A Prospective, Randomized Controlled Study on the Efficacy and Safety of Venetoclax Combined With 3-Day Decitabine (DEC3-VEN) Versus Venetoclax Combined With "2+6" DA Versus "3+7" DA Regimen in Adult Patients With Newly Diagnosed Acute Myeloid Leukemia
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 291
- 试验地点
- 1
- 主要终点
- Composite Complete Remission Rate after Induction Therapy
研究概览
简要总结
Protocol Title: A Prospective, Randomized Controlled Study of Venetoclax Plus 3-Day Decitabine (DEC3-VEN) Versus Venetoclax Plus "2+6" DA Versus "3+7" DA Regimen in Adult Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)
Objective: This is a prospective, open-label, randomized, multicenter, phase II trial designed to compare the efficacy and safety of three induction regimens-Venetoclax plus 3-day Decitabine (DEC3-VEN), Venetoclax plus "2+6" DA, and standard "3+7" DA-in adult patients with newly diagnosed, intensifiable AML.
Study Design: The study employs a prospective, randomized, controlled, multicenter design. A total of 291 eligible patients will be enrolled across approximately 10 centers in China and randomized in a 2:2:1 ratio to the three treatment arms.
Key Eligibility Criteria:
Inclusion: Aged 16-65 with newly diagnosed non-APL AML (excluding favorable CBF-AML), eligible for intensive chemotherapy, ECOG ≤2, and adequate organ function.
Exclusion: Prior AML treatment, secondary AML, active severe infection, significant cardiac comorbidity, or known hypersensitivity to the study drugs.
Interventions:
Induction:
Arm A (VEN+"2+6"DA): Venetoclax (D1-8), Daunorubicin (D2-3), Cytarabine (D2-7).
Arm B (DEC3-VEN): Venetoclax (D1-14), Decitabine (D4-6). FLT3/ITD+ patients add Sorafenib or Gilteritinib (D8-14).
Arm C ("3+7"DA): Daunorubicin (D1-3), Cytarabine (D1-7).
Consolidation (2 cycles):
Arms A/B: Venetoclax + Intermediate-Dose Cytarabine.
Arm C: High-Dose Cytarabine.
Consolidation (Subsequent cycles):
All arms receive multiple cycles of DA or HA regimens.
Maintenance (6-8 cycles):
Arms A/B: Venetoclax + Azacitidine.
Arm C: Azacitidine.
Main Outcome Measures:
Primary Endpoint: Composite Complete Remission Rate (CR + CRi) after induction.
Secondary Endpoints: Overall Survival (OS), CR rate, MRD-negative rate, Relapse-Free Survival (RFS), Event-Free Survival (EFS), and safety.
Keywords: Acute Myeloid Leukemia, Venetoclax, Decitabine, Consolidation Therapy, Maintenance Therapy, Randomized Controlled Trial.
详细描述
This Phase 3, open-label, randomized controlled trial employs a three-arm parallel design to evaluate the optimal integration of venetoclax into intensive chemotherapy for newly diagnosed AML. The study is designed to address the critical unmet need of balancing high remission rates with tolerability in fit adult AML patients.
Scientific Rationale for Treatment Arms:
Arm A (VEN+"2+6" DA) investigates a modified intensive regimen where daunorubicin exposure is limited to 2 days (vs. conventional 3 days) based on prior institutional data suggesting comparable efficacy with reduced cardiotoxicity. Arm B (DEC3-VEN) explores a novel combination of venetoclax with high-dose decitabine (20 mg/m² every 8 hours for 3 days), a regimen developed to enhance hypomethylating effects while limiting myelosuppression duration to approximately 2 weeks through shortened decitabine exposure. Arm C represents the standard "3+7" DA regimen as the reference arm.
Venetoclax Pharmacological Considerations:
The 100→200→400 mg dose ramp-up over 2-3 days is implemented for tumor lysis syndrome (TLS) prophylaxis, with extended dosing through Day 8 (Arm A) or Day 14 (Arm B) based on the pharmacokinetic principle of sustained BCL-2 inhibition. For FLT3-ITD positive patients in Arm B, sorafenib or gilteritinib is added from Day 8 to target dual oncogenic pathways.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subjects who are suitable for enrollment in this study must meet all of the following criteria:
- •Except for APL or carrying t(8) that meet the diagnostic criteria (WHO2022 criteria) of the World Health Organization; 21)/(RUNX1::RUNX1TI)、inv(16)(p13.1q22) 、 t(16; 16) (p13.1q22) 、 t(16; 16)/CBFβ::myh11) and other acute myeloid leukemia other than one of the abnormal karyotypes;
- •Except for acute panmyeloproliferative disease with myelofibrosis and myeloid sarcoma, the World Health Organization AML classification is AML without separate classification;
- •Newly diagnosed AML patients with male or female, age greater than or equal to 16 years old and less than 65 years old, patients are considered suitable for intensive chemotherapy;
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤2 at the time of enrollment;
- •The patient has not received previous AML therapy (except for hydroxyurea and Ara-C<1.0g/d for reducing tumor compounds);
- •Pass the following laboratory test indicators (performed within 7 days before treatment):
- •1) Aspartate aminotransferase (ALT), alanine aminotransferase (AST) and alkaline phosphatase (ALP) ≤3× upper limit of normal (ULN), serum bilirubin ≤2×ULN; Serum cardiac enzymes < 2.0× ULN; Unless it is thought to be a leukemic organ involvement.
- •Creatinine ≥ 30 mL/min, calculated by the Cockcroft Gault formula or measured by 24-hour urine collection;
- •7. Female subjects of childbearing potential must have a negative pregnancy test result within 72 hours before the start of treatment; Not planning to become pregnant during the study and within 6 months after the last dose of study drug, and negative urine or serum pregnancy test results at screening. Men must use a latex condom during any sexual contact with WOCBP, even if they have had a successful vasectomy, and must agree to avoid childbearing (during treatment and for 6 months after the last dose of study drug).
- •8. Life expectancy exceeds 2 months;
- •9. Informed consent must be signed before the start of all specific study procedures, and the informed consent form must be signed by the patient or his immediate family; Considering the patient's condition, if the patient's signature is not conducive to the treatment of the condition, the legal guardian or the patient's immediate family will sign the informed consent form.
排除标准
- •Subjects who meet any of the following criteria are not eligible for this study:
- •AML with BCR-ABL1; or CML sudden change period;
- •Treated patients (refers to those who have received induction chemotherapy in the past, regardless of the efficacy);
- •Subjects with acute panmyelopathy with myelofibrosis or myelosarcoma as defined by WHO 2016;
- •Secondary leukemia (mainly refers to those who belong to the treatment-related AML subcategory of the World Health Organization (WHO 2016) AML classification and those with a history of pre-stage MDS and/or MPD);
- •Patients with other hematological diseases (such as hemophilia, myelofibrosis, etc., who are not suitable for inclusion; Those with previous blood picture abnormalities, except for bone marrow examination, MDS and MPD are allowed to be selected);
- •Pregnant or lactating patients;
- •Those who are allergic to any drugs involved in this study;
- •Use of strong or moderate CYP7A inducers within 3 days before the start of study treatment;
- •Suffering from malignant tumors of other organs (those who need treatment);
- •Obvious abnormal liver and kidney function, exceeding the enrollment criteria;
- •Active cardiac disease, defined as one or more of the following:
- •Myocardial infarction less than 6 months from enrollment in the study;
- •History of arrhythmias requiring medication or severe clinical symptoms;
- •Uncontrolled or symptomatic congestive heart failure (> NYHA Grade 2);
- •Uncontrolled or symptomatic angina;
- •Left ventricular ejection fraction below the lower limit of the normal range;
- •12. Patients with severe infectious diseases (uncured tuberculosis, pulmonary aspergillosis), known infection with human immunodeficiency virus (HIV) or active hepatitis B or C; Subjects with uncontrollable infection.
- •13. Subjects with evidence of central nervous system leukemia before treatment;
- •14. Subjects with epilepsy, dementia or other abnormal mental states that require medication and cannot understand or follow the protocol;
- •15. Restriction of oral drug intake or gastrointestinal absorption;
- •16. Those who are not suitable for enrollment in the opinion of the investigator;
结局指标
主要结局
Composite Complete Remission Rate after Induction Therapy
时间窗: At the end of Cycle 1 (each cycle is 28 days)
Percentage of patients achieving composite complete remission (CR + CRi) after induction therapy (defined as the first 28-day cycle of treatment). Complete remission (CR) and CR with incomplete hematologic recovery (CRi) are defined according to the European LeukemiaNet (ELN) 2022 criteria. Response is assessed by bone marrow aspiration and biopsy performed at a central laboratory between Day 21 and Day 28 of the induction cycle (or upon count recovery). The measurement unit is the percentage of patients achieving CR or CRi among all randomized patients (intention-to-treat population).
次要结局
- Overall Survival (OS)(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months)
- MRD-negative remission rate(At the end of Cycle 1 (each cycle is 28 days))
- Relapse-Free Survival (RFS)(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months)
- Event-Free Survival (EFS)(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months)
- safety profile(At the end of Cycle 1 (each cycle is 28 days))
研究者
ZePing Zhou
DR.
The Second Affiliated Hospital of Kunming Medical University