955 A phase I study of concomitant CPT-11 (C) and 5FU (F) combination: Preliminary results

CPT-11, a DNA topoisomerase I inhibitor has been confirmed to demonstrate an anti-tumor effect specially against colorectal cancer (CRC). In order to define the best schedule combining the most two active agents in CRC, we initiated in June 94 a phase I study at the starting dose (level 1) of C 200 mg/m 2 (over 30 minutes) and F (500 mg/m 2 on day 1 to 5 by IV bolus administration). To find a sequence-dependent toxicity, C was given at day 0 on cycle 1 (CF) and at day 6 on cycle 2 (FC), then the better tolerated cycle was continued. Escalation schedule initially projected for C was 200, 230, 260, 300, 350, 400, 450 and 500 mg/m 2 . A death occurred at the level 1 (fatal dyspnea in a patient with a bulky mediastinal involvement), probably not related to the treatment, but we decided to reduce 5FU to 375 mg/m 2 /day. Characteristics of the 16 patients entered in the study are following: median age: 57 years (range: 40–70), sex: 12 males, 4 females, PS: 0: 9, 1: 7; all patients had solid tumors refractory to previous treatment (colorectal: 12, oesophagus: 2, lung: 1, pancreas: 1). Level CPT-11/5FU No. pts No. Cycles Diarrhea gr.III/IV Neutropenia gr III/IV 1 200/500 2 2 1/0 1/1 2 200/375 8 34 3/1 0/0 3 230/375 6 12/0 0/0 3/0 5 hospitalizations (1 at level 3) occurred (2 for IV fluid administration) and alopecia was reported in 1 patient (level 3). Further escalation is warranted to determine the maximal tolerated dose. A pharmacodynamic study is underway to investigate potential interactions between C, F and SN38 according to the schedule administrations.