A phase I study of anti-kinase insert domain-containing receptor antibody, IMC-1C11, in patients with liver metastases from colorectal carcinoma.
Clin Cancer Res
; 9(4): 1323-32, 2003 Apr.
Article
en En
| MEDLINE
| ID: mdl-12684400
ABSTRACT
PURPOSE:
Angiogenesis plays an important role in colorectal cancer progression. Stimulation of vascular endothelial growth factor receptor (VEGFR), a transmembrane glycoprotein, results in endothelial mitogenesis. Within this family of receptors, VEGFR 2/kinase-insert-domain-containing receptor (KDR) appear to be principally up-regulated during tumorigenesis. A chimeric anti-KDR antibody, IMC-1C11, blocks VEGFR-KDR interaction and inhibits VEGFR-induced endothelial cell proliferation. This trial seeks to assess the safety, tolerability and feasibility of targeting an important pathway in tumorigenesis. EXPERIMENTALDESIGN:
In a dose-escalation, single-agent study of IMC-1C11, we enrolled 14 patients with colorectal carcinoma and hepatic metastases. Safety-, pharmacokinetic-, immunogenicity-, and magnetic resonance imaging-assessed alteration of vascular effects of IMC-1C11 were evaluated in this trial. IMC-1C11 was infused weekly at 0.2 mg/kg (n = 3), 0.6 mg/kg (n = 4), 2.0 mg/kg (n = 3), and 4.0 mg/kg (n = 4) for 4 weeks, which constituted a cycle.RESULTS:
No grade-3 or -4 IMC-1C11-related toxicities were observed. Minor grade-1 bleeding events were observed in four patients [0.2 mg/kg (n = 1) and 0.6 mg/kg (n = 3)]. Each resolved quickly and required no intervention. The starting dose of IMC-1C11 was selected to achieve a C(max) of approximately 5 micro g/ml. This concentration prevented KDR phosphorylation in vitro. Pharmacokinetic analysis demonstrated that the plasma t(1/2) and C(max) were dose dependent with a plasma t(1/2) of 67 +/- 3 h at the 4-mg/kg dose level. Human antichimeric antibodies were detected in 7 of 14 patients. The antibodies to IMC-1C11 inhibited the circulation of the agent in two patients. One patient had prolonged stable disease for seven cycles (28 weeks). The mean changes in tumor-influx volume-transfer constant k(in) (min(-1)) and enhancement factor after 4 weeks of therapy were significantly decreased compared with pretreatment values in 11 patients.CONCLUSION:
IMC-1C11 was both safe and well tolerated. Drug levels of IMC-1C11 were reliably predicted. Further clinical investigation of anti-VEGFR/KDR agents is warranted.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Carcinoma
/
Neoplasias Colorrectales
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Receptor 2 de Factores de Crecimiento Endotelial Vascular
/
Péptidos y Proteínas de Señalización Intercelular
/
Neoplasias Hepáticas
/
Anticuerpos
/
Anticuerpos Monoclonales
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Clin Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
2003
Tipo del documento:
Article
País de afiliación:
Estados Unidos