Phase I and Pharmacokinetic Study of Prinomastat, a Matrix Metalloprotease Inhibitor
Purpose: Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these MMPs has been postulated to block tumor invasion and metastasis. This Phase I, dose-escalation study was designed to evaluate the acute and chronic toxicities of variou...
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Published in | Clinical cancer research Vol. 10; no. 3; pp. 909 - 915 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Philadelphia, PA
American Association for Cancer Research
01.02.2004
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Subjects | |
Online Access | Get full text |
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Summary: | Purpose: Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these
MMPs has been postulated to block tumor invasion and metastasis. This Phase I, dose-escalation study was designed to evaluate
the acute and chronic toxicities of various doses of prinomastat and to determine prinomastat pharmacokinetics.
Experimental Design: Seventy-five patients with advanced cancer were given 1, 2, 5, 10, 25, 50, or 100 mg prinomastat orally twice daily until
tumor progression or development of significant toxicities. Prinomastat pharmacokinetics were measured on day 29 of therapy.
Results: The primary toxicities identified were joint and muscle-related pain, which were generally reversible with treatment rest
and/or dose reduction. No dose-limiting toxicities were noted within the first 4 weeks of treatment, but grade 2–3 arthralgias
and myalgias were noted 2–3 months after initiation of therapy in >25% of patients at doses >25 mg twice a day. The frequency
and severity of symptoms were dose related. Plasma prinomastat concentrations greater than the K i for MMPs 2 and 9 were achieved at all of the dose levels.
Conclusions: Doses of 5–10 mg bid were recommended for additional trials, because this dose range was well tolerated for a treatment duration
of at least 3 months and achieves trough plasma concentrations 10–100-fold greater than the K i ( in vitro inhibition constant) for the targeted MMPs (2 and 9). |
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ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-0981-3 |