Inhibitors of DACs have shown great promise preclinically, but it is increasingly apparent that the activity of these agents is diverse and differs by cell type. While the DAC inhibitors vorinostat and romidepsin are approved for cutaneous T-cell lymphoma, the anti-neoplastic effects of DAC inhibitors are yet to be fully understood and exploited for B-cell malignancies. To understand the efficacy and mechanism of DAC inhibitors in relapsed hematologic malignancies, a prospective study of a truly potent class I/II DAC inhibitor is needed in which detailed correlative experiments can connect the cellular and anti-neoplastic effects. AR-42 is a class I/II DAC inhibitor designed by investigators at OSU to provide optimal DAC inhibitory activity. The phase I is accruing with detectable serum levels and unconfirmed responses have been observed in myeloma patients as a single agent without the fatigue and nausea characteristic of other class I/II DAC inhibitors. The overall objective of this application is to conduct a first-in-man phase I clinical trial of AR-42 in patients with relapsed lymphoma, myeloma, and CLL to document safety, obtain a response signal, and generate mechanistic data to confirm and extend in vitro observations. The central hypothesis of the application is that potent, broad deacetylase inhibition with AR-42 in relapsed hematologic malignancies will be safe and tolerable, with pharmacokinetic data that will optimize dose administration and correlative studies that will justify future combination strategies in phase Ib studies. We will test our central hypothesis by pursuing the following aims: 1) To perform a first-in-man study of AR-42 in relapsed lymphoma, chronic lymphocytic leukemia (CLL), and multiple myeloma patients in which patients will receive orally administered AR-42 Mon/Wed/Fri in cycles of 28 days (three weeks on, one week off) to determine dose limiting toxicity (DLT), maximum tolerated dose (MTD), and toxicity profile of AR-42;2a) To examine circulating CLL cells from patients before and after treatment with AR-42 to characterize global histone status by liquid chromatography/mass spectroscopy. This proposal provides a unique opportunity to assess prospectively and in unprecedented detail DAC inhibitor-mediated changes in histone post-translational modifications in cancer patients and to associate these changes with pharmacokinetic, biologic, and clinical data;2b) To evaluate apoptotic mechanisms in patients with circulating CLL cells in order to validate in vivo AR-42 mediated induction of the novel potential biomarker HR23B, induction of the anti-apoptotic protein Mcl-1, changes in the death-inducing signaling complex, and sensitization to TNF-Related Apoptosis Inducing Ligand (TRAIL)-mediated apoptosis. These results will provide the justification necessary to design rational combination strategies for AR-42 and potentially other DAC inhibitors;2c) Changes in the microRNA and mRNA signature of CD138+ plasma cells of myeloma patients after exposure to AR-42 using high-throughput microRNA/gene expression analysis Nano-String technologies, to provide a new window to the mechanisms of this drug class.
The proposed research is relevant to public health as new drugs are needed in patients with incurable relapsed hematologic cancers. This application proposes to conduct a first-in-man phase 1 clinical trial of AR-42, a novel deacetylase inhibitor, in patients with lymphoma, multiple myeloma, and chronic lymphocytic leukemia. Importantly, this study includes cutting-edge correlative experiments that may for the first time connect the anti- cancer effects of deacetylase inhibitors with biological changes in tumor cells from treated cancer patients. Improved understanding of how this class of drugs works will allow us to better utilize in future studies and will have broad applications for many other cancers.