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

项目摘要 多形性胶质母细胞瘤（GBM）是一种罕见而致命的癌症。GBM的一线治疗包括最大 手术切除，术后给予放疗，并伴随给予佐剂 替莫唑胺肿瘤复发几乎是不可避免的，由于显微镜下，浸润细胞被发现， 距离可见肿瘤边缘10厘米目前，没有有效的标准治疗复发性 （rGBM）和这种高度侵袭性的疾病导致诊断后15个月内死亡，并有5年的 存活率<10%。因此，对于rGBM的更好疗法存在明确且显著的临床需求。到 为了满足这一未满足的需求，SonALAsense正在开发声动力疗法（SDT），一种非侵入性药物设备 组合，以治疗rGBM。SDT结合使用MRI引导聚焦超声（MRgFUS）器械 一种叫做5-氨基乙酰丙酸的药物三个独立的实验室已经证明了 和ALA SDT在动物神经胶质瘤模型中的功效，其中动物首先用ALA给药， 在不升高大脑温度的能量下使用MRgFUS。MRgFUS激活的原卟啉IX（PpIX）， ALA的代谢产物，产生单线态氧，诱导神经胶质瘤的坏死和凋亡，其过程类似于 到光动力疗法PpIX的激活非侵入性地引起胶质瘤的消退，并延长了胶质瘤的生长。 生存在rGBM中进行的首次人体0/1期临床试验显示，ALA SDT耐受性良好， 与脱靶细胞或放射学效应相关，并提供了活性氧的直接证据 仅在治疗后4天，rGBM中的靶向肿瘤细胞形成和死亡。获得的这些0/1期数据 数据可以解释为ALA SDT治疗的动物胶质瘤模型效应成功地转化为人类胶质瘤模型效应。 rGBM患者。由于其非侵入性的性质，ALA SDT有独特的机会被多次使用 来延长生存时间因此，将在6个临床试验中心进行II期临床试验，以确定 最佳II期给药和方案，以全面评估疗效。这个直接进入第二阶段的项目 将集中在常春藤脑肿瘤中心的一个临床试验地点。这将通过以下方式实现： 实现三个目标。在目标1中，我们将入组单个患者队列，以确定最大耐受剂量， 单剂量计划的能量。在目标2中，我们将通过逐步提高 给药方案为2次然后3次治疗。在目标3中，我们将使用确定的给药和治疗方案 在目的1和2中，评价初步疗效，并在第1个月每周一次，第2个月每两周一次， 此后每月一次。本临床试验的完成将在我们的IND前会议上讨论FDA指南， 这项II期试验的安全性和临床数据将为II期结束时与 FDA将制定批准ALA SDT作为rGBM有效治疗方法的标准。最后， SonALAsense的ALA SDT联合疗法具有极大的潜力，可对rGBM患者及其 家庭改善成果。

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.