Phase I/II Study of 177Lu-DOTATATE in Children and Young Adults with Recurrent/Progressive High-Grade CNS Tumors and Meningiomas which Express Somatostatin Type 2A Receptors [9/24/21 IND]

177Lu-DOTATATE 在患有表达 2A 型生长抑素受体的复发性/进行性高级别 CNS 肿瘤和脑膜瘤的儿童和年轻人中的 I/II 期研究 [9/24/21 IND]

• 批准号: 10504651
• 负责人: Margot Lazow
• 金额: $ 78.48万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10504651
• 关键词: Phase; II; Study; 177Lu; DOTATATE

Project Summary/Abstract There is a critical need to develop novel effective, well-tolerated therapies for children and young adults with recurrent or progressive high-grade central nervous system (CNS) tumors and meningiomas, who currently have limited treatment options and an extremely poor prognosis. Somatostatin receptors regulate cell growth through complex downstream modulation of both proliferation and apoptosis signaling pathways, and thus represent a potential therapeutic target. 177Lu-DOTATATE, a radionuclide therapy which binds type-2A somatostatin receptors (SST2A) and delivers local radiation via beta particle emission, has recently gained FDA approval for the treatment of gastroenteropancreatic neuroendocrine tumors given efficacy and safety data in adults with these SST2A-expressing tumors. There is potential for successful expansion of 177Lu-DOTATATE to pediatric and young adult neuro-oncology, based upon growing evidence that many CNS tumors are characterized by high SST2A expression, exhibit corresponding uptake on somatostatin receptor imaging (e.g., DOTATATE PET), and have preliminary data demonstrating response (disease stabilization or regression) to somatostatin receptor- targeted therapy in case reports/series, suggesting sufficient CNS penetration to achieve therapeutic benefit. Minimal toxicity has been observed aside from a low prevalence of myelosuppression. We, therefore, are conducting a phase I/II trial assessing safety and efficacy of 177Lu-DOTATATE in pediatric and young adult patients with refractory SST2A-expressing high-grade CNS tumors (medulloblastoma and other embryonal tumors, high-grade gliomas including DIPG, and anaplastic ependymomas) and meningiomas, using both SST2A immunohistochemistry and DOTATATE PET imaging as screening criteria for eligibility to ensure presence of the target. The primary aims of this proposal are to (1) establish the maximally tolerated dose (MTD)/ recommended phase II dose (RP2D) of 177Lu-DOTATATE in pediatric patients with recurrent or progressive CNS tumors [Phase I arm] and (2) evaluate efficacy of 177Lu-DOTATATE in adolescent and young adult patients, administered at the FDA-approved adult dosing, assessed via 6-month progressive-free survival compared to historical controls [Phase II arm]. Several exploratory studies will be incorporated, with goals of (1) determining the prevalence, heterogeneity, and key clinical, radiographic, histopathologic, and molecular correlates of SST2A expression across pediatric and young adult CNS tumors, (2) identifying imaging (DOTATATE PET and MRI) and peripheral blood or cerebrospinal fluid (‘liquid biopsy’)- based molecular biomarkers predictive of response to 177Lu-DOTATATE, and (3) characterizing radiation dosimetry of 177Lu-DOTATATE to estimate tumor dose/CNS penetration and minimize toxicity risk, including in patients who received prior cranial radiation. If a preliminary efficacy signal is detected, further research will be planned to expand this targeted radiotherapy to a larger patient population with refractory brain/spine tumors and eventually incorporate 177Lu-DOTATATE into upfront treatment backbones for these aggressive diseases.

项目摘要/摘要 迫切需要开发新的有效、耐受性良好的治疗方法来治疗儿童和年轻人 复发或进展性高级别中枢神经系统肿瘤和脑膜瘤，目前 治疗选择有限，预后极差。生长抑素受体通过以下途径调节细胞生长 增殖和凋亡信号通路的复杂下游调控，因此代表着一种 潜在的治疗靶点。177Lu-DOTATE，一种结合2A型生长抑素的放射性核素疗法 受体(SST2A)，并通过β粒子发射提供局部辐射，最近获得FDA批准用于 成人胃肠胰脏神经内分泌肿瘤的疗效和安全性研究 这些表达SST2A的肿瘤。177Lu-DOTATE有成功扩展到儿科的潜力 和年轻人的神经肿瘤学，基于越来越多的证据表明，许多中枢神经系统肿瘤的特征是 SST2a高表达，在生长抑素受体成像(例如，DOTATE PET)上表现出相应的摄取， 并有初步数据表明对生长抑素受体的反应(疾病稳定或退化)- 病例报告/系列中的靶向治疗，建议有足够的中枢神经系统渗透以实现治疗益处。 除了骨髓抑制的发生率很低外，还观察到了最小的毒性。因此，我们是 进行一项I/II期试验，评估177 Lu-DOTATE在儿童和青年中的安全性和有效性 成人难治性SST2A高级别中枢神经系统肿瘤(髓母细胞瘤和其他 胚胎性肿瘤、包括DIPG在内的高级别胶质瘤和间变性室管膜瘤)和 应用SST2A免疫组织化学和DOTATE PET显像筛查脑膜瘤 确保目标存在的资格标准。这项建议的主要目的是(1)建立 ~(177)Lu-DOTATE在儿童中的最大耐受量(MTD)/推荐II期剂量(RP2D) 复发或进展的中枢神经系统肿瘤患者[I期ARM]和(2)评价177Lu-DOTATE的疗效 青少年和年轻成人患者，按FDA批准的成人剂量给药，通过6个月的评估 与历史对照相比，无进展生存[第二阶段ARM]。几项探索性研究将 合并，目标是(1)确定患病率、异质性和关键的临床、放射学、 儿童和年轻成人中枢神经系统肿瘤中SST2A表达的组织病理学和分子相关性， (2)识别成像(DOTATE PET和MRI)和外周血液或脑脊液(‘液体活检’)- 基于分子生物标志物的对177Lu-DOTATE反应的预测，以及(3)表征辐射 177Lu-DOTATE剂量学评估肿瘤剂量/中枢神经系统渗透并将毒性风险降至最低，包括在 接受过颅骨放射治疗的患者。如果检测到初步的疗效信号，将进行进一步的研究 计划将这种定向放射治疗扩大到更多患有难治性脑/脊柱肿瘤的患者群体 并最终将177 Lu-DOTATE纳入这些侵袭性疾病的前期治疗骨干中。