Patupilone is more soluble than taxanes and several times more potent in vitro. Most importantly, it is not a substrate for P-glycoprotein and other efflux selleck screening library pumps, and therefore retains activity against cells with a multidrug-resistant phenotype both in vitro and in vivo (O’Reilly et al, 2008). Supporting these preclinical concepts, patupilone has demonstrated activity in taxane-resistant patients (Hussain et al, 2009), and the drug is considered to be non-cross-resistant to common cytotoxic agents. Patupilone has a unique toxicity profile with little or no haematological toxicity and limited neurotoxicity, but significant gastrointestinal toxicity, primarily diarrhoea.

Prior clinical trials in patients with advanced CRC using a weekly schedule of patupilone showed modest efficacy, perhaps because the incidence of diarrhoea limited escalation of the dose intensity to a potentially therapeutic level (Poplin et al, 2003). We hypothesised that diarrhoea could be a greater problem in patients with previously treated mCRC because of prior chemotherapy or pelvic radiation, bowel resections or nutritional deficits. Consequently, it was proposed that proactive diarrhoea management guidelines that stress the importance of early detection and active symptom control could improve tolerability, increase dose intensity and improve efficacy (Wadler et al, 1998; Kornblau et al, 2000; Benson et al, 2004), as has been shown for irinotecan (Abigerges et al, 1994). Moreover, some data indicate that the use of glutamine and other nutritional supplements may help recovery of bowel mucosa (Gibson, 1998; Belluzzi et al, 2000; Bjorck et al, 2000; Daniele et al, 2001; Juntunen et al, 2001).

It was also hypothesised that prolonged infusion schedules of patupilone could be more effective or better tolerated as has been demonstrated for 5-fluorouracil (5-FU) and irinotecan (Meta-analysis Group in Cancer, 1998; Takimoto et al, 2000). The present phase I study was designed to evaluate the tolerability and maximum tolerated dose (MTD) of a 20-min, 24-h and 5-day infusion of patupilone every 3 weeks, together with prophylactic nutritional supplementation and active diarrhoea management in patients with pretreated mCRC.

Materials and methods Patient eligibility Patients had histologically confirmed, inoperable locally advanced or metastatic colon Drug_discovery cancer progressing after a minimum of one line of therapy with at least one measurable lesion, age 18 years, life expectancy 12 weeks, World Health Organization performance status of 0�C1 and no impairment of hepatic or renal function. Initially, the trial was designed to study patupilone as a second-line treatment. Because of significant advances in the second-line therapy of mCRC that resulted in the evolution of standard of care during the conduct of the trial, the protocol was later amended to allow the inclusion of patients with up to four prior lines of chemotherapy.