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.
Public Health Relevance Statement: PROJECT NARRATIVE Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor with no effective therapy and extremely poor prognosis (average 9 months of survival after diagnosis). Preclinical studies have shown that performing non-invasive sonodynamic therapy (SDT) through MRI-Guided Focused Ultrasound (MRgFUS) to activate a metabolite of 5-aminolevulinic acid (ALA) can slow growth of gliomas and greatly extend survival in animal models of glioma. With this promising data, and because MRgFUS and ALA are both already FDA-approved, SonALAsense will test the combination therapy of MRgFUS and ALA in a Phase 1/2 clinical trial that will establish dosing and safety for future clinical trials to improve the outcomes and survival in DIPG patients.
Project Terms: Adult; 21+ years old; Adult Human; adulthood; Age; ages; Aminolevulinic Acid; 5-ALA; 5-Amino-4-oxopentanoic Acid; 5-Aminolevulinic Acid; 5-amino-4-oxo-pentanoic acid; Amino-Levulinic Acid; Delta-Aminolevulinic Acid; d-Amino-Levulinic Acid; Animals; Breathing; Respiratory Aspiration; Respiratory Inspiration; inspiration; Biological Assay; Assay; Bioassay; Biologic Assays; Blood; Blood Reticuloendothelial System; Blood Pressure; Blood Volume; Body Weight; Brain; Brain Nervous System; Encephalon; Child; 0-11 years old; Child Youth; Children (0-21); youngster; High Pressure Liquid Chromatography; HPLC; High Performance Liquid Chromatography; High Speed Liquid Chromatography; Clinical Research; Clinical Study; Clinical Trials; Combined Modality Therapy; Multimodal Therapy; Multimodal Treatment; combination therapy; combined modality treatment; combined treatment; multi-modal therapy; multi-modal treatment; Diagnosis; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Electrocardiogram; ECG; EKG; Electrocardiography; Ethics; ethical; Fluorescence; Future; Glioma; Glial Cell Tumors; Glial Neoplasm; Glial Tumor; Neuroglial Neoplasm; Neuroglial Tumor; glial-derived tumor; neuroglia neoplasm; neuroglia tumor; Goals; Growth; Generalized Growth; Tissue Growth; ontogeny; Cyclic GMP; Guanosine Cyclic Monophosphate; cGMP; Half-Life; Heart Rate; Cardiac Chronotropism; Hospitals; Human; Modern Man; Laboratories; Liver; hepatic body system; hepatic organ system; Magnetic Resonance Imaging; MR Imaging; MR Tomography; MRI; MRIs; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; NMR Imaging; NMR Tomography; Nuclear Magnetic Resonance Imaging; Zeugmatography; Marketing; Metabolism; Intermediary Metabolism; Metabolic Processes; Methods; Minor; Nausea and Vomiting; Necrotic; Necrosis; Parents; Patients; Pharmacokinetics; Drug Kinetics; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Plasma; Pons; Pons Cerebelli; Pons Varolii; Pontine; Pontine structure; Program Development; General Radiology; Radiology; Radiology Specialty; Recommendation; Safety; gastric; Stomach; Technology; Temperature; Testing; Time; Translating; Ultrasonic Therapy; ultrasound energy; ultrasound therapy; Urine; Urine Urinary System; Visual Aid; Work; protoporphyrin IX; Singlet Oxygen; Singlet Dioxygen; Family Leave; Apoptosis; Apoptosis Pathway; Programmed Cell Death; tumor progression; cancer progression; neoplasm progression; neoplastic progression; Blood specimen; Blood Sample; Area; Clinical; Phase; Childhood Brain Tumor; pediatric brain neoplasm; pediatric brain tumor; Childhood Brain Neoplasm; Evaluation; pediatric; Childhood; Hepatotoxic effect; Liver Toxicity; Toxic effect on liver cells; hepatic toxicity; hepatoxicity; Hepatotoxicity; neuro-surgeon; Neurosurgeon; Personal Medical History; Personal Medical History Epidemiology; Medical History; Therapeutic; Intravenous; Life; programs; Oral; Location; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Operative Surgical Procedures; Visit; meetings; experience; cohort; Animal Models and Related Studies; model of animal; model organism; Animal Model; Toxicities; Toxic effect; Speed; Laboratory Study; Devices; Abscission; Extirpation; Removal; Surgical Removal; resection; Excision; Bypass; Maximal Tolerated Dose; Maximally Tolerated Dose; Maximum Tolerated Dose; PUVA; Photochemotherapy; Photodynamic Therapy; neoplasm/cancer photoradiation therapy; PUVA Photochemotherapy; Modeling; Sampling; assay development; Therapeutic Uses; Address; Dose; Data; Detection; Dose-Limiting; Measurable; Clinical Data; Common Terminology Criteria for Adverse Events; CTCAE; Common Toxicity Criteria; Enrollment; enroll; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Process; preclinical study; pre-clinical study; design; designing; pre-clinical therapy; preclinical therapy; commercialization; tumor; FDA approved; standard of care; effective therapy; effective treatment; pediatric patients; child patients; Adverse drug event; Focused Ultrasound; Formulation; improved outcome; Diffuse intrinsic pontine glioma; DIPG; clinical development; side effect; Phase I/II Clinical Trial; Phase 1/2 Clinical Trial; Prognosis; ultrasound
