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

Purpose: 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 expand...

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Bibliographic Details
Published in:Molecular cancer therapeutics 2005-06, Vol.4 (6), p.948-955
Main Authors: Weng, David E, Masci, Paul A, Radka, Susan F, Jackson, T Elise, Weiss, Patricia A, Ganapathi, Ram, Elson, Paul J, Capra, William B, Parker, Vann P, Lockridge, Jennifer A, Cowens, J Wayne, Usman, Nassim, Borden, Ernest C
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
angiogenesis inhibitor
Angiogenesis Inhibitors - adverse effects
Angiogenesis Inhibitors - pharmacokinetics
Angiogenesis Inhibitors - therapeutic use
Female
Humans
Immunohistochemistry
Male
Middle Aged
Neoplasms - blood supply
Neoplasms - drug therapy
Neoplasms - genetics
Neoplasms - pathology
ribozyme
RNA, Catalytic - adverse effects
RNA, Catalytic - genetics
RNA, Catalytic - pharmacokinetics
RNA, Catalytic - therapeutic use
Treatment Outcome
Vascular Endothelial Growth Factor Receptor-1 - genetics
Vascular Endothelial Growth Factor Receptor-1 - metabolism
VEGFR-1
von Willebrand factor
von Willebrand Factor - metabolism
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Summary:Purpose: 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 ≥6 months, with the longest treatment duration of ≥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.
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.MCT-04-0210