Phase I or II Study of Ribociclib in Combination With Topotecan-Temozolomide or Everolimus in Children With Advanced Malignancies: Arms A and B of the AcSe-ESMART Trial
Phase I or II Study of Ribociclib in Combination With Topotecan-Temozolomide or Everolimus in Children With Advanced Malignancies: Arms A and B of the AcSe-ESMART Trial
复制标题
DOI：
10.1200/jco.21.01152
复制
发表时间：
2021-11-10
影响因子：
45.3
通讯作者：
Geoerger, Birgit
中科院分区：
文献类型：
--
作者：
Bautista, Francisco;Paoletti, Xavier;Geoerger, Birgit
AcSe-ESMART是一项概念验证、I期或II期平台试验，旨在探索分子富集癌症人群中的靶向药物。A组和B组旨在分别确定CDK 4/6抑制剂ribociclib与托泊替康和替莫唑胺（TOTEM）或依维莫司的推荐II期剂量和活性，患者和方法在TOTEM后每天口服Ribociclib一次，持续16天，持续5天（A组）或21天，与依维莫司一起口服，每天一次，持续28天。日周期（B组）。剂量递增遵循连续再评估方法，活性评估遵循Ensign设计。根据细胞周期或PI 3 K/AKT/mTOR信号通路的分子改变，对32例患者进行了分组，A组14例，B组18例，31例接受了治疗。肉瘤14例（43.8%），脑肿瘤13例（40.6%）。主要毒副反应为白细胞减少、中性粒细胞减少和淋巴细胞减少。推荐的II期剂量为ribociclib 260 mg/m2每日一次、替莫唑胺100 mg/m2每日一次和拓扑替康0.5 mg/m2每日一次（A组）以及ribociclib 175 mg/m2每日一次和依维莫司2.5 mg/m2每日一次（B组）。药代动力学分析证实了ribociclib对依维莫司暴露的药物相互作用。A组2例患者（14.3%）的最佳缓解为疾病稳定，B组7例（41.2%），包括1例T急性淋巴细胞白血病患者，原始细胞计数显著降低。在25例患者（81%）和9例稳定疾病患者中的8例中存在考虑富集的改变;白血病表现出CDKN 2A/B和PTEN缺陷。观察到的活性信号启动了在两种途径中富含分子改变的人群中对ribociclib-依维莫司组合的后续研究。(C)2021年美国临床肿瘤学会
PURPOSE AcSe-ESMART is a proof-of-concept, phase I or II, platform trial, designed to explore targeted agents in a molecularly enriched cancer population. Arms A and B aimed to define the recommended phase II dose and activity of the CDK4/6 inhibitor ribociclib with topotecan and temozolomide (TOTEM) or everolimus, respectively, in children with recurrent or refractory malignancies.PATIENTS AND METHODS Ribociclib was administered orally once daily for 16 days after TOTEM for 5 days (arm A) or for 21 days with everolimus orally once daily continuously in a 28-day cycle (arm B). Dose escalation followed the continuous reassessment method, and activity assessment the Ensign design. Arms were enriched on the basis of molecular alterations in the cell cycle or PI3K/AKT/mTOR pathways.RESULTS Thirty-two patients were included, 14 in arm A and 18 in arm B, and 31 were treated. Fourteen patients had sarcomas (43.8%), and 13 brain tumors (40.6%). Main toxicities were leukopenia, neutropenia, and lymphopenia. The recommended phase II dose was ribociclib 260 mg/m(2) once a day, temozolomide 100 mg/m(2) once a day, and topotecan 0.5 mg/m(2) once a day (arm A) and ribociclib 175 mg/m(2) once a day and everolimus 2.5 mg/m(2) once a day (arm B). Pharmacokinetic analyses confirmed the drug-drug interaction of ribociclib on everolimus exposure. Two patients (14.3%) had stable disease as best response in arm A, and seven (41.2%) in arm B, including one patient with T-acute lymphoblastic leukemia with significant blast count reduction. Alterations considered for enrichment were present in 25 patients (81%) and in eight of nine patients with stable disease; the leukemia exhibited CDKN2A/B and PTEN deficiency.CONCLUSION Ribociclib in combination with TOTEM or everolimus was well-tolerated. The observed activity signals initiated a follow-up study of the ribociclib-everolimus combination in a population enriched with molecular alterations within both pathways. (C) 2021 by American Society of Clinical Oncology