Valspodar, a non-immunosuppressive analog of cylosporine, is a potent P-glycoprotein (MDR1) inhibitor. As MDR1-mediated efflux of chemotherapeutic agents from leukemic blasts may contribute to drug resistance, a phase 1 study of valspodar combined with mitoxantrone and etoposide in pediatric patients with relapsed or refractory leukemias was performed.Patients received a valspodar-loading dose (2 mg/kg) followed by a 5-day continuous valspodar infusion (8, 10, 12.5, or 15 mg/kg/day) combined with lower than standard doses of mitoxantrone and etoposide. The valspodar dose was escalated using a standard 3 + 3 phase I design.Twenty-one patients were evaluable for toxicity and 20 for response. The maximum tolerated dose (MTD) of valspodar was 12.5 mg/kg/day, combined with 50% dose-reduced mitoxantrone and etoposide. The clearance of mitoxantrone and etoposide was decreased by 64% and 60%, respectively, when combined with valspodar. Dose-limiting toxicities included stomatitis, ataxia, and bone marrow aplasia. Three of 11 patients with acute lymphoblastic leukemia (ALL) had complete responses while no patient with acute myeloid leukemia (AML) had an objective response. In vitro studies demonstrated P-glycoprotein expression on the blasts of 5 of 14 patients, although only 1 had inhibition of rhodamine efflux by valspodar.While this regimen was tolerable, responses in this heavily pretreated population were limited to a subset of patients with ALL.
View details for DOI 10.1002/pbc.22366
View details for Web of Science ID 000275935700009
View details for PubMedID 20209646