Cardiac Safety Data for Casopitant, a Neurokinin-1 Receptor Antagonist, Given with Anthracycline.
Authors: M. Ewer, S. Grunberg, S. Ranganathan, S. Lane, M. Russo
Journal: Cancer Research (2009)

Abstract Objectives: The NK-1 receptor antagonist casopitant is a promising agent for the prevention of chemotherapy-related and postoperative nausea and vomiting. However, findings suggestive of cardiac damage were noted in animal studies of long-term administration of casopitant at supratherapeutic doses. Cardiac evaluation of the concomitant use of casopitant with anthracyclines was therefore of particular interest due to myocyte loss associated with anthracycline use.Methods: Chemotherapy-naïve patients receiving anthracyclines as part of a Phase III moderately emetogenic chemotherapy study regimen were randomized to receive ondansetron and dexamethasone plus one of the following casopitant regimens: single-dose 150-mg oral casopitant (ORAL1); 3-day IV/oral casopitant (90 mg IV/50 mg oral/50 mg oral) (IV/ORAL); 3-day oral casopitant (150/50/50 mg) (ORAL3); or placebo. Serial cardiac troponin (cTnI) levels were measured using the Beckman assay. Although this assay is generally considered reliable within the range of 0.04-0.5 ng/mL, levels below the limit of quantitation (LOQ) (&amp;lt;0.04 ng/mL) were also evaluated in an attempt to identify patterns of change below LOQ. Further cardiac assessment consisting of left ventricular ejection fraction (LVEF) monitoring was conducted in patients with cTnI levels ³0.12 ng/mL.Results: In total, 611 patients were evaluated: 155 ORAL1, 145 IV/ORAL, 159 ORAL3, and 152 placebo; no risk factor variation between groups was observed. Adverse events were balanced across treatment groups. Cardiovascular adverse events occurred in 3% of patients in each of the placebo, ORAL1, and ORAL/IV groups and in 2% of the ORAL3 group. Three patients (0.5%) had cTnI &amp;gt;0.12 ng/mL (1 each IV/ORAL, ORAL3, and placebo); all LVEF determinations were normal at follow-up, with the exception of 1 patient with mitral regurgitation but normal ejection fraction. A total of 59 patients (9.7%) had median cTnI 0.04-0.12 ng/mL. Of the remaining patients with cTnI below LOQ, median baseline levels across groups were similar (ORAL1 and IV/ORAL 0.008 ng/mL; ORAL3 0.01 ng/mL; placebo 0.009 ng/mL). After 4 cycles of anthracycline, median cTnI increased to 0.02 ng/mL in all groups, with no difference noted between casopitant and placebo groups.Conclusions: Thorough monitoring of cardiac-related toxicities including cardiac (S)AEs, ECG, and ejection fraction data showed no evidence of increased risk of cardiac damage in the casopitant groups compared with control. Subclinical elevations in cTnI occurred in patients receiving anthracyclines but were not considered to be related to or accentuated by simultaneous administration of casopitant. cTnI elevations were similar across treatment groups and were well below rates reported in the literature for a patient population receiving higher doses of anthracycline. Use of appropriate cardiac biomarkers in ranges below those commonly used to detect infarction may be valuable to detect or exclude subclinical toxicity of potentially cardiotoxic agents used in combination. Additional analysis is ongoing. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1118.