A Phase Ib Study of Liposomal Mitoxantrone Combined With Azacitidine and Venetoclax in Newly Diagnosed Elderly or Unfit Patients With Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 30
- 主要终点
- Dose-Limiting Toxicity (DLT)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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-
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Venetoclax (Drug)
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.
干预措施: Azacitidine (Drug)
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.
干预措施: Liposome Mitoxantrone (Drug)
结局指标
主要结局
Dose-Limiting Toxicity (DLT)
时间窗: Cycle 1(up to 42 days)
To evaluate the safety, tolerability, and RP2D of the VAM regimen in newly diagnosed elderly/unfit AML patients.
Incidence of treatment-related adverse events
时间窗: 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
Composite complete remission (CRc) rate
时间窗: 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)
次要结局
- 60-day postinduction mortality(Up to approximately 60 days)
- Complete remission (CR) rate(Up to approximately eight weeks)
- Complete remission with incomplete hematologic recovery (CRi) rate(Up to approximately eight weeks)
- Morphologic leukemia-free state (MLFS) rate(Up to approximately eight weeks)
- Event-free survival (EFS)(Up to approximately 5 years)
- Overall survival (OS)(Up to approximately 5 years)
- Relapse-free Survival (RFS)(Up to approximately 5 years)
- Duration of Response (DoR)(Up to approximately 5 years)
- 30-day postinduction mortality(Up to approximately 30 days)
- Measurable Residual Disease (MRD) negative rate by flow cytometry(Up to approximately eight weeks)
- Measurable Residual Disease (MRD) negative rate by molecular testing(Up to approximately eight weeks)