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/m2/96 h followed by filgrastim (5 microg/kg/day s.c.) beginning 24 h after the paclitaxel and continued until granulocyte recovery. Cycles were repeated every 21 days. Patients with refractory solid tumors were eligible; however, only one previous chemotherapy regimen was allowed. The dose of paclitaxel was escalated by 20 mg/m2/96 h in subsequent cohorts until dose-limiting toxicity (DLT) occurred. Pharmacokinetic analysis was performed by quantitating paclitaxel concentrations at baseline, 24, 48, 72 and 96 h after the start of the paclitaxel infusion. Twenty-one patients were entered into this trial of which 19 were evaluable. A total of 52 treatment cycles were administered. DLT was seen in two of four patients at 200 mg/m2/96 h, and consisted of diarrhea, mucositis and granulocytopenic infection. The MTD of the 96 h paclitaxel infusion was 180 mg/m2 with filgrastim support. Mucosal and granulocyte toxicity were correlated with steady-state paclitaxel concentrations (Css) greater than 0.100 micromol/l. In the presence of liver function test 1.5 times or lower than normal, metastatic liver disease did not alter paclitaxel Css. Objective responses were observed in non-small cell lung cancer, small cell lung cancer and melanoma. The recommended phase II dose of paclitaxel infused over 96 h with filgrastim support is 180 mg/m2. Paclitaxel Css correlate with mucosal and granulocyte toxicity. In the presence of normal enzymatic function, metastatic liver disease does not affect paclitaxel clearance.
Department of Medicine and Pharmacy, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 27599, USA.
M A
MA
Socinski
P N
PN
Mudd
K M
KM
Radomski
A
A
Steagall
P
P
Lawrence
S
S
Bernard
S P
SP
Letrent
P
P
Gonzalez
K L
KL
Brouwer
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D018288:Carcinoma, Small Cell / Q000188:drug therapy; D002851:Chromatography, High Pressure Liquid; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood; D011994:Recombinant Proteins; D012878:Skin Neoplasms / Q000188:drug therapy; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D017239:Paclitaxel; D000069585:Filgrastim