A clinical trial of zosuquidar plus gemtuzumab ozogamicin (GO) in relapsed or refractory acute myeloid leukemia (RR AML): evidence of efficacy based on leukemic blast P-glycoprotein functional phenotype.

purposeTo evaluate safety, tolerability, potential efficacy, and pharmacodynamics (PD) of zosuquidar (Zos) in combination with gemtuzumab ozogamicin (GO) in elderly patients with relapsed or refractory (RR) acute myeloid leukemia (AML).

methodsPatients with RR AML (N = 41) were treated with Zos as a 48-h continuous intravenous infusion initiated 4 h prior to a 2-h infusion of GO on days 1 and 15. P-glycoprotein (P-gp) status of the patients' leukemic blasts and PD determinations were assessed with ex vivo bioassays. Patient outcomes were analyzed for the total cohort and as stratified into P-gp-positive (P-gp +) and P-gp-negative (P-gp‒) subgroups.

resultsThe eligible cohort exhibited a 34% overall remission rate (ORR), a composite of patients that exhibited complete remission (CR), CR with incomplete platelet recovery, or morphologic remission. Patients with 1st relapsed disease exhibited 40% ORR. P-gp phenotype did not significantly predict ORR. However, the P-gp + subgroup exhibited a greater median overall survival (OS) of 6.0 months vs. 1.8 months for patients in the P-gp‒ subgroup (p = 0.01). PD analyses revealed 90-95% inhibition of blast P-gp function during Zos infusion. Treatment related toxicities were observed and resolved with decrease or discontinued Zos or GO dosages.

conclusionsZos plus GO elicited appreciable ORR for an elderly patient population with RR AML. The greater OS of the P-gp + subgroup vs. the P-gp‒ subgroup suggests that patients with P-gp + leukemic blasts were being more effectively targeted by GO with Zos co-therapy. The poorer OS of the P-gp‒ subgroup suggests activity of Zos-insensitive multidrug resistant mechanisms. CLINICAL TRIALS: GOV IDENTIFIER: NCT00233909; First posted October 06, 2005.