肿瘤细胞治疗研究
英文原题：The PACMAN-Hu19 Trial: a Study of the Safety and Feasibility of Locally Produced, CD19-targeted and Human CAR T-cell Therapy in Children and Young Adults With Relapsed or Refractory B-cell Malignancies
⚠ 该试验的登记信息已有 16 个月未更新， 页面上显示的「尚未开始招募」可能已经失效。联系研究中心之前，建议先到 ClinicalTrials.gov 核对登记原文的最新状态与联系方式。
这是一项 I/II 期注册临床试验，评估 CAR-T 细胞治疗白血病、淋巴瘤的安全性、可行性及初步疗效。当前状态：尚未开始招募。计划入组 18 例。试验地点：欧洲 · 乌得勒支（共 2 个中心）。登记号：NCT07020260。
不限性别 · ≥ 1 Year 且 ≤ 45 Years
纳入标准：
1. 年龄1-45岁。
2. 患有复发或难治性CD19+血液系统恶性肿瘤的患者，包括但不限于：
1. B-NHL，如伯基特淋巴瘤（BL）、新发或转化的弥漫性大B细胞淋巴瘤（DLBCL）、淋巴母细胞淋巴瘤（LBL）、原发性纵隔B细胞淋巴瘤（PMBCL）或惰性淋巴瘤类型，且无法获得市售CAR T细胞疗法，或根据医疗需求，当前市售CAR T细胞疗法的生产时间不可接受。
或
2. B细胞前体ALL，市售CAR T细胞疗法失败，或BCP-ALL适应症无法获得市售CAR T细胞疗法，或根据紧急医疗需求，当前市售CAR T细胞疗法的生产时间不可接受（后者需由申办方确认）。
3. 可测量疾病：
1. 对于B-NHL，根据Lugano分类至少有一个可测量病灶。
2. 对于BCP-ALL，筛选时通过分子MRD、形态学或流式细胞术检测，骨髓中原始细胞至少应达到0.1%（=10-3）。
4. 患者必须已用尽或不适合所有具有治愈潜力的注册治疗方案。
5. 足够的体能状态评分：
1. 儿童<16岁：Lansky体能状态≥60。
2. 儿童年龄≥16岁且<18岁：Karnofsky体能状态≥60。
3. 成人≥18岁：ECOG体能状态0、1或2（仅当由基础疾病导致时允许ECOG体能状态3）。
6. 有生育潜力的患者必须愿意并能够从首次化疗输注开始至末次研究治疗给药后12个月内使用高效避孕方法。
7. 患者必须愿意在末次研究治疗给药后12个月内停止母乳喂养。
8. 患者必须同意在接受huCAR19 T细胞治疗后不捐献血液或器官。
9. 根据当地法律和法规签署书面知情同意书。
研究I期部分的附加纳入标准：
10. 研究I期部分的前三名患者必须年龄在12-45岁，此后，一旦在先前或当前剂量水平中≥60%的患者达到BCA替代终点，且先前剂量水平发生≤1例DLT，即可招募1-45岁任何年龄的患者。
排除标准：
1. 有症状性CNS受累的患者将被排除。症状缓解和控制后，患者可重新筛选。
2. 活动性未控制或危及生命的感染。
3. HTLV-1、HTLV-2、HIV-1、HIV-2、乙型肝炎（HbsAg阳性）或丙型肝炎（抗-HCV阳性）感染。当可进行抗病毒预防或治疗时，可考虑病毒载量检测不到的慢性控制性乙型或丙型肝炎感染，或病毒载量<50 IU/ml且CD4+ T细胞计数>200/ml的控制性HIV感染。
4. 中性粒细胞绝对计数<0.5x109/L，除非由基础疾病引起。
5. 血小板计数<25x109/L，除非由基础疾病引起。
6. 胆红素和/或转氨酶≤2.5 x ULN，除非由基础疾病引起。
7. 肾功能不全，定义为：
1. 对于成人（≥18岁），肾小球滤过率（GFR）< 45 ml/min/1.73 m2，按肾脏病饮食改良（MDRD）公式计算：
预测GFR（ml/min/1.73 m2）= 186 x（血清肌酐，单位umol/L / 88.7）- 1.154 x（年龄，岁）- 0.203 x（若患者为女性则0.742）x（若患者为黑人则1.212）。
2. 对于儿童（<18岁），根据性别/年龄的血清肌酐如下（单位µmol/l）：
年龄 男性 女性 0至< 2岁 53 70 2至< 6岁 70 70 6至< 10岁 88 88 10至< 13岁 106 106 13至< 16岁 132 123 16至< 19岁 150 123
8. 肺功能不足，定义为基线血氧饱和度<92%，若非由基础疾病引起。
9. 心功能不足：
1. 不稳定型心绞痛或不稳定性心律失常。
2. NYHA分级>II。
3. 经超声心动图或MUGA扫描证实LVSF<28%或LVEF<45%。
10. 合并恶性肿瘤需要治疗或筛选前<3个月接受过治疗，但经治愈性治疗的皮肤基底细胞癌除外。
11. 妊娠期女性。
12. 根据研究者判断无法参与本研究的患者。
13. 不愿意或无法遵守方案指南或随访的患者。
14. 筛选前<12周接受过异基因干细胞移植，或筛选前<4周接受过DLI，或存在需要全身治疗的活性GVHD。仅需局部类固醇治疗的皮肤GVHD是允许的。
15. 对活性物质过敏
Inclusion Criteria:
1. 1-45 years of age.
2. Patients with relapsed or refractory CD19+ hematological malignancies including, but not limited to:
1. B-NHL such as Burkitt lymphoma(BL), de novo or transformed diffuse large B cell lymphoma (DLBCL), lymphoblastic lymphoma (LBL), primary mediastinal B cell lymphoma (PMBCL) or indolent lymphoma types with no access to commercially available CAR T-cell therapy or for whom the current production time for commercially available CAR T-cell therapy is not acceptable based on medical need.
OR
2. B-cell precursor ALL failing commercially available CAR T-cell therapy, or for BCP-ALL indications with no access to commercially available CAR T-cell therapy, or for whom the current production time for commercially available CAR T-cell therapy is not acceptable based on urgent medical need (the latter needs to be confirmed by the sponsor).
3. Measurable disease:
1. For B-NHL at least one measurable lesion according to the Lugano classification.
2. For BCP-ALL at least 0.1% (=10-3) of blasts should be present in the bone marrow measured by molecular MRD, morphology or flow cytometry at screening.
4. Patients must have exhausted or are ineligible for all registered therapeutic options with curative potential.
5. Adequate performance score:
1. Children \<16 years: Lansky performance status ≥ 60 .
2. Children age ≥16 years and \<18 years Karnofsky performance status ≥ 60.
3. Adults ≥18 years ECOG performance status 0, 1 or 2 (ECOG performance status 3 is allowed only when due to underlying disease).
6. Patients from childbearing potential must be willing and able to use highly effective methods of birth control from first chemotherapy infusion through 12 months after administering the last study treatment.
7. Patients must be willing to abstain from breast feeding through 12 months after administering the last study treatment.
8. Patients must agree to refrain from donating blood or organs following treatment with huCAR19 T-cells.
9. Written informed consent per local law and regulations.
Additional inclusion criteria phase I part of the study:
10. The first three patients in the phase I part of the study must be aged 12-45 years, thereafter patients of any age between 1-45 years can be recruited once surrogate endpoint of BCA is reached in ≥60% patients in previous or current dose level and ≤1 DLT occurred at the previous dose level.
Exclusion Criteria:
1. Patients with symptomatic CNS involvement will be excluded. After resolution and control of symptoms, patients can be rescreened.
2. Active uncontrolled or life-threatening infections.
3. Infection with HTLV-1, HTLV-2, HIV-1, HIV-2, hepatitis B (HbsAg positive) or hepatitis C (anti-HCV positive). Chronic controlled hepatitis B or C infection with undetectable viral load or controlled HIV infection with viral load \<50 IU/ml and CD4+ T-cell count \>200/ml may be considered when antiviral prophylaxis or therapy can be administered.
4. Absolute neutrophil count \<0.5x109/L unless caused by underlying disease.
5. Platelet count \<25x109/L unless caused by underlying disease.
6. Bilirubin and/or transaminases ≤ 2.5 x ULN, unless caused by underlying disease.
7. Renal insufficiency, defined as:
1. For adults (≥18 years) glomerular filtration rate (GFR) \< 45 ml/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease (MDRD) equation:
predicted GFR (ml/min/1.73 m2) = 186 x (serum creatinine in umol/L / 88.7) - 1.154 x (age in years) - 0.203 x (0.742 if patient is female) x (1.212 if patient is black).
2. For children (\<18 years) a serum creatinine based on gender/age as follows (in µmol/l):
Age Male Female 0 to \< 2 years 53 70 2 to \< 6 years 70 70 6 to \< 10 years 88 88 10 to \< 13 years 106 106 13 to \< 16 years 132 123 16 to \< 19 years 150 123
8. Inadequate pulmonary function defined as baseline oxygen saturation \<92%, if not caused by underlying disease.
9. Inadequate cardiac function:
1. Unstable angina or unstable cardiac arrhythmias.
2. NYHA classification \>II.
3. LVSF \<28% or LVEF \<45% confirmed by echocardiogram or MUGA scan.
10. Concurrent malignancy requiring treatment of having been treated \<3 months before screening except for curatively treated basal cell carcinoma of the skin.
11. Pregnant women.
12. Patients unable to participate in the study according to investigator judgement.
13. Patients not willing or unable to adhere to protocol guidelines or follow-up.
14. Treatment with allogeneic stem cell transplantation \<12 weeks from screening or DLI \<4 weeks from screening or active GVHD requiring systemic treatment. Cutaneous GVHD requiring only topical steroids is allowed.
15. Hypersensitivity to the active substance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：Recommended phase 2 dose (RP2D) · The endpoint to measure this primary objective is the incidence of dose limiting toxicities (DLTs). · Within 28 days after huCAR19 infusion.
次要终点：To assess preliminary activity at day 28 for the BCP-ALL cohort and the overall response rate for the B-NHL cohort；Duration of response, including the duration of B-cell aplasia；Survival estimates.；The feasibility to produce HuCAR19 in the target population.
受试者将在治疗第0天接受单次剂量的huCAR19 T细胞输注。
PACMAN是一项I/II期单臂、开放标签、多中心研究，评估使用Miltenyi Prodigy本地生产的人源CD19 CAR-T（huCAR19）在复发/难治性CD19+血液恶性肿瘤儿童、青少年和年轻成人中的安全性，这些患者没有可用的标准治疗。
PACMAN is a phase I/II single arm, open-label, multi-center study evaluating the safety of human CD19 CAR-T (huCAR19) produced locally using the Miltenyi Prodigy in children, adolescents and young adults with relapsed/refractory CD19+ hematological malignancies for whom no standard of care treatment is available.
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