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 Drevs, J. Articles by Unger, C. Search for Related Content PubMed PubMed Citation Articles by Drevs, J. Articles by Unger, C. Related Articles Related Editorial Social Bookmarking                            What's this?

Phase I Clinical Study of AZD2171, an Oral Vascular Endothelial Growth Factor Signaling Inhibitor, in Patients With Advanced Solid Tumors

Joachim Drevs, Patrizia Siegert, Michael Medinger, Klaus Mross, Ralph Strecker, Ute Zirrgiebel, Jan Harder, Hubert Blum, Jane Robertson, Juliane M. Jürgensmeier, Thomas A. Puchalski, Helen Young, Owain Saunders, Clemens Unger

From the Tumor Biology Center; MR Development and Application Center, Albert Ludwigs University; ProQinase GmbH; University Hospital, Freiburg, Germany; AstraZeneca, Macclesfield, Cheshire, United Kingdom; and AstraZeneca, Wilmington, DE

Address reprint requests to Joachim Drevs, MD, PhD, Clinic Sanafontis, An den Heilquellen 2, 79111 Freiburg, Germany; e-mail: drevs{at}sanafontis.com

Purpose AZD2171 is a highly potent oral selective inhibitor of vascular endothelial growth factor (VEGF) signaling. This phase I study was designed to evaluate the safety and tolerability of increasing doses of AZD2171, with additional assessments of pharmacokinetics, pharmacodynamics, and efficacy.

Patients and Methods In part A, 36 patients with solid tumors and liver metastases refractory to standard therapies received once-daily oral AZD2171 (0.5 to 60 mg). Doses were escalated in successive cohorts until the maximum-tolerated dose was identified. In part B, patients with (n = 36) or without (n = 11) liver metastases were randomly assigned to receive once-daily AZD2171 (20, 30, or 45 mg). In both parts, treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed.

Results Eighty-three patients received AZD2171, which was generally well tolerated at doses of 45 mg/d or less; the most frequently reported dose-related adverse events were diarrhea, dysphonia, and hypertension. The most common DLT was hypertension (n = 7), which occurred at AZD2171 doses of 20 mg and higher. After a single dose, maximum plasma (peak) drug concentration after single-dose administration (C_max) was achieved 1 to 8 hours postdosing with an arithmetic mean half-life associated with terminal slope of a semilogarithmic concentration-time curve (t_1/2z) of 22 hours. Pharmacodynamic assessments demonstrated time-, dose-, and exposure-related decreases in initial area under the curve, defined over 60 seconds post-contrast arrival in the tissue (iAUC₆₀) using dynamic contrast-enhanced magnetic resonance imaging, as well as dose- and time-dependent reductions in soluble VEGF receptor 2 levels. Preliminary evidence of efficacy included two confirmed partial responses and 22 patients with stable disease; effects on tumor size appeared to be dose related.

Conclusion Once-daily oral AZD2171 at doses of 45 mg or less was generally well tolerated and was associated with encouraging antitumor activity in patients with a broad range of advanced solid tumors.

Presented in part at the Gastrointestinal Cancers Symposium, San Francisco, CA, January 26-28, 2006; at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004; and at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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

Related Editorial

• Hypertension, Proteinuria, and Antagonism of Vascular Endothelial Growth Factor Signaling: Clinical Toxicity, Therapeutic Target, or Novel Biomarker?
  Willem J. van Heeckeren, Jose Ortiz, Matthew M. Cooney, and Scot C. Remick
  JCO 2007 25: 2993-2995 [Full Text]

This article has been cited by other articles:

				J. P.B. O'Connor, R. A.D. Carano, A. R. Clamp, J. Ross, C. C.K. Ho, A. Jackson, G. J.M. Parker, C. J. Rose, F. V. Peale, M. Friesenhahn, et al. Quantifying Antivascular Effects of Monoclonal Antibodies to Vascular Endothelial Growth Factor: Insights from Imaging Clin. Cancer Res., November 1, 2009; 15(21): 6674 - 6682. [Abstract] [Full Text] [PDF]

				C.-I. Wong, T.-S. Koh, R. Soo, S. Hartono, C.-H. Thng, E. McKeegan, W.-P. Yong, C.-S. Chen, S.-C. Lee, J. Wong, et al. Phase I and Biomarker Study of ABT-869, a Multiple Receptor Tyrosine Kinase Inhibitor, in Patients With Refractory Solid Malignancies J. Clin. Oncol., October 1, 2009; 27(28): 4718 - 4726. [Abstract] [Full Text] [PDF]

				J. Iwasaki and S.-i. Nihira Anti-angiogenic Therapy Against Gastrointestinal Tract Cancers Jpn. J. Clin. Oncol., September 1, 2009; 39(9): 543 - 551. [Abstract] [Full Text] [PDF]

				F. A.L.M. Eskens, N. Steeghs, J. Verweij, J. L. Bloem, O. Christensen, L. van Doorn, J. Ouwerkerk, M. J.A. de Jonge, J. W.R. Nortier, J. Kraetzschmar, et al. Phase I Dose Escalation Study of Telatinib, a Tyrosine Kinase Inhibitor of Vascular Endothelial Growth Factor Receptor 2 and 3, Platelet-Derived Growth Factor Receptor {beta}, and c-Kit, in Patients With Advanced or Metastatic Solid Tumors J. Clin. Oncol., September 1, 2009; 27(25): 4169 - 4176. [Abstract] [Full Text] [PDF]

				R. S. Herbst, D. Hong, L. Chap, R. Kurzrock, E. Jackson, J. M. Silverman, E. Rasmussen, Y.-N. Sun, D. Zhong, Y. C. Hwang, et al. Safety, Pharmacokinetics, and Antitumor Activity of AMG 386, a Selective Angiopoietin Inhibitor, in Adult Patients With Advanced Solid Tumors J. Clin. Oncol., July 20, 2009; 27(21): 3557 - 3565. [Abstract] [Full Text] [PDF]

				P. Bhargava VEGF kinase inhibitors: how do they cause hypertension? Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2009; 297(1): R1 - R5. [Abstract] [Full Text] [PDF]

				H. Izzedine, S. Ederhy, F. Goldwasser, J. C. Soria, G. Milano, A. Cohen, D. Khayat, and J. P. Spano Management of hypertension in angiogenesis inhibitor-treated patients Ann. Onc., May 1, 2009; 20(5): 807 - 815. [Abstract] [Full Text] [PDF]

				L. Horn and A. B. Sandler Angiogenesis in the Treatment of Non-Small Cell Lung Cancer Proceedings of the ATS, April 15, 2009; 6(2): 206 - 217. [Abstract] [Full Text] [PDF]

				E. Chen, D. Jonker, I. Gauthier, M. MacLean, J. Wells, J. Powers, and L. Seymour Phase I Study of Cediranib in Combination with Oxaliplatin and Infusional 5-Fluorouracil in Patients with Advanced Colorectal Cancer Clin. Cancer Res., February 15, 2009; 15(4): 1481 - 1486. [Abstract] [Full Text] [PDF]

				S. J. Crabb, D. Patsios, E. Sauerbrei, P. M. Ellis, A. Arnold, G. Goss, N. B. Leighl, F. A. Shepherd, J. Powers, L. Seymour, et al. Tumor Cavitation: Impact on Objective Response Evaluation in Trials of Angiogenesis Inhibitors in Non-Small-Cell Lung Cancer J. Clin. Oncol., January 20, 2009; 27(3): 404 - 410. [Abstract] [Full Text] [PDF]

				A. Idbaih, F. Ducray, M. Sierra Del Rio, K. Hoang-Xuan, and J.-Y. Delattre Therapeutic Application of Noncytotoxic Molecular Targeted Therapy in Gliomas: Growth Factor Receptors and Angiogenesis Inhibitors Oncologist, September 1, 2008; 13(9): 978 - 992. [Abstract] [Full Text] [PDF]

				C. A. Heckman, T. Holopainen, M. Wirzenius, S. Keskitalo, M. Jeltsch, S. Yla-Herttuala, S. R. Wedge, J. M. Jurgensmeier, and K. Alitalo The Tyrosine Kinase Inhibitor Cediranib Blocks Ligand-Induced Vascular Endothelial Growth Factor Receptor-3 Activity and Lymphangiogenesis Cancer Res., June 15, 2008; 68(12): 4754 - 4762. [Abstract] [Full Text] [PDF]

				J. O. Curwen, H. L. Musgrove, J. Kendrew, G. H.P. Richmond, D. J. Ogilvie, and S. R. Wedge Inhibition of Vascular Endothelial Growth Factor-A Signaling Induces Hypertension: Examining the Effect of Cediranib (Recentin; AZD2171) Treatment on Blood Pressure in Rat and the Use of Concomitant Antihypertensive Therapy Clin. Cancer Res., May 15, 2008; 14(10): 3124 - 3131. [Abstract] [Full Text] [PDF]

				S. A. Laurie, I. Gauthier, A. Arnold, F. A. Shepherd, P. M. Ellis, E. Chen, G. Goss, J. Powers, W. Walsh, D. Tu, et al. Phase I and Pharmacokinetic Study of Daily Oral AZD2171, an Inhibitor of Vascular Endothelial Growth Factor Tyrosine Kinases, in Combination With Carboplatin and Paclitaxel in Patients With Advanced Non-Small-Cell Lung Cancer: The National Cancer Institute of Canada Clinical Trials Group J. Clin. Oncol., April 10, 2008; 26(11): 1871 - 1878. [Abstract] [Full Text] [PDF]

				W. J. van Heeckeren, J. Ortiz, M. M. Cooney, and S. C. Remick Hypertension, Proteinuria, and Antagonism of Vascular Endothelial Growth Factor Signaling: Clinical Toxicity, Therapeutic Target, or Novel Biomarker? J. Clin. Oncol., July 20, 2007; 25(21): 2993 - 2995. [Full Text] [PDF]