This Article Full Text Full Text (PDF) Erratum (v18,p2793) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fracasso, P. M. Articles by Egorin, M. J. Search for Related Content PubMed PubMed Citation Articles by Fracasso, P. M. Articles by Egorin, M. J.

Phase I Study of Paclitaxel in Combination With a Multidrug Resistance Modulator, PSC 833 (Valspodar), in Refractory Malignancies

From the Department of Medicine, Washington University School of Medicine, St Louis, MO; Marlene and Stewart Greenebaum Cancer Center and Department of Medicine, University of Maryland School of Medicine, Baltimore, and Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD; and Novartis Pharmaceuticals Corporation, East Hanover, NJ.

Address reprint requests to Paula M. Fracasso, MD, PhD, Washington University School of Medicine, Box 8056, 660 South Euclid Ave, St Louis, MO 63110; email pfracass{at}imgate.wustl.edu

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of paclitaxel when given with PSC 833 (valspodar) to patients with refractory solid tumors.

PATIENTS AND METHODS: Patients were initially treated with paclitaxel 175 mg/m² continuous intravenous infusion (CIVI) over 3 hours. Subsequently, 29 hours of treatment with CIVI PSC 833 was started 2 hours before paclitaxel treatment was initiated. In this combination, the starting dose of paclitaxel was 52.5 mg/m². Paclitaxel doses were escalated by 17.5 mg/m² increments for four subsequent cohorts. Each cohort consisted of three patients with the exception of the last cohort, which consisted of six patients. Data for the pharmacokinetics of paclitaxel with and without concurrent PSC 833 administration were obtained.

RESULTS: All 18 patients completed at least one course of concurrent treatment (median, two courses; range, one to six) and were evaluable for toxicity. The MTD for paclitaxel with PSC 833 was 122.5 mg/m². Neutropenia was the DLT. All patients had PSC 833 blood concentrations greater than 1,000 ng/mL before, during, and 24 hours after the paclitaxel infusion. PSC 833 produced small increases in the paclitaxel peak plasma concentrations and areas under the concentration-time curve. However, PSC 833 greatly prolonged the terminal phase of paclitaxel, resulting in plasma paclitaxel concentrations of more than 0.05 µmol/L for much longer than expected. As a result, myelosuppression was comparable to that produced by full-dose paclitaxel given without PSC 833. Of the 16 patients who were assessable for response, one patient experienced a partial response and an additional nine patients experienced disease stabilization after paclitaxel treatment alone.

CONCLUSION: Treatment with paclitaxel 122.5 mg/m² as a 3-hour CIVI concurrent with a 29-hour CIVI of PSC 833 results in acceptable toxicity. The addition of PSC 833 alters the pharmacokinetics of paclitaxel, which explains the enhanced neutropenia experienced by patients treated with this drug combination.

This article has been cited by other articles:

				S.-J. Kim, H. Uehara, S. Yazici, J. E. Busby, T. Nakamura, J. He, M. Maya, C. Logothetis, P. Mathew, X. Wang, et al. Targeting platelet-derived growth factor receptor on endothelial cells of multidrug-resistant prostate cancer. J Natl Cancer Inst, June 7, 2006; 98(11): 783 - 793. [Abstract] [Full Text] [PDF]

				R. Advani, B. L. Lum, G. A. Fisher, J. Halsey, D. L. Chin, C. D. Jacobs, and B. I. Sikic A phase I trial of liposomal doxorubicin, paclitaxel and valspodar (PSC-833), an inhibitor of multidrug resistance Ann. Onc., December 1, 2005; 16(12): 1968 - 1973. [Abstract] [Full Text] [PDF]

				P. M. Fracasso, L. J. Goldstein, D. P. de Alwis, J. S. Rader, M. A. Arquette, S. A. Goodner, L. P. Wright, C. L. Fears, R. J. Gazak, V. A. M. Andre, et al. Phase I Study of Docetaxel in Combination with the P-Glycoprotein Inhibitor, Zosuquidar, in Resistant Malignancies Clin. Cancer Res., November 1, 2004; 10(21): 7220 - 7228. [Abstract] [Full Text] [PDF]

				S. E. Bates, S. Bakke, M. Kang, R. W. Robey, S. Zhai, P. Thambi, C. C. Chen, S. Patil, T. Smith, S. M. Steinberg, et al. A Phase I/II Study of Infusional Vinblastine with the P-Glycoprotein Antagonist Valspodar (PSC 833) in Renal Cell Carcinoma Clin. Cancer Res., July 15, 2004; 10(14): 4724 - 4733. [Abstract] [Full Text] [PDF]

				G. D. Leonard, T. Fojo, and S. E. Bates The Role of ABC Transporters in Clinical Practice Oncologist, October 1, 2003; 8(5): 411 - 424. [Abstract] [Full Text] [PDF]

				E. M. Kemper, A. E. van Zandbergen, C. Cleypool, H. A. Mos, W. Boogerd, J. H. Beijnen, and O. van Tellingen Increased Penetration of Paclitaxel into the Brain by Inhibition of P-Glycoprotein Clin. Cancer Res., July 1, 2003; 9(7): 2849 - 2855. [Abstract] [Full Text] [PDF]

				G. Xu and H. L. McLeod Strategies for Enzyme/Prodrug Cancer Therapy Clin. Cancer Res., November 1, 2001; 7(11): 3314 - 3324. [Abstract] [Full Text] [PDF]

				P. M. Fracasso, M. F. Brady, D. H. Moore, J. L. Walker, P. G. Rose, L. Letvak, T. M. Grogan, and W. P. McGuire Phase II Study of Paclitaxel and Valspodar (PSC 833) in Refractory Ovarian Carcinoma: A Gynecologic Oncology Group Study J. Clin. Oncol., June 15, 2001; 19(12): 2975 - 2982. [Abstract] [Full Text] [PDF]

				M. Baekelandt, G. Lehne, C. G. Trope, I. Szanto, P. Pfeiffer, B. Gustavssson, and G. B. Kristensen Phase I/II Trial of the Multidrug-Resistance Modulator Valspodar Combined With Cisplatin and Doxorubicin in Refractory Ovarian Cancer J. Clin. Oncol., June 15, 2001; 19(12): 2983 - 2993. [Abstract] [Full Text] [PDF]

				R. A. Peck, J. Hewett, M. W. Harding, Y.-M. Wang, P. R. Chaturvedi, A. Bhatnagar, H. Ziessman, F. Atkins, and M. J. Hawkins Phase I and Pharmacokinetic Study of the Novel MDR1 and MRP1 Inhibitor Biricodar Administered Alone and in Combination With Doxorubicin J. Clin. Oncol., June 15, 2001; 19(12): 3130 - 3141. [Abstract] [Full Text] [PDF]

				I. Chico, M. H. Kang, R. Bergan, J. Abraham, S. Bakke, B. Meadows, A. Rutt, R. Robey, P. Choyke, M. Merino, et al. Phase I Study of Infusional Paclitaxel in Combination With the P-Glycoprotein Antagonist PSC 833 J. Clin. Oncol., February 1, 2001; 19(3): 832 - 842. [Abstract] [Full Text] [PDF]

				A. Patnaik, E. Warner, M. Michael, M. J. Egorin, M. J. Moore, L. L. Siu, P. M. Fracasso, S. Rivkin, I. Kerr, M. Litchman, et al. Phase I Dose-Finding and Pharmacokinetic Study of Paclitaxel and Carboplatin With Oral Valspodar in Patients With Advanced Solid Tumors J. Clin. Oncol., November 1, 2000; 18(21): 3677 - 3689. [Abstract] [Full Text] [PDF]