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 Hoekstra, R. Articles by de Vries, E. G.E. Search for Related Content PubMed PubMed Citation Articles by Hoekstra, R. Articles by de Vries, E. G.E. Social Bookmarking                            What's this?

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of the Thrombospondin-1–Mimetic Angiogenesis Inhibitor ABT-510 in Patients With Advanced Cancer

From the Department of Medical Oncology, Erasmus MC, University Medical Center, Rotterdam; Department of Medical Oncology and Pulmonology, University Hospital Groningen, Groningen, the Netherlands; and Abbott Laboratories, Chicago, IL.

Address reprint requests to Ronald Hoekstra, MD, Department of Internal Medicine, Twenteborg Hospital, PO Box 7600, 7600 SZ, Almelo, the Netherlands; e-mail: r.hoekstra{at}zgt.nl

PURPOSE: ABT-510 is an angiogenesis inhibitor derived from thrombospondin-1, a naturally occurring inhibitor of angiogenesis. We investigated ABT-510, which was administered subcutaneously in patients with advanced solid malignancies, to assess safety, pharmacokinetics, and serum markers of angiogenesis.

PATIENTS AND METHODS: ABT-510 was administered subcutaneously as a continuous infusion (100 mg/24 h) and bolus injections (100, 200, and 260 mg once daily; 50 and 100 mg twice daily) in 28-day cycles.

RESULTS: Thirty-nine patients received a total of 144 treatment cycles. Administration by continuous infusion was hampered by the onset of painful skin infiltrates at the injection site. In the bolus injection regimens, the most common toxicities observed were mild injection-site reactions and fatigue. Maximum-tolerated dose was not defined, but 260 mg was defined as the maximum clinically practical dose. ABT-510 pharmacokinetics were linear across the dosage ranges tested, and the potential therapeutic threshold (plasma concentrations > 100 ng/mL > 3 h/d) was achieved with all dose regimens. Median serum basic fibroblast growth factor (bFGF) levels decreased from 14.1 pg/mL (range, 0.5 to 77.7 pg/mL) at baseline to 3.2 pg/mL (range, 0.2 to 29.4 pg/mL) after 56 days of treatment (P = .003). No correlations with time on study or ABT-510 dose or exposure were observed for individual changes in bFGF. Stable disease lasting for six cycles or more was seen in six patients.

CONCLUSION: ABT-510 demonstrated a favorable toxicity profile and linear and time-independent pharmacokinetics with biologically relevant plasma concentrations. The significant number of patients with prolonged stable disease and the convenient method of dosing merit further studies with this angiogenesis inhibitor.

Supported by Abbott Laboratories, Chicago, IL.

Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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

This article has been cited by other articles:

				J. CORONELLA, L. LI, K. JOHNSON, S. PIRIE-SHEPHERD, G. ROXAS, and N. LEVIN Selective Activity Against Proliferating Tumor Endothelial Cells by CVX-22, A Thrombospondin-1 Mimetic CovX-BodyTM Anticancer Res, June 1, 2009; 29(6): 2243 - 2252. [Abstract] [Full Text] [PDF]

				R. Hasina, L. E. Martin, K. Kasza, C. L. Jones, A. Jalil, and M. W. Lingen ABT-510 Is an Effective Chemopreventive Agent in the Mouse 4-Nitroquinoline 1-Oxide Model of Oral Carcinogenesis Cancer Prevention Research, April 1, 2009; 2(4): 385 - 393. [Abstract] [Full Text] [PDF]

				J. Greenaway, J. Henkin, J. Lawler, R. Moorehead, and J. Petrik ABT-510 induces tumor cell apoptosis and inhibits ovarian tumor growth in an orthotopic, syngeneic model of epithelial ovarian cancer Mol. Cancer Ther., January 1, 2009; 8(1): 64 - 74. [Abstract] [Full Text] [PDF]

				L. H. Baker, E. K. Rowinsky, D. Mendelson, R. A. Humerickhouse, R. A. Knight, J. Qian, R. A. Carr, G. B. Gordon, and G. D. Demetri Randomized, Phase II Study of the Thrombospondin-1-Mimetic Angiogenesis Inhibitor ABT-510 in Patients With Advanced Soft Tissue Sarcoma J. Clin. Oncol., December 1, 2008; 26(34): 5583 - 5588. [Abstract] [Full Text] [PDF]

				N. T. Fernando, M. Koch, C. Rothrock, L. K. Gollogly, P. A. D'Amore, S. Ryeom, and S. S. Yoon Tumor Escape from Endogenous, Extracellular Matrix-Associated Angiogenesis Inhibitors by Up-Regulation of Multiple Proangiogenic Factors Clin. Cancer Res., March 1, 2008; 14(5): 1529 - 1539. [Abstract] [Full Text] [PDF]

				S. Ebbinghaus, M. Hussain, N. Tannir, M. Gordon, A. A. Desai, R. A. Knight, R. A. Humerickhouse, J. Qian, G. B. Gordon, and R. Figlin Phase 2 Study of ABT-510 in Patients with Previously Untreated Advanced Renal Cell Carcinoma Clin. Cancer Res., November 15, 2007; 13(22): 6689 - 6695. [Abstract] [Full Text] [PDF]

				X. Zhang, J. Xu, J. Lawler, E. Terwilliger, and S. Parangi Adeno-Associated Virus-Mediated Antiangiogenic Gene Therapy with Thrombospondin-1 Type 1 Repeats and Endostatin Clin. Cancer Res., July 1, 2007; 13(13): 3968 - 3976. [Abstract] [Full Text] [PDF]

				J. S. Isenberg, Y. Jia, J. Fukuyama, C. H. Switzer, D. A. Wink, and D. D. Roberts Thrombospondin-1 Inhibits Nitric Oxide Signaling via CD36 by Inhibiting Myristic Acid Uptake J. Biol. Chem., May 25, 2007; 282(21): 15404 - 15415. [Abstract] [Full Text] [PDF]

				Q. Yang, Y. Tian, S. Liu, R. Zeine, A. Chlenski, H. R. Salwen, J. Henkin, and S. L. Cohn Thrombospondin-1 Peptide ABT-510 Combined with Valproic Acid Is an Effective Antiangiogenesis Strategy in Neuroblastoma Cancer Res., February 15, 2007; 67(4): 1716 - 1724. [Abstract] [Full Text] [PDF]

				D. D. Roberts, J. S. Isenberg, L. A. Ridnour, and D. A. Wink Nitric Oxide and Its Gatekeeper Thrombospondin-1 in Tumor Angiogenesis Clin. Cancer Res., February 1, 2007; 13(3): 795 - 798. [Abstract] [Full Text] [PDF]

				M. Aghi, S. D. Rabkin, and R. L. Martuza Angiogenic Response Caused by Oncolytic Herpes Simplex Virus-Induced Reduced Thrombospondin Expression Can Be Prevented by Specific Viral Mutations or by Administering a Thrombospondin-Derived Peptide Cancer Res., January 15, 2007; 67(2): 440 - 444. [Abstract] [Full Text] [PDF]

				A. Rusk, E. Cozzi, M. Stebbins, D. Vail, J. Graham, V. Valli, J. Henkin, R. Sharpee, and C. Khanna Cooperative Activity of Cytotoxic Chemotherapy with Antiangiogenic Thrombospondin-I Peptides, ABT-526 in Pet Dogs with Relapsed Lymphoma Clin. Cancer Res., December 15, 2006; 12(24): 7456 - 7464. [Abstract] [Full Text] [PDF]

				R. van Amerongen and A. Berns TXR1-mediated thrombospondin repression: a novel mechanism of resistance to taxanes? Genes & Dev., August 1, 2006; 20(15): 1975 - 1981. [Full Text] [PDF]

				J. A. Gietema, R. Hoekstra, F. Y. F. L. de Vos, D. R. A. Uges, A. van der Gaast, H. J. M. Groen, W. J. Loos, R. A. Knight, R. A. Carr, R. A. Humerickhouse, et al. A phase I study assessing the safety and pharmacokinetics of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 with gemcitabine and cisplatin in patients with solid tumors Ann. Onc., August 1, 2006; 17(8): 1320 - 1327. [Abstract] [Full Text] [PDF]