Phase I clinical evaluation of ZD6126, a novel vascular-targeting agent, in patients with solid tumors
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Background ZD6126 is a novel vascular-targeting agent that disrupts the endothelial tubulin cytoskeleton causing selective occlusion of tumor vasculature and extensive tumor necrosis. This Phase I clinical study was conducted to evaluate the dose and administration schedule of ZD6126. Methods Adult patients with solid tumors refractory to existing treatments received a 10-min, single-dose intravenous infusion of ZD6126 every 14 or 21 days. Subsequent dose escalation was performed, based on the incidence of adverse events (AEs) within the first cycle of drug administration. Blood samples were obtained for pharmacokinetic analysis, and the effects of ZD6126 on tumor vasculature were visualized using DCE-MRI technology. Results Forty-four patients received ZD6126 (5−112 mg/m2 in the 21-day schedule, n = 35; 40−80 mg/m2 in the 14-day schedule, n = 9). Common AEs were similar in both groups and included abdominal pain, nausea and vomiting, which appeared to be dose related. The incidence of abdominal pain at 112 mg/m2 in the 21-day study prevented further dose escalation. Pharmacokinetic studies confirmed that ZD6126 is rapidly hydrolyzed to ZD6126 phenol. There was no difference in the pharmacokinetics of ZD6126 phenol upon repeat administration or between the two dosing regimens. DCE-MRI evaluation has demonstrated the antivascular effects of ZD6126. Conclusions This study identified that ZD6126 administered every 2 or 3 weeks at 80 mg/m2 was well tolerated, with mild but manageable gastrointestinal AEs. In approximately 11% (5 out of 44) of patients, ZD6126 was associated with cardiac events categorized as dose limiting toxicities (one patient with asymptomatic decreased left ventricular ejection fraction (LVEF), two with increased troponin concentrations, one with myocardial ischemia, and one with ECG signs of myocardial ischemia).
KeywordsTolerability Maximum tolerated dose Pharmacokinetics Vascular-targeting agent Tubulin cytoskeleton ZD6126
This study was supported by AstraZeneca, Inc.
- 2.Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342PubMedCrossRefGoogle Scholar
- 12.Evelhoch JL, LoRusso PM, He Z, DelProposto Z, Polin L, Corbett TH, Langmuir P, Wheeler C, Stone A, Leadbetter J, Ryan AJ, Blakey DC, Waterton JC (2004) Magnetic resonance imaging measurements of the response of murine and human tumors to the vascular-targeting agent ZD6126. Clin Cancer Res 10:3650–3657PubMedCrossRefGoogle Scholar
- 15.AstraZeneca Corp (2003) Investigator’s brochure. ZD6126—a vascular targeting agentGoogle Scholar
- 18.Gadgeel SM, LoRusso PM, Wozniak AJ, Wheeler C (2002) A dose-escalation study of the novel vascular-targeting agent, ZD6126, in patients with solid tumors. Proc Am Soc Clin Oncol 21 (abstract 438)Google Scholar
- 19.DelProposto Z, LoRusso P, Latif Z, Morton P, Wheeler C, Barge A, Evelhoch J (2002) MRI evaluation of the effects of the vascular-targeting agent ZD6126 on tumor vasculature. Proc Am Soc Clin Oncol 21 (abstract 440)Google Scholar
- 20.Landis CS, Li X, Telang FW, Coderre JA, Micca PL, Rooney WD, Latour LL, Vetek G, Palyka I, Springer CS Jr (2000) Determination of the MRI contrast agent concentration time course in vivo following bolus injection: effect of equilibrium transcytolemmal water exchange. Magn Reson Med 44:563–574PubMedCrossRefGoogle Scholar
- 21.Leach MO, Brindle KM, Evelhoch JL, Griffiths JR, Horsman MR, Jackson A, Jayson GC, Judson IR, Knopp MV, Maxwell RJ, McIntyre D, Padhani AR, Price P, Rathbone R, Rustin GJ, Tofts PS, Tozer GM, Vennart W, Waterton JC, Williams SR, Workman P (2005) The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. Br J Cancer 92:1599–1610PubMedCrossRefGoogle Scholar
- 23.Jameson MB, Thompson PI, Baguley BC, Evans BD, Harvey VJ, Porter DJ, McCrystal MR, Small M, Bellenger K, Gumbrell L, Halbert GW, Kestell P (2003) Clinical aspects of a phase I trial of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent. Br J Cancer 88:1844–1850PubMedCrossRefGoogle Scholar
- 24.Oliver R, Wheeler C, Langmuir P, Melezinek I, Stone A (2004) Evaluation of the role of body-surface-area dose adjustment of ZD6126, a novel vascular-targeting agent. Proc Am Soc Clin Oncol 22 (abstract 3065)Google Scholar
- 25.Galbraith SM, Maxwell RJ, Lodge MA, Tozer GM, Wilson J, Taylor NJ, Stirling JJ, Sena L, Padhani AR, Rustin GJ (2003) Combretastatin A4 phosphate has tumor antivascular activity in rat and man as demonstrated by dynamic magnetic resonance imaging. J Clin Oncol 21:2831–2842PubMedCrossRefGoogle Scholar
- 26.Galbraith SM, Rustin GJ, Lodge MA, Taylor NJ, Stirling JJ, Jameson M, Thompson P, Hough D, Gumbrell L, Padhani AR (2002) Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging. J Clin Oncol 20:3826–3840PubMedCrossRefGoogle Scholar