Presentado Domingo 6 de Mayo :
Plitidepsin cardiac safety analysis.
Abstract No: e13599
Author(s): A. Soto-Matos, S. Szyldergemajn, S. Extremera, B. Miguel-Lillo, V. Alfaro, C. Coronado, P. Lardelli, E. Roy, C. S. Corrado, C. M. Kahatt; PharmaMar, Colmenar Viejo, Madrid, Spain
Abstract:
Background: Plitidepsin (Aplidin, APL) is a cyclic depsipeptide of marine origin in phase II/III development in cancer patients (pts). It induces apoptosis through rapid and sustained JNK activation. Some depsipeptides have been linked to increased cardiac toxicity. Methods: Clinical databases were searched for cardiac adverse events (CAEs) in studies with single-agent APL as of Nov08. Demographic, clinical, and pharmacological variables were explored by univariate and multivariate regression logistic analysis.
Results: Forty-six of the 578 pts (8.0%) treated had at least 1 CAE; of these 1.9% (11) were APL-related. No fatal cases occurred. CAEs were classified into 3 main groups. The most frequent were rhythm abnormalities (RA) (n=31; 5.4%), whereas atrial fibrillation (AF)/flutter accounted for most cases (n=15; 2.6%). Of note, no cases of life-threatening ventricular arrhythmias occurred. The myocardial injury events (MI) (n=17; 3.0%) included possible ischemic related events as well as non-ischemic events. Finally, miscellaneous (M) (n=6; 1.0%) included all other CAEs that did not fit in neither prior one. None of the M events was related to APL. Significant associations were found with prostate or pancreas cancer diagnosis (p=0.002), known baseline cardiac risk factors (p=0.002), myalgia at baseline (p=0.004), lower Hgb levels (p= 0.006) and grade ≥ 2 hypokalemia (p=0.006). Treatment-related variables, such as APL dose, N of cycles or schedule did not result in any association. ECGs performed before and after APL administration (n=136) did not show any relevant effect on QTc interval. None of the PK parameters analyzed (Cmax and AUC from day 0 to day 28) had any significant impact on the probability of developing a CAE.
Conclusions: The most frequent type of CAEs observed were AF/atrial flutter, although its incidence was not different to what is reported in age-matched healthy population. All other type of CAEs were rare. No dose- cumulative pattern was observed; moreover, no treatment-related variables were associated with CAEs. Relevant risk factors identified were related to pts condition and/or disease-related characteristics rather than to drug exposure. Data available on 578 adult pts with advanced cancer treated with singe-agent APL supports a safe cardiac profile.