia M
AU  - Lorusso PM
FAU - McCoon, Patricia
AU  - McCoon P
FAU - Tang, Weifeng
AU  - Tang W
FAU - Krebs, Annetta D
AU  - Krebs AD
FAU - Curt, Gregory
AU  - Curt G
FAU - Eckhardt, S Gail
AU  - Eckhardt SG
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20130711
PL  - England
TA  - Oncologist
JT  - The oncologist
JID - 9607837
RN  - 0 (AZD 1480)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrimidines)
RN  - EC 2.7.10.2 (JAK2 protein, human)
RN  - EC 2.7.10.2 (Janus Kinase 2)
SB  - IM
MH  - Dose-Response Relationship, Drug
MH  - Drug-Related Side Effects and Adverse Reactions/classification/pathology
MH  - Female
MH  - Humans
MH  - Janus Kinase 2/*antagonists & inhibitors/genetics
MH  - Male
MH  - Neoplasms/*drug therapy/genetics/pathology
MH  - Pyrazoles/*administration & dosage
MH  - Pyrimidines/*administration & dosage
MH  - Signal Transduction
PMC - PMC3720635
COIS- Disclosures of potential conflicts of interest may be found at the end of this 
      article.
EDAT- 2013/07/13 06:00
MHDA- 2014/03/19 06:00
PMCR- 2014/07/01
CRDT- 2013/07/13 06:00
PHST- 2013/07/13 06:00 [entrez]
PHST- 2013/07/13 06:00 [pubmed]
PHST- 2014/03/19 06:00 [medline]
PHST- 2014/07/01 00:00 [pmc-release]
AID - theoncologist.2013-0198 [pii]
AID - 3842329 [pii]
AID - 10.1634/theoncologist.2013-0198 [doi]
PST - ppublish
SO  - Oncologist. 2013;18(7):819-20. doi: 10.1634/theoncologist.2013-0198. Epub 2013 
      Jul 11.