PHASE-I AND PHARMACOLOGICAL STUDY OF THE COMBINATION PACLITAXEL AND CARBOPLATIN AS FIRST-LINE CHEMOTHERAPY IN STAGE-III AND STAGE-IV OVARIAN-CANCER

Purpose: To determine the maximum-tolerated dose for the combination p aclitaxel and carboplatin administered every 4 weeks and to gain more insight into the pharmacokinetics and pharmacodynamics of this combina tion in previously untreated ovarian cancer patients, Patients and Met hods: Thirty-five chemotherapy-naive patients with suboptimally debulk ed stage III (tumor masses > 3 cm) and stage IV ovarian cancer were en tered onto this phase I trial in which paclitaxel was administered as a 3-hour intravenous (IV) infusion at dosages of 125 to 225 mg/m(2) im mediately followed by carboplatin over 30 minutes at dosages of 300 to 600 mg/m(2). A total of six courses was planned, followed by a second -look laparoscopy/laparotomy. patients with a response and/or minimal residual disease at second-look laparoscopy received three additional courses, Twenty-six patients participated in the pharmacokinetic part of the study, Results: The most important hematologic toxicity encount ered was neutropenia, Neutropenia was more pronounced for the higher d ose levels (DLs) and was cumulative. Thrombocytopenia was mild in the first eight DLs, but increased during the treatment courses, Nonhemato logic toxicities consisted mainly of vomiting, neuropathy, fatigue, ra sh, pruritus, myalgia, and arthralgia. Dose-limiting toxicities (DLTs) in this trial were neutropenic fever, thrombocytopenia that required platelet transfusions, and cumulative neuropathy. Of 33 patients asses sable for response, 26 major responders (78%, 20 complete response [CR ] and six partial response [PR]) were documented, The maximal concentr ation (C-max) of paclitaxel and the area under the concentration-time curve (AUG) were not different from the historical data for paclitaxel as a single agent. Retrospective analysis using a modified Calvert fo rmula showed that the measured carboplatin AUCs in plasma ultrafiltrat e (pUF) were 30% +/- 3.4% less than the calculated carboplatin AUC. Ne utropenia was more pronounced than could be expected on the basis of t he historical times above a threshold concentration greater than 0.1 m u mol/L (T greater than or equal to 0.1 mu mol/L) or 0.05 mu mol/L (T greater than or equal to 0.05 mu mol/L), and thrombocytopenia was less than could be expected from historical sigmoidal E-max models. Conclu sion: The combination of paclitaxel 200 mg/ m(2) and carboplatin 550 m g/m(2) every 4 weeks is a well-tolerated treatment modality, The pacli taxel-carboplatin combination is highly active in stage III (bulky) an d stage IV ovarian cancer, No indications for a pharmacokinetic drug-d rug interaction between carboplatin and paclitaxel were found, (C) 199 7 by American Society of Clinical Oncology.