Phase I, pharmacokinetic, and pharmacodynamic study of carboplatin and topotecan administered in two different schedules

Abstract

2561 Background: Preclinical studies showed sequence dependent synergy of the combination of topoisomerase I inhibitors and platinum agents. This trial was designed to determine the safety and maximum tolerated dose (MTD), pharmacokinetics (PK) and pharmacodynamics (PD) of carboplatin (carbo) and topotecan (topo) in patients (pts) with solid malignancies in two different schedules. Methods: In part 1, pts received carbo as a 60 min IV infusion on day 1 and topo as a 30 min IV infusion on days 1, 2 and 3 (C→T). The sequence of drug administration was reversed in part 2 of the study (T→C): topo on days 1, 2, and 3, followed by carbo on day 3. In both schedules, the PK was determined of each agent in plasma and the TopI catalytic activity and Pt-DNA adducts in white blood cells (WBC) and tumor tissue. Results: 41 pts were included in this trial. Dose-limiting toxicities (DLTs) during C→T included grade (G) 4 thrombocytopenia and febrile neutropenia. The MTD was reached at carbo target AUC 4 min.mg/mL and topo 0.5 mg/m2/day. DLTs during T→C included G4 neutropenia, thrombocytopenia and neutropenic fever, G3 nausea and G4 vomiting. Carbo target AUC 6 min.mg/mL and topo 0.9 mg/m2/day was the MTD in this schedule. No schedule dependent differences in PK were found (clearance (Cl) of unbound carbo: 0.6 vs 0.7 mL/min, p=0.14; Cl of total topo: 24.1 vs 29.6 L/h, p=0.08; Cl of topo lactone: 84.5 vs 83.7 L/h, p=0.96). WBC and tumor samples were collected from 30 and 27 pts, respectively. Pt-DNA levels were not schedule dependent in WBC (range C→T = 0.44–4.13, and T→C = 0.22–6.07 fmol*h/μg DNA) and in tumor tissue (range C→T = 0.20–0.96, and T→C = 0.62–1.8 fmol/μg DNA). Also, no schedule dependent effects were seen in TopI catalytic activity in WBC and tumor tissue. However, myelotoxicity was clearly more evident in the C→T schedule. One pt with ovarian cancer had a complete response (T→C schedule), 2 pts with ovarian cancer (C→T schedule) and 3 pts treated in the T→C schedule (ovarian, SCLC and gastric cancer) had a partial response. Conclusions: T→C was better tolerated as both hematological and non-hematological toxicities were milder. Other than the investigated PD factors must explain the schedule dependent differences in toxicities. No significant financial relationships to disclose.