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: 10261586
• 负责人: Adam M Sonabend
• 金额: $ 50.1万
• 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/10261586
• 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; Diagnostic radiologic examination; 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; Ultrasonography; 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; safety testing; temozolomide; tumor; tumor growth; 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. !

抽象/总结