A phase I study combining high-dose (HD) topotecan (TPC) plus cyclophosphamide (CPM) with blood stem cells support in poor prognosis ovarian carcinoma (OC): The ITOV 01bis protocol

Abstract

16061 Background: TPC and CPM-based CT may be proposed as 2nd-line chemotherapy (CT) after taxanes/platinum-compounds in refractory/relapsed OC. We have previously shown that the maximum tolerated dose (MTD) of TPC used as a single agent was 45 mg/m2 in a 5-d administration schema (ITOV 01 protocol - Lotz et al, BMT 2006, 37: 669). Method: We decided herein to combine TPC at a dose ranging from 8 to 10 mg/m2/d x 5d (30’ daily perfusion) to a fixed HD CPM (60 mg/kg/d x 2d) until the MTD of TPC was reached. Three pts were to be treated at each planned dose level (8.0, 8.5, 9.0, 9.5, 10 mg/m2/d). Limiting toxicity was defined as one toxic death (excluding sepsis) or grade (G) 4 non-hematological toxicity. In this event, a further 3 pts were to be recruited at the same dose level. Mobilization to collect 3x106 CD34+/kg BW (6x106 if a 2nd HD course using TPC alone was planned) was performed with CPM + filgrastim. Results: From 09/02 to 05/06, 26 pts (median age, 54, range: 21–64) were included (platinum-refractory/relapse - 15 pts, initial stage FIGO IV - 5 pts, residual disease at 2nd-look - 6 pts). Three pts failed to be collected, one progressed before and one progressed after mobilization, so that 21 pts were able to complete their 1st course. Six received a second cycle of HD TPC. One septicemia-related toxic death occurred at level 8 mg/m2/d. Median durations of G4 neutropenia & thrombocytopenia observed during the first course of HDCT were 10 & 9 d. No patients experienced G4 diarrhea. One pt experienced a G4 cutaneous toxicity at level 8.5 and 2/3 at level 9.5 mg/m2/d. MTD of TPC combined with CPM was consecutively set up at 9.0 mg/.m2/d x 5d. Pharmacokinetic data (Cmax, AUC) will be available. Conclusion: The MTD of TPC combined with CPM was set up at 9 mg/m2/d x 5d, i.e., 45 mg/m2. The forthcoming ITOV 04 protocol will combine HD TPC and Carboplatin (AUC 20) in patients whose relapse occurs between 6 and 12 months after platinum- based first-line CT. No significant financial relationships to disclose.