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

摘要/摘要 胶质母细胞瘤(GBM)的药物治疗几乎总是失败的，尽管在临床前已经显示出有效 模型，或用于治疗其他实体肿瘤。失败的一个重要原因是药物渗透不足。 跨越血脑屏障(BBB)。脉冲超声(US)配合静脉注射 微泡会瞬间扰乱血脑屏障，增强药物向大脑的输送。对于病人来说，这需要 超声波可以绕过厚厚的人类头骨。在这里，我们使用了一个植入头盖骨窗口的美国设备 已在一期临床试验中成功测试。先前的研究表明，血脑屏障中断，且持续时间较长 超声介导的血脑屏障联合卡铂治疗复发的GBM患者的无进展生存 化疗。然而，美国的血脑屏障阻断对肿瘤周围人类药物浓度的真实影响 大脑仍然未知，而在肿瘤周围组织中获得足够的药物浓度是治疗 靶向手术切缘以外的浸润性GBM细胞。紫杉醇(PTX)对小鼠肾小球基底膜有极强的抗炎作用。 临床前模型。先前探索PTX在GBM中作用的临床研究表明，在肿瘤周围脑组织中 毒品是检测不到的。此外，传统PTX配方中使用的溶剂乳油™具有 神经毒性。因此，尽管PTX仍然是治疗GBM最有效的药物之一，但它不能被开发。 由于血脑屏障渗透性差和与车辆相关的毒性。我们最近的工作表明，一种新型的FDA- 不含乳油™的白蛋白结合PTX(Abraxane®，ABX)的批准配方很好 与传统的PTX相比，耐受性和表现出更好的脑和其他组织渗透。总部位于美国的BBB中断 将PTX脑组织浓度提高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大脑浓度。我们假设ABX在美国的交付将是 耐受性，显著增加肿瘤周围脑组织中的PTX浓度，并为患者提供生存益处 复发的基底膜患者。为了调查这一点，我们将进行美国增强交付ABX的I/II阶段试验 复发的基底膜患者。我们将确定安全性和MTD，并评估疗效的早期迹象(目标1)。我们 将使用第二代可植入的美国设备，其声学体积是最初的9倍 原型，我们使用ABX，一种在所有临床前模型中比之前研究的更有效的药物 卡铂。我们将活检并测量肿瘤不同区域和浸润性周围组织中的PTX浓度。 美国血脑屏障中断后的肿瘤组织(目标2)。重复核磁共振成像将允许确定是否 血脑屏障中断的领域与当地疾病控制和预防进展有关(目标3)。这些研究 将1)确定美国的BBB阻断联合ABX输注的安全性，2)量化 血脑屏障阻断对PTX脑浓度的影响，以及3)提供临床和放射学疗效评估。 好了！

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. !