Pediatric Neuro-Oncology, Dana-Farber Boston Children's Cancer Blood Disorders Center, Harvard Medical School, Boston, Massachusetts, USA; The Royal Marsden Hospital, Sutton, Surrey, UK; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Medical Oncology, Azienda USL-IRCCS Institute of Neurological Science, Bologna, Italy; Institut Curie and University Paris Descartes, Paris, France; Division of Haematology/Oncology at The Hospital for Sick Children, Toronto, Ontario, Canada; Sir James Spence Institute of Child Health Royal Victoria Infirmary, Newcastle, UK; Seattle Children's Hospital, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA; The Royal Children's Hospital, Children's Cancer Center, Melbourne, Australia; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA; Catholic University of the Sacred Heart, Rome, Italy; Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Paediatric Oncology Unit, Great Ormond Street Hospital, London, UK; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA; Gustave Roussy, Department of Pediatric and Adolescent Oncology, University Paris-Sud, Université Paris-Saclay, Villejuif, France.
Neuro Oncol. 2017 Oct 19;19(11):1542-1552. doi: 10.1093/neuonc/nox109.
BACKGROUND: Sonidegib (LDE225) is a potent, selective hedgehog (Hh) inhibitor of Smoothened. This study explored the safety and pharmacokinetics of sonidegib in children with relapsed/recurrent tumors followed by a phase II trial in pediatric and adult patients with relapsed medulloblastoma (MB) to assess tumor response. METHODS: Pediatric patients aged ≥1 to <18 years were included according to a Bayesian design starting at 372 mg/m2 of continuous once daily oral sonidegib. Tumor samples were analyzed for Hh pathway activation using a validated 5-gene Hh signature assay. In phase II, pediatric patients were treated at the recommended phase II dose (RP2D) while adults received 800 mg daily. RESULTS: Sixteen adult (16 MB) and 60 pediatric (39 MB, 21 other) patients with an age range of 2-17 years were enrolled. The RP2D of sonidegib in pediatric patients was established at 680 mg/m2 once daily. The phase II study was closed prematurely. The 5-gene Hh signature assay showed that the 4 complete responders (2 pediatric and 2 adult) and 1 partial responder (adult) all had Hh-activated tumors, while 5 patients with activated Hh had either stable disease (n = 3) or progressive disease (n = 2). No patient with an Hh-negative signature (n = 50) responded. The safety profile for pediatric patients was generally consistent with the one established for adult patients; however, growth plate changes were observed in prepubertal pediatric patients. CONCLUSIONS: Sonidegib was well tolerated and the RP2D in pediatric patients was 680 mg/m2 once daily. Five of the 10 MB patients with activated Hh pathway demonstrated complete or partial responses.
背景：Sonidegib（LDE225）是一种有效的、选择性的 Hedgehog（Hh）抑制剂，作用于 Smoothened。本研究旨在探讨复发/难治性肿瘤患儿应用 Sonidegib 的安全性和药代动力学，并进一步在复发髓母细胞瘤（MB）患儿和成人患者中开展 II 期临床试验，以评估肿瘤的应答情况。 方法：根据贝叶斯设计方案，纳入年龄≥1 岁且＜18 岁的儿科患者，起始剂量为 372mg/m2，每日口服 Sonidegib 持续给药。采用经验证的 5 基因 Hh 特征分析方法检测肿瘤组织中 Hh 通路的激活情况。在 II 期临床试验中，儿科患者采用推荐的 II 期剂量（RP2D）治疗，而成年患者接受 800mg 每日给药。 结果：共纳入 16 例成年（16 例 MB）和 60 例儿科（39 例 MB，21 例其他肿瘤）患者，年龄 2-17 岁。儿科患者的 RP2D 确定为 680mg/m2，每日一次。II 期临床试验提前终止。5 基因 Hh 特征分析显示，4 例完全应答者（2 例儿科患者，2 例成年患者）和 1 例部分应答者（成年患者）的肿瘤均存在 Hh 激活，而 5 例 Hh 激活的患者中，有 3 例疾病稳定，2 例疾病进展。未观察到 Hh 阴性特征（n=50）的患者有应答。儿科患者的安全性与成年患者的安全性一致，但在青春期前的儿科患者中观察到生长板改变。 结论：Sonidegib 具有良好的耐受性，儿科患者的 RP2D 为 680mg/m2，每日一次。在 10 例 Hh 通路激活的 MB 患者中，有 5 例患者观察到完全或部分应答。
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