Dataset Information

Evaluation of an alternative ruxolitinib dosing regimen in patients with myelofibrosis: an open-label phase 2 study.

ABSTRACT: BACKGROUND:Ruxolitinib improves splenomegaly and symptoms in patients with intermediate-2 or high-risk myelofibrosis; however, nearly half develop grade 3/4 anemia and/or thrombocytopenia, necessitating dose reductions and/or transfusions. We report findings from an open-label phase 2 study exploring a dose-escalation strategy aimed at preserving clinical benefit while reducing hematological adverse events early in ruxolitinib treatment. METHODS:Patients with myelofibrosis received ruxolitinib 10 mg twice daily (BID), with incremental increases of 5 mg BID at weeks 12 and 18 for lack of efficacy (maximum, 20 mg BID). Symptom severity was measured using the Myelofibrosis Symptom Assessment Form Total Symptom Score (MFSAF TSS). RESULTS:Forty-five patients were enrolled, 68.9% of whom had a Dynamic International Prognostic Scoring System score of 1 to 2 (i.e., intermediate-1 disease risk). Median percentage change in spleen volume from baseline to week 24 was -?17.3% (??10% reduction achieved by 26 patients [57.8%]), with a clear dose response. Median percentage change in MFSAF TSS from baseline at week 24 was -?45.6%, also with a dose response. The most frequent treatment-emergent adverse events were anemia (26.7%), fatigue (22.2%), and arthralgias (20.0%). Grade 3/4 anemia (20.0%) and dose decreases due to anemia (11.1%) or thrombocytopenia (6.7%) were infrequent. CONCLUSIONS:A dose-escalation approach may mitigate worsening anemia during early ruxolitinib therapy in some patients with myelofibrosis. TRIAL REGISTRATION:ClinicalTrials.gov identifier, NCT01445769 . Registered September 23, 2011.

SUBMITTER: Talpaz M

PROVIDER: S-EPMC6081850 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Evaluation of an alternative ruxolitinib dosing regimen in patients with myelofibrosis: an open-label phase 2 study.

Talpaz Moshe M Erickson-Viitanen Susan S Hou Kevin K Hamburg Solomon S Baer Maria R MR

Journal of hematology & oncology 20180807 1

<h4>Background</h4>Ruxolitinib improves splenomegaly and symptoms in patients with intermediate-2 or high-risk myelofibrosis; however, nearly half develop grade 3/4 anemia and/or thrombocytopenia, necessitating dose reductions and/or transfusions. We report findings from an open-label phase 2 study exploring a dose-escalation strategy aimed at preserving clinical benefit while reducing hematological adverse events early in ruxolitinib treatment.<h4>Methods</h4>Patients with myelofibrosis receive ...[more]

PMID: 30086777

Similar Datasets

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:BackgroundMyelofibrosis is a chronic myeloproliferative neoplasm characterised by splenomegaly, cytopenias, bone marrow fibrosis, and debilitating symptoms including fatigue, weight loss, and bone pain. Mutations in Janus kinase-2 (JAK2) occur in approximately 50% of patients. The only approved JAK2 inhibitor for myelofibrosis is the dual JAK1 and JAK2 inhibitor, ruxolitinib. 58-71% of patients treated with ruxolitinib in clinical trials so far have not achieved the primary endpoint of 35% or more reduction in spleen volume from baseline assessed by MRI or CT. Furthermore, more than 50% of patients discontinue ruxolitinib treatment after 3-5 years. On the basis of this unmet need, we investigated the efficacy and safety of fedratinib, a JAK2-selective inhibitor, in patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofibrosis.MethodsThis single-arm, open-label, non-randomised, phase 2, multicentre study, done at 31 sites in nine countries, enrolled adult patients with a current diagnosis of intermediate or high-risk primary myelofibrosis, post-polycythaemia vera myelofibrosis, or post-essential thrombocythaemia myelofibrosis, found to be ruxolitinib resistant or intolerant after at least 14 days of treatment. Other main inclusion criteria were palpable splenomegaly (≥5 cm below the left costal margin), Eastern Cooperative Oncology Group performance status of 2 or less, and life expectancy of 6 months or less. Patients received oral fedratinib at a starting dose of 400 mg once per day, for six consecutive 28-day cycles. The primary endpoint was spleen response (defined as the proportion of patients with a ≥35% reduction in spleen volume as determined by blinded CT and MRI at a central imaging laboratory). We did the primary analysis in the per-protocol population only (patients treated with fedratinib, for whom a baseline and at least one post-baseline spleen volume measurement was available) and the safety analysis in all patients receiving at least one dose of fedratinib. This trial was registered with ClinicalTrials.gov, number NCT01523171.FindingsBetween May 8, 2012, and Aug 29, 2013, 97 patients were enrolled and received at least one dose of fedratinib. Of 83 assessable patients, 46 (55%, 95% CI 44-66) achieved a spleen response. Common grade 3-4 adverse events included anaemia (37 [38%] of 97 patients) and thrombocytopenia (21 [22%] of 97), with 18 (19%) patients discontinuing due to adverse events. Seven (7%) patients died during the study, but none of the deaths was drug related. Suspected cases of Wernicke's encephalopathy in other fedratinib trials led to study termination.InterpretationThis phase 2 study met its primary endpoint, suggesting that patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofibrosis might achieve significant clinical benefit with fedratinib, albeit at the cost of some potential toxicity, which requires further evaluation. Fedratinib development in this setting is currently being assessed.FundingSanofi.

Project description:BackgroundWilms' tumor 1 (WT1) is overexpressed in various malignancies. DSP-7888 Dosing Emulsion, also known as ombipepimut-S (United States Adopted Name; International Nonproprietary Name: adegramotide/nelatimotide), is an investigational therapeutic cancer vaccine comprising two synthetic peptides derived from WT1 to promote both cytotoxic T-lymphocyte (CTL) and helper T-lymphocyte-mediated immune responses against WT1-expressing tumors.ObjectiveThe aim of this study was to report the results from a phase I dose-escalation study (NCT02498665) that evaluated DSP-7888, administered either intradermally (ID) or subcutaneously (SC), in patients with recurrent or advanced malignancies associated with overexpression of WT1.Patients and methodsIn this phase I dose-escalation study, patients with recurrent or advanced malignancies associated with overexpression of WT1 who progressed on, were intolerant to, or not a candidate for standard therapy or who presented with a malignancy that had no definite standard therapy received escalating doses of ID or SC DSP-7888 in a rolling-six study design. DSP-7888 3.5, 10.5, or 17.5 (ID only) mg was administered until disease progression or other discontinuation event. Primary objectives were safety, tolerability, and identification of the recommended phase II dose (RP2D). Overall survival (OS) and WT1-specific CTL induction were included as secondary and exploratory objectives, respectively.ResultsTwenty-four patients received either ID (3.5 mg, n = 4; 10.5 mg, n = 3; 17.5 mg, n = 3) or SC DSP-7888 (3.5 mg, n = 9; 10.5 mg, n = 5). No dose-limiting toxicity was observed. The most frequent treatment-emergent adverse event was injection site reactions (ID, 100% [10/10]; SC, 35.7% [5/14]); all were grade 1 or 2. Four patients (ID 17.5 mg, n = 1; SC 3.5 mg, n = 1; SC 10.5 mg, n = 2) had stable disease, 16 had progressive disease, and four were not evaluable. Median (95% confidence interval) OS duration was 180.0 (136.0-494.0) days. Among evaluable patients, WT1-specific CTL induction was observed in 66.7% (6/9) and 41.7% (5/12) of those administered ID and SC DSP-7888, respectively.ConclusionsDSP-7888 Dosing Emulsion was well tolerated, with no dose-limiting toxicities, in patients with recurrent or advanced malignancies. Higher WT1-specific CTL induction activity was noted with ID compared with SC administration; because of this, the ID route was selected for further evaluation in the clinical program.Trial registrationClinicalTrials.gov identifier: NCT02498665.

Dataset Information

Evaluation of an alternative ruxolitinib dosing regimen in patients with myelofibrosis: an open-label phase 2 study.

Publications

Evaluation of an alternative ruxolitinib dosing regimen in patients with myelofibrosis: an open-label phase 2 study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets