A Safety and Feasibility Study to Evaluate Blood-Brain Barrier Disruption Using Exablate MR-Guided Low Intensity Focused Ultrasound With Microbubbles in Combination With Preferentially Expressed Antigen of Melanoma (PRAME), Survivin, and Wilms Tumor 1 (WT1)-Targeting Tumor Associated Antigen-specific T-Cell Infusion in Patients With Newly Diagnosed Diffuse Midline Glioma (LIFT)
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 45
- 主要终点
- Safety Evaluation
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 3 Years 至 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
- •Exclusion Criteria:
- •Exclusion Criteria for Screening and Procurement:
- •Tumor not visible on any pre-LIFT therapy imaging
- •Previous participation in other conventional or investigational chemotherapy, molecularly targeted therapy, or immunotherapy (Exceptions: Temozolomide during radiation in Group B patients is allowed; Bevacizumab use is allowed)
- •Disseminated disease
- •Primary disease in the spinal cord
- •Clinical or radiologic evidence of increased intracranial pressure
- •For a participant with a ventricular peritoneal (VP) shunt or similar device: presence of a device that, in the judgment of the institutional neurosurgeon (based on a technical evaluation of the screening non-contrast CT imaging and Exablate system target mapping), would interfere with safe delivery of the Exablate BBBD procedure
- •Previous or current uncontrolled infection/s
- •Known HIV infection
- 另有 51 项未显示
研究组 & 干预措施
Patients with newly diagnosed pontine DMG (Group A)
Participants will be patients, ages 3 to 25 years, with newly diagnosed pontine DMG (Group A) who have undergone irradiation as part of their upfront therapy. Participants must not have received prior conventional or investigational chemotherapy, targeted therapy, or immunotherapy, except bevacizumab. Biopsy is not required.
干预措施: TAA-T Cell (Biological)
Patients with newly diagnosed pontine DMG (Group A)
Participants will be patients, ages 3 to 25 years, with newly diagnosed pontine DMG (Group A) who have undergone irradiation as part of their upfront therapy. Participants must not have received prior conventional or investigational chemotherapy, targeted therapy, or immunotherapy, except bevacizumab. Biopsy is not required.
干预措施: BBB Disruption (Device)
Participants with newly diagnosed thalamic DMG (Group B)
Participants will be patients, ages 3 to 25 years, with newly diagnosed thalamic DMG (Group B) who have undergone irradiation as part of their upfront therapy. With the exception of temozolomide administered concurrently with radiation and bevacizumab, participants must not have received prior conventional or investigational chemotherapy, targeted therapy, or immunotherapy. Biopsy is required.
干预措施: TAA-T Cell (Biological)
Participants with newly diagnosed thalamic DMG (Group B)
Participants will be patients, ages 3 to 25 years, with newly diagnosed thalamic DMG (Group B) who have undergone irradiation as part of their upfront therapy. With the exception of temozolomide administered concurrently with radiation and bevacizumab, participants must not have received prior conventional or investigational chemotherapy, targeted therapy, or immunotherapy. Biopsy is required.
干预措施: BBB Disruption (Device)
结局指标
主要结局
Safety Evaluation
时间窗: 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
时间窗: 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.
次要结局
- Feasibility of multiple cycles(Ends when all planned LIFT treatment cycles completed)
- Treatment efficacy(Within 3 years of last treatment)
- Treatment response based on the iRANO/RAPNO criteria(Within 3 years of last treatment)
研究者
Luca Szalontay
Neuro-oncologist
Children's National Research Institute