Dose-finding, pharmacokinetic and phase II study of docetaxel in combination with gemcitabine in patients with inoperable non-small cell lung cancer.

Background: The good efficacy-toxicity ratio of both docetaxel and gemcitabine in non-small cell lung cancer (NSCLC) stimulates the investigation of the combination of these drugs as a first line chemotherapy. This two-step study firstly aimed at determining the maximum tolerated and recommended doses of docetaxel given every 3 weeks in combination with a fixed dose of gemcitabine; the phase I study paid particular attention to pharmacokinetics. Afterwards, the safety and efficacy of the recommended dose was carefully assessed in the phase II-step.
Methods: The following range of docetaxel dosages were tested in the phase I study; 60, 75, 85, and 100 mg m(-2) given on day 8 in combination with gemcitabine 1000 mg m(-2) delivered on days 1 and 8 of a 3-week cycle. Haematopoietic growth factors were not allowed. The treatment was delivered on an outpatient basis. Main eligibility criteria consisted of stage III b or IV histologically proven NSCLC, Eastern Co-operative Oncology Group (ECOG) performance status PS < or =2, age < or =70 years, measurable disease, adequate blood counts, chemistry, and no symptomatic brain metastasis.
Results: Four centres enrolled 49 patients (eight having been pre-treated); 16 in phase I and 33 in phase II. The maximal tolerated dose was almost reached at the last dose level (i.e. docetaxel, 100 mg m(-2)). Consequently, we considered the 85 mg m(-2) level as the recommended dose. There was a positive relationship of the docetaxel dose to the area under the curve of this drug. Toxicity was assessable in all patients. Among the 200 cycles delivered, 192 were assessable for this feature. Main toxicity was grade 3-4 neutropenia affecting 23 patients (47% of the population; 23% of the cycles). Six febrile episodes were recorded leading to two treatment-related deaths. Another patient died from congestive cardiac failure. In addition, six patients experienced interstitial pneumonitis, (one half considered as severe), two of them having received the recommended dose. All patients recovered from this toxicity after corticosteroids. Fourteen patients out of the whole population (29%; 95% CI [17-43], including ten patients receiving the recommended dose), achieved an objective response. Median follow-up was 14 months (range, 0.3-29.4). Median survival was 11.2 months (95% CI [8.3-13.2]), and the 1-year survival rate was 45%.
Conclusion: Gemcitabine, 1000 mg m(-2) days 1 and 8 in combination with docetaxel, 85 mg m(-2), day 8, given every 3 weeks could be considered as an active regimen with manageable toxicities in locally advanced or metastatic NSCLC. This study deserves further comparisons with classical platinum-based regimens.