Phase I Evaluation of Sequential Topoisomerase Targeting with Irinotecan/Cisplatin Followed by Etoposide in Patients with Advanced Malignancy 1 Edward J. Licitra, Viral Vyas, Kathy Nelson, Rita Musanti, Stephanie Beers, Cecilia Thomas, Elizabeth Poplin, Sharon Smith, Yong Lin, Larry. J. Schaaf, Joseph Aisner, Murugesan Gounder, Rajeev Rajendra, Ahamed Saleem, Deborah Toppmeyer, and Eric H. Rubin 2 Departments of Medicine and Pharmacology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey 08901 ABSTRACT Purpose: To investigate pharmacologically guided ad- dition of etoposide to a weekly irinotecan/cisplatin chemo- therapy. Patients and Methods: Patients with advanced nonhe- matologic malignancies were eligible. Treatment consisted of i.v. administration of 50 mg/m 2 irinotecan and 20 mg/m 2 cisplatin on days 1, 8, 15, and 22 of a 42-day cycle or on days 1 and 8 of a 21-day cycle. Etoposide was administered in a dose-escalating fashion 2 days after each dose of irinotecan/ cisplatin, either i.v. as a single dose or p.o. as two doses administered 12 h apart. Pharmacologic analyses included measurement of plasma concentrations of irinotecan, SN-38, and SN-38 glucuronide, as well as quantitation of topoi- somerase protein levels in peripheral blood mononuclear cells (PBMNCs). Results: A total of 40 patients with a variety of malig- nancies received 122 cycles of therapy. Dose-limiting toxic- ities included neutropenia and diarrhea, with the 21-day cycle tolerated better than the 42-day cycle. For the 21-day cycle, the maximum tolerated dose was 75 mg/m 2 for i.v. etoposide and 85 mg/m 2 for oral etoposide. Objective re- sponses were observed in four patients with previously treated mesothelioma, gastric, breast, and ovarian cancer, respectively. PBMNC levels of topoisomerase II were increased at the time of etoposide administration in two patients, with these patients having the highest SN-38 glu- curonide peak-plasma-concentration and area-under- the-curve values among 15 patients with available pharma- cokinetic data. One of these patients had a partial response to therapy. Conclusions: Pharmacologically guided administration of etoposide in combination with irinotecan/cisplatin using a 21-day cycle is associated with acceptable toxicity and sig- nificant antitumor activity. The finding that PBMNC topoi- somerase II protein levels increased after irinotecan/ cisplatin treatment in two of six patients supports the continued development of sequential topoisomerase target- ing in the treatment of malignancy. INTRODUCTION Topoisomerase-targeting drugs are important in the treat- ment of a wide variety of solid and hematologic malignancies. These drugs function by stabilizing a normally transient reaction intermediate that involves covalent linkage of a topoisomerase (Top) 3 molecule to DNA (1). The resulting structural DNA abnormalities, which include single-strand breaks for Top1- targeting drugs and double-strand breaks for Top2-targeting drugs, ultimately trigger cell death. Recent data also implicate ubiquitin and ubiquitin-like proteins as determinants in cell death induced by topoisomerase-targeting drugs (2–5). There are five human topoisomerase enzymes: three (Top1, Top2, and Top2) are known to be effective antitumor drug targets. The anthracyclines and epipodophyllotoxins are among the commonly used Top2-targeting drugs, whereas the camptoth- ecins are currently the only Top1-targeting drugs approved for clinical use. Several preclinical studies indicate that resistance to drugs that target Top1 confers hypersensitivity to drugs that target Top2 and vice versa (reviewed in Ref. 6). Previous studies exploring this concept in clinical settings involved either con- current or sequential administration of Top1- and Top2-target- ing drugs. Results from some of these studies indicated that Top2 levels are often transiently elevated in peripheral blood mononuclear cells (PBMNCs) obtained from patients treated with camptothecins (7, 8). Xenograft studies indicate that sim- ilar transient Top2 protein increases can occur in tumor tissue (9). Because elevations in Top2 protein levels in tumor cells should confer hypersensitivity to Top2-targeting drugs, yet con- current Top1- and Top2-targeting can be antagonistic (10), we Received 9/12/02; revised 12/16/02; accepted 12/20/02. 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. 1 Supported by United States Public Health Service Grant CA71535 (to E. H. R.), the Cancer Institute of New Jersey, and by Pharmacia, Inc. 2 To whom requests for reprints should be addressed, at CINJ, 195 Little Albany St., New Brunswick, NJ 08901. Fax: 732-235-7735; E-mail ehrubin@umdnj.edu. 3 The abbreviations used are: Top, topoisomerase; PBMNC, peripheral blood mononuclear cell; DLT, dose-limiting toxicities; MTD, maximum-tolerated dose; CBC, complete blood count; SN-38G, SN-38 glucuronide; AUC, area(s) under the curve. 1673 Vol. 9, 1673–1679, May 2003 Clinical Cancer Research Cancer Research. on December 7, 2021. © 2003 American Association for clincancerres.aacrjournals.org Downloaded from