Phase ICombining a P-Glycoprotein Inhibitor , MS 209 , in Combinationwith Docetaxel in Patients with AdvancedMalignancies
Purpose:The purpose of this study was to investigate the safety and tolerability of MS209, a potent inhibitor of P-glycoprotein, when given in combination with docetaxel and to determine whetherMS209 affects docetaxel pharmacokinetics. Experimental design: Patients with advanced solid malignancies were eligible for this phase I trial. Docetaxel as1-hour infusionwasgivenalone during the first cycle.MS209was introducedas of cycle 2 and given orally 30 minutes after docetaxel infusion. The dose escalation scheme followed a modified Fibonacci model with six steps (docetaxel, 60-100 mg/m and MS209, 300-1,200 mgper body). Results:Atotalof 30patientswere treatedat five dose levels.Dose-limiting toxicitieswere febrile neutropenia, infection, stomatitis, dysphagia, and fatigue. The maximum tolerated dose was reached at level 5 (docetaxel, 80-MS: 1,200). Pharmacokinetic analysis failed to show a strong pharmacokinetic interaction between the two compounds, but at the highest dose levels, there is a trend to an increase of docetaxel AUCwhen this agent is given in combinationwithMS209. Conclusion:MS209 can be given in combination with docetaxel, with limited effect on docetaxel toxicity or pharmacokinetics. Resistance to chemotherapy agents is a major obstacle to successful treatment of malignancies. Multidrug resistance, which shows, regardless of its different mechanisms of action, cross-resistance to the major anticancer agents, including anthracyclines, alkaloids, podophyllotoxins, and taxanes, is one of the significant obstacles to cancer chemotherapy. Such a resistance can be observed in cancer cells after repeated chemotherapy (acquired resistance), or in cancer cells which may have already been resistant (refractory) before initiation of chemotherapy (intrinsic resistance), typically described in refractory cancer such as pancreatic cancer (1). The effectiveness of natural product–derived anticancer drugs is limited by the ability of many cancer cells to display an intrinsic or acquired multidrug resistance phenotype. Multidrug resistance is often associated with the expression of transmembrane efflux proteins resulting in a decreased drug accumulation (2). Among the family of ATP-binding cassette proteins, the Pgp170 is the most extensively characterized. Expression of this protein is sufficient to confer multidrug resistance in cell culture and in animal models of human cancers (3). Attempts to improve anticancer therapy by coadministration of P-glycoprotein inhibitors to date have been disappointing (4). However, many of the earliest P-glycoprotein inhibitors were compounds developed for other clinical uses and lacked sufficient potency and/or specificity to adequately test a clinical hypothesis. Many exhibited nontargeted related toxicities that compromised the achievement of therapeutic exposures (5). MS209 was developed specifically as a selective P-glycoprotein inhibitor (Fig. 1; ref. 6). MS209 alone had no antitumor activity. The metabolites of MS209 showed marginal enhancement of efficacy of antitumor agents and no significant cellular toxicity. In preclinical models, MS209 enhanced antitumor effects of anticancer agents including Adriamycin, vincristine, paclitaxel, and docetaxel multidrug resistant tumor cell lines (7). It also enhanced the efficacy of anticancer agents against cancer cells sensitive to anticancer agents. MS209 in combination with Adriamycin was more effective than Adriamycin alone against transplanted murine tumors, multidrug-resistant murine tumors, and human tumors transplanted to nude mouse (8). The efficacy is considered to be due to an increase of Adriamycin concentration in tumor tissue. Cancer Therapy: Clinical Authors’ Affiliations: Institut Curie, Paris, France; Centre Oscar Lambret, Lille, France; Centre Georges François Leclerc, Dijon, France; and European Organization for Research and Treatment of Cancer/New Drug Development Group, Brussels, Belgium Received11/15/04; revised 5/3/05; accepted 6/6/05. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Note: Presented in part at the AACR/National Cancer Institute/European Organization for Research and Treatment of Cancer International Conference, Miami, 2001. Presented in part at theAACR/National Cancer Institute/European Organization for Research and Treatment of Cancer International Conference, Frankfurt, Germany, 2002. Requests for reprints: Véronique Diéras, Department of Medical Oncology, Institut Curie, 26 rue d’Ulm, 75005 Paris, France. Phone: 33-1-44-32-4675; Fax: 33-1-44-32-4671; E-mail: veronique.dieras@curie.net. F2005 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-04-2316 www.aacrjournals.org Clin Cancer Res 2005;11(17) September 1, 2005 6256 Cancer Research. on October 15, 2017. © 2005 American Association for clincancerres.aacrjournals.org Downloaded from When taken together, these characteristics indicate that MS209 warrants investigation in reversing clinical drug resistance mediated by P-glycoprotein. For docetaxel, the 170-kDa P-glycoprotein, encoded by the MDR-1 gene, is one of the mechanisms conferring resistance (9, 10). Therefore, we initiated a phase I trial designed to determine the safety and tolerability of MS209 when given in combination with docetaxel. The study was also designed to evaluate whether biologically effective plasma concentrations of MS209 could be achieved in cancer patients who received the drug orally and the effects of MS209 on docetaxel pharmacokinetics and toxicity.