Abstract
Purpose: A fully human monoclonal antibody to anti–αv integrins (CNTO 95) has been shown to inhibit angiogenesis and tumor growth in preclinical studies. We assessed the safety and pharmacokinetics of CNTO 95 in patients with advanced refractory solid tumors.
Experimental Design: In this phase I trial, CNTO 95 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg) was infused on days 0, 28, 35, and 42, and clinical assessments, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and [18F]-2-fluorodeoxyglucose positron emission tomography (FDG-PET) were done. Patients achieving stable disease or better were eligible for extended dosing every 3 weeks for up to 12 months.
Results: Among the 24 enrolled patients, CNTO 95 was associated with one episode of grade III and four episodes of grade II infusion-related fever (all responded to acetaminophen). Of the six patients who received extended dosing, one patient (10.0 mg/kg), with cutaneous angiosarcoma, had a 9-month partial response. Pre- and post-treatment lesion biopsies confirmed tumor cell αv integrin expression, as well as CNTO 95 penetration of the tumor and localization to tumor cells in association with reduced bcl-2 expression. A lesion in one patient (10.0 mg/kg) with stable ovarian carcinosarcoma was no longer detectable by FDG-PET by day 49. Exposure to CNTO 95 seemed to increase in a greater-than-dose-proportional manner; dose-dependent mean half-life ranged from 0.26 to 6.7 days.
Conclusions: CNTO 95 was generally well tolerated. Six patients received extended therapy, including one patient with a prolonged response. Biopsy data confirmed tumor localization and pharmacodynamic activity.
- anti–αv integrin
- human monoclonal antibody
- angiogenesis
Footnotes
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Grant support: Centocor Research and Development, Inc., Malvern, PA. (The investigator analyzed and interpreted the data and approved the content of the manuscript before submission).
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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Note: This work was previously presented at major American and European oncology conferences in 2004 and 2005.
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Disclosures: Mihaela C. Munteanu, Marian T. Nakada, Jeffery A. Nemeth, Hugh M. Davis, Qun Jiao, Uma Prabhakar, Zhihui Lang, Robert E. Corringham, and Robert A. Beckman are or were Centocor employees at the time the study was conducted.
- Accepted January 25, 2007.
- Received November 27, 2006.
- Revision received January 15, 2007.
Volume 13, Issue 7
