vosaroxin and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

This study of vosaroxin evaluated dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics (PK), clinical activity and pharmacodynamics in relapsed/refractory leukemia. Dosing was weekly (days 1, 8 and 15) or twice weekly (days 1, 4, 8 and 11). Seventy-three treated patients had a median age of 65 years, 85% had acute myeloid leukemia and 78% had refractory disease. Weekly schedule: 42 patients received 18-90 mg/m(2); MTD was 72 mg/m(2). Twice-weekly schedule: 31 patients received 9-50 mg/m(2); MTD was 40 mg/m(2). DLT was stomatitis; primary non-hematologic toxicity was reversible gastrointestinal symptoms and febrile neutropenia. Thirty-day all-cause mortality was 11%. Five patients had complete or incomplete remissions; median duration was 3.1 months. A morphologic leukemia-free state (bone marrow blast reduction to <5%) occurred in 11 additional patients. Antileukemic activity was associated with total dose or weekly time above 1 μmol/l plasma vosaroxin concentration (P<0.05). Vosaroxin exposure was dose proportional over 9-90 mg/m(2). The average terminal half-life was ~25 h and clearance was non-renal. No induction or inhibition of vosaroxin metabolism was evident. Vosaroxin-induced DNA damage was detected as increased intracellular γH2AX. Vosaroxin had an acceptable safety profile, linear PK and encouraging clinical activity in relapsed/refractory leukemia.

Topics: Adult; Aged; Aged, 80 and over; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Naphthyridines; Neoplasm Recurrence, Local; Neoplasm Staging; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Salvage Therapy; Thiazoles; Treatment Outcome; Young Adult

Voreloxin is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, inducing site-selective DNA damage. Voreloxin is in clinical studies, as a single agent and in combination with cytarabine, for the treatment of acute myeloid leukemia (AML). The preclinical studies reported here were performed to investigate the activity of voreloxin alone and in combination with cytarabine, in support of the clinical program.. Is single agent voreloxin active in preclinical models of AML? Does the combination of voreloxin and cytarabine enhance the activity of either agent alone?. Inhibition of proliferation was studied in three cancer cell lines: HL-60 (acute promyelocytic leukemia), MV4-11 (AML), and CCRF-CEM (Acute lymphoblastic leukemia). Combination index (CI) analysis established the effect of the drugs in combination. A mouse model of bone marrow ablation was used to investigate in vivo efficacy of the drugs alone and in combination. Peripheral white blood cell and platelet counts were followed to assess marrow impact and recovery.. Voreloxin and cytarabine alone and in combination exhibited cytotoxic activity in human leukemia cell lines and in vivo. The two drugs had additive or synergistic activity in vitro and supra-additive activity in vivo. Bone marrow ablation was accompanied by reductions in peripheral white blood cells and platelets that were reversible within 1 week, consistent with the AML treatment paradigm.. These data support ongoing clinical evaluation of voreloxin both alone and in combination with cytarabine for the treatment of AML.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Blood Platelets; Bone Marrow Cells; Cell Proliferation; Cytarabine; Disease Models, Animal; Drug Synergism; Female; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Leukocytes; Mice; Naphthyridines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thiazoles