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

描述（由申请人提供）：dac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种多样的，并且因细胞类型而异。虽然DAC抑制剂伏立诺他和罗米地辛已被批准用于皮肤t细胞淋巴瘤，但DAC抑制剂的抗肿瘤作用尚未完全了解并用于b细胞恶性肿瘤。为了了解DAC抑制剂在复发性恶性血液病中的疗效和机制，需要对真正有效的I/II类DAC抑制剂进行前瞻性研究，并进行详细的相关实验，将其细胞作用和抗肿瘤作用联系起来。AR-42是一种I/II类DAC抑制剂，由俄勒冈州立大学的研究人员设计，可提供最佳的DAC抑制活性。I期试验正在积累，血清水平可检测到，在骨髓瘤患者中观察到未经证实的反应，作为单一药物，没有其他I/II类DAC抑制剂的疲劳和恶心特征。本申请的总体目标是在复发性淋巴瘤、骨髓瘤和CLL患者中进行AR-42的首次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，以确认和扩展体外观察。该申请的中心假设是，AR-42在复发的血液恶性肿瘤中有效，广泛的去乙酰化酶抑制将是安全且耐受的，药代动力学数据将优化剂量给药，相关研究将证明未来Ib期研究的联合策略。我们将通过以下目标来验证我们的中心假设：1)在复发性淋巴瘤、慢性淋巴细胞白血病（CLL）和多发性骨髓瘤患者中进行AR-42的首次人体研究，患者将在28天的周期（3周，1周）中每周一/三/五口服AR-42，以确定AR-42的剂量限制毒性（DLT）、最大耐受剂量（MTD）和毒性特征；2a)检测AR-42治疗前后患者的循环CLL细胞，通过液相色谱/质谱法表征整体组蛋白状态。该提案提供了一个独特的机会，以前所未有的细节前瞻性评估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、生物学和临床数据联系起来；2b)评估循环CLL细胞患者的凋亡机制，以验证AR-42介导的新型潜在生物标志物HR23B的诱导，抗凋亡蛋白Mcl-1的诱导，死亡诱导信号复合物的变化，以及对tnf相关凋亡诱导配体（TRAIL）介导的细胞凋亡的致敏性。这些结果将为设计AR-42和其他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/基因表达分析纳米链技术研究AR-42暴露后骨髓瘤患者CD138+浆细胞microRNA和mRNA特征的变化，为研究该类药物的作用机制提供新的窗口。

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.