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[Cancer Research 62, 3408-3416, June 15, 2002]
© 2002 American Association for Cancer Research

Clinical Investigations

A Phase I Pharmacokinetic and Translational Study of the Novel Vascular Targeting Agent Combretastatin A-4 Phosphate on a Single-Dose Intravenous Schedule in Patients with Advanced Cancer1

Afshin Dowlati, Kelly Robertson, Matthew Cooney, William P. Petros, Michael Stratford, John Jesberger, Niusha Rafie, Beth Overmoyer, Vinit Makkar, Bruce Stambler, Anne Taylor, John Waas, Jonathan S. Lewin, Keith R. McCrae and Scot C. Remick2

Division of Hematology/Oncology, Department of Medicine [A. D., M. C., B. O., V. M., J. W., K. R. M., S. C. R.], and Division of Cardiology, Department of Medicine [B. S.], Case Western Reserve University (CWRU), School of Medicine, Cleveland, Ohio, 44106; Developmental Therapeutics Program, Comprehensive Cancer Center at University Hospitals of Cleveland and CWRU [A. D., K. R., B. O., V. M., K. R. M., S. C. R.], and Division of Magnetic Resonance Imaging, Department of Radiology, University Hospitals of Cleveland and CWRU, School of Medicine [J. J., N. R., J. S. L.], Cleveland, Ohio 44106; Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506 [W. P. P.]; Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex, HA6 2JR, United Kingdom [M. S.]; Division of Cardiology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455 [A. T.]

Combretastatin A-4 phosphate (CA4P) is a novel antitumor vascular targeting agent, the first agent of this class of compounds to enter the clinic. We performed a Phase I trial to determine the maximum-tolerated dose, safety, and pharmacokinetic profile of CA4P on a single-dose i.v. schedule. We also obtained preliminary data on its effect on tumor blood flow using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) techniques and cell adhesion molecules at the higher-dose levels. Twenty-five assessable patients with advanced cancer received a total of 107 cycles over the following dose escalation schema: 18, 36, 60, 90 mg/m2 as a 10-min infusion and 60 mg/m2 as a 60-min infusion at 3-week intervals. There was no significant myelotoxicity, stomatitis, or alopecia. Tumor pain was a unique side effect, which occurred in 10% of cycles, and there were four episodes of dose-limiting toxicity at dosages >=60 mg/m2, including two episodes of acute coronary syndrome. Pharmacokinetics revealed rapid dephosphorylation of the parent compound (CA4P) to combretastatin A4 (CA4), with a short plasma half-life (~30 min). A significant (P < 0.03) decline in gradient peak tumor blood flow by DCE-MRI in six of seven patients treated at 60 mg/m2 was observed. A patient with anaplastic thyroid cancer had a complete response and is alive 30 months after treatment. The toxicity profile is consistent with a drug that is "vascularly active" and devoid of traditional "cytotoxic" side effects. Dosages <=60 mg/m2 as a 10-min infusion define the upper boundary of the maximum-tolerated dose.




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