Blood-brain barrier disruption with implantable ultrasound to enhance paclitaxel delivery: A Phase 1-2 clinical trial in recurrent glioblastoma

通过植入式超声破坏血脑屏障以增强紫杉醇输送：复发性胶质母细胞瘤的 1-2 期临床试验

• 批准号: 10472056
• 负责人: Adam M Sonabend
• 金额: $ 50.55万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472056
• 关键词: Abraxane; Albumins; Area; Biopsy; Blood - brain barrier anatomy; Brain; Brain Glioblastoma; Brain Injuries; Brain Neoplasms; Brain region; Bypass; Carboplatin; Cell Line; Cells; Clinical; Clinical Research; Clinical Trials; Clinical assessments; Controlled Clinical Trials; Cremophor; Devices; Disease; Dose; Drug Delivery Systems; Excision; Exhibits; Exposure to; FDA approved; Failure; Formulation; Generations; Glioblastoma; Glioma; Human; Implant; Infusion procedures; Location; Magnetic Resonance Imaging; Malignant neoplasm of brain; Maps; Maximum Tolerated Dose; Measures; Mediating; Medical; Microbubbles; Microtubule Stabilization; Operative Surgical Procedures; Paclitaxel; Patients; Pattern; Penetration; Perfusion; Peripheral Nerves; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase I Clinical Trials; Phase I/II Clinical Trial; Phase I/II Trial; Physiologic pulse; Plasma; Postoperative Period; Pre-Clinical Model; Primates; Procedures; Progression-Free Survivals; Radiation therapy; Recurrence; Residual Tumors; Role; Safety; Sampling; Solid Neoplasm; Solvents; Sonication; Source; Surgical margins; Survival Rate; Technology; Testing; Thick; Tissues; Toxic effect; Treatment Protocols; Tumor Tissue; Ultrasonic wave; Work; base; blood-brain barrier disruption; blood-brain barrier penetration; bone; brain tissue; brain volume; chemotherapy; cohort; comparative efficacy; contrast enhanced; cranium; design; disorder control; efficacy evaluation; first-in-human; glioma cell line; human study; implantable device; implantation; improved; improved outcome; intravenous injection; neurotoxicity; novel; novel therapeutic intervention; prevent; primary endpoint; prototype; radiological imaging; safety testing; temozolomide; tumor; tumor growth; ultrasound; uptake

ABSTRACT/SUMMARY Drug therapy in glioblastoma (GBM) almost invariably fails in patients despite having shown efficacy in preclinical models, or in the treatment of other solid tumors. One important reason for failure is insufficient drug penetration across the blood-brain barrier (BBB). Pulsed-ultrasound (US) with concomitant injection of intravenous microbubbles transiently disrupts the BBB, enhancing delivery of drugs to the brain. In patients this requires ultrasound waves to bypass the thick human skull. Here we use an US device implanted into a skull window that has been successfully tested in Phase 1 clinical trials. Prior studies have shown BBB disruption, and prolonged progression-free survival of recurrent GBM patients treated with US-mediated BBB and carboplatin chemotherapy. Yet, the true effect of US-based BBB disruption on drug concentrations in peri-tumoral human brain remains unknown, while achieving adequate drug concentrations in the peri-tumoral tissue is key for targeting infiltrating GBM cells beyond surgical margins. Paclitaxel (PTX) is exquisitely potent against GBM in preclinical models. Prior clinical studies exploring PTX’s role in GBM showed that in the peri-tumoral brain the drug was undetectable. Moreover, Cremophor™, the solvent used in conventional PTX formulations has neurotoxicity. Thus, whereas PTX remains one of the most potent drugs against GBM, it cannot be exploited due to poor BBB penetration and vehicle-related toxicity. Our recent work demonstrates that a novel FDA- approved formulation of albumin-bound PTX (Abraxane®, ABX) that does NOT contain Cremophor™, is well tolerated and exhibits better brain and other tissue penetration than conventional PTX. US-based BBB disruption increased PTX brain tissue concentrations 5-fold. Our premise is that PTX will be effective against human GBM if sufficient tumor and brain concentrations are achieved. We hypothesize that US-based delivery of ABX will be tolerated, substantially increase PTX concentrations in peri-tumoral brain, and provide a survival benefit for recurrent GBM patients. To investigate this, we will conduct a Phase I/II trial of US-enhanced delivery of ABX for recurrent GBM patients. We will determine safety and MTD, and evaluate for early-signs of efficacy (Aim 1). We will use a 2nd generation implantable US device that covers a 9-fold broader sonication volume than the initial prototypes, and we use ABX, a drug that is far more potent in all preclinical models than the previously studied carboplatin. We will biopsy and measure PTX concentrations in various zones of the tumor and infiltrated peri- tumoral tissue following US-based BBB disruption (Aim 2). Repeat MRI will allow for determination whether the field of BBB disruption is associated with local disease control and prevents progression (Aim 3). These studies will 1) determine the safety of US-based BBB disruption with concomitant ABX infusion, 2) quantify the effect of BBB disruption on PTX brain concentrations, and 3) provide clinical and radiographic assessment of efficacy. !

摘要/摘要 尽管在临床前表现出有效性，但胶质母细胞瘤（GBM）的药物治疗几乎总是失败 模型，或治疗其他实体瘤。失败的一个重要原因是药物渗透不足 穿过血脑屏障（BBB）。脉冲脉冲（US），并随附注射静脉注射 微泡会瞬时破坏BBB，从而增强了药物向大脑的递送。在患者中，这需要 超声波绕过厚实的人头骨。在这里，我们使用植入的美国设备 在第1阶段临床试验中已成功测试。先前的研究表明BBB破坏并延长 用US介导的BBB和卡铂治疗的复发性GBM患者的无进展生存率 化学疗法。然而，基于美国的BBB破坏对肿瘤周期人类药物浓度的真正影响 大脑仍然未知，同时在肿瘤组织中实现足够的药物浓度是 靶向超出手术边缘的浸润GBM细胞。紫杉醇（PTX）与GBM的潜力完全潜力 临床前模型。先前探索PTX在GBM中作用的临床研究表明，在肿瘤周围的大脑中 药物是无法检测的。此外，Cremophor™，常规PTX公式中使用的解决方案具有 神经毒性。那就是PTX仍然是针对GBM的最有效的药物之一，但不能被利用 由于BBB渗透不良和与媒介物相关的毒性，因此。我们最近的工作表明，一种新颖的FDA- 不包含Cremophor™的白蛋白结合的PTX（Abraxane®，ABX）的批准配方很好 与常规PTX相比，耐受性并表现出更好的大脑和其他组织穿透性。基于美国的BBB中断 PTX脑组织浓度增加了5倍。我们的前提是PTX将对人类GBM有效 如果达到足够的肿瘤和脑浓度。我们假设美国的ABX交付将是 耐受性，大大增加了肿瘤周围的PTX浓度，并为 复发性GBM患者。为了调查这一点，我们将对ABX的US增强交付的I/II期试验 复发性GBM患者。我们将确定安全性和MTD，并评估效率的早期符号（AIM 1）。我们 将使用第二代植入式美国设备，该设备覆盖比初始的超声音量更高的宽度。 原型，我们使用ABX，在所有临床前模型中都比先前研究的药物更有潜力 卡铂。我们将活检并测量肿瘤各个区域中的PTX浓度，并浸润。 基于美国的BBB破坏后的肿瘤组织（AIM 2）。重复MRI将允许确定是否 BBB破坏领域与局部疾病控制有关并防止进展（AIM 3）。这些研究 1）确定与伴随ABX输注的基于美国的BBB破坏的安全性，2）量化 BBB对PTX脑浓度的破坏，以及3）提供效率的临床和放射学评估。 呢