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/总结 尽管在临床前显示出疗效，但胶质母细胞瘤 (GBM) 的药物治疗几乎总是失败 模型或其他实体瘤的治疗。失败的重要原因之一是药物渗透不足 穿过血脑屏障（BBB）。脉冲超声（US）同时静脉注射 微泡会暂时扰乱血脑屏障，从而增强药物向大脑的输送。对于患者来说，这需要 超声波绕过厚厚的人类头骨。在这里，我们使用植入颅骨窗的美国设备 已在1期临床试验中获得成功。先前的研究表明血脑屏障受到破坏，并且长期 接受超声介导的 BBB 和卡铂治疗的复发性 GBM 患者的无进展生存期 化疗。然而，美国 BBB 破坏对肿瘤周围人类药物浓度的真正影响 大脑仍然未知，而在肿瘤周围组织中达到足够的药物浓度是关键 靶向手术边缘以外的浸润 GBM 细胞。紫杉醇 (PTX) 对 GBM 具有极其有效的作用 临床前模型。先前探索 PTX 在 GBM 中的作用的临床研究表明，在肿瘤周围的大脑中 药物是检测不到的。此外，传统 PTX 配方中使用的溶剂 Cremophor™ 神经毒性。因此，虽然 PTX 仍然是对抗 GBM 最有效的药物之一，但它不能被利用 由于 BBB 渗透性差和与车辆相关的毒性。我们最近的工作表明，一种新颖的 FDA- 经批准的白蛋白结合 PTX（Abraxane®、ABX）配方不含 Cremophor™，效果良好 与传统 PTX 相比，其耐受性更强，并且具有更好的大脑和其他组织渗透性。美国 BBB 中断 PTX 脑组织浓度增加 5 倍。我们的前提是 PTX 对人类 GBM 有效 如果达到足够的肿瘤和脑浓度。我们假设 ABX 在美国的交付将是 耐受性，显着增加肿瘤周围脑中的 PTX 浓度，并为患者提供生存益处 复发性 GBM 患者。为了调查这一点，我们将进行美国增强的 ABX 交付的 I/II 期试验 复发性 GBM 患者。我们将确定安全性和 MTD，并评估早期疗效迹象（目标 1）。我们 将使用第二代植入式美国设备，其超声处理范围比最初的设备大 9 倍 原型，我们使用 ABX，这种药物在所有临床前模型中都比之前研究的药物更有效 卡铂。我们将进行活检并测量肿瘤各个区域和浸润周围的 PTX 浓度。 美国 BBB 破坏后的肿瘤组织（目标 2）。重复 MRI 将可以确定是否 BBB 破坏领域与局部疾病控制和预防进展相关（目标 3）。这些研究 将 1) 确定美国 BBB 破坏并同时输注 ABX 的安全性，2) 量化以下效果 BBB 破坏对 PTX 脑浓度的影响，3) 提供临床和放射学疗效评估。 ！