Phase I/II Pharmacodynamic Study of the P-Glycoprotein (Pgp) Inhibitor Zosuquidar Administered by Continuous Infusion (CIV) with Daunorubicin (DNR) and Cytarabine (ARA-C) as Primary Therapy in Older Patients with Acute Myeloid Leukemia (AML)

• Published in: Blood Vol. 108; no. 11; p. 422
• Main Authors: Lancet, Jeffrey, Baer, Maria R., Cripe, Larry D., List, Alan F., Marcelletti, John F., Multani, Pratik S., Sikic, Branimir I.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 16.11.2006
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V108.11.422.422

Pgp expression in AML increases with age and adversely affects treatment response and survival. Zosuquidar is a potent and highly specific Pgp inhibitor with minimal pharmacokinetic (PK) interaction with conventional xenobiotic antineoplastics. Previous studies established that plasma concentrations > 170 ng/mL achieve complete functional inhibition of Pgp. Prolonged Pgp blockade is necessary to optimize antineoplastic sensitization in resistant cells in vitro, but was not applied previously. Specifically, the 72-hour CIV schedule of zosuquidar in this trial differs from the 6-hour infusion employed in the E3999 Phase III trial of this agent. We initiated a Phase I/II trial of zosuquidar as a 72-hr CIV in older patients with newly diagnosed AML. Objectives of the Phase I study were to establish safety and determine the dose necessary to achieve a sustained zosuquidar plasma level > 170 ng/mL with in vivo validation of Pgp functional inhibition. Eligibility included ages 55–75, ECOG PS 0–2, adequate end-organ function, and Pgp activity by functional assay (Phase II only). Phase II objective is to determine the complete remission rate (CR) in Pgp+ patients. Planned zosuquidar dose levels of 700 mg/d and 800 mg/d were based upon PK modeling predicting achievement of plasma inhibitory concentrations [> 170 ng/mL] in 93% and 97% of patients, respectively, within 4 hours. Zosuquidar was initiated 4 hrs prior to the first doses of DNR (45 mg/m2/d x 3d) and ARA-C (100 mg/m2/d CIV x 7d) and continued for 72 hrs. Patients who achieved a CR received up to 2 cycles of consolidation with the same agents using an abbreviated schedule. The Phase I portion of the trial has been completed with 16 patients: 10 patients received 700 mg/d of zosuquidar and 6 patients, 800 mg/d. The median age was 66; M/F was 9/7; cytogenetics: adverse (6), intermediate (7), favorable (1) and unknown (2); de novo/secondary AML: 8/8; Pgp+ by functional assay (11). Phase I DLTs included one death due to respiratory failure on Day 8 of induction (700 mg/d); one patient with delayed bone marrow recovery and one patient with Grade 3 reversible delirium (800 mg/d). Early death (< 30 days) occurred in 1 patient. Other adverse events attributed to zosuquidar include reversible tremor (48%), dizziness (15%) and confusion (11%). Mean zosuquidar steady-state concentrations were 220±57 ng/mL (700 mg/d) and 462±222 ng/mL (800 mg/d), with a median of 49–52 hours above 170 ng/mL. Pharmacodynamic studies using circulating NK cells as an index of Pgp activity showed near complete inhibition (>90%) by 4 hours that was sustained throughout the infusion in all patients tested. Based upon these data, the recommended Phase II dose of zosuquidar by 72-hr CIV is 700 mg/d. An additional 9 Pgp+ patients have been enrolled to the Phase II trial. Among the total 20 evaluable Pgp+ patients, 10 (50%) have achieved CR or CRp. Zosuquidar 700 mg/d administered by CIV with DNR/ARA-C is well tolerated and achieves rapid and sustained Pgp inhibition at steady state plasma levels, with preliminary evidence of clinical benefit in Pgp+ patients. Accrual to the Phase II trial is ongoing.