肿瘤细胞治疗研究
英文原题：GD2 CAR T Cells in Diffuse Intrinsic Pontine Gliomas (DIPG) & Spinal Diffuse Midline Glioma(DMG)
这是一项 I 期注册临床试验，评估 GD2CAR-T 细胞治疗胶质瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 97 例。试验地点：美国 · 斯坦福（共 1 个中心）。登记号：NCT04196413。
不限性别 · ≥ 2 Years 且 ≤ 60 Years
纳入标准：
1. 疾病状态：诊断为H3K27M突变型弥漫性中线胶质瘤（DMG）
2. H3K27M或H3K27I突变。经CLIA检测确认。
3. 年龄：大于或等于2岁且小于或等于60岁。
4. 既往治疗：
* 完成标准一线放疗后至少4周。
* 自任何既往全身治疗以来必须已过去至少3周或5个半衰期（以较短者为准），但全身性抑制性/刺激性免疫检查点治疗需要3个月。
* Dordaviprone（Modeyso），以前称为ONC201，可作为既往治疗使用，但——与其他抗癌药物一样——必须在入组前至少5个半衰期停止给药
5. 体能状态：
年龄>16岁的受试者：Karnofsky≥60%或东部肿瘤协作组（ECOG）体能状态为0或1；年龄≤16岁的受试者：Lansky量表≥60%。
因瘫痪而无法行走、但可坐轮椅的受试者，在评估体能评分时将被视为可活动。
6. 正常器官和骨髓功能（允许按机构标准进行支持治疗，即非格司亭、输血）i. ANC≥1000/uL ii. 血小板计数≥100,000/uL iii. 绝对淋巴细胞计数≥150/uL iv. 血红蛋白≥8 g/dL v. 充分的肾功能、肝功能、肺功能和心功能，定义为：
- 肌酐在年龄对应的机构正常范围内（即
成人≤2 mg/dL或根据下表在<18岁儿童中）或肌酐清除率（按Cockcroft Gault公式估算）≥60 mL/min
血清ALT/AST≤3.0 ULN（1级）
* 总胆红素≤1.5 mg/dl，但Gilbert综合征受试者除外。
* 心脏射血分数≥45%，经ECHO确定无具有生理意义的显著心包积液证据，且无临床显著的ECG发现
* 室内空气下基线氧饱和度>92%
7. 妊娠试验 有生育能力的女性必须血清或尿液妊娠试验阴性（接受过手术绝育的女性不被视为有生育能力）或NA
8. 避孕 有生育能力或使女方受孕可能的受试者必须愿意从入组本研究时起、直至接受预处理方案后四（4）个月或只要外周血或CSF中可检测到GD2CART细胞期间采取避孕措施。
9. 能够提供知情同意。所有≥18岁的受试者必须能够提供知情同意。对于<18岁的受试者，其法定授权代表（LAR）（即父母或监护人）必须提供知情同意。儿科受试者将被纳入适合其年龄的讨论，适当时，>7岁者将获得书面同意。如果未成年人在参与本研究期间达到成年年龄，他/她将被要求作为成人重新同意。
排除标准：
1. 对于剂量递增阶段：小脑蚓部或小脑半球的大块肿瘤累及（小脑脚受累可接受），或经研究者评估认为使受试者面临不可接受的脑疝风险的丘脑病变。
对于剂量扩展阶段：经研究者评估认为使受试者面临不可接受的脑疝风险的大块病变。允许丘脑DMG。
2. 经临床研究者判定，存在临床显著的吞咽功能障碍/吞咽困难或明显的延髓功能障碍；或经临床研究者判定，C6/7以上的原发性颈髓肿瘤存在高呼吸功能受损风险。
3. 当前正在接受高于生理替代水平的全身性皮质类固醇治疗。
4. 持续使用膳食补充剂、替代疗法或极端饮食调整，或使用任何未经研究者批准的药物
5. 既往接受过CAR治疗。
6. 既往接受过免疫调节治疗，但在至少3个月洗脱期后接受检查点抑制剂治疗除外。
7. 未控制的真菌、细菌、病毒或其他感染。既往诊断的感染若患者继续接受抗微生物治疗且对治疗有反应、临床稳定，则允许入组。
8. 诊断为以下持续感染：
* HIV，
* 乙型肝炎（HBsAg阳性）或
* 丙型肝炎病毒（抗-HCV阳性）。若有乙型肝炎或丙型肝炎病史，但定量PCR和/或核酸检测显示病毒载量检测不到，则允许入组。
9. 临床显著的全身性疾病或医学状况（如显著的心脏、肺部、肝脏或其他器官功能障碍），经主要研究者判断可能干扰对研究方案安全性或有效性的评估及其要求。
10. 妊娠或哺乳期女性。
11. 经研究者判断，受试者不太可能完成所有方案要求的研究访视或程序，包括随访访视，或无法遵守参与研究的要求。
12. 已知对本研究中使用的任何药物/试剂过敏。
13. 原发性免疫缺陷或自身免疫性疾病史（如克罗恩病、类风湿关节炎、系统性红斑狼疮），且在最近2年内需要全身性免疫抑制/全身性疾病修饰药物治疗
* 所有受试者档案必须包含支持性文件以确认受试者资格。
确认方法可包括但不限于实验室检查结果、影像学检查结果、受试者自我报告和病历审查。
*26岁以下者请联系Ashley Jacobs，26岁及以上者请联系Monica Reddy
INCLUSION CRITERIA
1. Disease Status: Diagnosis of H3K27M mutant diffuse midline glioma (DMG)
2. H3K27M or H3K27I mutation. Confirmed by CLIA test.
3. Age: Greater than or equal to 2 year of age and less than or equal to 60 years of age.
4. Prior Therapy:
* At least 4 weeks following completion of standard upfront radiation therapy.
* At least 3 weeks post chemotherapy or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy, except for systemic inhibitory/stimulatory immune checkpoint therapy that requires 3 months.
* Dordaviprone (Modeyso), previously known as ONC201, may be taken as prior therapy but - just as with other anti-cancer medications - administration must cease at least 5 half-lives prior to enrollment
5. Performance Status:
Subjects \> 16 years of age: Karnofsky ≥ 60% OR Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; Subjects ≤ 16 years of age: Lansky scale ≥ 60%.
Subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
6. Normal Organ and Marrow Function (supportive care is allowed per institutional standards, i.e. filgrastim, transfusion) i. ANC ≥ 1000/uL ii. Platelet count ≥ 100,000/uL iii. Absolute lymphocyte count ≥ 150/uL iv. Hemoglobin ≥ 8 g/dL v. Adequate renal, hepatic, pulmonary and cardiac function defined as:
\- Creatinine within institutional norms for age (i.e.
≤ 2 mg/dL in adults or according to table below in children \<18 years) OR creatinine clearance (as estimated by Cockcroft Gault Equation) ≥ 60 mL/min
Serum ALT/AST ≤ 3.0 ULN (grade 1)
* Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert's syndrome.
* Cardiac ejection fraction ≥ 45%, no evidence of physiologically significant pericardial effusion as determined by an ECHO, and no clinically significant ECG findings
* Baseline oxygen saturation \> 92% on room air
7. Pregnancy Test Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization are not considered to be of childbearing potential) or NA
8. Contraception Subjects of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four (4) months after receiving the preparative regimen or for as long as GD2CART cells are detectable in peripheral blood or CSF.
9. Ability to give informed consent. All subjects ≥ 18 years of age must be able to give informed consent. For subjects \<18 years old their legal authorized representative (LAR) (i.e. parent or guardian) must give informed consent. Pediatric subjects will be included in age appropriate discussion and written assent will be obtained for those \> 7 years of age, when appropriate. If a minor becomes of age during participation of this study, he/she will be asked to reconsent as an adult.
EXCLUSION CRITERIA:
1. For Dose Escalation: Bulky tumor involvement of cerebellar vermis or hemispheres (pontocerebellar peduncles involvement is acceptable), or thalamic lesions that in the investigator's assessment place the subject at unacceptable risk for herniation.
For Dose Expansion: Bulky disease that in the investigator's assessment place the subject at unacceptable risk for herniation. Thalamic DMG is permitted.
2. Clinically significant swallowing dysfunction/dysphagia or prominent medullary dysfunction, as determined by the clinical investigator; or primary cervical cord tumors above C6/7 that represent a high risk of respiratory compromise, as determined by the clinical investigator.
3. Current systemic corticosteroid therapy above physiologic replacement levels.
4. Ongoing use of dietary supplements, alternative therapies or extreme diet modifications or any medication not approved by the investigators
5. Prior CAR therapy.
6. Prior immunomodulatory therapy, except for checkpoint inhibitor therapy after at least 3 month wash-out.
7. Uncontrolled fungal, bacterial, viral, or other infection. Previously diagnosed infection for which the patient continues to receive antimicrobial therapy is permitted if responding to treatment and clinically stable.
8. Diagnosed ongoing infection with:
* HIV,
* Hepatitis B (HBsAg positive) or
* Hepatitis C virus (anti-HCV positive). A history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative PCR and/or nucleic acid testing.
9. Clinically significant systemic illness or medical condition (e.g. significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgement of the principal investigator is likely to interfere with assessment of safety or efficacy of the investigational regimen and its requirements.
10. Women who are pregnant or breastfeeding.
11. In the investigator's judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation.
12. Known sensitivity or allergy to any agents/reagents used in this study.
13. Primary immunodeficiency or history of autoimmune disease (e.g. Crohns, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years
* All subject files must include supporting documentation to confirm subject eligibility.
The method of confirmation can include, but is not limited to, laboratory test results, radiology test results, subject self-report, and medical record review.
\*Anyone under 26, please contact Ashley Jacobs and anyone 26 and older, please contact Monica Reddy以上为辅助阅读译文。是否适合入组须由主治医生判断，最终以登记平台与研究者确认为准。
主要终点：Rate of successful manufacture of GD2CART using a retroviral vector in the Miltenyi CliniMACS Prodigy system · The percentage of apheresis samples (fresh or frozen) will be determined for each dose cohort. · 14 days after apheresis；Safety of the dose, route and schedule of GD2CART and lymphodepleting chemotherapy in subjects with H3K27M-mutant DMG · Incidence and severity of dose limiting toxicities (DLTs) after initial dose of GD2.BB.z.iCasp9-CAR T cells (GD2CART) in each Arm, at each dose level tested by disease cohort · 28 days after infusion；Safety of GD2CART at RP2D, route and schedule of GD2CART in expansion cohorts of subjects with H3K27M-mutant DMG · Suspected adverse events and serious adverse events following chemotherapy preparative regimen and infusion of GD2CART." · 28 days after infusion
次要终点：Radiographic Response Rate；Overall Survival (OS)；Progression-Free Survival (PFS)；Post-progression survival (PPS)；Measure resolution of toxicity
GD2CART 将在第 0 天对住院的 DIPG 或脊髓 DMG 受试者给药 在采用环磷酰胺和氟达拉滨进行清淋预处理化疗方案后，经静脉给药 * 剂量水平 -1：3x10^5 转导 T 细胞/kg（± 20%） * 剂量水平 1：1x10^6 转导 T 细胞/kg（± 20%） * 剂量水平 2：3x10^6 转导 T 细胞/kg（± 20%）
GD2CART 将在第 0 天对住院的 DIPG 或脊髓 DMG 受试者给药 不经清淋预处理化疗，经脑室内给药 * 剂量水平 -1：10x10^6 转导 T 细胞（±20%） * 剂量水平 1：30x10^6 转导 T 细胞（±20%） * 剂量水平 2：50x10^6 转导 T 细胞（±20%） * 剂量水平 3：100x10^6 转导 T 细胞（±20%）
GD2CART 将在第 0 天对住院的 DIPG 或脊髓 DMG 受试者以递增剂量给药 在采用环磷酰胺和氟达拉滨进行清淋预处理化疗方案后，经脑室内给药 * 剂量水平 -1：10x10^6 转导 T 细胞（±20%） * 剂量水平 1：30x10^6 转导 T 细胞（±20%） * 剂量水平 2：50x10^6 转导 T 细胞（±20%）
GD2CART 将在第 0 天对住院的 DIPG、脊髓 DMG 或具有高风险特征的受试者以递增剂量给药。 在采用利妥昔单抗、环磷酰胺和氟达拉滨进行清淋预处理化疗方案后，经脑室内给药 * 剂量水平 -1：10x10^6 转导 T 细胞（±20%） * 剂量水平 1：30x10^6 转导 T 细胞（±20%） * 剂量水平 2：50x10^6 转导 T 细胞（±20%）
本研究的主要目的是检验靶向GD2的CAR T细胞（GD2CART）能否成功制备并安全地给予患有H3K27M突变型弥漫性中线胶质瘤（DMG）的儿童和成人。符合条件的受试者可能患有发生在脑桥（称为弥漫性内生性脑桥胶质瘤，DIPG）、脊髓或大脑其他区域（如丘脑）的DMG。
The primary purpose of this study is to test whether CAR T cells targeting GD2 (GD2CART) can be successfully made and safely given to children and adults with H3K27M-mutant diffuse midline glioma (DMG). Eligible subjects may have DMG arising in the pons (called difuse intrinisic pontine glioma, DIPG), the spinal cord, or other areas of the brain such as a thalamus
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