A Phase I Study of Single Agent Flavopiridol in B-Cell *

B 细胞中单药 Flavopiridol 的 I 期研究 *

基本信息

批准号：
7282709
负责人：
Thomas S Lin
金额：
$ 25.46万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-21 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7282709
关键词：
Acute Age Apoptosis Area Under Curve Autologous Autologous Stem Cell Transplantation B-Cell NonHodgkins Lymphoma B-Lymphocytes Binding Bolus Infusion C-terminal Cell Death Cells Chronic Lymphocytic Leukemia Clinical Clinical Research Clinical Trials Condition Continuous Intravenous Infusion Cultured Tumor Cells Cyclin D1 Cyclin-Dependent Kinase Inhibitor Cytolysis Data Disease Dose Dose-Limiting Drug Kinetics Dyspnea Fever Follicular Lymphoma Genetic Risk Growth Hour Human Hypotension Hypoxia IL8 gene Immunoglobulins In Vitro Indolent Inflammatory Infusion procedures Interleukin-10 Interleukin-6 Intervention Intravenous Bolus Intravenous infusion procedures Lymphoma Mantle Cell Lymphoma Maximum Tolerated Dose Medical Messenger RNA Mutation Natural Immunity Natural Killer Cells Pain Patients Pharmaceutical Preparations Pharmacodynamics Phase Phase I Clinical Trials Phase II Clinical Trials Phosphorylation Plasma Plasma Proteins Prophylactic treatment Protein Binding RNA Polymerase II Rate Refractory Refractory Disease Relapse Research Design Research Personnel Risk Schedule Serine Serum Proteins Site Stem cells Syndrome TP53 gene Tachycardia Toxic effect Treatment Protocols Tumor Lysis Syndrome Week cytokine flavopiridol in vivo lymphoid neoplasm neoplastic cell novel pharmacokinetic model programs protein expression response tumor

项目摘要

DESCRIPTION (provided by applicant): Mantle cell lymphoma (MCL) and indolent B-cell non-Hodgkin's lymphomas (B-NHL) such as follicle center lymphoma are not curable with current therapies, and many patients with relapsed aggressive B-NHL are not candidates for autologous stem cell transplantation. Thus, novel treatments for relapsed B-NHL are needed. Flavopiridol is a cyclin-dependent kinase inhibitor that induces apoptosis in lymphoid tumor cells in vitro. Clinical trials using 24-72-hour continuous IV infusion or 1-hour bolus dosing showed modest clinical activity in MCL and chronic lymphocytic leukemia (CLL). We subsequently demonstrated that flavopiridol has high serum protein binding. Pharmacokinetic modeling suggested that administration of flavopiridol by 30-minute IV bolus followed by 4-hour IV infusion would achieve in vivo plasma drug concentrations needed to induce apoptosis. An ongoing phase I trial using this schedule in relapsed and refractory CLL has shown remarkable clinical activity, with acute tumor lysis and a response rate of 43%. We seek to explore our novel dosing regimen of flavopiridol in patients with relapsed B-NHL. Specific Aim 1 is to perform a phase I study of flavopiridol using this dosing schedule in patients with relapsed B-NHL, in order to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and toxicity profile of this dosing schedule in 1) indolent B-NHL, 2) MCL, and 3) aggressive B-NHL. We seek to gain preliminary evidence on the clinical activity of this dosing schedule, in order to identify specific B-NHL types in which to pursue subsequent phase II studies. Specific Aim 2 is to determine the pharmacokinetics and pharmacodynamics of flavopiridol, given by this schedule, in patients with relapsed B-NHL. We will determine whether Cmax, Css and AUC correlate with modulation of pharmacodynamic targets including 1) RNA polymerase II phosphorylation at the serine 2 and 5 C-terminal domain (CTD) sites and 2) mRNA and protein expression of Mel-1, Bcl-6 and cyclin D1. In addition, we will assess the effect of flavopiridol on T, B and NK-cells and quantitative immunoglobulin levels. Finally, we will examine whether acute infusion toxicity to flavopiridol is accompanied by release of inflammatory cytokines such as TNF-a, IFN-y, IL-6, IL-8 and IL-10.

描述（由申请人提供）：套细胞淋巴瘤（MCL）和惰性 B 细胞非霍奇金淋巴瘤（B-NHL），例如滤泡中心淋巴瘤，目前的疗法无法治愈，并且许多患有复发性侵袭性 B-NHL 的患者也无法治愈。自体干细胞移植的候选人。因此，需要针对复发 B-NHL 的新疗法。 Flavopiridol 是一种细胞周期蛋白依赖性激酶抑制剂，可在体外诱导淋巴肿瘤细胞凋亡。使用 24-72 小时连续静脉输注或 1 小时推注给药的临床试验显示，在 MCL 和慢性淋巴细胞白血病 (CLL) 中具有适度的临床活性。我们随后证明黄吡醇具有高血清蛋白结合率。药代动力学模型表明，通过 30 分钟静脉推注，然后 4 小时静脉输注给予黄酮吡醇，可达到诱导细胞凋亡所需的体内血浆药物浓度。一项正在进行的 I 期试验使用该方案治疗复发性和难治性 CLL，显示出显着的临床活性，具有急性肿瘤溶解和 43% 的缓解率。我们寻求探索针对复发性 B-NHL 患者的新型黄吡醇给药方案。具体目标 1 是在复发性 B-NHL 患者中使用该给药方案进行黄吡醇的 I 期研究，以确定该给药方案的剂量限制毒性 (DLT)、最大耐受剂量 (MTD) 和毒性特征1) 惰性 B-NHL，2) MCL，以及 3) 侵袭性 B-NHL。我们寻求获得有关该给药方案临床活性的初步证据，以确定特定的 B-NHL 类型，以进行后续的 II 期研究。具体目标 2 是确定按此方案给予的黄吡醇在复发 B-NHL 患者中的药代动力学和药效学。我们将确定 Cmax、Css 和 AUC 是否与药效学靶标的调节相关，包括 1) RNA 聚合酶 II 丝氨酸 2 和 5 C 末端结构域 (CTD) 位点的磷酸化以及 2) Mel-1、Bcl- 的 mRNA 和蛋白表达6和细胞周期蛋白D1。此外，我们将评估 flavopiridol 对 T、B 和 NK 细胞以及定量免疫球蛋白水平的影响。最后，我们将检查黄酮吡醇的急性输注毒性是否伴随炎症细胞因子的释放，如 TNF-a、IFN-y、IL-6、IL-8 和 IL-10。