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

针对患有无法手术的复发性或难治性高级别胶质瘤的儿童、青少年和年轻人的新型靶向放射治疗的 1b 期开放标签研究

• 批准号: 10602610
• 负责人: Jarrod Longcor
• 金额: $ 103.48万
• 依托单位: CELLECTAR BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602610
• 关键词: Adolescent and Young Adult; Adult; Advanced Malignant Neoplasm; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cancer cell line; Cell Proliferation; Cell Survival; Central Nervous System Neoplasms; Child; Childhood; Childhood Glioma; Clinical; Clinical Research; Clinical Trials; Control Groups; Data; Development; Diagnostic; Disease; Disease-Free Survival; Dose; Enrollment; Evaluation; Excision; Exposure to; External Beam Radiation Therapy; FDA approved; Glioma; Half-Life; Hematologic Neoplasms; I131 isotope; Image; In Vitro; Investigation; Label; Lesion; Lipids; MRI Scans; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of thyroid; Medical; Membrane Microdomains; Microscopic; Monitor; Morbidity - disease rate; Nature; Neuroblastoma; Non-Hodgkin' s Lymphoma; Normal Cell; Normal tissue morphology; Patients; Pediatric Neoplasm; Peripheral; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase Ib Clinical Trial; Phospholipid Ethers; Phosphorylcholine; Population; Population Study; Primary carcinoma of the liver cells; Prognosis; Progression-Free Survivals; Property; Radiation exposure; Radio; Radioactive; Radiolabeled; Radiopharmaceuticals; Reaction Time; Recurrence; Refractory; Relapse; Risk; Rodent Model; Safety; Scanning; Series; Signal Pathway; Soft tissue sarcoma; Solid; Subgroup; Surgical margins; Targeted Radiotherapy; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Treatment Protocols; Tumor Volume; Venous; X-Ray Computed Tomography; Xenograft Model; analog; appropriate dose; arm; base; cancer cell; cancer type; chemotherapy; clinical development; dosimetry; efficacy evaluation; in vivo; intravenous administration; mouse model; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; open label; patient prognosis; pediatric patients; preclinical study; primary endpoint; radiation delivery; radiological imaging; response; secondary endpoint; single photon emission computed tomography; standard care; targeted agent; targeted delivery; targeted radiotherapeutic; treatment response; tumor; tumor growth; uptake; virtual

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.

抽象的 没有已知的小儿高级神经胶质瘤（HGGS）的治疗方法，这意味着所有患者最终都会进展，并且 患者的预后非常差，总生存期5年低于20％。有很高的未满足需求 新药，包括靶向放射性药物，最好具有越过血脑屏障的能力 并且具有特定于癌症的摄取，因为在第一或第二行中没有FDA批准的治疗 此时复发/耐火（R/R）设置。这些孩子经常被批准的毒品对待 对于几乎没有数据的类似成人指示，可以支持小儿HGG人群的使用或受到限制 在临床试验中进行研究。 CLR 131是一种包括核心的放射性碘化疗法 磷脂醚（PLE）类似物，18-（P-偶氮基）八甲苯二甲基磷胆碱，用碘131标记放射性标记。 癌细胞选择性的PLE和相关脂质的摄取涉及选择性插入脂质筏中。 恶性细胞比正常细胞具有更大量的脂质筏，这些脂质筏在空间上组织 信号通路并调节细胞增殖和存活。 CLR 131利用靶向肿瘤的特性 PLES提供靶向辐射到恶性肿瘤细胞的靶向输送，并最大程度地减少辐射暴露于 正常组织。此外，PLE和CLR 131证明了越过血脑屏障的能力 并提供足够的摄取对中枢神经系统肿瘤的摄取，从而改善了无进展生存率，总体 生存和应答率。 CLR 131是从一系列PLES中鉴定为啮齿动物中最佳输送剂的 型号。碘131被选为放射性成分，因为它的八天半衰期且已建立了良好的成分 多种成年和小儿癌类型的治疗能力。 CLR 131的治疗假设为 在非临床研究的数据中支持使用体外癌细胞系以及体内肿瘤的鼠 包括神经母细胞瘤，几种软组织肉瘤和血液系统恶性肿瘤的模型。迄今为止，结束 150名成人和小儿晚期R/R癌症患者已接受CLR 131，作为第1阶段和第2阶段的一部分 不同类型的癌症（包括固体和血液癌）中的临床试验，表明CLR 131可显着抑制肿瘤生长和对照组的总体生存益处。我们是 提出一个多中心，开放标签的1B剂量研究研究，以评估CLR的静脉内给药 131只有25名儿童，青少年和年轻人重复或难治性恶性HGG两剂 （每个剂量组25名儿童）。我们预测CLR 131在这项扩大的小儿人群研究中，将有一个 小儿和成年患者在相似水平的癌症患者和成年患者中观察到的安全性相似。这 计划下一步是一项关键阶段2/3研究，以评估CLR 131在儿童，青少年和 复发或难治性恶性HGG的年轻人。