Phase 1 of AR-42 in relapsed CLL, lymphoma, myeloma

描述(由申请人提供)：DAC的抑制剂在临床前显示出巨大的前景，但越来越明显的是，这些药物的活性是多样化的，并因细胞类型而不同。虽然DAC抑制剂voinostat和romidessin已被批准用于皮肤T细胞淋巴瘤，但DAC抑制剂的抗肿瘤作用尚未被充分了解和开发用于B细胞恶性肿瘤。为了了解DAC抑制剂对复发性恶性血液病的疗效和机制，需要一项真正有效的I/II类DAC抑制剂的前瞻性研究，在这项研究中，详细的相关实验可以将细胞效应和抗肿瘤效应联系起来。AR-42是俄亥俄州立大学研究人员设计的一种I/II类DAC抑制剂，可提供最佳的DAC抑制活性。随着可检测到的血清水平的增加，I期正在累积，并且在骨髓瘤患者中观察到了未经证实的反应，作为一种单一药物，没有其他I/II类DAC抑制剂所特有的疲劳和恶心。这项应用的总体目标是在复发性淋巴瘤、骨髓瘤和慢性淋巴细胞性白血病患者中进行AR-42的第一人I期临床试验，以证明安全性，获得反应信号，并产生机制数据来证实和扩大体外观察。该应用的中心假设是，用AR-42对复发的恶性血液病进行有效、广泛的脱乙酰酶抑制将是安全和可耐受的，药代动力学数据将优化剂量给药，相关研究将证明Ib期研究中未来的组合策略是合理的。我们将通过追求以下目标来验证我们的中心假说：1)对AR-42在复发淋巴瘤、慢性淋巴细胞白血病(CLL)和多发性骨髓瘤患者中进行第一人研究，其中患者将接受AR-42 Mon/Wed/Fri口服，周期为28天(开始三周，休息一周)，以确定AR-42的剂量限制毒性(DLT)、最大耐受量(MTD)和毒性概况；2a)通过液相色谱/质谱仪检测AR-42治疗前后患者的循环CLL细胞，以表征全局组蛋白状态。这项提议提供了一个独特的机会来前瞻性地和前所未有地详细地评估DAC抑制剂介导的癌症患者组蛋白翻译后修饰的变化，并将这些变化与药代动力学、生物学和临床数据相关联：2b)评估循环CLL细胞患者的凋亡机制，以便在体内验证AR-42介导的新的潜在生物标记物HR23B的诱导、抗凋亡蛋白Mcl-1的诱导、死亡诱导信号复合体的变化以及对肿瘤坏死因子相关的凋亡诱导配体(TRAIL)介导的凋亡的增敏。这些结果将为设计AR-42和潜在的其他DAC抑制剂的合理组合策略提供必要的依据：2c)利用高通量microRNA/基因表达分析纳米串技术，研究AR-42暴露后骨髓瘤患者CD138+浆细胞的microRNA和mRNA签名的变化，从而为该药物的作用机制提供新的窗口。 公共卫生相关性：拟议的研究与公共健康相关，因为无法治愈的复发性血液病患者需要新药。这项申请建议在淋巴瘤、多发性骨髓瘤和慢性淋巴细胞白血病患者中进行AR-42的第一阶段临床试验，AR-42是一种新的脱乙酰酶抑制剂。重要的是，这项研究包括尖端的相关实验，这些实验可能首次将脱乙酰酶抑制剂的抗癌效果与接受治疗的癌症患者的肿瘤细胞的生物学变化联系起来。对这类药物如何发挥作用的更好理解将使我们能够在未来的研究中更好地利用，并将在许多其他癌症中有广泛的应用。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.