Pharmacokinetic and biomarker analysis in a phase II trial of the HDAC inhibitor romidepsin, FK228
Authors: Richard Piekarz, Erin Gardner, Zhirong Zhan, Victoria Luchenko, Seth Steinberg, David Liewehr, Kenneth Steadman, Robin Frye, William Figg, Miles Prince, Steve Allen, Jasmine Zain, Mark Kirschbaum, Susan Bates
Journal: Cancer Research (2008)

5831  HDAC inhibitors, HDIs, are a new class of anticancer agents postulated to control tumor cell growth through effects on gene expression as well as alterations in acetylation of cytoplasmic proteins. Interest in the clinical development of the HDIs was spurred by the responses observed in patients with T-cell lymphoma to romidepsin, FK228, among others.  While these agents have been developed using classical pharmacological parameters, biomarkers of molecular activity using tumor or surrogate tissue could inform the search for a dose sufficient for biological activity, allowing lower doses, improved tolerability, and facilitating combination studies. We incorporated biomarker evaluations in our ongoing phase II trial of romidepsin for patients with cutaneous or peripheral T-cell lymphoma with the goal of identifying markers that could predict activity or resistance.  To date, 78 patients with CTCL have been accrued in 3 cohorts to our ongoing multi-institutional trial of romidepsin for patients with recurrent or refractory T-cell lymphoma. Romidepsin is administered as a 4 hr infusion on days 1, 8, and 15 of a 28 d cycle, starting at 14 mg/m2. Complete and partial responses have been observed in patients with CTCL, with a complete response in a patient with Sezary syndrome ongoing for over 62 months and a partial response ongoing for over 74 months in a patient with tumor stage disease.  Molecular endpoint analysis was performed in normal and malignant circulating peripheral mononuclear cells, PBMCs. We developed an immuno-dot blot assay to quantitate change of histone acetylation. Increased histone acetylation in PBMCs of 2-fold or greater from 13 of 18 patients at 4 hrs or 7 of 14 at 24 hrs was noted. Since MDR1 gene expression is known to be directly induced by these agents we evaluated the effect of treatment on the expression of MDR1. RT-PCR of RNA demonstrated a 2-fold or greater increased expression of MDR-1 in PBMCs from 9 of 21 patients at 4 hr, 6 of 18 at 24 hr and 3 of 11 at 48 hour.  Pharmacokinetic analysis has been completed for 35 patients. We were able to compare biomarker analysis and pharmacokinetic data using Spearman’s correlation coefficient. A moderate association was noted between induction of histone acetylation at 24 hr and Cmax, r=0.57 and p=0.031, in 14 patients, and AUC, r=0.61 and p=0.037, in 12 patients. Findings for clearance were comparable. A weak to moderate association was noted between the pharmacokinetic parameters and MDR1 expression. No association was noted with response.  HDAC inhibitors are agents with promising clinical activity. It is possible to use surrogate markers to assay biochemical activity; biomarkers correlate with pharmacokinetic parameters. Clinical development of these agents should include strategies to identify molecular markers of response.