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 cancer

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...

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Bibliographic Details
Published in:	Cancer research (Chicago, Ill.) Ill.), 2002-06, Vol.62 (12), p.3408-3416
Main Authors:	DOWLATI, Afshin, ROBERTSON, Kelly, TAYLOR, Anne, WAAS, John, LEWIN, Jonathan S, MCCRAE, Keith R, REMICK, Scot C, COONEY, Matthew, PETROS, William P, STRATFORD, Michael, JESBERGER, John, RAFIE, Niusha, OVERMOYER, Beth, MAKKAR, Vinit, STAMBLER, Bruce
Format:	Article
Language:	eng
Subjects:	Adult Aged Antineoplastic agents Antineoplastic Agents, Phytogenic - adverse effects Antineoplastic Agents, Phytogenic - pharmacokinetics Antineoplastic Agents, Phytogenic - pharmacology Biological and medical sciences Cell Adhesion Molecules - blood Chemotherapy Dose-Response Relationship, Drug Drug Administration Schedule Female Humans Infusions, Intravenous Magnetic Resonance Angiography Male Medical sciences Middle Aged Neoplasms - blood supply Neoplasms - drug therapy Neoplasms - metabolism Neovascularization, Pathologic - drug therapy Neovascularization, Pathologic - metabolism Pharmacology. Drug treatments Stilbenes - adverse effects Stilbenes - pharmacokinetics Stilbenes - pharmacology
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Summary:	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/m(2) as a 10-min infusion and 60 mg/m(2) 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 > or =60 mg/m(2), 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 (approximately 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/m(2) 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 < or =60 mg/m(2) as a 10-min infusion define the upper boundary of the maximum-tolerated dose.
ISSN:	0008-5472 1538-7445