title: A phase I, open-label, multi-center study of the JAK2 inhibitor AZD1480 in patients with myelofibrosis.
abstract: The anti-tumor activity of AZD1480, a potent, selective inhibitor of Janus-associated kinases 1 and 2, was demonstrated in preclinical models of myeloproliferative neoplasms. In a phase I clinical study, 35 patients with myelofibrosis received 2.5-70mg AZD1480 orally once daily (QD) or 10 or 15mg twice daily (BID) continuously during repeated 28-day cycles. Two patients experienced dose-limiting toxicities: one patient in the 2.5mg QD cohort had a grade 3 lung infiltration/acute pneumonia, and one patient receiving 50mg QD had grade 3 presyncope. Dosing was stopped at 70mg QD after the first patient experienced an adverse neurological event (AE) and evidence of low-grade neurological toxicity in patients on lower doses after the initial month of therapy became apparent. The most common AZD1480-related AEs were dizziness and anemia. AZD1480 was absorbed quickly and eliminated from the plasma rapidly, with a mean terminal half-life of 2.45-8.06h; accumulation was not observed after repeated daily dosing for 28 days. Four patients showed evidence of clinical improvement based on IWG-MRT 2006 criteria. AZD1480 was relatively well tolerated, however, low-grade, reversible neurological toxicity was therapy limiting and led to study termination.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Hoffman
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: John
authors.initials: J
authors.lastname: Mascarenhas
authors.affiliation: Institut de Cancérologie Gustave Roussy, Villejuif Cedex, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.affiliation: Institut de Cancérologie Gustave Roussy, Villejuif Cedex, France.
authors.forename: Ratislav
authors.initials: R
authors.lastname: Bahleda
authors.affiliation: AstraZeneca, Boston, MA, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: McCoon
authors.affiliation: AstraZeneca, Wilmington, DE, USA.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: Institut de Cancérologie Gustave Roussy, Villejuif Cedex, France. Electronic address: ribrag@igf.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Ribrag
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D004244:Dizziness / Q000139:chemically induced; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000201:enzymology; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: C545606:AZD 1480; D011720:Pyrazoles; D011743:Pyrimidines; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: AZD1480; JAK2 mutation; Myelofibrosis