Phase I trial of fixed dose-rate gemcitabine in combination with carboplatin in chemonaive advanced non-small-cell lung cancer: a Cancer Therapeutics Research Group study

To determine the maximally tolerated dose (MTD) of gemcitabine administered at a fixed dose-rate of 10 mg/m(2) per min in combination with fixed dose carboplatin, to evaluate the toxicity of this regimen and to determine the pharmacokinetics of plasma gemcitabine. Patients with advanced stage non-sm...

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Bibliographic Details
Published in:	Cancer chemotherapy and pharmacology Vol. 52; no. 2; pp. 153 - 158
Main Authors:	SOO, Ross A, LIM, Hong L, WANG, Ling Z, LEE, How S, MILLWARD, Michael J, TOK, Lay T, LEE, Soo C, LEHNERT, Manfred, GOH, Boon C
Format:	Journal Article
Language:	English
Published:	Berlin Springer 01-08-2003 Springer Nature B.V
Subjects:	Adult Aged Antineoplastic agents Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - blood Antineoplastic Combined Chemotherapy Protocols - therapeutic use Area Under Curve Biological and medical sciences Carboplatin - administration & dosage Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - pathology Chemotherapy Deoxycytidine - administration & dosage Deoxycytidine - analogs & derivatives Dose-Response Relationship, Drug Female Humans Infusions, Intravenous Lung Neoplasms - drug therapy Lung Neoplasms - pathology Male Maximum Tolerated Dose Medical sciences Middle Aged Neoplasm Staging Pharmacology. Drug treatments Treatment Outcome Antineoplastic agent Human Lung disease Drug combination Gemcitabine Respiratory disease Non-small- cell lung cancer Administration schedule Malignant tumor Bronchopulmonary Chemotherapy Treatment Antimetabolic Fixed dose Carboplatin Phase I trial Phase I study Bronchus disease Advanced stage Fluorine Organic compounds Pyrimidine nucleoside Dose Platinum II Complexes Non small cell carcinoma
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Summary:	To determine the maximally tolerated dose (MTD) of gemcitabine administered at a fixed dose-rate of 10 mg/m(2) per min in combination with fixed dose carboplatin, to evaluate the toxicity of this regimen and to determine the pharmacokinetics of plasma gemcitabine. Patients with advanced stage non-small-cell lung cancer (NSCLC) received carboplatin (AUC 5) on day 1 followed by gemcitabine at a fixed dose rate of 10 mg/m(2) per min in escalating durations of infusion on days 1 and 8 every 21 days. Pharmacokinetic sampling was obtained on day 1, cycle 1 of treatment. A total of 15 patients received carboplatin and gemcitabine in cohorts of three to six patients at three dose levels. The doses of gemcitabine studied were 600, 750, and 900 mg/m(2). The MTD was reached at 900 mg/m(2). Dose-limiting toxicities were thrombocytopenia and liver failure, and with repeated dosing neutropenia was commonly observed. The recommended phase II dose of gemcitabine was 750 mg/m(2). Partial responses were observed at 600 and 750 mg/m(2) of gemcitabine. Plasma gemcitabine did not reach steady state except in one patient with the durations of infusion studied. Plasma concentrations, however, were above 10 micro mol/l between 20 and 90 min in all patients. Gemcitabine administered as a 75-min infusion at a fixed dose rate of 10 mg/m(2)/min on days 1 and 8 in combination with carboplatin on day 1 every 21 days is tolerable and active in NSCLC. Pharmacokinetic studies demonstrated that the target plasma gemcitabine concentration above 10 micro mol/l was achieved. Further studies are warranted to compare this regimen against standard regimens of carboplatin and gemcitabine.
ISSN:	0344-5704 1432-0843
DOI:	10.1007/s00280-003-0637-5