A phase I dose escalation study of the matrix metalloproteinase inhibitor BAY 12-9566 administered orally in patients with advanced solid tumours

Background: This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced solid tumours, and to identify the maximum tolerated dose and dose for use in subsequent studies. Patients and methods: BAY 12-9566 was administered to 29 patients at doses ranging from 100 mg o.d. to 1600 mg (given either 400 mg q.i.d. or 800 mg b.i.d.). Blood samples for pharmacokinetic analyses were drawn on days 1–5, day 15 and days 29 and 30. Patients were continued on daily oral treatment of BAY 12-9566 until a dose limiting toxicity or tumour progression occurred. Results: A maximum tolerated dose was not defined because plasma levels of BAY 12-9566 could not be sufficiently increased, even with escalating doses of drug. Pharmacokinetic analysis suggested that absorption was saturable at higher doses. The predominant toxicities related to drug were asymptomatic reversible effects on platelets and transaminases and mild anemia. There were no significant musculoskeletal toxicities. No objective responses were seen at the doses tested, but stable disease was observed in some patients based on tumour measurements. Conclusions: The recommended dose of BAY 12-9566 for further studies is 800 mg b.i.d. as this dose provides maximal plasma levels that can be achieved with a convenient dosing schedule for a chronically administered oral agent