A Novel Dosing Schedule of Flavopiridol in CLL

描述(由申请人提供)：慢性淋巴细胞白血病(CLL)的进展与p53基因的突变或缺失有关。P53功能异常的慢性淋巴细胞性白血病患者预后较差，对氟达拉滨或利妥昔单抗无效。Alemtuzumab是目前该人群中唯一有效的治疗方法，具有显著的输液、血液学和感染毒性。因此，迫切需要对p53功能障碍的CLL患者有效的新疗法。一种依赖于细胞周期蛋白的激酶抑制剂，无论P53的状态如何，都能诱导CLL细胞的凋亡。在CLL中使用24-72小时连续静脉输注程序的初步研究显示没有临床活性。随后，我们证明了贝托吡哆醇具有很高的血清蛋白结合力。药代动力学模型表明，通过30分钟的静脉推注和4小时的静脉滴注给药，可以在体内达到诱导CLL细胞凋亡的血药浓度。使用该时间表进行的I期试验的初步结果已在有p53功能障碍的复发CLL患者中取得临床反应，急性肿瘤溶解已被观察到为剂量限制性毒性(DLT)。具体目标1是在复发的慢性淋巴细胞性白血病患者中使用该给药方案进行一期研究。为了安全地确定该药物的毒性和DLT(除肿瘤溶解外)，对氟达拉滨难治性CLL患者进行患者内剂量递增，这些患者没有经历严重的肿瘤溶解，并且对周期1有反应。我们将获得关于具有高危遗传特征的患者中阿福比利临床活性的初步数据。在特定的目标2中，我们将使用这个时间表来检查贝托吡酯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靶点的调节有关，特别是RNA聚合酶II的磷酸化和Mcl-1的表达。我们还将开发和验证一个群体药代动力学模型，以解释和预测血浆阿福比利浓度、毒性和药理反应之间的关系。我们假设这一给药计划将调整药效学目标并显示临床活性。我们计划在高危慢性淋巴细胞性白血病患者中进行该方案的第二阶段研究。

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.