Sonodynamic therapy using MRI-guided focused ultrasound in combination with 5-aminolevulinic acid to treat recurrent glioblastoma multiforme

使用 MRI 引导聚焦超声联合 5-氨基乙酰丙酸的声动力疗法治疗复发性多形性胶质母细胞瘤

• 批准号: 10699858
• 负责人: Stuart Marcus
• 金额: $ 69.48万
• 依托单位: SONALASENSE INC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699858
• 关键词: Address; Adjuvant; Aftercare; Aminolevulinic Acid; Animals; Apoptosis; Area; Brain; Brain Neoplasms; Cell Death; Cells; Cessation of life; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; Common Terminology Criteria for Adverse Events; Conduct Clinical Trials; Data; Devices; Diagnosis; Disease; Dose; Dose Limiting; Enrollment; Excision; Family; Focused Ultrasound; Future; Glioblastoma; Glioma; Grant; Human; Incidence; Infiltration; Intravenous; Laboratories; Left; Magnetic Resonance Imaging; Malignant Neoplasms; Maximum Tolerated Dose; Microscopic; Modeling; Nature; Necrosis Induction; Operative Surgical Procedures; PUVA Photochemotherapy; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Phase 0/1 Clinical Trial; Phase II Clinical Trials; Process; Prognosis; Radiation therapy; Reactive Oxygen Species; Recommendation; Recurrence; Recurrent tumor; Reporting; Safety; Schedule; Singlet Oxygen; Site; Small Business Innovation Research Grant; Surgically-Created Resection Cavity; Survival Rate; Temperature; Therapy Clinical Trials; Toxic effect; Translating; Translations; Treatment Protocols; Treatment-related toxicity; Ultrasonic Therapy; cellular targeting; clinical center; cohort; design; effective therapy; efficacy evaluation; first-in-human; improved; improved outcome; meetings; neoplastic cell; neuro-oncology; objective response rate; phase II trial; pre-Investigational New Drug meeting; preclinical study; protoporphyrin IX; radiological imaging; response; side effect; standard of care; temozolomide; tumor; ultrasound

PROJECT SUMMARY Glioblastoma multiforme (GBM) is a rare and deadly cancer. First line treatment for GBM includes maximal surgical resection with radiotherapy administered post-surgery, and concomitant administration of adjuvant temozolomide. Tumor recurrence is nearly inevitable due to the microscopic, infiltrating cells that are found centimeters from the margin of visible tumor mass. There is currently no effective standard of care for recurrent (rGBM) and this highly aggressive disease leads to death within 15 months after diagnosis and has a 5-year survival rate of <10%. Therefore, there is a clear and significant clinical need for better therapies for rGBM. To address this unmet need, SonALAsense is developing sonodynamic therapy (SDT), a non-invasive drug-device combination, to treat rGBM. SDT uses an MRI-Guided Focused Ultrasound (MRgFUS) device in combination with a drug called 5-aminolevulinic acid (ALA). Three independent laboratories have demonstrated the safety and efficacy of ALA SDT in animal glioma models where the animals were dosed first with ALA and then treated with MRgFUS at energies that do not raise brain temperature. MRgFUS activated Protoporphyrin IX (PpIX), a metabolite of ALA, created singlet oxygen that induced necrosis and apoptosis in the glioma in a process similar to photodynamic therapy. Activation of PpIX non-invasively caused regression of the gliomas and extended survival. A first-in-human Phase 0/1 clinical trial in rGBM showed that ALA SDT was well-tolerated and not associated with off-target cellular or radiographic effects and provided direct evidence of reactive oxygen species formation and targeted tumor cell death in rGBM only 4 days after treatment. These Phase 0/1 data obtained to date may be interpreted as the successful translation of ALA SDT-treated animal glioma model effects to human rGBM patients. Due to its non-invasive nature, ALA SDT has the unique opportunity to be used multiple times to extend survival. Therefore, a Phase 2 clinical trial will be conducted at 6 clinical trial sites to determine the optimal Phase 2 dosing and schedule to comprehensively evaluate efficacy. This Direct to Phase II project will focus on one clinical trial site at the Ivy Brain Tumor Center. This will be accomplished through the execution of 3 Aims. In Aim 1, we will enroll single patient cohorts to determine maximum tolerated dose and energy for a single dose schedule. In Aim 2, we will determine the recommended schedule by escalating the dosing schedule to 2 then 3 treatments. In Aim 3, we will use the dosing and treatment schedule identified in Aims 1 and 2 to evaluate preliminary efficacy and follow patients weekly in month 1, biweekly in month 2, and monthly thereafter. Completion of this clinical trial will address FDA guidance in our pre-IND meeting and the safety and clinical data from this Phase 2 trial will provide the basis for an end of Phase 2 meeting with the FDA to establish criteria for the approval of ALA SDT as an effective treatment for rGBM. Ultimately, SonALAsense’s ALA SDT combination therapy has great potential to positively impact rGBM patients and their families by improving outcomes.

项目摘要 胶质母细胞瘤多形（GBM）是一种罕见且致命的癌症。 GBM的第一行治疗包括最大 放疗后进行手术后手术后进行手术切除，并伴随进行调整 替莫唑胺。由于发现的微观，浸润细胞，肿瘤复发几乎是不可避免的 可见肿瘤质量边缘的Cenimeter。目前尚无反复护理标准 （RGBM）和这种高度侵略性的疾病在诊断后的15个月内导致死亡，并且有5年 存活率<10％。因此，对RGBM的更好疗法有明显而巨大的临床需求。到 满足了这种未满足的需求，Sonalasense正在开发超声疗法（SDT），这是一种非侵入性药物设备 组合，治疗RGBM。 SDT使用组合使用MRI引导聚焦超声（MRGFUS）设备 用称为5-氨基乙烯酸（ALA）的药物。三个独立实验室已经证明了安全性 并在动物神经胶质瘤模型中易于使用ALA SDT，首先将动物与ALA涂过，然后处理 MRGFUS处于不会升高大脑温度的能量。 MRGFUS活化的原核IX（PPIX），A ALA的代谢产生的单线氧，在类似的过程中诱导神经胶质瘤的坏死和凋亡 进行光动力疗法。 PPIX非侵入性的激活引起神经胶质瘤的回归并扩展 生存。 RGBM中的第一个人类阶段0/1临床试验表明，ALA SDT耐受性良好，而不是 与脱靶细胞或X线摄影作用相关，并提供了活性氧的直接证据 治疗后4天仅在RGBM中形成并靶向肿瘤细胞死亡。这些阶段的0/1数据获得了 日期可以解释为ALA SDT处理的动物神经胶质瘤模型对人类的成功翻译 RGBM患者。由于其非侵入性，ALA SDT有多次使用的独特机会 延长生存。因此，将在6个临床试验地点进行2期临床试验以确定 最佳阶段2剂量和时间表以全面评估有效性。直接进入第二阶段项目 将重点放在常春藤脑肿瘤中心的一个临床试验部位上。这将通过 执行3个目标。在AIM 1中，我们将招募单个患者队列，以确定最大耐受剂量和 单剂量时间表的能量。在AIM 2中，我们将通过升级来确定建议的时间表 给2个治疗时间表的剂量时间表。在AIM 3中，我们将使用确定的剂量和治疗时间表 在AIMS 1和2中评估初步效率并每周在第1个月中每两周关注患者，第2个月， 此后每月。该临床试验的完成将在我们的IND会议上解决FDA指南， 该第2阶段试验的安全性和临床数据将为第二阶段会议结束与 FDA建立标准以批准ALA SDT作为RGBM的有效治疗方法。最终， Sonalasense的ALA SDT组合疗法具有巨大的潜力，可以积极影响RGBM患者及其 通过改善结果来家庭。