This Article Full Text Full Text (PDF) 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 Eckhardt, S. G. Articles by Rowinsky, E. K. Search for Related Content PubMed PubMed Citation Articles by Eckhardt, S. G. Articles by Rowinsky, E. K. Social Bookmarking                            What's this?

Phase I and Pharmacologic Study of the Tyrosine Kinase Inhibitor SU101 in Patients With Advanced Solid Tumors

S. Gail Eckhardt, Jinee Rizzo, Kevin R. Sweeney, Gillian Cropp, Sharyn D. Baker, Maura A. Kraynak,, John G. Kuhn, Miguel A. Villalona-Calero, Lisa Hammond, Geoffrey Weiss, Allison Thurman, Lon Smith, Ronald Drengler, John R. Eckardt, Judy Moczygemba, Alison L. Hannah, Daniel D. Von Hoff, Eric K. Rowinsky

From the Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX; South Texas Oncology and Hematology, PA, San Antonio, TX; Department of Medicine, Division of Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX; School of Pharmacy, University of Connecticut, Farmington, CT; and Sugen, Inc, Redwood City, CA.

Address reprint requests to S. Gail Eckhardt, MD, Cancer Therapy and Research Center, 8122 Datapoint Dr, Suite 700, San Antonio, TX 78229; email geckhardt{at}saci.org

PURPOSE: To evaluate the clinical feasibility and pharmacologic behavior of the platelet-derived growth factor (PDGF) tyrosine kinase inhibitor SU101, administered on a prolonged, intermittent dosing schedule to patients with advanced solid malignancies.

PATIENTS AND METHODS: Twenty-six patients were treated with SU101 doses ranging from 15 to 443 mg/m² as a 24-hour continuous intravenous (IV) infusion weekly for 4 weeks, repeated every 6 weeks. Pharmacokinetic studies were performed to characterize the disposition of SU101 and its major active metabolite, SU0020. Immunohistochemical staining of PDGF- and -ß receptors was performed on malignant tumor specimens obtained at diagnosis.

RESULTS: Twenty-six patients were treated with 52 courses (187 infusions) of SU101. The most common toxicities were mild to moderate nausea, vomiting, and fever. Two patients experienced one episode each of grade 3 neutropenia at the 333 and 443 mg/m² dose levels. Dose escalation of SU101 above 443 mg/m²/wk was precluded by the total volume of infusate required, 2.5 to 3.0 L. Individual plasma SU101 and SU0020 concentrations were described by a one-compartment model that incorporates both first-order formation and elimination of SU0020. SU101 was rapidly converted to SU0020, which exhibited a long elimination half-life averaging 19 ± 12 days. At the 443 mg/m²/wk dose level, trough plasma SU0020 concentrations during weeks 2 and 4 ranged from 54 to 522 µmol/L. Immunohistochemical studies revealed PDGF- and -ß receptor staining in the majority (15 of 19) of malignant neoplasms.

CONCLUSION: SU101 was well tolerated as a 24-hour continuous IV infusion at doses of up to 443 mg/m²/wk for 4 consecutive weeks every 6 weeks. Although further dose escalation was precluded by infusate volume constraints, this SU101 dose schedule resulted in the achievement and maintenance of substantial plasma concentrations of the major metabolite, SU0020, for the entire treatment period.

Deceased.

This work was supported in part by a grant from Sugen, Inc.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				D. Uygur, H. Aytan, S. Zergeroglu, and S. Batioglu Leflunomide--an Immunomodulator--Induces Regression of Endometrial Explants in a Rat Model of Endometriosis Reproductive Sciences, July 1, 2006; 13(5): 378 - 383. [Abstract] [PDF]

				D. P. Lee, J. M. Skolnik, and P. C. Adamson Pediatric Phase I Trials in Oncology: An Analysis of Study Conduct Efficiency J. Clin. Oncol., November 20, 2005; 23(33): 8431 - 8441. [Abstract] [Full Text] [PDF]

				C. V. Ustach and H.-R. C. Kim Platelet-Derived Growth Factor D Is Activated by Urokinase Plasminogen Activator in Prostate Carcinoma Cells Mol. Cell. Biol., July 15, 2005; 25(14): 6279 - 6288. [Abstract] [Full Text] [PDF]

				E N van Roon, T L T A Jansen, M A F J van de Laar, M Janssen, J P Yska, R Keuper, P M Houtman, and J R B J Brouwers Therapeutic drug monitoring of A77 1726, the active metabolite of leflunomide: serum concentrations predict response to treatment in patients with rheumatoid arthritis Ann Rheum Dis, April 1, 2005; 64(4): 569 - 574. [Abstract] [Full Text] [PDF]

				G.C. Jayson, G.J.M. Parker, S. Mullamitha, J.W. Valle, M. Saunders, L. Broughton, J. Lawrance, B. Carrington, C. Roberts, B. Issa, et al. Blockade of Platelet-Derived Growth Factor Receptor-Beta by CDP860, a Humanized, PEGylated di-Fab', Leads to Fluid Accumulation and Is Associated With Increased Tumor Vascularized Volume J. Clin. Oncol., February 10, 2005; 23(5): 973 - 981. [Abstract] [Full Text] [PDF]

				M. L. Wahl, T. L. Moser, and S. V. Pizzo Angiostatin and Anti-angiogenic Therapy in Human Disease Recent Prog. Horm. Res., January 1, 2004; 59(1): 73 - 104. [Abstract] [Full Text]

				M. V. Blagosklonny and A. B. Pardee Exploiting Cancer Cell Cycling for Selective Protection of Normal Cells Cancer Res., June 1, 2001; 61(11): 4301 - 4305. [Abstract] [Full Text] [PDF]

				Y.-J. Ko, E. J. Small, F. Kabbinavar, A. Chachoua, S. Taneja, D. Reese, A. DePaoli, A. Hannah, S. P. Balk, and G. J. Bubley A Multi-Institutional Phase II Study of SU101, a Platelet-derived Growth Factor Receptor Inhibitor, for Patients with Hormone-Refractory Prostate Cancer Clin. Cancer Res., April 1, 2001; 7(4): 800 - 805. [Abstract] [Full Text]

				E. L. Korn, S. G. Arbuck, J. M. Pluda, R. Simon, R. S. Kaplan, and M. C. Christian Clinical Trial Designs for Cytostatic Agents: Are New Approaches Needed? J. Clin. Oncol., January 1, 2001; 19(1): 265 - 272. [Abstract] [Full Text] [PDF]

				L. M. Strawn, F. Kabbinavar, D. P. Schwartz, E. Mann, L. K. Shawver, D. J. Slamon, and J. M. Cherrington Effects of SU101 in Combination with Cytotoxic Agents on the Growth of Subcutaneous Tumor Xenografts Clin. Cancer Res., July 1, 2000; 6(7): 2931 - 2940. [Abstract] [Full Text]

				F. R. Khuri and J. M. Kurie Antisense Approaches Enter the Clinic Clin. Cancer Res., May 1, 2000; 6(5): 1607 - 1610. [Full Text] [PDF]

				G. Hudes Signaling Inhibitors in the Clinic: New Agents and New Challenges J. Clin. Oncol., April 1, 1999; 17(4): 1093 - 1093. [Full Text] [PDF]