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

描述(申请人提供)：套细胞淋巴瘤(MCL)和惰性B细胞性非霍奇金淋巴瘤(B-NHL)，如滤泡中心淋巴瘤，目前的治疗方法不能治愈，许多复发的侵袭性B-NHL患者不适合自体干细胞移植。因此，需要新的治疗方法来治疗复发的B-NHL。黄吡哆醇是一种细胞周期蛋白依赖性的激酶抑制剂，可在体外诱导淋巴肿瘤细胞的凋亡。使用24-72小时持续静脉输注或1小时团注的临床试验显示，MCL和慢性淋巴细胞白血病(CLL)的临床活性不高。随后，我们证明了黄烷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，可以达到诱导细胞凋亡所需的体内药物浓度。正在进行的使用该方案治疗复发和难治性CLL的I期试验显示出显著的临床活性，急性肿瘤溶解，有效率为43%。我们试图探索在复发性B-NHL患者中应用黄吡醇的新剂量方案。具体目标1是在复发性B-NHL患者中使用该给药方案进行一期研究，以确定该给药方案在1)惰性B-NHL、2)MCL和3)侵袭性B-NHL中的剂量限制毒性(DLT)、最大耐受量(MTD)和毒性分布。我们试图获得关于这一给药方案的临床活性的初步证据，以便确定特定的B-NHL类型，以便进行后续的II期研究。具体目的2是确定该时间表给出的黄吡醇在复发性B-NHL患者中的药代动力学和药效学。我们将确定Cmax、Css和AUC是否与药效学指标的调节有关，包括：1)丝氨酸2和5 C末端结构域(CTD)的RNA聚合酶II磷酸化；2)MEL-1、Bcl-6和细胞周期蛋白D1mRNA和蛋白的表达。此外，我们还将评估黄烷醇对T、B、NK细胞和定量免疫球蛋白水平的影响。最后，我们将检查急性输注毒性是否伴随着炎性细胞因子如肿瘤坏死因子-α、干扰素-γ、白介素6、白介素8和白介素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.