Elsevier

Leukemia Research

Volume 33, Issue 8, August 2009, Pages 1055-1061
Leukemia Research

A phase I trial of continuous infusion of the multidrug resistance inhibitor zosuquidar with daunorubicin and cytarabine in acute myeloid leukemia

https://doi.org/10.1016/j.leukres.2008.09.015Get rights and content

Abstract

Zosuquidar is a potent and specific inhibitor of P-glycoprotein (P-gp). In preliminary experiments, blockade of P-gp for at least 12 h was required to reverse daunorubicin resistance. Because of the short half-life of zosuquidar, we performed a phase I trial of this drug as a 72-h infusion (CIV) in 16 patients during leukemic induction with daunorubicin and cytarabine. Study goals were to establish safety and determine the dose required for P-gp inhibition in NK cells and AML blasts. >90% P-gp inhibition was achieved within 2 h at a plasma threshold of 132 ng/ml zosuquidar. The recommended phase II dose of zosuquidar is 700 mg/day.

Introduction

The prognosis of acute myeloid leukemia (AML) is especially poor in older patients, due to factors that include adverse cytogenetics, poor performance status, higher incidence of secondary leukemia, and the multidrug resistance (MDR) phenotype [1], [2], [3], [4]. In patients over age 60, complete response (CR) rates are generally less than 50% and median survival is less than 1 year [1], [2], [3], [4], [5], [6], [7].

The most prevalent form of MDR in AML is high expression of the multidrug transporter, P-glycoprotein (P-gp), encoded by the MDR1 (ABCB1) gene [8]. The incidence of P-gp expression increases with age, with more than 70% of AML specimens positive in patients older than 60 [4]. Anthracyclines, an important component of most induction regimens in AML, are P-gp substrates, and their efflux may serve as a key mechanism of treatment failure, affecting complete response rate and survival in AML [4], [8], [9], [10], [11], [12]. Pharmacologic inhibition of P-gp in AML has been studied in clinical trials utilizing various agents, including cyclosporine, PSC-833, and quinine [8], [10], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22]. Several of these trials failed to demonstrate efficacy; however, three randomized trials utilizing cyclosporine or quinine as MDR inhibitors resulted in clinical benefit in older patients with AML, secondary AML, and high-risk myelodysplastic syndrome (MDS) [10], [19], [20], [21].

Zosuquidar is a potent and highly selective inhibitor of P-gp with several properties that make it unique among MDR inhibitors [23], [24], [25], [26], [27], [28], [29], [30]. Because of a high degree of selectivity for P-gp, this agent has less potential for drug interactions than other inhibitors, enabling the co-administration of full doses of standard chemotherapy [24], [27], [28]. Preclinical experience with zosuquidar in animals demonstrated reversal of P-gp-mediated drug resistance without significantly enhanced toxicity from the chemotherapeutic agents doxorubicin, paclitaxel, and etoposide [23]. Early clinical studies of zosuquidar given in combination with anthracyclines demonstrated acceptable safety profiles and minimal PK interactions with doxorubicin or daunorubicin [27], [28]. In a previous phase I trial in AML, zosuquidar by short infusions in combination with daunorubicin and cytarabine was well tolerated [25].

Based upon the unique pharmacologic properties of zosuquidar as a P-gp inhibitor, along with preclinical data presented here which suggested an advantage to continuous drug exposure, we performed a phase I trial of continuous infusion (CIV) zosuquidar combined with daunorubicin and cytarabine in older patients with previously untreated AML. Study objectives were to establish the safety of this regimen and determine the dose required for sustained P-gp inhibition in CD56+ lymphocytes and AML blasts.

Section snippets

Zosuquidar scheduling and reversal of resistance to daunorubicin in MDR cells

The effect of various durations of exposure to zosuquidar on reversal of resistance to daunorubicin was determined using a modified tetrazolium (MTT) cell proliferation assay [31]. The P-gp expressing human sarcoma line, MES-SA/Dx5 [32], was exposed to zosuquidar (300 nM) from 2 to 72 h, over a range of daunorubicin concentrations. Reversal of resistance to daunorubicin was assessed by comparison with drug sensitivity in the non-P-gp MES-SA parental cell line. At 2, 4, 6, 8, 10, 12, 24, 48, and 72

Patient demographics

Between August 2005 and January 2006, 16 patients were enrolled onto the trial. The characteristics of the patients are shown in Table 1. Twelve patients were positive for P-gp functional activity in leukemic blasts, and seven patients (44%) had a prior history of myelodysplastic syndrome.

Toxicities

Six patients were treated initially with zosuquidar at 700 mg/day, without DLT, and then 4 more added for a total of 10 patients in this cohort. One DLT, respiratory failure progressing to adult respiratory

Discussion

Despite the strong rationale for P-gp as a therapeutic target in AML, clinical trials with pharmacologic inhibitors of P-gp have had limited clinical success [8], [10], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22]. Possible reasons for the mixed results include excess toxicities related to modulating drugs or their interactions with chemotherapeutic agents, incomplete P-gp inhibition, lack of selection of suitable subsets of patients, non-specificity of the MDR inhibitor, and

Conflict of interest

J.F.F. and P.S.M. are employees of Kanisa Pharmaceutical, Inc., and A.F.L., R.F., and B.I.S. are consultants for the company.

Acknowledgments

This research was supported by Kanisa Pharmaceuticals, Inc.

Contributors: All of the authors participated in the study design, gathering of the data and interpretation of the results, reviewed and revised the paper, and approved the final draft. The initial draft of the paper was written by J.E.L.

Role of the funding source: Two of the authors of this paper are employees of the funding source, Kanisa Pharmaceuticals. They participated with all the other authors in the design of the study, the

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1

Presently at the University of Maryland Greenebaum Cancer Center, Baltimore, MD, USA.

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