Prior anti-neoplastic agents other than 5-FU are summarised in Table 1. Main exclusion figure 2 criteria included brain metastases, ileostomy or colostomy, history of pelvic radiotherapy, grade >1 diarrhoea at baseline and use of prophylactic loperamide. All patients provided written, informed consent and approval was obtained from the ethics committees at the participating institutions and regulatory authorities. The study followed the Declaration of Helsinki and good clinical practice guidelines. Table 1 Patient demographics and treatment disposition Study design Patupilone was administered every 3 weeks either as a 20-min infusion (20MI), 24-h continuous infusion (CI-1D) or 5-day continuous infusion (16-h per day over 5 days; 16HI-5D) with planned dose levels of 6.5, 7.0, 7.5, 8.0, 9.0 and 10.

0mgm�C2 until disease progression, unacceptable toxicity or withdrawal of consent. A standard 3+3 design was used to determine MTD (Storer, 1989). Initially, three patients were enrolled at each dose level. Dose escalation proceeded in the absence of more than one of six patients with dose-limiting toxicities (DLTs) in the first two cycles of treatment. If two or more patients presented with DLT at a dose level, enrolment of patients to that dose level was discontinued and the immediately preceding dose level was considered the MTD. Definition of DLTs The DLT was defined as any one of the following drug-suspected toxicities (National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 2.

0): (a) haematological: grade 2 or 3 neutropenia persisting >2 weeks beyond the scheduled start date of the next cycle; grade 3 with absolute neutrophils count (ANC) <1000��l�C1 and fever 38.5��C (febrile neutropenia); grade 4 neutropenia with ANC <500��l�C1 for 5 days duration; platelet count <20000mm�C3 or need for platelet transfusion; platelet count <75000mm�C3 for >2 weeks beyond the scheduled start date of the next cycle and (b) non-haematological: total bilirubin 2.0 �� upper limit of normal (ULN); grade 4 serum glutamic oxaloacetic transaminase/serum glutamate pyruvate transaminase (SGOT/SGPT); grade 3 SGOT/SGPT; Cilengitide any grade 3 nausea or grade 3 vomiting or diarrhoea persisting for >7 days, despite maximal medical treatment; any other grade 3 adverse event (AE) (except myalgia and/or arthralgia that responds to symptomatic therapy); creatinine 3.0 �� ULN; any grade 2 neurotoxicity; any death considered related to study drug. Diarrhoea management and nutritional supplement Based on the guidelines for management of chemotherapy-induced diarrhoea (CID) (Wadler et al, 1998; Kornblau et al, 2000; Benson et al, 2004), an algorithm for the diagnosis and treatment of diarrhoea toxicity was established to potentially lessen its severity and duration.