Ei. Heath et al., Phase I trial of the matrix metalloproteinase inhibitor BAY12-9566 in patients with advanced solid tumors, CANC CHEMOT, 48(4), 2001, pp. 269-274
Purpose: Matrix metalloproteinases (MMPs) are a family of proteolytic enzym
es that are believed to be involved in primary and metastatic tumor growth
by degrading the basement membrane and changing the extracellular matrix to
facilitate invasion of malignant cells and angiogenesis. Overexpression of
MMPs has been documented in various solid tumors. BAY12-9566 is a selectiv
e inhibitor of MMPs, in particular MMP-2. -3. and -9. The purpose of this t
rial was to define the maximum tolerated dose (MTD), dose-limiting toxiciti
es (DLT), safety profile, pharmacokine tics and pharmacodynamics of orally
administered BAY12-9566 in patients with incurable solid tumors. Methods: T
he starting dose of BAY12-9566 for this single institution, outpatient phas
e I study was 100 mg/day orally. Patients were allowed to receive drug for
up to 12 months. A total of 27 patients with various solid malignancies inc
luding colorectal, breast, lung, cervical and ovarian cancers were enrolled
at doses from 100 to 1600 mg/day. Patients were evaluated weekly while on
treatment. Relevant radiologic examination was performed every 8 weeks to d
ocument and follow sites of measurable or evaluable disease. Results: Toxic
ities from BAY12-9566 included liver injury test abnormalities, anemia, sho
ulder and back pain, thrombocytopenia, mild nausea and fatigue, diarrhea, r
ash and deep vein thrombosis. No toxicity greater than grade III was observ
ed. As doses were increased from 100 to 400 to 1600 mg/day, even in divided
doses, less than proportional increases in AUC were observed. At the highe
st dose level of 1600 mg/day, the day 29 AUC (3778.00 mg(.)h/1) remained si
milar to the day 29 AUC (3312.60 mg(.)h/1) at the dose level of 1200 mg/day
. No responses were seen, but 14 patients remained on study with stable dis
ease for 4 to 26 months. Conclusions: BAY 12-9566 was well tolerated at dos
es as high as 800 mg orally twice daily. Although mild alterations in liver
injury tests., platelet count and hematocrit were noted, these were not do
se-limiting. The drug was well absorbed. However, the absence of proportion
al increases in AUC with doses greater than 800 mg and the achievement of C
ss in the range associated with biologic activity in preclinical models led
to the selection of 800 mg twice daily for further evaluation in phase III
trials.