Arlene Taylor

Efficacy and Safety of Caspofungin for Treatment of Invasive Aspergillosis in Patients Refractory to or Intolerant of Conventional Antifungal Therapy

BACKGROUNDnInvasive aspergillosis (IA) is an important cause of morbidity and mortality among immunocompromised patients. Echinocandins are novel antifungal molecules with in vitro and in vivo activity against Aspergillus species.nnnMETHODSnWe investigated the efficacy and safety of caspofungin in the treatment of IA. Ninety patients with IA who were refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B, or triazoles were enrolled to receive caspofungin.nnnRESULTSnEfficacy was assessed for 83 patients who had infection consistent with definitions of IA and who received >or=1 dose of study drug. Common underlying conditions included hematologic malignancy (48% of patients), allogeneic blood and marrow transplantation (25% of patients), and solid-organ transplantation (11% of patients). Seventy-one patients (86%) were refractory to and 12 patients (14%) were intolerant of previous therapy. A favorable response to caspofungin therapy was observed in 37 (45%) of 83 patients, including 32 (50%) of 64 with pulmonary aspergillosis and 3 (23%) of 13 with disseminated aspergillosis. Two patients discontinued caspofungin therapy because of drug-related adverse events. Drug-related nephrotoxicity and hepatotoxicity occurred infrequently.nnnCONCLUSIONnCaspofungin demonstrated usefulness in the salvage treatment of IA.

Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double-blind study.

PurposeAprepitant was shown previously to be effective for prevention of chemotherapy-induced nausea and vomiting (CINV) with moderately emetogenic chemotherapy (MEC) in breast cancer patients receiving an anthracycline and cyclophosphamide (AC)-based regimen. This study assessed aprepitant in patients receiving a broad range of MEC regimens with a variety of tumor types.MethodsThis phase III, randomized, gender-stratified, double-blind trial enrolled patients with confirmed malignancies, naïve to MEC or highly emetogenic chemotherapy, who were scheduled to receive a single dose of at least one MEC agent. Patients received an aprepitant triple-therapy regimen (aprepitant, ondansetron, and dexamethasone) or a control regimen (ondansetron and dexamethasone) administered orally. Primary and key secondary efficacy endpoints were proportions of patients with no vomiting and complete response (no vomiting and no rescue medication), respectively, during the 120xa0h post-chemotherapy.ResultsOf 848 randomized patients, 77% were female, and 52% received non-AC-based antineoplastic regimens. Significantly, more patients in the aprepitant group achieved no vomiting and complete response, regardless of whether they received AC or non-AC regimens, in the 120xa0h after chemotherapy. Overall, the incidences of adverse events were generally similar in the aprepitant (62.8%) and control groups (67.2%).ConclusionsThe aprepitant regimen provided superior efficacy in the treatment of CINV in a broad range of patients receiving MEC (non-AC or AC) in both no vomiting and complete response endpoints. Aprepitant was generally well tolerated. These results show the benefit of including aprepitant as part of the standard antiemetic regimen for cancer patients receiving MEC.

Multicenter, noncomparative study of caspofungin in combination with other antifungals as salvage therapy in adults with invasive aspergillosis

Caspofungin inhibits synthesis of β‐1,3‐glucan, an essential component of the Aspergillus cell wall. This echinocandin has demonstrated efficacy (45% success) as salvage monotherapy of invasive aspergillosis (IA). Interest remains as to whether caspofungin, in combination with other antifungal classes, can improve the efficacy against IA.

A Multicenter, Double-Blind Trial of a High-Dose Caspofungin Treatment Regimen versus a Standard Caspofungin Treatment Regimen for Adult Patients with Invasive Candidiasis

BACKGROUNDnThe standard caspofungin treatment regimen (50 mg/day after a 70-mg dose on day 1) is effective and well tolerated for the treatment of invasive candidiasis, but experience with higher doses of caspofungin is limited. We evaluated the safety and efficacy of caspofungin at 3 times the standard dosing regimen.nnnMETHODSnPatients with proven invasive candidiasis were randomized to receive a standard or high-dose (150 mg/day) caspofungin treatment regimen. Safety was assessed in all patients as treated. Efficacy was assessed as a secondary objective in a full-analysis-set population. A favorable overall response was defined as symptom resolution and microbiological clearance at the end of caspofungin therapy.nnnRESULTSnA total of 204 patients were included in the safety analysis (104 received the standard regimen, and 100 received the high-dose regimen), and 197 were included in the efficacy analysis (102 and 95 in the standard and high-dose treatment groups, respectively). Patient demographic characteristics, neutropenia status (6.7% and 8.0% had neutropenia, respectively), and Acute Physiology and Chronic Health Evaluation II scores (mean, 16.5 and 17, respectively) were similar between treatment groups. Significant drug-related adverse events occurred in 1.9% of patients receiving the standard regimen and 3.0% of patients receiving the high-dose regimen (difference, 1.1%; 95% confidence interval, -4.1% to 6.8%). The most-common drug-related adverse events in the standard and high-dose treatment groups were phlebitis (3.8% and 2.0%, respectively), increased alkaline phosphatase level (6.9% and 2.0%, respectively), and increased aspartate transaminase level (4.0% and 2.0%, respectively). Overall, 71.6% of patients who received the standard regimen and 77.9% of patients who received the high-dose regimen had favorable overall responses (difference, 6.3%; 95% confidence interval, -5.9% to 18.4%; not statistically significant). Mortality at 8 weeks after therapy was similar between groups.nnnCONCLUSIONSnBoth caspofungin dosing regimens were effective and well tolerated in patients with invasive candidiasis. No safety concerns were found for caspofungin at a dosage of 150 mg/day.

A Randomized, Double-Blind, Multicenter Study of Caspofungin Versus Liposomal Amphotericin B for Empiric Antifungal Therapy in Pediatric Patients With Persistent Fever and Neutropenia

Background: Persistently febrile neutropenic children at risk for invasive fungal infections receive empiric antifungal therapy as a standard of care. However, little is known about the role of echinocandins and liposomal amphotericin B (L-AmB) for empiric antifungal therapy in pediatric patients. Methods: Patients between the ages of 2 to 17 years with persistent fever and neutropenia were randomly assigned to receive caspofungin (70 mg/m2 loading dose on day 1, then 50 mg/m2 daily [maximum 70 mg/d]) or l-AmB (3 mg/kg daily) in a 2:1 ratio. Evaluation of safety was the primary objective of the study. Efficacy was also evaluated, with a successful outcome defined as fulfilling all components of a prespecified 5-part composite endpoint. Suspected invasive fungal infections were evaluated by an independent, treatment-blinded adjudication committee. Results: Eighty-two patients received study therapy (caspofungin 56, l-AmB 26), and 81 were evaluated for efficacy (caspofungin 56; l-AmB 25). Outcomes for safety and efficacy endpoints were similar for both study arms. Adverse drug-related event rates [95% confidence interval] were similar between the caspofungin and l-AmB groups (clinical 48.2% [34.7–62.0] versus 46.2% [26.6–66.6]; laboratory 10.7% [4.0–21.9] versus 19.2% [6.6–39.4]). Serious drug-related adverse events occurred in 1 (1.8%) of caspofungin-treated patients and 3 (11.5%) of l-AmB-treated patients. Overall success rates [95% CI] were 46.4% [33.4–59.5] for caspofungin and 32.0% [13.7–50.3] for l-AmB. Conclusions: Caspofungin and l-AmB were comparable in tolerability, safety, and efficacy as empiric antifungal therapy for persistently febrile neutropenic pediatric patients.

Combined data from two phase III trials of the NK1 antagonist aprepitant plus a 5HT3 antagonist and a corticosteroid for prevention of chemotherapy-induced nausea and vomiting: effect of gender on treatment response

Goals of workPrevention of chemotherapy-induced nausea and vomiting (CINV) with standard antiemetics has been more difficult to achieve in female patients. Data from two phase III trials of the NK1 antagonist aprepitant were assessed for potential effect of gender on treatment response.Patients and methods1,044 patients receiving cisplatin (≥70xa0mg/m2) were randomly assigned to control regimen [ondansetron (O) 32xa0mg i.v. and dexamethasone (D) 20xa0mg p.o. on dayxa01; D 8xa0mg twice daily on days 2–4] or aprepitant (A) regimen (A 125xa0mg p.o. plus O 32xa0mg and D 12xa0mg on dayxa01; A 80xa0mg and D 8xa0mg once daily on days 2–3; and D 8xa0mg on dayxa04). The primary endpoint was overall complete response (no emesis and no rescue therapy over days 1–5). Data were analyzed by a modified intent-to-treat approach. Between-treatment comparisons for each gender were made using logistic regression.Main resultsWomen comprised 42 and 43% of the aprepitant and control groups, respectively. In the control group, 41% of women had overall complete response compared with 53% of men. In the aprepitant group, 66% of women had overall complete response compared with 69% of men.ConclusionThe addition of aprepitant may negate the adverse prognostic effect of female gender on the prevention of CINV in patients receiving highly emetogenic chemotherapy.

Aprepitant in adolescent patients for prevention of chemotherapy-induced nausea and vomiting: a randomized, double-blind, placebo-controlled study of efficacy and tolerability.

The neurokinin‐1 receptor antagonist aprepitant, plus a 5HT3 antagonist and corticosteroid is well‐tolerated and effective in preventing chemotherapy‐induced nausea and vomiting in adults but has not been formally assessed in adolescents.

Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3 trial

BACKGROUNDnOral aprepitant, a neurokinin-1 receptor antagonist, is recommended in combination with other anti-emetic agents for the prevention of nausea and vomiting associated with moderately or highly emetogenic chemotherapy in adults, but its efficacy and safety in paediatric patients are unknown. We did this phase 3 trial to examine the safety and efficacy of such treatment in children.nnnMETHODSnIn this final analysis of a phase 3, randomised, multicentre, double-blind study, patients aged 6 months to 17 years with a documented malignancy who were scheduled to receive either moderately or highly emetogenic chemotherapy were randomly assigned with an interactive voice response system to an age-based and weight-based blinded regimen of aprepitant (125 mg for ages 12-17 years; 3·0 mg/kg up to 125 mg for ages 6 months to <12 years) plus ondansetron on day 1, followed by aprepitant (80 mg for ages 12-17 years; 2·0 mg/kg up to 80 mg for ages 6 months to <12 years) on days 2 and 3, or placebo plus ondansetron on day 1 followed by placebo on days 2 and 3; addition of dexamethasone was allowed. Randomisation was stratified according to patient age, planned use of chemotherapy associated with very high risk of emetogenicity, and planned use of dexamethasone as an anti-emetic. Ondansetron was dosed per the product label for paediatric use or local standard of care. The primary efficacy endpoint was the proportion of patients who achieved complete response (defined as no vomiting, no retching, and no use of rescue medication) during the 25-120 h (delayed phase) after initiation of emetogenic chemotherapy. Efficacy and safety analyses were done with all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT01362530.nnnFINDINGSnBetween Sept 22, 2011, and Aug 16, 2013, 307 patients were randomly assigned at 49 sites in 24 countries to either the aprepitant group (155 patients) or to the control group (152 patients). Three patients in the aprepitant group and two in the control group did not receive study medication, and thus were excluded from analyses. 77 (51%) of 152 patients in the aprepitant group and 39 (26%) of 150 in the control group achieved a complete response in the delayed phase (p<0·0001). The most common grade 3-4 adverse events were febrile neutropenia (23 [15%] of 152 in the aprepitant group vs 21 [14%] of 150 in the control group), anaemia (14 [9%] vs 26 [17%]), and decreased neutrophil count (11 [7%] vs 17 [11%]). The most common serious adverse event was febrile neutropenia (23 [15%] patients in the aprepitant group vs 22 [15%] in the control group).nnnINTERPRETATIONnAddition of aprepitant to ondansetron with or without dexamethasone is effective for the prevention of chemotherapy-induced nausea and vomiting in paediatric patients being treated with moderately or highly emetogenic chemotherapy.nnnFUNDINGnMerck & Co., Inc.

1337PDEFFECTS OF PATIENT CHARACTERISTICS ON THE EFFICACY AND SAFETY OF APREPITANT IN A PEDIATRIC POPULATION

– In the primary analysis from this study, treatment with aprepitant resulted in a greater proportion of patients achieving complete response (CR) in the delayed phase (25–120 hours after chemotherapy initiation) than the standard regimen alone (51% vs 26%, P < 0.0001) 7 • CR was defined as “no vomiting or retching and no use of rescue medication” – CR was also greater with the aprepitant regimen vs the control regimen in the acute (66% vs 52%; P = 0.0135) and overall phases (40% vs 20%; P = 0.0002) 7

1338PDEMESIS RATE AND RESCUE MEDICATION USE IN CHILDREN USING APREPITANT TO PREVENT CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING (CINV)

ABSTRACT Aim: Aprepitant, in combination with a 5HT3-antagonist and a corticosteroid, is indicated for prevention of CINV due to highly/moderately emetogenic chemotherapy (chemo) in adults. To evaluate aprepitant for CINV prevention in children, a phase III, randomized, double-blind, active-comparator study was conducted in pediatric patients (NCT01362530). Methods: Patients ages 12-17 years (y) undergoing highly/moderately emetogenic chemo received aprepitant capsule 125u2003mg + ondansetron before chemo (Day 1) + aprepitant capsule 80u2003mg (Days 2-3), OR placebo (Days 1-3) + ondansetron (Day 1). Patients 6 months to Results: Efficacy and safety were evaluated in 152 aprepitant and 150 control patients. The proportion of patients experiencing no emetic episodes was higher in the aprepitant regimen vs the control regimen during both acute (71.1% vs 53.3%) and delayed (55.3% vs 28.0%) phases. The median time to first vomiting (overall) was significantly longer for aprepitant vs control (94.5 vs 26.0 hours; P Conclusions: In pediatric patients with cancer receiving emetogenic chemo, the 3-day aprepitant regimen prevented emetic episodes and reduced the need for rescue medication compared with a 5HT3-antagonist regimen without aprepitant. Disclosure: H.J. Kang: Received research funding from Merck & Co., Inc. MK869 PN208 study involvement; S. Loftus: Full-time employee of Merck & Co., Inc., with stock ownership; A. Taylor: Full-time employee of Merck & Co., Inc.; C. Dicristina: Full-time employee of Merck & Co., Inc.; S. Green: Full-time employee of Merck & Co., Inc., with stock ownership. All other authors have declared no conflicts of interest.