PHASE-I TRIAL OF PACLITAXEL AND GEMCITABINE ADMINISTERED EVERY 2 WEEKS IN PATIENTS WITH REFRACTORY SOLID TUMORS

Purpose. Paclitaxel and gemcitabine possess broad spectra of clinical activity, distinct mechanisms of cytotoxicity, and are differentially affected by mutations in cell-cycle regulatory proteins, such as bcl-2 . This phase I trial was designed to identify the maximum tolerated do se (MTD) and dose limiting toxicities (DLT) of paclitaxel and gemcitab ine when both drugs were given together on a once-every-two-week sched ule in patients with solid tumors. Patients and methods. A total of 37 patients were treated at nine different dose levels ranging from pacl itaxel 75-175 mg/m(2) administered over three hours followed by gemcit abine 1500-3500 mg/m(2) administered over 30-60 minutes. Both drugs we re administered on day 1 of a 14-day cycle. Dose escalation was perfor med in a stepwise manner in which the dose of one drug was escalated w hile the dose of the other drug was kept constant. Results: Dose limit ing toxicity (DLT) was observed at dose level 9: paclitaxel 175 mg/m(2 ) and gemcitabine 3500 mg/m(2) in the form of grade 4 neutropenia last ing for greater than or equal to 5 days (one patient) and grade 3 elev ation of alanine aminotransferase (AST/SGPT) (one patient). An analysi s of delivered dose intensity (DI) over the first three cycles reveale d that higher dosages of both drugs were delivered at dose level 7, pa clitaxel 150 mg/m(2) and gemcitabine 3000 mg/m(2) dose level, than at the MTD, dose level 8, paclitaxel 150 mg/m(2) and gemcitabine 3500 mg/ m(2). Partial responses were confirmed in two patients with transition al cell carcinoma (one of the bladder, one of the renal pelvis) and in one patient with adenocarcinoma of unknown primary. Conclusions: Pacl itaxel and gemcitabine is a promising drug combination that can be adm inistered safely and repetitively on an every-other-week schedule. Usi ng this drug administration schedule, the recommended phase II dose is paclitaxel 150 mg/m(2) and gemcitabine 3000 mg/mg(2).