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Phase I investigation of recombinant anti-human vascular endothelial growth factor antibody in patients with advanced cancer

Phase I investigation of recombinant anti-human vascular endothelial growth factor antibody in patients with advanced cancer,10.1016/j.ejca.2004.11.02

Phase I investigation of recombinant anti-human vascular endothelial growth factor antibody in patients with advanced cancer   (Citations: 17)
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Gordon C. Jayson, Clive Mulatero, Malcolm Ranson, Jamal Zweit, Alan Jackson, Lynn Broughton, John Wagstaff, Leif Hakansson, Gerard Groenewegen, Jeremy Lawrance, Meina Tang, Linda Waukhttp://academic.research.microsoft.com/io.ashx?type=5&id=31365535&selfId1=0&selfId2=0&maxNumber=12&query=
We assessed the tolerability, safety, pharmacokinetics and dose-limiting toxicity (DLT) of the recombinant humanized IgG4 anti-vascular endothelial growth factor (VEGF) monoclonal antibody, HuMV833, in patients with advanced cancer. Cohorts of patients with progressive solid tumours received escalating doses of HuMV833 as a 1-h intravenous (I.V.) infusion on days 1, 15, 22, and 29. Twenty patients (median Eastern Cooperative Oncology Group (ECOG) score 1) were accrued. HuMV833 infusions were well tolerated and there were no grade III or IV toxicities definitely related to the antibody. Grade I or II toxicities probably related to the antibody included fatigue, dyspnoea and rash. There were two episodes of asymptomatic hypocalcaemia, one at grade III and one grade IV, which were recorded in early follow-up. There were eight grade I episodes of asymptomatic elevation of activated partial thromboplastin time (APTT) and two grade III events; one in a patient receiving 1mg/kg and the other receiving extended doses of 10mg/kg. Pharmacokinetic analysis revealed a non-linear kinetic and an elimination half-life of between 8.2 (0.3mg/kg) and 18.7 (10mg/kg) days. One patient with ovarian cancer experienced a partial response (PR) of 9months duration and eight had disease stabilisation (SD) including one patient with colorectal carcinoma whose disease was stable for 14months. In 13 of the 14 samples taken from 12 patients, the plasma concentration of hepatocyte growth factor (HGF) was reduced 24h after drug administration. HuMV833 is safe and lacked DLT at doses up to 10mg/kg on this schedule. Multiple doses were well tolerated, despite occasional asymptomatic elevations in APTT. By combining pharmacokinetic, pharmacodynamic and toxicity data, we can identify doses of 1 and 3mg/kg for further investigation. HuMV833 appears to possess some clinical activity.
Journal: European Journal of Cancer - EUR J CANCER , vol. 41, no. 4, pp. 555-563, 2005
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