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Objective: Obexelimab is an investigational, bifunctional, noncytolytic monoclonal antibody that binds CD19 and FcyRIIb to inhibit B cells, plasmablasts, and plasma cells. This trial evaluated the efficacy and safety of obexelimab in the treatment of patients with systemic lupus erythematosus (SLE). Methods: During screening, patients with active, non–organ‐threatening SLE received corticosteroid injections to ameliorate symptoms while immunosuppressants were withdrawn (≤10 mg/day prednisone equivalent and ≤400 mg/day hydroxychloroquine allowed). Patients with improved disease activity were randomized 1:1 to obexelimab 5 mg/kg intravenously or placebo once every 2 weeks until week 32 or loss of improvement (LOI). Results: In this study, 104 patients were randomized. Analysis of the primary endpoint, proportion of patients reaching week 32 without LOI, used an efficacy‐evaluable (EE) population defined as patients who completed the study or withdrew for flare or treatment‐related toxicity. This endpoint did not reach statistical significance: 21 of 50 obexelimab‐treated patients (42.0%) versus 12 of 42 patients (28.6%) treated with a placebo (P = 0.183). Time to LOI was increased in obexelimab‐treated patients versus patients treated with a placebo in the EE (hazard ratio [HR] 0.53, P = 0.025) and intention‐to‐treat (HR 0.59, P = 0.062) populations. In obexelimab‐treated patients, B cells decreased approximately 50%, and trough concentration and inclusion in baseline gene expression clusters with high B cell pathway modules were associated with increased time to LOI. Obexelimab was associated with infusion reactions but was generally safe and well‐tolerated. Conclusion: Although the primary endpoint was not reached, secondary analysis showed time to LOI was significantly increased in obexelimab‐treated patients, and analysis of patient subsets defined by gene expression patterns at baseline suggests a responding subpopulation. [ABSTRACT FROM AUTHOR]

Rolapitant (Varubi) is a neurokinin‐1 receptor antagonist approved for the prevention of chemotherapy‐induced nausea and vomiting. Rolapitant is primarily metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. Unlike other neurokinin‐1 receptor antagonists, rolapitant is neither an inhibitor nor an inducer of CYP3A4 in vitro. The objective of this analysis was to examine the pharmacokinetics of rolapitant in healthy subjects and assess drug‐drug interactions between rolapitant and midazolam (a CYP3A substrate), ketoconazole (a CYP3A inhibitor), or rifampin (a CYP3A4 inducer). Three phase 1, open‐label, drug‐drug interaction studies were conducted to examine the pharmacokinetic interactions of orally administered rolapitant with midazolam, rolapitant with ketoconazole, and rolapitant with rifampin. The pharmacokinetic profiles of midazolam and 1‐hydroxy midazolam metabolites were essentially unchanged when coadministered with rolapitant, indicating the lack of a clinically relevant inhibition or induction of CYP3A by rolapitant. Coadministration of ketoconazole with rolapitant had no effects on rolapitant maximum concentration and resulted in an approximately 20% increase in the area under the concentration‐time curve of rolapitant, suggesting that strong CYP3A inhibitors have minimal inhibitory effects on rolapitant exposure. Repeated administrations of rifampin appeared to reduce rolapitant exposure, resulting in a 33% decrease in maximum concentration and 87% decrease in area under the concentration‐time curve from time zero to infinity. Coadministration of rolapitant did not affect the exposure of midazolam. Rifampin coadministration resulted in lower concentrations of rolapitant, and ketoconazole coadministration had no or minimal effects on rolapitant exposure. Rolapitant was safe and well tolerated when coadministered with ketoconazole, rifampin, or midazolam. No new safety signals were reported compared with previous studies of rolapitant. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Background. Imiquimod is currently approved for the treatment of genital warts and has been shown to decrease recurrences of genital herpes in the guinea pig model of genital herpes. Therefore, we evaluated the safety and potential of topical imiquimod to decrease the rate of recurrence in humans with a history of recurrent herpes labialis. Methods. Forty-seven subjects with recurrent herpes labialis applied imiquimod 5% (n = 30) or vehicle cream (n = 17) to recurrent lesion(s) on days 1, 3, and 5 of the study (day 1 of observation occurred within 48 h after recurrence of lesion). Subjects were seen at the study centers between each dose and 3 days after application of the final dose or until resolution of the lesion. Results. After application to recurrent lesions, local erythema, edema, scabbing and/or flaking, pain, burning, and maximal lesion size were significantly greater in the imiquimod group than in the vehicle group. The study was terminated early because of severe local adverse events that occurred in 5 recipients of imiquimod. The median time until the next recurrence was, however, increased from 50 days in the vehicle group to 91 days in the imiquimod group (P = .018). Conclusions. Application of imiquimod 5% cream to herpes labialis lesions was associated with a delay in the time to the first recurrence after treatment, but severe local inflammation occurred in some individuals. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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 < .001]; absolute benefit [AB] = 10.6%), delayed (55.7% vs 44.3% [P < .001]; AB = 11.4%), and acute (70.5% vs 64.3% [P = .030]; AB = 6.2%) phases. Similar results were observed in the carboplatin‐based chemotherapy group, with significantly more patients receiving rolapitant than control reporting NN in the overall (62.5% vs 51.2% [P = .023]; AB = 11.3%) and delayed (64.1% vs 53.6% [P = .034]; AB = 10.5%) phases. In the AC‐based chemotherapy group, patients receiving rolapitant or control reported similar NN rates during the overall and delayed phases. Rolapitant effectively prevents nausea during the overall and delayed phases in patients receiving cisplatin‐ or carboplatin‐based chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract: 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 <20% lower in those with moderate hepatic impairment versus healthy controls. Fraction of unbound rolapitant was comparable in all groups for rolapitant and M19. Rolapitant was well tolerated in all groups, without serious adverse events. Pharmacokinetic differences between healthy subjects and those with mild or moderate hepatic impairment are unlikely to pose a safety risk and do not warrant predefined dosage adjustment in the presence of hepatic impairment. [ABSTRACT FROM AUTHOR]

Rolapitant, a selective and long-acting neurokinin-1 receptor antagonist, is approved in an oral formulation for the prevention of delayed chemotherapyinduced 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. [ABSTRACT FROM AUTHOR]

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 < 0.001), nausea score (55.3 vs 53.5, p < 0.05), and vomiting score (59.2 vs 55.8, p < 0.001) versus control; similar results were observed in the MEC/AC study for FLIE total score (112.7 vs 108.6, p < 0.001), nausea score (54.1 vs 52.3, p < 0.05), and vomiting score (58.6 vs 56.3, p < 0.001). A higher proportion of patients reported no impact on daily life with rolapitant than with control in the MEC/AC study (73.2 vs 67.4, p = 0.027).Conclusions: Compared with control, rolapitant improved quality of life in patients receiving HEC or MEC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective Rolapitant, 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 methods Patients 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. Results Significantly more patients receiving rolapitant than control reported no emesis or interfering nausea (combined measure) in cycles 2 ( p = 0.006), 3 ( p < 0.001), 4 ( p = 0.001), and 5 ( p = 0.021). Over cycles 1−6, time-to-first emesis was significantly longer with rolapitant than with control ( p < 0.001). The incidence of treatment-related adverse events during cycles 2–6 was similar in rolapitant (5.5%) and control (6.8%) arms. No cumulative toxicity was observed. Conclusions Over multiple cycles of MEC or HEC, rolapitant provided superior CINV protection and reduced emesis and nausea interfering with daily life compared with control and remained well tolerated. [ABSTRACT FROM AUTHOR]

Purpose: 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).Methods: This randomized, double-blind, active-controlled, global study was conducted in patients receiving cisplatin-based chemotherapy ≥70 mg/m(2). 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.Results: 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 < 0.05) higher with rolapitant 180 mg vs. active control in the overall, acute, and delayed phases. Treatment-related adverse events were largely considered related to the chemotherapy and included constipation, headache, fatigue, and dizziness which were mostly mild or moderate and were similar across treatment groups.Conclusion: All doses of rolapitant were well tolerated and showed greater CR rates than active control. Rolapitant 180 mg demonstrated significant clinical efficacy for preventing CINV in the overall, delayed, and acute phases for patients receiving HEC. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy-induced nausea and vomiting is a common side-effect of many antineoplastic regimens and can occur for several days after treatment. We aimed to assess the neurokinin-1 receptor antagonist rolapitant, in combination with a serotonin (5-HT3) receptor antagonist and dexamethasone, for the prevention of chemotherapy-induced nausea and vomiting in patients with cancer after administration of moderately emetogenic chemotherapy or regimens containing an anthracycline and cyclophosphamide.Methods: We conducted a global, randomised, double-blind, active-controlled, phase 3 study at 170 cancer centres in 23 countries. We included patients with cancer aged 18 years or older, who had not received moderately or highly emetogenic chemotherapy before, 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 allocate patients to receive either oral rolapitant (one 180 mg dose; rolapitant group) or a placebo that was identical in appearance (active control group) 1-2 h before administration of moderately emetogenic chemotherapy. Patients were stratified by sex. All patients also received granisetron (2 mg orally) and dexamethasone (20 mg orally) on day 1 (except for patients receiving taxanes as part of moderately emetogenic chemotherapy, who received dexamethasone according to the package insert) and granisetron (2 mg orally) on days 2-3. Every cycle was a minimum of 14 days. In up to five subsequent cycles, patients received the same study drug they were assigned in cycle 1, unless they chose to leave the study or were removed at the treating clinician's discretion. 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 study site compliant with Good Clinical Practice [GCP]). The primary endpoint was the proportion of patients achieving a complete response (defined as no emesis or use of rescue medication) in the delayed phase (>24-120 h after initiation of chemotherapy) in cycle 1. This study is registered with ClinicalTrials.gov, number NCT01500226. The study has been completed.Findings: Between March 5, 2012, and Sept 6, 2013, 1369 patients were randomised to receive either rolapitant (n=684) or active control (n=685). 666 patients in each group 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 receiving rolapitant had complete responses in the delayed phase than did those receiving active control (475 [71%] vs 410 [62%]; odds ratio 1·6, 95% CI 1·2-2·0; p=0·0002). The incidence of adverse events was similar in the rolapitant and control groups, with the most frequently reported treatment-related treatment-emergent adverse events being fatigue, constipation, and headache. For cycle 1, the most common grade 3-4 adverse event in the rolapitant versus active control groups was neutropenia (32 [5%] vs 23 [3%] patients). No serious adverse event was treatment-related, and no treatment-related treatment-emergent adverse event resulted in death.Interpretation: Rolapitant in combination with a 5-HT3 receptor antagonist and dexamethasone is well tolerated and shows superiority over active control for the prevention of chemotherapy-induced nausea and vomiting during the 5-day (0-120 h) at-risk period after administration of moderately emetogenic chemotherapy or regimens containing an anthracycline and cyclophosphamide.Funding: TESARO, Inc. [ABSTRACT FROM AUTHOR]

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-HT3 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 [<1%] vs two [<1%]), hiccups (three [<1%] vs four [<1%]), constipation (two [<1%] vs three [<1%]), and dyspepsia (two [<1%] vs three [<1%]). For cycle 1, the most common grade 3-5 adverse events in patients allocated rolapitant versus active control were neutropenia (HEC-1: nine [3%] vs 14 [5%]; HEC-2: 16 [6%] vs 14 [5%]), anaemia (HEC-1: one [<1%] vs one [<1%]; HEC-2: seven [3%] vs two [<1%]), and leucopenia (HEC-1: six [2%] vs two [<1%]; HEC-2: two [<1%] vs two [<1%]). No serious treatment-emergent adverse events were treatment related, and no treatment-related treatment-emergent adverse events resulted in death.Interpretation: Rolapitant in combination with a 5-HT3 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. [ABSTRACT FROM AUTHOR]