Peds IMPACT: Phase I Study -To Assess Safety and Feasibility of IL-8 Receptor Modified Patient-derived Activated CD70 CAR T Cell Therapy in Newly Diagnosed and Recurrent CD70+ Pediatric High-Grade Gliomas (pHGG) and Diffuse Intrinsic Pontine Glioma (ndDIPG)
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 24
- 试验地点
- 2
- 主要终点
- Incidence of investigational treatment related severe toxicity (Dose-limiting toxicity event)
研究概览
简要总结
This is a phase I study to assess the safety and feasibility of IL-8 receptor modified patient-derived activated CD70 CAR T cell therapy in newly diagnosed and recurrent CD70+ Pediatric High-Grade Gliomas (pHGG) and Diffuse Intrinsic Pontine Glioma (ndDIPG)
详细描述
Identified newly-diagnosed or recurrent/progressive pediatric CD70+ HGG and newly diagnosed CD70+ DIPG patients (after first 2 HGG patients are treated) will be enrolled in this clinical trial study prior to initiation of standard-of-care chemo-radiation. Prior to initiation of chemoradiation, PBMCs will be collected through peripheral venipuncture. After tumor CD70 status is confirmed, the 8R-70CAR T cell production will start.
4 weeks (+/- 1) post completion of radiation, pediatric patients, based on institutional policy, will initiate adjuvant chemo with dose-intensified TMZ 75-100 mg/m2/day x 21 days for up to 3 cycles. 8R-70CAR T cells will be administered at day 21-24 of the TMZ cycle as a single intravenous (IV) infusion, or for pediatric patients not receiving adjuvant chemo once 8R-70CAR T cells. Pediatric patients will receive lymphodepletion prior to CAR T cell administration.
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
- 4 Years 至 30 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •At enrollment:
- •Patients with a histologically confirmed diagnosis of:
- •Newly diagnosed high-grade glioma (WHO Grade III or IV)
- •Newly diagnosed DIPG (after first 2 HGG patients are treated)
- •Recurrent or progressive high-grade glioma
- •Age 4-18 years old for ndHGG. Age 4-30 for rHGG. Age 4-30 for nd DIPG.
- •Patients with M+ disease without gliomatosis cerebri (see definition under
排除标准
- •) ARE eligible.
- •Patients with primary spinal cord tumors ARE eligible.
- •CD70 positive (≥5%, 1+) The tumors from the surgical resection by immunohistochemistry will be confirmed by validated assay performed at UF Health Pathology, CLIA certified Lab.
- •CD70 tumor expression performed on paraffin-embedded tumor specimens will be evaluated. Tumor expression will be scored on a scale of 0 to 3 staining intensity:
- •0 = Negative
- •= Low level
- •= Moderate level
- •= High level The criteria for inclusion will be at least 5% of the cells scoring 1+ staining intensity (> 5%, 1+).
- •Karnofsky Performance Status (KPS, for patients >16yo) or Lansky Performance Score (LPS, for patients ≤16yo) of > 60% (Appendix C)
- •Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score provided the neurological deficit is stable.
- •Organ Function:
- •CBC with differential with adequate bone marrow function as defined below:
- •Absolute neutrophil count (ANC) ≥ 1000 cells/mm
- •Platelet count ≥ 75,000 cells/mm
- •(Unsupported, no transfusion within 4 days.)
- •Hemoglobin ≥ 8 g/dl. (May receive transfusions)
- •Adequate renal function as defined below:
- •Serum creatinine < 1.5 x institutional upper limit of normal for age and gender. Patients who do not meet the criteria but have a 24-hour Creatinine Clearance or GFR (radioisotope or iothalamate) ≥ 70 mL/min/1.73 m2 are eligible.
- •Adequate hepatic function as defined below:
- •Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) for age
- •ALT ≤ 3 times institutional upper limits of normal for age
- •AST ≤ 3 times institutional upper limits of normal for age
- •Patients with neurological deficits should have deficits that are stable for a minimum of 7 days prior to enrollment.
- •Signed parental permission and, as appropriate, assent from pediatric patients age ≥
- •If the patient's mental status precludes their informed consent, the legally authorized representative may give informed consent. Consent or permission/assent will be obtained at screening (before PBMC collection) and before treatment with CAR T-cells.
- •For females with childbearing potential, a negative serum pregnancy test at enrollment.
- •Women of childbearing potential (WOCBP) must be willing to use an acceptable contraceptive method to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of the study drug.
- •Males with female partners of childbearing potential must agree to practice adequate contraceptive methods throughout the study and should avoid conceiving children for 24 weeks following the last dose of the study drug.
- •Prior Therapy for recurrent Cohort only:
- •Patients with recurrent or progressive disease must have received prior radiotherapy +/- chemotherapy.
- •Patients must have recovered from the acute treatment related toxicities (≤ Grade 1) prior to enrollment.
- •Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment. Patients must have received their last dose of non-myelosuppressive chemotherapy at least 7 days prior to enrollment.
- •Patients must have received their last dose of the investigational or biologic agent ≥ 7 days prior to study enrollment. Monoclonal antibody treatment and agents with known prolonged half-lives: Patient must have received their last dose of the agent ≥ 28 days prior to study enrollment.
- •Patients with recurrent or progressive HGG must have had their last fraction of:
- •Craniospinal irradiation, whole brain radiation, total body irradiation or radiation to spine ≥ 6 weeks (42 days) prior to enrollment.
- •Focal irradiation ≥ 14 days prior to enrollment.
- •≥ 12 weeks (84 days) since autologous stem cell transplant prior to enrollment.
- •> 42 days since completion of any other type of adoptive cellular therapy prior to enrollment
- •Prior to lymphodepletion and therapy:
- •Appropriate bridging therapy (radiation/re-irradiation and/or salvage chemotherapy, dependent on cohort) was initiated within 7 weeks of surgery RT or other protocol directed anti-cancer therapy is without significant toxicity that persisted over 4 weeks.
- •Early postoperative progression: Patients who progress during radiation treatment that are clinically stable and meet eligibility criteria prior to the start of lymphodepletion may continue on study. If these criteria are not met, these patients will be withdrawn from the study.
- •Neurologic Status
- •In patients with neurological deficits, deficits should be stable for a minimum of 7 days prior to the start of treatment. A baseline detailed neurological exam should clearly document the neurological status of the patient prior to the start of treatment.
- •In patients with seizure disorders, seizures must be well controlled prior to the start of treatment.
- •Performance Status Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) (Appendix C) assessed within one week prior to the start of treatment must be ≥ 60%.
- •Organ Function Patients must have adequate organ and bone marrow function as defined in Section 3.
- •Pregnancy Testing Female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to the start of treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- •Corticosteroids: A maximum dose of 0.75 mg/kg/day with maximum of 4mg/day.
- •No active infection: No fever exceeding 38.5 °C and no acute antibiotics, antiviral, or antifungal PO or IV therapy.
- •Exclusion Criteria:
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研究组 & 干预措施
Recurrent High Grade Glioma (rHGG)
Participants will receive either 8R-70CAR T 1 x 10^7 cells/kg or 1 x 10^8 cells/kg
干预措施: Ex-Vivo expanded autologous IL-8 receptor (CXCR2) modified CD70 CAR (8R-70CAR) T cells (Biological)
Newly Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG)
Participants will receive either 8R-70CAR T 1 x 10^7 cells/kg or 1 x 10^8 cells/kg
干预措施: Ex-Vivo expanded autologous IL-8 receptor (CXCR2) modified CD70 CAR (8R-70CAR) T cells (Biological)
Newly Diagnosed High Grade Glioma (ndHGG)
Participants will receive either 8R-70CAR T 1 x 10^7 cells/kg or 1 x 10^8 cells/kg
干预措施: Ex-Vivo expanded autologous IL-8 receptor (CXCR2) modified CD70 CAR (8R-70CAR) T cells (Biological)
结局指标
主要结局
Incidence of investigational treatment related severe toxicity (Dose-limiting toxicity event)
时间窗: administration of 8R-70CAR T to 28 days post-infusion
Safety is defined as the adverse events (AEs), serious adverse events (SAEs) and dose-limiting toxicities (DLT) observed throughout the trial.
Prevalence of enrolled subjects who receive a qualified immunotherapy investigational product.
时间窗: Enrollment up to 18 weeks
Feasibility will be measured by the number of patients who receive 8R-70CAR T-cell that met the FDA IND defined quality assurance and quality control release criteria. A minimum of 66.7 % of enrolled subjects must achieve this criterion for the feasibility endpoint.
Maximum tolerated dose (MTD) dose-finding endpoint based on Dose-Limiting-Toxicity (DLT) incidence
时间窗: administration of 8R-70CAR T to 28 days post-infusion
Determination of the maximum tolerated dose (MTD) of 8R-70CAR T cells based on the incidence of investigational treatment-related severe toxicity (dose-limiting toxicity events)
次要结局
未报告次要终点