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（由申请人提供）：慢性淋巴细胞白血病（CLL）的进展与p53基因的突变或缺失相关。 p53 功能障碍的 CLL 患者预后较差，并且对氟达拉滨或利妥昔单抗没有反应。阿仑单抗是目前对该人群唯一有效的治疗方法，具有显着的输注、血液和感染毒性。因此，迫切需要对 p53 功能失调的 CLL 患者有效的新疗法。 Flavopiridol 是一种细胞周期蛋白依赖性激酶抑制剂，无论 p53 状态如何，都会诱导 CLL 细胞凋亡。使用 24-72 小时连续静脉输注方案治疗 CLL 的初步研究显示没有临床活性。我们随后证明法沃吡多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 小时静脉输注给予法沃吡多，可达到诱导 CLL 细胞凋亡的体内血浆药物浓度。使用该方案正在进行的 I 期试验的初步结果已在患有 p53 功能障碍的复发性 CLL 患者中取得了临床缓解，并且已观察到急性肿瘤溶解是剂量限制性毒性 (DLT)。具体目标 1 是使用该给药方案对复发性 CLL 患者进行 favopiridol 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），将对没有经历严重肿瘤溶解且对第 1 周期有反应的氟达拉滨难治性 CLL 患者进行患者内剂量递增。关于法沃吡多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，我们将使用此时间表检查法沃吡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沃吡多浓度、毒性和药理反应之间的关系。我们假设该给药方案将调节药效学目标并显示出临床活性。我们计划在高危 CLL 患者中开展该方案的 II 期研究。