This is an open-label phase 1 safety and feasibility study evaluating a novel combination therapy for Diffuse Midline Glioma (DMG), an aggressive brain tumor with a very poor prognosis - an average one-year overall survival. This study combines blood-brain barrier (BBB) disruption (BBBD) using low-intensity focused ultrasound (LIFU) and microbubble treatment, and intravenous infusion of autologous, tumor multi-antigen associated specific cytotoxic T lymphocyte (TAA-T) therapy. The TAA-T cell investigational product in this protocol is manufactured to target Preferentially Expressed Antigen of Melanoma (PRAME), Wilms Tumor 1 (WT1), and survivin.
Age ≥ 3 and ≤ 25 years
Diagnosis of pontine or thalamic DMG
Group A: newly diagnosed pontine DMG after completion of standard radiation therapy; radiographic diagnosis is defined as tumors with a pontine epicenter and diffuse intrinsic involvement of the pons - tissue diagnosis is not required
Group B: newly diagnosed thalamic DMG after completion of standard radiation therapy; tissue diagnosis is required NOTE: Tumor extending outside of the pons or the thalamus can remain eligible if the LIFU treatment is not contraindicated based on the neurosurgeon's assessment and the tumor does not meet any of the
The first procurement blood draw must occur between 4 and 14 weeks after completion of radiation therapy for Group A, and between 4 and 22 weeks after completion of radiation therapy for Group B
Lansky/Karnofsky rating ≥ 60 (participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for purposes of assessing performance status)
Head circumference ≥ 49 cm
Hemoglobin ≥ 8 g/dL, unsupported
Parallel
TAA-T Cell
Biological/VaccineIntravenous tumor associated antigen specific T cell (TAA-T) infusion.
BBB Disruption
DeviceBBB disruption using the Exablate 4000 Type 2 System with DEFINITY microbubbles.
Safety Evaluation
Number of participants with adverse events (graded by the CTCAE Version 6.0), serious adverse events, laboratory abnormalities, changes in vital signs, and changes in neurologic examination after the first LIFT therapy cycle and after subsequent cycles.
Feasibility evaluation
Clinical feasibility will be measured as the proportion of participants with successfully manufactured TAA-T cell product who receive LIFT therapy as intended and are evaluable throughout the DLT period. Clinical feasibility will be considered met if ≥70% of such participants complete at least one cycle of planned LIFT therapy.
Feasibility of multiple cycles
Of participants who received at least one cycle of LIFT therapy and have TAA-T cell product remaining for subsequent cycle/s, the proportion of participants who remain eligible and receive all three planned LIFT therapy cycles, and those who receive two of the three planned cycles, will be assessed. Clinical reasons for discontinuation will be described.
Treatment efficacy
Progression-free survival (PFS) and overall survival are defined as the interval of time between the date of diagnosis and the earliest date of documentation of progressive disease, or death (for any reason), respectively.
Treatment response based on the iRANO/RAPNO criteria
Overall disease response assessment: incidence of complete response (CR), partial response (PR), minimal response (MR), stable disease (SD), or progressive disease (PD) following LIFT therapy.
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Children's National Research Institute
Lead sponsor
Focused Ultrasound Foundation
Collaborator
