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Objectives The data reported are from a trial designed to determine, in patients with advanced cancer, the maximum tolerated dose and pharmacokinetics of calcitriol when administered with paclitaxel, an agent whose antitumor activity in in vitro and in vivo studies has been shown to be enhanced by calcitriol. An additional goal was to evaluate the relationship between calcitriol dose and hypercalcemia. Methods Calcitriol was given orally for 3 consecutive days each week, and paclitaxel (80 mg/m2) was given intravenously weekly. Thirty-six patients were treated in cohorts composed of 3 to 9 patients, at escalating dose levels of calcitriol. The starting dose of calcitriol was 4 μg for 3 consecutive days each week, and the maximum dose administered was 38 μg for 3 consecutive days each week. The preparation of calcitriol used in this trial was a commercially available caplet (0.5 μg per caplet). Serum calcitriol concentrations were measured by radioimmunoassay. Detailed assessments of calcitriol pharmacokinetics were performed in 26 patients. Results There was substantial interpatient variation in peak serum calcitriol concentrations (Cmax), time to reach Cmax, and area under the concentration versus time curve (AUC). Serum calcitriol AUC was not proportional to calcitriol dose (P = .0014). AUC for the 24-hour period after calcitriol administration [AUC (0–24)] at 38 μg was only 4 times that at 4 μg, instead of the 9.5-fold increase expected for a proportional relationship. Calcitriol plasma concentrations of 600 to 1440 pg/mL were achieved. No dose-limiting toxicity occurred in this trial. Conclusions Despite variability in absorption, very high doses of calcitriol can be safely administered with paclitaxel. The high calcitriol serum concentrations achieved in this study approach those that, both in vitro and in vivo, potentiate the cytotoxicity of taxanes and platinum analogs. Clinical Pharmacology & Therapeutics (2002) 72, 648–659; doi: 10.1067/mcp.2002.129305

Summary Purpose To evaluate the safety and efficacy of docetaxel and carboplatin as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods In this multicenter, phase II trial, 33 patients with previously untreated stage IIIB (n = 8) or IV (n = 25) NSCLC received intravenous infusions of docetaxel 80 mg/m2 followed immediately by carboplatin dosed to AUC of 6 mg/ml/min (Calvert's formula) every three weeks. Patients also received dexamethasone 8 mg orally twice daily for three days beginning one day before each docetaxel treatment. Filgrastim was not allowed during the first cycle and was added only if a patient experienced febrile neutropenia or grade 4 neutropenia lasting ≥ 7 days. Results There were 1 complete and 11 partial responses for an objective response rate of 43% (95% CI: 24%–63%) in 28 evaluable patients and 36% (95% CI: 20%–55%) in the intent-to-treat population. The median duration of response was 5.5 months (range 3.0–12.5 months). The median survival was 13.9 months (range 1–35+ months); one-year survival was 52%. The most common toxicity was hematologic, which included grade 4 neutropenia (79% of patients and 7% percent of cycles) and febrile neutropenia (15% of patients); there were no episodes of grade 3 or 4 infection. The most common severe nonhematologic toxicities were asthenia (24%) and myalgia (12%); there were no grade 3 or 4 neurologic effects. Conclusions The combination of docetaxel and carboplatin has an acceptable toxicity profile and is active in the treatment of previously untreated patients with advanced NSCLC. This combination is being evaluated in a randomized phase III trial involving patients with advanced and metastatic NSCLC.

PURPOSE: To determine the maximum-tolerated dose of paclitaxel with carboplatin with and without filgrastim support in patients with metastatic non–small-cell lung cancer (NSCLC) and to investigate the pharmacokinetics of paclitaxel and carboplatin and correlate these with the pharmacodynamic effects. PATIENTS AND METHODS: Thirty-six chemotherapy-naive patients with metastatic NSCLC were entered into this phase I dose-escalation and pharmacokinetic study. Paclitaxel was initially administered as a 24-hour infusion at a fixed dose of 135 mg/m2, and the carboplatin dose was escalated in cohorts of three patients, using Calvert's formula [dose(mg) = area under the concentration time curve (glomerular filtration rate + 25)], to target areas under the concentration time curve (AUCs) of 5, 7, 9, and 11 mg/mL × minute. A measured 24-hour urinary creatinine clearance was substituted for the glomerular filtration rate. Once the maximum-tolerated AUC (MTAUC) of carboplatin 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 reduced to one level below the MTAUC. RESULTS: Myelosuppression was the major dose-limiting toxicity. Thrombocytopenia was observed at a carboplatin AUC of 11 mg/mL × minute after course 2 and thereafter. End-of-infusion plasma paclitaxel concentrations and median duration of time above 0.05 μM were similar in course 1 versus course 2 at the 135 and 175 mg/m2 dose levels. The neutropenia experienced by patients was consistent with that observed in patients who had received paclitaxel alone. Measured carboplatin AUCs were approximately 12% (20% v 3% with course 1 v course 2, respectively) below the desired target, with a standard deviation of 34% at all dose levels. A sigmoid-maximum effect model describing the relationship between relative thrombocytopenia and measured free platinum exposure indicated that patients who received the combination of carboplatin with paclitaxel experienced less severe thrombocytopenia than would be expected from carboplatin alone. Of the 36 patients entered onto the study, one experienced a complete response and 17 had partial responses, for an overall response rate of 50%. The recommended doses of paclitaxel (24-hour infusion) and carboplatin for future phase II studies of this combination are (1) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL × minute without filgrastim support; (2) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 9 mg/mL × minute with filgrastim support; and (3) paclitaxel 225 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL × 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 pharmacokinetic interaction between paclitaxel and carboplatin, but there is a pharmacodynamic, platelet-sparing effect on this dose-limiting toxicity of carboplatin.