Phase I and pharmacologic study of the specific matrix metalloproteinase inhibitor BAY 12-9566 on a protracted oral daily dosing schedule in patients with solid malignancies.
OBJECTIVE
To evaluate the feasibility of administering BAY 12-9566, a matrix metalloproteinase (MMP) inhibitor with relative specificity against MMP-2, MMP-3, and MMP-9, on a protracted oral daily dosing schedule in patients with advanced solid malignancies. The study also sought to determine the principal toxicities of BAY 12-9566, whether plasma BAY 12-9566 steady state concentrations (C(ss)) of biologic relevance could be sustained for prolonged periods, and whether BAY 12-9566 affected plasma concentrations of MMP-2, MMP-9, and tissue inhibitor of MMP-2 (TIMP-2).


METHODS
Patients with solid malignancies were treated with BAY 12-9566 at daily oral doses ranging from 100 to 1,600 mg. BAY 12-9566 dose schedules included 100 mg once daily, 400 mg once daily, 400 mg twice daily, 400 mg three times daily, 400 mg four times daily, and 800 mg twice daily. Plasma was collected to study the range of BAY 12-9566 C(ss) values achieved, and exploratory studies were performed to assess the effects of BAY 12-9566 on plasma concentrations of MMP-2, MMP-9, and TIMP-2.


RESULTS
Twenty-one patients were treated with 47 28-day courses of BAY 12-9566. The most common side effects were headache, nausea, vomiting, abnormalities in hepatic functions, and thrombocytopenia, which were rarely clinically significant. BAY 12-9566 was well tolerated on all dose schedules, and there was no consistent dose-limiting toxicity that precluded treatment in the range of dose schedules evaluated. Instead, dose escalation was terminated because BAY 12-9566 plasma C(ss) values increased less than proportionately and plateaued as the daily dose was increased within the dose range of 100 to 1,600 mg/d, suggesting saturable drug absorption. Mean plasma C(ss) values achieved with all dose schedules exceeded BAY 12-9566 concentrations required to inhibit MMPs in vitro and in vascular invasion and tumor proliferation in vivo models. There were no consistent effects of BAY 12-9566 on the plasma concentrations of MMP-2 and MMP-9 over the continuous dosing period at any dose schedule level. However, plasma levels of TIMP-2 seemed to increase in a dose-dependent manner (r(2) =.50, P =.046).


CONCLUSIONS
The recommended dose of BAY 12-9566 for subsequent disease directed studies is 800 mg twice daily, which resulted in biologically relevant plasma C(ss) values and an acceptable toxicity profile. Although exploratory studies of MMPs in plasma were not revealing, it is conceivable that some tumor types and disease settings are more likely to produce more readily quantifiable levels of activated MMPs than others. Therefore, attempts to identify and quantify surrogate markers of MMP inhibitory effects should continue to be performed in disease-directed studies in more homogenous patient populations.
Rowinsky
E K
EK
Institute for Drug Development, University of Texas Health Science Center, Brooke Army Medical Center, San Antonia, USA. erowinskf@saci.org
Humphrey
R
R
Hammond
L A
LA
Aylesworth
C
C
Smetzer
L
L
Hidalgo
M
M
Morrow
M
M
Smith
L
L
Garner
A
A
Sorensen
J M
JM
Von Hoff
D D
DD
Eckhardt
S G
SG
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001713:Biphenyl Compounds; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000097:blood / Q000187:drug effects; D061965:Matrix Metalloproteinase Inhibitors; D020714:Maximum Tolerated Dose; D008666:Metalloendopeptidases / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009930:Organic Chemicals; D010654:Phenylbutyrates; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000097:blood / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; D010654:Phenylbutyrates; D019716:Tissue Inhibitor of Metalloproteinase-2; C113281:Bay 12-9566; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9