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

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Abstract
To determine the maximally tolerated dose (MTD) of gemcitabine administered at a fixed dose-rate of 10 mg/m2 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/m2 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/m2. The MTD was reached at 900 mg/m2. 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/m2. Partial responses were observed at 600 and 750 mg/m2 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 μmol/l between 20 and 90 min in all patients. Gemcitabine administered as a 75-min infusion at a fixed dose rate of 10 mg/m2/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 μmol/l was achieved. Further studies are warranted to compare this regimen against standard regimens of carboplatin and gemcitabine.

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