Phase I and pharmacologic study of irinotecan and amrubicin in advanced non-small cell lung cancer

We conducted a Phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with amrubicin, a topoisomerase II inhibitor. The aim was to determine the maximum tolerated dose (MTD) of amrubicin combined with a fixed dose of CPT-11 as well as the dose-limiting toxicities (DLT) of this c...

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Published in:Cancer chemotherapy and pharmacology 2007-03, Vol.59 (4), p.419-427
Main Authors: YANAIHARA, Tomoko, YOKOBA, Masanori, ARAI, Susumu, KOBAYASHI, Hirosuke, YANASE, Nobuo, ABE, Tadashi, MASUDA, Noriyuki, ONODA, Sayaka, YAMAMOTO, Michiko, RYUGE, Shinichiro, HAGIRI, Shintaro, KATAGIRI, Masato, WADA, Mayuko, MITSUFUJI, Hisashi, KUBOTA, Masaru
Format: Article
Language:English
Subjects:
Anthracyclines - administration & dosage
Anthracyclines - adverse effects
Anthracyclines - pharmacokinetics
Antineoplastic agents
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Biological and medical sciences
Camptothecin - administration & dosage
Camptothecin - adverse effects
Camptothecin - analogs & derivatives
Camptothecin - pharmacokinetics
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - mortality
Female
Humans
Lung Neoplasms - drug therapy
Lung Neoplasms - mortality
Male
Medical sciences
Middle Aged
Pharmacology. Drug treatments
Pneumology
Tumors of the respiratory system and mediastinum
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Summary:We conducted a Phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with amrubicin, a topoisomerase II inhibitor. The aim was to determine the maximum tolerated dose (MTD) of amrubicin combined with a fixed dose of CPT-11 as well as the dose-limiting toxicities (DLT) of this combination in patients with advanced non-small cell lung cancer. Eleven patients with stage IIIB or IV disease were treated at 3-week intervals with amrubicin (5-min intravenous injection on days 1-3) plus 60 mg/m2 of CPT-11 (90-min intravenous infusion on days 1 and 8). The starting dose of amrubicin was 25 mg/m2, and it was escalated in 5 mg/m2 increments until the maximum tolerated dose was reached. The 30 mg/m2 of amrubicin dose was one dose level above the MTD, since three of the five patients experienced DLT during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the DLT, while thrombocytopenia was only a moderate problem. Amrubicin did not affect the pharmacokinetics of CPT-11, SN-38 or SN-38 glucuronide. Except for one patient, the biliary index on day-1 correlated well with the percentage decrease of neutrophils in a sigmoid Emax model. There were five partial responses among 11 patients for an overall response rate of 45%. The combination of amrubicin and CPT-11 seems to be active against non-small cell lung cancer with acceptable toxicity. The recommended dose for Phase II studies is 60 mg/m2 of CPT-11 (days 1 and 8) and 25 mg/m2 of amrubicin (days 1-3) administered every 21 days.
ISSN:0344-5704
1432-0843
DOI:10.1007/s00280-006-0279-5