Phase I and Pharmacokinetic Study of Once-Daily Dosing of Intravenously Administered Busulfan in the Setting of a Reduced-Intensity Preparative Regimen and Allogeneic Hematopoietic Stem Cell Transplantation as Immunotherapy for Renal Cell Carcinoma

Abstract

We performed a Phase I and pharmacokinetic study of once-daily, intravenously administered busulfan in the setting of a reduced-intensity preparative regimen and matched sibling donor allogeneic stem cell transplantation for treatment of metastatic renal cell carcinoma. Seven male patients with metastatic renal cell carcinoma received intravenously administered busulfan at 3.2 mg/kg once daily on day -10 and day -9, fludarabine at 30 mg/m2 on day -7 through day -2, and equine antithymocyte globulin at 15 mg/kg per day on day -5 through day -2. The mean area under the plasma concentration-time curve (AUC) and the half-life of the first dose of intravenously administered busulfan were 6,253 microM x minute (range, 5,036-7,482 microM x minute) and 3.37 hours (range, 2.54-4.00 hours), respectively. The AUC was higher than predicted from extrapolation of AUC data for the same total dose of intravenously administered busulfan divided into four doses daily. Patients experienced greater than expected regimen-related toxicity for a reduced-intensity preparative regimen, and the study was stopped. In conclusion, this preparative regimen was associated with unacceptable regimen-related toxicity among patients with metastatic renal cell carcinoma.