Drug and energy dose-escalation study of SONALA-001 sonodynamic therapy in the treatment of 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， 5-氨基乙酰丙酸（ALA; SONALA-001）。三个独立的实验室 证明了ALA SDT在动物神经胶质瘤模型中的安全性和有效性，其中动物首先给药 用ALA处理，然后用MRgFUS在不升高脑温度的能量下处理。MRgFUS激活 原卟啉IX（PpIX）是ALA的代谢产物，产生单线态氧，诱导细胞坏死和凋亡。 神经胶质瘤的治疗过程类似于光动力疗法。PpIX的激活非侵入性地引起了 神经胶质瘤和延长生存期。我们也有数据支持ALA SDT是安全的，耐受性良好， 复发性多形性胶质母细胞瘤的成人患者，并导致靶向氧化应激和伴随 肿瘤组织中的细胞凋亡，在没有热效应的情况下，类似于动物模型的结果。SONALA-001 是指定用于治疗所有恶性神经胶质瘤的孤儿药和研究新药（IND） FDA批准了申请。本R 01的目标是执行II期临床试验， 为DIPG中ALA SDT的后续试验提供安全性和有效性数据。作为三个临床试验基地之一 在参与该试验的过程中，Ivy脑肿瘤中心将在多达9个队列中招募12名DIPG患者。本试验将 出于道德原因不受控制。首先，我们将确定ALA代谢和PpIX的血浆PK 合成，因为这是ALA的第一种静脉（IV）制剂。其次，我们将确定最大 耐受剂量（MTD）或推荐的II期剂量的MRgFUS能量联合IV ALA。三是 通过随访患者长达12个月来确定ALA SDT的安全性和有效性。成功完成 这项试验将确定一个安全的剂量，以进行下一阶段的临床开发，其中DIPG患者将 每月接受SDT治疗，尝试使用安全的 IV剂量的ALA与最佳剂量的MRgFUS组合。该开发计划的目标是 获得FDA上市批准所需的临床数据，并将这种联合疗法商业化， 没有治疗选择的DIPG患者。ALA SDT有可能成为第一个成功的治疗方法 对于DIPG，在医学史上第一次，DIPG儿童的父母不仅希望 他们的孩子的生命可以延长，而且所使用的联合治疗是无创的， 副作用是可以忍受的

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; SONALA-001). 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. We also have data that support that ALA SDT is safe and well-tolerated in adult patients with recurrent glioblastoma multiforme, and leads to targeted oxidative stress and accompanying apoptosis in tumor tissue, in the absence of a thermal effect, similar to the animal model results. SONALA-001 is Orphan Drug designated for the treatment of all malignant gliomas and an Investigational New Drug (IND) application was cleared to proceed by the FDA. The goal of this R01 is to execute a Phase 2 clinical trial to provide safety and efficacy data for subsequent trials of ALA SDT in DIPG. As one of three clinical trial sites participating in this trial, the Ivy Brain Tumor Center will enroll 12 DIPG patients in up to 9 cohorts. This trial will be uncontrolled for ethical reasons. First, we will determine blood plasma PK of ALA metabolism and PpIX synthesis as this is the first intravenous (IV) formulation of ALA. Second, we will determine the maximum tolerated dose (MTD) or recommended Phase 2 dose of MRgFUS energy combined with IV ALA. Third, we will determine safety and efficacy of ALA SDT by following patients for up to 12 months. Successful completion of this trial will identify a safe dose 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.