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Petty, W.J. et al.

W. Jeffrey Petty, Antonius A. Miller, Thomas P. McCoy, Patricia E. Gallagher, E. Ann Tallant, Frank M. Torti,

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-(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.[1]

References

Phase I and pharmacokinetic study of angiotensin-(1-7), an endogenous antiangiogenic hormone. Petty, W.J., Miller, A.A., McCoy, T.P., Gallagher, P.E., Tallant, E.A., Torti, F.M. Clin. Cancer Res. (2009) [Pubmed]

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