Abstract
Abstract 754 Introduction:The identification of mutations in JAK2 in myeloproliferative neoplasms (MPN) has led to the hypothesis that tyrosine kinase inhibitors will have therapeutic benefit. CEP701 (lestaurtinib, Cephalon Oncology), an orally available multikinase inhibitor, has been tested extensively in acute myeloid leukemia (AML) as a FLT3 inhibitor. CEP701 also inhibits JAK2 with an in vitro IC50 of 1 nM, and selectively inhibits primary cells from patients with MPN. Limitations of the drug in AML studies (doses ranging from 60 to 100 mg BID) have included gastrointestinal toxicity, low free drug levels related to in vivo plasma protein binding, and, as a consequence, incomplete target inhibition. Further, a maximum tolerated dose (MTD) for CEP701 has not yet been reached. Methods:The Myeloproliferative Disorders Research Consortium (MPD-RC) is conducting a multicenter, open label dose escalation phase I study of a new, capsule formulation of CEP701 in subjects with myelofibrosis (primary or evolved from polycythemia vera or essential thrombocytosis) who have the JAK2 V617F mutation. Patients are entered into cohorts in a classic 3+3 design with CEP701 administered orally at BID dosing of 80mg, 100mg, 120mg, 140mg, and 160mg for a minimum of 28 consecutive days. In the absence of a dose limiting toxicity, patients may continue treatment for 6 months, with the option to extend if responding. Results:Four of five dose levels from 80 mg – 160 mg PO BID have been tested. 80 mg and 100 mg were tested using the older liquid formulation; subsequent cohorts (100 mg – 160 mg) have or will be treated with the capsule formulation. No MTD has been reached at doses up to 140 mg; the final dosing cohort is accruing at the time of this submission (full data will be available from the phase I for reporting at the time of the meeting). Of 19 patients enrolled, 5 (26%) are females, 68% have primary myelofibrosis and the remaining patients have post-PV or post-ET myelofibrosis; 26% have had a prior thrombotic event and 47% a prior hemorrhagic event. At baseline 12 of 19 patients had at least 1 adverse prognostic factor by the Lille classification system. 9 patients (47%) of 19 available had a normal karyotype at baseline; the remaining had at least one cytogenetic abnormality. 7 of 19 patients continue to receive study drug with one subject treated for more than 1 year (range 1 to 54+ weeks). There were 2 drug-attributable grade 3/4 non-hematologic toxicities: 2 subjects receiving the 100 mg liquid formulation experienced grade 3 diarrhea. Diarrhea was the most common grade ≥2 adverse event, affecting 5 of the 7 subjects treated with the liquid formulation and 2 of 12 subjects treated with the capsule formulation (both at the 140 mg dose level). Nausea was also common, with 2/7 (liquid) and 2/12 (capsule) patients experiencing grade 2 toxicity. There was one death in a patient at the 100mg (liquid) cohort, who died from hepatic failure following surgery in the setting of cirrhosis, deemed to be unrelated to CEP701. All patients had splenomegaly at baseline with spleen sizes ranging from 2 cm – 30 cm below the left costal margin (mean of 16.7. s.d., 7.6). Spleen size reduced markedly from baseline through 20 weeks (linear mixed models, p <0.001); the median decrease in spleen size from baseline to last observation was 6.4 cm with a range from an increase of 3 cm to a decrease of 11.5 by last observation on study. 9 of the 13 patients enrolled on doses through 120 had a follow up observation at 12 weeks or longer with median reductions in spleen size of 6.8 cm by 12 weeks (range from increase of 2 cm to decrease of 14 cm). Only one subject receiving >120 mg has reached 12 weeks of treatment. The median baseline JAK2 T% (mutant) in peripheral blood granulocytes was 66.4% (range 16.2 – 99.6%). In the 5 patients with measurements at baseline and at either 12 or 24 weeks on study (last on study visit), JAK2 T% was markedly decreased (one sample Wilcoxon rank sum test, p – 0.06, 2-sided), with a median of 49.6% (range 34-96) at last on study observation; the median change from baseline to their last study observation was 8.6% (range 0.2 – 40.3). Taken together, these data demonstrate that CEP701 administered as a capsule formulation is safe at dose levels higher than those previously tested. CEP701 treatment decreases JAK2 V617F allelic burden and decreases spleen size, suggesting both biologic and clinical activity. Disclosures:Carroll:Sanofi Aventis Corp: Research Funding; Cephalon Oncoloy: Consultancy.
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