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).
Acknowledgements
The authors would like to thank Ed Hellriegel (Teva Pharmaceuticals) for performing pharmacokinetics measurements, Ipsogen for generously supplying the Ipsogen MutaQuant Kits, and Austin Bailey, PhD and Deborah Kennedy, MD (formerly of Cephalon Oncology) for their facilitation with the study initiation, as well as their expertise and experience with lestaurtinib. We would also like to thank the dedicated research nurses, pharmacists and clinical research associates of the MPD-RC for their hard work and effort in this study.
Potential conflict of interest
Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
This study was supported by the MPD-RC, which is funded by the NCI (P01CA108671). A National Institutes of Health Research Career Development Award supported E. O. Hexner (K23HL093366). Lestaurtinib was supplied to the MPD-RC for this trial by Teva Pharmaceuticals.
Supplementary material available online
Supplementary Methods and Tables I–III showing further data