The aim of this phase I/II study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities of chronic oral
etoposide given on days 1-10 followed by rescue with subcutaneous (s.c.)
granulocyte-macrophage colony-stimulating factor (
GM-CSF) on days 12-19 as second-line
chemotherapy in
platinum-pretreated patients (pts) with advanced ovarian
carcinoma. Cohorts of three to six pts were treated with doses of oral
etoposide from 750 mg m(-2) cycle(-1) escalated to 1250 mg m(-2) cycle(-1) over 10 days, every 3 weeks. Subcutaneous
GM-CSF, 400 mug once daily, days 12-19, was added if dose-limiting
granulocytopenia was encountered. In total, 18 pts with a median Karnofsky index of 80% (range, 70-100%) and a median time elapsed since the last
platinum dose of 10 months (range, 1-24 months), 30% of whom showed visceral
metastases, were treated at four dose levels (DLs) of oral
etoposide on days 1-10 of each cycle as follows: DL 1, 750 mg m(-2) cycle(-1), without
GM-CSF, three pts; DL 2, 1000 mg m(-2) cycle(-1), without
GM-CSF, three pts; DL 3, 1000 mg m(-2) cycle(-1), with
GM-CSF, six pts; and DL 4, 1250 mg m(-2) cycle(-1), with
GM-CSF, six pts. All pts were assessable for toxicity and 16 pts for response. Dose-limiting toxicity (DLT) was reached at DL 4 by three of six pts, showing World Health Organization (WHO) toxicity grade 4. One patient died from gram-negative
sepsis associated with
granulocytopenia grade 4. Two more pts developed uncomplicated
granulocytopenia grade 4. Thus, we recommend that DL 3 can be used for further phase II evaluation (i.e. oral
etoposide 1000 mg m(-2) cycle(-1), days 1-10, followed by s.c.
GM-CSF 400 mug, days 12-19). The clinical complete or partial responses in each patient cohort were: DL 1, one of three pts; DL 2, one of three pts; DL 3, three of five pts; and DL 4, two of five pts. In conclusion, in this phase I/II study, we defined the MTD and the dose recommended for the
therapy with oral
etoposide given over 10 days followed by s.c.
GM-CSF in
platinum-pretreated patients with advanced
ovarian cancer. Our data demonstrate encouraging activity of this regimen and strongly support its further investigation in a phase II study.