Abstract 3778: Pharmacokinetic, safety and efficacy of high dose simvastatin in refractory and relapsed chronic lymphocytic leukemia (CLL) patients

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Statins are established as safe and effective anti-hypercholesterolemia drugs. Preclinical evidence shows that statins exhibit antitumor activity against different tumors by reducing prenylation of small GTPase molecules, which play a critical role in intracellular cancer cell signaling. However, these effects have only been noted at higher concentrations, which cannot be achieved with the typical dosing. In a Phase I trial, simvastatin was well tolerated by patients with relapsed or refractory myeloma or lymphomas at amaximum tolerated dose (MTD) of 7.5mg/kg twice daily. However, the pharmacokinetic (PK) was not defined and it is unknown if simvastatin plasma concentrations can reach the levels necessary for the antitumor activity observed in vitro. Here we evaluated the PK, safety and efficacy of high dose simvastatin in the context of a pilot trial enrolling patients with recurrent and refractory CLL. Methods: Patients received simvastatin orally at 7.5mg/kg twice a day for 7 days during a 21 day cycle for 6 cycles. During study treatment, patients underwent weekly or bi-weekly evaluations that included physical examination, complete blood counts and comprehensive chemistry profiles. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (version 3.0). The NCI CLL revised guidelines for diagnosis and treatment were utilized to determine the level of clinical response. Blood samples were collected during cycle 1 at predose, 15 min and 1,2,3,6,8, and 12 hr and at predose on day-7. Simvastatin lactone and acid concentrations were measured in plasma and peripheral blood mononuclear cells (PBMCs) using a validated HPLC-MS/MS assay. Biochemical assays assessing the apoptotic effects of simvastatin were also performed in CLL cell samples (the predose and day-7) obtained from the treated patients. Results: Patients were accrued in this pilot trial. High dose simvastatin was well tolerated and there were no signs of serious adverse effects. Simvastatin exposure was dose proportional (AUC and Cmax) as compared to the doses used to treat hyperlipidemia. Exposure was lower than that required for in vitro cytotoxicity against immortalized cells. Simvastatin exposure in both plasma and PBMCs was variable with an AUC12hr (%CV) of 800.6 hr*ng/ml (88.6%) and 11.03 hr*ng/mg (119.4%), respectively. Following 7 days exposure to high dose simvastatin, CLL cells had increased the expression of cleaved PARP, an apoptotic marker. Conclusion: Preliminary results show that high dose simvastatin is well tolerated with no signs of serious side effects. Although plasma concentrations were lower than that required for in-vitro cytotoxicity, the simvastatin concentrations achieved in the clinic induced apoptosis in patient CLL cells. Further studies in CLL patients are warranted to demonstrate its efficacy alone or in combination therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3778. doi:1538-7445.AM2012-3778