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.
Socinski
M A
MA
Department of Medicine and Pharmacy, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 27599, USA.
Mudd
P N
PN
Radomski
K M
KM
Steagall
A
A
Lawrence
P
P
Bernard
S
S
Letrent
S P
SP
Gonzalez
P
P
Brouwer
K L
KL
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