ALBERT

Description: Background: Activating mutations in the pseudokinase domain of JAK2 occur at a high frequency in Philadelphia chromosome-negative myeloproliferative disorders (MPDs). Increasing JAK2 V617F allele burden has been shown to correlate with disease severity (bone marrow dysfunction, organomegaly and constitutional symptoms), which is consistent with exaggerated JAK2 signaling playing a central role in MPDs. INCB018424 is a potent and selective JAK1/2 inhibitor currently being evaluated in the clinic for the treatment of MPDs including primary myelofibrosis (PMF), post-polycythemia vera and essential thrombocythemia myelofibrosis (Post-PV/ET MF). Methods: The percentage of mutant JAK2 V617F relative to wild-type JAK2 was determined in peripheral blood using a quantitative single-nucleotide extension assay. The assay is based on the single nucleotide extension of a DNA primer that anneals adjacent to the V617F mutation. The percentage of JAK2 V617F in bone marrow was determined using pyrosequencing as previously described. The relationship between JAK2 V617F allele burden and clinical phenotype was assessed with samples obtained at study entry. JAK2 V617F allele burden was assessed in nineteen PMF and Post-PV/ET MF patients treated with 25 mg BID INCB018424 for a minimum of three months using peripheral blood and bone marrow. Results: There is an excellent correlation in the JAK2 V617F allele burden between samples obtained from bone marrow and peripheral blood, suggesting that the fraction of cells bearing the mutant clone remains stable during hematopoiesis in this patient group. The mean %V617F values were 59%, 80% and 86% for Post-ET MF (n=2), Post-PV MF (n=8) and PMF (n=9) patients. V617F allele burden correlated with spleen size, absolute neutrophil count (ANC) and Body Mass Index (BMI) in this patient population (R2 values if 0.61, 0.17 and 0.44, respectively), with a higher allele burden predicting larger spleen size, a higher ANC and a lower BMI. Eighteen of the nineteen evaluable JAK2 V617F-positive patients had baseline JAK2 V617F values above 50%, with the mean %V617F value for all evaluable patients being 81%, implying that the majority of hematopoietic stem cells contain the mutant allele in this patient population. During INCB018424 therapy (at least 3 months of treatment) in these patients, profound improvements in clinical endpoints including reduction or resolution of splenomegaly and constitutional symptoms are observed, yet only a modest decrease in JAK2 V617F allele burden is seen in both bone marrow and peripheral blood (13% and 9 % decrease from baseline, respectively, at 3 months). Conclusions: While the patient group is small and heterogeneous in nature, clinical correlates of V617F allele burden observed in myelofibrosis patients in this study are similar to those reported in PV. In addition, despite profound clinical improvements in these patients, V617F allele burdens do not change dramatically suggesting that the clinical activity of INCB018424 might involve inhibition of downstream signaling in cells harboring activating JAK2 mutations rather than changing the allele burden.

Description: Abstract 756 Background: Myelofibrosis (MF) is the most serious of chronic myeloproliferative neoplasms (MPNs) for which there is no approved therapy. Exaggerated JAK2 signaling, either by gain-of-function mutations (eg, JAK2V617F) or high circulating levels of JAK1/2 activating cytokines (eg, interleukin [IL]-6), is believed to play a key role in MPN pathogenesis. INCB018424 (424), a selective oral inhibitor of JAK1/2, has demonstrated clinical benefits including reduction of splenomegaly and improvement of symptoms in a Phase I/II trial in MF patients. Thrombocytopenia was identified as the dose limiting toxicity occurring in 30% of patients at 25mg BID. Methods: Patients with primary, post-PV or post-ET MF were enrolled in the study. Following the characterization of multiple dosing regimens, an individually optimized dose regimen strategy was developed, based on available efficacy and safety data. In a subset of patients, spleen volume change was measured by MRI at 1, 3 and 6 months of treatment in order to establish an objective measure of spleen response. The impact of 424 on MF associated symptoms was assessed using a validated instrument, MFSAF (Mesa et al., Leukemia Research 2009). As a surrogate marker of functional benefit, exercise capacity was assessed with a standardized 6-minute walk test (6MWT) at baseline, 1, 3 and 6 months of therapy. Results: 155 patients were enrolled in the study, with median duration of treatment of 1+ years and the duration of drug exposure of 〉150 patient years (76 patients received 〉1 year of therapy). Clinical responses have been maintained over the entire duration of treatment and most patients remain on therapy (115 of 155 patients; 74%). Progression to AML occurred in 3 patients, which is below the expected frequency based on published data (Barosi et al., Blood 2007). SAEs related to 424 occurred in 12 patients, and are generally related to bone marrow suppression or return of or exacerbation of signs and symptoms of MF when therapy is discontinued. Further optimization of the dosing regimen utilized baseline platelet count to determine the starting dose (10 or 15mg BID) and allowed dose titration after 1 and 2 months of therapy; most patients were optimized to 15 or 20mg BID. This approach significantly reduced the incidence of thrombocytopenia (1 yr of 424 therapy. Disclosures: Verstovsek: Incyte: Research Funding. Bradley:Incyte Corporation: Employment, Equity Ownership. Erickson-Viitanen:Incyte Corporation: Employment, Equity Ownership. Vaddi:Incyte Corporation: Employment, Equity Ownership. Levy:Incyte Corporation: Employment, Equity Ownership.

Description: Abstract 311 Background: Identification of a dominant gain-of-function mutation in a JAK2 kinase, JAK2V617, in myeloproliferative diseases such as polycythemia vera (PV) and essential thrombocythemia (ET), provided the foundation for the development of a molecularly targeted therapy for these diseases. Exaggerated JAK2 signaling is believed to play a dominant role in PV and ET by driving unchecked differentiation and proliferation of erythrocyte and thrombocyte precursors. While PV and ET are managed by phlebotomy and/or cytoreductive therapies such as hydroxyurea and anagrelide in the majority of patients, patients who fail these treatments have limited therapeutic options. INCB018424, a potent, selective inhibitor of JAK1 and JAK2, with demonstrated efficacy in MF (PMF, post-PV & post-ET MF), was evaluated for clinical activity in patients refractory to or intolerant of treatment with hydroxyurea. Methods: A phase II trial of INCB018424 is being conducted in advanced PV (n= 34) and ET (n=39) patients. Following an initial phase in which three dose regimens; 10 mg BID, 25 mg BID, and 50 mg QD; were evaluated in each patient population (n=6-8/dose), starting doses of 10 mg BID in PV patients and 25 mg BID in ET patients were chosen based on efficacy and tolerability to explore in an expansion cohort. Dose modifications were allowed to normalize Hct, platelet, and WBC counts. Clinico-hematological response 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 or CR. Greater than 75% of patients have at least 2 of 3 hematological parameters (Hct %, platelet count, WBC count) within normal ranges vs 38% of patients at baseline. Mean Hct% was 46.5 ± 4.3 (mean ± SD) at baseline; 37.5 ± 4.6 at month 3; and 39 ± 3.9 at month 6. Mean WBC count (109/L) was 15.2 ± 10.3 at baseline: 9.8 ± 6.1 at month 3; and 10.4 ± 5.5 at month 6. Mean platelet count (× 109/L) was 553 ± 231 at baseline: 378 ± 158 at month 3; and 311 ± 127 at month 6. 24 patients were phlebotomy-dependent in the 6 months prior to study; all became phlebotomy independent within two weeks of initiating INCB018424. 21 patients had palpable splenomegaly at baseline, ranging from 1 to 21 cm below the costal margin (9.1 ± 5.3 cm). 60% experienced a ≥ 50% reduction in spleen size in the first month which has been sustained over 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 sustained improvement. Marked improvement was noted in bone pain, night sweats, and fever. AEs of at least Grade 2 severity reported in more than 1 patient were anemia (12%) and thrombocytopenia (6%) all of which were reversible upon dose interruption or modification. ET patients: 39 patients completed 3 months of treatment; 17 patients have completed ≥ 6 months of treatment; 3 have discontinued. 61% of patients have achieved PR or CR. Greater than 50% of patients have at least 2 of 3 hematological parameters (Hct%, platelet count, WBC count) within normal ranges. Mean platelet counts (× 109/L) were 1059 ± 517 at baseline; 578 ± 435 at month 1; 681.2 ± 250.8 at month 3; and 584.4 ± 151 at month 6. Mean WBC count (× 109/L) was 9.3 ± 5.3 at baseline: 7.4 ± 2.7 at month 3; and 6.9 ± 1.4 at month 6. Of four patients with splenomegaly, all have a 〉 50% reduction in spleen size. Marked improvement was noted in bone pain, pruritus, weakness, night sweats and abnormal finger sensations. AEs of at least Grade 2 severity reported in more than 1 patient were anemia (18%) and neutropenia (6%) all of which were reversible upon dose interruption or modification. Conclusions: In PV patients, normalization of hematology parameters with elimination of the need for phlebotomy, marked decreases in splenic volume, and significant effects on symptoms have been demonstrated. Similar changes were noted in ET patients. Given that leukocytosis is an independent risk factor for thrombosis in PV and in ET, the lowering of WBC counts described in this study may be associated with additional clinical benefit along with normalization of Hct% in PV and decreases in platelet counts in ET patients. In this study, INCB018424 is a well tolerated, effective therapy in patients with advanced PV and ET refractory to hydroxyurea treatment. Disclosures: Verstovsek: AstraZeneca: Research Funding; Exelixis: Research Funding; 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 investigational agents.. Rambaldi:Diasorin S.p.A.: Consultancy, Honoraria. Rosen:Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Southern California Lymphoma Group, Inc.: Membership on an entity's Board of Directors or 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's Board of Directors or advisory committees, Speakers Bureau; Amgen : Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tower Cancer Research Foundation: Employment. Levy:Incyte Corporation: Employment, Equity Ownership. Bradley:Incyte Corporation: Employment, Equity Ownership. Schacter:Incyte Corporation: Employment, Equity Ownership. Garrett:Incyte Corporation: Employment. Vaddi:Incyte Corporation: Employment, Equity Ownership. Contel:Incyte Corporation: Employment, Equity Ownership.