This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Diéras, V. Articles by Fumoleau, P. Search for Related Content PubMed PubMed Citation Articles by Diéras, V. Articles by Fumoleau, P.

Phase I Combining a P-Glycoprotein Inhibitor, MS209, in Combination with Docetaxel in Patients with Advanced Malignancies

Authors' Affiliations: ¹ Institut Curie, Paris, France; ² Centre Oscar Lambret, Lille, France; ³ Centre Georges François Leclerc, Dijon, France; and ⁴ European Organization for Research and Treatment of Cancer/New Drug Development Group, Brussels, Belgium

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{at}curie.net.

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 whether MS209 affects docetaxel pharmacokinetics.

Experimental design: Patients with advanced solid malignancies were eligible for this phase I trial. Docetaxel as 1-hour infusion was given alone during the first cycle. MS209 was introduced as 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/m² and MS209, 300-1,200 mg per body).

Results: A total of 30 patients were treated at five dose levels. Dose-limiting toxicities were 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 AUC when this agent is given in combination with MS209.

Conclusion: MS209 can be given in combination with docetaxel, with limited effect on docetaxel toxicity or pharmacokinetics.

This article has been cited by other articles:

				J. W. Polli, J. E. Humphreys, K. A. Harmon, S. Castellino, M. J. O'Mara, K. L. Olson, L. St. John-Williams, K. M. Koch, and C. J. Serabjit-Singh The Role of Efflux and Uptake Transporters in N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, Lapatinib) Disposition and Drug Interactions Drug Metab. Dispos., April 1, 2008; 36(4): 695 - 701. [Abstract] [Full Text] [PDF]

				K. Katayama, S. Yoshioka, S. Tsukahara, J. Mitsuhashi, and Y. Sugimoto Inhibition of the mitogen-activated protein kinase pathway results in the down-regulation of P-glycoprotein Mol. Cancer Ther., July 1, 2007; 6(7): 2092 - 2102. [Abstract] [Full Text] [PDF]