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A phase I clinical trial of a ribozyme-based angiogenesis inhibitor targeting vascular endothelial growth factor receptor-1 for patients with refractory solid tumors.

AbstractPURPOSE:
This study intended to determine the maximum tolerated dose, safety, pharmacokinetic variables, clinical response, and pharmacodynamic markers of daily s.c. administration of Angiozyme.
PATIENTS AND METHODS:
Patients with refractory solid tumors were enrolled in a dose escalation and expanded cohort design. Dose escalation involved cohorts of patients at doses of 10, 30, 100, or 300 mg/m(2)/d for 29 days. A second component enrolled 15 additional patients at a daily dose of 100 mg/m(2). Patients were eligible to continue on therapy until disease progression.
RESULTS:
Thirty-one patients were enrolled and 28 were evaluable (range, 29-505 days; median, 89.5 days). A maximum tolerated dose was not defined by toxicity but rather by the maximal deliverable dose of 300 mg/m(2)/d. Grade 1 to 2 injection site reactions were the most common toxicities. One patient in the 300 mg/m(2) group experienced a reversible grade 3 injection site reaction. Angiozyme showed dose-dependent plasma concentrations with good bioavailability. Surrogate markers showed Angiozyme localization in tumor biopsies and a significant increase in serum von Willebrand factor antigen, a marker for endothelial cell dysfunction. Although Angiozyme-reactive antibody production was noted for some patients, no antibody-related adverse events were noted. Seven of 28 (25%) evaluable patients had stable disease for >or =6 months, with the longest treatment duration of > or =16 months. Two patients (nasopharyngeal carcinoma and melanoma) showed minor responses.
CONCLUSION:
Angiozyme was well tolerated with satisfactory pharmacokinetic variables for daily s.c. dosing. Results have provided the basis for subsequent clinical trials of this first-of-class biologically targeted therapeutic.
AuthorsDavid E Weng, Paul A Masci, Susan F Radka, T Elise Jackson, Patricia A Weiss, Ram Ganapathi, Paul J Elson, William B Capra, Vann P Parker, Jennifer A Lockridge, J Wayne Cowens, Nassim Usman, Ernest C Borden
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 4 Issue 6 Pg. 948-55 (Jun 2005) ISSN: 1535-7163 [Print] United States
PMID15956252 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Angiogenesis Inhibitors
  • RNA, Catalytic
  • von Willebrand Factor
  • Vascular Endothelial Growth Factor Receptor-1
Topics
  • Adult
  • Aged
  • Aged, 80 and over
  • Angiogenesis Inhibitors (adverse effects, pharmacokinetics, therapeutic use)
  • Female
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Neoplasms (blood supply, drug therapy, genetics, pathology)
  • RNA, Catalytic (adverse effects, genetics, pharmacokinetics, therapeutic use)
  • Treatment Outcome
  • Vascular Endothelial Growth Factor Receptor-1 (genetics, metabolism)
  • von Willebrand Factor (metabolism)

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