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

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），如滤泡中心淋巴瘤，目前的治疗方法无法治愈，许多复发性侵袭性B-NHL患者不适合自体干细胞移植。因此，需要用于复发性B-NHL的新治疗。Flavopiridol是一种细胞周期蛋白依赖性激酶抑制剂，在体外诱导淋巴肿瘤细胞凋亡。使用24-72小时连续IV输注或1小时推注给药的临床试验在MCL和慢性淋巴细胞白血病（CLL）中显示出适度的临床活性。我们随后证明，flavopiridol具有高血清蛋白结合。药代动力学模型表明，通过30分钟IV推注然后4小时IV输注给予flavopiridol将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期临床试验使用这种方案治疗复发性和难治性CLL，显示出显著的临床活性，急性肿瘤溶解和43%的反应率。我们寻求探索我们的新的剂量方案flavopiridol复发性B-NHL患者。具体目的1是在复发性B-NHL患者中使用该给药方案进行Flavopiridol的I期研究，以确定该给药方案在1）惰性B-NHL、2）MCL和3）侵袭性B-NHL中的剂量限制性毒性（DLT）、最大耐受剂量（MTD）和毒性特征。我们寻求获得这种给药方案的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是确定通过该方案给予的flavopiridol在复发性B-NHL患者中的药代动力学和药效学。我们将确定Cmax、Css和AUC是否与药效学靶点的调节相关，包括1）丝氨酸2和5 C末端结构域（CTD）位点的RNA聚合酶II磷酸化和2）Mel-1、Bcl-6和细胞周期蛋白D1的mRNA和蛋白表达。此外，我们还将评估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flavopiridol的急性输注毒性是否伴随炎性细胞因子如TNF-α、IFN-γ、IL-6、IL-8和IL-10的释放。

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.