Phase 2 Study of Venetoclax-containing Therapy in Combination With HLA-mismatched Mobilized Peripheral Blood Mononuclear Cell Infusion for Newly Diagnosed Acute Myeloid Leukemia
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Overall survival (OS)
研究概览
简要总结
The purpose of this study is to evaluate whether HLA-mismatched donor G-CSF mobilized peripheral blood mononuclear cell (GPBMC) infusion with venetoclax-containing regimens (microtransplant, MST) could improve survival in adult patients with newly diagnosed acute myeloid leukemia (AML).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age >=18 years, male or female, non-limited by race or ethnicity.
- •No prior anti-acute leukemia treatment (including hypomethylators for leukemia or MDS) with the exception that prior hydroxyurea and/or leukapheresis are permitted.
- •Confirmed acute myeloid leukemia in accordance with WHO criteria with a WBC count < 25 × 109/L.
- •Adequate hepatic function including alanine transaminase (ALT) and aspartate aminotransferase (AST )<= 3 × upper limit of normal(ULN), and total bilirubin <= 1.5 × ULN.
- •Adequate renal function including serum creatinine <= 2 × ULN or CrCl>= 40mL/min.
- •LVEF measured by echocardiogram is within the normal range (LVEF > 50%).
- •The subject must have one donor who is >= 18 years old and HLA matched at 0-7/10 loci (i.e., at least 3 HLA loci must be mismatched). In addition, the donor voluntarily donates hematopoietic stem cells and signs the consent form.
- •Each subject (or his/her legal representatives) must sign the Informed Consent Form (ICF), indicating that he/she understands the purpose and procedures of research, and is willing to participate in research.
- •Donor inclusion criteria: The donor meets the institution's criteria for related peripheral blood hematopoietic stem cell donors. The donor must be able to tolerate the cell separation and collection process, and sign the Informed Consent Form.
排除标准
- •Acute promyelocytic leukemia, myeloid sarcoma, chronic myeloid leukemia accelerated phase and blast crisis.
- •Uncontrolled infection or hemorrhage.
- •Cardiovascular disease with clinical significance, such as uncontrolled or highly symptomatic cardiac arrhythmias, congestive heart failure, or myocardial infarction within 6 months prior to screening, or New York Heart Association (NYHA) function class 3 (moderate) or class 4 (severe) heart disease.
- •Uncontrolled autoimmune disease or requiring immunosuppression treatment.
- •History of severe blood infusion reaction.
- •Nursing women, women of childbearing potential with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception.
- •Psychiatric disorder or cognitive impairment that in the researcher's judgment would make the subject not likely to adhere to the protocol requirements.
- •Any major surgery within 4 weeks before enrollment.
- •Life-threatening illness other than AML or uncontrolled intercurrent illness.
研究组 & 干预措施
Participants fit for intensive therapy
This cohort will include patients fit for intensive therapy.
Induction phase:
Genetically low-risk patients Venetoclax 100mg on Day 4, 200mg on Day 5, 400mg on Days 6-11 orally; Daunorubicin 60mg/m2 or idarubicin 12mg/m2 IV daily on Days 1-3; Cytarabine 100mg/m2 IV daily on Days 1-7. No more than two cycles. Continue to consolidation phase if achieving CR/CRi.
Genetically intermediate/high-risk patients Venetoclax 100mg on Day 1, 200mg on Day 2, 400 mg on Days 3-28 orally; Azacitidine 75mg/m2 SC daily on Days 1-7. 28 days per cycle, and no more than two cycles. Continue to consolidation phase if achieving CR/CRi and refuse allogeneic HSCT.
Consolidation phase:
Patients < 60 years Cytarabine 1.5g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
Patients ≥ 60 years Cytarabine 1g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
干预措施: Venetoclax (Drug)
Participants fit for intensive therapy
This cohort will include patients fit for intensive therapy.
Induction phase:
Genetically low-risk patients Venetoclax 100mg on Day 4, 200mg on Day 5, 400mg on Days 6-11 orally; Daunorubicin 60mg/m2 or idarubicin 12mg/m2 IV daily on Days 1-3; Cytarabine 100mg/m2 IV daily on Days 1-7. No more than two cycles. Continue to consolidation phase if achieving CR/CRi.
Genetically intermediate/high-risk patients Venetoclax 100mg on Day 1, 200mg on Day 2, 400 mg on Days 3-28 orally; Azacitidine 75mg/m2 SC daily on Days 1-7. 28 days per cycle, and no more than two cycles. Continue to consolidation phase if achieving CR/CRi and refuse allogeneic HSCT.
Consolidation phase:
Patients < 60 years Cytarabine 1.5g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
Patients ≥ 60 years Cytarabine 1g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
干预措施: Azacitidine (AZA) (Drug)
Participants fit for intensive therapy
This cohort will include patients fit for intensive therapy.
Induction phase:
Genetically low-risk patients Venetoclax 100mg on Day 4, 200mg on Day 5, 400mg on Days 6-11 orally; Daunorubicin 60mg/m2 or idarubicin 12mg/m2 IV daily on Days 1-3; Cytarabine 100mg/m2 IV daily on Days 1-7. No more than two cycles. Continue to consolidation phase if achieving CR/CRi.
Genetically intermediate/high-risk patients Venetoclax 100mg on Day 1, 200mg on Day 2, 400 mg on Days 3-28 orally; Azacitidine 75mg/m2 SC daily on Days 1-7. 28 days per cycle, and no more than two cycles. Continue to consolidation phase if achieving CR/CRi and refuse allogeneic HSCT.
Consolidation phase:
Patients < 60 years Cytarabine 1.5g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
Patients ≥ 60 years Cytarabine 1g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
干预措施: Daunorubicin (Drug)
Participants fit for intensive therapy
This cohort will include patients fit for intensive therapy.
Induction phase:
Genetically low-risk patients Venetoclax 100mg on Day 4, 200mg on Day 5, 400mg on Days 6-11 orally; Daunorubicin 60mg/m2 or idarubicin 12mg/m2 IV daily on Days 1-3; Cytarabine 100mg/m2 IV daily on Days 1-7. No more than two cycles. Continue to consolidation phase if achieving CR/CRi.
Genetically intermediate/high-risk patients Venetoclax 100mg on Day 1, 200mg on Day 2, 400 mg on Days 3-28 orally; Azacitidine 75mg/m2 SC daily on Days 1-7. 28 days per cycle, and no more than two cycles. Continue to consolidation phase if achieving CR/CRi and refuse allogeneic HSCT.
Consolidation phase:
Patients < 60 years Cytarabine 1.5g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
Patients ≥ 60 years Cytarabine 1g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
干预措施: Idarubicin（IDA） (Drug)
Participants fit for intensive therapy
This cohort will include patients fit for intensive therapy.
Induction phase:
Genetically low-risk patients Venetoclax 100mg on Day 4, 200mg on Day 5, 400mg on Days 6-11 orally; Daunorubicin 60mg/m2 or idarubicin 12mg/m2 IV daily on Days 1-3; Cytarabine 100mg/m2 IV daily on Days 1-7. No more than two cycles. Continue to consolidation phase if achieving CR/CRi.
Genetically intermediate/high-risk patients Venetoclax 100mg on Day 1, 200mg on Day 2, 400 mg on Days 3-28 orally; Azacitidine 75mg/m2 SC daily on Days 1-7. 28 days per cycle, and no more than two cycles. Continue to consolidation phase if achieving CR/CRi and refuse allogeneic HSCT.
Consolidation phase:
Patients < 60 years Cytarabine 1.5g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
Patients ≥ 60 years Cytarabine 1g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
干预措施: Cytarabine (Ara-C) (Drug)
Participants fit for intensive therapy
This cohort will include patients fit for intensive therapy.
Induction phase:
Genetically low-risk patients Venetoclax 100mg on Day 4, 200mg on Day 5, 400mg on Days 6-11 orally; Daunorubicin 60mg/m2 or idarubicin 12mg/m2 IV daily on Days 1-3; Cytarabine 100mg/m2 IV daily on Days 1-7. No more than two cycles. Continue to consolidation phase if achieving CR/CRi.
Genetically intermediate/high-risk patients Venetoclax 100mg on Day 1, 200mg on Day 2, 400 mg on Days 3-28 orally; Azacitidine 75mg/m2 SC daily on Days 1-7. 28 days per cycle, and no more than two cycles. Continue to consolidation phase if achieving CR/CRi and refuse allogeneic HSCT.
Consolidation phase:
Patients < 60 years Cytarabine 1.5g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
Patients ≥ 60 years Cytarabine 1g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
干预措施: GPBMC infusion (Biological)
Participants unfit for intensive therapy but fit for lower intensity therapy
This cohort will include patients unfit for intensive therapy but fit for lower intensity therapy at diagnosis according to Ferrara 2013 criteria.
Induction phase:
Venetoclax 100mg on Day 1, 200mg on Day 2, 400 mg on Days 3-28 orally; Azacitidine 75mg/m2 SC daily on Days 1-7. 28 days per cycle, and no more than two cycles. Re-evaluate unfitness and continue to consolidation phase if achieving CR/CRi and refuse allogeneic HSCT.
Consolidation phase:
Convert to "fit" patients and < 60 years Cytarabine 1.5g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
Convert to "fit" patients and ≥ 60 years Cytarabine 1g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
Still "unfit" patients Venetoclax 400 mg on Days 1-14 orally; Azacitidine 75mg/m2 SC daily on Days 1-7. Infuse donor GPBMCs on Day 15. 28 days per cycle until progression or untolerated.
干预措施: Venetoclax (Drug)
Participants unfit for intensive therapy but fit for lower intensity therapy
This cohort will include patients unfit for intensive therapy but fit for lower intensity therapy at diagnosis according to Ferrara 2013 criteria.
Induction phase:
Venetoclax 100mg on Day 1, 200mg on Day 2, 400 mg on Days 3-28 orally; Azacitidine 75mg/m2 SC daily on Days 1-7. 28 days per cycle, and no more than two cycles. Re-evaluate unfitness and continue to consolidation phase if achieving CR/CRi and refuse allogeneic HSCT.
Consolidation phase:
Convert to "fit" patients and < 60 years Cytarabine 1.5g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
Convert to "fit" patients and ≥ 60 years Cytarabine 1g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
Still "unfit" patients Venetoclax 400 mg on Days 1-14 orally; Azacitidine 75mg/m2 SC daily on Days 1-7. Infuse donor GPBMCs on Day 15. 28 days per cycle until progression or untolerated.
干预措施: Azacitidine (AZA) (Drug)
Participants unfit for intensive therapy but fit for lower intensity therapy
This cohort will include patients unfit for intensive therapy but fit for lower intensity therapy at diagnosis according to Ferrara 2013 criteria.
Induction phase:
Venetoclax 100mg on Day 1, 200mg on Day 2, 400 mg on Days 3-28 orally; Azacitidine 75mg/m2 SC daily on Days 1-7. 28 days per cycle, and no more than two cycles. Re-evaluate unfitness and continue to consolidation phase if achieving CR/CRi and refuse allogeneic HSCT.
Consolidation phase:
Convert to "fit" patients and < 60 years Cytarabine 1.5g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
Convert to "fit" patients and ≥ 60 years Cytarabine 1g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
Still "unfit" patients Venetoclax 400 mg on Days 1-14 orally; Azacitidine 75mg/m2 SC daily on Days 1-7. Infuse donor GPBMCs on Day 15. 28 days per cycle until progression or untolerated.
干预措施: Cytarabine (Ara-C) (Drug)
Participants unfit for intensive therapy but fit for lower intensity therapy
This cohort will include patients unfit for intensive therapy but fit for lower intensity therapy at diagnosis according to Ferrara 2013 criteria.
Induction phase:
Venetoclax 100mg on Day 1, 200mg on Day 2, 400 mg on Days 3-28 orally; Azacitidine 75mg/m2 SC daily on Days 1-7. 28 days per cycle, and no more than two cycles. Re-evaluate unfitness and continue to consolidation phase if achieving CR/CRi and refuse allogeneic HSCT.
Consolidation phase:
Convert to "fit" patients and < 60 years Cytarabine 1.5g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
Convert to "fit" patients and ≥ 60 years Cytarabine 1g/m2 IV every 12 hours on Days 1, 2, 3; Venetoclax 400mg on Days 1-7. Infuse donor GPBMCs on Day 8. Totally 3-4 cycles.
Still "unfit" patients Venetoclax 400 mg on Days 1-14 orally; Azacitidine 75mg/m2 SC daily on Days 1-7. Infuse donor GPBMCs on Day 15. 28 days per cycle until progression or untolerated.
干预措施: GPBMC infusion (Biological)
结局指标
主要结局
Overall survival (OS)
时间窗: Measured up to 4 years after the last participant is enrolled
OS is defined as the number of days from the date of initiation of treatment to the date of death.
Event-free Survival (EFS)
时间窗: Measured up to 4 years after the last participant is enrolled
EFS is defined as the number of days from initiation of treatment to the date of progressive disease, relapse from CR or CRi, treatment failure or death from any cause.
次要结局
- Complete remission (CR) and complete remission with incomplete marrow recovery (CRi)(Measured up to 2 years after the last participant is enrolled)
- Partial remission (PR)(Measured up to 2 years after the last participant is enrolled)
- Non-relapse Mortality (NRM)(Measured up to 4 years after the last participant is enrolled)