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A Phase I and Pharmocokinetic Study of Exatecan Mesylate Administered As a Protracted 21-Day Infusion in Patients with Advanced Solid Malignancies1

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A Phase I and Pharmocokinetic Study of Exatecan Mesylate Administered As a Protracted 21-Day Infusion in Patients with Advanced Solid Malignancies1 Vol. 9, 2527–2537, July 2003 Clinical Cancer Research 2527 A Phase I and Pharmocokinetic Study of Exatecan Mesylate Administered as a Protracted 21-Day Infusion in Patients with Advanced Solid Malignancies1 Mitchell A. Garrison, Lisa A. Hammond, Results: Thirty-one patients were treated with 100 Charles E. Geyer, Jr., Garry Schwartz, courses of exatecan at 6 dose-schedule levels. The incidence of the principal dose-limiting toxicities, neutropenia and Anthony W. Tolcher, Leslie Smetzer, thrombocytopenia, was unacceptably high at exatecan doses Jose A. Figueroa, Murray Ducharme, John Coyle, exceeding 0.15 mg/m2/day as a 21-day CIVI, which was Chris H. Takimoto, Robert L. De Jager, and determined to be the MTD for both MP and HP patients. Eric K. Rowinsky2 The pharmacokinetics of exatecan were dose-proportional, and mean [coefficient of variation (percentage) steady-state Brooke Army Medical Center, San Antonio, Texas [M. A. G., G. S.]; Institute for Drug Development, Cancer Therapy and Research Center concentration (plasma concentration at steady-state)] values and The University of Texas Health Science Center at San Antonio, ranged from 6.88 (80.6) to 19.41 (74.2) ng/ml at exatecan San Antonio, Texas [L. A. H., A. W. T., L. S., C. H. T., E. K. R.]; dose levels ranging from 0.15 to 0.30 mg/m2/day, which are Joe Arrington Cancer Center, Lubbock, Texas [C. E. G., J. A. F.]; similar to IC50 values against human tumor cell lines treated MDS Pharma Services, Montreal, Canada [M. D.]; and Daiichi for shorter periods. Mean pharamacokinetic parameters for Pharmaceutical Corp., Montvale, New Jersey [J. C., R. L. D.] total exatecan derived from a compartmental model in- cluded clearance and volume of distribution values of 1.39 2 ABSTRACT (86.9) liters/h/m and 39.66 (197.4) liters, respectively. Two HP patients with non-small cell lung and unknown primary Purpose: The purpose of this study was to assess the carcinomas had partial responses, and objective evidence of feasibility of administering exatecan, a water-soluble, potent anticancer activity and clinical benefit were noted in several camptothecin analogue, as a protracted 21-day continuous other individuals. i.v. infusion (CIVI). The study also sought to determine the Conclusions: The administration of exatecan as a 21- maximum tolerated dose (MTD) of exatecan on a 21-day day CIVI at doses as high as 0.15 mg/m2/day is safe and CIVI schedule, characterize its pharmacokinetic behavior, feasible for both MP and HP patients. The characteristics of and seek preliminary evidence of anticancer activity. the myelosuppressive effects of exatecan on this schedule, Experimental Design: Exatecan dose-schedule develop- the paucity of severe nonhematological toxicities, and docu- ment was performed in two stages using the modified Con- mented anticancer activity in several drug-refractory malig- tinual Reassessment Method and single patient cohorts. nancies warrant further evaluation of the merits of admin- First, patients with advanced solid malignancies were 2 istering exatecan by either a CIVI or alternate drug delivery treated with exatecan (0.15 mg/m /day) as a CIVI for 5 days, systems to achieve protracted systemic exposure. and the duration of the CIVI was incrementally increased from 5 to 21 days. In the second stage of the study, the dose INTRODUCTION was incrementally increased to derive a tolerable dose of The rationale for developing the hexacyclic camptothecin exatecan administered as 21-day CIVI. The MTD was de- analogue exatecan (DX-8951f; [1S,9S]-1-amino-9-ethyl-5- fined for both minimally pretreated (MP) and heavily pre- fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]- treated (HP) patients as the highest dose level at which the pyrano[3Ј,4Ј:6,7]-indolizino[1,2-b]quinoline-10,13(9H,15H)- incidence of dose-limiting toxicity does not exceed 20%. dione monomethanesulfonate dihydrate; exatecan mesylate; Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan; Fig. 1) is based on its favorable physicochemical features, which may portend a greater therapeutic advantage than other camptothecin ana- Received 10/17/02; revised 1/27/03; accepted 2/13/03. logues (1–3). Unlike irinotecan, exatecan is inherently active The costs of publication of this article were defrayed in part by the and does not require enzymatic activation, which may accentu- payment of page charges. This article must therefore be hereby marked ate the fundamentally large interindividual variability in the advertisement in accordance with 18 U.S.C. Section 1734 solely to pharmacological and toxicological profiles of camptothecin an- indicate this fact. 3 1 Supported in part by the Frederic C. Bartter Clinical Research Unit of alogues (1–4). Exatecan is also a more potent inhibitor of topo the Audie Murphy Veterans Administration Hospital through NIH Grant M01RR01346. Presented, in part, at the 19th and 20th annual meetings of the American Society of Clinical Oncology, New Orleans, Louisiana, May 19–23, 2000 and San Francisco, California, May, 12–15, 2001. 2 To whom requests for reprints should be addressed, at Institute for 3 The abbreviations used are: topo, topoisomerase; ANC, absolute neu- Drug Development, Cancer Therapy and Research Center, 7979 trophil count; AUC, area under the plasma concentration-time curve; Wurzbach Road, 4th Floor Zeller Building, San Antonio, TX 78229. Phone: Css, plasma concentration at steady-state; CIVI, continuous i.v. infusion; (210) 616-5945; Fax: (210) 616-5865; E-mail: [email protected]. CL, clearance; DLT, dose-limiting toxicity; Emax, maximal effect model; Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2003 American Association for Cancer Research. 2528 Phase I Study of Exatecan Fig. 1 Structure of the active exate- can lactone (left) undergoing reversi- ble pH-dependent hydrolysis to its in- active open-ring form (right). I than either camptothecin, topotecan, or SN-38 (10-hydroxy-7- though objective antitumor activity has been observed with ethylcamptothecin), the active metabolite of irinotecan (4–9). It exatecan on several schedules in Phase I and II evaluations, the is 3- and 10-fold more potent than SN-38 and topotecan, re- preponderance of activity has been associated with divided- spectively, at inhibiting topo I extracted from murine P388 dosing schedules. In addition to tumor regressions reported in leukemia cells, with IC50 values of 0.975, 2.71, 9.52, and 23.5 Phase I studies in several types of lower and upper gastrointes- ␮g/ml for exatecan, SN-38, topotecan, and camptothecin, re- tinal malignancies, small and non-small cell lung cancers, and spectively (5). In addition, IC50 values against a panel of 32 refractory acute leukemias, prominent and consistent antitumor human cancer cell lines averaged 6- and 28-fold lower than activity has been noted in Phase II evaluations in untreated and those of SN-38 and topotecan, respectively (5). Exatecan has previously treated patients with advanced pancreatic, hepatocel- demonstrated impressive activity against human tumor xe- lular, and biliary carcinomas (4, 16–21). nografts of colon, lung, breast, renal, and gastric origin, and its The prominent schedule-dependent antineoplastic activity efficacy has generally been superior to those of topotecan and noted with exatecan in preclinical studies, the impressive clin- irinotecan (5, 9). Although impressive activity has been ob- ical results achieved with divided-dosing schedules to date, and served on both single- and divided-dosing schedules, superior the intriguing clinical activity with other topo I-targeting agents, efficacy against human tumor xenografts has generally been particularly topotecan, administered as a protracted infusion noted with divided-dosing schedules (4, 5, 9). served, in part, as the rationale for evaluating the feasibility of The impressive preclinical antitumor spectra of exatecan administering exatecan as a protracted CIVI (22–24). Another may be due, in part, to the fact that it is not a substrate for the reason for evaluating exetacan as a protracted infusion is that the Pgp multidrug transporter, in contrast to topotecan, 9-amino- toxicological and pharmacokinetic information ascertained from camptothecin, and SN-38, which are weak Pgp substrates (10– such studies could potentially serve as a foundation for devel- 13). The lack of cross-resistance of Pgp-overexpressing neo- opmental studies of DE-310, a novel slow-release polymer of plasms is suggested by the comparable activity of exatecan exatecan undergoing staggered development with exatecan (25). against human lung cancer PC-6 and its Pgp-overexpressing The principal objectives of this Phase I and pharmacokinetic variant, PC-6/vincristine (6). Similarly, exatecan possesses study were to: (a) determine the MTD of exatecan in patients roughly equivalent potencies against PC-6 and a SN-38-resistant with advanced malignancies by first progressively prolonging subline characterized by impaired SN-38 accumulation without the duration of the CIVI from 5 to 21 days and then successively Pgp overexpression, and the antitumor activities of exatecan increasing the exatecan dose; (b) characterize the toxicities were similar against human pancreatic cancers SUIT-2 and associated with exatecan on protracted dose schedules; (c) de- KP-1N and their respective sublines with acquired resistance to termine whether biologically relevant pharmacological param- irinotecan in vivo and SN-38 in vitro, presumably due to reduced eters can be achieved; (d) identify the recommended dose for levels of topo I mRNA and protein (8). Although the signifi- Phase II development; and (e) seek preliminary evidence for cance of its lack of Pgp substrate affinity is unclear, exatecan is antitumor activity. a known substrate for breast cancer resistance protein, which appears to confer drug resistance in vitro (14, 15). The feasibility of administering exatecan on a broad range PATIENTS AND METHODS of dose schedules has been evaluated in Phase I studies in Patient Selection. Patients with histologically confirmed patients with advanced solid malignancies (4, 16–18).
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