Mg BID In Patients Research Articles

Net Clinical Benefit of Low Dose Rivaroxaban in Coronary Heart Disease: A Systematic Review and Meta-Analysis

Introduction US Food and Drug Administration has recently approved the use of rivaroxaban 2.5mg BID in patients with coronary heart disease based on Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial. However, it's unclear whether there is net clinical benefit with use of rivaroxaban in such patients. Therefore, we did a systematic review and meta-analysis to evaluate the effects of rivaroxaban on clinical outcomes in coronary heart disease patients. Methods: Embase, Ovid, Pubmed and Scopus were extensively searched from inception of these databases to April 2019 by two independent reviewers. Only randomized controlled trials of low dose rivaroxaban (2.5 mg BID) reporting mortality and cardiovascular outcomes of interest in baseline coronary heart disease patients (≥ 18 years) with at least 1000 patients and follow-up of ≥ 1 year were included. The co-primary outcomes were cardiovascular mortality and all-cause mortality. The secondary endpoints were myocardial infarction (MI), stroke, major adverse cardiovascular events, major bleeding and cerebral nervous system (CNS) bleeding. Cochrane Collaboration's tool was used for risk of bias assessment. Statistical heterogeneity was quantified using I2 statistics whereas publication bias was assessed with Eggers regression test. We combined estimates using DerSimonian and Laird random effects models. Outcomes were reported as hazard ratios (HR) with 95% confidence intervals (CI). Results: Five randomized control trials including 39,979 patients were included in our meta-analysis. Trials ATLAS and Commander HF used placebo as their control while COMPASS and GEMINI ACS-1 used aspirin as control. Pioneer AF-PCI used vitamin K antagonist as the control. Mean age (SD) of the patients was 65.6 ± 3.7 years with 74.3% females. Mean follow up in years was 1.6 ±0.5. Majority of the patients in each trial had hypertension. Our pooled analysis showed reduction in all-cause mortality (HR, 0.85, 95% CI, 0.72-1.00, P=0.05), cardiovascular mortality (HR, 0.83, 95% CI, 0.70-1.00, P=0.05), MI (HR, 0.88, 95% CI, 0.78-1.00, P=0.05) and stroke (HR, 0.70, 95% CI, 0.53-0.94, P=0.02) with low dose rivaroxaban. No significant difference in risk of bleeding was observed (HR, 1.45, 95% CI, 0.83-2.51, P=0.19). Our pooled analysis also showed reduction in major cardiovascular events (HR, 0.91, 95% CI, 0.85-0.98, P=0.01). CNS bleeding was only reported by ATLAS and COMPASS trials and net effect showed no statistically significant bleeding risk (HR, 1.63, 95% CI, 0.70-3.79, P=0.26). Conclusion: Our data suggest that the use of rivaroxaban is associated with reduction in all-cause and cardiovascular mortality in coronary heart disease patients without significantly increasing the risk of bleeding. To further decrease the residual risk of cardiovascular events in coronary heart disease patients, low dose rivaroxaban can be considered by clinicians. Disclosures No relevant conflicts of interest to declare.

Dabigatran Treatment of Acute Non-Cardioembolic Ischaemic Stroke: A Randomised Controlled Trial

Background: Transient ischaemic attack (TIA) and minor ischaemic stroke patients are at high risk for recurrent events. Anticoagulants are associated with reduced recurrent ischemic stroke rates, but also increased risk of haemorrhagic transformation (HT). Dabigatran, a novel oral anticoagulant associated with reduced risk of intracranial bleeding compared with warfarin in atrial fibrillation patients, has not been assessed in acute brain ischemia. We hypothesised that HT rates are not increased by dabigatran relative to aspirin after acute ischaemic stroke/TIA. Methods: DAbigatran Treatment of Acute Stroke II (DATAS II) was a prospective, randomised open label, blinded endpoint trial of dabigatran versus aspirin in acute stroke/TIA (clinicatrials.gov NCT02295826). Non-cardio-embolic stroke/TIA patients (NIHSS score ≤9, infarct volume < 25 ml) who did not receive thrombolytic therapy or thrombectomy were randomised 1:1 to dabigatran 150 mg BID (110 mg BID in patients ≥80 or if CrCl <50 ml/min) or aspirin (81 mg OD). Magnetic resonance imaging was performed prior to randomisation and was repeated at day 30, with clinical assessments at 30 and 90 days. Imaging endpoints were ascertained centrally by readers blinded to treatment. The primary endpoint was symptomatic HT within 37 days of randomisation. Secondary endpoints included asymptomatic HT and recurrent cerebral infarcts. Findings: A total of 305 patients, mean age 66±13.21 years, were randomised to dabigatran or aspirin a mean of 40.10±19.44 hours after symptom onset. The qualifying event was a TIA in 21%, and ischaemic stroke in79% of patients. Median NIHSS (IQR) was 1 (0-2), and mean infarct volume 3.2±6.5 ml. No symptomatic HT occurred. Asymptomatic petechial HT developed in 11/142 (7.8%) of dabigatran-assigned patients and 5/142 (3.5%) of aspirin-assigned patients (RR=2.32, 95% CI 0.78, 6.85). Baseline infarct volume predicted incident HT (OR 1.07; 95% CI 1.03-1.12, p=0.0026). Incident covert infarcts on day 30 imaging occurred in 9/142 (6.3%) of dabigatran and 14/142 (9.8%) of aspirin patients (RR=0.62, 95% CI 0.26, 1.48). There were no major bleeding events with either treatment. Interpretation: Dabigatran given to patients with acute minor non-cardioembolic ischaemic stroke/TIA was safe and was associated with a risk of HT similar to aspirin. Trial Registration Number: clinicatrials.gov NCT02295826 Funding Statement: DATAS II was funded by the Canadian Institutes for Health Research (G327075). Declaration of Interests: Dr. Butcher has served as an advisory board consultant and received speaker’s fees and investigatorinitiated grant support from Boehringer-Ingelheim, Bayer, BMS-Pfizer and Servier. Dr. Sharma has served as an advisory board consultant and or received speaker’s fees and investigator-initiated grant support from Boehringer-Ingelheim, Bayer, BMS-Pfizer, Daiichi Sankyo and Servier. Dr. Benavente has served as an advisory board consultant and or received speaker’s fees from Boehringer-Ingelheim, Bayer, BMS-Pfizer and Servier. Dr. Field has served as an advisory board consultant and received speaker’s fees from BoehringerIngelheim, Bayer, BMS-Pfizer and Servier and investigator-initiated grant support from BoehringerIngelheim and Bayer (study medication). Dr. Hill has served as a consultant for Boehringer-Ingelheim. He has received grants to the University of Calgary from Medtronic, Stryker, Boehringer-Ingelheim Canada, Bayer Canada. Dr. Gioia has received speaker honoraria from Bayer, and BMS Pfizer and has served as an advisory board consultant for Bayer, and Servier Inc. Dr. Coutts has served as an advisory board consultant for BMS-Pfizer. Boehringer-Ingelheim is providing study drug for an investigator-initiated study led by Dr. Coutts. Ethics Approval Statement: The trial was approved by research ethics review boards at each institution.

Effectiveness of mebeverine in patients with post-cholecystectomy gastrointestinal spasm: results of prospective observational program "odyssey".

To assess the effectiveness of mebeverine 200 mg BID in patients with post-cholecystectomy gastrointestinal spasm not requiring surgical treatment. 218 patients were included in 16 clinical centers in 14 cities in Russia. All patients had post-cholecystectomy gastrointestinal spasms, not requiring surgical treatment and received mebeverine (Duspatalin®) 200 mg BID. The observational assessment period lasted from the moment of their inclusion into the study up to 6 weeks post inlusion. The therapy results were evaluated using visual analog scales (GPA and 11-point numeric rating scale) by patient self-assessment of the dynamics of spasm/discomfort and other post-cholecystectomic gastrointestinal symptoms after 2 and 6 weeks of treatment. Gastrointestinal Quality of Life Index (GIQLI) was used to assess patient quality of life. All 218 patients completed the 2-week mebeverine treatment course, 101 of them finished the 6-week course ("prolonged population"). Significant positive changes in the relief of abdominal pain and dyspepsia were noted as well as normalization of stool frequency and consistency. A more marked change in values was observed during prolonged (up to 6 weeks) therapy. Both 2-week and 6-week mebeverine courses led to a normalization of patient quality of life. After 6 week therapy, an effect of mebeverine on the quality of life 91% of patients was observed comparable to cholecystectomy itself, speficially related to the quality of life subscore 'symptoms'. The results of our study demonstrate that mebeverine (Duspatalin®) therapy leads to an effective elimination of clinical symptoms associated with post-cholecystectomy GI-spasm disorders, like abdominal pain, symptoms of dyspepsia and stooldisorders. A more marked change in values was observed during prolonged (up to 6 weeks) therapy.

A pooled analysis of the safety of tofacitinib as monotherapy or in combination with background conventional synthetic disease-modifying antirheumatic drugs in a Phase 3 rheumatoid arthritis population

ObjectiveThis post-hoc, pooled analysis of Phase 3 studies of tofacitinib examined the safety of tofacitinib 5 and 10 mg twice daily (BID) when used as monotherapy versus combination therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis (RA). MethodsPooled data from six double-blind, randomized controlled Phase 3 studies of tofacitinib 5 and 10 mg BID in patients with RA were analyzed for safety and stratified by administration as monotherapy (ORAL Solo: NCT00814307 and ORAL Start: NCT01039688) or in combination with csDMARDs (ORAL Sync: NCT00856544, ORAL Standard: NCT00853385, ORAL Scan: NCT00847613, and ORAL Step: NCT00960440), and by glucocorticoid use at baseline. Safety assessments included incidence rates (IRs) for serious adverse events (SAEs), discontinuations due to AEs, serious infection events, and herpes zoster (HZ), and were evaluated throughout the duration of the Phase 3 studies. ResultsIn total, 3881 patients were included in the safety analysis (monotherapy studies: n = 1380; combination therapy studies: n = 2501). IRs for selected AEs of interest were generally numerically lower in patients who received tofacitinib 5 and 10 mg BID as monotherapy than as combination therapy (SAEs: IR [range] 6.21–6.72 versus IR 10.17–13.46; discontinuations due to AEs: IR 5.53–6.18 versus IR 10.80–11.01; serious infections: IR 1.57–1.66 versus IR 3.39–3.56; HZ: IR 1.95–2.93 versus IR 4.37–4.99, respectively), irrespective of tofacitinib dose or glucocorticoid use. There were too few patients and events within the placebo group to fully evaluate effect between combination therapy and monotherapy. ConclusionsSafety profiles were generally similar between patients receiving monotherapy and combination therapy; however, selected safety events of interest, including HZ and serious infections, showed lower IRs with non-overlapping 95% confidence intervals for tofacitinib all monotherapy versus combination therapy. Tofacitinib monotherapy may, therefore, have fewer safety events compared with combination therapy, and have a favorable risk-benefit profile in patients with active RA who are intolerant to csDMARDs.

Sa1761 - Efficacy and Safety of Dose Escalation to Tofacitinib 10 Mg Bid for Patients with Ulcerative Colitis Following Loss of Response on Tofacitinib 5 Mg Bid Maintenance Therapy: Results from Octave Open

Sa1761 - Efficacy and Safety of Dose Escalation to Tofacitinib 10 Mg Bid for Patients with Ulcerative Colitis Following Loss of Response on Tofacitinib 5 Mg Bid Maintenance Therapy: Results from Octave Open

TRITON2: An international, multicenter, open-label, phase II study of the PARP inhibitor rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination deficiency (HRD).

TPS388 Background: Up to 25% of patients with advanced prostate cancer, including mCRPC, have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM or another homologous recombination (HR) DNA repair gene that can serve as a molecular marker to select those who may respond to poly(ADP-ribose) polymerase inhibitors (PARPis). PARPis are lethal to cells with HRD, and PARPi treatment has shown preliminary evidence of an antitumor effect in patients with mCRPC who harbor a mutation in an HR DNA repair gene (Mateo et al. N Engl J Med. 2015;373:1697-708). These data provide a compelling rationale for evaluating rucaparib, a potent PARP1, PARP2 and PARP3 inhibitor, in patients with mCRPC associated with HRD. Methods: TRITON2 (NCT02952534) is a phase 2 study evaluating rucaparib 600 mg BID in patients with mCRPC. Patients with a deleterious germline or somatic BRCA1, BRCA2 or ATM mutation (per prior local test or central test during screening) will be enrolled into 1 of 2 cohorts based on the presence or absence of measurable visceral and/or nodal disease. An exploratory cohort will enroll patients with an alteration in any of 12 other prespecified HR genes (eg, RAD51C, RAD51D and PALB2), with or without measurable visceral and/or nodal disease. Patients must have progressed on androgen receptor signaling–directed therapy and 1 prior taxane-based chemotherapy for mCRPC. Patients who received prior treatment with a PARPi, mitoxantrone, cyclophosphamide or platinum-based chemotherapy are excluded. The primary endpoint is objective response rate measured using modified RECIST v1.1/PCWG3 for patients with soft-tissue disease and prostate-specific antigen response for patients with nonmeasurable disease. Secondary endpoints include duration of response, radiographic progression-free survival, overall survival, clinical benefit rate and safety. Pretreatment blood samples collected from all patients will enable development of a plasma-based companion diagnostic to select patients who may benefit from rucaparib treatment. Patients (≈160) will be enrolled at &gt; 100 sites worldwide. Clinical trial information: NCT02952534.

DOP026 Efficacy and safety of dose escalation to tofacitinib 10 mg BID for patients with ulcerative colitis following loss of response on tofacitinib 5 mg BID maintenance therapy: results from OCTAVE open

DOP026 Efficacy and safety of dose escalation to tofacitinib 10 mg BID for patients with ulcerative colitis following loss of response on tofacitinib 5 mg BID maintenance therapy: results from OCTAVE open

Increased Thromboembolic Events With Dabigatran Compared With Vitamin K Antagonism in Left Ventricular Assist Device Patients: A Randomized Controlled Pilot Trial.

Left ventricular assist device-supported patients are usually anticoagulated with a combination of aspirin and vitamin K antagonists. Long-term vitamin K antagonist therapy can be complicated by unstable international normalized ratio values and patient-related compliance problems. Therefore, direct thrombin inhibitors may represent an alternative to vitamin K antagonists. Thirty HeartWare ventricular assist device patients with stable renal function were planned for this prospective, randomized, open-label, single-center study. Patients were randomized to receive either phenprocoumon or dabigatran in addition to aspirin for long-term anticoagulation. Treatment duration was scheduled for 1 year and stopped after observation of a primary end point. Dabigatran dose was 110 and 75 mg BID in patients with normal or impaired renal function (glomerular filtration rate >80 mL/min or between 80 and 30 mL/min, respectively). The study was stopped prematurely for safety reasons after 16 patients (61±8 years, 1 female) were randomized. Thromboembolic events occurred in 4 subjects receiving dabigatran (50%) and in 1 receiving phenprocoumon (13%; P=0.28). No major bleeding was recorded, and no patient died during the study. Median time to treatment termination was significantly shorter in dabigatran patients (8.5 versus 12.0 months; P=0.015). Thromboembolic events on dabigatran led to early termination of a randomized controlled trial of dabigatran versus phenprocoumon in left ventricular assist device patients. https://www.clinicaltrials.gov. Unique identifier: NCT02872649.

Impact of Body Weight Adjusted Dose on Efficacy and Safety of Radotinib in Chronic Myeloid Leukemia

▪Background: Radotinib is a BCR-ABL tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myeloid leukemia in chronic phase (CP-CML). It is typically administered as a fixed dose; however, a subanalysis of the Phase 2 study (Leuk Lymphoma. DOI 10.3109/10428194.2015.1113278) demonstrated that as the dose adjusted for body weight (Dose/BW) increased the risk of dose-limiting toxicity (DLT) significantly.Aims: To assess the impact of Dose/BW of radotinib on the occurrence of DLT as well as on the achievement of major molecular response (MMR) using the clinical data obtained from the Phase 3 studyMethods: The Phase 3 study involved 160 CP-CML patients who were randomly assigned to a fixed dose of radotinib 300 mg BID or 400 mg BID regardless of BW. The authors performed a logistic regression analysis to evaluate the relationship between daily Dose/BW and the probability of achieving MMR at 12 months as well as experiencing DLT by 12 months. Chi-square test and Kaplan-Meier analysis (log-rank test) were utilized to compare the incidence of MMR and DLT, respectively, according to specific Dose/BW cut-offs.Results:Efficacy. Dose/BW of radotinib was negatively associated with the rate of MMR when controlled for gender (p = 0.033). That is, increasing Dose/BW rather decreased the likelihood of achieving MMR. More specifically, patients who received ≥13 mg/kg/d showed a significantly lower rate of MMR at 12 months (35%) than those who received <13 mg/kg/d (56%) (p = 0.045). Safety. Dose/BW of radotinib was positively associated with the rate of DLT (p = 0.003). A Dose/BW cut-off 13 mg/kg/d yielded the largest difference in the rate of DLT, such that the patients who received ≥13 mg/kg/d had a substantially higher rate of DLT (91%) than those who received <13 mg/kg/d (57%) (p <0.001). The time at which 50% of patients experienced their first DLT was also much earlier in the ≥13 mg/kg/d group (83 days) than in the <13 mg/kg/d group (194 days) (p <0.001).Conclusion: Dose adjustment of radotinib based on BW is warranted so as not to exceed 13 mg/kg/d. Therefore, a two-tier weight-based dosing regimen was developed: radotinib 300 mg BID for patients who weigh 60 kg or less, and 400 mg BID for patients who weigh more than 60 kg. A prospective clinical trial would be needed to confirm the efficacy and safety of this new dosing regimen. DisclosuresNoh:Il-Yang Pharmaceutical: Research Funding. Jung:Il-Yang Pharmaceutical: Research Funding. Park:Il-Yang Pharmaceutical: Employment. Jo:Il-Yang Pharmaceutical: Employment. Shin:Il-Yang Pharmaceutical: Employment. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding. Lee:Il-Yang Pharmaceutical: Research Funding.

Ruxolitinib Restores Normal Telomere Length in Patients with Myelofibrosis

Introduction Telomeres are specialized structures of repetitive nucleotide sequences that cap the ends of human chromosomes able to maintain genome stability and protect the cell from progressive DNA shortening. Some recent reports describe reduced telomere length in myelofibrosis (MF) regardless of hydroxycarbamide therapy, suggesting a possible prognostic relevance for this biomarker. As yet, no studies have investigated telomere dynamics following treatment with ruxolitinib. Methods Eight primary MF and 3 post ET MF patients were given 15 mg or 20 mg of oral ruxolitinib twice daily (BID) depending on baseline platelet counts. The drug dose was escalated to 25mg BID in patients with an inadequate response and reduced when platelet counts dropped to <100,000/μL. Treatment was stopped when platelet levels fell below 50.000/μL. Telomere lengths were analyzed by quantitative PCR (q-PCR) as described by Cawthon (2002) and assessed before and after ruxolitinib at a median of 1000 days (range 113-1152). The relative telomere length (RTL) was determined as the telomere (T) to single copy gene (36B4) (S) ratio (T/S) normalized to a reference sample (K-562 DNA). Peripheral blood samples were also collected from 11 age and sex matched healthy controls. Results Median age at diagnosis was 72 years (range 53-83). The JAK2 V617F mutation was detected in 7 patients, while CALR and MPL were found in 2 and 1 patient, respectively. One patient was triple negative. All patients had splenomegaly with a median enlargement of 17 cm below the costal margin. Based on IPSS scores, 6 patients were assigned to the intermediate-2 risk category and 5 to the high risk category. Ruxolitinib was administered for a median of 1000 days (range 113-1152). Overall, patients received a median of 22 grams of ruxolitinib (range 4.6-44.5). Splenomegaly decreased by 60% (range 20-100%). Overall, BM fibrosis was improved in 35% of the cases and remained stable in 65%. Related samples Wilcoxon signed rank test performed before treatment with ruxolitinib, showed that mean RTL was shorter in patients compared to age and sex matched healthy controls (1.08 vs 1.26, respectively; p=0.09). After treatment, median RTL increased significantly (1.30 vs 1.08; p=0.018), showing overlapping values with the healthy controls. Median RTL elongation from baseline was 15% (Figure). Univariate and multivariate analyses included the following parameters: primary MF, presence of the JAK2 V617F mutation, high IPSS score, a decrease in splenomegaly of >50%, >50% bone marrow (BM) cellularity before and after treatment, pre and post treatment WHO scores for BM fibrosis of 3-4, duration of treatment >1000 days, total drug dose of >22 grams. Variables with a p-value lower than 0.2 in univariate analysis were included in multivariate analysis using a multi-step forward binary logistic regression model, where RLT >15% from baseline was considered a dependent variable. Only pre-treatment BM cellularity of >50% significantly correlated with >15% telomere elongation (p=0.004). Conclusion In our small cohort of patients, ruxolitinib proved capable of improving BM fibrosis and restoring telomere lengths to normal values. It is possible that ruxolitinib mediates modulation of the BM microenvironment, thereby stimulating stem cell hematopoiesis. It follows that peripheral blood telomere elongation could be indicative of the stem cellÕs ability to self-renew. This finding, if confirmed, would open a debate about the rationale of treatment with telomerase inhibitors in MF patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Consistent effect of nintedanib on decline in FVC in patients across subgroups based on HRCT diagnostic criteria: results from the INPULSIS® trials in idiopathic pulmonary fibrosis (IPF)

Background: The randomized, placebo-controlled, 52-week INPULSIS® trials assessed efficacy and safety of nintedanib 150 mg bid in patients with IPF. Nintedanib significantly reduced annual rate of FVC decline vs. placebo (primary endpoint) in both trials). Key secondary endpoints were time to first acute exacerbation and change from baseline in SGRQ total score, both over 52 weeks.

Effect of baseline FVC on decline in lung function with nintedanib in patients with idiopathic pulmonary fibrosis (IPF): results from the INPULSIS® trials

Background: The two replicate, randomised, placebo-controlled, 52-week INPULSIS® trials assessed the efficacy and safety of nintedanib 150 mg bid in patients with IPF. Patients with FVC ≥50% predicted were included. The primary endpoint, the annual rate of FVC decline, was significantly reduced in the nintedanib group compared with placebo in both trials, consistent with slowing of disease progression. Key secondary endpoints were time to first acute exacerbation and change from baseline in SGRQ total score, both over 52 weeks.

Phase 1b and Pharmacokinetic Study of Idelalisib in Japanese Patients with Relapsed or Refractory (R/R) Indolent B-Cell Non-Hodgkin Lymphoma (iNHL) or Chronic Lymphocytic Leukemia (CLL)

Background: Increased phosphatidylinositol-3-kinase delta (PI3Kd) activity drives proliferation and survival of malignant B-cells and mediates trafficking to lymphoid tissues. Idelalisib, a first-in-class, selective, oral inhibitor of PI3Kd, is approved in combination with rituximab for patients with relapsed CLL and as monotherapy in patients with relapsed/refractory (R/R) follicular lymphoma (FL) in North America and the EU.Methods: Six Japanese patients were enrolled between October 2014 and November 2014. This is an open-label 6+6 study design for continuous dosing of idelalisib 150mg BID in patients with R/R CLL and iNHL until PD or intolerable toxicity. The primary objective was to evaluate the 28-day safety, tolerability and pharmacokinetics of idelalisib and its metabolite GS-563117. The primary endpoint was the incidence of dose-limiting toxicity (DLT) defined as grade 4 hematological toxicities persisting for >14 days, grade ≥3 non-hematological toxicities, grade >3 laboratory abnormalities, red cell transfusion, and a therapeutic platelet transfusion. Key inclusion criteria were: age ≥20 yrs, patient of Japanese ancestry. Key exclusion criteria were known histological transformation to an aggressive histology, history of iNHL or CLL with CNS involvement. Response assessments as per modified Hallek 2008 and Cheson criteria 2007 were performed using CT scans at pre-determined time points by investigators.Results: Baseline characteristics included 3 patients each with CLL (2/3 refractory, 1/3 relapsed) or FL (3/3 refractory), and median age was 64 years (range 49-74). Median number of prior Rx regimens was 3.5 (range 1-6). Prior therapies included bendamustine plus rituximab (67%), R-CHOP (67%), and R-CVP (33%). No Japanese patients experienced a DLT within the 28-day window. The PK of idelalisib and GS-563117 were comparable between Japanese and non-Japanese patients; non-Japanese PK data predicted from preceding Phase 2 and Phase 3 studies. The most common treatment-emergent any grade/≥ grade 3 AEs in increasing frequency were gastritis (33%/0%), pyrexia (33%/0%), transaminases increased (33%/33%), chest pain (17%/0%), decreased appetite (17%/17%), diarrhea (17%/17%), neutrophil count decreased (17%/17%) and common laboratory abnormalities were decreased WBC (50%/17%), decreased neutrophil count (50%/17%), increased ALT (33%/17%), and increased AST (17%/17%). At the time of this analysis, a total of 3 patients experienced serious AEs (50%); decreased appetite, diarrhea, and increased transaminases. Investigator response assessments were 5/6 (83%) patients achieving partial response (PR) and 1/6 (17%) stable disease.Conclusions: Continuous dosing of idelalisib demonstrated a manageable safety profile with promising efficacy in Japanese patients with R/R CLL and FL. The PK of idelalisib and GS-563117 were comparable between Japanese and non-Japanese patients. The study was registered at ClincalTrials.gov (NCT02242045). DisclosuresKinoshita:Gilead Sciences: Research Funding. Fukuhara:Gilead Sciences: Research Funding. Nagai:Gilead Sciences: Research Funding. Izutsu:Gilead Sciences: Research Funding. Kobayashi:Gilead Sciences: Research Funding. Higuchi:Gilead Sciences: Research Funding. Harigae:Gilead Sciences: Research Funding. Tokunaga:Gilead Sciences: Research Funding. Adewoye:Gilead Sciences: Employment, Equity Ownership. Robeson:Gilead Sciences: Employment, Equity Ownership. Sharma:Gilead Sciences: Employment, Equity Ownership. Fukui:Gilead Sciences: Research Funding. Gao:Gilead Sciences: Employment, Equity Ownership. Christenson:Gilead Sciences: Employment, Equity Ownership. Tobinai:Gilead Sciences: Research Funding.

Molecular Response in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated With Nilotinib: ENESTnext Update

study population the achievement of MMR and CCyR as well as the OS, PFS and EFS were similar to previous published data. Reaching high survival rates with first generation TKIs in a country with limited resources can be a reasonable option to approach CML patients.

Tolerability of Nintedanib (BIBF 1120) in Combination with Docetaxel: A Phase 1 Study in Japanese Patients with Previously Treated Non–Small-Cell Lung Cancer

This phase I, open-label study evaluated the safety/tolerability and maximum tolerated dose of second-line nintedanib combined with docetaxel in Japanese patients with advanced non-small-cell lung cancer. Eligible patients received docetaxel 60 or 75 mg/m(2) (day 1) plus nintedanib 100, 150, or 200 mg twice daily (bid; days 2-21) in 21-day cycles. Standard 3 + 3 dose escalations were performed separately in patient cohorts with a body surface area (BSA) of less than 1.5 m(2) (BSA <1.5) and BSA greater than or equal to 1.5, respectively. Forty-two patients (17 BSA <1.5, 25 BSA ≥ 1.5) were treated. The maximum tolerated dose of nintedanib was 150 and 200 mg bid in patients with BSA less than 1.5 and BSA greater than or equal to 1.5 (BSA ≥ 1.5), respectively, in combination with 75 mg/m(2) of docetaxel. Dose-limiting toxicities (all grade 3 hepatic enzyme elevations) occurred in 12 patients (six per cohort). Drug-related adverse events included neutropenia (95%), leukopenia (83%), fatigue (76%), alopecia (71%), decreased appetite (67%), and elevations in alanine aminotransferase (64%) and aspartate aminotransferase (64%). All hepatic enzyme elevations were reversible and manageable with dose reduction or discontinuation. Among 38 evaluable patients, 10 (26%) had a partial response and 18 (47%) had stable disease. Continuous treatment with second-line nintedanib combined with docetaxel was manageable and showed promising signs of efficacy in Japanese patients with advanced non-small-cell lung cancer.

Efficacy of Once Daily Darunavir/Ritonavir in PI-Naïve, NNRTI-Experienced Patients in the ODIN Trial.

Background. An exploratory subanalysis of the ODIN trial was performed to evaluate the efficacy of darunavir/ritonavir (DRV/r) 800/100 mg OD versus 600/100 mg BID in patients who were NNRTI-experienced but PI-naïve. Methods. ODIN was a phase III, 48-week study comparing DRV/r OD versus BID in 590 treatment-experienced patients with no DRV resistance-associated mutations (RAMs) at screening. Patients received DRV/r 800/100 mg OD or DRV/r 600/100 mg BID plus ≥2 NRTIs. Of the 590 patients randomized, 272 (46%) were NNRTI-experienced but PI-naïve. Results. Overall, 272 patients received DRV/r OD (n = 135) or BID (n = 137) plus ≥2 optimised NRTIs. The mean age was 39 years; 35% were female; 27% were Black, 24% Caucasian, 26% Oriental/Asian, and 23% other races; 17% were recruited in South Africa; and 48% had non-B HIV-1 subtypes. Mean baseline plasma HIV-1 RNA load was 4.10 log10⁡ copies/mL; median CD4 cell count was 258 cells/μL. At week 48, 111/135 (82%) of DRV/r OD and 109/137 (80%) of DRV/r BID patients achieved an HIV-1 RNA load <50 copies/mL. No patient developed primary PI RAMs. Conclusion. DRV/r 800/100 mg OD in combination with ≥2 optimised NRTIs led to virological suppression <50 copies/mL in 82% of NNRTI-experienced, PI-naïve patients by week 48.

A Randomised Comparison of the Sequential Addition of the FLT3 Inhibitor Lestaurtinib (CEP701) to Standard First Line Chemotherapy for FLT3-Mutated Acute Myeloid Leukemia: The UK Experience

Activating mutations of the receptor tyrosine kinase FLT3 are seen at diagnosis in one-third of younger adults with acute myeloid leukemia (AML) and are associated with an increased risk of relapse. FLT3 remains the subject of intense clinical interest as a therapeutic target. To date FLT3-targeted monotherapy has produced only transient clinical responses with no prospective trial producing an overall survival benefit. Here we report the results of the first randomised trial of a FLT3 inhibitor (Lestaurtinib, CEP701) given sequentially to chemotherapy as first line treatment for newly-diagnosed AML. FLT3-mutated patients entering the UK MRC AML15 and UK NCRI AML17 trials between January 2007 and October 2012 were randomised to receive either oral Lestaurtinib 80mg bid, or placebo, for up to 28 days after each of 4 courses of chemotherapy. Based on early pharmacokinetic data provision was made for dose reduction to 40mg bid for patients on concomitant azole anti-fungal drugs.500 patients were randomised (175 AML15, 325 AML17). Median age was 49yrs (5-68, only 5 were <16yrs.). 94% patients had de novo AML, 5% secondary AML and 1% high risk MDS. The majority of patients (89%) had cytogenetically intermediate risk disease with 6% favourable and 5% adverse risk. Median presenting WBC was 28.0x109/l (0.2-363); 381 patients (74%) had FLT3-ITD mutations, 127 (23%) FLT3-TKD point mutations and 12 (2%) both types; 207 patients (41%) had concomitant mutated NPM1. All characteristics were balanced between the arms.Results: No difference in remission rate was seen between the arms (CR/CRi: Lestaurtinib 92% vs Control 94%. OR 1.37 [0.68-2.78] p=0.4). The respective 5-year RFS was 40% vs 37%, HR 0.87 (0.68-1.12) p=0.3; cumulative incidence of relapse 52% vs 54%, HR 0.87 (0.67-1.13) p=0.3 and OS at 5 years 46% vs 43%, HR 0.89 (0.68-1.13) p=0.3 did not differ between arms. [Display omitted] 43% of patients were transplanted in both Lestaurtinib and control arms (130/300 and 85/200 respectively); 133 transplants were in CR1, 63 in CR2; 188 were allografts. When the data were censored at SCT the lack of difference in clinical outcome persisted (HR 0.97 [0.71-1.33] p=0.8).Stratified analyses involving age, sex, diagnosis (de novo/secondary/MDS), cytogenetic group, performance status, ITD vs TKD, ITD allelic %, NPM1 status, Gemtuzumab ozogamicin (GO) or not in induction and concomitant use of azoles were undertaken to identify evidence of subgroup benefit with Lestaurtinib. No significant interactions were seen, with some evidence of survival benefit in patients receiving GO (p=0.09 for interaction). In patients receiving concomitant azole treatment there was a significant survival benefit with Lestaurtinib (HR 0.57 (0.36-0.92) p=0.02) although the test for interaction was not significant (p=0.2). Course 1 day 14 plasma trough Lestaurtinib levels were significantly higher in azole-treated patients than in those not receiving azoles (median 4517 vs 3085ng/ml, p=0.03). In AML17 patients treated with GO and azoles, survival with Lestaurtinib at 4 years was 61% compared to 28% in the control arm (p=0.02)Minimal difference in toxicity was seen between the 2 arms, with the exception of slight excess nausea/diarrhea with Lestaurtinib in course 2. Supportive care requirements were slightly increased with Lestaurtinib with a borderline-significant 1-day increase in median time to platelet recovery following course 2 (p=0.05).Conclusion: Lestaurtinib may be safely combined with intensive chemotherapy in younger patients with newly-diagnosed FLT3-mutated AML. No overall clinical improvement was seen with Lestaurtinib, although there was a suggestion of benefit in patients also receiving GO in induction: in Lestaurtinib-treated patients receiving both GO and azoles, survival was 61%. The potential clinical benefit of GO with adequate FLT3 inhibition requires prospective validation.(We are grateful to Cephalon for the provision of Lestaurtinib for this study) DisclosuresKnapper:Cephalon: Consultancy, Research Funding. Off Label Use: Tyrosine kinase inhibitor Lestaurtinib (CEP701) used off-label in a randomised controlled trial in FLT3-mutated acute myeloid leukemia.

Deep Molecular Response in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated With Nilotinib: ENESTnext Update

Abstract Background: The BCR-ABL tyrosine kinase inhibitor nilotinib elicits faster and deeper molecular responses (MRs) vs imatinib in patients with CML-CP. Achievement of sustained deep MR is associated with improved long-term outcomes and is a key criterion for entry into treatment-free remission (TFR) studies. Given the importance of accurately measuring deep MR in patients with CML, increasingly sensitive techniques are needed for monitoring minimal residual disease. In ENESTnext, MR to nilotinib was assessed using conventional methodology (real-time quantitative reverse transcriptase polymerase chain reaction [RQ-PCR]) and a novel microfluidic digital PCR assay that is &gt; 1 log more sensitive than standard RQ-PCR. Methods: In this single-arm, open-label, multicenter study (NCT01227577), adults with CML-CP diagnosed within 6 months of enrollment were treated with nilotinib 300 mg twice daily (BID) for up to 2 years. Dose escalation to nilotinib 400 mg BID for patients with suboptimal response or treatment failure (per modified European LeukemiaNet 2009 recommendations) was permitted per physician discretion. RQ-PCR evaluation of peripheral blood samples was performed by a central laboratory (monthly for the first 3 months and every 3 months thereafter) according to the International Scale (IS). The primary endpoint is the rate of confirmed (≥ 2 samples taken 3 months apart) MR4.5 (≥ 4.5-log reduction of BCR-ABL transcript levels; BCR-ABLIS ≤ 0.0032%) with 2 years of nilotinib therapy; complete cytogenetic response (CCyR) and major MR (MMR; 3-log reduction of BCR-ABL transcript levels; BCR-ABLIS ≤ 0.1%) were evaluated as secondary endpoints. Per protocol, assessment of cytogenetic response was not required at specified time points for all patients on study. In an exploratory analysis, samples from patients with confirmed MR4.5by conventional RQ-PCR were also evaluated using the more sensitive Fluidigm digital PCR platform. The data cutoff date for this analysis was April 30, 2014. Results: A total of 128 patients were enrolled (median age, 56.5 years [range, 21.0-89.0 years]); 64 patients (50.0%) were male and 103 (80.5%) were Caucasian. As of the data cutoff, 45 patients (35.2%) had completed the study, 49 (38.3%) remained on treatment, and 34 (26.6%) had discontinued early. With a median treatment duration of 12.7 months, 88 (68.8%), 94 (73.4%), and 32 (25.0%) patients achieved CCyR, MMR, and MR4.5, respectively, at any time (Table). Of 32 patients who achieved MR4.5, 14 achieved MR4.5 by 6 months. A total of 169 samples from 32 patients with confirmed MR4.5 by conventional RQ-PCR were analyzed by digital PCR. Using the digital PCR platform, 6 of these patients initially had detectable BCR-ABL transcripts that subsequently became undetectable with continued nilotinib therapy. Of the remaining 26 patients, 12 had BCR-ABL transcripts that were initially undetectable and remained undetectable by digital PCR, 12 had detectable BCR-ABL transcripts that remained detectable, and 2 had undetectable BCR-ABL transcripts that became detectable. The most common (≥ 4 patients) grade 3/4 adverse events (AEs) regardless of relationship to study drug were increased lipase (n = 14), thrombocytopenia (n = 11), neutropenia (n = 8), hypophosphatemia (n = 5), anemia (n = 4), and nausea (n = 4). Reasons for study discontinuation were AEs (n = 15), unsatisfactory therapeutic effect (n = 5), withdrawn consent (n = 4), death (n = 3; causes of death were other malignancy, pneumonia, and not specified/no AE [n = 1 each]), protocol deviation (n = 3), abnormal laboratory values (n = 2), loss to follow-up (n = 1), and administrative problems (n = 1). Conclusions: Frontline treatment with nilotinib 300 mg BID in patients with newly diagnosed CML-CP led to rapid achievement of MR4.5 as assessed with conventional RQ-PCR. As &gt; 40% of samples with at least MR4.5according to standard RQ-PCR were positive using the digital PCR assay, this tool may have potential in evaluating MR to determine eligibility for TFR studies. Table Response CCyRa MMR MR4.5 Patients with response, n (%) 88 (68.8) 94 (73.4) 32 (25.0) Time to response, n (%) &lt; 3 mo 26 (20.3) 21 (16.4) 2 (1.6) 3 to &lt; 6 mo 42 (32.8) 41 (32.0) 12 (9.4) 6 to &lt; 12 mo 16 (12.5) 22 (17.2) 11 (8.6) 12 to &lt; 18 mo 4 (3.1) 9 (7.0) 7 (5.5) ≥ 18 mo 0 1 (0.8) 0 a Cytogenetic response was not assessed in all patients at all time points. Disclosures Mauro: Novartis Oncology: Consultancy; Bristol Myers Squibb: Consultancy; Ariad: Consultancy; Pfizer: Consultancy. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Rizzieri:Sanofi: Consultancy; Celgene: Consultancy, Speakers Bureau. Keir:Novartis: Employment, Equity Ownership. Yi:Novartis Pharmaceuticals: Employment. Heinrich:Novartis: Consultancy, Patents &amp; Royalties, Research Funding; MolecularMD: Consultancy, Equity Ownership. Goldberg:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; Pfizer: Research Funding. Kuriakose:Teva: Speakers Bureau; Alexion: Speakers Bureau. Radich:Novartis: Consultancy, Research Funding; Ariad: Consultancy.

Cost-effectiveness of dabigatran versus vitamin K antagonists for the prevention of stroke in patients with atrial fibrillation: A French payer perspective

Atrial fibrillation is the main cause of stroke, but the risk can be reduced, usually with vitamin K antagonists (VKAs) such as warfarin. The RE-LY atrial fibrillation study demonstrated that the rates of stroke and systemic embolism with dabigatran (an oral direct thrombin inhibitor) were similar to or lower than those with warfarin. To estimate the cost-effectiveness, from a French payer perspective, of dabigatran (150 or 110mg bid for patients<or≥80 years, respectively) versus warfarin. Cost-effectiveness was modeled using a Markov model in a cohort of 10,000 patients with atrial fibrillation followed over their lifetime. Events accounted for included ischemic stroke, systemic embolism, transient ischemic attack, hemorrhage, myocardial infarction and death. The model patient population matched the RE-LY patients. Dabigatran was compared with "trial-like" warfarin and "real-world" prescribing. Risks of clinical events were obtained from RE-LY. Event and follow-up costs were based on the French national tariff or published literature. Clinical events, QALYs, total costs and incremental cost-effectiveness ratios (ICERs) were calculated. The ICERs of dabigatran compared with "trial-like" warfarin and "real-world" prescribing were €15,838/QALY and €7473/QALY, respectively. Deterministic and probabilistic sensitivity analyses showed these to be robust to uncertainty and variability in the model parameters. The ICER for dabigatran was below €24,000/QALY or €36,000/QALY in 71% or 92%, respectively, of the simulations when compared with "trial-like" warfarin and 100% and 100%, respectively, when compared with "real-world" prescribing. This study suggests that the use of dabigatran in French atrial fibrillation patients is cost-effective, according to usually accepted thresholds.

Abstract 61: Safety and Feasibility of Acute Dabigatran Therapy in Minor Ischemic Stroke Patients Without Atrial Fibrillation.

Introduction: Transient Ischemic Attack (TIA) and Minor ischemic stroke (MIS) patients are at high risk for recurrent events. Older anticoagulants are associated with a reduction in recurrent events, but also an increase in hemorrhagic transformation (HT). Dabigatran etexilate (DE), a novel oral anticoagulant that is associated with reduced risk of intracranial bleeding in atrial fibrillation (AF) patients, may be an effective therapy in this population. DE is not indicated within 14 days of ischemic stroke, due to an absence of data. We tested the feasibility and safety of initiating DE therapy within 24 h of TIA/MIS. Methods: We designed a 50 patient single arm open label treatment trial. The primary endpoint was symptomatic HT within 30 days of enrolment. All patients underwent MRI prior to treatment. TIA/MIS patients (NIHSS score ≤3) with a DWI lesion were prospectively treated with DE 150 mg BID (110 mg BID in patients ≥ 80 or if CrCl &lt;40 ml/min). Treatment began within 24 h of onset and continued for 30 days. Patients with known atrial fibrillation (AF) were excluded. Patients were re-imaged at day 7 and 30, with clinical assessment to 90 days. Results: Forty-three of 50 patients have been enrolled to date (March 2012-August 2013). The mean age was 66±12 years and median (IQR) NIHSS was 1 (2). Median baseline DWI volume was 0.89(1.9) ml. The median time from onset to initial DE dose was 18.5 (12.2) h. Therapy was completed in 41 patients and discontinued in two (withdrawal of consent (1) and dysphagia (1)). Two patients died within the 90 day study period, both after completion of DE therapy. No patients experienced systemic bleeding or symptomatic intracranial hemorrhage. One patient had asymptomatic HT (ECASS grade, HI1) on day 7, which resolved by day 30 despite continuing DE. No patients experienced recurrent clinical stroke. New asymptomatic DWI lesions developed in 7 (16%) patients by day 30. Conclusion: These preliminary data suggest DE may be used safely in acute TIA/MIS patients and larger randomized trials are warranted. The low HT rate may make DE an ideal antithrombotic for use immediately after TIA/ischemic stroke.