Phase 1 Trial of Autologous HER2-specific CAR T Cells in Pediatric Patients With Refractory or Recurrent Ependymoma
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 50
- 试验地点
- 15
- 主要终点
- Number of Subjects with Dose-Limiting Toxicity (DLT) in Phase I Arm
研究概览
简要总结
This is a Phase I study to evaluate the safety profile of a type of immune therapy called HER2 CAR T cells (short for HER2 chimeric antigen receptor T cells). In addition to looking for side effects, we will study how well this treatment works against a brain tumor called ependymoma that has come back after treatment (recurrent) or has not responded well to treatment (progressive) in children. The HER2 CAR T cells used in this trial are made from the patient's own blood. A new gene, called the HER2 CAR, will be inserted into patient's T cells to allow them recognize a protein on the tumor called HER2. These HER2-specific CAR T cells may be able to target and kill ependymoma tumors that express HER2. This research is also studying how doable it is to provide this type of CAR T cell treatment to children being treated at different hospitals.
详细描述
PBTC-059 is a multicenter, Phase I and Surgical study of the treatment HER2-specific CAR T cells for patients with refractory or recurrent ependymoma.
Phase I
The primary objectives of the Phase I study are to determine the safety of intravenous injection of HER2-specific CAR T cells after lymphodepleting chemotherapy, and to evaluate the multicenter feasibility of administering up to three infusions of HER2-CAR T cells after lymphodepletion.
Patients will receive one infusion of HER2psecific CAR T cells after lymphodepleting chemotherapy. Following recovery from their first treatment (no earlier than 8 weeks and no later than 12 weeks), patients will resume treatment with HER2-specific CAR T cells for up to 2 infusions after lymphodepleting chemotherapy if they meet laboratory parameters.
The length of time on study for patients enrolled on the Phase I study is anticipated to be 9 months on treatment. Patients will then be followed for 15 years after treatment.
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
- 1 Year 至 22 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Criteria for Screening
- •Patient must have a diagnosis of ependymoma that is recurrent or progressive. All tumors must have histologic verification either at the time of diagnosis or recurrence.
- •Prior Therapy
- •Patient must have received standard of care therapy including maximal safe surgical resection followed by local adjuvant radiation therapy prior to enrollment.
- •Adequate Pre-trial Tumor Tissue
- •Patient must have adequate pre-trial tumor material available to determine HER2 status. Tumor tissue from the most recent resection or biopsy of recurrent disease in preferred. If unavailable, tumor tissue from prior recurrences or from the time of initial diagnosis is acceptable.
- •a. One exception will be patients who have previously received HER2-directed therapy (including but not limited to trastuzumab); these patients will need evaluation of tumor HER2 status after stopping treatment due to the possibility of HER2 downregulation or loss.
- •Tumor biopsy will not be performed for the purpose of HER2 screening. Patients will not be eligible for screening on PBTC-059 if tumor tissue is not available or inadequate for HER2 testing. Tumor screening by Immunohistochemistry (IHC) will be done centrally using the testing method validated at Texas Children's Hospital. Sample for screening must be shipped within 7 days of enrollment for screening.
- •Known HIV Positivity
- •Patients that are known to be HIV-positive are ineligible due to the unknown safety and efficacy of infusing these patients with CAR T cells genetically modified using retroviral vectors. Additionally, the immunosuppression used for treatment in this study will pose an unacceptable risk.
- •Patient must be ≥ 1 but ≤ 21 years of age at the time of screening consent.
- •Screening Consent
- •The patient or parent/guardian can understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Age- and developmentally appropriate assent should be obtained as required by institutional guidelines.
- •Potential Eligibility for Study Treatment Enrollment
- •Patients are screened for this trial should be reasonably anticipated to meet the criteria for treatment described in Section 3.3 if their tumor is HER2-positive.
- •Criteria for Procurement
- •All subjects must meet following inclusion and exclusion eligibility criteria at the time of peripheral blood procurement for manufacturing the HER2 CAR T-cell product. No exceptions will be given. All clinical and laboratory evaluations to establish eligibility for procurement must be done within 14 days prior to enrollment. See Section 6.1 for details of laboratory requirements and planning of procurement blood collection date.
- •Procurement Inclusion Criteria
- •Patient must have been screened and determined to have a diagnosis of a HER2-positive recurrent or progressive ependymoma.
- •Performance Score
- •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 of procurement must be ≥ 60%. 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 as described in Section 3.3.1.
- •Prior Therapy
- •Patients must have received last dose of cytotoxic chemotherapy greater than 21 days preceding the date of enrollment for procurement.
- •Organ Function
- •Patient must have adequate organ and bone marrow function as defined below:
- •Peripheral absolute neutrophil count (ANC) > 1.0 x 109 cells/L
- •Platelet count ≥ 75 100 x 109 cells/L (unsupported, defined as no platelet transfusion within 4 days)
- •Hemoglobin ≥ 8 g/dL (may receive red blood cell transfusions)
- •Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) for age
- •Alanine transaminase (ALT /SGPT) and Aspartate aminotransferase(AST/SGOT) ≤ 3 x institutional upper limit of normal (ULN) for age
- •Serum creatinine < 1.5 x institutional upper limit of normal for age and gender. Patients that do not meet the criteria but have a 24-hour Creatinine Clearance or Glomerular filtration rate (GFR) (radioisotope or iothalamate) ≥ 70 mL/min/1.73 m2 are eligible.
- •Pulmonary Function
- •Oxygen saturation as measured by pulse oximetry is ≥ 93% on room air.
- •Concomitant Medication
- •Patients who are receiving systemic corticosteroids must be on a stable or decreasing dose for at least two weeks prior to procurement, and corticosteroid dose must be less than or equal to dexamethasone 0.75 mg/m2/day (or equivalent). Use of topical, ocular, intranasal, or inhaled corticosteroids are permitted.
- •Procurement Consent
- •The patient or parent/guardian can understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Age- and developmentally appropriate assent should be obtained as required by institutional guidelines.
- •Potential Eligibility for Study Enrollment
- •Patients whose blood samples have been successfully procured for this trial should be reasonably anticipated to meet the criteria for treatment described in Section 3.3 and to begin treatment within 180 days from the date of procurement. The treatment slot will not be held beyond the specified 180 days, and such patients may not be able to receive treatment on this study depending on slot availability.
- •Procurement
排除标准
- •1. Known HIV Positivity
- •Patients who are known to be HIV-positive are ineligible due to the unknown safety and efficacy of infusing these patients with CAR T cells genetically modified using retroviral vectors. Additionally, the immunosuppression used for treatment in this study will pose an unacceptable risk.
- •Criteria for Treatment
- •All Phase I (Stratum 1) and Surgical (Stratum 2) subjects must meet following inclusion and exclusion eligibility criteria at the time of enrollment for treatment. No exceptions will be given. Imaging studies must be done within 14 days prior to enrollment. All other clinical and laboratory evaluations to establish eligibility for treatment must be done 7 days prior to enrollment.
- •Treatment Inclusion Criteria
- •Patients with a histologically confirmed diagnosis of HER2 positive ependymoma that is recurrent or progressive. Histologic verification may be from time of diagnosis or time of recurrence. In cases where there is question of recurrence, histologic verification, or verification of progression on follow up imaging is required prior to enrolling for protocol treatment.
- •Disease Status
- •Phase I (Stratum 1) - Patients must have evaluable disease to be eligible. Evaluable disease includes either measurable OR non-measurable disease, defined as follows:
- •Measurable disease (enhancing or non-enhancing tumor):
- •at least 1 cm, or
- •at least two times (in both perpendicular diameters) the MRI slice thickness, plus the interslice gap.
- •Non-measurable disease (tumor that is too small to be accurately measured):
- •less than 1 cm in at least one perpendicular dimension, or
- •less than two times the MRI slice thickness, plus the interslice gap.
- •Note: Leptomeningeal disease is considered non-measurable but evaluable.
- •Surgical Study (Stratum 2) - Patients with measurable disease (Section 3.3.1.2.1) in whom tumor resection is clinically indicated and feasible after the CAR T cell infusion.
- •Patient must be ≥ 1 but ≤ 22 years of age at the time of enrollment for treatment.
- •HER2 CAR T cell product
- •The patient must have, at a minimum, one prescribed dose of the cryopreserved, autologous HER2 CAR T cell product available for infusion.
- •Prior Anti-neoplastic Therapy
- •Cytotoxic chemotherapy: Patients must not have received cytotoxic chemotherapy for at least 28 days prior to study enrollment for treatment and must have recovered from the acute treatment related toxicities (defined as < grade 1 if not defined in eligibility criteria; excludes alopecia) prior to entering this study.
- •Biological, targeted, or investigational agents (anti-neoplastic): Patients must have a period of at least 28 days from the last receipt of said drug and must have recovered from all acute toxic effects.
- •For agents that have known acute adverse events occurring beyond 28 days after administration, this period must be extended beyond the time during which adverse events are known to occur.
- •Monoclonal antibodies, checkpoint inhibitors, and other agents with known prolonged half-lives: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent ≥ 28 days prior to study enrollment.
- •Adoptive cellular therapies: Patient must have recovered from any acute toxicity potentially related to the cellular product and received their last dose of the cellular product at least 90 days prior to study enrollment. (Note: Patients who have previously received an adoptive cellular therapy may continue long-term follow up evaluations per the prior study's evaluation schedule as needed for assessment of long-term toxicities including genotoxicity.)
- •Radiation: Patients must have had their last fraction of:
- •a. Craniospinal irradiation, whole brain radiation, total body irradiation or radiation to >50% of pelvis or spine ≥ 3 months prior to enrollment (90 days) prior to enrollment.
- •b. Focal palliative irradiation to the tumor ≥ 42 days prior to enrollment. c. Patients who receive tumor-directed radiation (non-palliative) should have confirmed disease progression on the imaging study done at least 6 weeks after the completion of the last fraction of radiation.
- •Surgery: Patients must have not had surgery within 14 days of enrollment for treatment and must have adequate wound healing and recovered from other acute effects from surgery. One exception is the placement of central venous catheter which will be allowed at any time point until treatment initiation on the study.
- •Growth Factors
- •Patients must be off all colony-forming growth factor(s) for at least 7 days prior to enrollment (e.g., filgrastim, sargramostim, or erythropoietin). 14 days must have elapsed if the patient received a long-acting formulation.
- •Corticosteroids
- •Patients who are receiving systemic corticosteroids must be on a stable or decreasing dose for at least 14 days prior to enrollment for treatment, and corticosteroid dose must be less than or equal to dexamethasone 0.5 mg/m2/day (or equivalent) during the 14 days preceding enrollment. Use of topical, ocular, intranasal, or inhaled corticosteroids are permitted.
- •Neurologic Status
- •In patients with neurological deficits, deficits should be stable for a minimum of 7 days prior to enrollment. A baseline detailed neurological exam should clearly document the neurological status of the patient at the time of enrollment for treatment on the study.
- •Patients with seizure disorders may be enrolled if seizures are well controlled.
- •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 of enrollment must be ≥ 60%. 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.
- •Organ Function
- •Patients must have adequate organ and bone marrow function as defined in Section 3.2.1.
- •Pregnancy Prevention
- •Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study.
- •Informed Consent
- •The patient or parent/guardian can understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Age- and developmentally appropriate assent should be obtained as required by institutional guidelines.
- •Patients who meet eligibility criteria per Section 3.3.1.2.1 must be enrolled using Phase I treatment consent (Stratum 1).
- •Patients who meet eligibility criteria per Section 3.3.1.2.2 must be enrolled using Surgical Study treatment consent (Stratum 2).
- •Treatment Exclusion Criteria
- •Patients with Bulky Tumors on Imaging Studies
- •Bulky tumors will be defined as those:
- •> 6 cm in single maximum dimension, or
- 另有 28 项未显示
研究组 & 干预措施
Treatment (HER2 CAR T cells), Phase I Arm
Patients receive lymphodepletion chemotherapy with cyclophosphamide IV daily on Days -7 to -6 and fludarabine IV daily on Days -5 to -1. Patients receive HER2 CAR T cells IV on Day 0. Treatment repeats every 8 to 12 weeks for 2 additional cycles in the absence of disease progression or unacceptable toxicity.
干预措施: HER2 Specific CAR T Cell (Biological)
Treatment (HER2 CAR T cells), Surgical Arm
Patients receive lymphodepletion chemotherapy with cyclophosphamide IV daily on Days -7 to -6 and fludarabine IV daily on Days -5 to -1. Patients receive HER2 CAR T cells IV on Day 0 followed by surgical tumor resection 4-6 weeks following HER2 CAR T cell infusion. Treatment repeats every 8 to 15 weeks for 2 additional cycles in the absence of disease progression or unacceptable toxicity.
干预措施: HER2 Specific CAR T Cell (Biological)
结局指标
主要结局
Number of Subjects with Dose-Limiting Toxicity (DLT) in Phase I Arm
时间窗: Up to 42 days following the first CAR T cell infusion
DLT is defined as an adverse event that is at least possibly attributed to the investigational agent (HER2 CAR T cells) that occurs during the dose-finding period (the first 42 days following the first CAR T cell infusion) regardless of expectedness with a few exceptions, for which Section 6.4 of the protocol provides more details. All patients in Safety/Feasibility cohort who received at least 1 dose of HER2 CAR T cells are included in the assessment.
Number of Subjects with Dose-Limiting Toxicity (DLT) in Surgical Arm
时间窗: Up to 42 days following the first CAR T cell infusion
DLT is defined as an adverse event that is at least possibly attributed to the investigational agent (HER2 CAR T cells) that occurs during the dose-finding period (the first 42 days following the first CAR T cell infusion) regardless of expectedness with a few exceptions, for which Section 6.4 of the protocol provides more details. All patients in Surgical cohort who received at least 1 dose of HER2 CAR T cells are included in the assessment.
Percentage of Subjects whose Treatment Delivery Meets Feasibility Criteria
时间窗: Approximately 3 months after enrollment for treatment
Assessment of feasibility is in the context of conducting an investigator-initiated (not industry sponsored) multi-institutional trial of CAR T cells. This would specifically include the feasibility of manufacturing the cells at one center and shipping them to other sites for administration and the infusion process. If more than 25% of patients cannot be treated as intended due to manufacturing, shipping or administration related causes (jointly considered as feasibility criteria), this would be considered unacceptable. If the treatment is not delivered as intended due to one or more manufacturing, shipping, or administration related causes, this instance will be counted as feasibility failure for that subject.
次要结局
- Presence of intra-tumoral HER2 CAR T Cells following First Infusion in Surgical Arm(Approximately 3 months after enrollment for treatment)
- Expansion and Persistence of HER2 CAR T Cells at First Infusion in patients who received this treatment(Approximately 3 months after enrollment for treatment)
- Presence of HER2 CAR T Cells following Third Infusion in Surgical Arm(Approximately 9 months after enrollment for treatment)
- Event-free Survival (EFS)(Up to 2 years from the initiation of protocol treatment)
- Expansion and Persistence of HER2 CAR T Cells at Third Infusion in patients who received this treatment(Approximately 10 months after enrollment for treatment)
- Best antitumor Response of Infused HER2 CAR T Cells in Phase I Arm(Up to 15 years from the initiation of protocol treatment)
- Best Antitumor Response of Infused HER2 CAR T Cells in Surgical Arm(Up to 15 years from the initiation of protocol treatment)
- Expansion and Persistence of HER2 CAR T Cells at Second Infusion in patients who received this treatment(Approximately 7 months after enrollment of treatment)
- Presence of HER2 CAR T Cells following Second Infusion in Surgical Arm(Approximately 6 months after enrollment for treatment)
- Overall Survival (OS)(2 years from the initiation of protocol treatment)