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。具有功能障碍p53的CLL患者预后较差，对氟达拉滨或利妥昔单抗无反应。阿仑妥珠单抗是目前该人群中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，迫切需要对p53功能失调的CLL患者有效的新疗法。黄吡醇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小时连续静脉输注的初步研究显示没有临床活性。我们随后证明，favopridol具有高血清蛋白结合。药代动力学模型表明，favopridol静脉给药30分钟，然后静脉输注4小时，可以达到诱导CLL细胞凋亡的体内血浆药物浓度。一项正在进行的I期试验的初步结果显示，在p53功能障碍的复发性CLL患者中取得了临床反应，并且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favopridol的I期研究。为了安全地确定该药的毒性和DLT（除肿瘤溶解外），将对氟达拉滨难治性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，并且对第1周期有反应。我们将获得关于favopridol在高危遗传特征患者中的临床活性的初步数据。在特定目标2中，我们将使用该计划检查法比吡多尔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一个人群药代动力学模型，以解释和预测血浆中favopridol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靶点并显示临床活性。我们计划在高风险CLL患者中进行该计划的II期研究。

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.