Clinical Development of Rhenium Nanoliposomes (RNL186) for Glioblastoma

铼纳米脂质体 (RNL186) 治疗胶质母细胞瘤的临床开发

• 批准号: 10242665
• 负责人: Andrew Jacob Brenner
• 金额: $ 58.19万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-09 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242665
• 关键词: Address; Adult; Agreement; Algorithms; Animals; Bioluminescence; Blinded; Brain; Brain Neoplasms; Canis familiaris; Catheters; Charge; Chelating Agents; Chemistry; Cholesterol; Clinical Research; Combined Modality Therapy; Convection; Custom; Data; Diagnostic radiologic examination; Distant; Dose; Encapsulated; Enrollment; Glioblastoma; Glioma; Goals; Hour; Infusion procedures; Injections; Investigation; Isotopes; Laboratories; Laboratory Study; Lipids; Liposomes; Luciferases; Malignant Glioma; Malignant neoplasm of brain; Methods; Modeling; Nanotechnology; National Cancer Institute; Normal tissue morphology; Operative Surgical Procedures; Organ; Pathologic; Patients; Pharmaceutical Preparations; Phase; Prospective Studies; Protocols documentation; Radiation; Radiation Dose Unit; Radiation therapy; Radioactivity; Radiobiology; Radioisotopes; Radionuclide therapy; Rattus; Reagent; Recurrence; Residual Tumors; Rhenium; Route; Safety; Scheme; Shapes; Site; Techniques; Testing; Therapeutic; Time; Tissues; Toxic effect; U251; United States Food and Drug Administration; Xenograft Model; animal data; aqueous; arm; base; chemotherapy; clinical development; cohort; experience; experimental study; good laboratory practice; improved; lipophilicity; mathematical model; nanoliposome; nanoparticle; novel therapeutics; open label; particle; phase 1 study; primary endpoint; radiation absorbed dose; safety study; simulation; spatiotemporal; technology development; tumor

Glioblastoma (GBM) is the most common and most aggressive of the primary malignant brain tumor in adults, with a median overall survival of 19.6 months following multi-modality therapy. The main limiting factor in delivering a tumoricidal radiation dose is the toxicity to surrounding brain. Therapeutic radionuclides, due to a short tissue path and differences in radiobiology, have the potential to extend the therapeutic window for radiation in GBM. However, a carrier is needed to deliver the isotope to the brain and maintain its localization at the desired site, as otherwise they quickly disperse. Liposomal encapsulation has the potential to facilitate radioisotope retention within the tissue, but a method for the efficient loading of liposomes with the radioisotopes was needed. This has been an essential limiting factor in the development of this technology, and has now been successfully addressed. To overcome this, we have developed an encapsulation method using a custom lipophilic molecule (BMEDA) that carries the rhenium radionuclides into the aqueous compartment of the liposome nanoparticles. The final investigational product is Rhenium nanoliposomes (186RNL). To characterize the retention, tolerability, and activity of 186RNL, we performed intratumoral infusions of 186RNL in rats bearing glioblastoma tumors. Increasing doses as high as 30-fold typical external beam doses consistently showed that animals tolerated all doses without evidence of harm, and were associated with marked survival differences. In addition, many of the rats had no residual tumor. A toxicity study was performed in beagles with 186RNL or blank control nanoliposomes and produced no significant changes systemically or in the brains of dogs at 24 hours or 14 Days. In order to further characterize the drug product and address chemistry, manufacturing, and control concerns of FDA, we entered into a collaborative agreement with the Nanotechnology Characterization Laboratory (NCL) of the National Cancer Institute (NCI). NCL was provided with manufacturing protocols, reagents, and representative lots manufactured at the UTHSA. No significant difference was observed between RNL manufactured at the two sites and with marked stability of final product observed. The drug was cleared by the FDA to proceed to clinical study shortly thereafter. It is our specific hypothesis that 186RNL can safely be administered to patients with recurrent progressive GBM at much higher radiation doses than can be achieved with current techniques, and that treatment with 186RNL will markedly improve survival in GBM patients. Continued clinical development is warranted. We therefore propose to test the maximum tolerable dose and safety profile of 186RNL in patients with recurrent glioma, determine the efficacy of 186RNL in recurrent glioblastoma, and to develop and validate a mathematical model to predict the distribution of 186RNL. The immediate goal of this Aim is to use early time point, patient-specific data, to calibrate a mechanism-based model, thereby allowing for the accurate prediction of the distribution of 186RNL as a function of time. This model will be developed using data established in Aim 1, then used before delivery of 186RNL in the selection of the optimal point of injection in in Aim 2.

胶质母细胞瘤（GBM）是成年人中最常见和最具侵略性的原发性恶性脑肿瘤， 多模式疗法后，总体生存期为19.6个月。主要限制因素 输送肿瘤辐射剂量是对周围大脑的毒性。由于A 短组织路径和放射生物学的差异具有扩展辐射治疗窗口的潜力 在GBM中。但是，需要载体将同位素传递给大脑并保持其本地化 所需的网站，否则它们很快就会分散。脂质体封装有可能促进 在组织内的放射性同位素保留率，但一种用放射性同位素有效加载脂质体的方法 需要。这一直是该技术开发的基本限制因素，现在已经 成功解决。为了克服这一点，我们使用自定义开发了一种封装方法 亲脂分子（BMEDA），将rad核素携带到rad核的水室 脂质体纳米颗粒。最终的研究产物是鼻nanoliposomes（186RNL）。 为了表征186RNL的耐受性，耐受性和活性，我们进行了186RNL的肿瘤内输注 在带有胶质母细胞瘤肿瘤的大鼠中。增加剂量高达30倍的典型外束剂量 表明动物耐受所有剂量而没有损害的剂量，并且与显着的生存有关 差异。此外，许多大鼠没有残留肿瘤。在Begles中进行了毒性研究 186RNL或空白对照纳米脂质体，没有系统或在狗的大脑中产生重大变化 在24小时或14天。为了进一步描述药物并解决化学，制造业， 和控制FDA的控制问题，我们与纳米技术达成了一项合作协议 国家癌症研究所（NCI）的特征实验室（NCL）。 NCL提供了制造 在UTHSA生产的协议，试剂和代表性地块。没有观察到显着差异 在两个地点生产的RNL之间，并观察到最终产品的明显稳定性。该药物是 此后不久，由FDA清除了进行临床研究。我们的具体假设是186rnl可以 安全地对复发性GBM的患者施用，辐射剂量要高得多 通过当前技术实现，使用186RNL的治疗将显着提高GBM患者的生存。 有必要继续临床发展。因此，我们建议测试最大可耐受剂量和安全性 在复发性神经胶质瘤患者中的186RNL概况，确定186RNL在复发性胶质母细胞瘤和 开发和验证数学模型以预测186RNL的分布。直接目标 目的是使用早期时间点，特定于患者的数据来校准基于机制的模型，从而允许 准确预测186RNL作为时间的函数。该模型将使用 在AIM 1中建立的数据，然后在交付186RNL之前使用，以选择最佳注射点 在目标2中。