Phase I clinical evaluation of weekly administration of the novel vascular-targeting agent, ZD6126, in patients with solid tumors.
OBJECTIVE
ZD6126 is a novel vascular-targeting agent that induces selective effects on the morphology of endothelial cells by disrupting the tubulin cytoskeleton. This leads to cell detachment and tumor vessel congestion, resulting in extensive central necrosis in a range of tumor xenograft models. Results from a phase I dose-escalation study of ZD6126 are reported.


METHODS
Thirty-two patients with advanced cancer received weekly ZD6126 infusion (5 to 28 mg/m2). Assessments for safety and pharmacokinetics were performed. Circulating endothelial cells (CECs) were quantified as a pharmacodynamic marker of vascular damage.


RESULTS
Maximum concentrations of the active species were observed 5 to 25 minutes from the start of infusion, and decayed in a biexponential manner with a half-life of 1 to 3 hours. Maximum serum concentration and area under the time-concentration curve increased with dose in a linear fashion across the dose range of 5 to 28 mg/m2. One patient treated at 10 mg/m2 with a history of ischemic heart disease experienced acute myocardial infarction 2 weeks after drug discontinuation. Four others had asymptomatic creatine phosphokinase-muscle-brain elevation. Maximum-tolerated dose (MTD) was reached at 20 mg/m2/wk. Dose-limiting toxicities at 28 mg/m2 were hypoxia caused by pulmonary embolism and an asymptomatic decrease in left ventricular ejection fraction. No objective antitumor responses were observed. CEC levels increased in the hours after infusion, indicating potential effect of the compound on the vasculature. CONCLUSION ZD6126 administered as a weekly infusion was clinically well tolerated. The MTD was reached at 20 mg/m2.
Beerepoot
Laurens V
LV
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
Radema
Sandra A
SA
Witteveen
Els O
EO
Thomas
Tawnie
T
Wheeler
Catherine
C
Kempin
Sanford
S
Voest
Emile E
EE
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002452:Cell Count; D003402:Creatine Kinase / Q000097:blood; D042783:Endothelial Cells / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D013318:Stroke Volume / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D000970:Antineoplastic Agents; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; D003402:Creatine Kinase