bay-12-9566 and Thrombocytopenia

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade the extracellular matrix during the processes of invasion, metastasis and angiogenesis. BAY 12-9566 (BAY) is a selective, non-peptidic biphenyl inhibitor of MMPs, with nanomolar inhibitory activity against MMP-2, -3 and -9, and anti-invasive, anti-metastatic and anti-angiogenic activity in a variety of tumor models. This phase I study of oral BAY was conducted to evaluate the safety and pharmacokinetics of BAY when administered in combination with etoposide (VP-16) or in combination with VP-16 and carboplatin (CBDCA) in subjects with advanced cancer. The first cohort of patients (n=8) received a cycle of VP-16, 60 mg/m, followed 1 week later by a fixed daily oral dose of BAY, 800 mg b.i.d., to which three potential possible doses of VP-16 (low dose: 60 mg/m; mid dose: 90 mg/m; high dose: 120 mg/m) were added every 3 weeks as tolerated. The second cohort (n=5) received VP-16 (120 mg/m) and CBDCA (AUC=5) followed 1 week later by a fixed daily oral dose of BAY (800 mg) b.i.d., to which VP-16 (120 mg/m) and CBDCA (AUC=5) were added. Dose-limiting toxicity (DLT) was defined as toxicity grade 3 or above. Maximum tolerated dose was declared if two or more patients experienced DLT. A performance status of 0-2 and acceptable organ function were required for eligibility. Plasma concentrations of BAY and VP-16 were measured to investigate pharmacokinetic interactions. Eight eligible patients with a variety of tumor types (median age 64 years, range 44-76) were enrolled in the first cohort, six of who whom completed all three levels of VP-16. Progressive disease occurred in five of the eight patients; three patients continued on study with treatment. Drug level and pharmacokinetics analysis of BAY and VP-16 were also determined. The combination of BAY and VP-16 was tolerable in the first cohort, permitting enrollment of the second cohort. In the second cohort (n=5), the combination of BAY, VP-16 and CDBCA was intolerable at the doses used due to excessive hematologic toxicity in the first five patients enrolled. Pharmacokinetics and toxicity analysis was performed for this group of patients. Only Level 1 of treatment was completed for Cohort II. At this point the study was halted due to toxicity and the results of an interim analysis that failed to demonstrate sufficient clinical activity of this compound in other clinical trials. We conclude that the combination of BAY and VP-16 was well

Topics: Adult; Aged; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Biphenyl Compounds; Carboplatin; Cohort Studies; Colonic Neoplasms; Enzyme Inhibitors; Etoposide; Female; Humans; Male; Matrix Metalloproteinase Inhibitors; Melanoma; Middle Aged; Neoplasms; Neoplasms, Unknown Primary; Neutropenia; Organic Chemicals; Phenylbutyrates; Thrombocytopenia; Thymoma; Treatment Outcome; Vomiting

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes 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 selective inhibitor of MMPs, in particular MMP-2, -3. and -9. The purpose of this trial was to define the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, pharmacokinetics and pharmacodynamics of orally administered BAY12-9566 in patients with incurable solid tumors.. The starting dose of BAY12-9566 for this single institution, outpatient phase 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 including colorectal, breast, lung, cervical and ovarian cancers were enrolled at doses from 100 to 1,600 mg/day. Patients were evaluated weekly while on treatment. Relevant radiologic examination was performed every 8 weeks to document and follow sites of measurable or evaluable disease.. Toxicities from BAY12-9566 included liver injury test abnormalities, anemia, shoulder and back pain. thrombocytopenia, mild nausea and fatigue, diarrhea, rash and deep vein thrombosis. No toxicity greater than grade III was observed. As doses were increased from 100 to 400 to 1,600 mg/day, even in divided doses, less than proportional increases in AUC were observed. At the highest dose level of 1600 mg/day, the day 29 AUC (3778.00 mg x h/l) remained similar to the day 29 AUC (3312.60 mg x h/l) at the dose level of 1200 mg/day. No responses were seen, but 14 patients remained on study with stable disease for 4 to 26 months.. BAY12-9566 was well tolerated at doses as high as 800 mg orally twice daily. Although mild alterations in liver injury tests, platelet count and hematocrit were noted, these were not dose-limiting. The drug was well absorbed. However, the absence of proportional increases in AUC with doses greater than 800 mg and the achievement of Css 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.

Topics: Administration, Oral; Adult; Aged; Anemia; Antineoplastic Agents; Area Under Curve; Biphenyl Compounds; Dose-Response Relationship, Drug; Humans; Liver; Middle Aged; Neoplasms; Organic Chemicals; Phenylbutyrates; Thrombocytopenia