A phase I pharmacokinetic and pharmacodynamic study of s-3304, a novel matrix metalloproteinase inhibitor, in patients with advanced and refractory solid tumors.
OBJECTIVE
Matrix metalloproteinases (MMP) play a fundamental role in cancer development and progression. S-3304 is a potent, orally active, noncytotoxic inhibitor of MMPs, primarily MMP-2 and MMP-9, that prolongs survival in mice xenografts and is well tolerated in healthy volunteers.


METHODS
The aims of this phase I clinical trial were to determine the maximum tolerated dose, dose-limiting toxicities, pharmacokinetic profile, and intratumoral MMP inhibitory activity of single-agent S-3304 in advanced and refractory solid tumors. MMP activity was determined by film in situ zymography (FIZ). Patients had tumor biopsies before and after S-3304 administration and were also evaluated for response and survival.


RESULTS
Four dose levels were explored [DL1-DL4 or 800, 1,600, 2,400, and 3200 mg twice daily (BID), respectively], and 32 patients were enrolled. Toxicities were mostly gastrointestinal. The maximum tolerated dose was not reached, but dose escalations beyond DL4 were impractical (number of capsules needed). S-3304 steady-state concentrations were reached by day 8, and day 1 mean C(max) and AUC(0-8) increases were less than dose proportional. After S-3304 administration, 17 of 18 patients experienced inhibition of MMP activity by FIZ. Strong mean inhibition of MMP activity was observed in DL1 to DL3. The negative mean inhibitory activity calculated for DL4 was due to one patient with a 397% MMP activity increase.


CONCLUSIONS
S-3304 is safe, well tolerated, and achieves plasma concentrations above those required to inhibit MMP-2 and MMP-9. Its intratumoral MMP inhibitory activity has been shown using FIZ, which is useful as a biomarker with this and other MMP inhibitors.
Chiappori
Alberto A
AA
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Eckhardt
S Gail
SG
Bukowski
Ronald
R
Sullivan
Daniel M
DM
Ikeda
Minoru
M
Yano
Yoshitaka
Y
Yamada-Sawada
Takuko
T
Kambayashi
Yoshikaze
Y
Tanaka
Kazushige
K
Javle
Milind M
MM
Mekhail
Tarek
T
O'bryant
Cindy L
CL
Creaven
Patrick J
PJ
D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000009:adverse effects* / Q000493:pharmacokinetics*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects*; D061965:Matrix Metalloproteinase Inhibitors; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D013876:Thiophenes / Q000009:adverse effects* / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D007211:Indoles; D061965:Matrix Metalloproteinase Inhibitors; C503948:S 3304; D013876:Thiophenes; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9