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 目前尚无已知的儿科高级别胶质瘤 (HGG) 治愈方法，这意味着所有患者最终都会进展并 患者的预后非常差，5年总生存率低于20%。有很高的未满足需求 新药，包括靶向放射性药物，最好能够穿过血脑屏障 并且具有癌症特异性吸收，因为在第一线或第二线中没有 FDA 批准的治疗方法 此时的复发/难治性 (r/r) 设置。这些儿童经常接受批准药物的超说明书治疗 对于类似的成人适应症，几乎没有数据支持在儿科 HGG 人群中使用，或者受到限制 临床试验中的研究药物。 CLR 131 是一种放射性碘疗法，其核心包括 磷脂醚 (PLE) 类似物，18-(对碘苯基)十八烷基磷酸胆碱，用碘 131 放射性标记。 癌细胞选择性摄取 PLE 和相关脂质涉及选择性插入脂筏中。 恶性细胞比正常细胞具有更多数量的脂筏，并且这些脂筏在空间上组织 信号通路并调节细胞增殖和存活。 CLR 131 利用肿瘤靶向特性 PLE 向恶性肿瘤细胞提供有针对性的放射治疗，并最大限度地减少放射暴露 正常组织。此外，PLE 和 CLR 131 已被证明能够穿过血脑屏障 并为中枢神经系统肿瘤提供足够的摄取，以改善总体无进展生存期 生存率和缓解率。 CLR 131 从一系列 PLE 中被确定为啮齿动物的最佳递送剂 模型。碘 131 被选为放射性成分，因为它的半衰期为 8 天，并且已被证实 对多种成人和儿童癌症类型的治疗能力。 CLR 131 的治疗假设是 得到使用体外癌细胞系以及体内荷瘤小鼠的非临床研究数据的支持 模型包括神经母细胞瘤、几种软组织肉瘤和血液恶性肿瘤。迄今为止，已结束 作为 1 期和 2 期的一部分，150 名患有晚期 r/r 癌症的成人和儿童患者已接受 CLR 131 针对不同类型癌症（包括实体癌和血液癌）的临床试验表明，CLR 与对照组相比，131 可显着抑制肿瘤生长并提高总体生存率。我们是 提议开展一项多中心、开放标签、1b 期剂量探索研究，评估 CLR 静脉给药 131 多达 25 名患有复发性或难治性恶性 HGG 的儿童、青少年和年轻人，服用两剂 （每个剂量组 25 名儿童）。我们预测，在这项扩大的儿科人群研究中，CLR 131 将具有 与在类似水平的儿童和成人癌症患者中观察到的安全性相似。这 计划的下一步是一项关键的 2/3 期研究，以评估 CLR 131 对儿童、青少年和 患有复发性或难治性恶性 HGG 的年轻人。