Vm. Macaulay et al., Phase I study of intrapleural batimastat (BB-94), a matrix metalloproteinase inhibitor, in the treatment of malignant pleural effusions, CLIN CANC R, 5(3), 1999, pp. 513-520
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 colorec
tal cancer, We recruited 18 patients with cytologically positive malignant
pleural effusions into a Phase I study of intrapleural BB-94, Three patient
s received single doses of BB-94 at each dose level: 15, 30, 60, 105, 135,
and 300 mg/m(2), Two patients were retreated with a second course at 60 and
105 mg/m(2). BB-94 was detectable in plasma 1 h after intrapleural adminis
tration, and peak levels of 20-200 ng/ml occurred after 4 h to 1 week. BB-9
4 persisted in the plasma for up to 12 weeks, at levels exceeding the IC(50
)s for target MMPs. Peak values were higher, and persistence in the plasma
was longer after higher doses of BB-9 1. 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%). T
oxicity seemed unrelated to BB-94 dose or plasma levels. Sixteen patients e
valuable for response required significantly fewer pleural aspirations in t
he 3 months after BB-94 compared with the 3 months before. Seven patients (
44%) required no further pleural aspiration until death/last follow-up, Aft
er 1 month, patients treated with 60-300 mg/m(2) BB-94 had significantly be
tter dyspnea scores, indicating improved exercise tolerance, compared with
baseline scores the day after BB-94, The maximum tolerated intrapleural dos
e remains to be defined, but it is clear that intrapleural BB-94 is well to
lerated, with evidence of local activity.