A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors
A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors
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DOI：
10.1158/1078-0432.ccr-16-2898
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发表时间：
2017-05-15
影响因子：
11.5
通讯作者：
Chi, Susan N.
中科院分区：
文献类型：
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作者：
Geoerger, Birgit;Bourdeaut, Franck;Chi, Susan N.
目的：细胞周期蛋白依赖性激酶（CDK）4/6抑制剂ribociclib（LEE 011）在神经母细胞瘤和恶性横纹肌样瘤（MRT）模型中显示出临床前活性。在这项I期研究中，在患有神经母细胞瘤、MRT或其他细胞周期蛋白D-CDK 4/6-INK 4-视网膜母细胞瘤通路改变的肿瘤的儿科患者中研究了ribociclib单药的最大耐受剂量（MTD）和推荐II期剂量（RP 2D）、安全性、药代动力学（PK）和初步活性。患者（1-21岁）接受递增的每日一次口服ribociclib剂量（3周给药/1周停药）。结果：32名患者（中位年龄5.5岁）接受了280、350或470 mg/m2的ribociclib治疗（中位年龄5.5岁）。3例患者出现3级疲劳（280 mg/m2; n = 1）或4级血小板减少（470 mg/m2; n = 2）的剂量限制性毒性。最常见的治疗相关不良事件（AE）为血液学：细胞减少（72%所有等级/63% 3/4级），白细胞减少症（63%/ 38%）、贫血（44%/3%）、血小板减少（44%/28%）和淋巴细胞减少（38%/19%），其次是呕吐（38%/0%）、疲乏（25%/3%）、恶心（25%/0%），QTc间期延长（22%/0%）。Ribociclib的暴露量在350和470 mg/m2 [相当于成人600（RP 2D）-900 mg]时呈剂量依赖性，患者间变异性高。9例患者的最佳总体缓解为疾病稳定（SD）（7例神经母细胞瘤，2例原发性CNS MRT）; 5例患者分别在6、6、8、12和13个周期以上达到SD。MTD（470 mg/m2）和RP 2D（350 mg/m2）与成人相当。SD延长的观察结果支持进一步研究ribociclib联合其他药物治疗神经母细胞瘤和MRT。(C)2017年AACR。
Purpose: The cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib (LEE011), displayed preclinical activity in neuroblastoma and malignant rhabdoid tumor (MRT) models. In this phase I study, the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D-CDK4/6-INK4-retinoblastoma pathway-altered tumors.Experimental Design: Patients (aged 1-21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off). Dose escalation was guided by a Bayesian logistic regression model with overdose control and real-time PK.Results: Thirty-two patients (median age, 5.5 years) received ribociclib 280, 350, or 470 mg/m(2). Three patients had dose-limiting toxicities of grade 3 fatigue (280 mg/m(2); n = 1) or grade 4 thrombocytopenia (470 mg/m(2); n = 2). Most common treatment-related adverse events (AE) were hematologic: neutropenia (72% all-grade/63% grade 3/4), leukopenia (63%/ 38%), anemia (44%/3%), thrombocytopenia (44%/28%), and lymphopenia (38%/19%), followed by vomiting (38%/0%), fatigue (25%/3%), nausea (25%/0%), and QTc prolongation (22%/0%). Ribociclib exposure was dose-dependent at 350 and 470 mg/m(2) [equivalent to 600 (RP2D)-900 mg in adults], with high interpatient variability. Best overall response was stable disease (SD) in nine patients (seven with neuroblastoma, two with primary CNS MRT); five patients achieved SD for more than 6, 6, 8, 12, and 13 cycles, respectively.Conclusions: Ribociclib demonstrated acceptable safety and PK in pediatric patients. MTD (470 mg/m(2)) and RP2D (350 mg/m2) were equivalent to those in adults. Observations of prolonged SD support further investigation of ribociclib combined with other agents in neuroblastoma and MRT. (C) 2017 AACR.