title: Phase I dose escalation study of lestaurtinib in patients with myelofibrosis.
abstract: We performed a multicenter, investigator initiated, phase I dose escalation study of the oral multi-kinase inhibitor lestaurtinib in patients with JAK2V617F positive myelofibrosis, irrespective of baseline platelet count. A total of 34 patients were enrolled. Dose-limiting toxicities were observed in three patients overall, at the 100 mg (n = 1) and 160 mg (n = 2) twice-daily dose levels. The maximum tolerated dose was 140 mg twice daily. Gastrointestinal toxicity was the most common adverse event. Sixteen patients were evaluable for response at 12 weeks. Seven patients had clinical improvement by International Working Group - Myeloproliferative Neoplasms Research and Treatment criteria. Meaningful reductions in JAK2V617F allele burden were not observed. To measure JAK2 inhibition in vivo, plasma from treated patients was assayed for its ability to inhibit phosphorylation of signal transducer and activator of transcription 5 (STAT5): doses lower than 140 mg had variable and incomplete inhibition. In this phase I study, although gastrointestinal adverse events were common, significant clinical activity with lestaurtinib was observed (ClinicalTrials.gov identifier: NCT00668421).
authors.affiliation: a Abramson Cancer Center at the University of Pennsylvania , Philadelphia , PA , USA.
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Hexner
authors.affiliation: b Tisch Cancer Center, Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: John
authors.initials: J
authors.lastname: Mascarenhas
authors.affiliation: c University of Utah , Salt Lake City , UT , USA.
authors.forename: Josef
authors.initials: J
authors.lastname: Prchal
authors.affiliation: d Weill Cornell Medical College and New York Presbyterian Hospital , New York , NY , USA.
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Roboz
authors.affiliation: e Greenbaum Cancer Center, University of Maryland , Baltimore , MD , USA.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
authors.affiliation: d Weill Cornell Medical College and New York Presbyterian Hospital , New York , NY , USA.
authors.forename: Ellen K
authors.initials: EK
authors.lastname: Ritchie
authors.affiliation: f Palo Alto Medical Foundation , Palo Alto , CA , USA.
authors.forename: David
authors.initials: D
authors.lastname: Leibowitz
authors.affiliation: b Tisch Cancer Center, Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Erin P
authors.initials: EP
authors.lastname: Demakos
authors.affiliation: b Tisch Cancer Center, Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Crystal
authors.initials: C
authors.lastname: Miller
authors.affiliation: b Tisch Cancer Center, Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: James
authors.initials: J
authors.lastname: Siuty
authors.affiliation: b Tisch Cancer Center, Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Kleczko
authors.affiliation: g Population Health & Environmental Medicine, New York University , New York , NY , USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Price
authors.affiliation: a Abramson Cancer Center at the University of Pennsylvania , Philadelphia , PA , USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Jeschke
authors.affiliation: h Myeloproliferative Disorders Laboratory, New York Blood Center , New York , NY , USA.
authors.forename: Rona
authors.initials: R
authors.lastname: Weinberg
authors.affiliation: i Section of Molecular Hematology , Department of Hematology/Oncology , University Medical Center Freiburg , Freiburg , Germany.
authors.forename: Titiksha
authors.initials: T
authors.lastname: Basu
authors.affiliation: i Section of Molecular Hematology , Department of Hematology/Oncology , University Medical Center Freiburg , Freiburg , Germany.
authors.forename: Heike L
authors.initials: HL
authors.lastname: Pahl
authors.affiliation: d Weill Cornell Medical College and New York Presbyterian Hospital , New York , NY , USA.
authors.forename: Attilio
authors.initials: A
authors.lastname: Orazi
authors.affiliation: b Tisch Cancer Center, Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Vesna
authors.initials: V
authors.lastname: Najfeld
authors.affiliation: j Hematology-Oncology Therapeutic Delivery Unit, Quintiles SpA , Milan , Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Marchioli
authors.affiliation: g Population Health & Environmental Medicine, New York University , New York , NY , USA.
authors.forename: Judith D
authors.initials: JD
authors.lastname: Goldberg
authors.affiliation: b Tisch Cancer Center, Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Silverman
authors.affiliation: b Tisch Cancer Center, Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Hoffman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002227:Carbazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005663:Furans; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000235:genetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D002227:Carbazoles; D005663:Furans; C119379:lestaurtinib; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: JAK2V617F; Lestuartinib; myelofibrosis; pharmacodynamics; pharmacokinetics; phase I trial