A Phase I Study of XL019, a Selective JAK2 Inhibitor, in Patients with Primary Myelofibrosis, Post-Polycythemia Vera, or Post-Essential Thrombocythemia Myelofibrosis
Neil P. Shah, MD, PhD1,
Lubomir Sokol, MD, PhD2,
Ronald Hoffman, MD4,
Alan F. List, MD5,
Jorge Cortes, MD3,
Hagop M Kantarjian6,
D. Gary Gilliland7,
Douglas O Clary, PhD8,*,
Lynne A. Bui, MD8 and
Martha Wadleigh, MD9
1 University of California - San Francisco, San Francisco, CA, USA, 2 H. Lee Moffitt Cancer Center, Tampa, FL, USA, 3 M.D. Anderson Cancer Center, Houston, TX, USA, 4 Hematology, Mount Sinai School of Medicine, New York, NY, USA, 5 H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA, 6 The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA, 7 Brigham and Womens Hospital, Boston, MA, USA, 8 Exelixis, Inc., South San Francisco, CA, USA, 9 Dana-Farber Cancer Inst., Boston, MA, USA
JAK2 V617F has been identified as a constitutive activatingmutation in approximately half of patients with myelofibrosis(MF). MF, a myeloproliferative disorder comprised of primarymyelofibrosis and the clinically indistinguishable entitiesof post-polycythemia vera or post essential thrombocythemiaMF, has been reported to have a median survival of 4 years [Dupriezet al. (1996) Blood 88:1013–18[Abstract/Free Full Text]]. No effective therapiesexist for patients with MF. XL019 is a potent, highly selectiveand reversible inhibitor of JAK2 which may have utility in treatingMF, by ameliorating hepato-splenomegaly, constitutional symptoms,and progressive anemia. The objectives of this phase 1 studyinclude safety evaluation, preliminary assessments of efficacyusing International Working Group (IWG) response criteria forMF, and evaluation of pharmacokinetic and pharmacodynamic endpoints.Pharmacodynamic evaluations include quantitative PCR for peripheralblood JAK2 V617F allele burden and erythropoietin-independentcolony formation. In addition, plasma and fixed blood samplesare being collected to evaluate changes in protein biomarkersand JAK2 signaling pathways. To date, XL019 has been studiedin 21 patients over multiple dose levels ranging from dosesof 25 mg to 300 mg using different schedules of administration(3 weeks on, 1 week off; QD; and QMWF). Median age was 64 years(range, 47–87 years) and 16 patients (76%) carried theJAK2V617F mutation. Additionally, one patient had a MPLW515Fmutation in the absence of a JAK2 mutation. No treatment-relatedhematologic adverse events (i.e. thrombocytopenia, anemia, neutropenia)have been observed to date. Reversible low-grade peripheralneuropathy (PNP) was observed in 7/9 patients treated at dailydoses of 100 mg (Grade 1: 5 patients; Grade 2: 2 patients).XL019 doses below 100 mg using 2 different dosing schedulesare currently being evaluated. To date, XL019 has resulted inreductions in splenomegaly and leukocytosis, stabilization ofhemoglobin counts, improvements in blast counts, and resolutionor improvement in generalized constitutional symptoms. The medianspleen size in 15 patients measured below the costal marginby palpation was 14cm (range, 3–26cm). Three of 15 patientswith palpable splenomegaly at baseline were JAK2 V617F mutationnegative and did not experience spleen size reduction. Twelveof 12 (100%) evaluable patients with an activating mutation(JAK2 V617F: 11 patients; MPLW515F: 1 patient) experienced reductionin spleen size and 5 (42%) had a 50% decline from baseline.Ten of 11 patients with JAK2V617F activating mutations and baselineconstitutional symptoms, reported improvements in generalizedconstitutional symptoms which include pruritus and fatigue.No significant non-hematologic or hematologic toxicity has beenobserved at the current dose level. On 25 mg dosing schedules,no signs of PNP have been observed with a follow-up period ofup to 4 months. Overall, XL019 has demonstrated encouragingclinical activity and is generally well tolerated.
Disclosures: Shah:Exelixis Inc: Consultancy, Membership onan entitys Board of Directors or advisory committees,Research Funding. List:Exelixis Inc.: Consultancy, Membershipon an entitys Board of Directors or advisory committees.Cortes:Exelixis Inc.: Consultancy, Membership on an entitysBoard of Directors or advisory committees. Clary:Exelixis Inc.:Employment, Equity Ownership. Bui:Exelixis Inc: Employment,Equity Ownership.
M. B. Sonbol, B. Firwana, A. Zarzour, M. Morad, V. Rana, and R. V. Tiu Comprehensive review of JAK inhibitors in myeloproliferative neoplasms
Therapeutic Advances in Hematology,
February 1, 2013;
15 - 35.