A phase I study of DX 8951f (exatecan mesylate for injection) in patients with renal dysfunction

Abstract

2069 Background: Exatecan mesylate is a novel camptothecin analog. Neutropenia and thrombocytopenia are its dose limiting toxicities (DLTs). Although the drug appears to be predominately cleared by the liver, the impact of renal dysfunction on its pharmacokinetic profile is unknown. Methods: A dose escalation study was performed with patients (pts) treated in pre-defined cohorts of renal dysfunction determined by 24-hour measured urine creatinine clearance - CrCL (Table 1). Once a DLT was observed, pts were stratified by prior therapy (heavily pre-treated-HP versus minimally pre-treated- MP). Exatecan was given daily x 5 every 21 days. Results: 32 pts have been accrued to this study. The number of DLT events observed for each group are: Normal - 1/6 pts at 0.5 mg/m²; Mild −1/7 HP pts at 0.4 mg/m²; Moderate −1/3 HP pts and 0/3 MP pts at 0.4 mg/m²and 1/1 MP pt at 0.5 mg/m²; Severe −0/2 HP pts at 0.1 mg/m². The mean total CL of exatecan per body surface area (BSA) for each group is presented in Table 1 and reported based on three different measurements of renal function. Each method has distinct advantages and disadvantages. The calculated CrCL is most applicable to clinical practice, while the Technitium GFR method is the most precise way of estimating GFR. Preliminary PK results tend to suggest that the CL of exatecan is similar between moderately impaired and normal subjects when stratifying patients according to their calculated CrCL, while the technitium GFR method seems to indicate that the CL of exatecan is the same between mild, moderate and severely impaired patients. Conclusions: The preliminary PK data suggests that dosage adjustments may not be necesssary for patients with renal dysfunction. The clinical data supports this as patients with mild or moderate dysfunction tolerate at least 0.4 mg/m². Further recruitment to the moderate and severe dysfunction groups is ongoing to further explore these findings.