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To combat cyber threats in the smart grid, an intrusion detection system can be integrated into the advanced metering infrastructure. Anomaly-based intrusion detection can detect even the tiniest changes in the parameter under investigation, whereas signature-based intrusion detection only recognises known attacks. The growing usage of smart grids necessitates the classification, identification, and implementation of countermeasures to threats. At the absolute least, smart grids must be protected against cyberattacks; thus, the highest level of information security must be offered. As a result of digitisation and the usage of more smart applications, the research looked at a variety of attack types, smart grid assaults, and major cyber threats on the voltage regulation. Machine learning techniques that analyse data in real time and formulate patterns to recognise an attack and scan through huge data for anomalies can be implemented into the advanced metering infrastructure (AMI) for intrusion detection for anomaly-based intrusion detection. The comparative test study done for the research found that the proposed method, median absolute deviation for anomaly identification in smart metering datasets, produced the most accurate and precise differentiations with the highest accuracy and precision. The median absolute deviation (MAD) algorithm model is trained using test data, and raw predictions are made, before true data are used to derive final test result parameters, precision, recall, and F1 scores. The methodology of the entire study is discussed in this paper, as well as how the MAD algorithm is best suited for anomaly-based intrusion detection, as well as result comparisons of other machine learning algorithms.

Rolapitant, a selective and long-acting neurokinin-1 receptor antagonist, is approved in an oral formulation for prevention of delayed chemotherapy-induced nausea and vomiting in adults. This pivotal open-label, randomized, single-dose, multicenter, parallel-group study assessed the bioequivalence of a single oral dose of 180 mg of rolapitant administered in tablet (2 × 90-mg tablets) or capsule (4 × 45-mg capsules) form in healthy male and female subjects. Blood samples for pharmacokinetic analysis were collected predose and at times up to 912 hours postdose. The rolapitant tablet was considered bioequivalent to the rolapitant capsule if the 90% confidence intervals for the ratios of the geometric means for rolapitant, observed maximum plasma concentration (Cmax ), and area under the curve from time 0 extrapolated to infinity (AUC0-∞ ) were within the 0.80-1.25 range. The pharmacokinetic profiles of the capsule group (n = 43) and tablet group (n = 44) were similar. The geometric mean ratios of Cmax and AUC0-∞ were 0.99 (0.89-1.11) and 1.05 (0.92-1.19), respectively, establishing bioequivalence of the rolapitant tablet and capsule formulations. Both formulations were well tolerated, with a similar incidence of treatment-emergent adverse events in the 2 groups.

Rolapitant is a selective and long-acting neurokinin-1 receptor antagonist approved in an oral formulation in combination with dexamethasone and a 5-hydroxytryptamine type 3 receptor antagonist for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. The pharmacokinetic and safety profiles of intravenous (IV) rolapitant were evaluated in two open-label, phase 1 trials in healthy subjects. Single ascending dose (SAD) and multiple ascending dose studies were conducted in one trial (PR-11-5012-C), and a supratherapeutic SAD study was conducted in a separate trial (PR-11-5022-C). In the SAD and supratherapeutic studies, rolapitant maximum plasma concentration, area under the plasma drug concentration-time curve (AUC) from time zero to time of last measured concentration, and AUC from time zero to infinity increased dose-proportionally following single IV infusions of 18 to 270 mg. In the multiple ascending dose study, following 10 daily IV infusions of rolapitant 18, 36, or 54 mg, the mean day 10:day 1 maximum concentration ratio was 1.97, 1.52, and 2.07, respectively, and the mean day 10:day 1 ratio of AUC from 0 to 24 hours was 4.30, 4.59, and 5.38, respectively, indicating drug accumulation over time. Across all studies, rolapitant was gradually eliminated from plasma, with a half-life of 135-231 hours. Rolapitant was safe and well tolerated across all studies, with no serious or severe rolapitant-related treatment-emergent adverse events. The most common rolapitant-related treatment-emergent adverse events were headache, dry mouth, and dizziness, which were predominantly mild in severity. Overall, the pharmacokinetic and safety profiles of IV rolapitant were consistent with those of the oral formulation.

Most patients receiving highly or moderately emetogenic chemotherapy experience chemotherapy‐induced nausea and vomiting without antiemetic prophylaxis. While neurokinin‐1 receptor antagonists (NK‐1RAs) effectively prevent emesis, their ability to prevent nausea has not been established. We evaluated the efficacy of the long‐acting NK‐1RA rolapitant in preventing chemotherapy‐induced nausea using post hoc analyses of data from 3 phase 3 trials. Patients were randomized to receive 180 mg oral rolapitant or placebo approximately 1‐2 hours before chemotherapy in combination with a 5‐hydroxytryptamine type 3 RA and dexamethasone. Nausea was assessed by visual analog scale during the acute (≤24 hours), delayed (>24‐120 hours), and overall (0‐120 hours) phases. Post hoc analyses by treatment group (rolapitant vs control) were performed on pooled data within patient subgroups receiving cisplatin‐based, carboplatin‐based, or anthracycline/cyclophosphamide (AC)‐based chemotherapy. In the cisplatin‐based chemotherapy group, significantly more patients receiving rolapitant than control reported no nausea (NN) in the overall (52.3% vs 41.7% [P

Rolapitant is a selective and long-acting neurokinin-1 receptor antagonist approved in an oral formulation in combination with other antiemetic agents for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. This was a phase 1 open-label, parallel-group pharmacokinetic and safety study of a single oral dose of 180 mg of rolapitant and its major active metabolite, M19, in subjects with mild and moderate hepatic impairment compared with healthy matched controls. Pharmacokinetics were assessed by a mixed-model analysis of variance of log-transformed values for maximum observed plasma concentration (Cmax ), observed time at Cmax (tmax ), area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC0-t ), and AUC from time 0 to 120 hours (AUC0-120 ), with hepatic group as a fixed effect. Mean rolapitant Cmax , AUC0-t , and AUC0-120 were similar in the mild hepatic impairment and healthy control groups. In subjects with moderate hepatic impairment, AUC0-t was similar and Cmax was 25% lower than in healthy controls. Mean M19 Cmax and AUC0-t were similar in the mild hepatic impairment group and healthy controls, but

IoT is the big buzzword in today’s technical fraternity. The implementation of 5G networks is also up in urban areas. This is perhaps fortunate from an IoT perspective, as IoT’s main applications will realize Smart automated cities’ dream. Enhanced mobile broadband (eMBB)-based services are far and wide dependent upon the bandwidth requirement for effective communication in Smart City applications. Modern-day signal processing techniques are widely reliant on adaptive filters for efficient applications like signal prediction, echo cancellation, noise cancellation, etc. In this work, the use of adaptive filters is performed for stationary and non-stationary signals. It is well known that adaptive filters’ performance and effect depend on their regulating parameters and noise variance. Therefore, the parameter step size and filter orders are varied, and the outcome of the variations on respective signals is noted. Simulation of these scenarios is discussed at length to ensure better insight of adaptive filters to researchers and engineers to select the appropriate filter for a specific application.

Rolapitant, a selective and long-acting neurokinin-1 receptor antagonist, is approved in an oral formulation for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. The objective of this pivotal study was to assess the bioequivalence of a single intravenous infusion of rolapitant versus a single oral dose of rolapitant. In this randomized, open-label phase 1 study, healthy volunteers were administered rolapitant as a 180-mg oral dose or a 30-minute 166.5-mg intravenous infusion. Blood samples for pharmacokinetic analysis were collected predose and at points up to 912 hours postdose. Criteria for bioequivalence of the intravenous dose versus the oral dose were met if the 90% confidence intervals (CIs) for the ratios of the geometric least-squares means (GLSMs) for the area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC0-t ) and AUC from time 0 extrapolated to infinity (AUC0-∞ ) for rolapitant were within 0.80-1.25. Mean rolapitant systemic exposure and half-lives were similar in the oral (n = 62) and intravenous (n = 61) rolapitant groups. The 90%CIs of the ratio of GLSMs were within the 0.80-1.25 range for AUC0-t (0.94-1.09) and AUC0-∞ (0.93-1.10). The incidence of treatment-emergent adverse events, all mild or moderate in severity, was similar in the intravenous and oral groups. A 166.5-mg intravenous infusion of rolapitant met the bioequivalence criteria based on AUC to a 180-mg oral dose and was well tolerated.

Rolapitant is a selective and long-acting neurokinin-1 receptor antagonist approved in an oral formulation in combination with other antiemetic agents for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. Four open-label phase 1 studies evaluated the safety and drug-drug interactions of a single dose of rolapitant given intravenously (166.5 mg) or orally (180 mg) with oral digoxin (0.5 mg) or sulfasalazine (500 mg), probe substrates for the P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), respectively. Administration of intravenous rolapitant with the substrates did not result in clinically significant effects on digoxin and sulfasalazine pharmacokinetics. In contrast, peak concentration and area under the curve for last quantifiable plasma concentrations increased by 71% (geometric mean ratio [GMR], 1.71; 90% confidence interval [CI], 1.49-1.95) and 30% (GMR, 1.30; 90%CI, 1.19-1.42), respectively, when rolapitant was coadministered orally with digoxin compared with digoxin alone; they increased by 140% (GMR, 2.40; 90%CI, 2.02-2.86) and 127% (GMR, 2.27; 90%CI, 1.94-2.65), respectively, when rolapitant was given orally with sulfasalazine compared with sulfasalazine alone. Adverse events were mild to moderate in severity in the absence or presence of rolapitant. There were no abnormal clinical laboratory or electrocardiogram findings. Thus, whether administered orally or intravenously, rolapitant was safe and well tolerated. Patients taking oral rolapitant with P-gp and BCRP substrates with a narrow therapeutic index should be monitored for potential adverse events; although increased plasma concentrations of these substrates may raise the risk of toxicity, they are not contraindicated.

Background: Patients (pts) with breast cancer often receive highly emetogenic chemotherapy, such as anthracycline plus cyclophosphamide (AC). Additionally, young age and female gender are risk factors for chemotherapy-induced nausea and vomiting (CINV) in response to emetogenic chemotherapy. We assessed the ability of the long-acting neurokinin-1 receptor antagonist (RA), rolapitant, in the prevention of CINV over multiple cycles in pts with breast cancer Methods: This is a post hoc analysis of the prevention of CINV in a subset of pts with breast cancer from 3 similarly-designed, randomized, placebo-controlled phase 3 trials in which pts received a single oral dose of 180 mg rolapitant or placebo before chemotherapy. All pts received an oral 5-HT3 RA + dexamethasone (active control). The regimens were cisplatin-based (n=36), AC-based (n=681) or other (n=166; carboplatin, cyclophosphamide, etc). Pts who completed cycle 1 could continue the same antiemetic treatment in multiple cycles. Endpoints for cycle 1 of chemotherapy included complete response (CR; no emesis and no use of rescue medication) and no emesis, and no nausea (maximum visual analogue scale [VAS] 24–120 h) phases. On days 6-8 of each subsequent chemotherapy cycle, pts self-reported the incidence of emesis or nausea interfering with normal daily life. Results: In cycle 1, CR in both the overall (62.9% rolapitant, 55.1% control; p=0.018) and delayed (66.7% rolapitant, 59.7% control; p=0.032) phases were higher with rolapitant vs control . Rolapitant also improved no emesis rates in the overall (74.4% rolapitant, 62.6% control; p Conclusions: Rolapitant added to 5-HT3 RA and dexamethasone therapy improved CINV control and was safe and well-tolerated in pts with breast cancer receiving multiple cycles of emetogenic chemotherapy, mostly AC and carboplatin, historically a high-risk population for CINV. Pt-Reported Response in Multiple Cycles, % (n/N)* No Emesis No Interfering Nausea CycleRolapitant 180 mgActive Controlp-value *Rolapitant 180 mgActive Controlp-value *288.3 (323/366)80.0 (308/385)0.00271.6 (262/366)68.3 (263/385)0.329390.5 (297/328)80.5 (293/364) Citation Format: Schwartzberg L, Navari R, Arora S, Powers D, Jordan K, Rapoport B. Rolapitant for the prevention of chemotherapy-induced nausea and vomiting in breast cancer patients receiving multiple cycles of emetogenic chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-15.

PURPOSE In the ENGOT-OV16/NOVA trial (ClinicalTrials.gov identifier: NCT01847274 ), maintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, prolonged progression-free survival in patients with platinum-sensitive, recurrent ovarian cancer who had a response to their last platinum-based chemotherapy. The objective of the study was to assess the clinical benefit and patient-reported outcomes in patients who had a partial response (PR) and complete response (CR) to their last platinum-based therapy. PATIENTS AND METHODS A total of 553 patients were enrolled in the trial. Of 203 patients with a germline BRCA mutation (g BRCAmut), 99 had a PR and 104 had a CR to their last platinum-based therapy; of 350 patients without a confirmed g BRCAmut (non–g BRCAmut), 173 had a PR and 177 had a CR. Post hoc analyses were carried out to evaluate safety and the risk of progression in these patients according to g BRCAmut status and response to their last platinum-based therapy. Ovarian cancer–specific symptoms and quality of life were assessed using the Functional Assessment of Cancer Therapy–Ovarian Symptom Index. RESULTS Progression-free survival was improved in patients treated with niraparib compared with placebo in both the g BRCAmut cohort (PR: hazard ratio [HR], 0.24; 95% CI, 0.131 to 0.441; P < .0001; CR: HR, 0.30; 95% CI, 0.160 to 0.546; P < .0001) and the non–g BRCAmut cohort (PR: HR, 0.35; 95% CI, 0.230 to 0.532; P < .0001; CR: HR, 0.58; 95% CI, 0.383 to 0.868; P = .0082). The incidence of any-grade and grade 3 or greater adverse events was manageable. No meaningful differences were observed between niraparib and placebo in PR and CR subgroups with respect to patient-reported outcomes. CONCLUSION Patients achieved clinical benefit from maintenance treatment with niraparib regardless of response to the last platinum-based therapy.

ImportancePatients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited. ObjectiveTo evaluate the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma. Design, Setting, and ParticipantsThe TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status. Median follow-up was 12.4 months (range, 1.2 to >= 23.0 months). Data were collected from April 15, 2016, through September 4, 2018, with September 4, 2018, as a data cutoff, and analyzed from September 4, 2018, through January 30, 2019. InterventionsThe recommended phase 2 dose (RP2D) was 200 mg of oral niraparib once daily and 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. Main Outcomes and MeasuresThe primary objectives of phase 1 were to evaluate dose-limiting toxic effects and establish the RP2D and dosing schedule. The primary objective of phase 2 was to assess objective response rate (ORR; complete plus partial responses). Results from the phase 1 ovarian carcinoma and TNBC cohorts and phase 2 ovarian carcinoma cohort are reported. Because of the similarity in the phase 1 and 2 ovarian carcinoma populations, the data were pooled to perform an integrated efficacy analysis. ResultsFourteen patients (9 with ovarian carcinoma and 5 with TNBC) in phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients (median age, 60 years [range, 46-83 years]). In the integrated efficacy phases 1 and 2 ovarian carcinoma population (60 of 62 evaluable patients), ORR was 18% (90% CI, 11%-29%), with a disease control rate of 65% (90% CI, 54%-75%), including 3 (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, 28 (47%) with stable disease, and 20 (33%) with progressive disease. The ORRs were consistent across subgroups based on platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status. Median duration of response was not reached (range, 4.2 to >= 14.5 months). At data cutoff, 2 patients with a response and 1 patient with stable disease continued to receive treatment. Conclusions and RelevanceNiraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab. Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy. Trial RegistrationClinicalTrials.gov identifier: NCT02657889

Purpose Addition of rolapitant to standard antiemetic therapy improved protection against chemotherapy-induced nausea and vomiting (CINV) in phase 3 trials of patients receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC). Here, we assessed the impact of CINV on the daily lives of patients receiving HEC or MEC using the Functional Living Index-Emesis (FLIE). Methods In three double-blind phase 3 studies, patients receiving HEC or MEC were randomized 1:1 to receive oral rolapitant 180 mg or placebo prior to chemotherapy plus 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone therapy. Patients completed the FLIE questionnaire on day 6 of cycle 1. Endpoints included FLIE total score, nausea and vomiting domain scores, and the proportion of patients with no impact on daily life (total score >108 [range 18–126]). We performed a prespecified analysis of the MEC/anthracycline-cyclophosphamide (AC) study and a post hoc analysis of two pooled cisplatin-based HEC studies. Results In the pooled HEC studies, rolapitant significantly improved the FLIE total score (114.5 vs 109.3, p

In the power system, voltage instability is one of the important issues and it may cause voltage sag, voltage swell, change in load and generation of harmonics. To tackle all these problems, the transmission power system makes use of an intelligent control model to improve the stability of power system. In this paper, a new adaptive neuro fuzzy inference system (ANFIS) based power system stabiliser (PSS) for the enhancement of voltage stability in power systems is proposed. A hybrid learning algorithm, which combines the least squares method and the back propagation algorithm, is used to train the ANFIS. The performance of the power system by using fuzzy based PSS is about 60.1% when compared to that of the conventional PSS. To evaluate the effectiveness of the proposed technique the performance of the proposed technique was compared with the results obtained by using fuzzy PSS model and its performance was analysed. Simulation results described in the paper demonstrate that the adaptive neuro-fuzzy based PSS can give 33.43% of improvement in voltage stability when compared to that of fuzzy based PSS over a wide range of operating conditions.

Summary Background Highly emetogenic chemotherapy induces emesis in almost all patients in the absence of prophylaxis. Guidelines recommend use of a neurokinin-1 (NK-1) receptor antagonist in conjunction with a 5-HT 3 receptor antagonist and corticosteroid in patients receiving highly emetogenic chemotherapy. We aimed to assess rolapitant, an NK-1 receptor antagonist, for prevention of chemotherapy-induced nausea and vomiting in patients with cancer after administration of cisplatin-based highly emetogenic chemotherapy. Methods We conducted two global, randomised, double-blind, active-controlled, phase 3 trials (HEC-1 and HEC-2) at 155 cancer centres (76 in HEC-1 and 79 in HEC-2) in 26 countries (17 in HEC-1 and 14 in HEC-2). We enrolled patients with cancer aged 18 years or older, who had not previously been treated with cisplatin, with a Karnofsky performance score of 60 or higher, and a predicted life expectancy of 4 months or longer. We used an interactive web-based randomisation system to randomly assign patients to treatment. Patients were stratified by sex and randomly allocated to either oral rolapitant (180 mg dose; rolapitant group) or a placebo that was identical in appearance (active control group) about 1–2 h before administration of highly emetogenic chemotherapy. All patients received granisetron (10 μg/kg intravenously) and dexamethasone (20 mg orally) on day 1, and dexamethasone (8 mg orally) twice daily on days 2–4. Every cycle was a minimum of 14 days. In up to five subsequent cycles, patients were allowed to receive the same study drug they were assigned in cycle 1, unless removed at the clinician's discretion. Patients could also choose to leave the study at any point. Efficacy analysis was done in the modified intention-to-treat population (comprising all patients who received at least one dose of study drug at a cancer centre compliant with Good Clinical Practice [GCP]). The primary endpoint was the proportion of patients achieving a complete response (no emesis or use of rescue medication) in the delayed phase (>24–120 h after initiation of chemotherapy) in cycle 1. These studies are registered with ClinicalTrials.gov, numbers NCT01499849 and NCT01500213. Both studies have been completed. Findings Between Feb 21, 2012, and March 12, 2014, 532 patients in HEC-1 and 555 patients in HEC-2 were randomly assigned to treatment. 526 patients in HEC-1 (264 rolapitant and 262 active control) and 544 in HEC-2 (271 rolapitant and 273 active control) received at least one dose of study drug at a GCP-compliant site and were included in the modified intention-to-treat population. A significantly greater proportion of patients in the rolapitant group had complete responses in the delayed phase than did patients in the active control group (HEC-1: 192 [73%] vs 153 [58%]; odds ratio 1·9, 95% CI 1·3–2·7; p=0·0006; HEC-2: 190 [70%] vs 169 [62%]; 1·4, 1·0–2·1; p=0·0426; pooled studies: 382 [71%] vs 322 [60%]; 1·6, 1·3–2·1; p=0·0001). The incidence of adverse events was similar across treatment groups. The most commonly reported treatment-related treatment-emergent adverse events in the rolapitant versus active control groups were headache (three [ vs two [ vs four [ vs three [ vs three [ vs 14 [5%]; HEC-2: 16 [6%] vs 14 [5%]), anaemia (HEC-1: one [ vs one [ vs two [ vs two [ vs two [ Interpretation Rolapitant in combination with a 5-HT 3 receptor antagonist and dexamethasone is well-tolerated and shows superiority over active control for the prevention of chemotherapy-induced nausea and vomiting during the at-risk period (120 h) after administration of highly emetogenic cisplatin-based chemotherapy. Funding TESARO, Inc.

Rolapitant is a selective, long-acting neurokinin-1 receptor antagonist, approved in the United States and Europe for prevention of delayed chemotherapy-induced nausea and vomiting in adults. This open-label study evaluated the effects of a new intravenous formulation of rolapitant on cytochrome P450 (CYP) enzyme (CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2D6) activity. On days 1 and 14, 36 healthy volunteers received a modified Cooperstown cocktail (midazolam 3 mg [CYP3A substrate], caffeine 200 mg [CYP1A2 substrate], S-warfarin 10 mg [CYP2C9 substrate] + vitamin K 10 mg, omeprazole 40 mg [CYP2C19 substrate], and dextromethorphan 30 mg [CYP2D6 substrate]). On day 7, subjects received the modified Cooperstown cocktail after 166.5-mg rolapitant infusion. On days 21, 28, and 35, subjects received oral dextromethorphan. Maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC0-last ) of probe drugs post- vs pre-rolapitant administration were assessed using geometric least-squares mean ratios (GMRs) with 90%CIs. The 90%CIs of the GMRs were within the 0.80-1.25 no-effect limits for caffeine and S-warfarin Cmax and AUC0-last . For midazolam Cmax and AUC0-last and omeprazole Cmax , the 90%CIs of the GMRs were marginally outside these limits. Intravenous rolapitant coadministration increased dextromethorphan exposure, peaking 14 days post-rolapitant administration (GMRs: Cmax , 2.74, 90%CI 2.21-3.40; AUC0-last , 3.36, 90%CI 2.74-4.13). Intravenous rolapitant 166.5 mg and probe drugs were well tolerated when coadministered. These data suggest that intravenous rolapitant is not an inhibitor of CYP3A, CYP2C9, CYP2C19, or CYP1A2 but is a moderate inhibitor of CYP2D6.

Background Rolapitant, a long-acting neurokinin (NK)1 receptor antagonist (RA), has demonstrated efficacy in prevention of chemotherapy-induced nausea and vomiting in patients administered moderately or highly emetogenic chemotherapy. Unlike other NK1 RAs, rolapitant does not inhibit or induce cytochrome P450 (CYP) 3A4, but it does inhibit CYP2D6 and breast cancer resistance protein (BCRP). To analyze potential drug–drug interactions between rolapitant and concomitant medications, this integrated safety analysis of four double-blind, randomized phase II or III studies of rolapitant examined adverse events (AEs) by use versus non-use of drug substrates of CYP2D6 or BCRP. Patients and methods Patients were randomized to receive either 180 mg oral rolapitant or placebo ∼1–2 h before chemotherapy in combination with a 5-hydroxytryptamine type 3 RA and dexamethasone. Data for treatment-emergent AEs (TEAEs) and treatment-emergent serious AEs (TESAEs) during cycle 1 were pooled across the four studies and summarized in the overall population and by concomitant use/non-use of CYP2D6 or BCRP substrate drugs. Results In the integrated safety population, 828 of 1294 patients (64%) in the rolapitant group and 840 of 1301 patients (65%) in the control group experienced at least one TEAE. Frequencies of common TEAEs were similar in the rolapitant and control populations. Overall, 53% of patients received CYP2D6 substrate drugs, none of which had a narrow therapeutic index (like thioridazine or pimozide), and 63% received BCRP substrate drugs. When grouped by concomitant use versus non-use of CYP2D6 or BCRP substrate drugs, TEAEs and TESAEs occurred with similar frequency in the rolapitant and control populations. Conclusions The results of this study support the safety of rolapitant as part of an antiemetic triple-drug regimen in patients receiving emetogenic chemotherapy, including those administered concomitant medications that are substrates of CYP2D6 or BCRP, such as ondansetron, docetaxel, or irinotecan.

The group of like-minded megadiverse countries (LMMCs), which harbours a wealth of biological and cultural diversity, adopted a Carta in 2016 to accelerate progress towards achieving Aichi Biodiversity Target 11. This paper presents the progress made over the last two years and an analysis of the LMMCs’ national priority actions; approved Global Environment Facility, GEF-5 and GEF-6 protected area-related biodiversity projects; and relevant targets, goals, and actions from National Biodiversity Strategies and Action Plans (NBSAPs). Through their recent actions, these countries have contributed to progress in Target 11, especially with respect to marine protected area expansion, where they contributed one-sixth of the area added in national waters over the past two years. Results indicate that if implemented as planned, actions proposed by the LMMCs will increase terrestrial and marine protected area coverage by 1,106,148 km 2 and 192,214 km 2 respectively. Of these commitments, 227,230 km 2 in terrestrial and 144,475 km 2 in marine protected areas have the highest chance of being implemented. In total, 741 commitments were identified from the above sources, with implications on the qualitative elements of Target 11 (coverage of areas important for biodiversity, areas important for ecosystem services, ecological representation, connectivity, effective management, equitable management, and integration into the wider landscapes and seascapes). Of these 741 commitments, 25% showed a strong likelihood of being implemented. The country-level analysis of all commitments indicates that equitable management and integration will show the most progress, measured against identified gaps, if commitments are implemented as proposed. This progress on the qualitative elements of Target 11 in the LMMCs will also provide benefits and co-benefits for other Aichi Targets and for the requirements of other multi-lateral environmental agreements, as well as at the global level.

Importance Poly(adenosine diphosphate-ribose) polymerase inhibitor and anti-programmed death receptor-1 inhibitor monotherapy have shown limited clinical activity in patients with advanced triple-negative breast cancer (TNBC). Objective To evaluate the clinical activity (primary) and safety (secondary) of combination treatment with niraparib and pembrolizumab in patients with advanced or metastatic TNBC. Design, setting, and participants This open-label, single-arm, phase 2 study enrolled 55 eligible patients with advanced or metastatic TNBC irrespective of BRCA mutation status or programmed death-ligand 1 (PD-L1) expression at 34 US sites. Data were collected from January 3, 2017, through October 29, 2018, and analyzed from October 29, 2018, through February 27, 2019. Interventions Patients were administered 200 mg of oral niraparib once daily in combination with 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. Main outcomes and measures The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points were safety, disease control rate (DCR; complete response plus partial response plus stable disease), duration of response (DOR), progression-free survival (PFS), and overall survival. Results Within the full study population of 55 women (median age, 54 years [range, 32-90 years]), 5 patients had confirmed complete responses, 5 had confirmed partial responses, 13 had stable disease, and 24 had progressive disease. In the efficacy-evaluable population (n = 47), ORR included 10 patients (21%; 90% CI, 12%-33%) and DCR included 23 (49%; 90% CI, 36%-62%). Median DOR was not reached at the time of the data cutoff, with 7 patients still receiving treatment at the time of analysis. In 15 evaluable patients with tumor BRCA mutations, ORR included 7 patients(47%; 90% CI, 24%-70%), DCR included 12 (80%; 90% CI, 56%-94%), and median PFS was 8.3 months (95% CI, 2.1 months to not estimable). In 27 evaluable patients with BRCA wild-type tumors, ORR included 3 patients (11%; 90% CI, 3%-26%), DCR included 9 (33%; 90% CI, 19%-51%), and median PFS was 2.1 months (95% CI, 1.4-2.5 months). The most common treatment-related adverse events of grade 3 or higher were anemia (10 [18%]), thrombocytopenia (8 [15%]), and fatigue (4 [7%]). Immune-related adverse events were reported in 8 patients (15%) and were grade 3 in 2 patients (4%); no new safety signals were detected. Conclusions and relevance Combination niraparib plus pembrolizumab provides promising antitumor activity in patients with advanced or metastatic TNBC, with numerically higher response rates in those with tumor BRCA mutations. The combination therapy was safe with a tolerable safety profile, warranting further investigation. Trial registration ClinicalTrials.gov identifier: NCT02657889.

Background: PARP inhibitor (PARPi) monotherapy has previously demonstrated clinical activity only in patients with a germline BRCA mutation (BRCAmut), while single-agent anti-programmed cell death protein 1 (PD-1) therapy has achieved response rates of only 5–20% in advanced triple negative breast cancer (TNBC). In preclinical studies, PARP inhibition enhanced anti-tumor immunity, increased infiltration of proliferating CD8+ T cells, and synergized with anti-PD-1 agents in BRCA wildtype (wt) tumors. TOPACIO is a fully enrolled, phase I/II trial of niraparib + pembrolizumab (pembro) in advanced TNBC. This combination achieved 28% objective response rate (ORR) and 50% disease control rate (DCR) in evaluable patients. Although activity was highest in patients with BRCAmut (ORR=60%; DCR=80%), durable clinical benefit was also observed in patients without BRCA mutations. In this study, we conducted exploratory biomarker analyses to evaluate their potential correlation with durable clinical benefit (any complete response [CR] or partial response [PR] regardless of duration or stable disease [SD] for ≥16 weeks) beyond BRCA mutations. Method: ORR was assessed by RECIST v1.1. Duration of disease control (DDC) was defined as time from first dose of study treatment to radiologic disease progression or death. Tumor mutational status of homologous recombination repair (HRR) and other DNA damage repair (DDR) pathway genes was determined using an NGS panel. Immunoprofiling was conducted using NanoString IO360 panel complimented with 30 DNA repair spike-ins. Tumor immune micro-environment was characterized using multiplex immuno-fluorescence (CycIF). PD-L1 status was determined using the Agilent/DAKO 22C3 IHC clinical trial assay. Results: Of 46 evaluable patients, 20 achieved durable clinical benefit (any CR/PR or SD≥16 weeks) with niraparib + pembro combination, of which 8 were tumor BRCA wild type (wt), and 1 was BRCA unknown. Of the 9 BRCAwt/unknown patients, 5 had deleterious mutations in HRR/DDR pathway genes, whereas the remaining 4 had no mutations (HRR/DDR wt). Mutations that were associated with response include CHEK1 (CR; DDC=10.3 mos), ATR (CR; DDC=6.4 mos), PALB2 (PR; DDC=3.5 mos), BLM (SD; DDC=8.1 mos), and NBN/RAD51C (SD; DDC=3.7 mos). Of 4 patients that had no identified mutations (HRR/DDR wt), 1 patient had CR; DDC=10.3 mos, and the remaining 3 patients had SD with DDC ranging from ∼4-8 mos. Of note, all 4 HRR/DDR wt patients were also PD-L1-negative. Table:Durable clinical benefit in BRCAwt/unknown patientsHRR/DRR MutationsPD-L1 StatusBest ResponseDDC (Months)CHEK1+CR10.3†ATR+CR6.4PALB2*UnknownPR3.5BLM-SD8.1NBN/RAD51C+SD3.7None-CR10.3†None-SD8.2None-SD4.2None-SD3.9*BRCA status unknown; †Treatment is ongoing. Conclusion: Patients with mutations beyond BRCA achieved durable clinical benefit with niraparib + pembro treatment; five of these patients had DDC >6 mos. Mutations in genes that are associated with the HRR/DDR pathway appear to confer sensitivity to niraparib + anti-PD1. Additional translational analyses, including immunoprofiling and CycIF, will be presented. Funding: TESARO, Inc., Waltham, MA, USA sponsored the study. Citation Format: Vinayak S, Tolaney SM, Schwartzberg L, Mita M, McCann G, Tan AR, Wahner Hendrickson A, Forero A, Anders C, Wulf G, Dillon P, Lynce F, Zarwan C, Erban J, Färkkilä A, Zhou Y, Buerstatte N, Graham JR, Arora S, Dezube B, Telli ML. Durability of clinical benefit with niraparib + pembrolizumab in patients with advanced triple-negative breast cancer beyond BRCA: (TOPACIO/Keynote-162) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-02.

BACKGROUND Rolapitant, a novel neurokinin‐1 receptor antagonist, provided effective protection against chemotherapy‐induced nausea and vomiting (CINV) in a randomized, double‐blind phase 3 trial of patients receiving moderately emetogenic chemotherapy or an anthracycline and cyclophosphamide regimen. The current analysis explored the efficacy and safety of rolapitant in preventing CINV in a subgroup of patients receiving carboplatin. METHODS Patients were randomized 1:1 to receive oral rolapitant (180 mg) or a placebo 1 to 2 hours before chemotherapy administration; all patients received oral granisetron (2 mg) on days 1 to 3 and oral dexamethasone (20 mg) on day 1. A post hoc analysis examined the subgroup of patients receiving carboplatin in cycle 1. The efficacy endpoints were as follows: complete response (CR), no emesis, no nausea, no significant nausea, complete protection, time to first emesis or use of rescue medication, and no impact on daily life. RESULTS In the subgroup administered carboplatin‐based chemotherapy (n = 401), a significantly higher proportion of patients in the rolapitant group versus the control group achieved a CR in the overall phase (0‐120 hours; 80.2% vs 64.6%; P < .001) and in the delayed phase (>24‐120 hours; 82.3% vs 65.6%; P < .001) after chemotherapy administration. Superior responses were also observed by the measures of no emesis, no nausea, and complete protection in the overall and delayed phases and by the time to first emesis or use of rescue medication. The incidence of treatment‐emergent adverse events was similar for the rolapitant and control groups. CONCLUSIONS Rolapitant provided superior CINV protection to patients receiving carboplatin‐based chemotherapy in comparison with the control. These results support rolapitant use as part of the antiemetic regimen in carboplatin‐treated patients. Cancer 2016;122:2418–2425. © 2016 American Cancer Society., The efficacy of rolapitant, a neurokinin‐1 receptor antagonist with a long duration of action, was examined in a subgroup of 401 patients with cancer who received carboplatin‐based chemotherapy in a phase 3 trial. In this population, a single oral dose of rolapitant (180 mg) combined with granisetron and dexamethasone provided statistically superior protection against chemotherapy‐induced nausea and vomiting in the delayed and overall phases in comparison with granisetron and dexamethasone alone, and it was well tolerated.

1011Background: Chemotherapy is a standard of care for TNBC despite its suboptimal efficacy. ≈15–20% of TNBC have BRCA1/2 mutations (mut); ≈75% of BRCA1 mut BCs are TN. Single agent poly(ADP-ribose) polymerase (PARP) inhibitors have clinical activity in pts with BRCA1/2 mutations (BRCAmut) BC and provide median PFS of 6 mos in pts with BRCAmut TNBC vs 3.5 mos for chemotherapy. Single-agent pembrolizumab (pembro), a programmed death 1(PD–1) inhibitor, has shown objective response rates (ORR) of 5–18% in previously treated TNBC. TOPACIO (NCT02657889) is a fully enrolled study evaluating the safety and efficacy of combination treatment with selective PARP1/2 inhibitor niraparib + pembro in pts with met TNBC. Methods: Pts received niraparib 200 mg orally once daily + pembro 200 mg IV on day 1 of each 21-day cycle. Primary efficacy endpoint was ORR and secondary endpoints included disease control rate (DCR = CR+PR+SD [stable disease]). Results: As of Jan 2018, 12 of 54 enrolled TNBC pts (22%) had deleterious B...

Rolapitant is a novel, long-acting neurokinin-1 (NK-1) receptor antagonist. This study evaluated the safety and efficacy of four different doses of rolapitant for prevention of chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC). This randomized, double-blind, active-controlled, global study was conducted in patients receiving cisplatin-based chemotherapy ≥70 mg/m2. Patients received a 9, 22.5, 90, or 180 mg oral dose of rolapitant or placebo with ondansetron and dexamethasone on day 1 of chemotherapy. The primary end point was complete response (CR; no emesis and no use of rescue medication) in the overall (0 to 120 h) phase of cycle 1. Other assessments were CR in delayed (24–120 h) and acute (0–24 h) phases, no emesis, no significant nausea, and no nausea. Four hundred fifty-four patients were randomized. All doses of rolapitant improved CR with the greatest benefit observed with rolapitant 180 mg vs. active control in the overall phase (62.5 and 46.7 %, p = 0.032) and in the acute (87.6 vs. 66.7 %, p = 0.001) and delayed (63.6 vs. 48.9 %, p = 0.045) phases. Rates for no emesis and no significant nausea were significantly (p

Background: In adults with asthma, hydrofluoralkane-134a beclomethasone dipropionate (HFA-BDP) extrafine aerosol provides equivalent asthma control at half the daily dose of conventional chlorofluorocarbon (CFC)-BDP. Objective: We sought to compare the efficacy and tolerability of switching from CFC-BDP to HFA-BDP at half the daily dose in children with stable asthma. Methods: This 6-month, open-label, randomized, multicenter study enrolled 520 children aged 5 to 11 years with well-controlled asthma receiving inhaled CFC-BDP or budesonide 200 to 800 μg/d x. (Four hundred fifty-two patients were using doses within the recommended range of 200-400 μg and were analyzed separately.) During a 4-week run-in period, patients used CFC-BDP plus a spacer (CFC-BDP+S) at approximately the same dose as they were using before study entry. Patients were then randomized in a 1:3 ratio to continue on CFC-BDP+S or switch to HFA-BDP Autohaler at half the daily dose. Results: The change from baseline in morning peak expiratory flow was significantly greater in patients receiving 100-200 μg of HFA-BDP compared with those receiving 200-400 μg of CFC-BDP+S at weeks 7 to 8 (8.5 and 0.4 L/min, respectively; P = .014), with continuing improvement in both groups over 6 months (12.2 and 12.4 L/min, respectively, at month 6). There were no significant differences between treatments in mean change from baseline in FEV 1 , percentage of days or nights without asthma symptoms, and daily β-agonist use over the 6-month treatment period. The proportion of patients who had one or more asthma exacerbations, the incidence of adverse events, and the percentage change from baseline in 24-hour urinary free cortisol levels were similar in the 2 treatment groups. Conclusions: This study confirms that asthma control can be well maintained in children when switching from CFC-BDP+S to an HFA-BDP Autohaler at doses as low as 100 to 200 μg/d. (J Allergy Clin Immunol 2002;110:45-50.)

224 Background: Nausea control remains an unmet need for patients receiving moderately or highly emetogenic chemotherapy (MEC, HEC). The objective of this analysis was to determine the effect of the neurokinin-1 (NK-1) receptor antagonist rolapitant (VARUBI) on the prevention of nausea in patients receiving either MEC or HEC. Methods: Post hoc analyses of nausea from three randomized, double-blind, active-controlled, phase 3 clinical trials were performed for carboplatin-based MEC (n = 401), non-carboplatin-based MEC (n = 228), total MEC (n = 629), anthracycline/cyclophosphamide (AC)-based chemotherapy (n = 703), and cisplatin-based HEC (n = 1070). Patients were randomized 1:1 to oral rolapitant 180 mg or placebo ~1–2 h before chemotherapy. All patients received active control: granisetron 2 mg oral or 10 mcg/kg IV and oral dexamethasone 20 mg. Granisetron was continued on days 2 and 3 for patients receiving MEC or AC-based therapy and dexamethasone 8 mg twice daily on days 2–4 for patients receiving HEC. Patients self-assessed nausea on days 1–6 using a 100-mm visual analog scale (VAS). Percentage of patients with no nausea (NN; maximum VAS < 5 mm) or no significant nausea (NSN; maximum VAS < 25 mm) was determined for overall, delayed, and acute phases of CINV in cycle 1. Results: Rates of NN in the carboplatin-based MEC and total MEC subgroups were significantly higher (P < 0.05) with rolapitant than active control in the delayed and overall phases. In the cisplatin-based HEC subgroup, rates of NN and NSN were significantly higher (P < 0.05) with rolapitant than active control in the delayed, acute, and overall phases. Conclusions: Rolapitant prevents nausea during all CINV phases in patients receiving cisplatin-based HEC, and during the delayed and overall phases in patients receiving carboplatin-based MEC. Clinical trial information: NCT01500226, NCT01499849, NCT01500213.

223 Background: Rolapitant, a long-acting neurokinin-1 receptor antagonist, protected against CINV in patients receiving highly or moderately emetogenic chemotherapy (HEC or MEC). Methods: In 3 double-blind phase 3 studies, patients were randomized to receive oral rolapitant 180 mg or placebo before administration of HEC or MEC. All patients received a 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone. In a post hoc analysis of 3 pooled studies (2 HEC and 1 MEC), we assessed the efficacy and safety of rolapitant in patients with gynecologic (ovarian, uterine, or cervical) cancer. Endpoints included complete response (CR; no emesis and no use of rescue medication), no emesis, no nausea (maximum visual analogue scale [VAS] < 5 mm), and complete protection (CP; no emesis, no use of rescue medication, and no significant nausea [maximum VAS < 25 mm]) in the overall (0–120 h), acute (≤ 24 h), and delayed (> 24–120 h) phases. Results: Of 201 patients with gynecologic cancer (60% ovarian, 28% uterine, and 12% cervical cancer), 55% received cisplatin-based HEC and 44% received MEC (99% of whom received carboplatin-based therapy). In the overall and delayed phases, improved rates of CR, no emesis, no nausea, and CP were observed with rolapitant compared with control (Table). The overall incidence of treatment-emergent adverse events was similar in the rolapitant and control groups (45% vs 54%). Conclusions: Rolapitant protected against overall and delayed CINV in patients with gynecologic cancer receiving HEC or MEC. Clinical trial information: NCT01500226, NCT01499849, NCT01500213. [Table: see text]

222 Background: Rolapitant (VARUBI) is a selective, long-acting neurokinin-1 receptor antagonist (RA) for the prevention of CINV. Rolapitant effectively prevented CINV in phase 3 trials of patients (pts) receiving highly or moderately emetogenic chemotherapy (HEC, MEC). While MEC and HEC regimens are commonly used to treat pts with gastrointestinal and colorectal cancers (GI/CRC), very few studies have evaluated the effectiveness of a neurokinin-1 RA regimen in these pts. We assessed the incidence of CINV and efficacy of rolapitant in a subset of pts with GI/CRC. Methods: This is a post hoc analysis of 3 similarly-designed, randomized, placebo-controlled trials. Pts with cancer of the esophagus, stomach, colon/rectum, or anus received a single oral dose of 180 mg oral rolapitant or placebo prior to HEC or MEC. All pts received a 5-hydroxytryptamine type 3 (5-HT3) RA and dexamethasone (active control). The HEC studies included cisplatin, and the MEC study carboplatin, oxaliplatin, irinotecan, epirubicin, and doxorubicin. Endpoints included complete response (CR; no emesis and no use of rescue medication), no emesis, no nausea (maximum visual analogue scale [VAS] < 5 mm), no significant nausea (maximum VAS < 25mm) and complete protection (CP; no emesis, no use of rescue medication, and no significant nausea) in the overall (0-120 h), acute (≤ 24 h), and delayed (> 24-120 h) phases. Results: Out of 188 GI/CRC pts, 101 pts received rolapitant and 87 received active control. Pts treated with rolapitant had significantly higher rates of CR, no nausea, no emesis, and CP in the overall phase (P < 0.05). Rolapitant was well-tolerated and overall incidence of treatment-emergent adverse events comparable in both groups. Conclusions: Addition of rolapitant to 5-HT3RA and dexamethasone therapy significantly improved CR, no nausea, no emesis, and CP in pts with GI/CRC receiving emetogenic chemotherapy. Clinical trial information: NCT01500226, NCT01499849, NCT01500213. [Table: see text]

10121Background: Addition of the neurokinin-1 receptor antagonist (RA) rolapitant to standard antiemetic therapy improved CINV control in a phase 3 trial of patients administered anthracycline/cycl...

Introduction: Rolapitant is a selective and long acting NK-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting (CINV). In vitro results indicated rolapitant mildly inhibited cytochrome P450 (CYP450) enzymes (2D6/2C9/2C19/2B6/2C8) at high concentrations (IC50s > 7 μM). The major metabolite SCH720881 did not inhibit these CYP enzymes. This study aimed to 1) evaluate the effects of rolapitant on the pharmacokinetics (PK) of CYP probe substrates (dextromethorphan [DET] for CYP2D6, tolbutamide [TOL] for CYP2C9, omeprazole [OMP] for CYP2C19, efavirenz [EFA] for CYP2B6 and repaglinide [REP] for CYP2C8), and 2) evaluate the safety and tolerability of rolapitant co-administered with these substrates in healthy subjects. Methods: This was an open-label, multi-part drug-drug interaction study in cohorts of 20 to 26 healthy subjects of orally-administered CYP probe substrates (Part-A: 30 mg DET; Part-B: 500 mg TOL plus 40 mg OMP; Part-C: 600 mg EFA; Part-D: 0.25 mg REP) in the absence and presence of single oral dose 180 mg rolapitant. Blood samples for determination of plasma concentration of CYP substrates and relevant metabolites were collected during 3 dosing periods in each part: 1) Period-1: CYP probe substrate alone as baseline; 2) Period-2: CYP probe substrate plus rolapitant concomitantly after a washout of probe given in Period 1 to evaluate the potential impact of rolapitant on probe substrate; and 3) Period-3: CYP probe substrate alone 7 days after the concomitant dose in Period-2 (approximating the peak time of metabolite SCH720881) to evaluate the impact of metabolite/rolapitant on probe substrate. Results: Rolapitant inhibited CYP2D6 following concomitant dose (Period-2) and 7 days after concomitant dose (Period-3), resulting in 2.2- to 3.3-fold higher exposure (Cmax and AUC) of DET. Rolapitant did not inhibit CYP2C9 following exposure to TOL. The exposure (Cmax & AUC) of CYP2C19 substrate OMP was minimally increased by rolapitant (1.1- to1.4-fold) and is unlikely to be clinically relevant. Rolapitant did not inhibit CYP2B6 or result in clinically relevant changes in exposure of EFA. Rolapitant did not inhibit CYP2C8 or result in clinically relevant changes in exposure of REP. There were no noteworthy adverse events or laboratory findings in any part of the study. Conclusions: Rolapitant was well-tolerated when co-administered with CYP probe substrates. Co-administration of rolapitant increased the exposure of DET. The inhibition of CYP2D6 can last at least 7 days following single dose of rolapitant. No clinically significant interaction was observed between rolapitant and substrates of CYP2C9, CYP2C19, CYP2B6 or CYP2C8; therefore no dosing adjustment is necessary for drugs which are metabolized by these CYPs. Citation Format: Xiaodong Wang, Zhi-Yi Zhang, Jing Wang, Sharon Lu, Sujata Arora, Lorraine Hughes, Jennifer Christensen, Vikram Kansra. Effects of rolapitant on the pharmacokinetics of dextromethorphan (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), efavirenz (CYP2B6), and repaglinide (CYP2C8) in healthy subjects. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C62.

Purpose Decitabine, a DNA-targeted hypomethylating agent, is approved by the United States Food and Drug Administration for treatment of patients with myelodysplastic syndromes (MDS) on a schedule of 15 mg/m2 administered via intravenous (IV) infusion every 8 hours for 3 days. This study assessed the efficacy and safety of an alternative dosing regimen administered on an outpatient basis in academic and community-based practices. Patients and Methods Patients were treated with decitabine 20 mg/m2 by IV infusion daily for 5 consecutive days every 4 weeks. Eligible patients were ≥ 18 years of age and had MDS (de novo or secondary) of any French-American-British (FAB) subtype and an International Prognostic Scoring System (IPSS) score ≥ 0.5. The primary end point was the overall response rate (ORR) by International Working Group (IWG 2006) criteria; secondary end points included cytogenetic responses, hematologic improvement (HI), response duration, survival, and safety. Results Ninety-nine patients were enrolled; the ORR was 32% (17 complete responses [CR] plus 15 marrow CRs [mCRs]), and the overall improvement rate was 51%, which included 18% HI. Similar response rates were observed in all FAB subtypes and IPSS risk categories. Among patients who improved, 82% demonstrated responses by the end of cycle 2. Among 33 patients assessable for a cytogenetic response, 17 (52%) experienced cytogenetic CR (n = 11) or partial response (n = 6). Conclusion Decitabine given on a 5-day schedule provided meaningful clinical benefit for patients with MDS, with more than half demonstrating improvement. This suggests that decitabine can be administered in an outpatient setting with comparable efficacy and safety to the United States Food and Drug Administration–approved inpatient regimen.

Treatment with one of the DNA methyltransferase inhibitors (DNMTIs, “hypomethylating agents”), azacitidine or decitabine, is now considered standard care for patients with higherrisk myelodysplastic syndromes (MDS) (1) – especially since results were released from the AZA-001 trial (2), which demonstrated a 9-month survival advantage with azacitidine therapy compared to supportive care. However, many patients with MDS do not respond to treatment with DNMTIs as they are currently used, and adverse events are common. It is desirable to be able to predict a priori which patients are most likely to benefit from DNMTI therapy, in order to spare patients unlikely to respond from the risks and cost of treatment, but there are currently no well-established molecular methods for DNMTI response prediction.(3) ATRX is an X-encoded chromatin-associated protein with an evolutionarily conserved Nterminal DNA methyltransferase (DNMT3-like) domain.(4) Germline mutations in ATRX cause a mental retardation-dysmorphology syndrome often associated with mild alpha thalassemia, which gave the gene its name (ATR-X syndrome: alpha thalassemia, retardation, X-linked) (5); in contrast, somatic point mutations in ATRX have been linked to acquired alpha thalassemia arising in the context of MDS, which may be present in as many as 8% of patients. (6-8) Germline mutations in ATRX are associated with widespread and diverse DNA methylation abnormalities across the genome.(9) Recent evidence suggests that the ATRX protein also has an important role in chromosome dynamics during mitosis, as ATRX-depleted cells exhibit defective sister chromatid cohesion and congression at the metaphase plate, as well as abnormal chromosome alignment. (10,11) Circumstantial evidence for a role of ATRX in neoplasia is increasing. In an array-based gene expression profiling study of 42 children with acute myeloid leukemia (AML) associated with somatic FLT3 mutations, the expression ratio of the transcription factor RUNX3 (formerly AML2) to ATRX predicted event-free survival (EFS).(12) In a subsequent study of 132 adults with de novo AML by another investigative group, low ATRX expression correlated with highrisk karyotype and poor clinical outcome.(13) Altered ATRX expression levels have also been reported in gene expression profiling experiments using prostate cancer primary cells (14), esophageal squamous cell carcinoma cell lines (15), chronic lymphocytic leukemia primary cells (Neil Kay, personal communication October 2007), and irradiated breast cancer cell lines (16).

209 Background: Rolapitant, a novel NK-1 receptor antagonist, showed efficacy in CINV prevention in patients (pts) receiving MEC (anthracycline/cyclophosphamide (AC) and other regimens) in a global phase 3 trial. Recent anti-emetic guidelines consider AC based regimens to be highly emetogenic. In this post hoc analysis, the efficacy and safety of rolapitant was assessed in Cycle 1 in pts receiving non-AC MEC, and in the subset of pts receiving carboplatin-based MEC. Methods: In a double-blind, active-controlled study, pts were randomized to oral rolapitant 180 mg or placebo 1–2 hours before MEC. All pts received granisetron 2 mg oral on days 1-3 and oral dexamethasone 20 mg on day 1. Complete response (CR = no emesis + no use of rescue medication), no emesis, and no nausea were assessed in overall (0-120 h), acute (0-24 h), and delayed ( > 24-120 h) phases. Results: CR was significantly (P < 0.01) higher with rolapitant than active control in overall and delayed phases in the carboplatin subset and in all 3 phases in the non-AC population (Table). No emesis rates were significantly (p < 0.05) higher with rolapitant in the carboplatin subset in the overall phase. No nausea rates were significantly (P < 0.05) higher with rolapitant in the overall and delayed phases in carboplatin-based MEC. Incidences of treatment-related AEs in Cycle 1 with rolapitant vs. active control were 11.3% vs. 6.7% in the carboplatin-based subset. Most common AEs with rolapitant and active control were constipation, fatigue, and headache. Conclusions: Rolapitant was superior to active control in preventing CINV in pts receiving non-AC MEC, including in the subgroup receiving carboplatin. Rolapitant was well tolerated with low incidence of AEs. Clinical trial information: NCT01500226. [Table: see text]

208 Background: Rolapitant, a novel NK-1 receptor antagonist, demonstrated efficacy in the prevention of CINV in pts receiving moderately- or highly emetogenic chemotherapy (MEC; HEC). In this post-hoc analysis, we evaluated safety and efficacy outcomes in pts receiving AC-based therapy, now considered HEC. Methods: This double-blind, active-controlled study randomized pts to oral rolapitant 180 mg plus granisetron 2 mg and dexamethasone 20 mg or granisetron/dexamethasone alone (active control). Complete response (CR = no emesis and no use of rescue medication), no emesis, no significant nausea, and time to emesis or rescue medication during overall, acute, and delayed phases and treatment-emergent adverse events (AEs) are presented. Results: 703 pts received AC-based therapy, of which 97% had breast cancer. CR was significantly higher for rolapitant vs. active control for delayed and overall phases in pts receiving AC-based therapy (Table). Time to first emesis or use of rescue medication was significantly longer with rolapitant vs. active control (between-group comparison, p = 0.032); median was not reached in either treatment arm. A significantly greater proportion of pts on rolapitant (73.0%) vs. active control (60.2%) had no emesis during the overall phase (p < 0.001). Rates of no significant nausea were similar for rolapitant (63.7%) and active control (62.4%) in the overall phase (p = 0.728). Treatment-related AEs (TRAEs) during Cycle 1 occurred in 8.7% and 8.8% of pts on rolapitant vs. active control. Most frequent TRAEs were constipation (2.9% vs. 2.7%), fatigue (2.3% vs. 2.2%), and headache (2.3% vs. 3.3%). Conclusions: Rolapitant was superior to active control in preventing CINV during delayed and overall phases after AC-based chemotherapy. The safety profiles of the rolapitant and control arms were similar. These results are consistent with those of the overall pt population in this study. Clinical trial information: NCT01500226. [Table: see text]

210 Background: The long-acting neurokinin-1 receptor antagonist (NK-1 RA) rolapitant has demonstrated efficacy for CINV prevention in patients receiving HEC and MEC during Cycle 1. The efficacy and safety of rolapitant was examined during subsequent cycles 2–6 in a pooled analysis. Methods: In 4 double-blind, active-controlled studies, patients were randomized to oral rolapitant 180 mg or placebo 1–2 hours before chemotherapy. All patients received active control: 5HT3 receptor antagonist + oral dexamethasone. Patients completing Cycle 1 could receive the same anti-emetic treatment in subsequent cycles. On Days 6-8 of subsequent cycles, patients self-reported the incidence of emesis, or of nausea interfering with normal daily life following Day 1 of chemotherapy. Results: A greater proportion of patients on rolapitant than on active control reported no emesis or interfering nausea separately for each subsequent cycle. Results of individual studies and pooled analysis are shown in the Table. During cycles 2-6, the incidence of treatment-related adverse events (AEs) was similar for rolapitant (5.5%) and control (6.8%). The most common treatment-related AEs were similar in both arms: constipation (rolapitant: 1.2%; control: 0.8%) and fatigue (rolapitant: 1.3%; control: 1.8%). Conclusions: Rolapitant was superior to active control in reducing CINV when administered over multiple cycles of moderately or highly emetogenic chemotherapy, with no increase in toxicity. Clinical trial information: NCT00394966 - NCT01500213 - NCT01500226 - NCT01499849. [Table: see text]

9615 Background: Rolapitant is a novel NK-1 receptor antagonist with a half-life of 180h, and does not inhibit CYP3A4 as other drugs do in the class, and therefore requires no dose modifications of...

9622 Background: Rolapitant, a novel NK-1 receptor antagonist, showed efficacy for prevention of CINV in patients (pts) receiving MEC (anthracycline/cyclophosphamide (A/C) and other regimens) in a ...

To assess the influence of orlistat, a lipase inhibitor, on the absorption of beta-carotene, an open-label, parallel, placebo-controlled, randomized, two-way crossover study was performed in 48 healthy volunteers between the ages of 19 and 58 years. Each subject received a single oral dose of 0, 30, 60, or 120 mg beta-carotene (12 subjects per dose level) on the fourth day of treatment with orlistat (120 mg) or placebo 3 times a day for 6 days. The treatments were separated by a washout period of at least 5 weeks. Serial blood samples were collected before and at appropriate intervals after administration of beta-carotene to determine plasma concentrations of unchanged beta-carotene. Short-term (3 to 6 days) treatment with orlistat did not alter endogenous profiles of beta-carotene in plasma. When beta-carotene was given during orlistat treatment, its absorption was reduced by approximately one-third. This reduction was consistent for all three dose levels of beta-carotene studied; however, the results for the 30-mg dose level were subject to greater variability, particularly for area under the concentration-time curve (AUC). It was concluded that two thirds of a supplemental dose of beta-carotene will be absorbed during orlistat treatment; this may be sufficient to achieve physiologic levels of beta-carotene with an appropriate dose of beta-carotene, should supplementation be needed in obese patients who have developed beta-carotene deficiency during therapy with orlistat.

To assess the influence of an orlistat-induced reduction in dietary fat absorption on the pharmacokinetics of digoxin, an open-label, placebo-controlled, randomized, two-way crossover study was performed in 12 healthy volunteers. Each subject received single 0.4-mg doses of digoxin (soft gelatin capsules) administered orally on the fourth day of orlistat (120 mg three times daily for 6 days) and placebo (three times daily for 6 days) treatment, separated by at least an 11-day washout period. Serial blood samples were collected before and at appropriate intervals after each digoxin dose to determine plasma concentrations of unchanged digoxin. The 90% confidence intervals for the ratio of geometric least-squares means (for Cmax, AUC0-48, AUC0-t, and AUC) and for the difference of arithmetic least-squares means (for tmax and lambda z) indicate that the pharmacokinetics of digoxin was not altered by treatment with orlistat. This results suggests that a approximately 30% reduction in dietary fat absorption will not change the efficacy of digoxin in cardiac patients.

7030 Background: Among pts with MDS, cytogenetic abnormalities predict transformation to acute myeloid leukemia or death. Cytogenetic responses suggest clonal suppression and may alter the natural ...

Objective. To assess the long-term safety of hydrofluoroalkane 134a (HFA)-beclomethasone dipropionate (BDP) extrafine aerosol administered by the Autohaler compared with chlorofluorocarbon (CFC)-BDP administered by a press-and-breathe metered-dose inhaler (pMDI) and spacer (+S) in the treatment of children with asthma. Methods. This 12-month, open-label, randomized, multicenter study enrolled 300 children who were aged 5 to 11 years and had well-controlled asthma on inhaled CFC-BDP or budesonide; 256 patients were using doses within the recommended range (200–400 μg) and were analyzed separately. Patients were randomized in a 1:3 ratio to continue on CFC-BDP+S at approximately the same dose as they were using before study entry or switch to HFA-BDP at half the daily dose. Results. Asthma control was well maintained in the HFA-BDP group as evidenced by lung function tests and asthma symptoms compared with CFC-BDP+S at approximately twice the dose. There were no significant differences between the HFA-BDP 100 to 200 μg and CFC-BDP+S 200 to 400 μg treatment groups in mean change from baseline in height (5.23 cm vs 5.66 cm at month 12, respectively) or mean growth velocity from day 1 to month 12 (5.27 cm/y vs 5.71 cm/y, respectively). There were no significant differences between groups in adrenal function tests or markers of bone metabolism. Conclusions. In this long-term study in children with asthma, extrafine HFA-BDP provided long-term maintenance of asthma control at approximately half the dose compared with CFC-BDP+S. There were no clinically meaningful differences between HFA-BDP extrafine aerosol and conventional CFC-BDP+S with regard to growth or other systemic effects.

ObjectiveRolapitant, a novel neurokinin-1 receptor antagonist (RA), was shown to protect against delayed chemotherapy-induced nausea and vomiting (CINV) during the first cycle of moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) in randomized, double-blind trials. This analysis explored the efficacy and safety of rolapitant in preventing CINV over multiple cycles of MEC or HEC.Patients and methodsPatients in one phase III MEC, one phase II HEC, and two phase III HEC clinical trials were randomized to receive oral rolapitant (180 mg) or placebo in combination with a 5-hydroxytryptamine type 3 RA and dexamethasone. Regardless of response in cycle 1, patients could continue the same antiemetic treatment for up to six cycles. On days 6−8 of each subsequent chemotherapy cycle, patients reported the incidence of emesis and/or nausea interfering with normal daily life. Post hoc analyses of pooled safety and efficacy data from the four trials were performed for cycles 2–6.ResultsSignificantly more patients receiving rolapitant than control reported no emesis or interfering nausea (combined measure) in cycles 2 (p = 0.006), 3 (p