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

摘要/总结 胶质母细胞瘤（GBM）的药物治疗几乎总是在患者中失败，尽管在临床前试验中已显示出疗效。 模型或其他实体瘤的治疗。失败的一个重要原因是药物渗透不足 通过血脑屏障（BBB）。脉冲超声（US）伴随静脉注射 微泡瞬时破坏血脑屏障，增强药物向大脑的递送。在患者中，这需要 超声波绕过厚厚的人类头骨。在这里，我们使用一种植入颅骨窗口的US设备， 已在1期临床试验中成功测试。先前的研究表明，血脑屏障破坏， 接受US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，基于美国的血脑屏障破坏对肿瘤周围人类肿瘤中药物浓度的真正影响是不确定的。 脑仍然是未知的，而在肿瘤周围组织中达到足够的药物浓度是关键， 靶向手术切缘以外的浸润性GBM细胞。紫杉醇（PTX）对GBM的作用非常有效， 临床前模型。探索PTX在GBM中的作用的先前临床研究显示，在肿瘤周围的脑中， 药物是无法检测的。此外，常规PTX制剂中使用的溶剂Cremophor™具有 神经毒性因此，尽管PTX仍然是抗GBM最有效的药物之一，但它不能被利用。 这是由于不良的BBB渗透和媒介物相关的毒性。我们最近的工作表明，一种新的FDA- 不含Cremophor™的白蛋白结合PTX（Abraxane®，ABX）的批准制剂是良好的， 耐受性和表现出比常规PTX更好的脑和其它组织渗透性。美国BBB中断 脑组织中的PTX浓度增加了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，美国的ABX交付将是 耐受，显著增加肿瘤周围脑中的PTX浓度，并为 复发性GBM患者。为了调查这一点，我们将进行一项I/II期试验， 复发性GBM患者。我们将确定安全性和MTD，并评估疗效的早期体征（目标1）。我们 将使用第二代植入式超声设备，其覆盖的超声体积是初始超声体积的9倍 原型，我们使用ABX，一种在所有临床前模型中比以前研究的药物更有效的药物 卡铂我们将在肿瘤和浸润性肿瘤的不同区域进行活检和测量PTX浓度- 基于US的BBB破坏后的肿瘤组织（Aim 2）。重复MRI将允许确定 BBB破坏的区域与局部疾病控制相关并防止进展（目的3）。这些研究 将1）确定伴随ABX输注的基于美国的BBB破坏的安全性，2）量化 BBB破坏对PTX脑浓度的影响，以及3）提供疗效的临床和放射学评估。 !

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. !