Abstract 1189: Phase I (phI) study evaluating the cardiac safety of oral chemotherapy s-1 in patients (pts) with advanced solid tumors.
Authors: Campone Mario , Frenel Jean Sébastien , Lichinitser Mikhail. R , Gorbunova Vera , Benedetti Fabio 
Published: August 2014

The incidence of cardiotoxicity (CTx) due to 5FU varies in the literature ranging from 1-68% of pts. Angina-like chest pain is the most common symptom of 5FU associated CTx. Cardiac arrhythmias, congestive heart failure, myocardial infarction, dilatative cardiomyopathy, cardiogenic shock, cardiac arrest or sudden death have been also reported. Most cases occur during or following initial treatment (trt) courses. Only 18% of pts developing CTx have a history of underlying cardiac disease. Capecitabine (Oral 5FU) is also associated with a non-negligible incidence (3-9%) of CTx (E. Yeh. JACC 2009). S-1 is a new oral formulation combining a 5FU prodrug (tegafur) and 2 targeted modulators of its metabolism (gimeracil and oteracil) to preserve efficacy and improve safety. We report the results of a European Ph1, evaluating the effect of S-1 on cardiac repolarization evaluated during S-1 trt under controlled conditions with assessment of 24hour (h) Holter monitor (HM) electrocardiograms (ECGs). Study design: Pts received S-1 30mg/m2 dose BID D1 to 14 q3w. This trial investigated the effect of S-1 vs baseline and placebo on cardiac repolarization QTc (corrected QT interval). During cycle 1, pts were assessed via 24h HM ECGs monitoring after each dose of S-1.

Results: 56 pts with advanced solid tumors were enrolled and final cardiac safety results analyzed on 49 pts:

- The 1-sided 95% upper confidence boundaries for QTc changes were completely within the 10 msec boundaries set by the ICH guideline.

- Mean changes relative to placebo (adjusted for baseline) following single-dose of S-1 did not indicate any effect on QTc.

-Following multiple dosing with S-1, any mean increases in QTc relative to placebo were below the threshold of regulatory concern.

Forty two (75.0%) pts reported 225 adverse events (AEs). Only 5 pts (8.9%) experienced trt-related Grade 3 or higher including anemia, neutropenia and diarrhea. Discontinuation of trt: 1 pt (Hand foot syndrome Gr2). No cardiac SAEs or trt-related AEs were observed. No syncope or arrhythmia reported (Gr1 atrial fibrillation: 1 pt and Gr1 tachycardia: 1 pt, unrelated to trt). S-1 was well-tolerated in heavily treated pts, with no unexpected trt-related AE that resulted in death or AEs leading to discontinuation of trt.

Conclusion: No effect on cardiac repolarization was observed among the 49 pts analysed and no cardiac SAE was reported. The good cardiac safety profile of S-1 is also supported by a survey performed in Japan on more than 4,000 pts treated with S-1 (F. Nagashima. IJGC 2005). No more than 0.2% all grades and 0.05% Gr3-4 cardiac events were observed, which compare favorably with the incidences reported for this class of drugs. In the context of published fluoropyrimidines related-cardiotoxicity, S-1 is probably a good option to treat patients efficiently with a low risk of severe cardiac event.

Citation Format: Mario Campone, Jean Sébastien Frenel, Mikhail. R Lichinitser, Vera Gorbunova, Fabio Benedetti. Phase I (phI) study evaluating the cardiac safety of oral chemotherapy s-1 in patients (pts) with advanced solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1189. doi:10.1158/1538-7445.AM2013-1189