Phase I study of the matrix metalloproteinase inhibitor, BAY 12-9566.
BACKGROUND
Matrix metalloproteinases (MMPs) are involved in tumor invasion and metastasis and have been implicated in breast, ovarian, colorectal, and lung cancer growth. We undertook a phase I study of BAY 12-9566, an inhibitor of MMP-2, MMP-9, and MMP-3, in patients with solid tumors to determine its safety, pharmacokinetics, and effects on potential surrogate markers of biologic activity.


METHODS
BAY 12-9566 was orally administered daily at four dose levels; 400 mg daily, 400 mg b.i.d., 400 mg t.i.d., and 800 mg b.i.d. Drug disposition was determined on days 1 and 29 with weekly trough levels measured during the first four weeks. Plasma vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and urinary pyridinoline and deoxypyridinoline crosslinks were determined at baseline, once weekly for four weeks, and then every four weeks.


RESULTS
Thirteen patients were entered on trial. BAY 12-9566 was well tolerated, with only one grade 3 headache, one grade 3 anemia, one grade 3 thrombocytopenia, and no musculoskeletal effects. The median treatment duration was 57 days (range 7-560). Mean trough levels of BAY 12-9566 on day 28 ranged from 80.5 to 108.6 mg/l. Plasma trough levels were 1500-42,000-fold above the Ki's for MMP-2, MMP-3, and MMP-9 at the 800 mg p.o. b.i.d. dose level. There was no significant change in VEGF, bFGF, pyridinoline, and deoxypyridinoline crosslinks with BAY 12-9566 administration.


CONCLUSIONS
The recommended dose for further testing is 800 mg p.o. b.i.d.
Erlichman
C
C
Mayo Clinic Cancer Center, Rochester, Minnesota, USA. erlichman.charles@mayo.edu
Adjei
A A
AA
Alberts
S R
SR
Sloan
J A
JA
Goldberg
R M
RM
Pitot
H C
HC
Rubin
J
J
Atherton
P J
PJ
Klee
G G
GG
Humphrey
R
R
D000328:Adult; D000596:Amino Acids / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000097:blood; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D009930:Organic Chemicals; D010654:Phenylbutyrates; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000596:Amino Acids; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D008222:Lymphokines; D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; D010654:Phenylbutyrates; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; C015484:pyridinoline; C036020:deoxypyridinoline; C113281:Bay 12-9566; D020782:Matrix Metalloproteinases