Clinical phase II study and pharmacological evaluation of rubitecan in non-pretreated patients with metastatic colorectal cancer-significant effect of food intake on the bioavailability of the oral camptothecin analogue.

A randomised, open label phase II study was performed in patients with advanced colorectal cancer to evaluate the safety, toxicity and antineoplastic activity of the topoisomerase I-inhibitor rubitecan. A cross-over design was chosen to determine the intrapatient variation of the bioavailability and pharmacokinetics of the anticancer agent depending on the timing of food intake in relation to the oral drug administration. Patients with previously untreated metastatic disease received two single oral doses of rubitecan 1.5 mg/m2 for assessment of the pharmacokinetics. They were randomised to have the first administration either after an overnight fasting period or immediately after a high calorie breakfast, and crossed over to the alternative schedule after a one-week washout period. After completion of the pharmacokinetic sampling, treatment continued with rubitecan given orally at a dose of 1.5 mg/m2/day, to be increased up to 2.0 mg/m2/day, under fasting conditions for 5 consecutive days per week until disease progression. 19 patients entered the trial after informed consent was obtained. A total number of 35 treatment cycles (median 2, range 1-4) were administered. All patients were evaluable for safety. The toxicity profile of rubitecan was generally mild to moderate, with sporadic cases of grade 4 toxicities (Common Toxicity Criteria (CTC) version 2.0) diarrhoea, leucopenia and neutropenia. None of 15 evaluable patients achieved an objective response. The majority had early disease progression. 14 patients were evaluable for pharmacokinetic analysis. The bioavailability of rubitecan was found to be strongly dependent on the timing of food intake with a fasted-to-fed ratio for C(max) of 1.98 (two-tailed P<0.001; ANOVA), T(max) 0.49 (P<0.001), AUC(0-8 h) 2.52 (P<0.001) and AUC(0-24 h) 1.64 (P=0.003). Rubitecan is well tolerated, but clinically inactive in colorectal cancer at the currently recommended dose and schedule. The bioavailability is strongly dependent on the timing of food intake in relation to the oral administration of the drug. The topoisomerase I-inhibitor should be administered under fasting conditions to achieve adequate drug exposure in future prospective trials in other tumour types.

RCT Entities:   Population Interventions Outcomes