A phase I study of anti-kinase insert domain-containing receptor antibody, IMC-1C11, in patients with liver metastases from colorectal carcinoma.

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.

EXPERIMENTAL DESIGN:

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.

• Authors: James A Posey, Thian C Ng, Baolian Yang, M B Khazaeli, Mark D Carpenter, Floyd Fox, Mike Needle, Harlan Waksal, Albert F LoBuglio
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 9 Issue 4 Pg. 1323-32 (Apr 2003) ISSN: 1078-0432 [Print] United States
• PMID: 12684400 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies
• Antibodies, Monoclonal
• Antineoplastic Agents
• IMC1C11
• Intercellular Signaling Peptides and Proteins
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Adult
• Aged
• Antibodies (chemistry)
• Antibodies, Monoclonal (therapeutic use)
• Antineoplastic Agents (pharmacology)
• Carcinoma (pathology)
• Cell Division
• Cells, Cultured
• Colorectal Neoplasms (pathology)
• Dose-Response Relationship, Drug
• Endothelium, Vascular (cytology)
• Female
• Humans
• Intercellular Signaling Peptides and Proteins (metabolism)
• Kinetics
• Liver Neoplasms (drug therapy, secondary)
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Perfusion
• Protein Structure, Tertiary
• Time Factors
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, chemistry, immunology)