Gemcitabine and vinorelbine in patients with advanced lung cancer: preclinical studies and report of a phase I trial

Purpose: This study was designed to assess the efficacy of gemcitabine plus vinorelbine using the mouse Lewis lung carcinoma model and to translate th is regimen to a phase I clinical study of these two agents in patients with advanced lung cancer. Materials and methods: Using the mouse Lewis lung ca ncer model, employing growth delay and isobologram analysis, we demonstrate d that gemcitabine, in combination with vinorelbine, produced additive acti vity with little increased toxicity over a wide range of doses. At the high est dose level studied, antagonism was observed. Based on these results, we initiated a phase I study of this combination at the Dana Farber Cancer In stitute (DFCI) in patients with untreated or once pretreated non-small-cell lung cancer (NSCLC) or once pretreated small-cell lung cancer (SCLC). Vino relbine (given in an intravenous bolus) and gemcitabine (given in a 30-min infusion) were initially administered to patients at a dose of 15 mg/m(2) a nd 500 mg/m(2), respectively, on days 1, 8, and 15 of a 28-day cycle. Seven dose levels were subsequently explored over the course of the study. There was no intrapatient dose escalation. Results: From November 1996 to March 1998, 40 patients were enrolled: 32 had NSCLC, 5 had SCLC and 3 had mixed d isease (both SCLC and NSCLC). The patients were evenly divided by gender, t he median age was 58 years (range 38 to 73 years), and the median ECOG perf ormance status was 1 (range 0 to 2). All patients had normal renal and hepa tic function and none had previously received gemcitabine or vinorelbine. T oxic reactions included mild to moderate fatigue, nausea, constipation, and , most significantly, neutropenia and thrombocytopenia. Phlebitis was a maj or problem when central venous lines were not used with 15% grade 1/2 event s. The day-15 dose was held in 43% of patients at the expanded dose. No tru e maximum tolerated dose was reached after completion of seven dose levels. Dose level 4 (22.5 mg/m(2) vinorelbine and 1000 mg/m(2) gemcitabine) was c hosen for expansion and future study due to the potential increased ability of patients to receive the full doses on time. Conclusions: We conclude th at this drug combination and dosage are feasible and have potential as eith er a front- or second-line chemotherapeutic regimen for advanced lung cance r, and phase II/III trials should be performed. However, hematologic toxici ties, as found in this study, could probably be reduced with treatment on d ays 1 and 8 every 21 days, and current literature would suggest this to be the preferred schedule.