Phase I and pharmacologic study of oral topotecan administered twice daily for 21 days to adult patients with solid tumors.

Creemers, Geert-Jan; Gerrits, C. J. H.; Eckardt, John R.; Schellens, Jan H.M.; Burris, Howard A.; Planting, A. S. T.; Rodriguez, G. I.; Loos, Walter J.; Hudson, I.; Broom, Colin; Verweij, Jaap; Hoff, Daniel D. Von

doi:10.1200/jco.1997.15.3.1087

Cited by 59 publications

(25 citation statements)

References 9 publications

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“…No doselimiting diarrhea was reported, as was the case for oral topotecan monotherapy (26,27). We speculate that topotecan has a local effect on the intestinal mucosa, and in combination with elacridar, the intestinal absorption is increased, which may affect the toxicity profile.…”

Section: Discussionmentioning

confidence: 99%

A Phase I, Randomized, Open-Label, Parallel-Cohort, Dose-Finding Study of Elacridar (GF120918) and Oral Topotecan in Cancer Patients

Kuppens

Witteveen²,

Jewell³

et al. 2007

Clinical Cancer Research

152

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Purpose: Breast cancer resistance protein (ABCG2) substantially limits the oral bioavailability of topotecan. Coadministration with elacridar, an inhibitor of breast cancer resistance proteinm ediated drug transport, increases the bioavailability of topotecan. The aim of this study was to establish the lowest effective dose of elacridar to obtain maximum oral bioavailability of topotecan and to determine the optimal schedule of coadministration of oral topotecan and elacridar. In the second part of this study, dose-limiting toxicities and maximum tolerated dose of oral topotecan coadministered with elacridar, at a daily times five regimen administered every 21 days, were established. Experimental Design: In part I, 20 patients were randomized to receive 100, 300, 500, 700, or 1,000 mg of elacridar on days 1 and 8 1 h before or simultaneously with 2.0 mg oral topotecan, which was also randomized. On day 15, all patients were treated with 1.5 mg/m 2 i.v. topotecan. In part II of the study, patients were treated daily with oral topotecan and with the lowest effective dose of elacridar following from part I. The maximum tolerated dose and dose-limiting toxicity were determined in cohorts of three patients. Blood samples were taken on days 1, 8, and 15 of part I and on day 1of cycles 1and 2 of part II. Results: Complete apparent oral bioavailability of topotecan (102 F 7%) for all treatment arms with elacridar in both schedules was seen in part I. In the topotecan dose escalation part, two dose-limiting toxicities were seen at the 2.5 mg topotecan dose level. Conclusion: The recommended schedule is 2.0 mg oral topotecan plus 100 mg elacridar administered concomitantly daily times five every 21days.

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Section: Discussionmentioning

confidence: 99%

A Phase I, Randomized, Open-Label, Parallel-Cohort, Dose-Finding Study of Elacridar (GF120918) and Oral Topotecan in Cancer Patients

Kuppens

Witteveen²,

Jewell³

et al. 2007

Clinical Cancer Research

152

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“…topotecan administered as daily 30-min infusions for 5 days has recently received marketing approval for the treatment of patients with ovarian cancer after failure of initial or subsequent platinum-based chemotherapy. An oral gelatin capsule formulation has now been developed (Creemers et al, 1997;Gerrits et al 1998). A phase I study has determined the maximum tolerated dose (MTD) for oral topotecan to be 2.3 mg m -2 for the daily times five dosing schedule (Gerrits et al, 1998).…”

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confidence: 99%

Oral topotecan: bioavailability and effect of food co-administration

et al. 1999

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SummaryThe aims of the study were twofold: (1) to evaluate the effect of food on the relative oral bioavailability of topotecan gelatin capsules in patients with solid tumours, and (2) to determine the absolute bioavailability of oral topotecan with reference to the intravenous (i.v.) formulation. The study had a randomized two-period cross-over design. On day 1 of the first treatment course patients were administered 2.3 mg m -2 day -1 of oral topotecan with or without a high-fat breakfast. They crossed over to receive the alternate regimen on day 2. In the second course (3 weeks later) fasted patients received topotecan orally (2.3 mg m -2 day -1 ) or i.v. (1.5 mg m -3 day). They crossed over to receive the alternate regimen on day 2. On days 3-5 of both treatment courses patients received oral topotecan. Plasma pharmacokinetics were performed on days 1 and 2 of the first and second course using a high-performance liquid chromatographic assay. Eighteen patients were enrolled in the study. The ratio of the area under the curve to infinity during fasted and high-fat treatment was 0.93 ± 0.23 (90% confidence interval (CI) 0.83-1.03). Maximal plasma concentrations of topotecan were similar after ingestion of the capsules with (10.6 ± 4.4 ng ml -1 ) or without food (9.2 ± 4.1 ng ml -1 ) (P = 0.130). The time needed to reach maximal plasma levels was significantly prolonged after food intake (median 3.1 h, range 2.8-6.1) compared to fasted conditions (2.0 h, range 1.1-8.1) (P = 0.013). The absolute bioavailability of topotecan averaged 42 ± 13% (90% CI 37-47%). The apparent terminal half-life was significantly longer after administration of oral topotecan (3.9 ± 1.0 h) than after i.v. administration (2.7 ± 0.4 h) (P < 0.001). Topotecan demonstrates suitable bioavailability for oral treatment. Co-administration of the topotecan gelatin capsules with a high-fat breakfast leads to a small decrease in absorption rate but does not affect the extent of absorption.Keywords: topotecan; oral; bioavailability; food 1380British Journal of Cancer (1999) 80(9), 1380-1386 © 1999 Cancer Research Campaign Article no. bjoc.1999 Received 10 June 1998 Revised 8 December 1998 Accepted 21 January 1999Correspondence to: VMM Herben, Slotervaart Hospital/The Netherlands Cancer Institute, Department of Pharmacy and Pharmacology, Louwesweg 6, 1066 EC Amsterdam, The Netherlands Oral topotecan: bioavailability and effect of food 1381

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“…Provisions for dose escalation were included on oral topotecan: for patients not having significant hematologic toxicity in the first two cycles, dose would be increased to 0.5 mg/m 2 bid in the third cycle. The oral dose was based on the <50% bioavailability, and the schedule on the known relationship of diarrhea with increasing duration of exposure (20,21). Pharmacokinetic studies as previously described (see below) were included in this portion of the study to compare steady-state blood levels of continuous infusion topotecan from our previous study (17), with those being achieved after oral topotecan.…”

Section: Methodsmentioning

confidence: 99%

“…Prolonged low-dose drug delivery may facilitate combination with other myelosuppressive drugs (17 -19) and may be particularly suitable for oral administration. The recommended phase II dose of single agent low-dose oral topotecan is 0.5 mg/m 2 twice daily for 21 days every 4 weeks, with dose-limiting toxicity being grade 4 diarrhea (20,21). In a randomized study of oral (2.3 mg/m 2 /d in two divided doses) versus i.v.…”

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confidence: 99%

Phase I Study of Combined Pegylated Liposomal Doxorubicin with Protracted Daily Topotecan for Ovarian Cancer

Mirchandani

Hochster

Hamilton

et al. 2005

Clinical Cancer Research

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Purpose: To determine the maximum tolerated dose and dose-limiting toxicity of Doxil with low-dose continuous infusion topotecan and subsequently with low-dose oral topotecan. Other specific aims were preliminary assessment of activity in advanced ovarian and tubal malignancies, pharmacokinetics of oral topotecan, and correlation of response with topoisomerase I and II expression in tumors. Methods: Eligible patients had histopathologically documented advanced cancers beyond standard therapy, performance status <2, and adequate organ functions. Doxil (30-40 mg/m 2 i.v.) was given on day 1, with topotecan either oral topotecan 0.4 mg/m 2 bid for 14 days or continuous infusion topotecan (0.3-0.4 mg/m 2 /d) for 14 to 21 days, in 28-day cycles. Fifty-seven patients, 23 with epithelial ovarian or tubal cancers were enrolled. Plasma levels of lactone form of topotecan were determined on patients receiving oral topotecan. Results: Grade 4 neutropenia and thrombocytopenia and grade 3 diarrhea were dose-limiting toxicities at the highest dose levels explored. Doxil (40 mg/m 2 /day 1) and continuous infusion topotecan at 0.4 mg/m 2 /days1to 14 could be safely given and is the recommended phase II dose. Oral topotecan was limited by low and erratic plasma topotecan levels and frequent gastrointestinal toxicity. Particularly long partial responses and stable disease were observed in patients with epithelial ovarian or tubal cancers. Clinical benefit (objective responses and stable diseases) correlated with elevated expression of both topoisomerases by immunohistochemistry in four of six epithelial ovarian or tubal cancer tumor samples. Conclusion: Doxil with 14-day topotecan infusion is a well-tolerated regimen and suitable for study in platinum-resistant or refractory ovarian or tubal cancers. Frequent gastrointestinal toxicity and/or erratic absorption complicate treatment with a longer topotecan infusion or with oral topotecan, respectively, and these combinations are not recommended.

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Phase I and pharmacologic study of oral topotecan administered twice daily for 21 days to adult patients with solid tumors.

Abstract: The DLT in this phase I study for chronic oral topotecan for 21 days was diarrhea. The recommended dose for phase II studies is 0.5 mg/m2 twice daily.

Cited by 59 publications

References 9 publications

A Phase I, Randomized, Open-Label, Parallel-Cohort, Dose-Finding Study of Elacridar (GF120918) and Oral Topotecan in Cancer Patients

A Phase I, Randomized, Open-Label, Parallel-Cohort, Dose-Finding Study of Elacridar (GF120918) and Oral Topotecan in Cancer Patients

Oral topotecan: bioavailability and effect of food co-administration

Phase I Study of Combined Pegylated Liposomal Doxorubicin with Protracted Daily Topotecan for Ovarian Cancer

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