OBJECTIVES: The aim of this study was to define the toxicity, maximum feasible dose (MFD), and pharmacokinetics (PK) of A6, a peptide derived from human urokinase plasminogen activator (uPA), in patients with advanced gynecologic cancers, and to explore anti-tumor activity and the effects of A6 on biomarkers of the urokinase system. METHODS: A6 was administered subcutaneously daily, and doses were escalated in cohorts of three to six subjects. Serial blood specimens were obtained for pharmacokinetics and levels of urokinase plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1). RESULTS: Sixteen patients were enrolled and eligible for evaluation. No serious drug-related adverse events or dose-limiting toxicity occurred. A6-related toxicities were limited to grades 1 and 2 adverse effects including local injection site reactions. Five patients had stable tumor measurements for at least 4 cycles, one of whom stayed on study for 12 months. One patient had a confirmed cancer antigen (CA)-125 response (decrease in CA-125 of >50%) with stable disease on CT scan after 14 cycles and continues on study. Time to peak plasma level of A6 was 1-2 h. C(max) is proportional to dose. The half-life of A6 was approximately 2 h. Baseline biomarker levels did not predict response and trends over time did not correlate with outcome. CONCLUSIONS: A6 given daily continuously is well tolerated at all dose levels, without any dose-limiting toxicity. Based on the preliminary activity of A6, a phase II trial is underway in ovarian cancer.
OBJECTIVES: The aim of this study was to define the toxicity, maximum feasible dose (MFD), and pharmacokinetics (PK) of A6, a peptide derived from humanurokinase plasminogen activator (uPA), in patients with advanced gynecologic cancers, and to explore anti-tumor activity and the effects of A6 on biomarkers of the urokinase system. METHODS: A6 was administered subcutaneously daily, and doses were escalated in cohorts of three to six subjects. Serial blood specimens were obtained for pharmacokinetics and levels of urokinase plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1). RESULTS: Sixteen patients were enrolled and eligible for evaluation. No serious drug-related adverse events or dose-limiting toxicity occurred. A6-related toxicities were limited to grades 1 and 2 adverse effects including local injection site reactions. Five patients had stable tumor measurements for at least 4 cycles, one of whom stayed on study for 12 months. One patient had a confirmed cancer antigen (CA)-125 response (decrease in CA-125 of >50%) with stable disease on CT scan after 14 cycles and continues on study. Time to peak plasma level of A6 was 1-2 h. C(max) is proportional to dose. The half-life of A6 was approximately 2 h. Baseline biomarker levels did not predict response and trends over time did not correlate with outcome. CONCLUSIONS: A6 given daily continuously is well tolerated at all dose levels, without any dose-limiting toxicity. Based on the preliminary activity of A6, a phase II trial is underway in ovarian cancer.
Authors: Michael A Gold; William E Brady; Heather A Lankes; Peter G Rose; Joseph L Kelley; Koen De Geest; Marta A Crispens; Kimberly E Resnick; Stephen B Howell Journal: Gynecol Oncol Date: 2012-03-22 Impact factor: 5.482
Authors: Timmy Mani; Fang Wang; William Eric Knabe; Anthony L Sinn; May Khanna; Inha Jo; George E Sandusky; George W Sledge; David R Jones; Rajesh Khanna; Karen E Pollok; Samy O Meroueh Journal: Bioorg Med Chem Date: 2013-01-09 Impact factor: 3.641
Authors: Songdong Meng; Debu Tripathy; Sanjay Shete; Raheela Ashfaq; Hossein Saboorian; Barbara Haley; Eugene Frenkel; David Euhus; Marilyn Leitch; Cynthia Osborne; Edward Clifford; Steve Perkins; Peter Beitsch; Amanullah Khan; Larry Morrison; Dorothee Herlyn; Leon W M M Terstappen; Nancy Lane; Jianqiang Wang; Jonathan Uhr Journal: Proc Natl Acad Sci U S A Date: 2006-11-01 Impact factor: 11.205
Authors: James F Curtin; Marianela Candolfi; Weidong Xiong; Pedro R Lowenstein; Maria G Castro Journal: Mol Cancer Ther Date: 2008-03 Impact factor: 6.261