Modulation of Resistance to antiangiogenic therapy: A clinical trial with correla

抗血管生成治疗耐药性的调节：correla 的临床试验

基本信息

批准号：
8112568
负责人：
JOHN F DE GROOT
金额：
$ 31.8万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-16 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8112568
关键词：
Angiogenesis Inhibitors Angiogenic Factor Biological Markers Blood Vessels Bone Marrow CSF3 gene CXCL1 gene Cells Cerebral Edema Chronic Clinical Clinical Data Clinical Trials Clinical Trials Design Data Development Dose Drug Delivery Systems Effectiveness Enrollment Fibroblast Growth Factor Frequencies Future Glioblastoma Glioma Growth Histologic Human Hypoxia IL8RB gene Infiltration Institution Laboratories Lomustine MMP9 gene Macrophage Colony-Stimulating Factor Measurement Measures Mediating Mediator of activation protein Modeling Monitor Myeloid Cells Neutrophil Infiltration Operative Surgical Procedures Outcome Pathologic Patients Peripheral Phase II Clinical Trials Plasma Population Progression-Free Survivals Randomized Recruitment Activity Recurrence Reporting Resistance Resistance development Sampling Schedule Specimen Time Tissues Vascular Endothelial Cell Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Vascular Permeabilities Vascular Proliferation Xenograft Model angiogenesis arm bevacizumab chemokine cohort cyclohexylchloroethylnitrosourea granulocyte improved in vivo inhibitor/antagonist macrophage monocyte monocyte colony stimulating factor neoplastic cell neutrophil novel peripheral blood phase 2 study pre-clinical prevent public health relevance rapid growth receptor resistance mechanism response therapy development therapy resistant tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Vascular proliferation is a pathologic hallmark of glioblastoma and studies have shown that the expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) is one mechanism by which tumors induce the formation of new blood vessels. Antiangiogenic therapy has been shown to rapidly decrease vascular permeability, reduce cerebral edema, and prolong progression free survival (PFS) in some patients with recurrent glioblastoma. However, patients with intrinsic resistance do not benefit from anti-VEGF therapy and those that initially respond acquire resistance limiting the long-term effectiveness of this approach. The mechanisms of resistance to anti-VEGF therapy are potentially many but recent reports suggest that bone marrow derived cells (BMDCs) may be important mediators of resistance. We have developed a novel clinical trial designed to potentially modulate the development of glioblastoma resistance to bevacizumab. Patients with recurrent glioblastoma will be randomized to receive standard dose bevacizumab or low-dose bevacizumab combined with lomustine given on day 3 during the "normalization window" to maximize drug delivery to tumor. The lower dose of bevacizumab will be utilized to both improve drug delivery and to prevent or delay the development of severe hypoxia which we have shown to be a prominent feature of glioblastoma tumors treated with chronic anti-VEGF therapy. To evaluate potential modulators of glioblastoma sensitivity and resistance to anti-VEGF therapy, this trial will assess changes in circulating chemokines and myeloid cells in the standard dose versus low dose arms. In Aim 1, we will determine if baseline plasma levels of monocytic and granulocytic chemokines are predictive of response to anti-VEGF therapy. Aim 2 will assess the recruitment of myeloid cells following anti-VEGF therapy. Aim 3 will assess the association between plasma chemokines, the number of myeloid cells infiltrated into glioblastoma samples and histologic markers of vascular proliferation at the time of surgery for recurrent glioblastoma. These studies are critical to establish which biomarkers are useful in predicting response and monitoring treatment progress, as well as for forming a baseline for future trials that incorporate therapies targeting myeloid cell populations. Inclusion of biomarker measurements into this phase II study represent unique strengths of our institution and will enhance our ability to assess the potential efficacy of an alternative bevacizumab dosing schedule in a multidimensional manner. PUBLIC HEALTH RELEVANCE: Despite the promising radiographic responses seen in patients with recurrent glioblastoma treated with antiangiogenic therapy, the long term effectiveness of this therapy remains limited by the development of resistance. Our clinical trial will attempt to modulate and delay the development of resistance to anti-VEGF therapy while exploring plasma chemokines and the myeloid cells they recruit as predictive markers of sensitivity and resistance to therapy.

描述（由申请人提供）：血管增殖是胶质母细胞瘤的病理标志，研究表明，促血管生成因子的表达（例如血管内皮生长因子（VEGF））是肿瘤诱导新血管形成的一种机制。抗血管生成疗法已显示出一些复发性胶质母细胞瘤患者的血管渗透性迅速降低血管渗透性，降低脑水肿和延长无进展生存期（PFS）。但是，具有内在抵抗力的患者并不能受益于抗VEGF疗法，而最初反应的患者会获得抗药性，从而限制了这种方法的长期有效性。对抗VEGF治疗的抗性机制可能有很多，但最近的报道表明，骨髓衍生的细胞（BMDC）可能是抗药性的重要介体。我们开发了一项新型的临床试验，旨在可能调节胶质母细胞瘤对贝伐单抗的耐药性的发展。复发性胶质母细胞瘤的患者将被随机分配，以接受标准剂量贝伐单抗或低剂量贝伐单抗，并在“归一化窗口”期间第3天给出的Lomustine结合使用，以最大程度地递送药物为肿瘤。较低剂量的贝伐单抗将被用于改善药物递送，并防止或延迟严重缺氧的发展，这是我们证明是用慢性抗VEGF治疗治疗的胶质母细胞瘤肿瘤的重要特征。为了评估胶质母细胞瘤敏感性和对抗VEGF治疗的耐药性的潜在调节剂，该试验将评估标准剂量与低剂量臂中循环趋化因子和髓样细胞的变化。在AIM 1中，我们将确定单核细胞和粒细胞趋化因子的基线血浆水平是否可以预测对抗VEGF治疗的反应。 AIM 2将评估抗VEGF治疗后髓样细胞的募集。 AIM 3将评估血浆趋化因子，髓样细胞的数量，渗透到胶质母细胞瘤样品中的髓样细胞数量以及在手术时的血管增生的组织学标志物，用于复发性胶质母细胞瘤。这些研究对于确定哪些生物标志物在预测反应和监测治疗进展以及形成以后试验的基线方面至关重要，该试验纳入了针对髓样细胞群体的疗法。将生物标志物测量纳入这一II期研究代表了我们机构的独特优势，并将增强我们以多维方式评估替代性贝伐单抗给药时间表的潜在功效的能力。公共卫生相关性：尽管在接受抗血管生成疗法治疗的复发性胶质母细胞瘤患者中看到了有希望的射线照相反应，但这种疗法的长期有效性仍受到抗药性发展的限制。我们的临床试验将试图调节和延迟抗VEGF疗法的耐药性，同时探索血浆趋化因子和髓样细胞，它们作为敏感性和对治疗的耐药性的预测标记。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma.

DOI：
10.1007/s11060-016-2195-9
发表时间：
2016-09
期刊：
JOURNAL OF NEURO-ONCOLOGY
影响因子：
3.9
作者：
Weathers, Shiao-Pei;Han, Xiaosi;Liu, Diane D.;Conrad, Charles A.;Gilbert, Mark R.;Loghin, Monica E.;O'Brien, Barbara J.;Penas-Prado, Marta;Puduvalli, Vinay K.;Tremont-Lukats, Ivo;Colen, Rivka R.;Yung, W. K. Alfred;de Groot, John F.
通讯作者：
de Groot, John F.