Phase I Clinical and Pharmacokinetic Evaluation of the Vascular-Disrupting Agent OXi4503 in Patients with Advanced Solid Tumors

• Published in: Clinical cancer research 2012-03, Vol.18 (5), p.1415-1425
• Main Authors: PATTERSON, Dan M, ZWEIFEL, Martin, CHAPLIN, Dai J, PADHANI, Anwar R, RUSTIN, Gordon J. S, MIDDLETON, Mark R, PRICE, Patricia M, FOLKES, Lisa K, STRATFORD, Michael R. L, ROSS, Phil, HALFORD, Sarah, PETERS, Jane, BALKISSOON, Jai
• Format: Article
• Language: English
• Subjects: Adult; Aged; Angiogenesis Inhibitors - pharmacokinetics; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Diphosphates - pharmacokinetics; Diphosphates - pharmacology; Diphosphates - therapeutic use; Female; Humans; Magnetic Resonance Imaging; Male; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - diagnosis; Neoplasms - drug therapy; Pharmacology. Drug treatments; Stilbenes - pharmacokinetics; Stilbenes - pharmacology; Stilbenes - therapeutic use; Treatment Outcome; Tumors; Young Adult
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-2414

Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents. Escalating doses of OXi4503 were given intravenously over 10 minutes on days 1, 8, and 15 every 28 days to patients with advanced solid tumors. Doses were escalated in single-patient cohorts from 0.06 to 1.92 mg/m(2), then expanded cohorts to 15.4 mg/m(2) in 43 patients. Common adverse drug reactions were hypertension, tumor pain, anemia, lymphopenia, and easily controllable nausea/vomiting and fatigue. Five patients experienced different drug-related dose-limiting toxicities, atrial fibrillation, increased troponin, blurred vision, diplopia, and tumor lysis. Prophylactic amlodipine failed to prevent adverse events. Pharmacokinetics showed dose-dependent linear increases in peak plasma concentrations and area under the curve value of OXi4503. One partial response was seen in a heavily pretreated patient with ovarian cancer. Dynamic contrast-enhanced MRI confirmed a dose effect and showed significant antivascular effects in 10 of 13 patients treated at doses of 11 mg/m(2) or higher. The maximum tolerated dose was 8.5 mg/m(2) but escalation to 14 mg/m(2) was possible with only temporary reversible cerebrovascular toxicity by excluding hypertensive patients. As a tumor response was seen at 14 mg/m(2) and maximum tumor perfusion reductions were seen at doses of 11 mg/m(2) or higher, the recommended phase II dose is from 11 to 14 mg/m(2).