Phase I and pharmacokinetic study of angiotensin-(1-7), an endogenous antiangiogenic hormone

Abstract

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 microg/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 microg/kg for this administration schedule.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

If patented, E.A. Tallant and P.E. Gallagher have a potential financial interest in the use of the peptide for this project.

Figures

Fig. 1

The renin-angiotensin system in cancer and antiangiogenic mechanisms targeted by Ang-(1-7).

Fig. 2

Plasma concentrations of Ang-(1-7) (A) on day 1 and (B) day 5 after log transformation.

Fig. 3

Comparison of plasma levels of PlGF (A and B) and VEGF (C and D) in patients who experienced clinical benefit versus those who did not experience clinical benefit. Statistical analyses evaluated changes over time on day 1 and differences between groups on day 5.