NANT 2021-02：随机化MIBG联合Vorinostat/Dinutuximab/Vorinostat + Dinutuximab
NANT 2021-02：一项针对复发或难治性神经母细胞瘤的随机II期研究，比较131I-MIBG联合伏立诺他与131I-MIBG联合迪努妥昔单抗以及131I-MIBG联合迪努妥昔单抗和伏立诺他的疗效
研究概览
详细说明
研究类型
注册 (估计的)
阶段
- 阶段2
联系人和位置
学习联系方式
- 姓名：Araz Marachelian, MD
- 电话号码：323-361-5687
- 邮箱：nantops@chla.usc.edu
学习地点
-
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California
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Los Angeles、California、美国、90027-0700
- Children's Hospital Los Angeles
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San Francisco、California、美国、94143
- UCSF Helen Diller Family Comprehensive Cancer Center
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Colorado
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Aurora、Colorado、美国、80045
- Children Hospital of Colorado
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Georgia
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Atlanta、Georgia、美国、30322
- Children's Healthcare of Atlanta
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Illinois
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Chicago、Illinois、美国、60614
- Children's Memorial Hospital - Chicago
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Massachusetts
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Boston、Massachusetts、美国、02115
- Childrens Hospital Boston, Dana-Farber Cancer Institute.
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Michigan
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Ann Arbor、Michigan、美国、48109
- C.S Mott Children's Hospital
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Ohio
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Cincinnati、Ohio、美国、45229-3039
- Cincinnati Children's Hospital Medical Center
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Pennsylvania
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Philadelphia、Pennsylvania、美国、19104-4318
- Children's Hospital of Philadelphia
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Tennessee
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Memphis、Tennessee、美国、38105
- St. Jude Children's Research Hospital
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接触：
- Sara Federico, MD
- 邮箱：sara.federico@stjude.org
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Texas
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Dalls、Texas、美国、75235
- University of Texas Southwestern
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接触：
- Tanya Watt, MD
- 邮箱：tanya.watt@utsouthwestern.edu
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Fort Worth、Texas、美国、76104
- Cook Children's Medical Center - Fort Worth
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Washington
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Seattle、Washington、美国、98105
- Children's Hospital and Regional Medical Center - Seattle
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参与标准
资格标准
适合学习的年龄
- 孩子
- 成人
接受健康志愿者
描述
纳入标准：
年龄 患者在注册时必须年龄≥1岁且<30岁。
诊断 患者必须通过组织学验证神经母细胞瘤和/或骨髓中肿瘤细胞检测伴有尿儿茶酚胺升高，诊断为神经母细胞瘤或结节性神经节母细胞瘤亚型。
疾病风险组 患者在注册时必须根据COG风险分类为高风险神经母细胞瘤。最初被认为是低风险或中风险但随后重新分类为高风险的患者也符合条件。
对先前治疗的反应（使用INRC定义）
患者必须至少满足以下一项：
- 在注册前任何时间高风险神经母细胞瘤诊断后出现复发/进展性疾病——无论对一线治疗的反应如何。（注意：这排除了最初被认为是低风险或中风险但进展为高风险疾病，但在高风险神经母细胞瘤诊断后未进展的患者）。
- 如果自高风险神经母细胞瘤诊断以来无复发/进展性疾病史，
- 难治性疾病：自高风险神经母细胞瘤诊断以来且至少4个诱导疗程后，最佳总体反应为无反应/疾病稳定。
持续性疾病：自高风险神经母细胞瘤诊断以来且至少4个诱导疗程后，最佳总体反应为轻微反应：
i. 如果持续性疾病患者有3个或更多MIBG摄取阳性部位（包括所有软组织和/或骨病变）或Curie评分≥3，则无需活检即可符合资格。
ii. 如果持续性疾病患者仅有1或2个MIBG摄取阳性部位（包括所有软组织和/或骨病变），则需要在注册时至少一个MIBG摄取阳性部位（骨髓、骨或软组织）进行活检确认神经母细胞瘤和/或神经节母细胞瘤。骨和/或软组织病变可在注册前任何时间点进行活检，骨髓必须在注册时进行。
疾病部位：MIBG摄取 患者必须在进入研究前21天内且在任何干预治疗后，至少有一个部位（骨或软组织）有MIBG摄取进入肿瘤的证据。参见排除标准。
自体外周血干细胞（PBSC）
- 外周血干细胞的最低剂量为1.5 x 10^6个活CD34+细胞/千克。未达到可用PBSC此最低要求的患者不符合资格。
- 除非中心有单独的FDA批准用于输注纯化干细胞，否则仅允许使用未纯化的干细胞。
- 对于体重超过理想体重（IBW）20%以上的患者，可使用调整体重计算PBSC剂量。
体能状态 患者必须有Lansky（≤16岁）或Karnofsky（>16岁）评分≥50。注意：因瘫痪无法行走但能使用轮椅的患者，在评估体能评分时将被视为可活动。
先前治疗 患者在注册前必须已从所有先前化疗、免疫治疗或放疗的急性毒性效应中完全恢复。
器官功能要求
血液功能：
无论骨髓疾病受累情况如何，患者必须满足以下血液学标准才能入组：
- ANC≥750/微升（无短效造血生长因子≤7天的血液检查记录资格，无长效造血生长因子≤14天的血液检查记录资格）；且
- 血小板计数≥50,000/微升，输血独立（无血小板输注或血小板生长因子≤7天的血液检查记录资格）。
肾功能 a. 患者必须有足够的肾功能，定义为年龄调整后血清肌酐≤年龄的1.5倍ULN。肝功能
- 总胆红素≤年龄的1.5倍ULN；且，
- SGPT（ALT）≤135 U/L（≤3倍ULN）。注意：对于ALT，所有地点的正常上限定义为45 U/L。
中枢神经系统（CNS）功能：
- 有脑实质内或软脑膜CNS疾病史的患者在入组时必须无临床或放射学证据显示活动性CNS疾病。
- 有颅底肿瘤伴直接颅内延伸的患者符合条件，只要无与病变相关的神经体征或症状。
心脏功能
- 通过超声心动图或放射性核素MUGA评估记录的正常射血分数（≥55%），或通过超声心动图记录的正常缩短分数（≥27%）。
- 校正QT（QTcF）间期≤480毫秒。肺功能 无休息时呼吸困难、运动不耐受或需氧的证据。生殖功能
a. 所有有生育潜力的女性（10岁及以上且无记录卵巢衰竭的女性患者）必须在注册前≤7天血清或尿液β-HCG阴性。
b. 有生育潜力的男性和女性受试者必须同意在研究期间或最后一次方案治疗后3个月内（以较长者为准）使用两种可接受的避孕方法（如宫内节育器、激素避孕药、带杀精剂的隔膜、带杀精剂的避孕套或禁欲）或避免异性性交。
排除标准：
怀孕、哺乳或不愿在研究期间使用有效避孕措施的患者将不纳入本研究，因存在胎儿和致畸不良事件的风险。
研究者认为可能无法遵守研究安全监测或辐射隔离要求的患者。
患有任何主要器官系统疾病且可能影响其耐受治疗能力的患者。
患者必须未接受过先前异基因干细胞移植。
接受过先前实体器官移植的患者。
患者必须未接受过先前全身照射。
接受血液透析的患者。
有活动性或未控制感染的患者。接受长期抗真菌治疗的患者如果培养阴性、无发热且符合其他器官功能标准，仍符合条件。
已知有活动性人类免疫缺陷病毒（HIV）感染、乙型肝炎或丙型肝炎病史。无临床发现或怀疑时无需检测。
因毒性而永久停用抗GD2抗体治疗、GM-CSF或伏立诺他的患者不符合资格。
先前接受过MIBG联合抗GD2单克隆抗体和/或组蛋白去乙酰化酶抑制剂治疗的患者
根据机构指南允许的最大总131I-MIBG剂量必须至少为计算或方案最大131I-MIBG剂量的90%，否则患者不符合资格。
有深静脉血栓病史且与中心静脉导管无关的患者。
患者拒绝参与NANT 2004-05，即NANT生物学研究。
有活动性MIBG非摄取性疾病证据的患者；先前治疗且稳定的非MIBG摄取性疾病患者仍符合条件。
先前MIBG治疗后最佳反应为疾病进展的患者。
131I-MIBG累积终身剂量大于20 mCi/千克的患者。
学习计划
研究是如何设计的？
设计细节
- 主要用途：治疗
- 分配：随机化
- 介入模型：并行分配
- 屏蔽：无（打开标签）
武器和干预
参与者组/臂 |
干预/治疗 |
|---|---|
|
实验性的：Arm A: 131I-MIBG + vorinostat
Patients assigned to Arm A will receive vorinostat orally once daily on Days 0 to 13 at a dose of 180 mg/m2/dose (maximum dose 400 mg). Patients will receive 131I-MIBG 18 mCi/kg (maximum dose 1200 mCi) on Day 1 and autologous stem cell infusion on Day 15 (plus 2 days or minus 1 day, hereafter abbreviated as +2/-1 days). There must be at least 24 hours between the last dose of vorinostat and stem cell infusion. Disease evaluation is to occur between days 43-57. The time interval between performing end of Course 1 disease evaluation and administration of Course 2 131I-MIBG is not to exceed 4 weeks. |
患者将在第1天接受131I-MIBG 18 mCi/kg（最大剂量1200 mCi）
其他名称：
Vorinostat将在第0-13天给药，剂量为180 mg/m2/次（最大剂量400 mg）。
其他名称：
|
|
实验性的：Arm B: 131I-MIBG + dinutuximab
Patients assigned to Arm B will receive 18 mCi/kg (maximum dose 1200 mCi) 131I-MIBG on Day 1 and autologous stem cell infusion on Day 15 (+2/-1 days). Dinutuximab 17.5 mg/m2/day is given intravenously on Days 8-11 and 29-32 of therapy. Disease evaluation is to occur between Days 43-57. In case of treatment delays with dinutuximab during Course 1, the time interval between performing end of Course 1 disease evaluation and administration of Course 2 131I-MIBG is not to exceed 4 weeks. |
患者将在第1天接受131I-MIBG 18 mCi/kg（最大剂量1200 mCi）
其他名称：
Dinutuximab 17.5 mg/m²/天在治疗第8-11天和第29-32天静脉给药
其他名称：
|
|
实验性的：Arm C: 131I-MIBG + vorinostat + dinutuximab
Patients assigned to Arm C will receive vorinostat 180 mg/m2/dose (maximum dose 400 mg) on Days 0 to 13, 131I-MIBG 18 mCi/kg (maximum dose 1200 mCi) on Day 1. Dinutuximab 17.5 mg/m2/day is given intravenously on Days 8-11 and 29-32 of therapy. Disease evaluation is to occur between Days 43-57. In case of treatment delays with dinutuximab during Course 1, the time interval between performing end of Course 1 disease evaluation and administration of Course 2 131I-MIBG is not to exceed 4 weeks. |
患者将在第1天接受131I-MIBG 18 mCi/kg（最大剂量1200 mCi）
其他名称：
Vorinostat将在第0-13天给药，剂量为180 mg/m2/次（最大剂量400 mg）。
其他名称：
Dinutuximab 17.5 mg/m²/天在治疗第8-11天和第29-32天静脉给药
其他名称：
|
研究衡量的是什么？
主要结果指标
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
Objective Tumor Response After One Course of Therapy
大体时间：43-57 days from study day 1
|
To identify the MIBG treatment regimen associated with the highest overall response rate after one course of treatment on the three arms.
The response evaluation was based on central review (intent to treat analysis).
Responders defined as meeting CR/MRD/PR criteria.
Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940).
RECST 1.1 criteria was used for measurable tumors with PR criteria > 30% decrease in target tumor size.
Curie score was used with PR criteria > 50% decrease in Curie score.
Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease.
Overall Response (OR)=CR+PR.
|
43-57 days from study day 1
|
次要结果测量
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
发生≥3级非血液学毒性的受试者人数
大体时间：从入组到方案治疗结束后30天内的所有毒性反应，平均约6个月
|
比较与每种131I-MIBG治疗方案相关的3级或以上毒性反应谱：131I-MIBG联合伏立诺他；131I-MIBG联合迪妥昔单抗；或131I-MIBG联合伏立诺他与迪妥昔单抗
|
从入组到方案治疗结束后30天内的所有毒性反应，平均约6个月
|
|
Objective Tumor Response After Two Courses of Therapy
大体时间：43-57 days from study day 1
|
To identify the MIBG treatment regimen associated with the highest overall response rate after two courses of treatment on the three arms.
The response evaluation was based on central review (intent to treat analysis).
Responders defined as meeting CR/MRD/PR criteria.
Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940).
RECST 1.1 criteria was used for measurable tumors with PR criteria > 30% decrease in target tumor size.
Curie score was used with PR criteria > 50% decrease in Curie score.
Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease.
Overall Response (OR)=CR+PR.
|
43-57 days from study day 1
|
|
Objective Bone Marrow Tumor Response After One Course of Therapy
大体时间：43-57 days from study day 1
|
To identify the MIBG treatment regimen associated with the highest bone marrow response rate after one course of treatment on the three arms.
The response evaluation was based on central review (intent to treat analysis).
Responders defined as meeting CR/MRD/PR criteria.
Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940).
RECST 1.1 criteria was used for measurable tumors with PR criteria > 30% decrease in target tumor size.
Curie score was used with PR criteria > 50% decrease in Curie score.
Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease.
Overall Response (OR)=CR+PR.
|
43-57 days from study day 1
|
|
Objective Bone Marrow Tumor Response After Two Courses of Therapy
大体时间：43-57 days from study day 1
|
To identify the MIBG treatment regimen associated with the highest bone marrow response rate after two courses of treatment on the three arms.
The response evaluation was based on central review (intent to treat analysis).
Responders defined as meeting CR/MRD/PR criteria.
Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940).
RECST 1.1 criteria was used for measurable tumors with PR criteria > 30% decrease in target tumor size.
Curie score was used with PR criteria > 50% decrease in Curie score.
Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease.
Overall Response (OR)=CR+PR.
|
43-57 days from study day 1
|
|
Objective Soft Tissue Tumor Response After One Course of Therapy
大体时间：43-57 days from study day 1
|
To identify the MIBG treatment regimen associated with the highest soft tissue response rate after one course of treatment on the three arms.
The response evaluation was based on central review (intent to treat analysis).
Responders defined as meeting CR/MRD/PR criteria.
Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940).
RECST 1.1 criteria was used for measurable tumors with PR criteria > 30% decrease in target tumor size.
Curie score was used with PR criteria > 50% decrease in Curie score.
Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease.
Overall Response (OR)=CR+PR.
|
43-57 days from study day 1
|
|
Objective Soft Tissue Tumor Response After Two Courses of Therapy
大体时间：43-57 days from study day 1
|
To identify the MIBG treatment regimen associated with the highest soft tissue response rate after two courses of treatment on the three arms.
The response evaluation was based on central review (intent to treat analysis).
Responders defined as meeting CR/MRD/PR criteria.
Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940).
RECST 1.1 criteria was used for measurable tumors with PR criteria > 30% decrease in target tumor size.
Curie score was used with PR criteria > 50% decrease in Curie score.
Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease.
Overall Response (OR)=CR+PR.
|
43-57 days from study day 1
|
|
Objective Bone Tumor Response After One Course of Therapy
大体时间：43-57 days from study day 1
|
To identify the MIBG treatment regimen associated with the highest bone response rate after one course of treatment on the three arms.
The response evaluation was based on central review (intent to treat analysis).
Responders defined as meeting CR/MRD/PR criteria.
Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940).
RECST 1.1 criteria was used for measurable tumors with PR criteria > 30% decrease in target tumor size.
Curie score was used with PR criteria > 50% decrease in Curie score.
Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease.
Overall Response (OR)=CR+PR.
|
43-57 days from study day 1
|
|
Objective Bone Tumor Response After Two Courses of Therapy
大体时间：43-57 days from study day 1
|
To identify the MIBG treatment regimen associated with the highest bone response rate after two courses of treatment on the three arms.
The response evaluation was based on central review (intent to treat analysis).
Responders defined as meeting CR/MRD/PR criteria.
Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940).
RECST 1.1 criteria was used for measurable tumors with PR criteria > 30% decrease in target tumor size.
Curie score was used with PR criteria > 50% decrease in Curie score.
Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease.
Overall Response (OR)=CR+PR.
|
43-57 days from study day 1
|
|
Objective MIBG Tumor Response After One Course of Therapy
大体时间：43-57 days from study day 1
|
To identify the MIBG treatment regimen associated with the highest MIBG response rate after one course of treatment on the three arms.
The response evaluation was based on central review (intent to treat analysis).
Responders defined as meeting CR/MRD/PR criteria.
Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940).
RECST 1.1 criteria was used for measurable tumors with PR criteria > 30% decrease in target tumor size.
Curie score was used with PR criteria > 50% decrease in Curie score.
Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease.
Overall Response (OR)=CR+PR.
|
43-57 days from study day 1
|
|
Objective MIBG Tumor Response After Two Courses of Therapy
大体时间：43-57 days from study day 1
|
To identify the MIBG treatment regimen associated with the highest MIBG response rate after two courses of treatment on the three arms.
The response evaluation was based on central review (intent to treat analysis).
Responders defined as meeting CR/MRD/PR criteria.
Response was based on NANT response criteria v1.2 (https://doi.org/10.1002/pbc.26940).
RECST 1.1 criteria was used for measurable tumors with PR criteria > 30% decrease in target tumor size.
Curie score was used with PR criteria > 50% decrease in Curie score.
Complete Response- disappearance of all target lesions, Curie score of 0 and no detectable bone marrow disease.
Overall Response (OR)=CR+PR.
|
43-57 days from study day 1
|
合作者和调查者
研究记录日期
研究主要日期
学习开始 (估计的)
初级完成 (估计的)
研究完成 (估计的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (实际的)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
与本研究相关的术语
其他相关的 MeSH 术语
其他研究编号
- NANT 2021-02
计划个人参与者数据 (IPD)
计划共享个人参与者数据 (IPD)？
药物和器械信息、研究文件
研究美国 FDA 监管的药品
研究美国 FDA 监管的设备产品
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