Phase I study of high dose etoposide phosphatase with filgrastim (G-CSF) in the treatment of advanced refractory malignancies

Abstract

Purpose: To define the maximum tolerated dose of etoposide phosphate when used with G-CSF in the treatment of patients with refractory malignancies.

Patients and methods: Eleven patients with advanced cancer refractory to standard therapy were treated with etoposide phosphate given over 1–2 hours on three consecutive days. The first cohort of patients received a total dose of 1596 mg/m² (equivalent to etoposide 1400 mg/m²); doses were escalated in subsequent patient cohorts. G-CSF 5 µg/kg was administered subcutaneously from day 4 until the total leukocyte count rose to > 10,000/µL. Two courses were given at 28 day intervals.

Results: Toxicity produced by high dose etoposide phosphate included myelosuppression and mucositis. Three of five patients treated at the 2280 mg/m² dose level (equivalent to etoposide 2000 mg/m²) had dose limiting toxicities (grade 4 leukopenia for 7 days, 2 patients; grade 4 mucositis + leukopenia, 1 patient). In addition, median days with severe thrombocytopenia (< 50,000/µL) rose to six days at this dose. Other toxicity was uncommon.

Conclusions: In pretreated patients, the maximum tolerated dose of etoposide phosphate with G-CSF is 1938 mg/m² (equivalent to etoposide 1700 mg/m²). Dose-limiting toxicities were myelosuppression and mucositis, as with high dose etoposide. Etoposide phosphate can be substituted for etoposide in high dose regimens; due to its greater solubility, administration can be more rapid, requires less fluid volume, and is not associated with acidosis.