A phase I and pharmacokinetic study of paclitaxel and epirubicin in advanced cancer

The objectives of this phase I trial were to determine the maximally tolera ted doses of the combination of epirubicin and paclitaxel with and without G-CSF (granulocyte colony stimulating factor) support and to investigate wh ether epirubicin pharmacokinetics are altered by paclitaxel. Patients with advanced cancer, performance status 0-2, and a normal left ventricular ejec tion fraction who had received up to 1 prior chemotherapy regimen were trea ted with epirubicin followed by a 3-hour infusion of paclitaxel repeated ev ery 3 weeks. Dose levels studied were (paclitaxel/epirubicin) 155/75, 175/7 5, 175/90, 200/90 mg/m(2) without G-CSF and 175/90 mg/m(2) with G-CSF. Thir ty-five patients were entered and all were assessable for toxicity. The dos e-limiting dose level was 175 mg/m(2) paclitaxel and 90 mg/m(2) epirubicin with limiting toxicities of febrile neutropenia, diarrhea and esophagitis. The addition of G-CSF did not allow escalation of epirubicin. No significan t cardiac toxicity was observed. Epirubicin pharmacokinetics were studied d uring the first 2 cycles in 6 patients, who were randomized to receive 1 cy cle with no interval between the completion of the epirubicin and the comme ncement of the paclitaxel infusion and the other cycle with a 72-hour inter val between the drugs. There was no substantial effect of paclitaxel on epi rubicin or epirubicinol pharmacokinetics, although there was a marginal inc rease in glucoronidation. In conclusion, paclitaxel 175 mg/m(2) and epirubi cin 75 mg/m(2) is recommended for phase II and III studies.