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


METHODS
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.
Petty
W Jeffrey
WJ
Department of Medicine, Section on Hematology and Oncology, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, USA. wpetty@wfubmc.edu
Miller
Antonius A
AA
McCoy
Thomas P
TP
Gallagher
Patricia E
PE
Tallant
E Ann
EA
Torti
Frank M
FM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000803:Angiotensin I / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy*; D010446:Peptide Fragments / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010455:Peptides / Q000737:chemistry
D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D010446:Peptide Fragments; D010455:Peptides; D000803:Angiotensin I; C118790:angiotensin I (1-7)