Phase 2, Randomized, Biomarker-driven Clinical Study in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With MCL-1 Dependence ≥30%
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 104
- 试验地点
- 38
- 主要终点
- Complete Response (CR) Rate in Patients With Relapsed or Refractory AML
研究概览
简要总结
The purpose of this two-stage Phase 2 study is to assess the clinical response (Complete Remission) of ACM (Alvocidib/Cytarabine/Mitoxantrone) compared to CM (Cytarabine/Mitoxantrone) treatment in refractory or relapsed AML patients with demonstrated MCL-1 dependence of ≥ 30% by mitochondrial profiling in bone marrow.
详细描述
In Stage 1 of the study, all eligible AML patients with demonstrated MCL-1 dependence of ≥ 30% by mitochondrial profiling in bone marrow will receive treatment with ACM.
In Stage 2, all eligible AML patients with demonstrated MCL-1 dependence of ≥ 30% by mitochondrial profiling in bone marrow will be randomized 1:1 to receive either treatment with ACM or CM.
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
- •Be between the ages of ≥18 and ≤65 years
- •Have an established, pathologically confirmed diagnoses of AML by World Health Organization (WHO) criteria excluding acute promyelocytic leukemia (APL-M3) with a bone marrow of >5% blasts based on histology or flow cytometry
- •Be in first relapse (within 24 months of CR) or have failed induction therapy* (no CR or CRi after treatment with an intensive regimen (eg, anthracycline/cytarabine ± etoposide, gemtuzumab ozogamicin, or cladribine).
- •*Induction therapy may involve 1 or 2 cycles of the same regimen. Efficacy assessment of induction therapy must be >21 days from the start of the previous induction cycle.
- •Demonstrate MCL-1 dependence of ≥30% by mitochondrial profiling in bone marrow.
- •Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2
- •Have a serum creatinine level ≤1.8 mg/dL
- •Have an alanine aminotransferase (ALT)/aspartate aminotransferase (AST) level ≤5 times upper limit of normal (ULN)
- •Have a total bilirubin level ≤2.0 mg/dL (unless secondary to Gilbert syndrome, hemolysis, or leukemia)
- •Have a left ventricular ejection fraction (LVEF) >45% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan
- •Be nonfertile or agree to use an adequate method of contraception. Sexually active patients and their partners must use an effective method of contraception associated with a low failure rate during and for at least 6 months after completion of study therapy.
- •Be able to comply with the requirements of the entire study.
- •Provide written informed consent prior to any study related procedure.
排除标准
- •Received more than 2 cycles of induction therapy for AML. Investigational agents as part of front-line therapy for AML may by acceptable following discussion with the Medical Monitor. Hydroxyurea is permitted (see #5 below).
- •Received any previous treatment with alvocidib or any other CDK inhibitor
- •Received a hematopoietic stem cell transplant within the previous 2 months
- •Have clinically significant graft versus host disease (GVHD), or GVHD requiring initiation or escalation of treatment within the last 21 days
- •Require concomitant chemotherapy, radiation therapy, or immunotherapy. Hydroxyurea is allowed up to the evening before starting (but not within 12 hours) of starting treatment on either arm.
- •Received >360 mg/m2 equivalents of daunorubicin
- •Have a peripheral blast count of >30,000/mm3 (may use hydroxyurea as in #5 above)
- •Received antileukemic therapy within the last 3 weeks (with the exception of hydroxyurea or if the patient has definite refractory disease). Refractory patients who received therapy within the last 3 weeks may be eligible with prior approval of the Medical Monitor.
- •Diagnosed with acute promyelocytic leukemia (APL, M3)
- •Have active central nervous system (CNS) leukemia
- •Have evidence of uncontrolled disseminated intravascular coagulation
- •Have an active, uncontrolled infection
- •Have other life-threatening illness
- •Have other active malignancies or diagnosed with other malignancies within the last 6 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia
- •Have mental deficits and/or psychiatric history that may compromise the ability to give written informed consent or to comply with the study protocol.
- •Are pregnant and/or nursing
- •Have received any live vaccine within 14 days prior to first study drug administration.
研究组 & 干预措施
ACM (Stage 1 / Stage 2)
A: alvocidib, 30 mg/m2 as a 30 minute intravenous (IV) bolus followed by 60 mg/m2 over 4 hours as an IV infusion administered daily on Days 1-3; C: cytarabine (ara-c), 2 gm/m2 by continuous IV infusion over 72 hours on Days 6-8; M: mitoxantrone (mitoxantrone hydrochloride), 40 mg/m2 by IV infusion over 1-2 hours starting 12 hours after completing cytarabine
干预措施: Alvocidib (Drug)
ACM (Stage 1 / Stage 2)
A: alvocidib, 30 mg/m2 as a 30 minute intravenous (IV) bolus followed by 60 mg/m2 over 4 hours as an IV infusion administered daily on Days 1-3; C: cytarabine (ara-c), 2 gm/m2 by continuous IV infusion over 72 hours on Days 6-8; M: mitoxantrone (mitoxantrone hydrochloride), 40 mg/m2 by IV infusion over 1-2 hours starting 12 hours after completing cytarabine
干预措施: Cytarabine (Drug)
ACM (Stage 1 / Stage 2)
A: alvocidib, 30 mg/m2 as a 30 minute intravenous (IV) bolus followed by 60 mg/m2 over 4 hours as an IV infusion administered daily on Days 1-3; C: cytarabine (ara-c), 2 gm/m2 by continuous IV infusion over 72 hours on Days 6-8; M: mitoxantrone (mitoxantrone hydrochloride), 40 mg/m2 by IV infusion over 1-2 hours starting 12 hours after completing cytarabine
干预措施: Mitoxantrone (Drug)
CM (Stage 2)
C: cytarabine (ara-c), 2 gm/m2 by continuous IV infusion over 72 hours on Days 1-3; M: mitoxantrone (mitoxantrone hydrochloride), 40 mg/m2 by IV infusion over 1-2 hours starting 12 hours after completing cytarabine
干预措施: Cytarabine (Drug)
CM (Stage 2)
C: cytarabine (ara-c), 2 gm/m2 by continuous IV infusion over 72 hours on Days 1-3; M: mitoxantrone (mitoxantrone hydrochloride), 40 mg/m2 by IV infusion over 1-2 hours starting 12 hours after completing cytarabine
干预措施: Mitoxantrone (Drug)
结局指标
主要结局
Complete Response (CR) Rate in Patients With Relapsed or Refractory AML
时间窗: Best response after at least 1 cycle through study completion approximately 4 years
Complete Remission (CR) rate = Percentage of patients achieving CR after Cycle 1 as defined in Stage 1 by the International Working Group (IWG) Criteria and 2010 European LeukemiaNet (EN) criteria in patients with relapsed or refractory AML with MCL-1 dependence \>30% and in Stage 2 by the 2017 ELN criteria. The study was terminated in January 2020 due to a steady and marked reduction in enrollment. Thus, the efficacy endpoints could not be analyzed. As sufficient efficacy results were not available to analyze patients based on the percentage of MCL-1 dependency the treatment efficacy was summarized by distributing the safety population into 6 groups based on whether the patients received the ACM vs CM regimen and their disease stages at study entry.
次要结局
未报告次要终点