Phase I trial of the matrix metalloproteinase inhibitor BAY12-9566 in patients with advanced solid tumors

Citation
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
Citations number
10
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER CHEMOTHERAPY AND PHARMACOLOGY
ISSN journal
0344-5704 → ACNP
Volume
48
Issue
4
Year of publication
2001
Pages
269 - 274
Database
ISI
SICI code
0344-5704(200110)48:4<269:PITOTM>2.0.ZU;2-D
Abstract
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.