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A Phase I and Pharmacokinetic Study of Irinotecan Given As a 7-Day

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A Phase I and Pharmacokinetic Study of Irinotecan Given As a 7-Day Vol. 10, 1657–1663, March 1, 2004 Clinical Cancer Research 1657 A Phase I and Pharmacokinetic Study of Irinotecan Given as a 7-Day Continuous Infusion in Metastatic Colorectal Cancer Patients Pretreated with 5-Fluorouracil or Raltitrexed Gianluca Masi,1 Alfredo Falcone,1 for activity, and we observed 3 (25%) partial responses, 2 Antonello Di Paolo,2 Giacomo Allegrini,1 (17%) minor responses, and 4 (33%) disease stabilizations. Romano Danesi,2 Cecilia Barbara,2 Conclusions: The administration of irinotecan as a 1 2 7-day continuous infusion every 21 days is feasible with Samanta Cupini, and Mario Del Tacca diarrhea being the dose-limiting toxicity; recommended 1Division of Medical Oncology, Department of Oncology, Civil 2 2 dose for Phase II studies is 20.0 mg/m /day. The comparison Hospital, Livorno, and Division of Pharmacology and of the present data with those obtained after a standard Chemotherapy, Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, Pisa, Italy 30–90 min. i.v. infusion of irinotecan demonstrates that continuous infusion improves the transformation of irinote- can to SN-38 and also results in increased glucuronidation of ABSTRACT the active metabolite. Antitumor activity in pretreated met- Purpose: The purpose is to determine the plasma phar- astatic colorectal cancer patients is encouraging. macokinetics, the maximum-tolerable dose and to prelimi- nary evaluate the antitumor activity of irinotecan admin- INTRODUCTION istered as a 7-day continuous infusion every 21 days in Irinotecan (CPT-11), a semisynthetic derivative of the nat- metastatic colorectal cancer patients pretreated with 5- ural alkaloid camptothecin, is a selective inhibitor of topoi- fluorouracil or raltitrexed. somerase I, a nuclear enzyme responsible for relaxation of Experimental Design: A total of 13 patients entered the supercoiled DNA during replication and transcription (1, 2). study. Three received irinotecan at 20 mg/m2/day (dose level Irinotecan has a broad spectrum of activity against solid I), 6 at 25 mg/m2/day (dose level II), and 4 at 22.5 mg/m2/day tumors; in particular, Phase III randomized studies in ad- (dose level III). In 8 patients, plasma levels of irinotecan and vanced colorectal cancer demonstrated improved survival its metabolites SN-38 and SN-38 glucuronide (SN-38glu) with irinotecan compared with best supportive care or 5- were measured by high-performance liquid chromatog- fluorouracil (5-FU) continuous infusion in patients pretreated raphy and main pharmacokinetic parameters, including with 5-FU (3, 4) and superior efficacy for the combination of steady-state concentration, area under the time-concentra- irinotecan/5-FU/leucovorin versus 5-FU/leucovorin in terms tion curve, and clearance, were calculated and normalized to of response rate, time to disease progression, and survival in the dose level of 22.5 mg/m2/day. chemotherapy-naı¨ve patients (5, 6). Results: Dose-limiting toxicity was grade 3–4 diarrhea, In vivo irinotecan is enzymatically converted to its ac- which occurred in 4 of 6 patients at dose level II and in 2 of tive metabolite SN-38 by carboxyl-esterase (CE); SN-38 4 patients at dose level III. Therefore, we defined 22.5 mg/ forms reversible complexes with DNA/topoisomerase I that m2/day the maximum-tolerable dose and 20.0 mg/m2/day the generates single-strand breaks in the DNA. Then, cell death recommended dose for Phase II studies. Hematological tox- occurs when the DNA replication fork reaches the SN-38/ icity was rare. The pharmacokinetic data provided evidence DNA-topoisomerase I cleavable complexes, resulting in irre- that continuous infusion increased the metabolism of irino- versible double-strand breaks. This process may require sev- tecan to SN-38 with respect to standard 30/90-min adminis- eral hours or days to be completed, and although irinotecan tration. Indeed, the steady-state concentration of irinotecan, and SN-38 have terminal half-lives of ϳ6–13 and 12–24 h, -SN-38, and SN-38glu were 42.7 ؎ 25.2, 14.9 ؎ 1.9, and respectively, after a short i.v. infusion (7–9), a more pro nmol/liter, respectively, and the area under the longed exposure might enhance the formation of lethal strand 3.5 ؎ 31.7 time-concentration curves of irinotecan, SN-38, and SN- breaks and cytotoxicity because of the increasing number of .(38glu were 6.94 ؎ 0.41, 1.92 ؎ 0.30, and 4.23 ؎ 0.52 cells entering into the S phase of the mitotic cycle (10, 11 hx␮mol/liter, respectively. Twelve patients were evaluable Some in vitro and in vivo studies suggest that camptothecin derivatives bind topoisomerase I predominantly in actively transcribed genes (12) and that irinotecan is more effective when administered in prolonged infusion schedules in tumor- Received 12/23/02; revised 10/20/03; accepted 11/26/03. bearing mice (13, 14). Furthermore, longer infusions produce The costs of publication of this article were defrayed in part by the lower peak-plasma drug concentration, and this might over- payment of page charges. This article must therefore be hereby marked come the rate-limiting enzyme deacetylation of irinotecan to advertisement in accordance with 18 U.S.C. Section 1734 solely to SN-38 (15) allowing a more efficient drug activation. Clini- indicate this fact. Requests for reprints: Gianluca Masi, Division of Medical Oncology, cal studies did not confirm the improved activity of irinote- Civil Hospital, Viale Alfieri, 36, 57121 Livorno, Italy. Phone: 39-0586- can administered as protracted infusion observed in tumor- 223458; Fax: 39-0586-223457; E-mail: [email protected]. bearing mice, but in the clinical setting, this method of Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2004 American Association for Cancer Research. 1658 Continuous Infusion of Irinotecan in Colorectal Cancer administration of irinotecan was evaluated only in small tients recruited at the immediately lower dose level had com- Phase I studies, including heavily pretreated patients; there- pleted at least the first cycle (21 days). At least 3 new patients fore, a proper evaluation of antitumor activity of infusional were recruited for each dose level. Three additional patients (for irinotecan is lacking. a total of 6) were treated at a dose level if 1 of the first 3 patients Two Phase I and pharmacokinetic trials in adult patients exhibited DLT. The MTD was defined as the dose level asso- with solid tumors demonstrated that the administration of irino- ciated with the same DLT in at least 2 of 3–6 patients. DLT was tecan as a prolonged i.v. infusion (96 h and 14 days) is feasible defined as any National Cancer Institute-Common Toxicity Cri- with diarrhea being the dose-limiting toxicity (DLT) and with teria grade 3–4 nonhematological toxicity, except for alopecia promising antitumor activity, especially in colorectal cancer and vomiting, any grade 4 neutropenia lasting Ͼ 5 days, or patients. Pharmacokinetic analysis showed a greater SN-38/ associated with fever Ն 38°C and any grade 4 thrombocytope- irinotecan area under the time-concentration curve (AUC) ratio nia occurring at any time during all of the treatment period. 2 (0.24 and 0.16, 96 h versus 14 days, respectively) compared After achieving the MTD at 25 mg/m /day, in consideration of 2 with the values observed after a 30–90 min infusion (approxi- the good tolerability of the starting dose of 20 mg/m /day, the mately 0.03–0.09) suggesting a more extensive metabolism of protocol was amended, and additional patients were treated at 2 irinotecan to SN-38 (16, 17). This observation may confirm the the intermediate dose of 22.5 mg/m /day. Therefore, the follow- 2 hypothesis of rate-limiting conversion of irinotecan to SN-38 ing dose levels were evaluated: 20 mg/m /day for 7 days (dose 2 and may explain, at least in part, the low dose-intensities achiev- level I); 25 mg/m /day for 7 days (dose level II); and 22.5 2 able with the continuous infusion schedules. mg/m /day for 7 days (dose level III). These findings demonstrate that protracted infusion are Treatment was administered every 3 weeks for a maximum associated to better irinotecan activation, but the schedules of nine cycles until evidence of disease progression, unaccept- evaluated in previous Phase I studies may be discommoding for able toxicity, or patient refusal. Treatment was delayed in case the patient and for the health care facilities. To evaluate a more one or more of the following were present on the day of drug 3 convenient schedule of irinotecan administration, we initiated a administration: neutrophils Ͻ 1,000/mm ; platelets Ͻ 100,000/ 3 Phase I study to define the maximum-tolerable dose (MTD) of mm ; and persistent diarrhea or stomatitis Ͼ grade 1. In case of irinotecan administered as a 7-day continuous infusion every 21 DLT, treatment was continued, after recovery, at the immedi- days, to determine the plasma pharmacokinetics of irinotecan, ately lower dose level or reduced by 25%. In case of life- SN-38 and SN-38 glucuronide (SN-38glu), and to preliminary threatening toxicities, treatment was discontinued or the dose evaluate the antitumor activity of this treatment in metastatic was reduced by 50%. colorectal cancer patients pretreated with 5-FU or raltitrexed. Neither antiemetic premedication nor prophylactic treat- ment with granulocyte colony-stimulating factor was routinely administered. In case of diarrhea, at the time of the first loose PATIENTS AND METHODS stool, patients were instructed to take 4 mg of loperamide Patients Selection. Main eligibility criteria included: followed by 2 mg every 2 h. Patients were allowed to stop taking histologically confirmed diagnosis of colorectal adenocarci- loperamide 12 h after the last episode of diarrhea.
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