Safety and efficacy of itacitinib, a selective JAK1 inhibitor, in advanced hepatocellular cancer: Phase 1b trial (JAKAL).

Overactivation of the JAK/STAT pathway is one of the drivers for the pathophysiology of hepatocellular carcinoma (HCC). We propose a Phase Ib study to evaluate the safety and efficacy of itacitinib, a selective JAK1 inhibitor, as a second-line treatment for patients with advanced or metastatic HCC.Twenty-five patients will receive 400 mg itacitinib orally daily, 28-day cycle. Safety will be reviewed prior to each cycle. Tumor response assessed every 2 months until disease progression, death or withdrawal. Tumor biopsies and blood samples will be taken for presence of JAK1 mutations.Activation of JAK/STAT pathway drives HCC development and is associated with immunotherapy resistance. Itacitinib is hypothesized to be safe and effective in HCC patients that have progressed after first-line therapies.Clinical Trial Registration: EudraCT: 2017-004437-81 NCT04358185 (ClinicalTrials.gov).

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Investigational Janus kinase inhibitors in development for myelofibrosis.

INTRODUCTION: Since the discovery of the activating V617F mutation in Janus kinase 2 (JAK2), a number of pharmacologic inhibitors of JAK2 have entered clinical trials for patients with myelofibrosis. However, ruxolitinib, approved in 2011, remains the only one currently available for treatment of myelofibrosis, with many others having been discontinued for toxicity, and considerable uncertainty surrounding the future of those still in development. Areas covered: The available clinical data on pacritinib and momelotinib, the two agents in the most advanced phases of clinical testing in myelofibrosis, are examined in detail. NS-018 and INCB039110, selective inhibitors of JAK2 and JAK1, respectively, are also discussed. Finally, the JAK2 inhibitors no longer in clinical development are summarized in tabular form. Expert opinion: The different agents evaluated clearly differ in their kinomes, toxicity profiles and potential for myelosuppression. If approved, the JAK2-specific non-myelosuppressive inhibitor pacritinib could fulfill a major unmet need, that of patients with significant cytopenias. However, toxicity concerns persist. The data from the pivotal trials of momelotinib do not support its approval, although improvement of anemia is an important benefit. Selective JAK1 inhibition alone is unlikely to succeed in myelofibrosis. In these circumstances, rational ruxolitinib-based combinations may represent the best way forward.

European Hematology Association - 20th Annual Congress (June 11-14, 2015 - Vienna, Austria).

The Annual Congress of the European Hematology Association, now in its 20th year, brought together specialists in all areas of hematology research to present new data on ongoing research and share innovative ideas to aid in the treatment and diagnosis of many hematological diseases. Clinical and translational research was presented along with technological advancement in diagnostics and risk-assessment strategies. The congress afforded attendees time for networking with representatives from many disciplines associated with hematological research, including academia, industry and patient advocacy groups. This report will cover the most interesting presentations relating to therapeutics for a range of hematological conditions.