A comparison of clinical pharmacodynamics of different administration schedules of oral topotecan (TPT, Hycamtin®)

Gerrits, C. J. H.; Schellens, Jhm; Burris, Howard A.; Planting, A. S. T.; Burg, M. van der; Beurden, Vera van; Loos, W. J.; Hudson, I.; Fields, Scott Z.; Hoff, Daniel D. Von; Verweij, Jaap

doi:10.1016/s0959-8049(97)86015-7

Cited by 21 publications

(25 citation statements)

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“…These differences in toxicity profile are probably related to the schedule of administration rather than the dose per cycle (highest in arm C) or the exposure to SN-38 per cycle (lowest in arm B). Schedule dependency of topo-isomerase I inhibitors, with regard to cytotoxicity, was also shown in vitro and in vivo in tumourbearing mice and in clinical studies with different camptothecins (Burris et al, 1992;Dodds and Rivory, 1999;Gerrits et al, 1999). The results of an early phase II study with irinotecan support the use of prolonged exposure schedules in patients with lymphomas (Ohno et al, 1990).…”

Section: Gastrointestinal Originmentioning

confidence: 75%

A randomised phase II multicentre trial of irinotecan (CPT-11) using four different schedules in patients with metastatic colorectal cancer

et al. 2004

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The purpose of this phase II trial was to compare the efficacy, safety and pharmacokinetics of four irinotecan schedules for the treatment of metastatic colorectal cancer. In total, 174 5-fluorouracil pretreated patients were randomised to: arm A (n ¼ irinotecan as a 14-day continuous infusion q3 weeks. No significant differences in efficacy across the four arms were observed, although a shorter time to treatment failure was noted for arm D (1.7 months; P ¼ 0.02). Overall response rates were in the range 5 -11%. Secondary end points included median survival (6.4 -9.4 months), and time to progression (2.7 -3.8 months) and treatment failure (1.7 -3.2 months). Similarly, there were no significant differences in the incidence of grade 3 -4 toxicities, although the toxicity profile between arms A, B, and C and D did differ. Generally, significantly less haematologic toxicity, alopecia and cholinergic syndrome were observed in arm D; however, there was a trend for increased gastrointestinal toxicity. Irinotecan is an effective and safe second-line treatment for colorectal cancer. The schedules examined yielded equivalent results, indicating that there is no advantage of the prolonged vs short infusion schedules.41

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Section: Gastrointestinal Originmentioning

confidence: 75%

A randomised phase II multicentre trial of irinotecan (CPT-11) using four different schedules in patients with metastatic colorectal cancer

et al. 2004

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“…To optimize efficacy and patient convenience while striving to decrease toxicity, alternative dosing strategies are being examined, including 21-day continuous infusion, daily × 3, and weekly schedules ( [26] and see Morris review pp 29-35 [27]). These alternate dosing regimens may allow for better toxicity profiles, sparing hematopoietic and mucosal progenitor cells while maintaining the therapeutic efficacy of topotecan treatment [28].…”

Section: Alternative Dosing Strategiesmentioning

confidence: 99%

Update on the Role of Topotecan in the Treatment of Recurrent Ovarian Cancer

Herzog

2002

The Oncologist

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Ovarian cancer is the fifth leading cause of cancer death in women. Most patients with ovarian cancer respond to first-line chemotherapy, but many relapse within 18 to 22 months. The development of efficacious salvage therapies that increase overall survival while maintaining quality of life is a great challenge in the treatment of this disease. Topotecan, a novel topoisomerase I inhibitor, is currently indicated for the treatment of recurrent metastatic carcinoma of the ovary. In patients with relapsed ovarian cancer, the overall response rates on treatment with topotecan range from 19%-33% in platinum-sensitive patients, 14%-18% in platinum-resistant patients, and 5%-11% in platinum-refractory patients. The proportion of patients achieving stable disease ranges between 17% in refractory and 48% in sensitive patients. In phase III studies, topotecan was shown to be equivalent in efficacy to both paclitaxel and liposomal doxorubicin as second-line therapy in patients with relapsed ovarian cancer. Further, non-cross-resistance between topotecan and paclitaxel was demonstrated in a third-line, phase III crossover study, suggesting that topotecan may be effective in the first-line setting with paclitaxel and/or platinum. Hematologic toxicities include neutropenia, thrombocytopenia, and anemia; however, these toxicities are usually short lived, noncumulative, and manageable with dose modifications, including low-dose topotecan regimens. Nonhematologic toxicities are usually mild to moderate in severity. These data support the use of topotecan for second-line therapy and suggest that topotecan may also be effective in first-line therapy. Further studies with topotecan alone and in combination with other agents are needed to fully characterize the role and sequencing of topotecan in the salvage and first-line settings. The Oncologist 2002;7(suppl 5):3-10

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“…This was unexpected as topotecan is water soluble, forms a chemically stable equilibrium between the lactone and the carboxylate form under physiologic conditions, and lacks significant systemic first-pass metabolism (12). Furthermore, in these early studies, only short treatment schedules of up to 5 days were feasible due to gastrointestinal side effects possibly resulting from unabsorbed topotecan (13). In a study by Ma et al, it was shown that topotecan is a substrate not only for P-glycoprotein, as previously reported by Chen et al, but also for breast cancer resistance protein (MXR, ABCG2; refs.…”

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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

147

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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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A comparison of clinical pharmacodynamics of different administration schedules of oral topotecan (TPT, Hycamtin®)

Cited by 21 publications

References 0 publications

A randomised phase II multicentre trial of irinotecan (CPT-11) using four different schedules in patients with metastatic colorectal cancer

A randomised phase II multicentre trial of irinotecan (CPT-11) using four different schedules in patients with metastatic colorectal cancer

Update on the Role of Topotecan in the Treatment of Recurrent Ovarian Cancer

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

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