Targeted Therapy for Lymphoid Malignancies

淋巴恶性肿瘤的靶向治疗

• 批准号: 8642167
• 负责人: JOHN C. BYRD
• 金额: $ 52.02万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8642167
• 关键词: 1-Phosphatidylinositol 3-Kinase; 17p13.1; Agammaglobulinaemia tyrosine kinase; Apoptosis; B-Lymphocytes; Bioavailable; Blood; Bone Marrow; Cell Proliferation; Cell Survival; Cells; Chronic Lymphocytic Leukemia; Chronic Myeloid Leukemia; Clinical; Data; Defect; Dependence; Development; Disease; Disease Progression; Disease remission; Frequencies; Future; Genetic; Genomic Instability; Genomics; Human; Immune; Immunosuppressive Agents; Indolent; Inferior; Location; Lymphocytosis; MAP Kinase Gene; Malignant lymphoid neoplasm; Mediating; Mus; Mutation; Myelogenous; Newly Diagnosed; Nodal; Non-Hodgkin' s Lymphoma; Oral; Outcome; Pathway interactions; Patients; Pattern; Pharmacodynamics; Phase; Phase II Clinical Trials; Phenotype; Phosphotransferases; Progression-Free Survivals; Protein Kinase; Proteins; Receptor Activation; Receptor Signaling; Receptors, Antigen, B-Cell; Refractory; Relapse; Resistance; Salvage Therapy; Sampling; Signal Pathway; Signal Transduction; Stream; Survival Rate; Therapeutic; Toxic effect; Translating; Tyrosine Kinase Inhibitor; Work; ZAP-70 Gene; adult leukemia; alemtuzumab; base; chromosome 17p loss; cohort; cytopenia; early experience; fludarabine; high risk; human disease; improved; inhibitor/antagonist; kinase inhibitor; leukemia; lymph nodes; mouse model; neoplastic cell; novel strategies; phase 1 study; public health relevance; research study; response; rituximab; treatment strategy; tumor

DESCRIPTION (provided by applicant): Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is incurable with current therapies. Additionally, certain subsets of CLL patients including del(17p13.1) and those with ZAP-70 un- methylated (ZAP-70+) disease do not respond well to therapy and have a shorter overall survival. Unlike CML, where targeted therapy toward a single disease-specific fusion kinase is possible, in CLL there has been no single disease-specific targets identified. Recent studies, however, have identified B-cell receptor (BCR) signaling including the PI3-kinase, NF-?B, and MAPK/ERK are constitutively active in the lymph node and bone marrow compartment of CLL where disease expansion occurs suggesting that this may be a potential target in CLL. Additionally, patients with ZAP-70+ disease have enhanced BCR signaling. Proximal BCR signaling results in activation of the Bruton agammaglobulinemia tyrosine kinase (Btk) and genetic loss of this kinase by mutation or deletion in mice or humans produces predominately a B-cell defect. Based upon this, we were first to pursue and demonstrate that the orally bioavailable, irreversible Btk inhibitor ibrutinib (PCI-32765) promotes direct apoptosis, inhibits cell proliferation, and blocks microenvironment stromal signals important to CLL cell survival. In conjunction our group has worked closely with Pharmacyclics to perform the first phase Ib/II study of ibrutinib in CLL where 90% of patients had clinical benefit. Therapy has been well tolerated and the estimated progression-free survival rate is 86% at 1 year in relapsed patients independent of del(17p) and improved outcome in those with ZAP-70+ disease. This proposal builds upon this early experience of ibrutinib by performing a more definitive phase II trial in relapsed CLL with a separate cohort of del(17p13.1) patients that includes pharmacodynamic experiments aimed at identifying subsets of patients most likely to gain durable remissions with ibrutinib monotherapy and also to study the features of CLL cells not eliminated with this treatment at 12 months. The specific aims of our proposal include: 1) To perform a phase II clinical trial of ibrutinib to determine the response and 2-year PFS among patients having versus lacking del(17p13.1) and the long-term toxicity of this agent administered as a continuous therapy; 2) To perform baseline and serial pharmacodynamic studies to determine if traditional genomic features, select BCR activation markers, and changes in miR marker expression are predictive for response and 2-year PFS; and 3) To perform studies derived from samples from patients participating in both this and the earlier completed single agent ibrutinib trial to determine the biologic features of tumor cells not cleare from the blood by 12 months and pharmacologic strategies to eliminate these. At completion of this proposal, we will have determined the efficacy of ibrutinib in relapsed del (17p13.1) CLL while also identifying features predictive of single agent activity of this agent and also of tumor cells not effectively eliminated by ibrutinib. These will guide future combination studies with Ibrutinib that has great potential to completely change the treatment paradigm of CLL.

描述（由申请人提供）：慢性淋巴细胞白血病（CLL）是最常见的成人白血病，目前的治疗方法无法治愈。此外，CLL患者的某些亚组，包括del（17p13.1）和患有ZAP-70未甲基化（ZAP-70+）疾病的那些患者对治疗反应不佳，并且具有较短的总生存期。与CML不同的是，针对单一疾病特异性融合激酶的靶向治疗是可能的，在CLL中没有确定单一疾病特异性靶点。最近的研究，但是，已经确定了B细胞受体（BCR）信号，包括PI 3-激酶，NF-？B和MAPK/ERK在发生疾病扩展的CLL的淋巴结和骨髓区室中是组成性活性的，表明这可能是CLL中的潜在靶点。此外，患有ZAP-70+疾病的患者具有增强的BCR信号传导。近端BCR信号传导导致布鲁顿无丙种球蛋白血症酪氨酸激酶（Btk）的活化，并且在小鼠或人中通过突变或缺失导致该激酶的遗传缺失主要产生B细胞缺陷。基于此，我们首先追求并证明口服生物可利用的不可逆Btk抑制剂伊曲替尼（PCI-32765）促进直接凋亡，抑制细胞增殖，并阻断对CLL细胞存活重要的微环境基质信号。我们的团队与Pharmacyclics密切合作，进行了第一项Ibrahim inib在CLL中的Ib/II期研究，其中90%的患者具有临床获益。治疗耐受性良好，在不依赖del（17 p）的复发患者中，1年时估计无进展生存率为86%，ZAP-70+疾病患者的结局改善。该提案建立在伊鲁替尼的早期经验基础上，通过在复发性CLL中使用单独的del（17p13.1）患者队列进行更确定的II期试验，包括药效学实验，旨在确定最有可能通过伊鲁替尼单药治疗获得持久缓解的患者亚组，并研究12个月时未消除的CLL细胞的特征。我们的提案的具体目的包括：1）进行一项伊曲替尼的II期临床试验，以确定有与无del的患者的反应和2年PFS。（17p13.1）和作为连续疗法施用的该药剂的长期毒性; 2）进行基线和系列药效学研究以确定传统基因组特征，选择BCR活化标志物，并且miR标记物表达的变化预测反应和2年PFS;和3）进行源自参与该试验和早期完成的单药伊曲替尼试验的患者的样品的研究，以确定12个月时未从血液中清除的肿瘤细胞的生物学特征和消除这些肿瘤细胞的药理学策略。在完成该提案时，我们将确定伊克替尼在复发性del（17p13.1）CLL中的疗效，同时还确定预测该药物的单药活性和肿瘤的特征。 细胞不能被伊布替尼有效清除。这些将指导未来与伊曲替尼的联合研究，伊曲替尼具有完全改变CLL治疗模式的巨大潜力。