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Leuk Lymphoma. 2015;56(9):2543-51. doi: 10.3109/10428194.2014.1001986. Epub 2015 Feb 20.

Phase I dose escalation study of lestaurtinib in patients with myelofibrosis.

Author information

1
a Abramson Cancer Center at the University of Pennsylvania , Philadelphia , PA , USA.
2
b Tisch Cancer Center, Icahn School of Medicine at Mount Sinai , New York , NY , USA.
3
c University of Utah , Salt Lake City , UT , USA.
4
d Weill Cornell Medical College and New York Presbyterian Hospital , New York , NY , USA.
5
e Greenbaum Cancer Center, University of Maryland , Baltimore , MD , USA.
6
f Palo Alto Medical Foundation , Palo Alto , CA , USA.
7
g Population Health & Environmental Medicine, New York University , New York , NY , USA.
8
h Myeloproliferative Disorders Laboratory, New York Blood Center , New York , NY , USA.
9
i Section of Molecular Hematology , Department of Hematology/Oncology , University Medical Center Freiburg , Freiburg , Germany.
10
j Hematology-Oncology Therapeutic Delivery Unit, Quintiles SpA , Milan , Italy.

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).

KEYWORDS:

JAK2V617F; Lestuartinib; myelofibrosis; pharmacodynamics; pharmacokinetics; phase I trial

PMID:
25563429
PMCID:
PMC5665563
DOI:
10.3109/10428194.2014.1001986
[Indexed for MEDLINE]
Free PMC Article

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