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

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-(17) 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 mu g/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 (PIGF) levels in patients with clinical benefit (P = 0.04) but not in patients without clinical benefit (P = 0.25). On day 5, PIGF 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 PIGF levels. The recommended phase 11 dose is 400 mu g/kg for this administration schedule. (Clin Cancer Res 2009;15(23):7398-404)