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.
Public Health Relevance Statement: PROJECT NARRATIVE Recurrent glioblastoma (rGBM) is a rare, aggressive cancer with no effective therapy and extremely poor prognosis. Preclinical studies have shown that non-invasive sonodynamic therapy (MRI-Guided Focused Ultrasound to activate Protoporphyrin IX, a metabolite of 5-aminolevulinic acid) selectively and rapidly kills gliomas and greatly extends survival in animal glioma models. Recent data from a first-in-man clinical trial in rGBM demonstrated that sonodynamic therapy is well-tolerated in humans with no off-target side effects, and supports a Phase 2 clinical trial in rGBM that will establish dosing, safety, and preliminary efficacy to inform future clinical trials to improve patient outcomes and survival.
Project Terms: therapy toxicity; treatment toxicity; treatment-associated toxicity; Treatment-related toxicity; improved outcome; objective response rate; Radiography; Roentgenography; radiologic imaging; radiological imaging; first in man; first-in-human; side effect; clinical center; Phase 0/I Clinical Trial; Phase 0/1 Clinical Trial; Prognosis; ultrasound; pre-Investigational New Drug meeting; Pre IND FDA meeting; Pre-IND mtg; pre-IND consultation; pre-IND discussion; pre-IND meeting; After Care; After-Treatment; post treatment; Aftercare; 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; Aminolevulinic Acid; Animals; Brain; Brain Nervous System; Encephalon; Brain Neoplasms; Brain Neoplasia; Brain Tumors; tumors in the brain; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cell Death; necrocytosis; Cells; Cell Body; Clinical Trials; Combined Modality Therapy; Multimodal Therapy; Multimodal Treatment; combination therapy; combined modality treatment; combined treatment; multi-modal therapy; multi-modal treatment; Cessation of life; Death; Diagnosis; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Family; Future; Glioblastoma; Grade IV Astrocytic Neoplasm; Grade IV Astrocytic Tumor; Grade IV Astrocytoma; glioblastoma multiforme; spongioblastoma multiforme; Glioma; Glial Cell Tumors; Glial Neoplasm; Glial Tumor; Neuroglial Neoplasm; Neuroglial Tumor; glial-derived tumor; neuroglia neoplasm; neuroglia tumor; Grant; Human; Modern Man; Incidence; Laboratories; 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; Patients; Radiation therapy; Radiotherapeutics; Radiotherapy; radiation treatment; treatment with radiation; Recommendation; Recurrence; Recurrent; Safety; Survival Rate; Temperature; Translating; Translations; translation; Treatment Protocols; Treatment Regimen; Treatment Schedule; Ultrasonic Therapy; ultrasound energy; ultrasound therapy; protoporphyrin IX; Singlet Oxygen; Singlet Dioxygen; temozolomide; Temodal; Temodar; methazolastone; Schedule; Apoptosis Pathway; Programmed Cell Death; Apoptosis; Active Oxygen; Oxygen Radicals; Pro-Oxidants; Reactive Oxygen Species; improved; Left; Site; Area; Clinical; Microscopic; Phase; Phase 2 Clinical Trials; phase II protocol; Phase II Clinical Trials; Infiltration; Intravenous; Nature; Recurrent tumor; Recurrent Neoplasm; neoplasm recurrence; Operative Surgical Procedures; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; meetings; meeting; neoplastic cell; Tumor Cell; cohort; cellular targeting; Toxic effect; Toxicities; Devices; Reporting; Excision; Abscission; Extirpation; Removal; Surgical Removal; resection; Maximum Tolerated Dose; Maximal Tolerated Dose; Maximally Tolerated Dose; PUVA Photochemotherapy; PUVA; Photochemotherapy; Photodynamic Therapy; neoplasm/cancer photoradiation therapy; Modeling; response; Address; Dose; Data; Dose Limiting; Necrosis Induction; Surgically-Created Resection Cavity; Intrasurgical Resection Cavity; Resection Cavity; Surgically-Created Cystic Resection Cavity; Clinical Data; Therapy Clinical Trials; Common Terminology Criteria for Adverse Events; CTCAE; Common Toxicity Criteria; Conduct Clinical Trials; Enrollment; enroll; Patient-Focused Outcomes; Patient outcome; Patient-Centered Outcomes; patient oriented outcomes; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Process; Adjuvant; preclinical study; pre-clinical study; designing; design; determine efficacy; efficacy analysis; efficacy assessment; efficacy determination; efficacy examination; evaluate efficacy; examine efficacy; efficacy evaluation; tumor; neurooncology; neuro-oncology; standard of care; effective treatment; effective therapy; phase 2 trial; phase II trial; Focused Ultrasound; therapeutic toxicity; therapy associated toxicity; therapy related toxicity
