A dose-escalating and pharmacologic study of bortezomib in adult cancer patients with impaired renal function

Abstract

2032 Background: Bortezomib is a highly selective and reversible inhibitor of the proteasome with activity in multiple myeloma and other malignancies. Patients (pts) with renal impairment have been treated in previous trials, but there has not been a systematic investigation into the effects of renal dysfunction on dosing. Study objectives were to characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profile of bortezomib, and to determine the maximum tolerated dose (MTD) in adults with advanced malignancy and renal insufficiency ranging in severity from mild to dialysis dependence. Methods: Fifty-one pts have received intravenous bortezomib at 0.7 mg/m2 up to the approved dose of 1.3 mg/m2 on days 1,4, 8, and 11 every 3 weeks. Pts were stratified by 24-hour creatinine clearance (CrCL) normalized to a body surface area of 1.73 m2 into five cohorts per the table . Doses were escalated in cohorts of three pts in groups B-E. Blood samples were assayed for bortezomib concentration, as well as the PD endpoint of 20S inhibition. Results: Escalation of bortezomib doses to 1.3 mg/m2 was well tolerated in all groups with CrCL ≥ 20 mL/min/1.73 m2. There has been only one instance of dose limiting toxicity (group C at 1.3 mg/m2) which did not prevent successful completion of this cohort. No patients discontinued therapy due to renal deterioration. Doses of 0.7 mg/m2 were tolerable in Group D patients (CrCL< 20 mL/min/1.73 m2 ). Five dialysis pts have been treated; 3 at 0.7 mg/m2, and 2 at 1.0 mg/m2. All tolerated therapy well, and accrual to Groups D and E continues. PK and PD assays are underway and the analysis will be reported in full. Conclusions: This study is the first comprehensive evaluation of bortezomib in pts with various degrees of renal insufficiency including dialysis dependence. Bortezemib at the approved dose of 1.3 mg/m2 on this schedule is well tolerated by pts with CrCL ≥ 20 mL/min/1.73 m2. Results of this trial will allow for dosing recommendations for bortezomib use in pts with renal insufficiency. [Table: see text] [Table: see text]