Modulating the tumor micro-environment in CLL using flavopiridol and lenalidomide

描述(申请人提供)：四种治疗药物通常用于治疗慢性淋巴细胞白血病(CLL)：氯氨丁苯、利妥昔单抗、氟达拉滨和阿仑图珠单抗。这些治疗后的反应和无进展生存(PFS)受到特定染色体异常的存在的影响。具体地说，25%-30%的患者存在不利的细胞遗传学，del(17p13.1)或del(11q22.3)，这些患者对氟达拉滨和利妥昔单抗方案无效。唯一已被批准的对这些遗传异常患者有效的药物是阿伦图珠单抗。不幸的是，这种药物的活性在巨大的腺病患者中是有限的，并与严重的免疫抑制和机会性感染有关。因此，需要新的具有遗传高危CLL活性的非免疫抑制治疗药物。两种已被证明对del(17p13.1)或del(11q22.3)患者有效的新型药物是黄烷醇和来那度胺。虽然这些药物单独有效，但大多数患者在单独接受这些药物治疗时只取得部分反应。因此，本项目的目标是联合应用来那度胺和来那度胺治疗复发的CLL。这两种药物都对复发/难治性细胞遗传学高风险CLL有效，利用不同的新作用机制，不会消耗T细胞，从而有可能为del(17p)和del(11q)患者开发耐受性良好的治疗方案，与目前接受的氟达拉滨或阿伦图珠单抗组合相比，该方案具有更高的疗效和更低的感染毒性。这项建议的具体目标包括：1)进行黄吡哆醇和来那度胺的I期剂量递增试验，以确定这两种药物联合治疗B细胞CLL患者(包括细胞遗传学不良的CLL患者)的特异性毒性、剂量限制毒性(DLT)、最大耐受量(MTD)和初步疗效；2)作为I阶段试验的一部分，进行详细的药代动力学和药效学分析。药效学评估将包括评估血浆白介素6(IL-6)水平；细胞内Mcl-1表达；天然免疫的变化，包括T、B和NK细胞亚群和定量免疫球蛋白水平；以及诱导表达B细胞共刺激/激活抗原，包括CD40、CD80、CD86和HLA-DR。一旦确定了黄烷醇和来那度胺的MTD，我们预计该方案在遗传高危慢性淋巴细胞性白血病患者中的II期研究将迅速发展，并在癌症和白血病B组和美国组间进行更大规模的验证性III期试验。最终，这种非免疫抑制疗法将被评估为遗传高危CLL患者的一线治疗。公共卫生相关性：慢性淋巴细胞性白血病是一种异质性疾病，患者生存期从几个月到几十年不等，对治疗的要求也不同。对于预后不良的疾病，开发具有活性的治疗方法是至关重要的。根据先前证实的黄烷醇和来那度胺在重度预治疗的巨大腺病患者中的疗效，以及del(17p13.1)或del(11q22.3)，我们假设联合治疗将比单一药物治疗提高应答率。在细胞遗传学不良的先前治疗和可能未治疗的慢性淋巴细胞白血病患者中，这种组合的未来第二阶段研究将根据这一第一阶段试验的毒性、有效性、药代动力学和药效学结果而开发。

DESCRIPTION (provided by applicant): Four therapeutic agents are commonly utilized for the treatment of chronic lymphocytic leukemia (CLL): chlorambucil, rituximab, fludarabine, and alemtuzumab. Response and progression-free survival (PFS) following these treatments is affected by the presence of selected chromosomal aberrations. Specifically, adverse cytogenetics, del(17p13.1) or del(11q22.3), are present in 25-30% of patients and these patients fail to respond to fludarabine and rituximab-containing regimens. The only approved drug with known efficacy in patients with these genetic abnormalities is alemtuzumab. Unfortunately, this drug's activity is limited in patients with bulky adenopathy and is associated with profound immunosuppression and opportunistic infections. Therefore, novel non-immunosuppressive therapeutic agents with activity in genetically high risk CLL are needed. Two such novel agents with proven efficacy in patients with del(17p13.1) or del(11q22.3) are flavopiridol and lenalidomide. Although these agents are actively individually, the majority of patients only achieve a partial response when receiving these drugs individually. Therefore, the goal of this project is to combine flavopiridol and lenalidomide for the treatment of patients with relapsed CLL. Both of these agents are active against relapsed/refractory cytogenetically high risk CLL, utilize different novel mechanisms of action, and do not deplete T-cells, leading to the potential development of a well tolerated regimen for patients with del(17p) and del(11q) with greater efficacy and less infectious toxicity than observed with currently accepted fludarabine or alemtuzumab combinations. The specific aims of this proposal include: 1) to perform a phase I dose escalation trial of flavopiridol and lenalidomide to determine the specific toxicities, dose limiting toxicity (DLT), maximum tolerated dose (MTD), and preliminary efficacy of this combination in patients with previously treated B-cell CLL, including CLL patients with adverse cytogenetics, and 2) to perform detailed pharmacokinetic and pharmacodynamic analyses as part of this phase I trial. Pharmacodynamic evaluations will include evaluation of plasma interleukin 6 (IL-6) levels; intracellular Mcl-1 expression; alterations in innate immunity including T, B, and NK-cell subsets and quantitative immunoglobulin levels; and induced expression of B-cell co-stimulatory/activation antigens including CD40, CD80, CD86, and HLA-DR. Once the MTD of flavopiridol and lenalidomide is determined, we anticipate rapid development of a phase II study of this regimen in patients with genetically high risk CLL with larger confirmatory phase III trials performed within the Cancer and Leukemia Group B and US Intergroup. Ultimately, this non- immunosuppressive regimen would be evaluated as front-line therapy for patients with genetically high risk CLL. PUBLIC HEALTH RELEVANCE: CLL is a heterogeneous disease where patient survivals range from months to decades and requirements for therapy vary. The development of therapies with activity in poor prognostic disease is essential. With the previously demonstrated efficacy of flavopiridol and lenalidomide in heavily pre-treated patients with bulky adenopathy and del(17p13.1) or del(11q22.3), we hypothesize combination therapy will improve response rates over single agent therapy alone. Future phase II studies of this combination in previously treated and potentially untreated CLL patients with adverse cytogenetics will be developed on the basis of the toxicity, efficacy, pharmacokinetic, and pharmacodynamic findings from this phase I trial.