Volociximab, a chimeric monoclonal antibody that specifically binds alpha5beta1 integrin: a phase I, pharmacokinetic, and biological correlative study.
OBJECTIVE
This study aimed to assess the safety and feasibility of administering volociximab, a chimeric monoclonal antibody that specifically binds to alpha(5)beta(1) integrin, and to determine the pharmacokinetics, pharmacodynamics, and preliminary evidence of antitumor activity.


METHODS
Patients with advanced solid malignancies were treated with escalating doses of volociximab i.v. administered over 60 minutes. Blood samples were assayed to determine plasma pharmacokinetic parameters, detect human antichimeric antibody formation, and determine the saturation of alpha5beta1 sites on peripheral blood monocytes.


RESULTS
Twenty-one patients received 223 infusions of volociximab at doses ranging from 0.5 to 15 mg/kg i.v. on days 1, 15, 22, 29, and 36; and weekly thereafter. Treatment was well tolerated, and dose-limiting toxicity was not identified over the range examined. Mild (grade 1 or 2), reversible fatigue was the principal toxicity of volociximab at the highest dose levels of 10 and 15 mg/kg. Nausea, fever, anorexia, headache, vomiting, and myalgias were mild and infrequent, and there was no hematologic toxicity. Volociximab had biexponential distribution; clearance was inversely related to increasing dose, and the half-life at 15 mg/kg was estimated as being 30 days. Three patients tested positive for anti-volociximab antibodies. Saturation of monocyte alpha5beta1 integrin sites was dose-dependent up to 15 mg/kg. There was one minor response (renal, 7 months) and one durable stable disease (melanoma, 14 months).


CONCLUSIONS
Volociximab can be safely administered at 15 mg/kg i.v. per week. The absence of severe toxicities and preliminary activity at the highest dose level warrants further disease-directed studies.
Ricart
Alejandro D
AD
Institute for Drug Development, Cancer Therapy and Research Center and The University of Texas Health Science Center at San Antonio, TX, USA.
Tolcher
Anthony W
AW
Liu
Glenn
G
Holen
Kyle
K
Schwartz
Garry
G
Albertini
Mark
M
Weiss
Geoffrey
G
Yazji
Salim
S
Ng
Chee
C
Wilding
George
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D039081:Integrin alpha5beta1 / Q000187:drug effects*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D039081:Integrin alpha5beta1; C516631:volociximab