A Phase 2 Study of INCB018424, An Oral, Selective JAK1/JAK2 Inhibitor, in Patients with Advanced Polycythemia Vera (PV) and Essential Thrombocythemia (ET) Refractory to Hydroxyurea.
Srdan Verstovsek, MD, PhD1,
Alessandro Rambaldi, MD3,
Giovanni Barosi, MD*,4,
Peter Rosen, MD5,
Richard Levy, MD*,6,
Edward C Bradley, MD*,7,
William M Garrett, MBA*,7,
Kris Vaddi, Ph.D.*,7,
Elisabetta Gattoni, MD*,9,
Tiziano Barbui*,3 and
1 Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, USA, 2 Division of Hematology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy, 3 Hematology, Ospedali Riuniti di Bergamo, Bergamo, Italy, 4 Unit Clin Epidemiol & Centre for the Study of Myelofibrosis, IRCCS Policlinico San Matteo Foundation, Pavia, Italy, 5 Tower Cancer Research Foundation, Beverly Hills, CA, USA, 6 Incyte, Wilmington, DE, USA, 7 Incyte Corporation, Wilmington, DE, USA, 8 Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy, 9 Laboratorio Epidemiologia Clinica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, 10 Department of Hematology, University of Pavia Medical School, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy, 11 Leukemia Room. T6-3849, Md. Anderson Cancer Center, Houston, TX, USA, 12 Department of Hematology, University of Florence, Florence, Italy
Background: Identification of a dominant gain-of-function mutation in aJAK2 kinase, JAK2V617, in myeloproliferative diseases such aspolycythemia vera (PV) and essential thrombocythemia (ET), providedthe foundation for the development of a molecularly targetedtherapy for these diseases. Exaggerated JAK2 signaling is believedto play a dominant role in PV and ET by driving unchecked differentiationand proliferation of erythrocyte and thrombocyte precursors.While PV and ET are managed by phlebotomy and/or cytoreductivetherapies such as hydroxyurea and anagrelide in the majorityof patients, patients who fail these treatments have limitedtherapeutic options. INCB018424, a potent, selective inhibitorof JAK1 and JAK2, with demonstrated efficacy in MF (PMF, post-PV& post-ET MF), was evaluated for clinical activity in patientsrefractory to or intolerant of treatment with hydroxyurea.
Methods: A phase II trial of INCB018424 is being conducted in advancedPV (n= 34) and ET (n=39) patients. Following an initial phasein which three dose regimens; 10 mg BID, 25 mg BID, and 50 mgQD; were evaluated in each patient population (n=6-8/dose),starting doses of 10 mg BID in PV patients and 25 mg BID inET patients were chosen based on efficacy and tolerability toexplore in an expansion cohort. Dose modifications were allowedto normalize Hct, platelet, and WBC counts. Clinico-hematologicalresponse criteria as defined by Barosi et al. (Blood, 2009)were used to assess response. PK and PD data are being collected.
Results:PV patients: 34 patients have completed 3 months of treatment; 20 have completed six months of treatment. 94% of patients have achieved PR orCR. Greater than 75% of patients have at least 2 of 3 hematologicalparameters (Hct %, platelet count, WBC count) within normalranges vs 38% of patients at baseline. Mean Hct% was 46.5 ±4.3 (mean ± SD) at baseline; 37.5 ± 4.6 at month3; and 39 ± 3.9 at month 6. Mean WBC count (109/L) was15.2 ± 10.3 at baseline: 9.8 ± 6.1 at month 3;and 10.4 ± 5.5 at month 6. Mean platelet count (x 109/L)was 553 ± 231 at baseline: 378 ± 158 at month3; and 311 ± 127 at month 6. 24 patients were phlebotomy-dependentin the 6 months prior to study; all became phlebotomy independentwithin two weeks of initiating INCB018424. 21 patients had palpablesplenomegaly at baseline, ranging from 1 to 21 cm below thecostal margin (9.1 ± 5.3 cm). 60% experienced a 50%reduction in spleen size in the first month which has been sustainedover the duration of treatment. In 57% of patients with splenomegaly,spleens became non-palpable. All patients with pruritus (n=26)have experienced rapid, statistically significant, and sustainedimprovement. Marked improvement was noted in bone pain, nightsweats, and fever. AEs of at least Grade 2 severity reportedin more than 1 patient were anemia (12%) and thrombocytopenia(6%) all of which were reversible upon dose interruption ormodification.
ET patients: 39 patients completed 3 months of treatment; 17 patients havecompleted 6 months of treatment; 3 have discontinued. 61% ofpatients have achieved PR or CR. Greater than 50% of patientshave at least 2 of 3 hematological parameters (Hct%, plateletcount, WBC count) within normal ranges. Mean platelet counts(x 109/L) were 1059 ± 517 at baseline; 578 ± 435at month 1; 681.2 ± 250.8 at month 3; and 584.4 ±151 at month 6. Mean WBC count (x 109/L) was 9.3 ± 5.3at baseline: 7.4 ± 2.7 at month 3; and 6.9 ± 1.4at month 6. Of four patients with splenomegaly, all have a >50% reduction in spleen size. Marked improvement was noted inbone pain, pruritus, weakness, night sweats and abnormal fingersensations. AEs of at least Grade 2 severity reported in morethan 1 patient were anemia (18%) and neutropenia (6%) all ofwhich were reversible upon dose interruption or modification.
Conclusions: In PV patients, normalization of hematology parameters withelimination of the need for phlebotomy, marked decreases insplenic volume, and significant effects on symptoms have beendemonstrated. Similar changes were noted in ET patients. Giventhat leukocytosis is an independent risk factor for thrombosisin PV and in ET, the lowering of WBC counts described in thisstudy may be associated with additional clinical benefit alongwith normalization of Hct% in PV and decreases in platelet countsin ET patients. In this study, INCB018424 is a well tolerated,effective therapy in patients with advanced PV and ET refractoryto hydroxyurea treatment.
Disclosures:Verstovsek:AstraZeneca: Research Funding; Exelixis: ResearchFunding; Incyte: Research Funding; Cephalon: Research Funding;SBIO: Research Funding. Off Label Use: INCB081424 from Incyte,XL019 from Exelixis, AZD1480 from AstraZeneca, CEP701 from Cephalon,SB1518 from SBIO. All ar JAK2 inhibitors and are investigationalagents.. Rambaldi:Diasorin S.p.A.: Consultancy, Honoraria.Rosen:Biogen Idec: Membership on an entity's Board of Directorsor advisory committees, Speakers Bureau; Southern CaliforniaLymphoma Group, Inc.: Membership on an entity's Board of Directorsor advisory committees, Speakers Bureau; Genentech: Honoraria,Membership on an entity's Board of Directors or advisory committees,Speakers Bureau; Celgene: Honoraria, Membership on an entity'sBoard of Directors or advisory committees, Speakers Bureau;Amgen : Honoraria, Membership on an entity's Board of Directorsor advisory committees, Speakers Bureau; Tower Cancer ResearchFoundation: Employment. Levy:Incyte Corporation: Employment,Equity Ownership. Bradley:Incyte Corporation: Employment, EquityOwnership. Schacter:Incyte Corporation: Employment, EquityOwnership. Garrett:Incyte Corporation: Employment. Vaddi:IncyteCorporation: Employment, Equity Ownership. Contel:Incyte Corporation:Employment, Equity Ownership.
* Asterisk with author names denotes non-ASH members.
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