Phase I evaluation of XL019, an oral, potent, and selective JAK2 inhibitor (original) (raw)
Related papers
Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis
New England Journal of Medicine, 2010
Background Myelofibrosis is a Philadelphia chromosome-negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor. Methods We conducted a phase 1−2 trial of INCB018424 in patients with JAK2 V617F−posi tive or JAK2 V617F−negative primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis. Results A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis. Conclusions INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed. (Funded by Incyte; ClinicalTrials.gov number, NCT00509899.
Beyond JAK2 Inhibitors: A Systematic Review of Management Strategies for Myelofibrosis
Blood, 2018
Introduction Drugs that target activating mutations of Janus Kinase 2 (JAK2) have been the backbone of myelofibrosis (MF) management. With recent advancements in our understanding of the underlying molecular mechanisms involved in myelofibrosis (MF) pathogenesis, numerous novel agents have been developed in the last decade. We have systematically reviewed the mechanisms of actions, efficacy and safety of these drugs. Methods A comprehensive literature research was performed using PubMed, Cochrane, EMBASE, Web of Science and Clinicaltrials.gov. We included all trials that were under development in phase I/II/III trials. Our search identified 1642 full-length manuscripts or abstracts with published results in the last decade were screened for relevant studies. Of these, 212 articles were finalized for our final analyses. Results Hedgehog inhibitors (saridegib, glasdegib and sonidegib) targets signaling membrane protein, smoothened. The combination of sonidegib + ruxulotinib (RUX) elic...
Haematologica, 2016
Combined Janus kinase 1 (JAK1) and JAK2 inhibition therapy effectively reduces splenomegaly and symptom burden related to myelofibrosis (MF) but is associated with dose-dependent anemia and thrombocytopenia. In this open-label phase 2 study, we evaluated the efficacy and safety of 3 dose levels of INCB039110, a potent and selective oral JAK1 inhibitor, in patients with intermediate- or high-risk MF and a platelet count ≥50x10(9)/L. Of 10, 45, and 32 patients enrolled in the 100 mg twice-daily, 200 mg twice-daily, and 600 mg once-daily cohorts, respectively, 50.0%, 64.4%, and 68.8% completed week 24. A ≥50% reduction in total symptom score (TSS) was achieved by 35.7% and 28.6% of patients in the 200 mg twice-daily cohort and 32.3% and 35.5% in the 600 mg once-daily cohort at week 12 (primary end point) and 24, respectively. By contrast, 2 patients (20%) in the 100 mg twice-daily cohort had ≥50% TSS reduction at weeks 12 and 24. For the 200 mg twice-daily and 600 mg once-daily cohorts...
JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders
F1000Research
JAK inhibitors have been developed following the discovery of the JAK2V617F in 2005 as the driver mutation of the majority of non-BCR-ABL1 myeloproliferative neoplasms (MPNs). Subsequently, the search for JAK2 inhibitors continued with the discovery that the other driver mutations (CALR and MPL) also exhibited persistent JAK2 activation. Several type I ATP-competitive JAK inhibitors with different specificities were assessed in clinical trials and exhibited minimal hematologic toxicity. Interestingly, these JAK inhibitors display potent anti-inflammatory activity. Thus, JAK inhibitors targeting preferentially JAK1 and JAK3 have been developed to treat inflammation, autoimmune diseases, and graft-versus-host disease. Ten years after the beginning of clinical trials, only two drugs have been approved by the US Food and Drug Administration: one JAK2/JAK1 inhibitor (ruxolitinib) in intermediate-2 and high-risk myelofibrosis and hydroxyurea-resistant or -intolerant polycythemia vera and ...
Leukemia
is an acquired clonal hematopoietic stem cell disorder associated with debilitating constitutional symptoms, extramedullary hematopoiesis resulting in splenomegaly, and a propensity to transform to a blast phase/acute myeloid leukemia (AML). The discovery of JAK inhibitors (JAKi) has been pivotal in the treatment of symptomatic MF by reducing spleen size, and alleviating cytokine-related symptom burden [1]. Despite this, up to 50% of MF patients discontinue JAKi by 2-3 years and only one quarter of patients remain on treatment at 5 years [2, 3]. Prospective trials of JAKi therapy provide little information after patients discontinue therapy and safety specific follow up is completed. Although survival following ruxolitinib cessation is poor, in the range 13-16 months, the clinical course and reasons for JAKi failure in MF patients are not well characterized [4-7]. Criteria for JAKi failure are variably defined in retrospective studies and second-line JAKi therapy trials [8-10]. JAKi therapy may fail for a variety of reasons including sub-optimal/loss of spleen response, severe cytopenias, progression to an accelerated or blast phase (AP/BP) of disease, secondary malignancies other than AML, recurrent severe infections, or other non-hematological toxicities. Recognition of patterns of failure is important to accurately characterize, and plan treatment strategies in these patients. We conducted a retrospective study analyzing a molecularly annotated, mature dataset of MF patients treated with JAKi followed in a prospective MPN registry (NCT02760238) at Princess Margaret Cancer Centre. We evaluated the impact of baseline clinical and molecular factors on clinical outcomes and therapy failure. We characterized different patterns of JAKi failure according to consensus criteria of the Canadian MPN Group (Supp. Table S1) [11] and its impact on survival. In a subset of patients with paired samples we evaluated the impact of clonal evolution on outcomes following JAKi failure. Cohort selection, study definitions, molecular, and statistical analysis are summarized in Appendix.
‘JAK–ing’ up the treatment of primary myelofibrosis
Current Opinion in Hematology, 2017
Purpose of review The article discusses the promising agents that are approved or currently under investigation for the treatment of myelofibrosis and reviews the ongoing Janus kinase (JAK) inhibitors-based combinatorial strategies in this setting. Recent findings Myelofibrosis is a Philadelphia-negative myeloproliferative neoplasm with constitutive JAK/STAT activation. The JAK-inhibitor ruxolitinib is the only approved drug for this disease in the United States and Europe based on two randomized phase III studies that demonstrated clinically meaningful reduction in spleen size, improvement in symptoms, quality of life, and an overall survival advantage with prolonged follow-up. Emerging data have revealed the complex molecular architecture of myelofibrosis with clonal evolution playing a central role in disease progression or transformation. These molecular pathways may explain the heterogeneous benefits obtained by JAK-inhibitors in patients with myelofibrosis. In addition, the genetic and epigenetic mutations appear to work in concert with overactive JAK/STAT signaling and contribute to myelofibrosis pathogenesis and prognosis, suggesting a potential to exploit them as potential therapeutic targets. Summary Combining JAK-inhibitors with agents that target parallel prosurvival pathways or agents that enhance hematopoiesis may enhance efficacy and/or mitigate on-target myelosuppression, thereby extending the therapeutic benefits observed with JAK-inhibitors alone.
Phase II trial of Lestaurtinib, a JAK2 inhibitor, in patients with myelofibrosis
Leukemia & Lymphoma, 2019
Declaration of interest statement In accordance with Taylor & Francis policy and my ethical obligation as a researcher, I am reporting that I, John Mascarenhas, am on the clinical trial steering committee for Incyte, Roche, and CTI Biopharma. In addition, clinical trial funding paid to my institution includes Incyte, Roche, Novartis, Merck, CTI Biopharma, Janssen, Celgene, and Promedior. I have disclosed those interests fully to Taylor & Francis, and I have in place an approved plan for managing any potential conflicts arising.
Blood, 2015
Pacritinib (SB1518) is a JAK2, JAK2(V617F) and FLT3 kinase inhibitor that does not inhibit JAK1. It demonstrated a favorable safety profile with promising efficacy in phase 1 studies in patients with primary and secondary myelofibrosis (MF). This multicenter phase 2 study further characterized the safety and efficacy of pacritinib in the treatment of patients with MF. Eligible patients had clinical splenomegaly poorly controlled with standard therapies, or were newly diagnosed with intermediate- or high-risk Lille Score. Patients with any degree of thrombocytopenia, anemia or neutropenia were eligible. Thirty-five patients were enrolled and treated with pacritinib. At entry, 40% had hemoglobin <10 g/dL and 43% had platelets <100,000/µL. Up to week 24, 8/26 (31%) evaluable patients achieved ≥ 35% decrease in MRI-determined spleen volume and 14/33 (42%) attained ≥ 50% reduction in spleen size by physical examination. Median MF symptom improvement was ≥50% for all symptoms except...