Phase I study of high-dose topotecan with haematopoietic stem cell support in the treatment of ovarian carcinomas: the ITOV 01 protocol

Abstract

Topotecan has demonstrated activity in ovarian carcinomas. In order to increase the tumour response rate and to define the maximum tolerated dose (MTD) of topotecan, we decided to develop a high-dose phase I regimen supported by stem cell support. High-doses schedules using a 1-day single administration have MTDs of 10.5 (24 h continuous infusion (CI)) or 22.5 mg/m 2 (30 min infusion). Five-day CI induces grade IV mucositis at high doses (MTDo12 mg/m 2 ). We chose to administer topotecan in a 5-day schedule with a 30 min daily infusion. Patients were scheduled to receive one cycle of therapy. The first dose level was 4.0 mg/m 2 /day  5 days. Limiting toxicities were defined as toxic death, grade IV nonhaematopoietic or haematopoietic toxicity 46 weeks. From August 1998 to April 2002, 49 patients were included. Forty-three patients have completed one course and 15 have received two cycles. One patient treated at level 7 mg/m 2 /day died of sepsis. Median duration of grade IV neutropenia was 9 days. Two episodes of grade IV diarrhoea were observed at level 9.5 mg/m 2 /day. Pharmacokinetic data were linear within the dose range of 4-9.0 mg/m 2 /day. The MTD was reached at 9 mg/m 2 / day  5 days.

A Phase I Trial of High-Dose Chemotherapy Combining Topotecan plus Cyclophosphamide with Hematopoietic Stem Cell Transplantation for Ovarian Cancer: The ITOV 01bis Study

“…However, responses rates were generally short and we did not observe prolonged survival without relapse among treated patients. Overall, the results from ITOV 01bis were disappointing and not better than the previous results obtained with high doses of topotecan when used as a monotherapy [25]. Thus, these negative results show that, in the setting of recurrent ovarian cancer, intensive therapy combining topotecan and cyclophosphamide is not currently clinically indicated.…”

“…The administration of high doses of topotecan was shown to be feasible, but doses higher than 9.5 mg/m 2 were associated with episodes of grade IV diarrhea [25,29,30], esophagitis and gastrointestinal hemorrhage [31], fever, vomiting, alopecia and cutaneous rash [29,30]. When administered at conventional doses, the combination of topotecan and cyclophosphamide induces nonhematological toxicities, including gastrointestinal dysfunction and stomatitis [26].…”

“…The dose of topotecan varied and the starting dose was 7.5 mg/m 2 /day. Based on the MTD previously set up for the administration of topotecan as monotherapy (9.0 mg/m 2 /day) [25], the topotecan dose was escalated up to 9.5 mg/kg/day until the MTD of the combination, based on dose-limiting toxicities, was determined. …”

“…However, in the context of transplantation this is no longer considered as a dose-limiting factor [24]. We have previously evaluated high-dose topotecan in a phase I study when combined with hematopoietic stem cell support and administration of the hematopoietic growth factor G-CSF [25]. Patients received an initial mobilization cycle (cyclophosphamide 3 mg/m 2 + G-CSF filgrastim 5 µg/kg/day) followed by high-dose topotecan monotherapy.…”

Phase I Study of Topotecan, Ifosfamide, and Etoposide (TIME) with Autologous Stem Cell Transplant in Refractory Cancer: Pharmacokinetic and Pharmacodynamic Correlates

“…Dose-limiting toxicity was diarrhea, and the MTD was determined to be 9.5 mg/m 2 /d × 5 days. A linear relationship between dose and AUC was observed (22). Litzow and colleagues from the Mayo Clinic dose escalated topotecan in combination with cyclophosphamide (1.5 g/m 2 /d) and carboplatin (200 mg/m 2 /d) all as 4-day continuous infusions prior to HCT in 16 patients with relapsed or persistent ovarian or primary peritoneal carcinoma (23).…”