Siremadlin 联合 Venetoclax 加阿扎胞苷治疗不适合化疗的急性髓性白血病 (AML) 成年参与者的研究。
在对一线维奈托克加阿扎胞苷治疗反应不佳的不适合成人 AML 参与者和新诊断不适合 AML 的参与者中，Ib/II 期开放标签剂量确认、概念证明研究证明 Siremadlin 联合维奈托克加阿扎胞苷高危临床特征
研究概览
详细说明
这项研究的主要目的是评估 siremadlin 联合维奈托克加阿扎胞苷是否可以增强不适合的 AML 患者的临床反应，而不会出现不可接受的治疗紧急毒性水平。 siremadlin 联合维奈托克加阿扎胞苷的推荐剂量将在扩展阶段进一步探索，并将在对一线维奈托克加阿扎胞苷反应不佳的参与者中评估实现完全缓解 (CR) 的初步疗效治疗。
该研究将分两部分进行。 第 1 部分（安全磨合）的主要目的是排除 siremadlin 与维奈托克加阿扎胞苷联合给药时的过度毒性，而第 2 部分（扩展）的主要目的是评估 siremadlin 与维奈托克联合给药时的初步疗效在各自的患者群体中加上阿扎胞苷。
研究治疗（siremadlin 联合维奈托克加阿扎胞苷）将按周期进行，计划持续 28 天，并将持续到参与者出现疾病进展/复发或不可接受的毒性。
在安全磨合部分，每组将招募 9-15 名参与者。 大约 3-6 名参与者将在起始剂量水平的 siremadlin 联合维奈托克加阿扎胞苷中独立入组。 如果确定起始剂量水平是安全的，将在剂量水平 +1 时招募大约 6-9 名额外参与者。 将召开安全审查会议，参与调查人员和赞助商团队将就 siremadlin 剂量做出决定，并确定扩展的推荐剂量。 大约 26 名患者将按照扩展部分的推荐剂量进行治疗。
研究类型
注册 (实际的)
阶段
- 阶段1
联系人和位置
学习地点
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Beersheba、以色列、8457108
- Novartis Investigative Site
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Jerusalem、以色列、9112001
- Novartis Investigative Site
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Budapest、匈牙利、H-1083
- Novartis Investigative Site
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Balcova
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Izmir、Balcova、土耳其（türkiye）、35340
- Novartis Investigative Site
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BO
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Bologna、BO、意大利、40138
- Novartis Investigative Site
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Oregon
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Portland、Oregon、美国、97239
- Oregon Health Sciences University
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Texas
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Dallas、Texas、美国、78246
- Texas Oncology Sammons Cancer Center
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Hong Kong、香港、999077
- Novartis Investigative Site
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Kuala Selangor、马来西亚、68000
- Novartis Investigative Site
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Kedah
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Alor Star、Kedah、马来西亚、05460
- Novartis Investigative Site
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参与标准
资格标准
适合学习的年龄
接受健康志愿者
描述
纳入标准：
- 签署知情同意书 (ICF) 之日的年龄：第 1 组和第 2 组：≥ 18 岁
-根据 WHO 2016 年分类（Arber 等人，2016 年）诊断为 AML 的参与者不符合标准诱导化疗的条件，并且： 第 1 组：已接受至少 2 个周期且不超过 4 个周期的一线维奈托克加阿扎胞苷治疗，并且有未达到 CR、CRi、CRh 或 MLFS。
第 2 组：新诊断的具有不良遗传风险分层的 AML（根据 ELN 2022）（TP53 突变阳性参与者除外）。
参与者必须被视为不符合以下定义的标准强化诱导化疗：
- 75岁；或者
- 年龄在 18 至 74 岁之间，至少患有以下合并症之一：东部合作肿瘤组 (ECOG) 表现状态为 2 或 3；需要治疗的充血性心力衰竭 (CHF) 或射血分数 ≤ 50% 或慢性稳定型心绞痛的心脏病史； DLCO ≤ 65% 或 FEV1 ≤ 65%。
参与者必须具有 ECOG 表现状态：
≥ 75 岁的参与者为 0 到 2。 或 0 至 3 为 ≥ 18 至 74 岁的参与者。
- 白细胞 < 25x109/升
- AST 和 ALT ≤ 3 × ULN
- 估计肾小球滤过率 (eGFR)≥ 60 mL/min/1.73 平方米
排除标准：
- 任何时候都曾接受过 MDM2 抑制剂治疗。
- TP53突变阳性的参与者。
- del17p 的参与者。
- 患有 AML-M3/APL（急性早幼粒细胞白血病）和 PML-RARA（早幼粒细胞白血病/视黄酸受体 α）或继发于唐氏综合症的 AML 的参与者。
- 接受 FLT3 抑制剂治疗的参与者
- 在开始研究治疗前 14 天内需要使用中度或强 CYP3A4 诱导剂治疗，或预计在整个研究期间接受中度或强 CYP3A4 诱导剂的参与者
- 需要使用治疗指数较窄的 CYP3A4/5 底物进行治疗的参与者。
其他协议定义的包含/排除标准可能在最后适用
学习计划
研究是如何设计的？
设计细节
- 主要用途：治疗
- 分配：非随机化
- 介入模型：单组作业
- 屏蔽：无（打开标签）
武器和干预
参与者组/臂 |
干预/治疗 |
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实验性的：Arm 1: Adult participants with unfit AML who responded sub-optimally to standard of care
Unfit adult participants with unfit AML who responded sub-optimally to at least 2 and not more than 4 cycles of first-line venetoclax plus azacitidine therapy.
Siremadlin was adminstered at a dose of 20 mg QD which could be increased based on toxicities; venetoclax was administered at 400 mg once daily and azacitidine was administered at 75 mg/m^2.
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Venetoclax 是一种每天口服一次 (QD) 的药片，有 10 毫克、50 毫克和 100 毫克三种规格。
Siremadlin 是一种每天口服一次 (QD) 的胶囊，有 10 毫克、20 毫克和 30 毫克规格
其他名称：
Azacitidine is a powder for suspension for injection or powder for solution for infusion taken intravenously or subcutaneously comes in 100 mg but was administered according to standard local clinical practice.
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实验性的：Arm 2: Adult participants with newly diagnosed unfit AML with high risk clinical features
Adult participants with unfit AML who were newly diagnosed and presenting with high-risk clinical features (which related to factors conferring to a low likelihood of response to venetoclax plus azacitidine) and with adverse genetic risk stratification (according to ELN 2022) (Except TP53 mutation positive participants).
Siremadlin was administered at a dose of 20 mg QD which could be increased based on toxicities; venetoclax was administered at 400 mg once daily and azacitidine was administered at 75 mg/m^2.
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Venetoclax 是一种每天口服一次 (QD) 的药片，有 10 毫克、50 毫克和 100 毫克三种规格。
Siremadlin 是一种每天口服一次 (QD) 的胶囊，有 10 毫克、20 毫克和 30 毫克规格
其他名称：
Azacitidine is a powder for suspension for injection or powder for solution for infusion taken intravenously or subcutaneously comes in 100 mg but was administered according to standard local clinical practice.
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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 |
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Percentage of participants with Dose Limiting Toxicities (DLTs) as per investigator assessment reported during the first cycle (separately in Arm 1 & Arm 2)
大体时间：From Cycle 1 Day 1 to Cycle 1 Day 28 (28 days)
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A dose-limiting toxicity (DLT) is defined as an adverse event (AE) or abnormal laboratory value considered by the Investigator to be at least possibly related to siremadlin as a single contributor or in combination with other component(s) of study treatment that occurs beginning the first day of siremadlin dosing in the study until end of cycle 1.
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From Cycle 1 Day 1 to Cycle 1 Day 28 (28 days)
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Percentage of participants achieving a complete remission (CR) rate at recommended dose for expansion (RDE) as per investigator assessment (Arm 1 only)
大体时间：At least 7 cycles (196 days)
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Assessed by CR rate.
CR rate is defined as the percentage of participants with best overall response of complete remission (CR) as per investigator assessment.
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At least 7 cycles (196 days)
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次要结果测量
结果测量 |
措施说明 |
大体时间 |
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PK 参数：siremadlin、venetoclax 和阿扎胞苷的 Tmax（第 1 组和第 2 组）
大体时间：长达 3 年
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Siremadlin、venetoclax 和阿扎胞苷的 PK 参数 Tmax 和浓度与时间曲线。
Tmax是给药后达到最大（峰）血浆、血液、血清或其他体液药物浓度的时间（时间）。
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长达 3 年
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药代动力学 (PK) 参数：西瑞玛林、维奈托克和阿扎胞苷的 AUC（第 1 组和第 2 组）
大体时间：最长3年
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AUC0-t：从零时间到指定时间点的浓度与时间曲线 (AUC) 下的面积。 AUClast 是从零时间到最后一个可量化浓度点（最后）的 AUC（质量 x 时间 x 体积 -1）。 AUCtau 是到给药间隔结束时的 AUC，因为在可能的情况下，将在西瑞玛林和维奈托克给药后 24 小时内收集 PK 样品。 如果连续给药，则在第 5 天（AUCtau，ss）假定达到稳态。 |
最长3年
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PK 参数：西瑞马林、维奈托克和阿扎胞苷的 Cmax（第 1 组和第 2 组）
大体时间：最长3年
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表征每组中西瑞马林、维奈托克和阿扎胞苷联合给药的 PK。
Cmax是给药后观察到的血浆、血液、血清或其他体液药物浓度的最大（峰值）（质量x体积-1）
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最长3年
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Percentage of participants achieving complete remission (CR) as per Investigator assessment (Arm 2 only)
大体时间：up to 3 years
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Assessed by CR rate.
CR rate is defined as the percentage of participants with best overall response of complete remission (CR) as per investigator assessment.
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up to 3 years
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Time from date of the first documented CR to the date of the first documented relapse or death due to any cause, whichever occurs first (Arm 1 and Arm 2 separately)
大体时间：up to 3 years
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Duration of CR is defined as time from the date of the first documented CR to the date of first documented relapse or death due to any cause, whichever occurs first. Assessment of duration of CR in participants who achieved a CR. This endpoint was not analyzed since the recommended dose was not determined due to early termination. |
up to 3 years
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Percentage of participants achieving CR or complete remission with partial hematological recovery (CRh) (Arm 1 & 2)
大体时间：up to 3 years
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Assessed by CR/CRh rate.
CR/CRh rate is defined as the percentage of participants with best overall response of either CR or CRh as per investigator assessment.
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up to 3 years
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Percentage of participants achieving CR or complete remission with incomplete hematological recovery (CRi) (Arm 1 and Arm 2)
大体时间：up to 3 years
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Assessed by CR/CRi rate.
CR/CRi rate is defined as the percentage of participants with best overall response of either CR or CRi as per investigator assessment.
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up to 3 years
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Time from the date of the first documented CR/CRh to the date of first documented relapse or death due to any cause, whichever occurs first (Arm 1 and Arm 2 separately)
大体时间：up to 3 years
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Assessed by duration of CR/CRh. Duration of CR/CRh is defined as time from the date of the first documented CR/CRi to the date of first documented relapse or death due to any cause, whichever occurs first. This endpoint will not be analyzed since the recommended dose was not determined due to early termination. |
up to 3 years
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Time from the date of the first documented CR/CRi to the date of first documented relapse or death due to any cause, whichever occurs first (Arm 1 and Arm 2 separately)
大体时间：up to 3 years
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Assessed by duration of CR/CRi. Duration of CR/CRi is defined as time from the date of the first documented CR/CRi to the date of first documented relapse or death due to any cause, whichever occurs first. This endpoint will not be analyzed since the recommended dose was not determined due to early termination |
up to 3 years
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Overall Survival (OS) (Arm 1 and Arm 2 separately)
大体时间：up to 3 years
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OS is the time from start of treatment to death due to any cause. This endpoint was not analyzed since the recommended dose was not determined due to early termination. |
up to 3 years
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Early mortality (Arm 1 and Arm 2)
大体时间：30 days & 60 days from start of study treatment
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Early mortality is the percentage of participants who died due to any cause from start of treatment until 30- and 60-day.
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30 days & 60 days from start of study treatment
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Percentage of CR- Measurable Residual Disease (MRD) negative overall and in participants achieving a CR, CR/CRh, and CR/CRi (Arm 1 and Arm 2)
大体时间：up to 3 years
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Assessed by MRD-negativity rate.
MRD negativity rate is defined as the percentage of participants with a CR/CRh/CRi-MRD negative sample.
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up to 3 years
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合作者和调查者
调查人员
- 研究主任：Novartis Pharmaceuticals、Novartis Pharmaceuticals
出版物和有用的链接
研究记录日期
研究主要日期
学习开始 (实际的)
初级完成 (实际的)
研究完成 (实际的)
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
- CHDM201I12201
- 2021-001165-21 (EudraCT编号)
计划个人参与者数据 (IPD)
计划共享个人参与者数据 (IPD)？
IPD 计划说明
诺华致力于与合格的外部研究人员共享患者水平数据的访问权限，并支持符合条件的研究的临床文件。 这些请求由独立审查小组根据科学价值审查和批准。 提供的所有数据均已匿名，以根据适用法律法规尊重参与试验患者的隐私。
该试验数据的可用性是根据 www.clinicalstudydatarequest.com 上描述的标准和过程
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