Department of Pediatrics College of Medicine, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, University of Cincinnati, Cincinnati, Ohio
Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Clin Cancer Res. 2021 May 1;27(9):2442-2451. doi: 10.1158/1078-0432.CCR-20-4078. Epub 2021 Feb 5.
Genomic aberrations in cell cycle and PI3K pathways are commonly observed in pediatric brain tumors. This study determined the MTD/recommended phase II dose (RP2D) of ribociclib and everolimus and characterized single-agent ribociclib concentrations in plasma and tumor in children undergoing resection.
Patients were enrolled in the phase I study according to a rolling 6 design and received ribociclib and everolimus daily for 21 and 28 days, respectively. Surgical patients received ribociclib at the pediatric RP2D (350 mg/m) for 7-10 days preoperatively followed by enrollment on the phase I study. Pharmacokinetics were analyzed for both cohorts.
Sixteen patients were enrolled on the phase I study (median age, 10.3 years; range, 3.9-20.4) and 6 patients in the surgical cohort (median age, 11.4 years; range: 7.2-17.1). Thirteen patients were enrolled at dose level 1 without dose-limiting toxicities (DLT). Two of the 3 patients at dose level 2 experienced DLTs (grade 3 hypertension and grade 4 alanine aminotransferase). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leukopenia. The RP2D of ribociclib and everolimus was 120 and 1.2 mg/m for 21 and 28 days, respectively. Steady-state everolimus exposures with ribociclib were 2.5-fold higher than everolimus administered alone. Ribociclib plasma, tumor concentrations, and cerebrospinal fluid (CSF) samples were collected. The mean tumor-to-plasma ratio of ribociclib was 19.8 (range, 2.22-53.4).
Ribociclib and everolimus were well-tolerated and demonstrated pharmacokinetic properties similar to those in adults. Potential therapeutic ribociclib concentrations could be achieved in CSF and tumor tissue, although interpatient variability was observed.
细胞周期和 PI3K 通路的基因组异常在小儿脑肿瘤中很常见。本研究旨在确定瑞博西利（ribociclib）和依维莫司（everolimus）的最大耐受剂量/推荐的 II 期剂量（RP2D），并对接受切除术的儿童的血浆和肿瘤中的单药瑞博西利浓度进行特征分析。
根据滚动 6 设计，患者入组进行 I 期研究，并分别接受瑞博西利和依维莫司每日治疗 21 天和 28 天。手术患者在术前接受小儿 RP2D（350mg/m）的瑞博西利治疗 7-10 天，然后入组 I 期研究。对两个队列均进行药代动力学分析。
16 名患者入组 I 期研究（中位年龄为 10.3 岁；范围：3.9-20.4），6 名患者入组手术队列（中位年龄为 11.4 岁；范围：7.2-17.1）。13 名患者在无剂量限制性毒性（DLT）的剂量水平 1 入组。2 名剂量水平 2 的患者出现 DLT（3 级高血压和 4 级丙氨酸转氨酶）。最常见的 3/4 级毒性是淋巴细胞减少、中性粒细胞减少和白细胞减少。瑞博西利和依维莫司的 RP2D 分别为 21 天和 28 天的 120mg/m 和 1.2mg/m。与单独给予依维莫司相比，瑞博西利稳态时的依维莫司暴露量增加了 2.5 倍。收集了瑞博西利的血浆、肿瘤浓度和脑脊液（CSF）样本。瑞博西利的平均肿瘤与血浆比值为 19.8（范围：2.22-53.4）。
瑞博西利和依维莫司耐受性良好，药代动力学特征与成人相似。虽然观察到个体间的差异，但瑞博西利可能在 CSF 和肿瘤组织中达到治疗浓度。
