A Phase 1b, Open-Label, Study of a Novel Targeted Radiotherapy in Children, Adolescents and Young Adults with Inoperable Relapsed or Refractory High Grade Glioma

摘要 目前还没有已知的治疗儿童高级别胶质瘤(HGG)的方法，这意味着所有患者最终都会进步和 患者预后很差，5年总生存率低于20%。有很高的未满足的需求 新药，包括靶向放射性药物，最好具有跨越血脑屏障的能力 有癌症特异性吸收，因为FDA没有批准的一线或二线或 此时的复发/难治(r/r)设置。这些儿童经常被批准使用非处方药物进行治疗。 对于类似的成人适应症，几乎没有数据支持在儿童HGG人群中使用，或受到限制 临床试验中的研究试剂。CLR 131是一种放射性碘化疗法，包括一个核心 磷脂醚(PLE)类似物，18-(对碘苯基)十八烷基磷胆碱，用碘-131放射性标记。 癌细胞选择性摄取PLE和相关的脂类包括选择性地插入脂筏。 恶性细胞具有比正常细胞多得多的脂筏，这些脂筏在空间上组织起来 信号通路和调节细胞的增殖和存活。CLR 131利用肿瘤靶向特性 为恶性肿瘤细胞提供有针对性的辐射，并将辐射暴露在最低限度 正常组织。此外，PLES和CLR 131已经证明了跨越血脑屏障的能力 并提供对中枢神经系统肿瘤的足够摄取，从而总体上改善无进展生存期 存活率和应答率。CLR131是从一系列的PLE中鉴定出来的啮齿动物的最佳递送剂 模特们。由于碘-131的半衰期长达8天，且具有良好的稳定性，因此被选为放射性成分。 治疗多种成人和儿童癌症类型的能力。CLR 131的治疗假说是 来自使用体外癌细胞系和体内荷瘤小鼠的非临床研究的数据支持 模型包括神经母细胞瘤、几种软组织肉瘤和血液系统恶性肿瘤。到目前为止，完毕 150名患有晚期r/r癌症的成人和儿童患者接受了CLR 131，作为第一阶段和第二阶段的一部分。 在不同类型的癌症(包括实体癌和血液癌)的临床试验表明，CLR 与对照组相比，131可显著抑制肿瘤生长，并使总体生存受益。我们是 提出一项评价CLR静脉给药的多中心、开放标记、1b期剂量发现研究 131次，用于多达25名复发或难治性恶性HGG的儿童、青少年和年轻人 (每剂量组25名儿童)。我们预测，在这项扩大的儿科人群研究中，CLR 131将有一个 与在儿童和成人癌症患者中观察到的相似剂量的安全性相似。这个 计划的下一步是一项关键的2/3阶段研究，以评估CLR 131在儿童、青少年和 患有复发或难治性恶性HGG的年轻人。

ABSTRACT There is no known cure for pediatric high grade gliomas (HGGs), meaning all patients eventually progress and the prognosis for patients is very poor with 5 year overall survival below 20%. There is a high unmet need for new drugs, including targeted radiopharmaceuticals, preferably with the ability to cross the blood-brain barrier and have cancer-specific uptake, as there are no FDA approved treatments in either the 1st or 2nd line or relapsed/refractory (r/r) setting at this time. These children are frequently treated off-label with drugs approved for similar adult indications with little to no data to support the use in a pediatric HGG population, or are restricted to investigational agents within clinical trials. CLR 131 is a radio-iodinated therapy comprising a core phospholipid ether (PLE) analogue, 18-(p-iodophenyl)octadecyl phosphocholine, radiolabeled with iodine-131. The cancer cell-selective uptake of PLEs and related lipids involves the selective insertion into lipid rafts. Malignant cells have far greater amounts of lipid rafts than normal cells and these lipid rafts spatially organize signalling pathways and regulate cell proliferation and survival. CLR 131 exploits the tumor-targeting properties of PLEs to provide a targeted delivery of radiation to malignant tumor cells and minimizes radiation exposure to normal tissues. Additionally, PLEs and CLR 131 have demonstrated the ability to cross the blood-brain barrier and provide sufficient uptake into CNS tumors to result in improvements in progression free survival, overall survival and response rates. CLR 131 was identified from a series of PLEs as the optimal delivery agent in rodent models. Iodine-131 was chosen as the radioactive constituent due to its eight-day half-life and well-established therapeutic capabilities in multiple adult and pediatric cancer types. The therapeutic hypothesis for CLR 131 is supported by data from nonclinical studies using in vitro cancer cell lines as well as in vivo tumor bearing murine models which include neuroblastoma, several soft tissue sarcomas and hematologic malignancies. To date, over 150 adult and pediatric patients with advanced r/r cancers have received CLR 131, as part of Phase 1 and 2 clinical trials in different types of cancers (including solid and hematological cancers), demonstrating that CLR 131 provides significant inhibition of tumor growth and an overall survival benefit over control groups. We are proposing a multi-center, open-label, Phase 1b dose finding study evaluating intravenous administration of CLR 131 in up to 25 children, adolescents and young adults with recurrent or refractory malignant HGG at two doses (25 children per dose group). We predict that CLR 131, in this expanded pediatric population study, will have a similar safety profile as was observed in pediatric and adult patients with cancer dosed at similar levels. The planned next step is a pivotal Phase 2/3 study to evaluate the efficacy of CLR 131 in children, adolescents and young adults with recurrent or refractory malignant HGG.