title: Phase I evaluation of XL019, an oral, potent, and selective JAK2 inhibitor.
abstract: This phase I study evaluated selective JAK2 inhibitor XL019 in 30 patients with myelofibrosis. The initial dose cohorts were 100, 200, and 300 mg orally on days 1-21 of a 28-day cycle. Central and/or peripheral neurotoxicity developed in all patients. Subsequently, patients were treated on lower doses; neurotoxicity was again observed, leading to study termination. Peripheral neuropathy resolved in 50%, and central neurotoxicity in all patients within months after therapy cessation. Myelosuppression was minimal. The terminal half-life of XL019 was approximately 21 h, with steady state reached by Day 8. International Working Group defined responses were seen in three (10%) patients.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: sverstov@mdanderson.org.
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Tam
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Wadleigh
authors.affiliation: H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Lubomir
authors.initials: L
authors.lastname: Sokol
authors.affiliation: University of California, San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Smith
authors.affiliation: Exelixis, Inc., South San Francisco, CA, USA.
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Bui
authors.affiliation: Exelixis, Inc., South San Francisco, CA, USA.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Song
authors.affiliation: Exelixis, Inc., South San Francisco, CA, USA.
authors.forename: Douglas O
authors.initials: DO
authors.lastname: Clary
authors.affiliation: University of California, San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Olszynski
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: University of California, San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D057239:Early Termination of Clinical Trials; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020258:Neurotoxicity Syndromes / Q000175:diagnosis / Q000209:etiology*; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011392:Proline / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C587876:XL019 compound; D011392:Proline; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: Inhibitor; JAK2; Mutation; Myelofibrosis; XL019