The mean age for all selleck chemicals patients in the study was 59 years and 30 (50%), 17 (28%) and 13 (22%) patients had 1, 2 or 3 prior lines of chemotherapy, respectively. All patients had at least one cycle of patupilone and were eligible for safety and efficacy assessments. Treatment administered and safety The numbers of cycles administered and reasons for discontinuation are detailed in Table 1. DLT was always constituted by persisting grade 3 or 4 diarrhoea. The MTD, as defined by the protocol, was not reached in the 20MI arm because no DLTs were observed. Similarly, the MTD was not reached in the CI-1D arm, although three diarrhoea DLTs (one each at 7.5, 8.0 and 9.0mgm�C2 dose levels) were observed (Table 2). The 16HI-5D arm was terminated after two DLTs (diarrhoea) occurred in two of the three patients treated with 6.

5mgm�C2 patupilone. Three patients died during the study; the cause of death was disease progression (n=2; CI-1D) and acute renal failure (n=1; 20MI arm). Table 2 Most frequent drug-related grade 3/4 adverse events and cycle 1 and 2 dose-limiting toxicities Gastrointestinal toxicity, mainly diarrhoea, was the most commonly observed AE associated with patupilone administration (Table 3). Diarrhoea (any grade) was noted in 25 (80%) of the patients in the 20MI arm, 19 (73%) of the patients in the CI-1D arm and 3 (100%) of the patients in the 16HI-5D arm. Grade 3 or 4 diarrhoea was observed in 11 (35%) of the patients in the 20MI arm, 4 (15%) of the patients in the CI-1D arm and 2 (67%) of the patients in the 16HI-5D arm.

Other common AEs included nausea, vomiting, anorexia, fatigue, abdominal pain and neuropathy. In general, there was an increase in the incidence and severity of AEs as the dose increased. However, with the exception of diarrhoea, few of these events were severe. Of note, little haematological, hepatic or cardiac toxicity was observed. No grade 3/4 events, including diarrhoea, were observed in the 20MI arm until dose 8.0mgm�C2. Incidences for two of the most frequent AEs (diarrhoea and neuropathy) as a function of dose are summarised in Table 2. In about half of the patients, AEs, which were most commonly diarrhoea, led to dose adjustment and/or interruption at some point during the treatment. Discontinuation due to AEs occurred in seven (23%), four (15%) and two (67%) patients in the 20MI, CI-1D and 16HI-5D arms, respectively (Table 1).

Table 3 Most common adverse events attributed to patupilone (at least 10% cumulative incidence or at least 1 grade 3/4 event) PK assessments Cycle 1 PK samples were available from Drug_discovery 10 of 31 patients in the 20MI arm, 22 of 26 patients in the CI-1D arm and all three patients in the 16HI-5D arm. The mean patupilone concentration�Ctime profiles by dose and infusion schedule after the first dose are shown in Figure 1A and B for the 20MI and CI-1D arm, respectively, and PK parameter estimates are summarised in Table 4.