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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Beerepoot, L. V. Articles by Voest, E. E. Search for Related Content PubMed PubMed Citation Articles by Beerepoot, L. V. Articles by Voest, E. E. Related Articles Related Editorial

Phase I Clinical Evaluation of Weekly Administration of the Novel Vascular-Targeting Agent, ZD6126, in Patients With Solid Tumors

Laurens V. Beerepoot, Sandra A. Radema, Els O. Witteveen, Tawnie Thomas, Catherine Wheeler, Sanford Kempin, Emile E. Voest

From the Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Medical Oncology, St Vincent's Comprehensive Cancer Center, New York, NY; and AstraZeneca, Boston, MA

Address reprint requests to Emile E. Voest, MD, PhD, Department of Medical Oncology (F02.126), University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands; e-mail: e.e.voest{at}azu.nl

PURPOSE: ZD6126 is a novel vascular-targeting agent that induces selective effects on the morphology of endothelial cells by disrupting the tubulin cytoskeleton. This leads to cell detachment and tumor vessel congestion, resulting in extensive central necrosis in a range of tumor xenograft models. Results from a phase I dose-escalation study of ZD6126 are reported.

PATIENTS AND METHODS: Thirty-two patients with advanced cancer received weekly ZD6126 infusion (5 to 28 mg/m²). Assessments for safety and pharmacokinetics were performed. Circulating endothelial cells (CECs) were quantified as a pharmacodynamic marker of vascular damage.

RESULTS: Maximum concentrations of the active species were observed 5 to 25 minutes from the start of infusion, and decayed in a biexponential manner with a half-life of 1 to 3 hours. Maximum serum concentration and area under the time-concentration curve increased with dose in a linear fashion across the dose range of 5 to 28 mg/m². One patient treated at 10 mg/m² with a history of ischemic heart disease experienced acute myocardial infarction 2 weeks after drug discontinuation. Four others had asymptomatic creatine phosphokinase–muscle-brain elevation. Maximum-tolerated dose (MTD) was reached at 20 mg/m²/wk. Dose-limiting toxicities at 28 mg/m² were hypoxia caused by pulmonary embolism and an asymptomatic decrease in left ventricular ejection fraction. No objective antitumor responses were observed. CEC levels increased in the hours after infusion, indicating potential effect of the compound on the vasculature.

CONCLUSION: ZD6126 administered as a weekly infusion was clinically well tolerated. The MTD was reached at 20 mg/m².

Supported by Grant No. 920-03-090 from the Dutch Society of Scientific Research (L.V.B.). Performed under sponsorship from AstraZeneca, Alderley Park, Macclesfield, United Kingdom, and Boston, MA.

Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, FL, and the 12th National Cancer Institute/European Organisation for Research and Treatment of Cancer/American Association of Cancer Research Symposium on Molecular Targets and Cancer Therapeutics, November 15-19, 2003, Boston, MA.

L.V.B. and S.A.R. contributed equally to this work.

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

Related Editorial

• Promise of New Vascular-Disrupting Agents Balanced With Cardiac Toxicity: Is It Time for Oncologists to Get to Know Their Cardiologists?
  Willem J. van Heeckeren, Shyam Bhakta, Jose Ortiz, Jeff Duerk, Matthew M. Cooney, Afshin Dowlati, Keith McCrae, and Scot C. Remick
  JCO 2006 24: 1485-1488 [Full Text]

This article has been cited by other articles:

				S. Gould, F. R. Westwood, J. O. Curwen, S. E. Ashton, D. W. Roberts, S. C. Lovick, and A. J. Ryan Effect of Pretreatment With Atenolol and Nifedipine on ZD6126-Induced Cardiac Toxicity in Rats J Natl Cancer Inst, November 21, 2007; 99(22): 1724 - 1728. [Abstract] [Full Text] [PDF]

				J. M. Rademaker-Lakhai, L. V. Beerepoot, N. Mehra, S. A. Radema, R. van Maanen, J. S. Vermaat, E. O. Witteveen, C. M. Visseren-Grul, L. Musib, N. Enas, et al. Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral Protein Kinase C {beta}-Inhibitor Enzastaurin in Combination with Gemcitabine and Cisplatin in Patients with Advanced Cancer Clin. Cancer Res., August 1, 2007; 13(15): 4474 - 4481. [Abstract] [Full Text] [PDF]

				A. Norden-Zfoni, J. Desai, J. Manola, P. Beaudry, J. Force, R. Maki, J. Folkman, C. Bello, C. Baum, S. E. DePrimo, et al. Blood-Based Biomarkers of SU11248 Activity and Clinical Outcome in Patients with Metastatic Imatinib-Resistant Gastrointestinal Stromal Tumor Clin. Cancer Res., May 1, 2007; 13(9): 2643 - 2650. [Abstract] [Full Text] [PDF]

				S. Senan and E. F. Smit Design of Clinical Trials of Radiation Combined with Antiangiogenic Therapy Oncologist, April 1, 2007; 12(4): 465 - 477. [Abstract] [Full Text] [PDF]

				J. Gamrekelashvili, C. Kruger, R. von Wasielewski, M. Hoffmann, K. M. Huster, D. H. Busch, M. P. Manns, F. Korangy, and T. F. Greten Necrotic Tumor Cell Death In Vivo Impairs Tumor-Specific Immune Responses J. Immunol., February 1, 2007; 178(3): 1573 - 1580. [Abstract] [Full Text] [PDF]

				Y. Shaked, F. Bertolini, U. Emmenegger, C. R. Lee, and R. S. Kerbel On the Origin and Nature of Elevated Levels of Circulating Endothelial Cells After Treatment With a Vascular Disrupting Agent J. Clin. Oncol., August 20, 2006; 24(24): 4040 - 4040. [Full Text] [PDF]

				L. V. Beerepoot, E. O. Witteveen, and E. E. Voest In Reply J. Clin. Oncol., August 20, 2006; 24(24): 4040a - 4041. [Full Text] [PDF]

				N. Mehra, M. Penning, J. Maas, L. V. Beerepoot, N. van Daal, C. H. van Gils, R. H. Giles, and E. E. Voest Progenitor Marker CD133 mRNA Is Elevated in Peripheral Blood of Cancer Patients with Bone Metastases. Clin. Cancer Res., August 15, 2006; 12(16): 4859 - 4866. [Abstract] [Full Text] [PDF]

				W. J. van Heeckeren, S. Bhakta, J. Ortiz, J. Duerk, M. M. Cooney, A. Dowlati, K. McCrae, and S. C. Remick Promise of New Vascular-Disrupting Agents Balanced With Cardiac Toxicity: Is It Time for Oncologists to Get to Know Their Cardiologists? J. Clin. Oncol., April 1, 2006; 24(10): 1485 - 1488. [Full Text] [PDF]