ZOSUQUIDAR TRIHYDROCHLORIDE DURING CONVENTIONAL INDUCTION AND POST-REMISSION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The remission rate and median overall survival of older adults (defined as age greater than 55 to 60 years of age) who are treated for newly diagnosed acute myeloid leukemia (AML) is approximately 50% and 12 months respectively. The primary reason for the poor prognosis is chemotherapy resistance. A very well characterized mechanism of chemotherapy resistance is the active efflux of drug medicated by the multdrug resistance protein (MDR1). The expression of MDR1 correlates with a reduced remission rate and median overall survival. Therefore, inhibition of MDR1 mediated efflux may improve treatment outcome. Zosuquidar trihydrochloride (LY335979) is a specific and potent modulator of MDR1-mediated efflux. Furthermore, it has minimal pharmacokinetic interactions with daunorubicin, an essential drug in the treatment of AML. The current clinical trial requires the collection and preservation of plasma samples for pharmacokinetic analysis of daunorubicin and cytarabine in the presence of placebo or Zosuquidar. The support of the GCRC is requested to process the samples of whole blood. Patients will not receive protocol therapy on the GCRC. Patients with newly diagnosed AML or advanced MDS will be admitted to the protected environment rooms of 5N University Hospital. Patients will receive conventional induction chemotherapy (three doses of daunorubicin given daily and continuous infusion of cytarabine) in addition to either placebo or zosuquidar for six hours daily with each dose of daunorubicin. Patients will have blood samples obtained for pharmacokinetic analysis of daunorubicin and cytarabine immediately prior to the third dose of daunorubicin and for the next four days (six samples).