Originally published as JCO Early Release 10.1200/JCO.2008.19.6683 on June 22 2009

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Safety, Pharmacokinetics, and Antitumor Activity of AMG 386, a Selective Angiopoietin Inhibitor, in Adult Patients With Advanced Solid Tumors

From The University of Texas M. D. Anderson Cancer Center, Houston, TX; and Premiere Oncology, Santa Monica; Landmark Imaging Medical Group, Los Angeles; and Amgen, Thousand Oaks, CA.

Corresponding author: Lee Rosen, MD, Premiere Oncology, California, 2020 Santa Monica Blvd, Suite 600, Santa Monica, CA 90404; e-mail: lrosen{at}premiereoncology.com.

Purpose AMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, Tie2. This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of AMG 386 in adults with advanced solid tumors.

Patients and Methods Patients in sequential cohorts received weekly intravenous AMG 386 doses of 0.3, 1, 3, 10, or 30 mg/kg.

Results Thirty-two patients were enrolled on the study and received AMG 386. One occurrence of dose-limiting toxicity was seen at 30 mg/kg: respiratory arrest, which likely was caused by tumor burden that was possibly related to AMG 386. The most common toxicities were fatigue and peripheral edema. Proteinuria (n = 11) was observed without clinical sequelae. Only four patients (12%) experienced treatment-related toxicities greater than grade 1. A maximum-tolerated dose was not reached. PK was dose-linear and the mean terminal-phase elimination half-life values ranged from 3.1 to 6.3 days. Serum AMG 386 levels appeared to reach steady-state after four weekly doses, and there was minimal accumulation. No anti–AMG 386 neutralizing antibodies were detected. Reductions in volume transfer constant (K^trans; measured by dynamic contrast-enhanced magnetic resonance imaging) were observed in 10 patients (13 lesions) 48 hours to 8 weeks after treatment. One patient with refractory ovarian cancer achieved a confirmed partial response (ie, 32.5% reduction by Response Evaluation Criteria in Solid Tumors) and withdrew from the study with a partial response after 156 weeks of treatment; four patients experienced stable disease for at least 16 weeks.

Conclusion Weekly AMG 386 appeared well tolerated, and its safety profile appeared distinct from that of vascular endothelial growth factor–axis inhibitors. AMG 386 also appeared to impact tumor vascularity and showed antitumor activity in this patient population.

Supported in part by Amgen.

Presented in part at the 43rd American Society of Clinical Oncology Annual Meeting, June 1-5, 2007, Chicago, IL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on JCO.org.

Clinical trial information can be found for the following: NCT00102830.

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