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 Thomas, J. P. Articles by Wilding, G. Search for Related Content PubMed PubMed Citation Articles by Thomas, J. P. Articles by Wilding, G. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Cancer Social Bookmarking                            What's this?

Phase I Pharmacokinetic and Pharmacodynamic Study of Recombinant Human Endostatin in Patients With Advanced Solid Tumors

James P. Thomas, Rhoda Z. Arzoomanian, Dona Alberti, Rebecca Marnocha, Fred Lee, Andreas Friedl, Kendra Tutsch, Amy Dresen, Peter Geiger, James Pluda, William Fogler, Joan H. Schiller, George Wilding

From the Department of Medicine, Section of Medical Oncology and University of Wisconsin Comprehensive Cancer Center, University of Wisconsin Medical School, Madison, WI; National Cancer Institute, Bethesda, MD; and EntreMed, Rockville, MD.

Address reprint requests to George Wilding, MD, University of Wisconsin Comprehensive Cancer Center, 600 Highland Avenue K6/5 CSC, Madison, WI 53792; email: gxw{at}medicine.wisc.edu.

Purpose: Endostatin is the first endogenous angiogenesis inhibitor to enter clinical trials. Laboratory investigations with endostatin have indicated broad antitumor activity coupled with remarkably low toxicity. A phase I trial of recombinant human endostatin was designed to evaluate toxicity and explore biologic effectiveness in patients with refractory solid tumors.

Patients and Methods: Endostatin was administered as a 1-hour intravenous infusion given daily for a 28-day cycle. A starting dose of 30 mg/m² was explored with subsequent dose escalations of 60, 100, 150, 225, and 300 mg/m². Assessment of serum pharmacokinetics was performed on all 21 patients. Western blot assay and mass spectroscopy were employed to evaluate endostatin metabolism. Circulating levels of endogenous proangiogenic growth factors were examined. Tumor and tumor blood supply were imaged by dynamic computed tomography (CT), magnetic resonance imaging, ultrasound, and positron emission tomography.

Results: Endostatin given on this schedule was essentially free of significant drug-related toxicity. Two transient episodes of grade 1 rash were observed. No clinical responses were observed. Endostatin pharmacokinetics were linear with dose, and serum concentrations were achieved that are associated with antitumor activity in preclinical models. No aggregate effect on circulating proangiogenic growth factors were seen, although several patients exhibited persistent declines in vascular endothelial growth factor levels while enrolled in the study. A few patients demonstrated changes in their dynamic CT scans suggestive of a decline in microvessel density, although overall, no consistent effect of endostatin on tumor vasculature was seen.

Conclusion: Endostatin given daily as a 1-hour intravenous infusion was well tolerated without dose-limiting toxicity at doses up to 300 mg/m².

Supported by NCI UO1 CA62491, NIH M01RR03186, Joanne and Roy Howard Prostate Cancer Research Fund, Foundation for the Cure of Prostate Cancer (CaPCure).

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

This article has been cited by other articles:

				B. Ng, J. Zakrzewski, M. Warycha, P. J. Christos, D. F. Bajorin, R. L. Shapiro, R. S. Berman, A. C. Pavlick, D. Polsky, M. Mazumdar, et al. Shedding of Distinct Cryptic Collagen Epitope (HU177) in Sera of Melanoma Patients Clin. Cancer Res., October 1, 2008; 14(19): 6253 - 6258. [Abstract] [Full Text] [PDF]

				T.-Y. Lee, R. M. Tjin Tham Sjin, S. Movahedi, B. Ahmed, E. A. Pravda, K.-M. Lo, S. D. Gillies, J. Folkman, and K. Javaherian Linking Antibody Fc Domain to Endostatin Significantly Improves Endostatin Half-life and Efficacy Clin. Cancer Res., March 1, 2008; 14(5): 1487 - 1493. [Abstract] [Full Text] [PDF]

				K. X. Cai, L. Y. Tse, C. Leung, P. K.H. Tam, R. Xu, and M. H. Sham Suppression of Lung Tumor Growth and Metastasis in Mice by Adeno-Associated Virus-Mediated Expression of Vasostatin Clin. Cancer Res., February 1, 2008; 14(3): 939 - 949. [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]

				T. Isayeva, D. Chanda, L. Kallman, I.-E. A. Eltoum, and S. Ponnazhagan Effects of Sustained Antiangiogenic Therapy in Multistage Prostate Cancer in TRAMP Model Cancer Res., June 15, 2007; 67(12): 5789 - 5797. [Abstract] [Full Text] [PDF]

				A. Jackson, J. P.B. O'Connor, G. J.M. Parker, and G. C. Jayson Imaging Tumor Vascular Heterogeneity and Angiogenesis using Dynamic Contrast-Enhanced Magnetic Resonance Imaging Clin. Cancer Res., June 15, 2007; 13(12): 3449 - 3459. [Abstract] [Full Text] [PDF]

				X.-Y. Chen, W. Zhang, W. Zhang, S. Wu, F. Bi, Y.-J. Su, X.-Y. Tan, J.-N. Liu, and J. Zhang Vaccination with viable human umbilical vein endothelial cells prevents metastatic tumors by attack on tumor vasculature with both cellular and humoral immunity. Clin. Cancer Res., October 1, 2006; 12(19): 5834 - 5840. [Abstract] [Full Text] [PDF]

				M. Basche, D. L. Gustafson, S. N. Holden, C. L. O'Bryant, L. Gore, S. Witta, M. K. Schultz, M. Morrow, A. Levin, B. R. Creese, et al. A Phase I Biological and Pharmacologic Study of the Heparanase Inhibitor PI-88 in Patients with Advanced Solid Tumors. Clin. Cancer Res., September 15, 2006; 12(18): 5471 - 5480. [Abstract] [Full Text] [PDF]

				S. C.M. Martinico, S. Jezzard, N. J. H. Sturt, G. Michils, S. Tejpar, R. K. Phillips, and G. Vassaux Assessment of Endostatin Gene Therapy for Familial Adenomatous Polyposis-Related Desmoid Tumors Cancer Res., August 15, 2006; 66(16): 8233 - 8240. [Abstract] [Full Text] [PDF]

				M. H. Kulke, E. K. Bergsland, D. P. Ryan, P. C. Enzinger, T. J. Lynch, A. X. Zhu, J. A. Meyerhardt, J. V. Heymach, W. E. Fogler, C. Sidor, et al. Phase II Study of Recombinant Human Endostatin in Patients With Advanced Neuroendocrine Tumors J. Clin. Oncol., August 1, 2006; 24(22): 3555 - 3561. [Abstract] [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]

				X.-P. Li, C. Y.S. Li, X. Li, Y. Ding, L. L.Y. Chan, P.-H. Yang, G. Li, X. Liu, J. S. Lin, J. Wang, et al. Inhibition of human nasopharyngeal carcinoma growth and metastasis in mice by adenovirus-associated virus-mediated expression of human endostatin Mol. Cancer Ther., May 1, 2006; 5(5): 1290 - 1298. [Abstract] [Full Text] [PDF]

				K. Ichinose, Y. Maeshima, Y. Yamamoto, H. Kitayama, Y. Takazawa, K. Hirokoshi, H. Sugiyama, Y. Yamasaki, K. Eguchi, and H. Makino Antiangiogenic Endostatin Peptide Ameliorates Renal Alterations in the Early Stage of a Type 1 Diabetic Nephropathy Model Diabetes, October 1, 2005; 54(10): 2891 - 2903. [Abstract] [Full Text] [PDF]

				A. H. G. Hansma, H. J. Broxterman, I. van der Horst, Y. Yuana, E. Boven, G. Giaccone, H. M. Pinedo, and K. Hoekman Recombinant human endostatin administered as a 28-day continuous intravenous infusion, followed by daily subcutaneous injections: a phase I and pharmacokinetic study in patients with advanced cancer Ann. Onc., October 1, 2005; 16(10): 1695 - 1701. [Abstract] [Full Text] [PDF]

				G. Liu, H. S. Rugo, G. Wilding, T. M. McShane, J. L. Evelhoch, C. Ng, E. Jackson, F. Kelcz, B. M. Yeh, F. T. Lee Jr, et al. Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Pharmacodynamic Measure of Response After Acute Dosing of AG-013736, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors: Results From a Phase I Study J. Clin. Oncol., August 20, 2005; 23(24): 5464 - 5473. [Abstract] [Full Text] [PDF]

				R. Hoekstra, F. Y.F.L. de Vos, F. A.L.M. Eskens, J. A. Gietema, A. van der Gaast, H. J.M. Groen, R. A. Knight, R. A. Carr, R. A. Humerickhouse, J. Verweij, et al. Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of the Thrombospondin-1-Mimetic Angiogenesis Inhibitor ABT-510 in Patients With Advanced Cancer J. Clin. Oncol., August 1, 2005; 23(22): 5188 - 5197. [Abstract] [Full Text] [PDF]

				P. Wells, R. N. Gunn, C. Steel, A. S. Ranicar, F. Brady, S. Osman, T. Jones, and P. Price 2-[11C]Thymidine Positron Emission Tomography Reproducibility in Humans Clin. Cancer Res., June 15, 2005; 11(12): 4341 - 4347. [Abstract] [Full Text] [PDF]

				H.-M. Cho, J. D. Rosenblatt, Y.-S. Kang, M. L. Iruela-Arispe, S. L. Morrison, M. L. Penichet, Y.-G. Kwon, T.-W. Kim, K. A. Webster, H. Nechustan, et al. Enhanced inhibition of murine tumor and human breast tumor xenografts using targeted delivery of an antibody-endostatin fusion protein Mol. Cancer Ther., June 1, 2005; 4(6): 956 - 967. [Abstract] [Full Text] [PDF]

				P. Nyberg, L. Xie, and R. Kalluri Endogenous Inhibitors of Angiogenesis Cancer Res., May 15, 2005; 65(10): 3967 - 3979. [Abstract] [Full Text] [PDF]

				G. Gasparini, R. Longo, M. Fanelli, and B. A. Teicher Combination of Antiangiogenic Therapy With Other Anticancer Therapies: Results, Challenges, and Open Questions J. Clin. Oncol., February 20, 2005; 23(6): 1295 - 1311. [Abstract] [Full Text] [PDF]

				J. C. Miller, H. H. Pien, D. Sahani, A. G. Sorensen, and J. H. Thrall Imaging Angiogenesis: Applications and Potential for Drug Development J Natl Cancer Inst, February 2, 2005; 97(3): 172 - 187. [Abstract] [Full Text] [PDF]

				M.A. GRANT and R. KALLUR Structural Basis for the Functions of Endogenous Angiogenesis Inhibitors Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 399 - 417. [Abstract] [PDF]

				E. L. Korn Nontoxicity Endpoints in Phase I Trial Designs for Targeted, Non-Cytotoxic Agents J Natl Cancer Inst, July 7, 2004; 96(13): 977 - 978. [Full Text] [PDF]

				W. R. Parulekar and E. A. Eisenhauer Phase I Trial Design for Solid Tumor Studies of Targeted, Non-Cytotoxic Agents: Theory and Practice J Natl Cancer Inst, July 7, 2004; 96(13): 990 - 997. [Abstract] [Full Text] [PDF]

				S. Ponnazhagan, G. Mahendra, S. Kumar, D. R. Shaw, C. R. Stockard, W. E. Grizzle, and S. Meleth Adeno-Associated Virus 2-Mediated Antiangiogenic Cancer Gene Therapy: Long-Term Efficacy of a Vector Encoding Angiostatin and Endostatin over Vectors Encoding a Single Factor Cancer Res., March 1, 2004; 64(5): 1781 - 1787. [Abstract] [Full Text] [PDF]

				J. A. Sparano, R. Gray, B. Giantonio, P. O'Dwyer, and R. L. Comis Evaluating Antiangiogenesis Agents in the Clinic: The Eastern Cooperative Oncology Group Portfolio of Clinical Trials Clin. Cancer Res., February 15, 2004; 10(4): 1206 - 1211. [Abstract] [Full Text] [PDF]

				P. E. Thorpe Vascular Targeting Agents as Cancer Therapeutics Clin. Cancer Res., January 15, 2004; 10(2): 415 - 427. [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]

				A. Abdollahi, K. E. Lipson, A. Sckell, H. Zieher, F. Klenke, D. Poerschke, A. Roth, X. Han, M. Krix, M. Bischof, et al. Combined Therapy with Direct and Indirect Angiogenesis Inhibition Results in Enhanced Antiangiogenic and Antitumor Effects Cancer Res., December 15, 2003; 63(24): 8890 - 8898. [Abstract] [Full Text] [PDF]

				S M Galbraith Antivascular cancer treatments: imaging biomarkers in pharmaceutical drug development Br. J. Radiol., December 1, 2003; 76(suppl_1): S83 - S86. [Full Text] [PDF]

				Q.-T. Le and A. J. Giaccia Therapeutic Exploitation of the Physiological and Molecular Genetic Alterations in Head and Neck Cancer Clin. Cancer Res., October 1, 2003; 9(12): 4287 - 4295. [Abstract] [Full Text] [PDF]

				S. M. Plum, A. D. Hanson, K. M. Volker, H. A. Vu, B. K. L. Sim, W. E. Fogler, and A. H. Fortier Synergistic Activity of Recombinant Human Endostatin in Combination with Adriamycin: Analysis of in Vitro Activity on Endothelial Cells and in Vivo Tumor Progression in an Orthotopic Murine Mammary Carcinoma Model Clin. Cancer Res., October 1, 2003; 9(12): 4619 - 4626. [Abstract] [Full Text] [PDF]

				J. M. Collins Functional Imaging in Phase I Studies: Decorations or Decision Making? J. Clin. Oncol., August 1, 2003; 21(15): 2807 - 2809. [Full Text] [PDF]

				B. B.Y. Ma, R. G. Bristow, J. Kim, and L. L. Siu Combined-Modality Treatment of Solid Tumors Using Radiotherapy and Molecular Targeted Agents J. Clin. Oncol., July 15, 2003; 21(14): 2760 - 2776. [Abstract] [Full Text] [PDF]