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¹ Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio; ² Sirna Therapeutics, Inc., Boulder, Colorado; and ³ Chiron Corp., Emeryville, California

Requests for reprints: David E. Weng, Taussig Cancer Center, Cleveland Clinic Foundation, Desk R-35, 9500 Euclid Avenue, Cleveland, OH 44195. Phone: 216-444-8375; Fax: 216-444-9464. E-mail: wengd{at}ccf.org

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/m²/d for 29 days. A second component enrolled 15 additional patients at a daily dose of 100 mg/m². 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/m²/d. Grade 1 to 2 injection site reactions were the most common toxicities. One patient in the 300 mg/m² 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.

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Received 8/17/04; revised 3/ 1/05; accepted 4/13/05.

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