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Purpose To determine the maximum tolerated dose (MTD) of F14512, a topoisomerase II inhibitor designed to target cancer cells through the polyamine transport system, (three-hour daily infusion given for 3 consecutive days every 3 weeks) in platinum-refractory or resistant ovarian cancer. Other objectives were safety, pharmacokinetics (PK), PK/pharmacodynamics relationship, and efficacy. Methods This was an open-label, dose-escalation, multicenter phase I study. Results Eleven patients were enrolled and were treated at dose levels (DLs) of 10 and 5 mg/m 2 /day. All patients received the 3 injections per cycle as per study protocol (median, 1 cycle (Ferlay et al. Int J Cancer 136:E359-386, 2015; Siegel et al. CA Cancer J Clin 65:5-29, 2015; Oronsky et al. Med Oncol 34:103, 2017; Barret et al. Cancer Res 68:9845-9853, 2008; Ballot et al. Apoptosis 17:364-376, 2012; Brel et al. Biochem Pharmacol 82:1843-1852, 2011; Gentry et al. Biochemistry 50:3240-3249, 2011; Kruczynski et al. Investig New Drugs 29:9-21, 2011; Chelouah et al. PLoS One 6:e23597, 2011)) with no dose reductions. At DL 10 mg/m 2 /day, 6 dose-limiting toxicities (DLTs) were reported (3/4 evaluable patients: 2 grade 3 febrile neutropenia, 1 grade 4 neutropenia lasting at least 7 days, 1 grade 3 nausea, 1 decreased appetite, and 1 grade 3 asthenia). At dose 5 mg/m 2 /day, 2 DLTs were reported (2/6 treated patients: 2 grade 3 febrile neutropenia). Both DLs were defined as MTD. Stable disease was reported as best overall response in 2 (40%) patients having both received 9 cycles, one at each DL. 90.9% of patients experienced grade 4 neutropenia, but for only one (9.1%) it was reported as a serious adverse event. Conclusion Although there was some encouraging efficacy signal, grade 4 neutropenia led to complications and it was decided to stop the study. A DL below 5 mg/m 2 /day was not tested as this would not allow reaching the minimum serum concentration needed for the pharmacological activity of the drug.

investigational new drugs

Phase I dose-escalation study of F14512, a polyamine-vectorized topoisomerase II inhibitor, in patients with platinum-refractory or resistant ovarian cancer