Liposomal Mitoxantrone Plus Azacitidine and Venetoclax in Newly Diagnosed Elderly or Unfit AML
A Phase Ib Study of Liposomal Mitoxantrone Combined With Azacitidine and Venetoclax in Newly Diagnosed Elderly or Unfit Patients With Acute Myeloid Leukemia
This prospective, open-label, multicenter phase Ib trial will evaluate the safety, tolerability, and RP2D of the VAM regimen (liposomal mitoxantrone + azacitidine [AZA] + venetoclax [VEN]) in elderly or unfit patients with newly diagnosed AML. A standard 3+3 dose escalation will enroll 12-30 patients, testing liposomal mitoxantrone at 8, 12, 16, and 20 mg/m². VEN duration (9 vs. 14 days) will be determined at the 8 mg/m² dose level, after which only liposomal mitoxantrone will be escalated while AZA and VEN will remain fixed.
Induction therapy will consist of up to two 28-day cycles. Responders achieving CR/CRi/MLFS will be eligible for up to 4 consolidation cycles (total ≤6 cycles), after which they will proceed to maintenance with either AZA+VEN or observation.
研究概览
研究类型
注册 (估计的)
阶段
- 阶段1
参与标准
资格标准
适合学习的年龄
- 成人
- 年长者
接受健康志愿者
描述
Inclusion Criteria:
Subjects eligible for enrollment in this study must meet all of the following criteria:
- Diagnosis of acute myeloid leukemia (AML) according to the WHO 2022 or ICC criteria, excluding acute promyelocytic leukemia (APL).
- No prior therapy for AML, except hydroxyurea for the management of hyperleukocytosis.
Meeting at least one of the following criteria:
- Age ≥ 75 years;
- Age 18-74 years with at least one of the following conditions precluding suitability for intensive chemotherapy:
i. ECOG performance status 2-3; ii. Cardiac dysfunction with left ventricular ejection fraction (LVEF) ≤ 50%; iii. Pulmonary dysfunction with diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 65% or forced expiratory volume in 1 second (FEV1) ≤ 65%; iv. Creatinine clearance 30-45 mL/min; v. Other major organ dysfunction or comorbidities that, in the investigator's judgment, render the patient unsuitable for intensive chemotherapy.
- ECOG performance status 0-3.
- Life expectancy ≥ 3 months.
- Patients of childbearing potential agree to use effective contraception during the treatment period and for at least 6 months after the last dose of study treatment.
- Voluntary written informed consent provided.
Exclusion Criteria:
Subjects who meet any of the following criteria will not be eligible for enrollment in this study:
- Acute promyelocytic leukemia (APL)..
- Active central nervous system (CNS) leukemia.
- Prior targeted therapy or chemotherapy for AML, excluding hydroxyurea.
- Uncontrolled active infection.
- Uncontrolled cardiovascular disease: New York Heart Association (NYHA) class III-IV heart failure, myocardial infarction or unstable angina within 6 months before enrollment, or uncontrolled hypertension.
- Left ventricular ejection fraction (LVEF) < 40%.
- Concurrent active malignancy, except for cured non-melanoma skin cancer, carcinoma in situ of the cervix, or localized prostate cancer.
- Known hypersensitivity to the study drugs or their excipients.
- Pregnant or breastfeeding women.
- Any other condition that, in the investigator's judgment, would make the patient unsuitable for study participation.
学习计划
研究是如何设计的？
设计细节
- 主要用途：治疗
- 分配：不适用
- 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 |
|---|---|
|
实验性的：Venetoclax, azacitidine combined with liposome mitoxantrone as induction regimen
The trial will employ a standard 3+3 dose escalation design, testing liposomal mitoxantrone at 8, 12, 16, and 20 mg/m². VEN duration (9 vs. 14 days) will be determined at the 8 mg/m² dose level, after which only liposomal mitoxantrone will be escalated while AZA and VEN will remain fixed. Venetoclax duration will be sequentially escalated (9 vs. 14 days), choosing the longest duration without dose-limiting toxicity (DLT) in 3-6 evaluable patients. The RP2D for liposomal mitoxantrone is the highest dose with ≤1 DLT in 6 patients; if DL4 is tolerated, RP2D = 20 mg/m² on day 1. |
Liposome Mitoxantrone: 8, 12, 16, and 20 mg/m², administered by intravenous drip (ivgtt) on day 1, every 4 weeks
Venetoclax(9 days): 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-9, administered orally (po), every 4 weeks Venetoclax(14 days): 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-14, administered orally (po), every 4 weeks
Azacitidine: 75 mg/m², administered subcutaneously (sc) on days 1-7, every 4 weeks
|
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 |
|---|---|---|
|
Dose-Limiting Toxicity (DLT)
大体时间：Cycle 1(up to 42 days)
|
To evaluate the safety, tolerability, and RP2D of the VAM regimen in newly diagnosed elderly/unfit AML patients.
|
Cycle 1(up to 42 days)
|
|
Incidence of treatment-related adverse events
大体时间：From day 1 of treatment to 28 days after the last dose
|
The safety of the drug was evaluated by NCI-CTC AE 5.0 standard which including hematologic and non-hematologic toxicity
|
From day 1 of treatment to 28 days after the last dose
|
|
Composite complete remission (CRc) rate
大体时间：Up to approximately eight weeks
|
Proportion of patients with complete remission (CR), complete remission with incomplete hematologic recovery (CRi) or morphologic leukemia-free state (MLFS)
|
Up to approximately eight weeks
|
次要结果测量
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
Complete remission (CR) rate
大体时间：Up to approximately eight weeks
|
Proportion of patients with complete remission (CR)
|
Up to approximately eight weeks
|
|
Complete remission with incomplete hematologic recovery (CRi) rate
大体时间：Up to approximately eight weeks
|
Proportion of patients with complete remission with incomplete hematologic recovery (CRi)
|
Up to approximately eight weeks
|
|
Morphologic leukemia-free state (MLFS) rate
大体时间：Up to approximately eight weeks
|
Proportion of patients with morphologic leukemia-free state (MLFS)
|
Up to approximately eight weeks
|
|
Event-free survival (EFS)
大体时间：Up to approximately 5 years
|
It is defined as the time from the start of study treatment to the occurrence of induction failure or disease progression or death from any cause (whichever occurs first)
|
Up to approximately 5 years
|
|
Overall survival (OS)
大体时间：Up to approximately 5 years
|
It is defined as the time from the start of study treatment to the death from any cause
|
Up to approximately 5 years
|
|
Relapse-free Survival (RFS)
大体时间：Up to approximately 5 years
|
It is defined as the time from the start of achieving remission to disease progression, death from any cause or the last follow-up
|
Up to approximately 5 years
|
|
Duration of Response (DoR)
大体时间：Up to approximately 5 years
|
It is defined as the time from the first documentation of CRc to relapse
|
Up to approximately 5 years
|
|
30-day postinduction mortality
大体时间：Up to approximately 30 days
|
It is defined as death from any cause within 30 days after the start of induction
|
Up to approximately 30 days
|
|
60-day postinduction mortality
大体时间：Up to approximately 60 days
|
t is defined as death from any cause within 60 days after the start of induction
|
Up to approximately 60 days
|
|
Measurable Residual Disease (MRD) negative rate by flow cytometry
大体时间：Up to approximately eight weeks
|
Among those who have achieved CR/CRh/CRi after induction, proportion of patients who is MRD-negative by flow cytometry
|
Up to approximately eight weeks
|
|
Measurable Residual Disease (MRD) negative rate by molecular testing
大体时间：Up to approximately eight weeks
|
Among those who have achieved CR/CRh/CRi after induction, proportion of patients who is MRD-negative by molecular testing
|
Up to approximately eight weeks
|
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
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