A phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia

Abstract

Vosaroxin is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II. This study assessed the safety and tolerability of vosaroxin plus cytarabine in patients with relapsed/refractory acute myeloid leukemia. Escalating vosaroxin doses (10-minute infusion; 10-90 mg/m(2); days 1, 4) were given in combination with cytarabine on one of two schedules: schedule A (24-hour continuous intravenous infusion, 400 mg/m(2)/day, days 1-5) or schedule B (2-hour intravenous infusion, 1 g/m(2)/day, days 1-5). Following dose escalation, enrollment was expanded at the maximum tolerated dose. Of 110 patients enrolled, 108 received treatment. The maximum tolerated dose of vosaroxin was 80 mg/m(2) for schedule A (dose-limiting toxicities: grade 3 bowel obstruction and stomatitis) and was not reached for schedule B (recommended phase 2 dose: 90 mg/m(2)). In the efficacy population (all patients in first relapse or with primary refractory disease treated with vosaroxin 80-90 mg/m(2); n=69), the complete remission rate was 25% and the complete remission/complete remission with incomplete blood count recovery rate was 28%. The 30-day all-cause mortality rate was 2.5% among all patients treated at a dose of 80-90 mg/m(2). Based upon these results, a phase 3 trial of vosaroxin plus cytarabine was initiated in patients with relapsed/refractory acute myeloid leukemia. (Clinicaltrials.gov identifier: NCT00541866).

Figure 1.

Patients’ disposition.

Figure 2.

Leukemia-free survival (LFS) and overall survival (OS) in patients with primary refractory and first relapsed AML (efficacy population). (A) LFS in patients with complete response (CR) or CR with incomplete blood count recovery (n = 19); patients were not censored for subsequent therapies such as maintenance therapy or transplantation. (B) OS in the efficacy population (n = 69).

Figure 3.

Pharmacodynamic analyses. (A) Peripheral blood mononuclear cells (PBMC) from a patient with acute myeloid leukemia (AML) (80% AML blasts; obtained from AllCells LLC; Emeryville, CA, USA) were treated ex vivo with vosaroxin, cytarabine, both agents combined, or vehicle for 5 or 24 h. Samples were analyzed for the induction of pDNA-PKcs with actin as a loading control. pDNA-PKcs is detectable 5 h after exposure to 0.5 μM vosaroxin, whereas a 24 h exposure is required for a comparable pharmacodynamic response to 1 μM cytarabine. Induction of both pS2056 and pT2609 was observed and pDNA-PKcs S2056 was selected as the pharmacodynamic marker for subsequent analyses. (B) To identify optimal time points for collection of clinical samples, induction of pDNA-PKcs following a 2 h exposure to vosaroxin was examined. PBMC from an AML patient (80% blasts; obtained from AllCells LLC) were treated ex vivo with a dose titration of vosaroxin or vehicle for 2 h. Samples were analyzed for the induction of pDNA-PKcs with actin as a normalizing control. Vosaroxin induced a strong pharmacodynamic response at this time point. (C) Example of changes in pDNA-PKcs and pCHK2 Ievels over time as detected via western blot analysis in PBMC collected from a patient treated with 34 mg/m² vosaroxin in combination with 400 mg/m² continuous intravenous cytarabine. Increased levels were observed by 2 h after treatment; this patient achieved a complete remission.