Selective Antigen Specific dTβRII-expressing T Cells and B7-H3 CAR T Cells in Subjects With Relapsed/Refractory Embryonal Tumors (SABRE)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 18
- 试验地点
- 2
- 主要终点
- To determine the safety of autologous CAR-TA T cells following LD chemotherapy in participants with relapsed/refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma and Wilms tumor.
研究概览
简要总结
This is a phase I dose-escalation study to determine the safety and feasibility of autologous CAR-TA T cells (B7-H3 CAR+ T cells administered with DNR-PRAME Tumor Antigen-specific T cells) following lymphodepleting chemotherapy in participants with relapsed/refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma and Wilms tumor.
Patients will be enrolled to one of three planned dose levels with B7-H3 CAR T cell dose determined based on the percentage of B7-H3 transduced cells (B7-H3+ population of cells), and dTBRII-transduced PRAME TA-specific T cell dose based on the total cell population. Both doses will be based on the recipient's body weight and combined in a 1:1 ratio.
The safety of the CAR-TA T cell product will be evaluated and the maximum tolerated dose (MTD) will be determined. The safety endpoint will be assessed by monitoring for dose limiting toxicities for 28 days following CAR-TA T cell administration.
详细描述
This protocol is designed as a phase I dose-escalation study. Procurement phase: During the procurement phase of this protocol, upon SABRE Procurement Consent and procurement eligibility confirmation, participants will undergo a non-mobilized apheresis for collection of mononuclear cells to be used for the CAR-TA T cell product manufacturing.
Treatment phase: Once the CAR-TA T cell products are released and patients are confirmed eligible for CAR-TA T cell product infusion, participants will undergo protocol therapy at participating site(s), consisting of a standard lymphodepleting chemotherapy preparative regimen with fludarabine and cyclophosphamide, followed by intravenous infusion of the combined CAR-TA T cell product. The DNR-TA T cells and B7-H3 CAR T cells will be generated and combined into a final product comprised of the two T cell components combined at a 1:1 ratio.
Patients will be enrolled to one of three CAR-TA T cell product dose levels (dose levels 1, 2 and 3). There are provisions in place to dose de-escalate for safety concerns (dose level -1).
Fludarabine will be administered intravenously once daily over 30 minutes, days -5 through -2 (4 doses in total). The dose of fludarabine will be 30 mg/m2 /day. Cyclophosphamide will be administered intravenously once daily over 30 minutes, days -5 and -4 (2 doses in total). The dose of cyclophosphamide will be 500 mg/m2 /day.
The first 3 patients enrolled on study will be ≥ 12 years of age at enrollment and treated at dose level 1 (1 x 10e6/kg). If no DLTs are observed in this cohort, enrollment at dose levels 2 (3 x 10e6/kg) and 3 (10 x 10e6/kg) will expand to include patients aged ≥ 1 year and < 24 years.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 23 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Recipient Inclusion Criteria for Procurement:
- •Diagnosis of relapsed/refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma, or Wilms tumor
- •Refractory disease, residual detectable disease or relapsed disease following available standard of care therapies with known clinical benefit for their specific tumor type, or unable to receive such therapies due to unacceptable toxicity or contraindication
- •Measurable or evaluable disease by imaging, as determined following most recent therapy
- •Age ≥ 1 year and < 24 years
- •Weight ≥ 10 kg
- •No systemic steroid exposure within 1 week of procurement
- •Karnofsky/Lansky score of ≥ 60 (See Appendix 3)
- •Participants of childbearing potential or capable of fathering a child must agree to use effective contraceptive measure/s (as described in Appendix 5) during study protocol participation through 6 months following the administration of the CAR-TA T cells
- •ANC > 500/µL
- •ALC > 1000/µL
- •Platelet count > 50,000/uL (level can be achieved with transfusion)
- •Bilirubin ≤ 2.5 mg/dL
- •Aspartate aminotransferase (AST)/Alanine transaminase (ALT) ≤ 5x the upper limit of normal for age
- •Serum creatinine Maximum serum creatinine (mg/dL) Age Male Female
- •to < 2 years 0.6 0.6
- •to < 6 years 0.8 0.8
- •6 to < 10 years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.2
- •≥ 16 years 1.7 1.4 OR Creatinine clearance or glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m for patients with levels above
- •For FOCBP: Negative pregnancy test
- •Pulse oximetry of > 90% on room air
- •Adequate cardiac function defined as:
- •Shortening fraction of ≥ 27% by echocardiogram, or
- •Ejection fraction of > 50% by echocardiogram or radionuclide angiogram (i.e., MUGA).
- •No acute neurological toxicity > grade 1 (with the exception of peripheral sensory neuropathy or controlled seizure disorder on anti-epileptics).
- •The following time frames must have elapsed between prior therapy completion and apheresis cell collection:
- •Myelosuppressive chemotherapy/immunomodulatory medications: At least 3 weeks, or 6 weeks if prior nitrosourea.
- •Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor. At least 14 days after receiving pegfilgrastim.
- •Biological agent, tyrosine kinase inhibitor, targeted agent, metronomic chemotherapy: At least 7 days since the completion of therapy with a biologic agent, tyrosine kinase inhibitor, targeted agent, or metronomic non-myelosuppressive regimen.
- •Monoclonal antibodies and checkpoint inhibitors: At least 3 weeks or 5 half-lives (whichever is shorter) since the last dose of a monoclonal antibody or checkpoint inhibitor.
- •Radiotherapy (XRT): At least 3 weeks since XRT, and at least 6 weeks if radiation involved the CNS or lung fields. Exception: There is no time restriction for palliative radiation with minimal bone marrow involvement and the patient has measurable/evaluable disease outside the radiation port or the site of radiation has documented progression.
- •Autologous stem cell transplant/infusion: At least 6 weeks from their infusion after an autologous stem cell infusion following myeloablative therapy. Patients who received an autologous stem cell infusion following non-myeloablative therapy do not have a wash-out period; they are eligible once they meet all other eligibility requirements, including recovery from acute side effects.
- •Investigational agent: at least 28 days since receiving an investigational agent.
- •Adult participant or the legally authorized representative (LAR) of a minor (defined as <18 years of age) must be 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.
- •Recipient Inclusion Criteria for CAR-TA T cell product Infusion:
- •No systemic steroid exposure within 1 week prior to protocol therapy initiation
- •Karnofsky/Lansky score of ≥ 60
- •ANC > 750/uL
- •Platelet count > 75,000/uL
- •Bilirubin ≤ 2.5 mg/dL
- •AST/ALT ≤ 5x the upper limit of normal for age
- •Serum creatinine Maximum serum creatinine (mg/dL) Age Male Female
- •1 to < 2 years 0.6 0.6 2 to < 6 years 0.8 0.8 6 to < 10 years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.2
- •≥ 16 years 1.7 1.4 OR Creatinine clearance or glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m for patients with levels above
- •For FOCBP: Negative pregnancy test
- •Participants of childbearing potential or capable of fathering a child must agree to use effective contraceptive measure/s through 6 months following the administration of the CAR-TA T cells
- •Adequate respiratory function defined as oxygen saturation 90% or higher on room air
- •For participants who underwent prior mediastinum-directed therapies (e.g., post radiation to chest): resolution of any respiratory symptoms
- •Adequate respiratory rate, defined as <30 breaths per minute for patients aged <18 years, and <25 breaths per minute for patients aged ≥18 years (respiratory rate may be repeated if initial value is thought to be temporarily abnormal; if repeated, 2 consecutive readings obtained ≥30 minutes apart must be adequate to be eligible)
- •No acute neurological toxicity > grade 1 (with the exception of peripheral sensory neuropathy or controlled seizure disorder on anti-epileptics).
- 另有 11 项未显示
排除标准
- •Recipient Procurement Exclusion Criteria:
- •Patients with known CNS disease.
- •Patients with uncontrolled infection/s or known HIV infection
- •Pregnant or lactating females.
- •Patients who have undergone previous allogeneic stem cell transplant.
- •Inability to tolerate leukapheresis (including any contraindication to the use of Anticoagulant Citrate Dextrose solution).
- •Recipient Exclusion Criteria for CAR-TA T cell product Infusions:
- •Patients with uncontrolled infections or known HIV infection.
- •Pregnant or lactating females
- •Whole lung/mediastinal radiation within 12 weeks
- •Clinically significant systemic illness or medical condition likely to interfere with assessment of safety or efficacy
- •Patients who have received any live vaccine in the six weeks prior to planned initiation of lymphodepletion
- •Any contraindication to lymphodepletion or to the use of Cyclophosphamide or Fludarabine, as per the clinical judgment of the PI or treating Sub-I
- •History of allergy or hypersensitivity to study product excipients (e.g., DMSO)
研究组 & 干预措施
This is single arm study.
Lymphodepleting chemotherapy regimen with cyclophosphamide and fludarabine will be administered prior to CAR-TA T cell product infusion. The DNR-TA T cells and B7-H3 CAR T cells will be generated and combined into a final product comprised of the two T cell components combined at a 1:1 ratio.
干预措施: Selective Antigen Specific dTβRII-expressing T cells combined with B7-H3 CAR T cells (Biological)
结局指标
主要结局
To determine the safety of autologous CAR-TA T cells following LD chemotherapy in participants with relapsed/refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma and Wilms tumor.
时间窗: Within 28 days from the CAR-TA T cell infusion
The safety endpoint will be assessed by monitoring for dose limiting toxicities (DLT) for 28 days following CAR-TA T cell investigational product administration.
To determine the manufacturing feasibility of autologous CAR-TA T cells following LD chemotherapy in participants with relapsed/refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma and Wilms tumor.
时间窗: Within 28 days from the CAR-TA T cell infusion
Manufacturing feasibility will be determined by the number of CAR-TA T cell products produced in sufficient quantities to meet the participant's assigned dose level for at least one infusion, with all product release testing criteria met.
To determine the clinical feasibility of autologous CAR-TA T cells following LD chemotherapy in participants with relapsed/refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma and Wilms tumor.
时间窗: Within 28 days from the CAR-TA T cell infusion
Clinical feasibility will be determined by the number of participants with a released product who are eligible and receive at least 1 infusion.
Grade 3 Cytokine Release Syndrome (CRS) lasting more than 14 days
时间窗: Within 28 days from the CAR-TA T cell infusion
Number of patients experiencing Grade 3 CRS with a duration greater than 14 days
Grade 3 or more immediate infusion-related adverse event
时间窗: Within 28 days from the CAR-TA T cell infusion
Number of patients experiencing Grade 3 or higher immediate infusion-related adverse events, assessed using the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0; Grades 1-5; higher grades indicate worse severity), occurring during or immediately following the CAR-TA T cell infusion.
Grade 4 or more Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS)
时间窗: Within 28 days from the CAR-TA T cell infusion
Number of patients experiencing Grade 4 or higher Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), assessed using the American Society for Transplantation and Cellular Therapy (ASTCT) CRS and ICANS Consensus Grading Criteria (Grades 1-5; higher grades indicate worse severity).
Grade 3 neurotoxicity or ICANS persisting for more than 72 hours
时间窗: Within 28 days from the CAR-TA T cell infusion
Number of patients experiencing Grade 3 neurotoxicity or ICANS with a duration greater than 72 hours. (severity grades assessed as per American Society for Transplantation and Cellular Therapy (ASTCT) CRS and ICANS Consensus Criteria)
Grade 4 or more Cytokine Release Syndrome (CRS)
时间窗: Within 28 days from the CAR-TA T cell infusion
Number of patients experiencing Grade 4 or higher Cytokine Release Syndrome (CRS), assessed using ASTCT CRS Consensus Grading Criteria (Grades 1-5; higher = worse).
Grade 3 or more Hemophagocytic Lymphohistiocytosis (HLH)
时间窗: Within 28 days from the CAR-TA T cell infusion
Number of patients experiencing Grade 3 or higher Hemophagocytic Lymphohistiocytosis (HLH), assessed using CTCAE v5.0.
Grade 3 or more fever lasting for more than 14 days
时间窗: Within 28 days from the CAR-TA T cell infusion
Number of patients experiencing fever of Grade 3 or higher, persisting longer than 14 days, assessed using CTCAE v5.0.
Grade 4 or more infection uncontrolled for more than 7 days
时间窗: Within 28 days from the CAR-TA T cell infusion
Number of patients experiencing infection of Grade 4 or higher severity that is uncontrolled for more than 7 days, assessed using CTCAE v5.0.
Any unexpected toxicity of Grade 2 or more
时间窗: Within 28 days from the CAR-TA T cell infusion
Number of patients experiencing unexpected toxicities of Grade 2 or higher, assessed using CTCAE v5.0.
Any expected toxicity above Grade 4
时间窗: Within 28 days from the CAR-TA T cell infusion
Number of patients experiencing expected toxicity above Grade 4 (i.e., Grade 5 toxicity), assessed using CTCAE v5.0.
Any expected toxicity above Grade 3 lasting longer than 72 hours
时间窗: Within 28 days from the CAR-TA T cell infusion
Number of patients experiencing expected toxicity greater than Grade 3, persisting longer than 72 hours, assessed using CTCAE v5.0.
Grade 2 toxicity persisting for more than 7 days AND considered intolerable to the patient and/or not controlled with standard supportive care
时间窗: Within 28 days from the CAR-TA T cell infusion
Number of patients experiencing Grade 2 toxicity persisting for more than 7 days that is intolerable to the patient and/or not controlled with standard supportive care, assessed using CTCAE v5.0.
次要结局
- Determine number of patients who respond to CAR-TA T cell therapy for treatment of diseases under study(Within 15 years of infusion of CAR-TA T cell therapy.)
- Overall Survival(Within 12 months of CAR-TA T cell infusion.)
- To characterize the in vivo immune milieu pre- and post-infusion of CAR-TA T cell product.(Within 15 years of infusion of CAR-TA T cell therapy.)
- To characterize transgene transduction efficiency (B7-H3 CAR and dTBRII) of the CAR-TA T cell product generated prior to infusion.(Within 15 years of infusion of CAR-TA T cell therapy.)
- To characterize reconstitution of anti-tumor immunity following infusion.(Within 15 years of infusion of CAR-TA T cell therapy.)
- To determine in vivo persistence of infused DNR-TA T cells and B7-H3 CAR T cells at 1-,3-, 6-, and 12-months following infusion of CAR-TA T cell product and evaluate the association with clinical response(Within 12 months of CAR-TA T cell infusion)
- To characterize PRAME specificity of the CAR-TA T cell product generated prior to infusion.(Within 15 years of infusion of CAR-TA T cell therapy.)
- To characterize phenotype of the CAR-TA T cell product generated prior to infusion.(Within 15 years of infusion of CAR-TA T cell therapy.)
- Progression(Within 12 months of CAR-TA T cell infusion.)
- Response to CAR-TA T cell therapy(Up to 5 years from the CAR-TA T cell infusion)
- Progression-free survival(Up to 12 months from the CAR-TA T cell infusion)
- Overall survival(Up to 12 months from the CAR-TA T cell infusion)
研究者
HMeany
Med Dir Solid Tumor Program
Children's National Research Institute