Patupilone in chemotherapy-pretreated patients with advanced colorectal cancer (CRC) receiving nutritional support and intensive diarrhea management: A phase I multicenter trial

Abstract

3593 Background: In previous clinical studies, a positive effect was noted in patients with CRC heavily pretreated with chemotherapy who received the novel microtubule stabilizer patupilone (EPO906; epothilone B) once-weekly or q3wk; however, susceptibility to diarrhea was high and response rates were modest. This dose-escalation trial examined the safety/efficacy of 3 patupilone regimens in chemotherapy-pretreated patients with CRC who received nutritional support and intensive diarrhea management. Methods: Patients with histologically confirmed CRC, without ileo- or colostomy or history of abdominal/pelvic irradiation, and who relapsed or were refractory after ≤4 prior chemotherapy regimens received nutritional support, intensive diarrhea management if needed, and patupilone as IV bolus q3wk or 1-or 5-day continuous IV (CIV) q3wk at doses of 6–10 mg/m2. Additional inclusion criteria: ≥1 measurable lesion; age ≥18 years; WHO performance status <2; no hepatic, renal, or hematologic impairment. Nutritional supplementation: ω-3 fatty acids, pre- and probiotics, antisecretory factor, and glutamine. Diarrhea management: appropriate clinical care, loperamide, opium tincture, codeine, and octreotide. Dose escalation was per protocol following a 3+3 design. The primary objective of this trial was to determine the maximum tolerated dose of the 3 patupilone treatment schedules in these patients. Results: Forty-four patients were enrolled: bolus, n = 22; 5-day CIV, n = 3; 1-day CIV, n = 19. Mean age 58.8 years; 95% Caucasian; 54% men. In the 5-day CIV arm, enrollment was closed at the 6.5-mg/m2 dose level since 2 dose-limiting toxicities (severe diarrhea) were reported. With bolus and 1-day CIV, the current doses are 10 and 9 mg/m2, respectively. The most common adverse events in the 43 patients evaluable for safety were diarrhea (70%), asthenia (23%), and nausea (21%). Grade 3 diarrhea occurred in 9 patients (21%). Overall response: 4 partial responses and 13 stable disease. Conclusions: Preliminary results suggest that patupilone monotherapy administered q3wk + intensive diarrhea management may prove beneficial in patients with CRC who progressed after 2–3 chemotherapy regimens. [Table: see text]