An Open-Label Study of CEP-701 in Patients with JAK2 V617F-Positive PV and ET: Update of 39 Enrolled Patients.
Authors: Moliterno Alison R , Hexner Elizabeth , Roboz Gail J. , Carroll Martin , Luger Selina , Mascarenhas John , Hoffman Ronald , Bensen-Kennedy Debra M 
Published: October 2019

Abstract
Abstract 753
Since the seminal discovery of the JAK2V617F mutation, small molecule inhibitors of JAK2 to treat patients with myeloproliferative neoplasms have been recently evaluated in a growing number of clinical trials. To date, there has been limited evaluation of the utility of such JAK2 inhibitors in patients with PV or ET. CEP-701 is an orally available, potent, low nanomolar inhibitor of both the wild-type and mutated JAK2 tyrosine kinase, with its inhibitory effect being demonstrated both in enzymatic and cellular assays. The present study is the first JAK2 inhibitor study to test the safety and efficacy of such an agent in high risk JAK2 V617F positive ET and PV patients. The primary endpoint was reduction in JAK2 V617F neutrophil allele burden. Secondary endpoints included reduction in phlebotomy rates; improvement in hemoglobin, white cell and platelet counts; reduction in hydroxyurea (HU) dose and spleen size; and the pharmacokinetics and pharmacodynamics of CEP-701. Enrollment was completed with 39 JAK2V617F-positive subjects, 27 PV and 12 ET, 22 females and 17 males, ages 38 to 80. The PV patients were a high risk group as defined by a median age of 65 years, neutrophil JAK2V617F allele burden of 76%, prevalence of prior thrombotic events of 19%, prior HU use in 44% and an average white cell count of 19,600/ul (range 3,500-78,600). The ET patients were also considered to be a high risk group as defined by a median age of 61.5 years, the prior use of HU in 100% of cases, and prevalence of prior thrombotic events of 25%; the median neutrophil JAK2V617F allele burden was 40%. More than half the patients had had their disease for 5 years or longer. To date, 15 of the patients have completed 18 weeks of treatment and 13 of these patients continue on the extension phase of the trial. Within 18 weeks, responses included a reduction spleen size of > 5cm or to non-palpable in 15/18 (83%) subjects and amelioration of pruritus in 5/5 patients studied. While reduction in phlebotomy requirement occurred in a number of phlebotomy dependent patients (3/5 evaluable at time of report), this effect was not evident in these patients until 6 months of therapy, and was not associated with concomitant reductions in white cell or platelet count. In fact, in many patients, platelet and white cell counts increased while on drug. A reduction in the JAK2 V617F allele burden of 15% or more was observed in 3 of the 15 patients at the 18 week assessment. The most common adverse events were gastrointestinal, which were dose related and improved over time. Serious adverse events have occurred, including 5 patients experiencing thrombotic events (3 venous (1 DVT, 1DVT/PE, 1 PVT), 2 arterial (1 TIA, 1 PAT)), and one non-serious DVT. We conclude that CEP-701 is biologically active agent in patients with JAK2 V617F positive PV and ET. Serious adverse events related to thrombosis, however, have occurred which to date have not been reported with the use of other JAK2 inhibitor trials involving patients with PMF. Though substantial symptomatic improvements have occurred, our data suggest, at a minimum, that JAK2 inhibitor therapy may not prevent thrombosis in high-risk patients with PV and ET. This risk of thrombosis may be a disease specific interaction in PV and ET patients since thrombosis has not been a frequent complication of CEP 701 therapy for other malignancies. Final 18 week data and cumulative extension data will be updated at the annual meeting.

Disclosures:
Roboz: Cephalon: Consultancy. Carroll:Cephalon consultancy: Consultancy; Sanofi Aventis Corporation: Research Funding; Kyowa Hakko Kirin Pharmaceutical: Research Funding. Bensen-Kennedy:cephalon: Employment.