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.

Purpose: To 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).

Methods: Patients 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.

Results: The 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.

Conclusions: Zos 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.

Gov Identifier: NCT00233909; First posted October 06, 2005.