Phase I and Pharmacokinetic Study of Angiotensin-(1-7), an Endogenous Antiangiogenic Hormone

• Published in: Clinical cancer research 2009-12, Vol.15 (23), p.7398-7404
• Main Authors: JEFFREY PETTY, W, MILLER, Antonius A, MCCOY, Thomas P, GALLAGHER, Patricia E, TALLANT, E. Ann, TORTI, Frank M
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors - pharmacokinetics; Angiogenesis Inhibitors - therapeutic use; angiotensin; Angiotensin I - pharmacokinetics; Angiotensin I - therapeutic use; Antineoplastic agents; Biological and medical sciences; Biomarkers, Tumor - metabolism; cancer; Cohort Studies; Dose-Response Relationship, Drug; Female; Humans; Male; Medical sciences; Middle Aged; Models, Biological; Neoplasms - blood; Neoplasms - drug therapy; Peptide Fragments - pharmacokinetics; Peptide Fragments - therapeutic use; Peptides - chemistry; Pharmacology. Drug treatments; placental growth factor; vascular endothelial growth factor
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-09-1957

Purpose: Angiotensin-(1-7) [Ang-(1-7)] is an endogenous peptide hormone of the renin-angiotensin system with antiproliferative and antiangiogenic properties. The primary objective of this study was to establish the recommended phase II dose of Ang-(1-7) for treating patients with advanced cancer. Secondary objectives were to assess toxicities, pharmacokinetics, clinical activity, and plasma biomarkers. Experimental Design: Patients with advanced solid tumors refractory to standard therapy were treated with escalating doses of Ang-(1-7) in cohorts of three patients. Ang-(1-7) was administered by s.c. injection once daily for 5 days on a 3-week cycle. Tumor measurements were done every two cycles and treatment was continued until disease progression or unacceptable toxicity. Results: Eighteen patients were enrolled. Dose-limiting toxicities encountered at the 700 μg/kg dose included stroke (grade 4) and reversible cranial neuropathy (grade 3). Other toxicities were generally mild. One patient developed a 19% reduction in tumor measurements. Three additional patients showed clinical benefit with stabilization of disease lasting more than 3 months. On day 1, Ang-(1-7) administration led to a decrease in plasma placental growth factor (PlGF) levels in patients with clinical benefit ( P = 0.04) but not in patients without clinical benefit ( P = 0.25). On day 5, PlGF levels remained lower in patients with clinical benefit compared with patients without clinical benefit ( P = 0.04). Conclusions: Ang-(1-7) is a first-in-class antiangiogenic drug with activity for treating cancer that is linked to reduction of plasma PlGF levels. The recommended phase II dose is 400 μg/kg for this administration schedule. (Clin Cancer Res 2009;15(23):7398–404)