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).

Keywords: JAK2V617F; Lestuartinib; myelofibrosis; pharmacodynamics; pharmacokinetics; phase I trial.

Conflict of interest statement

Disclosures of Potential Conflicts of Interest

The authors have no other relevant conflicts of interest to disclose.

Figures

Figure 1. Percent change in baseline palpable spleen length at week 12

Waterfall plot demonstrating percent change in palpable spleen length for each subject at week 12 and colored coded by dose level. A negative percent change indicates a reduction in spleen length. Fifteen patients with baseline palpable splenomegaly were evaluable for this analysis at week 12 of lestaurtinib treatment.

Figure 2. Plasma Concentration of lestaurtinib

Trough levels of lestaurtinib were measured in treated patients by HPLC with fluorescence detection. A: Mean and standard error are presented for each dose administered at time of collection (n = 24: n=2 at 60 and 80 mg; 3 at 100 mg, 5 at 120 mg, 9 at 140 mg and 3 at 160 mg). B: Plasma concentration plotted against spleen response at 3 months (n=12; p = 0.2964).

Figure 2. Plasma Concentration of lestaurtinib

Trough levels of lestaurtinib were measured in treated patients by HPLC with fluorescence detection. A: Mean and standard error are presented for each dose administered at time of collection (n = 24: n=2 at 60 and 80 mg; 3 at 100 mg, 5 at 120 mg, 9 at 140 mg and 3 at 160 mg). B: Plasma concentration plotted against spleen response at 3 months (n=12; p = 0.2964).

Figure 3. STAT5 Phosphorylation is variably inhibited at lower doses of lestaurtinib

BaF/3 EPOR-GFP JAK2 V617F cells were incubated in patient plasma and pSTAT5 fluorescence intensity was measured (panel A). A corresponding standard curve was generated using thawed inhibitor-naive plasma from patients with varying concentrations of lestaurtinib added (final concentrations of 2.5 – 50 μM). PhosphoSTAT5 activation is represented as a ratio of treated to untreated cells, as measured by mean fluorescence intensity (MFI, panel B). Plasma samples (baseline and trough levels) collected at designated time points were measured in parallel (panel C): MFI values for study samples (n=20) were converted to a percent of untreated; lines represent mean with SEM at each dose level. Horizontal lines are derived from the standard curve.