Because of these considerations, it was hypothesised that continuous infusion of patupilone could result in improved efficacy and fewer side effects. On the contrary, in the trial presented here, 24-h infusion and 5-day intermittent infusion showed no advantage over short-term infusion in terms of both toxicity and activity. secondly The rather high rates of DLTs at the lowest dose of the 16HI-5D arm suggest efficacy and tolerability profiles for prolonged infusions may be variable and drug specific. In this trial, since no grade 3 and 4 diarrhoea was observed in the 20MI arm until 8.0mgm�C2, further reductions in CID may be achieved through use of lower medication doses. For example, reduction of patupilone from 10.0 to 8.

0mgm�C2 in prostate cancer patients resulted in dramatic decrease in the incidence of severe diarrhoea while still maintaining encouraging efficacy data (Chi et al, 2011). Moreover, since mucosa inflammation may have a role in CID, investigation of anti-inflammatory agents such as steroids for improved tolerability has shown encouraging preclinical results in managing patupilone-induced diarrhoea (McSheehy et al, 2008). This strategy has been further explored in clinical trials and indeed emerging data suggest that high-dose prednisone appears to be effective in preventing patupilone-induced diarrhoea and may facilitate treatment with patupilone (Sridhar et al, 2010). Following an intravenous infusion, patupilone was distributed rapidly into tissues, resulting in a large volume of distribution and consistent with the extensive tissue uptake of patupilone observed in animal models (O’Reilly et al, 2008).

The low blood clearance and long terminal half-life of patupilone were in line with previous phase I studies (Rubin et al, 2005; Forster et al, 2007; Ten Bokkel Huinink et al, 2009). Although only a small number of samples were analysed, there was no evidence of drug accumulation with the 20MI administration of patupilone given every 3 weeks. The large variation in the volume of distribution and clearance of patupilone likely reflect interpatient variability in the tissue and plasma protein binding and biotransformation activities, respectively. Indeed, patupilone is mainly metabolised by carboxylesterases, which have shown large interindividual variability in their activities for various substrates (Hosokawa et al, 1995).

In this context, the assessment of the relationship between dose and systemic exposure was inconclusive, not only due to a lack of PK data within each arm, but also because of large interpatient variability and a small dosing range from 6.5 to 10.0mgm�C2. Accordingly, the relationship between systemic exposure of patupilone and toxicity (e.g. GSK-3 severe diarrhoea) could not be assessed conclusively. In conclusion, the present data indicate promising activity of patupilone administered as 20-min infusion in patients with previously treated mCRC.