A Novel Dosing Schedule of Flavopiridol in CLL

黄酮吡醇治疗 CLL 的新给药方案

• 批准号: 7025086
• 负责人: Thomas S Lin
• 金额: $ 28.83万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-02 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7025086
• 关键词: Bax gene /protein; DNA directed RNA polymerase; chronic lymphocytic leukemia; clinical research; clinical trial phase I; drug resistance; drug screening /evaluation; flavopiridol; fludarabine; gene expression; human subject; human therapy evaluation; neoplasm /cancer chemotherapy; neoplasm /cancer relapse /recurrence; p53 gene /protein; patient oriented research; pharmacokinetics; phosphorylation

DESCRIPTION (provided by applicant): Progression of chronic lymphocytic leukemia (CLL) is associated with mutation or deletion of the p53 gene. CLL patients with dysfunctional p53 have a poor prognosis and do not respond to fludarabine or rituximab. Alemtuzumab, the only current effective therapy in this population, has significant infusion, hematologic and infectious toxicities. Thus, novel therapies that are effective in p53-dysfunctional CLL patients are urgently needed. Flavopiridol, a cyclin-dependent kinase inhibitor, induces apoptosis in CLL cells irrespective of p53 status. Initial studies using a 24-72-hour continuous IV infusion schedule in CLL showed no clinical activity. We subsequently demonstrated that favopiridol has high serum protein binding. Pharmacokinetic modeling suggested that administration of favopiridol by 30-minute IV bolus followed by 4-hour IV infusion would achieve in vivo plasma drug concentrations that induce apoptosis in CLL cells. Preliminary results of an ongoing phase I trial using this schedule have achieved clinical responses in relapsed CLL patients with p53 dysfunction, and acute tumor lysis has been observed as a dose limiting toxicity (DLT). Specific Aim 1 is to perform a phase I study of favopiridol using this dosing schedule in patients with relapsed CLL. In order to safely define this drug's toxicity profile and DLT (other than tumor lysis), intra-patient dose escalation will be performed in patients with fludarabine-refractory CLL who do not experience severe tumor lysis and do respond to cycle 1. We will gain preliminary data on the clinical activity of favopiridol in patients with high-risk genetic features. In Specific Aim 2, we will examine the pharmacokinetics and pharmacodynamics of favopiridol using this schedule. We will determine whether Cmax, Css and AUC correlate with tumor lysis or modulation of pharmacodynamic targets, specifically RNA polymerase II phosphorylation and Mcl-1 expression. We will also develop and validate a population pharmacokinetic model to interpret and predict the relationship between plasma favopiridol concentrations, toxicity and pharmacologic response. We hypothesize that this dosing schedule will modulate pharmacodynamic targets and show clinical activity. We plan to proceed to phase II studies of this schedule in high-risk CLL patients.

描述（申请人提供）：慢性淋巴细胞白血病（CLL）的进展与p53基因突变或缺失相关。p53功能障碍的CLL患者预后不良，对氟达拉滨或利妥昔单抗无反应。Alemtuzumab是该人群目前唯一有效的治疗方法，具有显著的输注、血液学和感染毒性。因此，迫切需要在p53功能障碍的CLL患者中有效的新疗法。Flavopiridol是一种细胞周期蛋白依赖性激酶抑制剂，可诱导CLL细胞凋亡，与p53状态无关。在CLL中使用24-72小时连续IV输注方案的初始研究显示无临床活性。我们随后证明，favopiridol具有高血清蛋白结合。药代动力学建模表明，通过30分钟IV推注然后4小时IV输注施用法匹利多将实现诱导CLL细胞凋亡的体内血浆药物浓度。使用该方案的正在进行的I期试验的初步结果已经在具有p53功能障碍的复发性CLL患者中实现了临床应答，并且已经观察到急性肿瘤溶解作为剂量限制性毒性（DLT）。具体目标1是在复发性CLL患者中使用该给药方案进行法匹吡啶醇的I期研究。为了安全地确定该药物的毒性特征和DLT（肿瘤溶解除外），将在未发生重度肿瘤溶解且对周期1有应答的氟达拉滨难治性CLL患者中进行患者内剂量递增。我们将获得关于favopiridol在具有高风险遗传特征的患者中的临床活性的初步数据。在具体目标2中，我们将使用该时间表检查法匹利多的药代动力学和药效学。我们将确定Cmax、Css和AUC是否与肿瘤溶解或药效学靶点的调节相关，特别是RNA聚合酶II磷酸化和Mcl-1表达。我们还将开发和验证群体药代动力学模型，以解释和预测血浆法莫匹利多浓度、毒性和药理学反应之间的关系。我们假设该给药方案将调节药效学靶点并显示临床活性。我们计划在高风险CLL患者中进行该方案的II期研究。