Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis

Abstract

Few treatment options exist for patients with myelofibrosis (MF), and their survival is significantly shortened. Activating mutation of the JAK2 tyrosine kinase (JAK2(V617F)) is found in approximately 50% of MF patients. CEP-701 is a tyrosine kinase inhibitor that inhibits JAK2 in in vitro and in vivo experiments. We conducted a phase 2 clinical study of CEP-701 in 22 JAK2(V617F)-positive MF patients (80 mg orally twice daily), and 6 (27%) responded by International Working Group criteria (clinical improvement in all cases): reduction in spleen size only (n = 3), transfusion independency (n = 2), and reduction in spleen size with improvement in cytopenias (n = 1). Median time to response was 3 months, and duration of response was more than or equal to 14 months. No improvement was seen in bone marrow fibrosis or JAK2(V617F) allele burden. Phosphorylated STAT3 levels decreased from baseline in responders while on therapy. Eight patients (36%) experienced grade 3 or 4 toxicity, and 6 (27%) required dose reduction. Main side effects were myelosuppression (grade 3 or 4 anemia, 14%; and thrombocytopenia, 23%) and gastrointestinal disturbances (diarrhea, any grade, 72%; grade 3 or 4, 9%; nausea, grade 1 or 2 only, 50%; vomiting, grade 1 or 2 only, 27%). In conclusion, CEP-701 resulted in modest efficacy and mild but frequent gastrointestinal toxicity in MF patients. The study was registered at http://clinicaltrials.gov as NCT00494585.

Figure 1

MF patients who responded to CEP-701. (A) Spleen size measurements in MF patients who responded to CEP-701. Data are shown for 4 patients who had a decrease in spleen size on therapy. (B) JAK2^V617F allele burden in MF patients who responded to CEP-701. Data are shown for all 6 clinical responders.

Figure 2

Western blot analysis of STAT3 and P-STAT3 in mononuclear cells obtained from patients before and during therapy. (A) Nonresponders. (B) Responders. Time point at which samples were obtained is indicated. NR indicates nonresponder; and R, responder.