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Sustained-release ruxolitinib: Findings from a phase 1 study in healthy subjects and a phase 2 study in patients with myelofibrosis.

ABSTRACT: Ruxolitinib is the first Janus kinase (JAK) inhibitor approved for the treatment of myelofibrosis, where its efficacy is often associated with cytopenia. It is possible that the severity of cytopenia is in part driven by Cmax . A once-daily sustained-release (SR) formulation of ruxolitinib was therefore developed to decrease the Cmax /Cmin ratio relative to twice-daily immediate-release (IR) ruxolitinib. An SR formulation was identified based on pharmacokinetic evaluation in a phase 1 study in healthy adults (N = 9). This was followed by an open-label phase 2 study in patients with myelofibrosis (N = 41). Ruxolitinib SR treatment was well tolerated with blood cell counts relatively unchanged through week 16. In terms of efficacy, 7 patients (17.1%) had clinical improvement and 33 (80.5%) had stable disease. While this study has raised the possibility of an increased therapeutic index for ruxolitinib via an SR formulation, further studies are required to validate the hypothesis.

SUBMITTER: Verstovsek S

PROVIDER: S-EPMC6221065 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Sustained-release ruxolitinib: Findings from a phase 1 study in healthy subjects and a phase 2 study in patients with myelofibrosis.

Verstovsek Srdan S Yeleswaram Swamy S Hou Kevin K Chen Xuejun X Erickson-Viitanen Sue S

Hematological oncology 20180911 4

Ruxolitinib is the first Janus kinase (JAK) inhibitor approved for the treatment of myelofibrosis, where its efficacy is often associated with cytopenia. It is possible that the severity of cytopenia is in part driven by Cmax . A once-daily sustained-release (SR) formulation of ruxolitinib was therefore developed to decrease the Cmax /Cmin ratio relative to twice-daily immediate-release (IR) ruxolitinib. An SR formulation was identified based on pharmacokinetic e ...[more]

PMID: 30105794

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Project description:BackgroundAnemia is considered a negative prognostic risk factor for survival in patients with myelofibrosis. Most patients with myelofibrosis are anemic, and 35-54 % present with anemia at diagnosis. Ruxolitinib, a potent inhibitor of Janus kinase (JAK) 1 and JAK2, was associated with an overall survival benefit and improvements in splenomegaly and patient-reported outcomes in patients with myelofibrosis in the two phase 3 COMFORT studies. Consistent with the ruxolitinib mechanism of action, anemia was a frequently reported adverse event. In clinical practice, anemia is sometimes managed with erythropoiesis-stimulating agents (ESAs). This post hoc analysis evaluated the safety and efficacy of concomitant ruxolitinib and ESA administration in patients enrolled in COMFORT-II, an open-label, phase 3 study comparing the efficacy and safety of ruxolitinib with best available therapy for treatment of myelofibrosis. Patients were randomized (2:1) to receive ruxolitinib 15 or 20 mg twice daily or best available therapy. Spleen volume was assessed by magnetic resonance imaging or computed tomography scan.ResultsThirteen of 146 ruxolitinib-treated patients had concomitant ESA administration (+ESA). The median exposure to ruxolitinib was 114 weeks in the +ESA group and 111 weeks in the overall ruxolitinib arm; the median ruxolitinib dose intensity was 33 mg/day for each group. Six weeks before the first ESA administration, 10 of the 13 patients had grade 3/4 hemoglobin abnormalities. These had improved to grade 2 in 7 of the 13 patients by 6 weeks after the first ESA administration. The rate of packed red blood cell transfusions per month within 12 weeks before and after first ESA administration remained the same in 1 patient, decreased in 2 patients, and increased in 3 patients; 7 patients remained transfusion independent. Reductions in splenomegaly were observed in 69 % of evaluable patients (9/13) following first ESA administration.ConclusionsConcomitant use of an ESA with ruxolitinib was well tolerated and did not affect the efficacy of ruxolitinib. Further investigations evaluating the effects of ESAs to alleviate anemia in ruxolitinib-treated patients are warranted (ClinicalTrials.gov identifier, NCT00934544; July 6, 2009).

Project description:Myelofibrosis is a BCR-ABL1-negative myeloproliferative neoplasm characterized by anemia, progressive splenomegaly, extramedullary hematopoiesis, bone marrow fibrosis, constitutional symptoms, leukemic progression, and shortened survival. Constitutive activation of the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway, and other cellular pathways downstream, leads to myeloproliferation, proinflammatory cytokine expression, and bone marrow remodeling. Transplant is the only curative option for myelofibrosis, but high rates of morbidity and mortality limit eligibility. Several prognostic models have been developed to facilitate treatment decisions. Until the recent approval of fedratinib, a JAK2 inhibitor, ruxolitinib was the only available JAK inhibitor for treatment of intermediate- or high-risk myelofibrosis. Ruxolitinib reduces splenomegaly to some degree in almost all treated patients; however, many patients cannot tolerate ruxolitinib due to dose-dependent drug-related cytopenias, and even patients with a good initial response often develop resistance to ruxolitinib after 2-3 years of therapy. Currently, there is no consensus definition of ruxolitinib failure. Until fedratinib approval, strategies to overcome ruxolitinib resistance or intolerance were mainly different approaches to continued ruxolitinib therapy, including dosing modifications and ruxolitinib rechallenge. Fedratinib and two other JAK2 inhibitors in later stages of clinical development, pacritinib and momelotinib, have been shown to induce clinical responses and improve symptoms in patients previously treated with ruxolitinib. Fedratinib induces robust spleen responses, and pacritinib and momelotinib may have preferential activity in patients with severe cytopenias. Reviewed here are strategies to ameliorate ruxolitinib resistance or intolerance, and outcomes of clinical trials in patients with myelofibrosis receiving second-line JAK inhibitors after ruxolitinib treatment.

Dataset Information

Sustained-release ruxolitinib: Findings from a phase 1 study in healthy subjects and a phase 2 study in patients with myelofibrosis.

Publications

Sustained-release ruxolitinib: Findings from a phase 1 study in healthy subjects and a phase 2 study in patients with myelofibrosis.

Similar Datasets

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