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

使用黄酮吡醇和来那度胺调节 CLL 中的肿瘤微环境

• 批准号: 7658285
• 负责人: KRISTIE A BLUM
• 金额: $ 33.75万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7658285
• 关键词: Affect; Antigens; Area Under Curve; B-Cell Activation; B-Lymphocytes; CD80 gene; Cancer and Leukemia Group B; Chlorambucil; Chromosome abnormality; Chronic Lymphocytic Leukemia; Clinical; Combined Modality Therapy; Cytogenetics; Cytolysis; Development; Disease; Dose; Dose-Limiting; Down-Regulation; Drug Kinetics; Environment; Evaluation; Flare; Future; Gene Mutation; Goals; HLA-DR Antigens; Half-Life; IGH@ gene cluster; Immunoglobulins; Immunologics; Immunosuppression; Immunosuppressive Agents; Interleukin-6; Lymphatic Diseases; Lymphocyte; Malignant - descriptor; Maximum Tolerated Dose; Mediating; Molecular Abnormality; Natural Immunity; Natural Killer Cells; Opportunistic Infections; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase III Clinical Trials; Plasma; Progression-Free Survivals; Reaction; Refractory; Relapse; Staging; Steroids; Surface; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Subsets; TNFRSF5 gene; Therapeutic Agents; Time; Toxic effect; Treatment Protocols; Tumor Lysis Syndrome; Up-Regulation; ZAP-70 Gene; alemtuzumab; base; chromosome 17p loss; del(11q); flavopiridol; fludarabine; high risk; improved; in vivo; lenalidomide; novel; partial response; prognostic; prophylactic; prospective; public health relevance; response; rituximab; therapy development; tumor

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.

描述（由申请人提供）：四种治疗药物通常用于治疗慢性淋巴细胞白血病（CLL）：苯丁酸氮芥、利妥昔单抗、氟达拉滨和阿仑单抗。这些治疗后的缓解和无进展生存期（PFS）受选定染色体畸变的影响。具体来说，25-30%的患者存在不良细胞遗传学del（17p13.1）或del（11q22.3），这些患者对含氟达拉滨和利妥昔单抗的方案没有反应。在这些遗传异常患者中已知疗效的唯一获批药物是Alemtuzumab。不幸的是，这种药物的活性是有限的，在病人与巨大的淋巴结肿大，并与深刻的免疫抑制和机会性感染。因此，需要在遗传高风险CLL中具有活性的新型非免疫抑制治疗剂。在del（17p13.1）或del（11q22.3）患者中证明有效的两种此类新药是flavopiridol和来那度胺。虽然这些药物是单独有效的，但大多数患者在单独接受这些药物时仅获得部分反应。因此，本项目的目标是联合收割机flavopiridol和来那度胺治疗复发性CLL患者。这两种药物均对复发性/难治性细胞遗传学高风险CLL具有活性，利用不同的新型作用机制，并且不会消耗T细胞，从而可能为del（17 p）和del（11 q）患者开发一种耐受性良好的治疗方案，与目前接受的氟达拉滨或阿仑单抗联合治疗相比，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Flavopiridol和来那度胺的I期剂量递增试验，以确定该组合在先前治疗过的B细胞CLL患者（包括具有不良细胞遗传学的CLL患者）中的特异性毒性、剂量限制性毒性（DLT）、最大耐受剂量（MTD）和初步疗效，和2）进行详细的药代动力学和药效学分析，作为该I期试验的一部分。药效学评价将包括评价血浆白细胞介素6（IL-6）水平;细胞内Mcl-1表达;先天免疫（包括T、B和NK细胞亚群）的改变和定量免疫球蛋白水平;并诱导包括CD 40、CD 80、CD 86和HLA-DR在内的B细胞共刺激/活化抗原的表达。一旦确定了Flavopiridol和来那度胺的MTD，我们预期在癌症和白血病组B和美国国际组中进行的更大规模的确证性III期试验将快速发展该方案在遗传高危CLL患者中的II期研究。最终，这种非免疫抑制方案将被评估为遗传高风险CLL患者的一线治疗。公共卫生相关性：CLL是一种异质性疾病，患者生存期从数月到数十年不等，治疗要求各不相同。在预后不良的疾病中开发具有活性的疗法是至关重要的。根据先前证实的flavopiridol和来那度胺在重度预治疗的大腺病和del（17p13.1）或del（11q22.3）患者中的疗效，我们假设联合治疗将比单药治疗提高应答率。将根据该I期试验的毒性、疗效、药代动力学和药效学结果，在既往接受过治疗和可能未接受过治疗的细胞遗传学不良CLL患者中开展该组合的未来II期研究。