An NCIC-CTG phase I dose escalation pharmacokinetic study of the matrix metalloproteinase inhibitor BAY 12-9566 in combination with doxorubicin

Background: This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in combination with doxorubicin in patients with advanced solid tumours, and to identify the maximum tolerated dose of these agents in combination and the dose for use in subsequent studies. Patients and methods: 14 patients were entered onto 3 dose levels consisting of escalating doses of doxorubicin (50 mg/m2, 60 mg/m2 and 70 mg/m2) with 800 mg po bid BAY 12-9566. At all three dose levels, patients received doxorubicin alone in cycle one on day 1. Daily oral dosing with BAY 12-9566 was started on day 8 of cycle 1, and thus doxorubicin was given concurrently with BAY 12-9566 in cycle 2. Patients were continued on treatment until a dose limiting toxicity or tumour progression occurred. Results: Pharmacokinetic studies from cycles 1 and 2 from the patients treated in the first three dose levels demonstrated that the addition of BAY 12-9566 increased the AUC0-12h levels of doxorubicin by a median of 48%. No effects were seen on the BAY 12-9566 pharmacokinetic values. Two dose limiting toxicities were seen at the third dose level. One patient experienced grade 3 stomatitis in cycle 2, and another patient experienced grade 4 granulocytopenia in cycle 1 and grade 4 thrombocytopenia in cycle 2. Thus the maximum tolerated dose of 60 mg/m2 was declared. These toxicities were those that would have been expected from doxorubicin alone. Conclusions: BAY 12-9566 can be safely administered with full doses of doxorubicin without evidence of clinical interaction. The recommended dose of doxorubicin to be combined with BAY 12-9566 800 mg po b.i.d is 60 mg/m2, however, further development of BAY 12-9566 has been abandoned.