A phase I, open-label, multi-center study of the JAK2 inhibitor AZD1480 in patients with myelofibrosis

Srdan Verstovsek, Ronald Hoffman, John Mascarenhas, Jean Charles Soria, Ratislav Bahleda, Patricia McCoon, Weifeng Tang, Jorge Cortes, Hagop Kantarjian, Vincent Ribrag

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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 2.5-70. mg AZD1480 orally once daily (QD) or 10 or 15. mg twice daily (BID) continuously during repeated 28-day cycles. Two patients experienced dose-limiting toxicities: one patient in the 2.5. mg QD cohort had a grade 3 lung infiltration/acute pneumonia, and one patient receiving 50. mg QD had grade 3 presyncope. Dosing was stopped at 70. mg 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 2.45-8.06. h; 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.

Original languageEnglish (US)
Pages (from-to)157-163
Number of pages7
JournalLeukemia Research
Volume39
Issue number2
DOIs
StatePublished - Feb 1 2015
Externally publishedYes

Keywords

  • AZD1480
  • JAK2 mutation
  • Myelofibrosis

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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