Trial Information

A Phase I/II Study of Intensive-Dose Etoposide, Topotecan and Carboplatin (ETC) Followed by Autologous Stem Cell Rescue in Chemosensitive Ovarian Cancer Patients With Either Minimal Residual Disease or at First Relapse

OBJECTIVES: I. Determine the toxicity and potential efficacy of high dose chemotherapy (HDC)
comprised of etoposide, topotecan, and carboplatin (ETC) followed by autologous stem cell
transplantation in patients with ovarian epithelial cancer. II. Determine the maximum
tolerated dose of topotecan when combined with etoposide and carboplatin in these patients.
III. Determine the disease free survival (DFS) and overall survival (OS) in patients treated
with this regimen. IV. Measure the amount and subcellular location of DNA topoisomerase I
and II- alpha in ovarian cancer biopsies before HDC and at relapse to determine the role of
alterations of topoisomerases in the drug resistance of ovarian cancer. V. Correlate the
amount and location of both enzymes before HDC with clinical outcome (DFS and OS) and plasma
concentrations of topotecan and carboplatin in these patients. VI. Correlate the levels of
signal transducers and activators of transcription (STAT) and expression of bcl-2 family
proteins with response to chemotherapy and clinical outcome (DFS and OS) in these patients.
VII. Measure the levels of STAT and determine the expression of bcl-2 family proteins in
tumor biopsies before HDC and at relapse to determine the role of these cellular pathways in
drug response. VIII. Determine the pharmacokinetic and pharmacodynamic relationship of high
dose topotecan combined with carboplatin in these patients.

OUTLINE: This is a dose escalation study of topotecan. Mobilization: After completion of
salvage chemotherapy and within 6 weeks of second look laparotomy, patients receive
cyclophosphamide IV over 2 hours and paclitaxel IV over 2 hours for 2 days. Patients then
receive filgrastim (G-CSF) subcutaneously daily beginning 24 hours after completion of
chemotherapy and continuing until autologous peripheral blood stem cells (PBSC) are
harvested and selected for CD34+ cells. High dose chemotherapy: After priming chemotherapy
and within 6 weeks of second look laparotomy, patients receive carboplatin IV over 1 hour on
days -8 to -6; topotecan IV over 30 minutes on days -7 to -5 (beginning 12 hours after
completion of carboplatin infusion); and etoposide IV over 4 hours on days -5 to -3
(beginning 12 hours after completion of the last topotecan infusion). Cohorts of 4-12
patients receive escalating doses of topotecan until the maximum tolerated dose (MTD) is
determined. The MTD is defined as the dose preceding that at which 6 or more of 12 patients
experience dose limiting toxicity. Transplantation: PBSC are reinfused on day 0. Patients
are followed at 3 and 6 months, then annually thereafter.

PROJECTED ACCRUAL: Approximately 4-30 patients will be accrued for this study within 3-4
years.