Phase I trial, including pharmacokinetic and pharmacodynamic correlations,of combination paclitaxel and carboplatin in patients with metastatic non-small-cell lung cancer

Purpose: To determine the maximum-tolerated dose of paclitaxel with carbopl atin with and without filgrastim support in patients with metastatic non-sm all-cell lung cancer (NSCLC) and to investigate the pharmacokinetics of pac litaxel and carbaplatin and correlate these with the pharmacodynamic effect s. Patients and Methods: Thirty-six chemotherapy-naive patients with metastati c NSCLC were entered into this phase I dose-escalatian and pharmacokinetic study. paclitaxel was initially administered as a 24-hour infusion at a fix ed dose of 135 mg/m(2), and the carboplatin dose was escalated in cohorts o f three patients, using Calvert's formula [dose(mg) = area under the concen tration time curve (glomerular filtration rate + 25)], to target areas unde r the concentration time curve (AUCs) of 5, 7, 9, and 11 mg/mL x minute. A measured 24-hour urinary creatinine clearance was substituted for the glome rular filtration rate. Once the maximum-tolerated AUC (MTAUC) of carbaplati n was reached, the paclitaxel dose was escalated to 175, 200, and 225 mg/m2 . When the paclitaxel dose escalation began, the AUC of carboplatin was red uced to one level below the MTAUC, Results: Myelosuppression was the major dose-limiting toxicity. Thrombocyto penia was observed at a carbaplatin AUC of 11 mg/mL x minute after course 2 and thereafter. End-of-infusion plasma paclitaxel concentrations and media n duration of time above 0.05 mu M were similar in course 1 versus course 2 at the 135 and 175 mg/m2 dose levels, The neutropenia experienced by patie nts was consistent with that observed in patients who had received paclitax el alone. Measured carboplatin AUCs were approximately 12% (20% v 3% with c ourse 1 v course 2, respectively) below the desired target, with a standard deviation of 34% at all dose levels. A sigmoid-maximum effect model descri bing the relationship between relative thrombocytopenia and measured free p latinum exposure indicated that patients who received the combination of ca rboplatin with paclitaxel experienced less severe thrombocytopenia than wou ld be expected from carboplatin alone. Of the 36 patients entered onto the study, one experienced a complete response and 17 had partial responses, fo r an overall response rate of 50%, The recommended doses of paclitaxel (24- hour infusion) and carboplatin for future phase II studies of this combinat ion are(1) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute without filgrastim support; (2) paclitaxel 135 mg/m2 with a carbaplatin dose targeted to achieve an AUC of 9 mg/mL x minut e with filgrastim support; and (3) paclitaxel 225 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute with filgrastim support , Conclusion: The regimen of paclitaxel and carboplatin is well-tolerated and has promising activity in the treatment of NSCLC, There is no pharmacokine tic interaction between paclitaxel and carboplatin, but there is a pharmaco dynamic, platelet-sparing effect on this dose-limiting toxicity of carbopla tin. (C) 1999 by American Society of Clinical Oncology.