Tumor pharmacokinetics and pharmacodynamics of the CDK4/6 inhibitor ribociclib in patients with recurrent glioblastoma
Tumor pharmacokinetics and pharmacodynamics of the CDK4/6 inhibitor ribociclib in patients with recurrent glioblastoma
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DOI：
10.1007/s11060-019-03258-0
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发表时间：
2019-09-01
影响因子：
3.9
通讯作者：
Fadul, Camilo E.
中科院分区：
文献类型：
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作者：
Miller, Todd W.;Traphagen, Nicole A.;Fadul, Camilo E.
我们进行了一项Ib期研究（NCT 02345824），以确定ribociclib（一种细胞周期蛋白依赖性激酶4和6（CDK 4/6）的抑制剂）是否能穿透肿瘤组织并调节复发性胶质母细胞瘤（GBM）患者的下游信号通路，包括视网膜母细胞瘤蛋白（Rb）。方法研究参与者在手术切除复发性GBM前接受ribociclib（600 mg QD）治疗8-21天。在肿瘤组织、血浆和脑脊液（CSF）样本中测量ribociclib的总浓度和未结合浓度。我们通过免疫组织化学分析了从第一次（初始/研究前）和第二次（复发/研究中）手术中获得的肿瘤标本的Rb状态和CDK 4/6抑制的下游信号传导。Rb阳性复发性肿瘤的参与者在手术后继续进行21天的ribociclib治疗，7天的停药计划，并监测毒性和疾病进展。结果3例复发性Rb阳性GBM患者参加了本研究。血浆、CSF、MRI增强区、MRI非增强区和肿瘤核心区中的平均未结合（非活性）ribociclib浓度分别为0.337 μ M、0.632 μ M、1.242 nmol/g、0.484 nmol/g和1.526 nmol/g，超过了无细胞试验中抑制CDK 4/6的体外IC 50（0.04 μ M）。研究参与者之间对肿瘤组织中ribociclib CDK 4/6抑制的药效学标志物的调节不一致。没有参与者发生严重不良事件，但所有参与者都经历了早期疾病进展。结论这项研究表明，ribociclib在预测治疗有益的浓度下渗透复发性GBM组织。我们的研究无法证明药物活性的肿瘤药效学相关性。尽管耐受性良好，但ribociclib单药治疗复发性GBM似乎无效。
Introduction We conducted a phase Ib study (NCT02345824) to determine whether ribociclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), penetrates tumor tissue and modulates downstream signaling pathways including retinoblastoma protein (Rb) in patients with recurrent glioblastoma (GBM). Methods Study participants received ribociclib (600 mg QD) for 8-21 days before surgical resection of their recurrent GBM. Total and unbound concentrations of ribociclib were measured in samples of tumor tissue, plasma, and cerebrospinal fluid (CSF). We analyzed tumor specimens obtained from the first (initial/pre-study) and second (recurrent/on-study) surgery by immunohistochemistry for Rb status and downstream signaling of CDK4/6 inhibition. Participants with Rb-positive recurrent tumors continued ribociclib treatment on a 21-day-on, 7-day-off schedule after surgery, and were monitored for toxicity and disease progression. Results Three participants with recurrent Rb-positive GBM participated in this study. Mean unbound (pharmacologically active) ribociclib concentrations in plasma, CSF, MRI-enhancing, MRI-non-enhancing, and tumor core regions were 0.337 mu M, 0.632 mu M, 1.242 nmol/g, 0.484 nmol/g, and 1.526 nmol/g, respectively, which exceeded the in vitro IC50 (0.04 mu M) for inhibition of CDK4/6 in cell-free assay. Modulation of pharmacodynamic markers of ribociclib CDK 4/6 inhibition in tumor tissues were inconsistent between study participants. No participants experienced serious adverse events, but all experienced early disease progression. Conclusions This study suggests that ribociclib penetrated recurrent GBM tissue at concentrations predicted to be therapeutically beneficial. Our study was unable to demonstrate tumor pharmacodynamic correlates of drug activity. Although well tolerated, ribociclib monotherapy seemed ineffective for the treatment of recurrent GBM.