Vol. 4, 1153-1158, May /998 Clinical Cancer Research 1153 Oral Topotecan Given Once or Twice Daily for Ten Days: A Phase I Pharmacology Study in Adult Patients with Solid Tumors Cees J. H. Gerrits, Howard Burns, grade HI diarrhea. The maximum tolerated dose was 1.4 mg/ Jan H. M. Schellens, John R. Eckardt, m2/day. In the 10-day b.i.d. administration ofTPT, a total of 64 courses were studied in 20 patients. DLT was reached at a dose Andre S. T. Planting, Maria E. L. van der Burg, of 0.8 mg/m2 b.i.d. and consisted of CTC grade IV myelosup- Gayle I. Rodriguez, Walter J. Loos, pression and CTC grade IV diarrhea. The maximum tolerated Vera van Beurden, Ian Hudson, Scott Fields, dose was 0.7 mgfm2 b.i.d. Nonhematological toxicities with both Dan D. Von Hoff, and Jaap’ schedules included mild nausea and vomiting, fatigue, and Department of Medical Oncology, Rotterdam Cancer Institute (Daniel anorexia. Pharmacokinetics revealed a substantial variation of den Hoed Kliniek) and University Hospital. 3075 EA Rotterdam, the the area under the plasma concentration-lime curve of TN’ Netherlands [C. J. H. G., J. H. M. S., A. S. T. P., M. E. L. v. d. B.. lactone in both schedules. Significant correlations were ob- W. J. L., V. v. B., J. V.]; Cancer Therapy and Research Center, the served between the myelotoxicity parameters and the area University of Texas at San Antonio and Brooke Arms Medical Center, San Antonio, Texas 78245 [H. B., J. R. E., G. I. R.. under the plasma concentration-time curve at day 1 of TN’ D. D. V. H.]: and SmithKline Beecham Pharmaceuticals, United lactone o.d. and b.i.d. Kingdom [I. H]. and U.S.A. [S. F.] The DLT of 10 daily administrations of oral topotecan every 3 weeks consisted of a combination of myelosuppres- sion and diarrhea for both schedules studied. The recom- ABSTRACT mended doses for Phase II studies are 1.4 mg/m2/day for 10 Prolonged exposure to topotecan (TPT) in in vitro ex- days for the o.d. administration and 0.7 mg/m2 for the b.i.d. periments and in vivo studies in animals yielded the highest schedule. antitumor efficacy. An oral bioavailability of TPT of 32.- 44% enables convenient prolonged administration. Because INTRODUCTION of unpredictable diarrhea in the third week of the twice TPT2 (9-dimethylaminomethyl-lO-hydroxycamptothecin) daily (b.i.d.) 21-day schedule of p.o. administered TN’ and is a specific topoisomerase I inhibitor ( I - 8). Studies with a the finding of optimal down-regulation of topoisomerase I 5-day daily iv. administration every 3 weeks showed brief level after 10-14 days in mononuclear peripheral blood myelosuppression as the most important side effect, and prom- cells, a shorter period of administration (10 days) was cho- ising antitumor effects were reported in patients with small cell sen for Phase I and pharmacological studies of oral admin- lung cancer and in pretreated patients with ovarian cancer (9- istration of TPT. 19). Cytotoxicity of topoisomerase I inhibitors is more specific Adult patients with malignant solid tumors that were to the S-phase of the cell cycle, and preclinical in vitro and in refractory to standard forms of chemotherapy were entered. vivo studies indicate that prolonged exposure to low-dose topoi- Two dose schedules were studied: once daily (o.d.) and b.i.d. sornerase I inhibitors yields higher antitumor efficacy (20-25). administration for 10 days every 3 weeks. TPT o.d. for 10 The clinical feasibility of using prolonged exposure to TPT days was studied at dose levels 1.0, 1.4, and 1.6 mg/m2/day, was initially reported by Hochstcr et a!. (26) in a Phase I study and dose levels were 0.5, 0.6, 0.7, and 0.8 mg/rn2 with the using a 21-day continuous infusion every 28 days. Recent stud- 10-day b.i.d. schedule. Pharmacokinetics were performed on ies in humans reported a 32-44% bioavailability of TPT when days 1 and 8 of the first course using a validated high- it was given p.o. (27, 28). We have previously reported a Phase performance liquid chromatographic assay and noncom- I study with oral TPT given b.i.d. for 21 days in a 28-day cycle. partmental pharmacokinetic methods. Side effects were CTC grade III-IV diarrhea occurring during Nineteen patients were entered in the 10-day o.d. schedule, the third week of drug administration (29). In addition, it was with a total of 48 courses given. Dose-limiting toxicity (DLT) reported that topoisomerase down-regulation in peripheral blood was reached at 1.6 mglm2/day and consisted of common tox- mononuclear cells was optimal after 2 weeks in the Phase I icity criteria (CTC) grade IV thrombocytopeula and CTC study on 21-day continuous infusion of TPT (30). In view of these observations, it was considered of interest to also study shorter schedules of oral administration of TPT than the 21 -day schedule. In this Phase I study, we investigated o.d. and bid. Received 7/29/97; revised 1/23/98: accepted 2/3/98. oral TPT given for 10 days every 3 weeks. 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 I 8 U.S.C. Section 1 734 solely to indicate this fact. 2 The abbreviations used are: TPT, topotecan; bid., twice daily: CTC, I To whom requests for reprints should be addressed, at Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital common toxicity criteria; o.d., once daily; MTD, maximum tolerated Rotterdam, Groene Hillcdijk 301, 3075 EA Rottcrdam, the Netherlands. dose: DLT. dose-limiting toxicity: AUC, area under the plasma concen- Phone: 31-10-4391754; Fax: 31-10-485 1618. tration-time curve: civ., continuous iv. Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 1998 American Association for Cancer Research. 1 154 Oral Topotecan, Ten-Day Administration PATIENTS AND METHODS Patient Selection. Patients with a histologically con- Drug administration firmed diagnosis of a malignant solid tumor that was refractory o.d. bid. to standard forms of therapy were eligible. Other eligibility No. of patients entered 19 20 criteria included: age of 18 years; WHO performance score of No. of patients evaluable 19 18 2; an estimated life expectancy of 12 weeks; no anticancer Age therapy in the preceding 4 weeks (6 weeks for nitrosoureas or Median 53 55 mitomycin C); adequate hematopoetic (WBC, 4 X lO9fliter; Range 19-85 41-69 Sex platelets, 100 x l09/liter), hepatic (bilirubin within normal Female 8 7 limits; aspartate aminotransferase, alanine aminotransferase, Male 11 13 and/or alkaline phosphatase, 2 X upper limit of normal), and WHO performance renal [serum creatinine, l33 i.molflitcr (2.0 mg/dl)1 function. 0 12 12 I 7 7 Specific exclusion criteria included: active peptic ulcer or any 2 0 1 gastrointestinal condition that could alter absorption or motility Tumor types or patients taking H, antagonists or proton pump inhibitors. All Colorecta! 4 1 1 patients gave written informed consent. Ovarian 4 3 Treatment and Dose Escalation. On the basis of the SCLC” 3 1 NSCLC 2 1 data of Creemers et a!. (29), who demonstrated a MID of 0.5 Miscellaneous 6 4 mg/rn2 bid. for oral TPT in a 21-day schedule, the starting Prior treatment doses for the 10-day administrations were set at 0.5 mg/m2 b.i.d. Chemotherapy II 14 Radiotherapy I and I .0 mg/m2/day o.d. Courses were to be repeated every 21 I Both S I days, as tolerated. Immunotherapy 0 I TPT was supplied as capsules containing TPT-HC1, equiv- None 2 3 alent to 0.25, 0.50, or I .0 mg of the anhydrous free base. “ SCLC, small cell lung cancer . NSCLC, non-sm all cell lung can- Capsules had to be stored between 2#{176}Cand8#{176}C.Capsules were cer. taken with a glass of water in the morning on an empty stomach with a 2-h period of fasting. With bid. administration of TN’, the second dose was taken with an interval of I 2 h with a glass an indwelling i.v. cannula, prior to dosing, 15, 30, and 45 mm of water at least 10 mm before meals, preferably on an empty and I , 1 .5, 2.5, 3.5, 4.5, 8.5, and 12 h after administration of the stomach. Patients were treated as outpatients. Dose escalations drug on days I and 8 of the first course. For the b.i.d. schedule, were based on the prior dose level toxicity. this was done after the morning dose. The samples were imme- The MTD was defined as one dose level below the dose diately prepared and analyzed according to the method de- that induced DLTs, which were defined as CTC grade IV scribed previously (33). The lower limit of quantitation was 0.1 hematological toxicities and/or CTC grade III or higher nonhe- ng/ml for TN’ lactone, as well as for the hydroxy-acid. The matological toxicities during the first course in more than two of AUCs of TN’ lactone and hydroxy-acid were calculated by six patients. If grade IV neutropenia, grade III thrombocytope- noncompartmental analysis (linear-logarithmic trapezoideal nia or higher, and/or grade III or higher nonhematological method). The AUC(t) was calculated up to the last measured toxicity occurred during treatment days, TN’ administration was time point “t” because, in half of the cases with b.i.d.