PHASE-I AND PHARMACOLOGICAL STUDY OF THE NOVEL TOPOISOMERASE-I INHIBITOR 1-PIPERIDINO)-1-PIPERIDINO]CARBONYLOXYCAMPTOTHECIN (CPT-11) ADMINISTERED AS A 90-MINUTE INFUSION EVERY 3 WEEKS

1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11; Irinotecan ), a semisynthetic analogue of camptothecin (CPT) with broad preclinic al antitumor activity, has demonstrated impressive activity in phase I I trials in Japan in advanced small and non-small cell lung, colorecta l, cervical, and ovarian carcinomas, as well as in refractory lymphoma s and leukemias. In this phase I and pharmacological study, 90-min inf usions of CPT-11 were administered every 3 weeks at doses ranging from 100 to 345 mg/m2 to patients with solid malignancies. Acute, severe, and refractory vomiting, diarrhea, and/or abdominal cramps associated with flushing, warmth, and diaphoresis occurred in the immediate postt reatment period at the 240-mg/m2 dose level in several patients who we re not treated with premedications. The characteristics and temporal n ature of these toxicities, the prompt resolution of symptoms following treatment with diphenhydramine, and the successful use of a premedica tion regimen consisting of ondansetron and diphenhydramine in preventi ng these acute effects suggest that vasoactive substances are involved in the mediation of these acute toxicities. With the routine use of t hese premedications, there was no single toxicity type that limited th e escalation of CPT-11 doses. Instead, a constellation of severe hemat ological and gastrointestinal effects precluded the repetitive adminis tration of CPT-11 at doses above 240 mg/m2, the maximum tolerated dose and recommended phase 11 dose on this schedule. Major responses were observed in patients with advanced colorectal, cervical, and renal can cers. The disposition of total CPT-11 in plasma was fit by a biexponen tial kinetic model with renal elimination accounting for 37 +/- 4% (SE ) of total drug disposition. The C(max) for the active metabolite of C PT-11, 7-ethyl-10-hydroxycamptothecin (SN-38), was achieved at 2.2 +/- 0.1 h after treatment, and mean residence times for both CPT-11 and S N-38 were long, 9.1 and 10.0 h, respectively. Compared with topotecan, another CPT analogue under development, a larger proportion of total drug exposure was accounted for by the active lactone (closed-ring) fo rms of CPT-11 and SN-38; areas under the time-versus concentration cur ve for their respective lactone were 44 and 50% of areas under the tim e-versus-concentration curve for total CPT-11 and SN-38. Although inte rmittent dosing schedules appear to be superior to single dosing sched ules for CPT and some CPT analogues in preclinical tumor models, the m aintenance of biologically relevant concentrations of SN-38 for relati vely long durations may negate the potential pharmacological benefits of intermittent and continuous administration schedules for CPT-11. Th e clinical activity observed with CPT-11 on the single dosing schedule and the lack of severe diarrhea after repetitive dosing at the maximu m tolerated dose, which has been problematic on intermittent schedules , suggest that the single dosing schedule should be evaluated further in the phase II setting and in the development of combination chemothe rapy regimens, particularly those containing both CPT-11 and 5-fluorou racil in which diarrhea is a significant concern.