title: Phase I trial of the antivascular agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: magnetic resonance imaging evidence for altered tumor blood flow.
abstract: OBJECTIVE
  Combretastatin A4 (CA4) phosphate (CA4P) inhibits microtubule polymerization and is toxic to proliferating endothelial cells in vitro. It causes reversible vascular shutdown in established tumors in vivo, consistent with an antivascular mechanism of action. The present study investigated escalating doses of CA4P administered intravenously to patients with advanced cancer.
  
  
  METHODS
  Patients with solid malignancies and good performance status received CA4P as a 10-minute infusion daily for 5 days repeated every 3 weeks. Pharmacokinetic sampling was performed during cycle 1. Patients receiving >/= 52 mg/m2/d had serial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies to measure changes in tumor perfusion with CA4P treatment.
  
  
  RESULTS
  Thirty-seven patients received 133 treatment cycles. CA4P dose levels ranged from 6 mg/m2 to 75 mg/m2 daily. Severe pain at sites of known tumor was dose limiting at 75 mg/m2. Dose-limiting cardiopulmonary toxicity (syncope and dyspnea or hypoxia) was noted as well in two patients treated at 75 mg/m2. Other toxicities included hypotension, ataxia, dyspnea, nausea or vomiting, headache, and transient sensory neuropathy. Plasma CA4P and CA4 area under the concentration-time curve and maximal concentration values increased linearly with dose. Tumor perfusion, as measured by the first-order rate constant of gadolinium plasma to tissue transfer during DCE-MRI studies, was found to decrease in eight of 10 patients. Relationships were also demonstrated between perfusion changes and pharmacokinetic indices. A partial response was observed in a patient with metastatic soft tissue sarcoma, and 14 patients exhibited disease stability for a minimum of two cycles.
  
  
  CONCLUSIONS
  Doses of CA4P on a daily times five schedule of 52 to 65 mg/m2 were reasonably well-tolerated. The 52 mg/m2 dose is recommended for further study based on cumulative phase I experience with CA4P. Antitumor efficacy was observed, and the use of DCE-MRI provided a valuable noninvasive measure of the vascular effects of CA4P treatment.
authors.affiliation: University of Pennsylvania, 16 Penn Tower, 3400 Spruce St, Philadelphia, PA 19104, USA. james.stevenson@uphs.upenn.edu
authors.forename: James P
authors.initials: JP
authors.lastname: Stevenson
authors.forename: Mark
authors.initials: M
authors.lastname: Rosen
authors.forename: Weijing
authors.initials: W
authors.lastname: Sun
authors.forename: Maryann
authors.initials: M
authors.lastname: Gallagher
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Haller
authors.forename: David
authors.initials: D
authors.lastname: Vaughn
authors.forename: Bruce
authors.initials: B
authors.lastname: Giantonio
authors.forename: Ross
authors.initials: R
authors.lastname: Zimmer
authors.forename: William P
authors.initials: WP
authors.lastname: Petros
authors.forename: Michael
authors.initials: M
authors.lastname: Stratford
authors.forename: David
authors.initials: D
authors.lastname: Chaplin
authors.forename: Scott L
authors.initials: SL
authors.lastname: Young
authors.forename: Mitchell
authors.initials: M
authors.lastname: Schnall
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D003287:Contrast Media; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D013267:Stilbenes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014055:Tomography, Emission-Computed; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003287:Contrast Media; D013267:Stilbenes; C058728:fosbretabulin