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: 10705805
• 负责人: Jarrod Longcor
• 金额: $ 96.52万
• 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/10705805
• 关键词: Adolescent and Young Adult; Adult; Advanced Malignant Neoplasm; Brain; Brain Neoplasms; Cancer cell line; Cell Proliferation; Cell Survival; Central Nervous System Neoplasms; Child; Childhood; Childhood Glioma; Classification; 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; 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; Radioactive; Radiolabeled; Radiopharmaceuticals; Recommendation; Recurrence; Refractory; Relapse; 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; blood-brain barrier crossing; cancer cell; cancer type; cell type; chemotherapy; clinical development; dosimetry; efficacy evaluation; improved; 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; refractory cancer; 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.

摘要 儿童高级别胶质瘤（HGG）没有已知的治愈方法，这意味着所有患者最终都会进展， 患者的预后非常差，5年总生存率低于20%。有一个高度未满足的需求， 新药，包括靶向放射性药物，最好能穿过血脑屏障 并且具有癌症特异性摄取，因为在一线或二线中没有FDA批准的治疗方法， 复发/难治性（R/R）设置在这个时候。这些儿童经常使用批准的药物进行标签外治疗 用于类似的成人适应症，很少或没有数据支持在儿科HGG人群中使用，或受到限制 临床试验中的研究药物。放射性碘化疗法，其包含核 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PLEs和相关脂质涉及选择性插入脂筏。 恶性细胞的脂筏数量远多于正常细胞，这些脂筏在空间上是有序的 信号通路和调节细胞增殖和存活。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递送，并最大限度地减少 正常组织此外，PLEs和PDE 131已经证明了穿过血脑屏障的能力 并提供足够的CNS肿瘤摄取，以改善无进展生存期， 生存率和反应率。从一系列的PLEs中筛选出131作为啮齿动物体内的最佳给药药物 模型由于碘-131的半衰期为8天且已得到公认，因此被选为放射性成分 多种成人和儿童癌症类型的治疗能力。对131的治疗假设是 得到了使用体外癌细胞系以及体内荷瘤鼠的非临床研究数据的支持 包括神经母细胞瘤、几种软组织肉瘤和血液恶性肿瘤的模型。迄今为止， 作为第1阶段和第2阶段的一部分，150名患有晚期r/r癌症的成人和儿童患者接受了CLR 131治疗 在不同类型的癌症（包括实体癌和血液癌）中进行的临床试验表明， 131提供了对肿瘤生长的显著抑制和优于对照组的总体存活益处。我们 提出了一项多中心、开放标签、1b期剂量探索研究，评估静脉给药的利多卡因， 两次给药后，多达25例复发性或难治性恶性HGG儿童、青少年和年轻成人中发生131例 (25每个剂量组的儿童）。我们预测，在这项扩大的儿科人群研究中， 与在以相似水平给药的儿童和成人癌症患者中观察到的安全性特征相似。的 计划的下一步是一项关键的2/3期研究，以评估BMP 131在儿童，青少年和 复发性或难治性恶性HGG的年轻成人。