Aplidin Cardiac Safety Analysis.

Aplidin (plitidepsin) is a cyclic depsipeptide of marine origin, with activity in relapsed/refractory multiple myeloma and T-cell NHL[1]^,[2]. Some depsipeptides have been linked to increased cardiac toxicity in the literature[3]. PharmaMar Pharmacovigilance and Clinical Trials Data Management databases were reviewed for cardiac adverse events (CAEs) occurring during clinical trials evaluating plitidepsin as single-agent as of November 2008. Data were analyzed for potential risk factors associations with the occurrence of CAE by univariate and multivariate logistic regression analyses.

Forty-six of the 578 patients (8.0%) treated had at least one CAE. Eleven patients of 578 (1.9%) had CAE related to plitidepsin, none of them with fatal outcome.

CAEs were retrospectively classified into 3 main groups after clinical review of all available data. The most frequent type of CAE were rhythm abnormalities (RA) (n=31; 5.4%), whereas atrial fibrillation (AF)/flutter accounted for most cases (n=15; 2.6%). Most events occurred randomly during plitidepsin treatment. Of note, no cases of life-threatening ventricular arrhythmias have been reported to date. The myocardial injury events (MI) (n=17; 3.0%) included possible ischemic related events as well as non-ischemic events. Finally, miscellaneous events (M) (n=6; 1.0%) included all other cardiac events that did not fit into the aforementioned categories. None of the M events was related to plitidepsin

Demographic, clinical and pharmacological variables were explored by univariate and multivariate analysis. Significant association was 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 hemoglobin levels (p= 0.006) and ≥ grade 2 hypokalemia (p=0.006). Multivariate analysis confirmed all these associations. Importantly, treatment related variables, such as plitidepsin dose, number of cycles or schedule of administration did not result in any statistically significant association.

Serial ECGs performed before and after plitidepsin 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.

CAEs observed to date in plitidepsin trials fit into three clinical categories. The most frequent type observed was AF/atrial flutter, although its incidence was not different to what is reported in age-matched healthy population[4]. All other events were relatively infrequent. No dose-cumulative pattern was observed; moreover, neither plitidepsin dose nor schedule was associated with occurrence of CAEs. Relevant predisposing factors identified in univariate and multivariate analyses were related to patient's baseline and/or disease-related characteristics rather than to drug exposure or treatment-related variables. Data available on 578 adult patients with advanced cancer treated with singe-agent plitidepsin support a favorable cardiac safety profile.

• [1] Mateos MV, Cibeira MT, Richardson P et al. Blood 2008; 112(11): 3700.

• [2] Ferme C, Mateos MV, Szyldergemajn S et al. Blood 2008; 112(11): 1566.

• [3] Shah M., Binkley P. Chan K. et al. Clin Cancer Res 2006; 12(13): 3997-4003

• [4] Go A, Hylek E., Phillips K. et al. JAMA 2001, 285: 2370-2375.

Soto-Matos:PharmaMar SAU: Employment. Szyldergemajn:PharmaMar SAU: Employment. Gomez:PharmaMar SAU: Employment. Extremera:PharmaMar SAU: Employment. Miguel-Lillo:PharmaMar SAU: Employment. Alfaro:PharmaMar SAU: Employment. Coronado:PharmaMar SAU: Employment. Lardelli:PharmaMar SAU: Employment. Roy:PharmaMar SAU: Employment. Corrado:PharmaMar SAU: Employment. Yovine:PharmaMar SAU: Employment. Kahatt:PharmaMar SAU: Employment.