Phase I and pharmacokinetic study of CT-322 (BMS-844203), a targeted Adnectin inhibitor of VEGFR-2 based on a domain of human fibronectin.

Abstract

PURPOSE:

To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of CT-322 (BMS-844203), a VEGFR-2 inhibitor and the first human fibronectin domain-based targeted biologic (Adnectin) to enter clinical studies.

EXPERIMENTAL DESIGN:

Patients with advanced solid malignancies were treated with escalating doses of CT-322 intravenously (i.v.) weekly (qw), or biweekly (q2w). Plasma samples were assayed for CT-322 concentrations, plasma VEGF-A concentrations, and antidrug antibodies.

RESULTS:

Thirty-nine patients completed 105 cycles of 0.1 to 3.0 mg/kg CT-322 i.v. either qw or q2w. The most common treatment-emergent grade 1/2 toxicities were fatigue, nausea, proteinuria, vomiting, anorexia, and hypertension. Grade 3/4 toxicities were rare. Reversible proteinuria, retinal artery, and vein thrombosis, left ventricular dysfunction, and reversible posterior leukoencephalopathy syndrome were dose limiting at 3.0 mg/kg. The MTD was 2 mg/kg qw or q2w. CT-322 plasma concentrations increased dose proportionally. Plasma VEGF-A levels increased with dose and plateaued at 2 mg/kg qw. Anti-CT-322 antibodies developed without effects on pharmacokinetics, VEGF-A levels, or safety. Minor decreases in tumor measurements occurred in 4 of 34 evaluable patients and 24 patients had stable disease.

CONCLUSIONS:

CT-322 can be safely administered at 2 mg/kg i.v. qw or q2w and exhibits promising antitumor activity in patients with advanced solid tumors. The absence of severe toxicities at the MTD, demonstration of plasma drug concentrations active in preclinical models, and clinical pharmacodynamic evidence of VEGFR-2 inhibition warrant further development of CT-322 and suggest strong potential for Adnectin-based targeted biologics.

• Authors: Anthony W Tolcher, Christopher J Sweeney, Kyri Papadopoulos, Amita Patnaik, Elena G Chiorean, Alain C Mita, Kamalesh Sankhala, Eric Furfine, Jochem Gokemeijer, Lisa Iacono, Cheryl Eaton, Bruce A Silver, Monica Mita
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 2 Pg. 363-71 (Jan 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21224368 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Antineoplastic Agents
• CT-322
• Fibronectins
• Peptide Fragments
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Adult
• Aged
• Antibody Formation
• Antineoplastic Agents (adverse effects, immunology, pharmacokinetics, therapeutic use)
• Female
• Fibronectins (adverse effects, immunology, pharmacokinetics, therapeutic use)
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Molecular Targeted Therapy
• Neoplasms (drug therapy)
• Peptide Fragments (adverse effects, immunology, pharmacokinetics, therapeutic use)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors)