The least toxic time (LTT) of I varied by up to 8 hours according to sex in mice (Li et al. Cancer Res 2013). The translational relevance was investigated through a post-hoc analysis of a randomised trial, where the planned methodology did not identify the LTT of I combined with F, L and O (chronoIFLO) in the whole population.
199 MCC patients at 18 EU centers were randomised to receive chrono I (180 mg/m2 over 6-h, with peak delivery at 1:00, 5:00, 9:00, 13:00, 17:00 or 21:00) on day (d) 1, followed by fixed-time chrono O (20 mg/m2/d over 11.5 h; peak delivery at 16:00) and F-L (700 and 300 mg/m2/d, respectively, over 11.5h, with peak delivery at 4:00), for 4 d. ChronoIFLO was administered q3 weeks as 1st or 2nd line. The main endpoints were the circadian profiles of Grade (G) 3-4 toxicity and best objective response (OR), according to sex. Rhythmic trends were determined with cosinor using smoothed data through moving average.
The trial included 136 males (m; 68%) and 63 females (f; 32%), with similar characteristics among the 6 treatment groups. The rates of all G3-4 toxicities ranged from 64% to 69.6% in m, and from 50% to 93.3% in f according to I timing. The LTT was at 12:30 [95% CI, 11:30-13:30] in m (p = 0.002), and at 15:55 [12:40-19:08] in f (p = 0.05) for all G3-4 toxicities. G3-4 neutropenia varied >3-fold as a function of I timing (10 to 33.3% in m; 0 to 38.5% in f), and the least corresponded to I peak delivery at 11:00 [08:00-13:08] in m (p = 0.045) and 18:07 [15:07-21:08] (p = 0.047) in f. Similar circadian trends were found for mucosal G3-4 toxicities in both sexes. No timing effect was found for G3-4 diarrhoea. OR rates ranged from 38.9% to 80% in m, and 37.5% to 83.3% in f between groups, with most effective timing of I overlapping with LTT in m (14:50 [11:52-17:26], p = 0.039), but not in f (02:17, p = 0.074).
Optimal timing of I tolerability occurred 4 to 7 h earlier in m as compared to f, in agreement with prior mouse data. The relevance of sex for the determination of optimal efficacy timing is further supported here.
Clinical trial identification
Legal entity responsible for the study
Warwick Medical School
Warwick Medical School
All authors have declared no conflicts of interest.