A6, a urokinase plasminogen activator (uPA)-derived peptide in patients with advanced gynecologic cancer: a phase I trial

Gynecol Oncol. 2005 Oct;99(1):50-7. doi: 10.1016/j.ygyno.2005.05.023.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I

MeSH terms

  • Aged
  • Amino Acid Sequence
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / pharmacokinetics
  • Biomarkers, Tumor / blood
  • Dose-Response Relationship, Drug
  • Female
  • Genital Neoplasms, Female / blood
  • Genital Neoplasms, Female / drug therapy*
  • Genital Neoplasms, Female / metabolism
  • Humans
  • Injections, Subcutaneous
  • Middle Aged
  • Molecular Sequence Data
  • Peptide Fragments / administration & dosage*
  • Peptide Fragments / adverse effects*
  • Peptide Fragments / pharmacokinetics
  • Urokinase-Type Plasminogen Activator / administration & dosage*
  • Urokinase-Type Plasminogen Activator / adverse effects*
  • Urokinase-Type Plasminogen Activator / antagonists & inhibitors
  • Urokinase-Type Plasminogen Activator / blood
  • Urokinase-Type Plasminogen Activator / pharmacokinetics


  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Peptide Fragments
  • Urokinase-Type Plasminogen Activator
  • acetyl-lysyl-prolyl-seryl-seryl-prolyl-prolyl-glutamyl-glutamic acid amide