UCN-01 potently inhibits protein kinase C, phosphatidylinositide-dependent kinase-1, and checkpoint kinase 1, which are involved in regulating cell cycle progression. We designed a phase I study to determine the maximum tolerated dose (MTD) of UCN-01 with prednisone in patients with advanced malignancies.UCN-01 was administered as a continuous intravenous infusion over 72 h in cycle 1 and 36 h in subsequent cycles. Prednisone was given orally at 60 mg/m(2) per day for five consecutive days within each 28-day cycle. Standard dose escalation was employed, and MTD was defined as the dose at which no more than one of six patients experienced a dose-limiting toxicity (DLT). Plasma pharmacokinetics of UCN-01 were assessed.Fifteen patients received a total of 55 courses of treatment. The MTD and the recommended phase II dose of UCN-01 in this combination is 72 mg/m(2) total dose over 72 h for cycle 1 followed by 36 mg/m(2) per cycle over 36 h. All patients experienced hyperglycemia but responded to insulin treatment. Hypophosphatemia was a DLT in two patients. There were no cumulative toxicities. No objective responses were observed, but five patients had stable disease, including two patients with lymphoid malignancies who had prolonged disease stabilizations. UCN-01 has a long terminal half-life and low clearance; there was wide inter-patient variability in peak concentrations.UCN-01 can be safely administered in combination with prednisone without unacceptable toxicity. The prolonged stable disease in two patients with lymphoid malignancies is a proof of principle for the evaluation of cyclin-dependent kinase inhibitors in oncology.

作者：Shivaani, Kummar；Martin E, Gutierrez；Erin R, Gardner；William D, Figg；Giovanni, Melillo；Janet, Dancey；Edward A, Sausville；Barbara A, Conley；Anthony J, Murgo；James H, Doroshow

来源：Cancer chemotherapy and pharmacology 2010 年 65卷 2期