Phase I study of combined pegylated liposomal doxorubicin with protracted daily topotecan for ovarian cancer

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 topo...

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Vydáno v:Clinical cancer research Ročník 11; číslo 16; s. 5912
Hlavní autoři: Mirchandani, Deepu, Hochster, Howard, Hamilton, Anne, Liebes, Leonard, Yee, Herman, Curtin, John P, Lee, Sang, Sorich, Joan, Dellenbaugh, Cornelia, Muggia, Franco M
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 15.08.2005
Témata:
Administration, Oral
Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Diarrhea - chemically induced
DNA Topoisomerases, Type I - metabolism
DNA Topoisomerases, Type II - metabolism
Dose-Response Relationship, Drug
Doxorubicin - administration & dosage
Doxorubicin - adverse effects
Female
Humans
Immunohistochemistry
Infusions, Intravenous
Liposomes
Male
Middle Aged
Nausea - chemically induced
Neutropenia - chemically induced
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - enzymology
Ovarian Neoplasms - metabolism
Polyethylene Glycols
Topotecan - administration & dosage
Topotecan - blood
Topotecan - pharmacokinetics
Treatment Outcome
Vomiting - chemically induced
ISSN:1078-0432
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Shrnutí: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. Eligible patients had histopathologically documented advanced cancers beyond standard therapy, performance status <2, and adequate organ functions. Doxil (30-40 mg/m2 i.v.) was given on day 1, with topotecan either oral topotecan 0.4 mg/m2 bid for 14 days or continuous infusion topotecan (0.3-0.4 mg/m2/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. Grade 4 neutropenia and thrombocytopenia and grade 3 diarrhea were dose-limiting toxicities at the highest dose levels explored. Doxil (40 mg/m2/day 1) and continuous infusion topotecan at 0.4 mg/m2/days 1 to 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. 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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ISSN:1078-0432
DOI:10.1158/1078-0432.CCR-04-1240