Diffuse Intrinsic Pontine Glioma, Pontine Diffuse Midline Glioma, Thalamic Diffuse Midline Glioma
Conditions
Keywords
Low-intensity focused ultrasound, microbubble treatment, blood-brain barrier disruption, T cell therapy, TAA-T cell therapy, LIFU
Brief summary
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.
Detailed description
This is an open-label phase 1 safety and feasibility study evaluating a novel combination therapy for Diffuse Midline Glioma (DMG), studying blood-brain barrier disruption (BBBD) which is accomplished by utilizing the Exablate 4000 Type 2 system consisting of low intensity focused ultrasound (LIFU) paired with microbubbles. The term "microbubbles" refers specifically to DEFINITY® (perflutren lipid microsphere), an FDA-approved ultrasound contrast agent. In this study, however, DEFINITY® is being used as a mechanical resonator, and is investigational in this context. BBBD will be combined with TAA-T cell infusion and this combination is being referred to as "LIFT therapy". Each LIFT treatment consists of the LIFU-mediated BBBD procedure followed by TAA-T infusion, administered intravenously 30 minutes to 4 hours post BBBD on Day 0, with a strong preference for infusion as early as feasible within this window. Following each LIFT treatment, participants will undergo a safety monitoring period for a minimum of 28 days to a maximum of 70 days. Each LIFT treatment together with its respective safety monitoring period constitutes one cycle. The total duration of protocol therapy will include up to three cycles, depending on the number of TAA-T cells available and the participant's clinical status. By opening the BBB, the investigators aim to increase the infiltration of the TAA-T cells into the tumor, and by leveraging the effects of FUS, also to modify the tumor immune-microenvironment to become more favorable to immune infiltration. LIFT therapy presents a novel opportunity to not only enhance T-cell delivery but potentially enhance the immune response. Correlative biological studies will measure anti-tumor immunologic effects and will also assess potential biomarkers.
Interventions
BIOLOGICALTAA-T Cell
Intravenous tumor associated antigen specific T cell (TAA-T) infusion.
DEVICEBBB Disruption
BBB disruption using the Exablate 4000 Type 2 System with DEFINITY microbubbles.
Sponsors
Children's National Research Institute
Focused Ultrasound Foundation
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 25 Years
Healthy volunteers
No
Inclusion criteria
Inclusion Criteria for Screening and Procurement: * 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
Exclusion criteria
below * 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 * Organ function: * Hemoglobin ≥ 8 g/dL, unsupported * Absolute Neutrophil Count (ANC) ≥750/μL * Absolute Lymphocyte Count (ALC) \>500/μL * Platelets ≥75K, unsupported * Total Bilirubin ≤3x upper limit of normal (ULN) * AST/ALT ≤5x ULN * Serum creatinine ≤1.0 mg/dL or ≤1.5x ULN for age (whichever is higher) * Pulse oximetry \>90% on room air * If the participant is on corticosteroids, the dose must be stable or decreasing for at least 7 days prior to procurement, and the treating investigator must anticipate that steroids can be weaned to ≤ 0.4 mg/m2/day of dexamethasone or equivalent by the start of the first LIFT protocol therapy cycle * Deemed to be of sufficient size (≥10 kg) to provide the necessary blood volume for TAA-T generation with no contra-indications to research blood draw, as determined by the treating PI/Sub-I * Adult participant or LAR of minor participant demonstrates willingness to have intracerebroventricular access device placed prior to initiation of LIFT protocol therapy, if a suitable Rickham, Ommaya, or accessible VP shunt is not already in place at study entry * For females of childbearing potential (FOCBP): negative pregnancy test within 7 days prior to procurement (urine or serum) * Adult participant or LAR of minor participant capable of providing informed consent. When appropriate, pediatric participants ≥7 years of age will participate in an age-appropriate discussion and provide assent, unless an IRB-approved waiver of assent applies and documentation of the participant's eligibility for the waiver is maintained Inclusion Criteria for BBBD Procedure and TAA-T Infusion: * 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) * Group A: must have their initial planned LIFU and TAA-T infusion within 20 weeks from completion of radiation therapy; Group B: must have their initial planned LIFU and TAA-T infusion within 28 weeks from completion of radiation therapy * For participant with a history of prior intracranial surgery, at least 14 days must have elapsed since surgery and the participant must have fully recovered from acute surgical effects * For participant with a history of bevacizumab (Avastin) exposure, at least 28 days must have elapsed since the last dose * If on steroids, stable or decreasing dose ≤ 0.4 mg/m2/day of dexamethasone or equivalent on the date of eligibility confirmation for LIFT treatment * Stable or improving neurological status for ≥14 days prior to the date of eligibility confirmation for the first LIFU and TAA-T infusion, and for ≥7 days prior to the date of eligibility confirmation for subsequent cycles * Intracerebroventricular access device (such as an Ommaya or Rickham reservoir and catheter) or VP shunt present, and in a location that does not interfere with Exablate BBBD procedure * Organ function: * Hemoglobin ≥ 8 g/dL, unsupported * Absolute Neutrophil Count (ANC) ≥750/μL * Platelets ≥75K, unsupported * Normal coagulation studies: PT (\<14 sec) or PTT (\<36 sec), and INR (\<1.2) * Total Bilirubin ≤3x upper limit of normal (ULN) * AST/ALT ≤5x ULN * Serum creatinine ≤1.0mg/dL or ≤1.5x ULN for age (whichever is higher) * Pulse oximetry \>90% on room air * For FOCBP: negative pregnancy test (urine or serum) * Agree to use contraceptive measures for at least 6 months following final TAA-T infusion (when age appropriate) * Suitability for prolonged anesthesia for LIFU procedure, in the opinion of treating PI or qualified Sub-I * Agree to a brief course of steroids or bevacizumab or anti-cytokine agent/s if the treating investigator deems it clinically necessary in the context of clinical deterioration that may be attributed to the LIFT protocol therapy * Adult participant or LAR of a minor participant capable of providing informed consent. When appropriate, pediatric participants ≥7 years of age will participate in an age-appropriate discussion and provide assent, unless an IRB-approved waiver of assent applies and documentation of the participant's eligibility for the waiver is maintained * Adult participant or LAR of a minor participant must attest to the participant's ability to remain in close geographic proximity to CNH (within 60-mile radius) for the initial dose limiting toxicity (DLT) monitoring period, and for the first 14 days after each subsequent infusion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Evaluation | Within 28 days from last treatment | 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 | Within 28 days from last treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of multiple cycles | Ends when all planned LIFT treatment cycles completed | 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 | Within 3 years of last treatment | 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 | Within 3 years of last treatment | 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. |
Contacts
CONTACTLuca Szalontay, MD
CONTACTFahmida Hoq, MBBS
PRINCIPAL_INVESTIGATORLuca Szalontay, MD
Children's National Research Institute
Outcome results
None listed