Evaluation of the safety and efficacy of non-invasive sonodynamic therapy for diffuse intrinsic pontine glioma

项目摘要 弥漫性内在脑桥胶质瘤（DIPG）是一种罕见而致命的小儿脑肿瘤。他们非常 在脑桥中发现的侵袭性肿瘤，控制着身体许多最重要的功能， 呼吸血压和心率目前还没有有效的治疗DIPG的方法， 诊断后的中位生存期为7-11个月。因此，非常需要一种有效治疗癌症的方法。 DIPG。为了解决这一未满足的需求，SonALAsense正在开发声动力学疗法（SDT），一种非侵入性的 药物-器械组合，用于治疗DIPG。SDT使用MRI引导聚焦超声（MRgFUS）设备， 与一种名为5-氨基乙酰丙酸（ALA）的药物联合使用。三个独立的实验室已经证明 ALA SDT在动物神经胶质瘤模型中的安全性和有效性，其中动物首先给予ALA， 然后在不升高脑温的能量下用MRgFUS治疗。MRgFUS激活的原卟啉 ALA的代谢产物IX（PpIX）产生单线态氧，诱导神经胶质瘤的坏死和凋亡。 类似于光动力疗法。PpIX的激活非侵入性地引起胶质瘤的消退 延长生存期。该直接进入II期项目的目标是提供关于 在随后的ALA SDT临床试验中，与10 mg/kg静脉（IV）ALA联合使用的最佳MRgFUS能量剂量 在DIPG。这将通过执行三个目标来实现。在目标1中，我们将开发灵敏的检测方法， 以检测少量血液样品中的ALA和PpIX。在目标2中，我们将测定血浆 IV给药后ALA代谢和PpIX合成的药代动力学（PK），因为这是首次IV给药。 ALA制剂将用于儿童的治疗目的，重要的是要了解可能的 儿童和成人受试者之间的PK差异。在目标3中，我们将确定 使用ALA单次IV给药的DIPG患者中的ALA SDT，同时使用3个递增MRgFUS能量剂量队列。 这将有助于确定DIPG患者的最大耐受能量剂量和推荐的阶段 2剂量的MRgFUS能量与10 mg/kg IV ALA组合。成功完成此提案将 告知药物剂量范围研究。这些试验的完成对于进入下一阶段的临床研究至关重要。 开发，其中DIPG患者将每月接受SDT治疗，以尝试最大化效果 使用安全IV剂量的ALA联合最佳剂量的MRgFUS对这些患者的生存率的影响。的 本开发项目的目标是获得FDA上市批准所需的临床数据， 将这种组合疗法商业化，用于没有治疗选择的DIPG患者。ALA SDT拥有 有可能成为DIPG的第一种成功治疗方法，也是儿童父母病史中的第一次 与DIPG不仅有希望，他们的孩子的生命可以延长，但也安慰， 所使用的联合治疗是非侵入性的，并且具有极可耐受的副作用。

PROJECT SUMMARY Diffuse Intrinsic Pontine Gliomas (DIPG) are rare and deadly pediatric brain tumors. They are extremely aggressive tumors that are found in the pons, which controls many of the body's most vital functions such as breathing, blood pressure, and heart rate. There is no currently effective means of treatment for DIPG, and the median survival is 7-11 months after diagnosis. Thus, there is significant need for a method to effectively treat DIPG. To address this unmet need, SonALAsense is developing sonodynamic therapy (SDT), a non-invasive drug-device combination, to treat DIPG. 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. The goal of this Direct to Phase II program is to provide safety and efficacy data on the best MRgFUS energy doses to use with 10 mg/kg intravenous (IV) ALA for subsequent clinical trials of ALA SDT in DIPG. This will be accomplished through the execution of 3 Aims. In Aim 1, we will develop sensitive assays to detect ALA and PpIX in small blood sample volumes. In Aim 2, we will determine blood plasma pharmacokinetics (PK) of ALA metabolism and PpIX synthesis following IV dosing as this is the first time an IV formulation of ALA will be used for therapeutic purposes in children, and it is important to understand possible differences in PK between pediatric and adult subjects. In Aim 3, we will determine the safety and efficacy of ALA SDT in DIPG patients using a single IV dose of ALA while using 3 ascending MRgFUS energy dose cohorts. This will help determine both the maximum tolerated energy dose in DIPG patients and the recommended Phase 2 dose of MRgFUS energy in combination with 10 mg/kg IV ALA. Successful completion of this proposal will inform a drug dose ranging study. Completion of these trials are critical to proceed to the next stage of clinical development, in which DIPG patients will receive SDT therapy on a monthly basis to attempt to maximize effects on survival of these patients using a safe IV dose of ALA in combination with an optimal dose of MRgFUS. The goal of this development program is to obtain the clinical data necessary for FDA marketing approval and to commercialize this combination therapy for DIPG patients who have no therapeutic options. ALA SDT has the potential to be the first successful treatment for DIPG and for the first time in medical history parents of children with DIPG would not only have hope that the life of their child could be extended, but also the comfort that the combination therapy used is noninvasive and has extremely tolerable side effects.