肿瘤细胞治疗研究
英文原题：Immunotherapy of Relapsed Refractory Neuroblastoma With Expanded NK Cells
Immunotherapy of Relapsed Refractory Neuroblastoma With Expanded NK Cells
这是一项 I 期注册临床试验，评估 NK 细胞治疗神经母细胞瘤的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 13 例。试验地点：美国 · 洛杉矶、旧金山、亚特兰大、芝加哥（共 11 个中心）。登记号：NCT02573896。
不限性别 · ≤ 30 Years
纳入标准：
1. 患者在入组研究时年龄必须小于或等于30岁
2. 患者必须经组织学证实为神经母细胞瘤和/或在骨髓中证实有肿瘤细胞并伴有尿儿茶酚胺升高，从而确诊为神经母细胞瘤。
3. 根据研究入组时的COG风险分类，患者必须有高危神经母细胞瘤病史。最初被认为是低危或中危，但后来被重新分类为高危的患者也符合条件。
4. 所有患者必须至少具备以下一项
a) 复发/进展性疾病：在入组前任何时间诊断为高危神经母细胞瘤后，无论对一线治疗的反应如何 b) 自高危神经母细胞瘤诊断以来无复发/进展性疾病史 b1) 难治性疾病- 自高危神经母细胞瘤诊断以来最佳总体疗效为无反应/疾病稳定，且至少接受过4个周期的诱导治疗。自高危神经母细胞瘤诊断以来无复发/进展性疾病史。
b2) 持续性疾病- 自高危神经母细胞瘤诊断以来最佳总体疗效为未达部分缓解，且至少接受过4个周期的诱导治疗。自高危神经母细胞瘤诊断以来无复发/进展性疾病史。
5. 患者必须至少具备以下一项（病灶可接受过既往放疗，只要符合以下列出的其他标准）：
1. 对于复发/进展性或难治性疾病，至少一个MIBG阳性骨病灶。
2. 对于持续性疾病，如果患者有3个或以上MIBG阳性病灶，则无需活检。如果患者仅有1或2个MIBG阳性骨病灶部位，则需要在入组前任何时间点从入组时存在的至少一个MIBG阳性部位获取神经母细胞瘤或节细胞神经母细胞瘤的活检确认。
3. 对于MIBG非阳性肿瘤，患者必须至少有一个FDG阳性部位，并且在入组前任何时间从至少一个FDG阳性部位获取神经母细胞瘤和/或节细胞神经母细胞瘤的活检确认。
6. 在研究入组时，基于常规形态学（伴或不伴免疫细胞化学），双侧穿刺和活检的至少一个样本中骨髓中存在任意数量的神经母细胞瘤肿瘤细胞。
7. 至少一个符合TARGET病灶标准的软组织病灶，定义如下：
1. 大小：病灶可在至少一个维度上准确测量，最长直径≥ 10 mm，或对于淋巴结，短轴≥ 15 mm。符合大小标准的病灶将被视为可测量。
2. 除大小外，病灶需符合以下标准之一，但中枢神经系统实质病灶患者除外，其仅需符合大小标准：
b1) MIBG 亲和。对于复发/进展或难治性疾病的患者，无需活检。仅对于持续性疾病患者：如果患者仅有1或2个MIBG亲和病灶部位，则需要在入组时至少一个MIBG亲和部位进行神经母细胞瘤和/或节细胞神经母细胞瘤的活检确认。如果患者有3个或更多MIBG亲和病灶，则无需活检。
b2) MIBG非亲和肿瘤：患者必须至少有一个FDG亲和部位，并且在入组时至少一个FDG-PET亲和部位进行神经母细胞瘤和/或节细胞神经母细胞瘤的活检确认。
8. 至少一个不可测量的非靶软组织病灶，但活检阳性为神经母细胞瘤和/或节细胞神经母细胞瘤，或在入组前任何时间MIBG亲和。
9. 患者必须预期寿命至少12周，Lansky（≤16岁）或Karnofsky（>16岁）评分至少50。
10. 既往治疗 1. 患者必须在研究注册前从所有既往化疗、免疫治疗或放疗的急性毒性效应中完全恢复。
2. 患者不得在疾病评估后或本研究注册前指定时间段内接受以下所示治疗：
1. 骨髓抑制性化疗：注册前2周内不得接受。
2. 生物抗肿瘤药物-已知与血小板或ANC计数减少无关的药物（包括维A酸类）：注册前7天内不得接受。
3. 单克隆抗体：末次给药必须在方案治疗前至少7天或3个半衰期（以较长者为准），但不超过30天（且相关毒性恢复）。
4. 细胞治疗（例如修饰T细胞、NK细胞、树突状细胞等）：
不得在3周内接受且所有毒性已消退。
5. 放疗：注册前7天内不得接受小野放疗。
6. 造血干细胞移植：
7. IVIG
11) 所有患者必须具有足够的器官功能，定义为：
- 血液学功能：
1. 绝对吞噬细胞计数（APC=中性粒细胞和单核细胞）：≥ 1000/µL
2. 绝对中性粒细胞计数：≥750/µL
3. 绝对淋巴细胞计数 ≥ 500/µL
4. 血小板计数：≥ 50,000/µL，不依赖输血（1周内无血小板输注）
5. 血红蛋白 ≥ 10 g/dL（可输血）
6. 已知骨髓转移性疾病的患者只要符合上述血液学功能标准，即有资格参加研究。
* 肾功能：年龄调整血清肌酐 ≤ 年龄/性别正常值的1.5倍 或 肌酐清除率或GFR大于或等于60 cc/min/1.73m2
* 肝功能：总胆红素 ≤ 年龄正常值的1.5倍，且SGPT（ALT）135和SGOT（AST）≤ 正常上限的3倍。如果存在肝窦阻塞综合征（SOS），必须临床稳定或改善
* 心脏功能：超声心动图或放射性核素MUGA评估记录的射血分数正常，或超声心动图记录的心室短轴缩短率正常
* 肺功能：静息时无呼吸困难，无需吸氧。
12) 生殖状态：所有月经初潮后的女性必须具有阴性的β-HCG。男性和有生育能力的育龄女性在其参与期间必须使用有效的避孕措施。
13) 有其他持续严重医疗问题的患者必须在注册前获得研究主席的批准。
14) 患者在接受方案治疗期间不得接受任何其他抗癌药物或放疗。
15) 能够吞咽药片
排除标准：
1. 妊娠：月经初潮后的女孩定量血清B-HCG必须为阴性。
2. 哺乳期妇女不符合条件。
3. 活动性或未控制的感染
4. CNS转移。
5. 对沙利度胺过敏，包括在服用沙利度胺或类似药物时出现以脱屑性皮疹为特征的多形性红斑病史（仅限剂量水平4）。
6. 患者拒绝参与NANT 2004-05；除非该机构已获得NANT运营中心对NANT 2004-05强制注册的特殊豁免。
Inclusion Criteria:
1. Patients must be less than or equal to 30 years of age when registered on study
2. Patients must have a diagnosis of neuroblastoma either by histologic verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased urinary catecholamines.
3. Patients must have a history of high-risk neuroblastoma according to COG risk classification at the time of study registration. Patients who were initially considered low or intermediate-risk, but then reclassified as high-risk are also eligible.
4. All patients must have at least one of the following
a) Recurrent/progressive disease: after the diagnosis of high risk neuroblastoma at any time prior to enrollment regardless of response to frontline therapy b) No prior history of recurrent/progressive disease since the diagnosis of high risk neuroblastoma b1) Refractory disease- a best overall response of no response/stable disease since diagnosis of high risk neuroblastoma and at least 4 cycles of induction therapy. No prior history of recurrent/progressive disease since the diagnosis of high risk neuroblastoma.
b2) Persistent disease- a best overall response of no partial response since diagnosis of high risk neuroblastoma and at least 4 cycles of induction therapy. No prior history of recurrent/progressive disease since the diagnosis of high risk neuroblastoma.
5. Patients must have at least ONE of the following (lesions may have received prior radiation therapy as long as they meet the other criteria listed below):
1. For recurrent/progressive or refractory disease, at least one MIBG avid bone site.
2. For persistent disease, if a patient has 3 or more MIBG avid lesions, then no biopsy is required. If a patients has only 1 or 2 MIBG avid bone lesion sites then biopsy confirmation of neuroblastoma or ganglioneuroblastoma in at least one MIBG avid site present at the time of enrollment is required to be obtained at any time point prior to enrollment.
3. For MIBG non-avid tumors, patients must have at least one FDG avid site and a biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma at any time prior to enrollment from at least one FDG-avid site.
6. Any amount of neuroblastoma tumor cells in the bone marrow done at the time of study enrollment based on routine morphology with or without immunocytochemistry in at least one sample from bilateral aspirates and biopsies.
7. At least one soft tissue lesion that meets criteria for a TARGET lesion as defined by:
1. SIZE: Lesion can be accurately measured in at least one dimension with a longest diameter ≥ 10 mm, or for lymph nodes ≥ 15 mm on short axis. Lesions meeting size criteria will be considered measurable.
2. In addition to size, a lesion needs to meet one of the following criteria except for patients with parenchymal CNS lesions which only need to meet size criteria:
b1) MIBG avid. For patients with recurrent/progressive or refractory disease, no biopsy is required. For patients with persistent disease only: If a patient has only 1 or 2 MIBG avid lesions sites, then biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one MIBG avid site present at time of enrollment is required to be obtained. If a patient has 3 or more MIBG avid lesions, then no biopsy is required.
b2) MIBG non avid tumors: Patients must have at least one FDG avid site and biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one FDG-PET avid site present at the time of enrollment.
8. At least one non-target soft tissue lesion that is not measurable, but had a biopsy positive for neuroblastoma and/or ganglioneuroblastoma or is MIBG avid at any time prior to enrollment.
9. Patients must have a life expectancy of at least 12 weeks and a Lansky (≤16 years) or Karnofsky (\>16 years) score of at least 50.
10. Prior Therapy 1. Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study registration.
2\. Patients must not have received the therapies indicated below after disease evaluation or within the specified time period prior to registration on this study as follows:
1. Myelosuppressive chemotherapy: must not have received within 2 weeks prior to registration.
2. Biologic anti-neoplastics- agents not known to be associated with reduced platelet or ANC counts (including retinoids): must not have received within 7 days prior to registration.
3. Monoclonal antibodies: must have received last dose at least 7 days or 3 half-lives whichever is longer, but no longer than 30 days (with recovery of any associated toxicities), prior to protocol therapy.
4. Cellular Therapy (e.g. modified T cells, NK cells, dentritic cells etc.):
must not have received within 3 weeks and resolution of all toxicities.
5. Radiation: must not have received small port radiation within 7 days prior to registration.
6. Hematopoietic Stem Cell Transplant:
7. IVIG
11\) All patients must have adequate organ function defined as:
\- Hematological Function:
1. Absolute Phagocyte count (APC= neutrophils and monocytes): ≥ 1000/µL
2. Absolute Neutrophil count: ≥750/µL
3. Absolute Lymphocyte count ≥ 500/µL
4. Platelet count: ≥ 50,000/µL, transfusion independent (no platelet transfusions within 1 week)
5. Hemoglobin ≥ 10 g/dL (may transfuse)
6. Patients with known bone marrow metastatic disease will be eligible for study as long as they meet hematologic function criteria above.
* Renal Function: Age-adjusted serum creatinine ≤ to 1.5 x normal for age/gender OR creatinine clearance or GFR greater than or equal to 60 cc/min/1.73m2
* Liver Function: Total bilirubin ≤ 1.5 x normal for age, AND SGPT (ALT) 135 and SGOT (AST) ≤ 3 x upper limit of normal. Sinusoidal obstruction syndrome (SOS) if present, must be stable or improving clinically
* Cardiac Function: Normal ejection fraction documented by either echocardiogram or radionuclide MUGA evaluation OR Normal fractional shortening documented by echocardiogram
* Pulmonary Function: No dyspnea at rest, no oxygen requirement.
12\) Reproductive Status: All post-menarchal females must have a negative beta-HCG. Males and females of reproductive age and childbearing potential must use effective contraception for the duration of their participation.
13\) Patients with other ongoing serious medical issues must be approved by the study chairprior to registration.
14\) Patients may not receive any other anti-cancer agents or radiotherapy while on protocol therapy.
15\) Ability to Swallow Pills
Exclusion Criteria:
1. Pregnancy: Quantitative Serum B-HCG must be negative in girls who are post-menarchal.
2. Breast feeding women are not eligible.
3. Active or uncontrolled infection
4. CNS metastasis.
5. Hypersensitivity to thalidomide, including history of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs (dose level 4 only).
6. Patient declines participation in NANT 2004-05; unless the institution has been granted special exemption from mandatory registration on NANT 2004-05 by the NANT Operations Center.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：NK cell production feasibility (lowest dose level) · Proportion of patients whose NK cell product is at least 80% of 10\^7 NK cells per kg (sufficient cells to give at least 1 dose at the lowest dose level). · After cell expansion, day 4 of protocol therapy；NK cell production feasibility · Proportion of patients whose NK cell product is at least 80% of the planned dose for one dose · After cell expansion, day 4 of protocol therapy；MTD/RP2D determination · Proportion of patients with any Grade 3 or greater non-hematological toxicities on any course · all toxicities from enrollment through 30 days following end of protocol therapy
次要终点：Describe Non-Hematological Toxicities；Describe Hematological Toxicities；Overall Response
该组患者将在第5天接受指定剂量的NK细胞，并在第1-4天接受17.5 mg/m2/剂量的dinutuximab。剂量水平4的患者还将在治疗的第-6天至第14天期间接受25mg/m2/剂量的Lenalidomide。
这项NANT试验将确定自体扩增自然杀伤（NK）细胞与dinutuximab标准剂量联合使用时的最大耐受剂量（MTD），并将评估在扩增NK细胞与dinutuximab联合治疗的推荐II期剂量基础上加用来那度胺治疗难治性或复发性神经母细胞瘤患儿的可行性。
This NANT trial will determine the maximum tolerated dose (MTD) of autologous expanded natural killer (NK) cells when combined with standard dosing of dinutuximab and will assess the feasibility of adding lenalidomide at the recommended Phase II dose of the expanded NK cells with dinutuximab, for treatment of children with refractory or recurrent neuroblastoma.
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