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French J.A.,New York University | Abou-Khalil B.W.,Vanderbilt University | Leroy R.F.,Neurological Clinic of Texas | Yacubian E.M.T.,UNIFESP Escola Paulista de Medicina Hospital Sao Paulo | And 5 more authors.
Neurology | Year: 2011

Objective: To evaluate the efficacy and safety of ezogabine (United States adopted name)/retigabine (international nonproprietary name) (EZG[RTG]) 1,200 mg/day as adjunctive treatment in adults with drug-resistant epilepsy with partial-onset seizures with or without secondary generalization. Methods: RESTORE 1 was a multicenter, randomized, double-blind, parallel-group trial. Following a prospective 8-week baseline phase, patients entered an 18-week double-blind treatment period (6-week forced dose titration to EZG[RTG] 1,200 mg/day in 3 equally divided doses or placebo, followed by a 12-week maintenance phase). Results were analyzed on an intent-to-treat basis for the entire 18-week period and for patients reaching the maintenance phase. Results: In 306 patients randomized, 305 received EZG(RTG) 1,200 mg/day (n = 153) or placebo (n = 152). Median percent reduction in total partial-seizure frequency was 44.3% vs 17.5% (p < 0.001) for EZG(RTG) and placebo, respectively, during the 18-week double-blind period; responder rates (≥50% reduction in total partial-seizure frequency from baseline) were 44.4% vs 17.8% (p < 0.001). In 256 patients (EZG[RTG], 119; placebo, 137) entering the 12-week maintenance phase, median percent reduction in seizure frequency for EZG(RTG) vs placebo was 54.5% and 18.9% (p < 0.001), respectively; responder rates were 55.5% vs 22.6% (p < 0.001). The proportion of patients discontinuing due to treatment-emergent adverse events (TEAEs) was 26.8% (EZG[RTG]) vs 8.6% (placebo). Dizziness, somnolence, fatigue, confusion, dysarthria, urinary tract infection, ataxia, and blurred vision were the most common TEAEs reported by more patients treated with EZG(RTG) than placebo. Conclusions: This study demonstrates that EZG(RTG) is effective as add-on therapy for reducing seizure frequency in patients with drug-resistant partial-onset seizures. Classification of evidence: This study provides Class II evidence that EZG(RTG) 1,200 mg/day is effective as adjunctive therapy in adults with partial-onset seizures with or without secondary generalization. © 2011 by AAN Enterprises, Inc. All rights reserved.

Ardiani A.,U.S. National Cancer Institute | Farsaci B.,U.S. National Cancer Institute | Rogers C.J.,U.S. National Cancer Institute | Protter A.,Medivation Inc. | And 4 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Enzalutamide, a second-generation androgen antagonist, was approved by the U.S. Food and Drug Administration (FDA) for castration-resistant prostate cancer (CRPC) treatment. Immunotherapy has been shown to be a promising strategy for prostate cancer. This study was performed to provide data to support the combination of enzalutamide and immunotherapy for CRPC treatment. Experimental Design: Male C57BL/6 or TRAMP (transgenic adenocarcinoma of the mouse prostate) prostate cancer model mice were exposed to enzalutamide and/or a therapeutic vaccine targeting Twist, an antigen involved in epithelial-to-mesenchymal transition and metastasis. The physiologic and immunologic effects of enzalutamide were characterized. The generation of Twist-specific immunity by Twist-vaccine was assessed. Finally, the combination of enzalutamide and Twist-vaccine to improve TRAMP mice overall survival was evaluated. Results: Enzalutamide mediated immunogenic modulation in TRAMP-C2 cells. In vivo, enzalutamide mediated reduced genitourinary tissue weight, enlargement of the thymus, and increased levels of T-cell excision circles. Because no changes were seen in T-cell function, as determined by CD4 + T-cell proliferation and regulatory T cell (Treg) functional assays, enzalutamide was determined to be immune inert. Enzalutamide did not diminish the ability of Twist-vaccine to generate Twist-specific immunity. Twist was confirmed as a valid tumor antigen in TRAMP mice by immunohistochemistry. The combination of enzalutamide and Twist-vaccine resulted in significantly increased overall survival of TRAMP mice compared with other treatment groups (27.5 vs. 10.3 weeks). Notably, the effectiveness of the combination therapy increased with disease stage, i.e., the greatest survival benefit was seen in mice with advanced-stage prostate tumors. Conclusions: These data support the combination of enzalutamide and immunotherapy as a promising treatment strategy for CRPC. © 2013 American Association for Cancer Research.

Brodie M.J.,Epilepsy Unit | Lerche H.,University of Ulm | Lerche H.,University of Tubingen | Gil-Nagel A.,Epilepsy Program | And 5 more authors.
Neurology | Year: 2010

Objective: This study assessed the efficacy and safety of the neuronal potassium channel opener ezogabine (US adopted name; EZG)/retigabine (international nonproprietary name; RTG) as adjunctive therapy for refractory partial-onset seizures. Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial in adults with ≥4 partial-onset seizures per month receiving 1 to 3 antiepileptic drugs. EZG (RTG) or placebo, 3 times daily, was titrated to 600 or 900 mg/d over 4 weeks, and continued during a 12-week maintenance phase. Median percentage seizure reductions from baseline and responder rates (≥50% reduction in baseline seizure frequency) were assessed. Results: The intention-to-treat population comprised 538 patients (placebo, n = 179; 600 mg, n = 181; 900 mg, n = 178), 471 of whom (placebo, n = 164; 600 mg, n = 158; 900 mg, n = 149) entered the maintenance phase. Median percentage seizure reductions were greater in EZG (RTG)-treated patients (600 mg, 27.9%, p = 0.007; 900 mg, 39.9%, p < 0.001) compared with placebo (15.9%). Responder rates were higher in EZG (RTG)-treated patients (600 mg, 38.6%, p < 0.001; 900 mg, 47.0%, p < 0.001) than with placebo (18.9%). Treatment discontinuations due to adverse events (AEs) were more likely with EZG (RTG) than with placebo (placebo, 8%; 600 mg, 17%, 900 mg, 26%). The most commonly reported (>10%) AEs in the placebo, EZG (RTG) 600 mg/d, and EZG (RTG) 900 mg/d groups were dizziness (7%, 17%, 26%), somnolence (10%, 14%, 26%), headache (15%, 11%, 17%), and fatigue (3%, 15%, 17%). Conclusions: In this dose-ranging, placebo-controlled trial, adjunctive EZG (RTG) was effective and generally well tolerated in adults with refractory partial-onset seizures. Copyright © 2010 by AAN Enterprises, Inc.

Tombal B.,Catholic University of Louvain | Borre M.,Aarhus University Hospital | Rathenborg P.,Herlev Hospital | Werbrouck P.,AZ Groeninge Kortrijk | And 11 more authors.
The Lancet Oncology | Year: 2014

Background: The androgen receptor inhibitor enzalutamide is approved for the treatment of metastatic castration-resistant prostate cancer that has progressed on docetaxel. Our aim was to assess the activity and safety of enzalutamide monotherapy in men with hormone-naive prostate cancer. Methods: This trial is an ongoing open-label, single-arm, phase 2 study, done across 12 European sites. Men aged over 18 years, with hormone-naive prostate cancer for whom hormone therapy was indicated, and who had non-castration levels of testosterone and prostate-specific antigen (PSA) of 2 ng/mL or greater at screening, and an Eastern Cooperative Oncology Group score of 0, received oral enzalutamide 160 mg/day. The primary outcome was the proportion of patients with an 80% or greater decline in PSA at week 25. All analyses included all patients who had received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT01302041. Findings: 67 men were enrolled into the study. 62 patients (92·5%, 95% CI 86·2-98·8) had a decline in PSA of 80% or greater at week 25. The most commonly reported treatment-emergent adverse events up to week 25 were gynaecomastia (n=24), fatigue (n=23), nipple pain (n=13), and hot flush (n=12), all of which were of mild to moderate severity. Nine patients had a treatment-emergent adverse event of grade 3 or higher, most of which were reported in one patient each, except for pneumonia (grade 3, two patients) and hypertension (grade 3, four patients). Five patients reported serious adverse events, none of which were deemed to be treatment related. Interpretation: Our findings suggest that enzalutamide monotherapy in men with hormone-naive prostate cancer of varying severity provides a level of disease suppression, and was generally well tolerated. These findings provide a rationale for further investigation of clinical response and outcomes with enzalutamide in non-castrate men with prostate cancer. Funding: Astellas Pharma Inc, Medivation Inc. © 2014 Elsevier Ltd.

Saad F.,University of Montreal | De Bono J.,Institute of Cancer Research | Shore N.,Urologic | Fizazi K.,University Paris - Sud | And 5 more authors.
European Urology | Year: 2015

Background Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer (PCa) after docetaxel in the randomised, phase 3, double-blind, placebo-controlled, multinational Patients with Progressive Castration-Resistant Prostate Cancer Previously Treated with Docetaxel-Based Chemotherapy (AFFIRM) trial (NCT00974311). Prostate-specific antigen (PSA) is commonly used as a marker of PCa disease burden, and the relationship of baseline PSA level to consequent treatment effect is of clinical interest. Objective Exploratory analysis to evaluate any differences in patient characteristics and efficacy outcomes by baseline PSA level in the AFFIRM trial. Design, setting, and participants Post hoc subanalysis of all randomised patients (n = 1199) from the AFFIRM trial. Intervention Participants were randomly assigned in a two-to-one ratio to receive oral enzalutamide 160 mg/d or placebo. Outcome measurements and statistical analysis The major clinical efficacy end points were overall survival (OS), radiographic progression-free survival (rPFS), and time to PSA progression (TTPP) versus placebo; baseline characteristics, treatment duration, and subsequent antineoplastic therapy were compared by baseline PSA quartile. Results and limitations Baseline PSA quartiles corresponded to the following PSA groups: <40 ng/ml (n = 299), 40 to <111 ng/ml (n = 300), 111 to <406 ng/ml (n = 300), and ≥406 ng/ml (n = 300). Enzalutamide consistently improved OS, rPFS, and TTPP compared with placebo across all subgroups, regardless of baseline PSA level. Hazard ratios for improvements in OS were 0.55 (95% confidence interval [CI], 0.36-0.85), 0.69 (95% CI, 0.47-1.02), 0.73 (95% CI, 0.53-1.01), and 0.53 (95% CI, 0.39-0.73) for PSA groups 1-4, respectively. The post hoc design of this analysis was not statistically powered to assess the relationship between baseline PSA and clinical efficacy outcomes. Conclusions This post hoc analysis of the AFFIRM trial demonstrates consistent benefits in OS, rPFS, and TTPP with enzalutamide regardless of baseline disease severity, as assessed by PSA. Patient summary Exploratory post hoc analysis of the AFFIRM trial showed that enzalutamide improves overall survival, radiographic progression-free survival, and time to prostate-specific antigen progression compared with placebo regardless of baseline disease severity, as assessed by prostate-specific antigen. Trial registration ClinicalTrials.gov identifier NCT00974311. © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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