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

点击翻译按钮获取中文摘要

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.