A phase I study of gemcitabine and carboplatin in non-small cell lung cancer.

Gemcitabine has shown phase II activity against a range of solid tumor malignancies. This study evaluated a combination of gemcitabine and carboplatin in a phase I trial in 13 chemotherapy-naive patients with non-small cell lung cancer to determine the maximum tolerated dose of carboplatin in combination with gemcitabine. Gemcitabine at a dose of 1,000 mg/m2 was administered on days 1, 8, and 15 of a 28-day cycle and carboplatin was given as a 30. minute infusion immediately before gemcitabine on day 1. Carboplatin dosing was escalated and determined using the Calvert formula, and three patients were treated at the initial predicted dose of area under the curve (AUC) 4 mg/mL/min. Subsequently the carboplatin dose was escalated to a predicted AUC 5.2 mg/mL/min. Pharmacokinetic studies were performed measuring gemcitabine and carboplatin (total platinum) concentrations. Responses were assessed following two cycles of treatment and patients with stable disease or objective responses proceeded to receive a maximum of six cycles. Dose-limiting myelosuppression was identified at a predicted carboplatin AUC 5.2 mg/mL/min, with two patients developing grade 4 neutropenia and two patients grade 4 thrombocytopenia. However, these grade 4 toxicities were not associated with any serious sequelae. In this preliminary study, four partial responses were observed and the median length of survival for all patients was 45 weeks. Pharmacokinetic parameters for gemcitabine were similar to those in patients receiving 1,000 mg/m2 as a single agent, and for carboplatin showed that the delivered dose was slightly below the calculated dose. There was one treatment-related death due to cerebral edema. The combination was well tolerated by the majority of patients, and symptomatic toxicity was similar to single-agent gemcitabine. The combination of gemcitabine and carboplatin is well tolerated in patients with non-small cell lung cancer, with myelosuppression being the dose-limiting toxicity. Symptomatic toxicities were rare and outpatient treatment was easy. In view of the antitumor activity observed, further examination of this combination is warranted. In the first instance, alternate sequencing of the combination with gemcitabine followed by carboplatin is planned in an extended phase I study prior to phase II evaluation.