PHASE-I TRIAL OF A 96 H PACLITAXEL INFUSION WITH FILGRASTIM SUPPORT IN REFRACTORY SOLID TUMOR PATIENTS

A phase I study of a 96 h paclitaxel infusion with filgrastim support was performed to determine the toxicity, maximum-tolerated dose (MTD) and pharmacokinetics in patients with refractory solid tumors. In this phase I trial, the initial paclitaxel dose was 140 mg/m(2)/96 h follo wed by filgrastim (5 mu g/kg/day s.c.) beginning 24 h after the paclit axel and continued until granulocyte recovery. Cycles were repeated ev ery 21 days. Patients with refractory solid tumors were eligible; howe ver, only one previous chemotherapy regimen was allowed. The dose of p aclitaxel was escalated by 20 mg/m(2)/96 h in subsequent cohorts until dose-limiting toxicity (DLT) occurred. Pharmacokinetic analysis was p erformed by quantitating paclitaxel concentrations at baseline, 24, 48 , 72 and 96 h after the start of the paclitaxel infusion. Twenty-one p atients were entered into this trial of which 19 were evaluable. A tot al of 52 treatment cycles were administered. DLT was seen in two of fo ur patients at 200 mg/m(2)/96 h, and consisted of diarrhea, mucositis and granulocytopenic infection. The MTD of the 96 h paclitaxel infusio n was 180 mg/m(2) with filgrastim support. Mucosal and granulocyte tox icity were correlated with steady-state paclitaxel concentrations (C-s s) greater than 0.100 mu mol/l. In the presence of liver function test 1.5 times or lower than normal, metastatic liver disease did not alte r paclitaxel C-ss. Objective responses were observed in non-small cell lung cancer, small cell lung cancer and melanoma. The recommended pha se II dose of paclitaxel infused over 96 h with filgrastim support is 180 mg/m(2). Paclitaxel C-ss correlate with mucosal and granulocyte to xicity. In the presence of normal enzymatic function, metastatic liver disease does not affect paclitaxel clearance. [(C) 1998 Lippincott Wi lliams & Wilkins.].