title: 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.
abstract: 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.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University (CWRU), School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
authors.forename: Kelly
authors.initials: K
authors.lastname: Robertson
authors.forename: Matthew
authors.initials: M
authors.lastname: Cooney
authors.forename: William P
authors.initials: WP
authors.lastname: Petros
authors.forename: Michael
authors.initials: M
authors.lastname: Stratford
authors.forename: John
authors.initials: J
authors.lastname: Jesberger
authors.forename: Niusha
authors.initials: N
authors.lastname: Rafie
authors.forename: Beth
authors.initials: B
authors.lastname: Overmoyer
authors.forename: Vinit
authors.initials: V
authors.lastname: Makkar
authors.forename: Bruce
authors.initials: B
authors.lastname: Stambler
authors.forename: Anne
authors.initials: A
authors.lastname: Taylor
authors.forename: John
authors.initials: J
authors.lastname: Waas
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Lewin
authors.forename: Keith R
authors.initials: KR
authors.lastname: McCrae
authors.forename: Scot C
authors.initials: SC
authors.lastname: Remick
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D018810:Magnetic Resonance Angiography; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D013267:Stilbenes / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D015815:Cell Adhesion Molecules; D013267:Stilbenes; C058728:fosbretabulin