Phase II and pharmacologic study of topotecan administered as a 21-day continuous infusion to patients with colorectal cancer.

Creemers, Geert-Jan; Gerrits, C. J. H.; Schellens, Jan H.M.; Planting, A. S. T.; Burg, M.E.L. van der; Beurden, V. M. Van; Boer-Dennert, M. de; Harteveld, M.; Loos, Walter J.; Hudson, I.; Stoter, G.; Verweij, Jaap

doi:10.1200/jco.1996.14.9.2540

Cited by 59 publications

(17 citation statements)

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“…The median survival time in case of S-1 given to colorectal cancer patients was consistent with data obtained on leucovorin·5-FU or interferon·5-FU [43, 44]. Compared to S-1, docetaxel [45]and topotecan [46]were less effective in cases of colorectal cancers. Thus, S-1 shows promise for potent antineoplastic effects on gastrointestinal cancers.…”

Section: Discussionsupporting

confidence: 72%

An Early Phase II Study of Oral S-1, a Newly Developed 5-Fluorouracil Derivative for Advanced and Recurrent Gastrointestinal Cancers

et al. 1999

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5-Fluorouracil (5-FU) or a 5-FU derivative 1-(2-tetrahydrofuryl)-5-fluorouracil (FT) has been widely prescribed for patients with gastrointestinal cancer. However, the phosphorylation of 5-FU in the digestive tract causes gastrointestinal toxicities. 5-FU is also rapidly degraded to α-fluoro-β-alanine after contact with dihydropyrimidine dehydrogenase (DPDase) which is mainly present in the liver. Therefore, to overcome these metabolic events, S-1, an antitumor agent was developed, based on the biochemical modulation of FT by 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo), in a molar ratio of 1:0.4:1. The antineoplastic effect of S-1, was examined in Japanese patients with advanced gastric (G) or colorectal (C) cancer in a multicenter early phase II study involving 24 centers throughout Japan. The patients were prescribed a minimum of 2 courses of S-1 orally, with each course consisting of 75 or 50 mg (in terms of FT) twice a day for 28 days followed by withdrawal for 2 weeks. Thirty-one patients with G and 31 C were entered into this study. The clinical response and extent of toxicity were evaluated in G 28 and C 30 cases, respectively. Nine (32.1%) G patients and 14 (46.7%) C patients had been treated previously with other anticancer drugs. In G patients, there was a 53.6% (15/28) and in C patients a 16.7% (5/30) response rate (90% confidence interval G 38.4–68.1% and C 8.4–30.5%) with 15 (53.6%) (G) and 5 (16.7%) (C) partial responses (PR), and these responses persisted for 79 days (G) and 120 days (C) (median value). In particular, the response rate for the primary lesion was 27.8% (5/18) (G) and 33.3% (1/3) (C). No change (NC) in the disease was observed in 4 (14.3%) (G) and 13 (43.3%) (C) patients, and in 6 (21.4%) (G) and 7 (23.3%) (C) the disease progressed (PD). At the time of analysis, the median survival was 298 days (G) and 358 days (C). Major adverse effects consisted of gastrointestinal symptoms and myelosuppression while toxicities of grade 3 or more occurred in 35.7% (10/28) (G) and 33.3% (10/30) (C). Based on these data, S-1 is considered to have positive effects in patients with advanced gastrointestinal cancer.

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Section: Discussionsupporting

confidence: 72%

An Early Phase II Study of Oral S-1, a Newly Developed 5-Fluorouracil Derivative for Advanced and Recurrent Gastrointestinal Cancers

et al. 1999

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“…commun.]. Only minor activity and therefore disappointing results have been reported so far for topotecan given as 30-min infusion daily for 5 days, as well as for the continuous infusion in patients with colorectal cancer [78][79][80]. No dose-response relationship seems to exist in these patients [81], since no response and a surprisingly low progressionfree interval were observed when high topotecan doses were given with G-CSF support.…”

Section: Phase II and Phase Iii Studiesmentioning

confidence: 99%

Topotecan – A Novel Topoisomerase I Inhibitor: Pharmacology and Clinical Experience

et al. 1999

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Topotecan, a water-soluble analogue of camptothecin, is a newly available cytotoxic agent which acts as an inhibitor of topoisomerase I, an enzyme necessary for DNA replication. Topotecan is a semisynthetic product derived from camptothecin, which was discovered during a National Cancer Institute cytotoxic drug screening program almost 30 years ago. It acts by forming a stable covalent complex with the DNA/topoisomerase I aggregate, the so-called ‘cleavable complex’. This process leads to breaks in the DNA strand resulting in apoptosis and cell death. Topotecan possesses a serum half-life of approximately 3 h, a high volume of distribution with high tissue uptake and a low protein binding. The chemical structure is based on a lactone ring. Topotecan undergoes reversible hydrolysis from its biologically active lactone form to the open ring inactive carboxylate form. It is also able to penetrate the intact blood-brain barrier. Since most of the agent is excreted by the kidneys, dose adjustment is necessary when renal function is impaired. In contrast, pharmacokinetic behavior is unchanged in patients with limited hepatic function. The principal toxicity of topotecan when administered at standard doses is neutropenia, but thrombocytopenia and anemia occur as well, while the nonhematological toxicities are usually mild. Alopecia is frequently observed and some patients may suffer from pronounced fatigue. Most clinical data available are based on the following schedule: 1.5 mg/m² topotecan given as a 30-min infusion, days 1–5. There are currently only minimal data available regarding a dose–antitumor activity relationship. Other topotecan administration schedules are currently being investigated. Preclinical data suggest that continuous-infusion schedules may be a better application form in terms of both, toxicity and antitumor activity. However, clinical trials could not confirm these results to date. Results of phase II studies suggest considerable antitumor activity of single agent topotecan in small cell lung cancer and ovarian cancer patients. A randomized phase III trial of topotecan versus paclitaxel in ovarian cancer patients pretreated with cisplatin/cyclophosphamide has demonstrated that topotecan is as effective as paclitaxel in the second-line treatment of these patients. Activity of topotecan was also observed in non-small-cell lung cancer, refractory leukemias/myelodysplastic syndromes and in childhood sarcomas. Due to its unique mechanism of action and lack of cross-resistance, cisplatin, etoposide, cytarabine and paclitaxel are potential interacting partners for combination chemotherapy regimens. However, the best combination regimen as well as the optimal combination schedule have yet to be conclusively determined. The potential of topotecan in a variety of solid tumors, as well as its use in combination regimens for ovarian and small cell lung cancer is currently being investigated.

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“…In topotecan studies, the dose-limiting toxicity was also noncumulative myelosuppression, predominantly a severe neutropenia of brief duration not necessitating treatment delays (Rowinsky et al, 1992;Verweij et al, 1993). Thrombocytopenia and anaemia occurred mainly in regimens with prolonged intravenous topotecan administration (Hochster et al, 1994;Creemers et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

The bioavailability of oral GI147211 (GG211), a new topoisomerase I inhibitor

Gerrits

Schellens²,

Creemers³

et al. 1997

Br J Cancer

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Summary Topoisomerase I inhibitors are new compounds of interest for cancer chemotherapy. We performed a study with Gl147211, a new semisynthetic camptothecin analogue, to determine the absolute bioavailability of the drug given orally. Patients with a histologically confirmed diagnosis of a solid tumour refractory to standard forms of therapy were eligible for the study. Gi147211 was given orally on day 1 and as a 30-min infusion daily on days 2-5. The treatment course was repeated every 3 weeks. In subsequent patient cohorts, the dose of the oral formulation was escalated from 1.5 mg m-2 to 6.0 mg m-2; the dose for i.v. administration was fixed at 1.2 mg m-2. Plasma pharmacokinetics was performed on day 1 and 2 of the first course and on day 1 of the second course using a validated high-performance liquid chromatographic assay. Nineteen patients were entered into the study; one patient was not evaluable because the treatment course was stopped prematurely. Eighteen patients received a total of 47 treatment courses. The absolute bioavailability of G1147211 averaged 1.3 ± 5.2%. Drug appeared quickly in plasma with a median Tma, at 0.5 h. Fasting or fed state had no significant influence on the bioavailability of G1147211. The terminal half-life after administration of oral G1147211 was 6.85 ± 3.13 h, similar to the half-life after intravenous administration. The major toxicities were neutropenia and thrombocytopenia. Nadirs for neutropenia and thrombocytopenia occurred on day 8 and day 15 respectively. Other toxicities predominantly consisted of mild and infrequent nausea and vomiting, and fatigue. The oral administration of the drug is well tolerated. Oral administration of topoisomerase I inhibitor G1147211 results in a low bioavailability with relatively wide interpatient variation. The intravenous route of administration is advised for further development of this promising topoisomerase I inhibitor.

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Phase II and pharmacologic study of topotecan administered as a 21-day continuous infusion to patients with colorectal cancer.

Abstract: Topotecan administered as a 21-day continuous infusion exerts minor activity as single-agent therapy in patients with metastatic colorectal cancer.

Cited by 59 publications

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An Early Phase II Study of Oral S-1, a Newly Developed 5-Fluorouracil Derivative for Advanced and Recurrent Gastrointestinal Cancers

An Early Phase II Study of Oral S-1, a Newly Developed 5-Fluorouracil Derivative for Advanced and Recurrent Gastrointestinal Cancers

Topotecan – A Novel Topoisomerase I Inhibitor: Pharmacology and Clinical Experience

The bioavailability of oral GI147211 (GG211), a new topoisomerase I inhibitor

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