A Single-Center, Prospective, Single-Arm Phase II Clinical Study of Consolidation With High-Dose Cytarabine Following Deep Molecular Remission Induced by Gilteritinib Plus VA Regimen in Newly Diagnosed Intermediate-Risk Fit AML Patients With FLT3-ITD Mutation
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- Composite Complete Remission (CRc) Rate after 2 induction cycles
研究概览
简要总结
This clinical trial aims to evaluate whether molecular MRD-guided chemotherapy can effectively treat FLT3-ITD mutated AML and potentially replace allogeneic hematopoietic stem cell transplantation. It primarily seeks to answer:
- What is the complete remission rate after initial induction with Gilteritinib, Venetoclax, and Azacitidine?
- What are the survival rates and safety of subsequent high-dose cytarabine consolidation after two cycles of this induction therapy? As a single-arm study, outcomes will be compared against historical data from standard treatments (including transplant) to assess if the new strategy is equally or more effective.
Participants will:
- Undergo three cycles of high-dose cytarabine consolidation after two cycles of induction therapy, contingent upon achieving deep FLT3-ITD molecular remission.
- Start Gilteritinib maintenance therapy after consolidation if FLT3-ITD remains detectable, continuing until deep molecular remission is achieved again.
详细描述
This single-center, phase II trial evaluates a novel, transplant-sparing strategy for fit patients with newly diagnosed intermediate-risk acute myeloid leukemia (AML) harboring FLT3-ITD mutations. The central hypothesis is that achieving deep molecular remission-as measured by a highly sensitive assay termed "DeepScan" (Levis et al., Blood 2022)-can identify a subset of patients who may attain long-term survival without allogeneic hematopoietic stem cell transplantation (allo-HSCT).
The therapeutic strategy consists of a sequential three-phase approach:
Induction: Initial therapy combines the FLT3 inhibitor gilteritinib with venetoclax and azacitidine (the GVA regimen). This synergistic approach targets leukemia through concurrent inhibition of FLT3 and BCL-2 pathways, aiming to achieve high rates of complete remission and deep molecular clearance.
Consolidation: Patients who achieve deep FLT3-ITD negativity, as assessed by the "DeepScan" minimal residual disease (MRD) assay after induction therapy, will proceed to consolidation with high-dose cytarabine (2 g/m² twice daily for 3 days) for three cycles, concurrently with gilteritinib.
Maintenance: Patients maintaining deep FLT3-ITD negativity will receive gilteritinib monotherapy at 120 mg daily for 3 months. Those with detectable mutations will be withdrawn from the study.
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 59 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Each subject (or their legal representative) must sign an informed consent form (ICF) before any specific study procedures or tests, indicating that he/she understands the purpose and procedures of the study and is willing to participate.
- •Age ≥ 18 years or reaching the legal minimum adult age (whichever is greater) and ≤ 60 years (at screening);
- •Newly diagnosed acute myeloid leukemia with FLT3-ITD mutation according to the European LeukemiaNet (ELN) 2022 diagnostic criteria (no VAF requirement), with no low-risk or high-risk genetic features as defined by ELN
- •ECOG performance status ≤
- •Biochemical indicators must be within the following limits within 21 days before randomization and at baseline: ALT and AST ≤ 3× upper limit of normal (ULN); total bilirubin ≤ 3× ULN; serum creatinine ≤ 2× ULN or CrCl ≥ 40 mL/min. LVEF determined by echocardiography is within the normal range (LVEF > 50%).
排除标准
- •Diagnosed with acute promyelocytic leukemia (APL), BCR-ABL positive acute myeloid leukemia, or AML secondary to previous chemotherapy or radiotherapy.
- •History of other malignancies, except for adequately treated non-malignant skin melanoma, cured in situ tumors, or other solid tumors that have been treated and have had no evidence of disease for at least 2 years.
- •Assessed as unfit for intensive chemotherapy based on the following criteria: ECOG performance status ≥ 2 at screening; severe cardiac diseases (e.g., congestive heart failure requiring treatment, ejection fraction ≤ 50%, or chronic stable angina); severe pulmonary diseases (e.g., DLCO ≤ 65% or FEV1 ≤ 65%); creatinine clearance < 45 ml/min (calculated by Cockcroft-Gault equation), liver disease with total bilirubin > 1.5 times the normal upper limit (ULN); any other comorbidities deemed incompatible with intensive chemotherapy by the attending physician.
- •Uncontrolled fungal, bacterial, or viral infections.
- •Known active clinically relevant liver disease (e.g., active hepatitis B or C); known history of HIV infection (participants should undergo HIV testing before randomization).
- •History of allergy to any excipients in gilteritinib tablets.
- •Pregnant or breastfeeding women.
- •Other conditions deemed unsuitable for this study by the investigator.
研究组 & 干预措施
GVA + HDAC Consolidation + Gilteritinib Maintenance
This is a single-arm study contains three phases:
Phase I. Induction Therapy: Gilteritinib + Venetoclax + Azacitidine (GVA Regimen) for 2 cycles Phase II. Consolidation Therapy: Gilteritinib + High-Dose Cytarabine (HDAC) for 3 cycles Phase III. Maintenance Therapy: Gilteritinib monotherapy for up to 3 months
干预措施: GVA + HDAC Consolidation & Gilteritinib Maintenance (Drug)
结局指标
主要结局
Composite Complete Remission (CRc) Rate after 2 induction cycles
时间窗: At day 28 of cycle 2 of GVA induction therapy (each cycle is typically 28 days with 2-weeks intervals).
CRc is defined as the proportion of participants achieving CR or CRi based on 2022 ELN criteria. CR: Bone marrow blasts \<5%, ANC ≥1.0 x 10⁹/L, platelets ≥100 x 10⁹/L, no extramedullary disease, and transfusion independence. CRi: Bone marrow blasts \<5%, no extramedullary disease, and insufficient hematologic recovery to qualify for CR.
次要结局
- MRD Negativity Rate(At the time of CRc assessment (at day 28 of cycle 2).)
- Deep Molecular Negativity Rate (for FLT3-ITD)(At the time point for CRc assessment (at day 28 of cycle 2))
- Leukemia-Free Survival (LFS)(follow up 24 months.)
- Overall Survival (OS)(follow up 24 months)
- Cumulative Incidence of Molecular Relapse (mCIR)(follow up 24 months)
- Molecular Free Survival (mLFS)(follow up 24 months)
- Cumulative Incidence of Relapse (CIR)(follow up 24 months)
研究者
Jie Sun
Principle Attending, Associated Professor
First Affiliated Hospital of Zhejiang University