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: 10687851
• 负责人: Andrew Jacob Brenner
• 金额: $ 54.72万
• 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/10687851
• 关键词: Address; Adult; Agreement; Algorithms; Animals; Bioluminescence; Blinded; Brain; Brain Neoplasms; Calibration; Canis familiaris; Catheters; Charge; Chemistry; Cholesterol; Clinical Research; Combined Modality Therapy; Convection; Custom; Data; Distant; Dose; Encapsulated; Enrollment; Glioblastoma; Glioma; Goals; Hour; Infusion procedures; Injections; 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; Recommendation; Recurrence; Residual Neoplasm; Rhenium; Route; Safety; Scheme; Shapes; Site; Techniques; Testing; Therapeutic; Time; Tissues; Toxic effect; U251; United States Food and Drug Administration; Xenograft Model; absorption; animal data; aqueous; arm; chelation; chemotherapy; clinical development; cohort; efficacy evaluation; experience; experimental study; good laboratory practice; improved; lipophilicity; manufacture; mathematical model; nanoliposome; nanoparticle; novel therapeutics; open label; particle; phase 1 study; primary endpoint; radiation absorbed dose; radiological imaging; 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）是成人中最常见和最具侵袭性的原发性恶性脑肿瘤， 综合治疗后的中位总生存期为19.6个月。主要限制因素 递送杀肿瘤辐射剂量是对周围脑的毒性。治疗性放射性核素，由于 短的组织路径和放射生物学的差异，有可能扩大放射治疗窗口 在GBM。然而，需要载体来将同位素递送到大脑并保持其在大脑中的定位。 所需的位置，否则他们很快就会分散。脂质体包封有可能促进 放射性同位素保留在组织内，但是一种用放射性同位素有效装载脂质体的方法 是必要的这一直是该技术发展中的重要限制因素，并且现在已经被 成功解决。为了克服这个问题，我们开发了一种封装方法， 亲脂性分子（BMEDA），其将亲脂性放射性核素携带到细胞的水室中。 脂质体纳米粒。最终的研究产品是铼纳米脂质体（186 RNL）。 为了表征186RNL的保留、耐受性和活性，我们进行了186RNL的瘤内输注。 在患有胶质母细胞瘤的大鼠中。不断增加的剂量高达30倍的典型外部束剂量 表明动物耐受所有剂量，没有伤害的证据，并与显着的生存相关 差异此外，许多大鼠没有残留肿瘤。在比格犬中进行毒性研究， 186RNL或空白对照纳米脂质体，并且在犬的全身或脑中未产生显著变化 24小时或14天。为了进一步表征制剂并解决化学、生产， 和控制FDA的关注，我们进入了一个合作协议，与纳米技术 国家癌症研究所（NCI）的表征实验室（NCL）。NCL随生产提供 在UTHSA生产的方案、试剂和代表性批次。未观察到显著差异 在两个地点生产的RNL之间，观察到成品具有显著的稳定性。药 FDA批准后不久进行临床研究。我们的具体假设是，186RNL可以 安全地给予复发性进行性GBM患者，放射剂量远高于 用目前的技术实现，并且用186RNL治疗将显著改善GBM患者的存活率。 需要继续进行临床开发。因此，我们建议测试最大耐受剂量和安全性 186RNL在复发性胶质瘤患者中的分布，确定186RNL在复发性胶质母细胞瘤中的疗效，以及 开发并验证一个数学模型来预测186RNL的分布。这件事的直接目标是 目的是使用早期时间点的患者特异性数据来校准基于机制的模型，从而允许 准确预测186RNL随时间的分布。该模型将使用 目标1中建立的数据，然后在输送186RNL之前用于选择最佳注射点， 目标2