title: Clinical aspects of a phase I trial of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent.
abstract: The antitumour action of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is mediated through tumour-selective antivascular effects and cytokine induction. This clinical phase I trial was conducted to examine its toxicity, maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamics (PD). A secondary objective was to assess its antitumour efficacy. DMXAA was administered every 3 weeks as a 20-min i.v. infusion. Dose escalation initially followed a modified Fibonacci schema but was also guided by PK and toxicity. A total of 63 patients received 161 courses of DMXAA over 19 dose levels ranging from 6 to 4900 mg m(-2). DMXAA was well tolerated at lower doses and no drug-related myelosuppression was seen. Rapidly reversible dose-limiting toxicities were observed at 4900 mg m(-2), including confusion, tremor, slurred speech, visual disturbance, anxiety, urinary incontinence and possible left ventricular failure. Transient prolongation of the corrected cardiac QT interval was seen in 13 patients evaluated at doses of 2000 mg m(-2) and above. A patient with metastatic cervical carcinoma achieved an unconfirmed partial response at 1100 mg m(-2), progressing after eight courses. The results of PK and PD studies are reported separately. DMXAA has antitumour activity at well-tolerated doses.
authors.affiliation: Department of Clinical Oncology, Auckland Hospital, Private Bag 92024, Auckland, New Zealand. jameson@waikatodhg.govt.nz
authors.forename: M B
authors.initials: MB
authors.lastname: Jameson
authors.forename: P I
authors.initials: PI
authors.lastname: Thompson
authors.forename: B C
authors.initials: BC
authors.lastname: Baguley
authors.forename: B D
authors.initials: BD
authors.lastname: Evans
authors.forename: V J
authors.initials: VJ
authors.lastname: Harvey
authors.forename: D J
authors.initials: DJ
authors.lastname: Porter
authors.forename: M R
authors.initials: MR
authors.lastname: McCrystal
authors.forename: M
authors.initials: M
authors.lastname: Small
authors.forename: K
authors.initials: K
authors.lastname: Bellenger
authors.forename: L
authors.initials: L
authors.lastname: Gumbrell
authors.forename: G W
authors.initials: GW
authors.lastname: Halbert
authors.forename: P
authors.initials: P
authors.lastname: Kestell
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002319:Cardiovascular System / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009420:Nervous System / Q000187:drug effects; D016896:Treatment Outcome; D014966:Xanthenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D044004:Xanthones
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan