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BB-3644 is an oral, broad-spectrum matrix metalloproteinase inhibitor (MMPI) structurally related to marimastat and BB-94. It is also >10-fold more active than marimastat in inhibiting the processing of cell-bound TNF-alpha. Preclinical studies suggested a favourable toxicity profile when compared to marimastat, and therefore it was selected for clinical evaluation. Patients with advanced solid tumours against which established treatments had failed, or for which no satisfactory treatment exists and of good performance status, were eligible. Treatment consisted of twice daily (bd) oral BB-3644 for 84 days. The initial dose was 5 mg bd, and subsequent cohorts were treated with 10, 20 and 30 mg bd. In all, 22 patients were enrolled. The dose-limiting toxicity (DLT) was musculoskeletal pain. For 28 days of treatment with BB-3644, 20 mg bd was the maximum tolerated dose (MTD), as at 30 mg bd, six of nine patients developed significant musculoskeletal toxicity by day 28. Following chronic oral dosing (>28 days) with BB-3644, three of five patients treated at 10 mg bd developed musculoskeletal IDLT by day 84, defining the MTD as 5 ring bd. As dose-limiting musculoskeletal toxicity was encountered at doses of BB-3644 unlikely to provide an advantage over currently available MMPIs, further evaluation is not recommended,

Original publication

DOI

10.1038/Sj.Bjc.6601594

Type

Journal article

Journal

British Journal of Cancer

Publication Date

2004

Volume

90

Pages

800 - 804

Keywords

bb-3644 matrix metalloprotease inhibitor phase i pharmacokinetics advanced pancreatic-cancer gastric-cancer double-blind lung-cancer marimastat trial therapy placebo