Otsuka Pharma Research Articles

Ponatinib Safety and Efficacy in Japanese Patients with Philadelphia Positive Leukemia: Update of a Phase 1/2 Study

Background: Ponatinib is a potent pan–BCR-ABL tyrosine kinase inhibitor (TKI), active against native and mutated BCR-ABL, including T315I, and approved by the US FDA for the treatment of adult patients with chronic myeloid leukemia (CML; all phases) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) that is T315I-positive or for whom no other TKI therapy is indicated. This is the first study evaluating the safety and efficacy of ponatinib in Japanese patients.Methods: This is an ongoing phase 1/2, multi-center, open-label, dose-finding study of ponatinib in Japanese patients with CML who have experienced a failure of dasatinib or nilotinib therapy, or Ph+ ALL who have experienced a failure of prior TKIs because of resistance or intolerance (ClinicalTrials.gov ID: NCT01667133). Following completion of the dose-escalation portion, in which 2 doses of ponatinib (30 mg once daily n=6; 45 mg once daily n=6) were evaluated, 45 mg once daily was selected for further study in phase 2 (n=35) to confirm the anti-leukemic activity of ponatinib. In phase 2, the primary efficacy endpoints were major cytogenetic response (MCyR) for CP-CML and major hematologic response (MaHR) for AP, BP, or Ph+ ALL. Data from the phase 1 portion have been previously presented (Japanese Society of Hematology 2013). Herein we report data as of 3 Feb 2014 from the phase 2 portion.Results: As of 30 Sep 2013, enrollment was completed with 35 patients; median age was 62 (30-77) years; median time since diagnosis was 2 (0.2-26) years; 80% patients had received ≥2 prior TKIs. Diagnoses at baseline were 17 CP-CML, 2 AP-CML, 4 BP-CML, and 12 Ph+ ALL. Twenty-two (63%) patients were resistant to their last TKI therapy, and 17 (49%) had one or more BCR-ABL mutation at baseline; 14/35 (40%) patients had the T315I mutation. At the time of analysis, 19 (54%) patients remain on therapy (15 CP-CML, 2 AP-CML, 2 BP- CML, and 0 Ph+ ALL). Primary reasons for discontinuation include adverse events (AEs; n=2), lack of efficacy (n=4) and progressive disease (n=7, all Ph+ ALL who died). Median duration of exposure was 174 (3-539) days. Median dose intensity was 38 (11-45) mg/day. To date, 23 (66%) patients had their dose reduced. Ten (59%) CP-CML patients attained the primary efficacy endpoint of MCyR (6 CCyR, 4 MMR). The primary efficacy endpoint of MaHR was achieved by 10 (56%) patients: 2/2 AP-CML, 2/4 BP-CML and 6/12 Ph+ ALL patients. Major molecular response (MMR) was observed in 5 (14%) patients.Treatment-emergent AEs (TEAEs) were observed in all patients, most common TEAEs (≥30% any grade) were thrombocytopenia (60%), pyrexia (57%), rash (37%), and hypertension (34%). Serious TEAEs were observed in 13 (37%) patients, the most common was pyrexia (n=3). No cases of pancreatitis were observed. Overall, 4 (11%) patients experienced arterial thrombotic events, 3 (9%) patients experienced serious events (1 brain stem infarction, 2 myocardial infarctions) and 1 patient experienced a non-serious event (ECG T wave inversion).Conclusions: Initial data indicate ponatinib has substantial anti-leukemic activity in these heavily pretreated CML and Ph+ ALL Japanese patients; the primary efficacy endpoint was achieved in >50% patients. Additional follow-up will allow for a more complete assessment of the benefits and risks of ponatinib therapy in Japanese CML and Ph+ ALL patients. DisclosuresOff Label Use: Ponatinib is a BCR-ABL kinase inhibitor that has been approved by the US FDA for the treatment of adult patients with CML (all phases) or Ph+ ALL that is T315I-positive or for whom no other TKI therapy is indicated.. Tojo:Novartis: Research Funding, Speakers Bureau; BMS: Research Funding. Yamamoto:Novartis: Honoraria, Research Funding, Speakers Bureau, support of manuscript preparation, support of manuscript preparation Other; Pfizer : Research Funding, support of manuscript preparation, support of manuscript preparation Other; ARIAD: Research Funding. Takahashi:Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis, BMS, Kyowa Hakko Kirin, Chugai Pharma, Dainippon Sumitomo Pharma, Celgene, Janssen Pharma : Honoraria, Research Funding, Speakers Bureau; Takeda Pharma: Research Funding; Asahikasei Pharma: Honoraria. Kobayashi:ARIAD, Otsuka Pharma, Boehringer Ingelheim : Research Funding. Matsumura:Bristol-Myers Squibb: Honoraria; Novartis: Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Usui:ARIAD: data monitoring committee Other. Yanase:ARIAD: Employment, Equity Ownership. Hu:ARIAD: Employment, Equity Ownership. Naoe:ARIAD: Consultancy. Ohyashiki:ARIAD: Consultancy.

Gone Fishing (for Silent Atrial Fibrillation)

Atrial fibrillation (AF) is associated with a stubbornly elevated mortality (3.5% –4% per year in trials),1–4 at odds with the decline in mortality after a first myocardial infarction.5 Furthermore, the prevalence and incidence of AF are increasing as our societies get older,6 and treatment of other acute and chronic cardiac disorders that predispose to AF will further prolong the lives of patients at risk of AF. Hence, there is a need to improve outcomes in patients with AF.7 Article see p 930 AF can present in a variety of clinical scenarios. Some patients suffer so much that they seek specialist help to be relieved from the arrhythmia. Others present with diffuse symptoms, often including fatigue and shortness of breath, and are found to be in AF on clinical or ECG examination. In yet others, AF is an incidental finding when an irregular heartbeat is detected on physical examination and/or an ECG is recorded for other reasons, such as during preoperative assessment. In these patients, the diagnosis of AF is made in time to institute therapy, such as oral anticoagulation, rate control, rhythm control, and therapy of concomitant cardiovascular diseases.8 It is estimated that one third of patients with AF are asymptomatic. Paroxysmal AF, in particular, frequently occurs without patient awareness. Studies in which systematic ECG monitoring is used have suggested that 50% to 70% of AF episodes occur without patient symptoms.9 Some patients are particularly unfortunate, and the diagnosis of AF is made only after presentation with an AF-related complication. The most devastating complication of AF is an acute ischemic stroke. In others, paroxysmal, self-terminating AF may remain undiagnosed even after the …