Phase I Evaluation of a Fully Human Anti–αv Integrin Monoclonal Antibody (CNTO 95) in Patients with Advanced Solid Tumors

Abstract

in association with the Biotherapy Development Association Abstract Purpose: A fully human monoclonal antibody to anti^a v 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 [18 F]-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 a v 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 halflife 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.

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

“…The dose-dependent decreases in the clearance parameter reflected saturation of the antigen sink at the highest dose, i.e., 10 mg/kg. Interestingly, a partial prolonged response was observed in one patient with angiosarcoma, a tumor of malignant endothelial cells, after multiple-dose administration of the 10 mg/kg dose where the antigen sink was saturated (76). Similarly, nonlinear PK properties have been observed (76)).…”

“…Many of the antibodies in development or currently marketed recognize membraneassociated antigens (28,32,37,(71)(72)(73)(74)(75)(76)(77)(78)(79)(80). Interaction of antibodies with this class of target antigen can greatly impact their PK.…”

“…CNTO95 is a fully human monoclonal antibody against α v integrins that inhibits angiogenesis and tumor growth (76). The α v integrins are expressed on the surface of most epithelial tumors modulating cell proliferation and survival.…”

Cilengitide: An RGD Pentapeptide ανβ3 and ανβ5 Integrin Inhibitor in Development for Glioblastoma and Other Malignancies

“…Of note, phase I studies in advanced solid tumor patients with each of these MAbs confirmed their overall safety and lack of "class-associated" toxicities; in fact, a maximal tolerated dose (MTD) could not be identified in any of these dose-escalation trials. In addition, evidence of anti-tumor activity was observed despite the dose escalation study design [76][77][78].…”

Integrin αvβ3‐targeted cancer therapy

“…Other α v integrins, such as α v β 5 , can also mediate tumor angiogenesis, and there is evidence that α v β 3 and α v β 5 promote angiogenesis via distinct pathways: α v β 3 through bFGF and TNF-α, and α v β 5 through VEGF and TGF-α [Friedlander et al, 1995]. Therefore, the combination of two or more angiogenic pathway inhibitors may be more effective than any single blocking agents alone for anti-angiogenic cancer therapy [Mullamitha et al, 2007].…”