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Phase I Study of Intrapleural Batimastat (BB-94), a Matrix Metalloproteinase Inhibitor, in the Treatment of Malignant Pleural Effusions¹

Imperial Cancer Research Fund, Medical Oncology Unit [V. M. M., K. J. O., M. P. S., J. P. B., L. L., A. L. H., D. C. T.] and Department of Radiology [F. G.], Churchill Hospital, Oxford, OX3 7LJ, and British Biotech Pharmaceuticals Ltd., Oxford, OX4 5LY [C. S. M., P. B.], United Kingdom

Tumor cells and associated stromal cells secrete matrix metalloproteinases (MMPs), contributing to invasion, angiogenesis, and metastasis. Batimastat (BB-94) is a broad-spectrum MMP inhibitor that causes resolution of ascites and/or tumor growth delay in animal models of breast, ovarian, and colorectal cancer. We recruited 18 patients with cytologically positive malignant pleural effusions into a Phase I study of intrapleural BB-94. Three patients received single doses of BB-94 at each dose level: 15, 30, 60, 105, 135, and 300 mg/m². Two patients were retreated with a second course at 60 and 105 mg/m². BB-94 was detectable in plasma 1 h after intrapleural administration, and peak levels of 20–200 ng/ml occurred after 4 h to 1 week. BB-94 persisted in the plasma for up to 12 weeks, at levels exceeding the IC₅₀s for target MMPs. Peak values were higher, and persistence in the plasma was longer after higher doses of BB-94. The treatment was well tolerated. Toxic effects included low-grade fever for 24–48 h (6 of 18 patients, 33%) and reversible asymptomatic elevation of liver enzymes (8 patients, 44%). Toxicity seemed unrelated to BB-94 dose or plasma levels. Sixteen patients evaluable for response required significantly fewer pleural aspirations in the 3 months after BB-94 compared with the 3 months before. Seven patients (44%) required no further pleural aspiration until death/last follow-up. After 1 month, patients treated with 60–300 mg/m² BB-94 had significantly better dyspnea scores, indicating improved exercise tolerance, compared with baseline scores the day after BB-94. The maximum tolerated intrapleural dose remains to be defined, but it is clear that intrapleural BB-94 is well tolerated, with evidence of local activity.

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