Voreloxin, a first-in-class anticancer quinolone derivative, in relapsed/refractory solid tumors: a report on two dosing schedules.

Purpose: Voreloxin, a novel replication-dependent DNA-damaging agent, intercalates DNA and inhibits topoisomerase II. Voreloxin induces site-selective DNA double-strand breaks and apoptosis. We report the phase 1 experience of voreloxin in patients with relapsed/refractory solid tumors, including dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, and clinical activity. Experimental Design: Two dose-escalation studies evaluated voreloxin administered i.v. every 3 weeks (SPO-0001) or weekly for 3 weeks every 28 days (SPO-0002). In SPO-0001, patients were classified as heavily pretreated (HP) or minimally pretreated (MP) based on therapeutic history. Results: In the SPO-0001 study, 41 patients (24 HP/17 MP) were treated in eight dose cohorts (3-75 mg/m 2 ). At 60 mg/m 2 , four HP patients experienced DLTs: grade 4 neutropenia ( n = 3, one with fever) and grade 3 febrile neutropenia/pneumonia ( n = 1). At 75 mg/m 2 , two MP patients experienced DLTs: grade 4 neutropenia/thrombocytopenia ( n = 1) or grade 2 oral thrush for >29 days ( n = 1). Therefore, the MTD was 48 mg/m 2 (HP patients) and 60 mg/m 2 (MP patients). In the SPO-0002 study, 21 patients were treated in six dose cohorts (3-24 mg/m 2 ). At 18 mg/m 2 , two patients experienced DLTs: grade 3 neutropenia, one with pleural effusion (>14 days each). The MTD was 15 mg/m 2 . Voreloxin exhibited low clearance (2 L/h/m 2 ), a long terminal half-life (22 hours), and dose-proportional exposure. Overall, 31 of 62 patients had stable disease and 1 patient (ovarian cancer) had a partial response per Rustin criteria. Conclusions: Voreloxin showed an acceptable safety profile with clinical activity in patients with relapsed/refractory solid tumors. The MTD was schedule-dependent. Voreloxin is currently in clinical studies of ovarian cancer and acute myeloid leukemia. Clin Cancer Res; 16(7); OF1–9