Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer.
OBJECTIVE
We investigated the safety and pharmacokinetics of a recombinant human monoclonal antibody to vascular endothelial growth factor (rhuMAb VEGF) in patients with cancer.


METHODS
Cohorts of patients with metastatic cancer having failed prior therapy entered a phase I trial of rhuMAb VEGF administered by a 90-minute intravenous infusion at doses from 0.1 to 10.0 mg/kg on days 0, 28, 35, and 42. Patients underwent pharmacokinetic sampling on day 0 and had serum samples obtained during the subsequent 28 days. Response assessment was carried out on days 49 and 72.


RESULTS
Twenty-five patients with a median Eastern Cooperative Oncology Group performance status of 0 were accrued. There were no grade III or IV adverse events definitely related to the antibody. There were three episodes of tumor-related bleeding. Infusions of rhuMAb VEGF were well tolerated without significant toxicity. Grades I and II adverse events possibly or probably related to study drug included asthenia, headache, and nausea. Pharmacokinetics revealed a linear profile with a half-life of 21 days. There were no objective responses, though 12 patients experienced stable disease over the duration of the study.


CONCLUSIONS
rhuMAb VEGF was safely administered without dose-limiting toxicity at doses ranging up to 10 mg/kg. Multiple doses of rhuMAb VEGF were well tolerated, and pharmacokinetic studies indicate that doses of > or = 0.3 mg/kg have a half-life similar to that of other humanized antibodies. Subsequent trials will explore rhuMAb VEGF alone and in combination chemotherapy.
Gordon
M S
MS
Indiana University School of Medicine, Indianapolis, IN, USA. msgordon@u.arizona.edu
Margolin
K
K
Talpaz
M
M
Sledge
G W
GW
Holmgren
E
E
Benjamin
R
R
Stalter
S
S
Shak
S
S
Adelman
D
D
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004306:Dose-Response Relationship, Immunologic; D004334:Drug Administration Schedule; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000911:Antibodies, Monoclonal; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors