A Phase I Study of Vosaroxin Plus Azacitidine for Patients with Myelodysplastic Syndrome

Background: Although hypomethylating agents are the mainstay of treatment for myelodysplastic syndromes (MDS), these agents produce remissions in a minority of patients and are not curative. Vosaroxin is a first-in-class quinolone derivative that intercalates DNA and inhibits topoisomerase II activity, which is active and tolerable in acute myeloid leukemia (AML). The novel combination of vosaroxin and azacitidine was found to be synergistic in primary myeloblasts. This phase I/cohort expansion trial was conducted to study the combination of vosaroxin and azacitidine for patients with MDS.

Methods: Patients with MDS ≥ 18 years of age with cytopenias requiring transfusions, an IPSS score of intermediate-1 or greater, or CMML were eligible. The primary objective was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of vosaroxin when given in combination with a fixed dose of azacitidine (75 mg/m² /day). Vosaroxin was administered on days 1 and 4, and azacitidine on days 1-7 of a 28 day cycle, for up to 6 cycles in a 3+3 design.

Results: Thirteen patients were enrolled in the dose escalation phase. No patients received prior hypomethylating therapy. The median age was 65 years (range 38-77) with IPSS scores of intermediate-1 (INT-1), (n=4); intermediate-2 (INT-2), (n=7); and high risk (HR), (n=2). At the initial dose of 50mg/m² /day vosaroxin, 2 of 6 patients experienced a DLT (grade 4 hyperbilirubinemia, and grade 4 neutropenia >42 days). Additional incidences of ≥ grade 3 non-hematologic toxicity in this cohort included: febrile neutropenia (n=6), dysphagia (n=1), mucositis (n=3), infections (n=9), sepsis (n=3), and bleeding (n=3). The vosaroxin dose was de-escalated to 34 mg/m² /day, resulting in 1 of 6 patients with a DLT (grade 4 mucositis). Incidences of ≥ grade 3 non-hematologic toxicity in this cohort included febrile neutropenia (n=4) and infection (n=4). No patients died within 30 days of treatment. Twelve patients completed at least one cycle and were evaluable for response, assessed by modified IWG criteria (Table). Best response for each patient was as follows: stable disease, n=3; stable disease with hematologic improvement (HI)-neutrophils, n=1; marrow complete remission (CR), n=3; marrow CR with HI-platelets; n=2; marrow CR with HI-neutrophils, n=1; marrow CR with HI-erythroid, n=1; and marrow CR with HI-platelets and neutrophils, n=1. Of these twelve patients, five (42%) have proceeded on to allogeneic stem cell transplantation.

Conclusions: The MTD of vosaroxin in MDS patients was 34 mg/m² /day when given on days 1 and 4 with a fixed dose of 75 mg/m² of azacitidine on days 1-7. The major non-hematologic toxicities of febrile neutropenia, infections, and mucositis were expected based on the disease population and prior experiences with vosaroxin. The combination of vosaroxin and azacitidine showed promising activity with responses rates comparable or better than those generally observed with azacitidine alone. Additionally, the transplant rate observed was encouraging in this patient population with a median age of 65 years. A cohort expansion with plans to enroll an additional 20 patients at the MTD to further evaluate the tolerability and activity of the combination of vosaroxin and azacitidine in MDS patients is ongoing. In addition, correlative studies of the DNA damage response to the combination of vosaroxin and azacitidine from primary patient samples are in progress.