Phase I and Pharmacological Study of the Novel Topoisomerase I Inhibitor 7-Ethyl- 10-[4-(1-piperidino)- 1-piperidino] carbonyloxy camptothecin (CPT- 11) Administered as a Ninety-Minute Infusion Every 3 Weeks I

7-Ethyl-10[4-(1-piperidino)-l-piperidino]carbonyloxycamptothecin (CPT-11; Irinotecan), a semisynthetic analogue of camptothecin (CPT) with broad preclinical antitumor activity, has demonstrated impressive activity in phase II trials in Japan in advanced small and non-small cell lung, colorectal, cervical, and ovarian carcinomas, as well as in refractory lymphomas and leukemias. In this phase I and pharmacological study, 90-rain infusions of CPT-11 were administered every 3 weeks at doses ranging from 100 to 345 mg/m 2 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 posttreatment period at the 240-mg/m 2 dose level in several patients who were not treated with premedications. The characteristics and temporal nature of these toxicities, the prompt resolution of symptoms following treatment with diphenhydramine, and the successful use of a premedication regimen consisting of ondansetron and diphenhydramine in preventing these acute effects suggest that vasoactive substances are involved in the mediation of these acute toxicities. With the routine use of these premedications, there was no single toxicity type that limited the escalation of CPT-11 doses. Instead, a constellation of severe hematological and gastrointestinal effects precluded the repetitive administration of CPT-11 at doses above 240 mg/m 2, the maximum tolerated dose and recommended phase II dose on this schedule. Major responses were observed in patients with advanced colorectal, cervical, and renal cancers. The disposition of total CPT-11 in plasma was fit by a biexponential kinetic model with renal elimination accounting for 37 +4% (SE) of total drug disposition. The Cmax for the active metabolite of CPT-11, 7-ethyl-10hydroxycamptothecin (SN-38), was achieved at 2.2 -+ 0.1 h after treatment, and mean residence times for both CPT-11 and SN-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) forms of CPT-11 and SN-38; areas under the time-versus concentration curve for their respective lactone were 44 and 50 % of areas under the time-versus-concentration curve for total CPT-11 and SN-38. Although intermittent dosing schedules appear to be superior to single dosing schedules for CPT and some CPT analogues in preclinical tumor models, the maintenance of biologically relevant concentrations of SN-38 for relatively long durations may negate the potential pharmacological benefits of intermittent and continuous administration schedules for CPT-11. The clinical activity observed with CPT-11 on the single dosing schedule and the lack of severe diarrhea after repetitive dosing at the maximum 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 chemotherapy regimens, particularly those containing both CPT-11 and 5-fluorouracil in which diarrhea is a significant concern. Received 9/27/93; accepted 11/15/93. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. x Supported by a grant from Yakult Honsha Company, Tokyo, Japan, and Daiichi Pharmaceutical Company, Tokyo, Japan. Presented in part at the annual meeting of the American Society of Clinical Oncology, San Diego, CA, May 17-19, 1992. 2 To whom requests for reprints should be addressed, at The Johns Hopkins Oncology Center, Division of Pharmacology and Experimental Therapeutics, 1-121, 600 North Wolfe Street, Baltimore, MD 21287-8934. I N T R O D U C T I O N The nuclear enzyme topoisomerase I has been recently recognized as the subcellular target for CPT 3 and its analogues. Although CPT demonstrated activity in diverse tumor types in preclinical studies as well as in limited phase I and II trials in the 1960s (reviewed in Ref. 1), there was a lack of enthusiasm for developing CPT and CPT analogues at that time. In retrospect, this could be attributed to the lack of recognition that CPT possessed a novel mechanism of antineoplastic action, as well as severe and unpredictable nonhematological toxicities, particularly hemorrhagic cystitis and enteritis, which occurred in clinical trials that evaluated the open-ring sodium salt of CPT due to the aqueous insolubility of the closed-ring CPT lactone (1-7). Approximately two decades after the completion of clinical evaluations, the sodium salt of CPT was demonstrated to be a poor inhibitor of topoisomerase I and significantly less active than the closed-ring lactone (8). It is currently believed that the antitumor activity and toxicities noted with the open-ring CPT salt were due to conversion to the lactone in tumors and normal tissues, especially in acidic environments which favor the formation of the lactone (reviewed in Refs. 1 and 8-10). Because high doses of sodium CPT were used in these studies to compensate for the lower potency of the hydroxy acid salt compared with the CPT lactone, it is likely that high concentrations of the active lactone were formed in the acidic milieu of the bladder and stomach. After the novel mechanism of action and chemistry of CPT were elucidated, structure-activity studies were performed to define features of the molecule that are essential for cytotoxicity and to produce CPT derivatives with increased aqueous solubility under physiological conditions (8, 9, 11). Among the derivatives identified, CPT-11 (Fig. 1A), which was developed at the Yakult Central Institute for Microbiological Research (Tokyo, Japan), was found to be more active than CPT against diverse types of routine and human tumors as well as against pleiotropic drug-resistant tumors in vitro and in v ivo (12-20). Unlike CPT and topotecan, another water soluble CPT analogue undergoing broad clinical evaluations (reviewed in Refs. 1 and 21), CPT-11 has little inherent antitumor activity in vitro. Instead, CPT-11 is a prodrug that undergoes deesterification to SN-38 (Fig. 1B) which has 100-1000-fold more topoisomerase I-inhibitory activity than CPT-11 in vitro and probably a slower plasma elimination rate than the parent compound (22-24). Similar to both CPT and topotecan, the active lactone forms of both CPT-11 and SN-38 exist in a pH-dependent equilibrium with their respective less potent open-ring hydroxy acid species. More basic pHs, including physiological pH, favor the formation of the hydroxy acid forms (1, 9, 10). 3 The abbreviations used are: CPT, camptothecin; ANC, absolute neutrophil count; AUC, area under the time-versus-concentration curve; AUMC, area under the moment curve; CPT-11, 7-ethyl-10-[4-(1-piperidino)-l-piperidino]carbonyloxycampthothecin; DLT, dose-limiting toxicity; ECG, electrocardiogram; HPLC, high-performance liquid chromatography; MTD, maximum tolerated dose; MR, minor response; PR, partial response; SN-38, 7-ethyl-10-hydroxycamptothecin; tl/2elim, harmonic mean terminal half-life of elimination; Tmax, time of maximum concentration.