A Phase 3, Randomized, Controlled, Open-label, Clinical Study of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Low-Blast Acute Myelogenous Leukemia
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 454
- 试验地点
- 202
- 主要终点
- Event-Free Survival (EFS)
研究概览
简要总结
The purpose of this study is to determine whether the combination of pevonedistat and azacitidine improves event-free survival (EFS) when compared with single-agent azacitidine. (An event is defined as death or transformation to AML in participants with MDS or CMML, whichever occurs first, and is defined as death in participants with low-blast AML).
详细描述
The drug being tested in this study is called pevonedistat. Pevonedistat is being tested to treat people with higher-risk myelodysplastic syndromes (HR MDS), chronic myelomonocytic leukemia (CMML) and low-blast acute myelogenous leukemia (AML) as a combination treatment with azacitidine. This study will look at the overall survival, event-free survival and response to treatment in people who take pevonedistat and azacitidine when compared to people who take single-agent azacitidine.
The study will enroll approximately 450 participants. Once enrolled, participants will be randomly assigned in 1:1 ratio (by chance, like flipping a coin) to one of the two treatment groups in 28-day treatment cycles:
- Pevonedistat 20 mg/m^2 and azacitidine 75 mg/m^2 combination
- Single-agent azacitidine 75 mg/m^2
All participants will receive azacitidine via intravenous or subcutaneous route. Participants randomized to the combination arm will also receive pevonedistat intravenous infusion.
This multi-center trial will be conducted Spain, Belgium, Brazil, Canada, Czech Republic, France, Germany, Israel, Italy, the United States, Australia, Greece, Japan, Mexico, Poland, Russia, Korea, Turkey, China and United Kingdom. The overall time to participate in this study is approximately 63 months. Participants will attend the end-of-treatment visit 30 days after the last dose of study drug or before the start of subsequent anti-neoplastic therapy if that occurs sooner.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Has morphologically confirmed diagnosis of myelodysplastic syndromes (MDS) or CMML (i.e., with white blood cell [WBC] <13,000/microliter [mcL]) or low-blast acute myelogenous leukemia (AML).
- •Has MDS or CMML and must also have one of the following Prognostic Risk Categories, based on the Revised International Prognostic Scoring System (IPSS-R):
- •Very high (>6 points).
- •High (>4.5-6 points).
- •Intermediate (>3-4.5 points): a participant determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of >=5% bone marrow myeloblasts.
- •Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or
- •Participants with AML (20%-30% blasts) must have a treatment-related mortality (TRM) score >=4 for intensive, induction chemotherapy as calculated using the simplified model described by Walter and coworkers.
- •Calculation of TRM score:
- •0 for (age <61 years), +2 for (age 61-70 years), +4 for (age >=71 years).
- •+ 0 for (PS=0), +2 for (PS=1), +4 for (PS >1).
- •+ 0 for (platelets <50), +1 for (platelets >=50).
排除标准
- •Has previous treatment for HR MDS or CMML or low-blast AML with chemotherapy or other antineoplastic agents including hypomethylating agent (HMAs) such as decitabine or azacitidine. Previous treatment is permitted with hydroxyurea and with lenalidomide, except that lenalidomide may not be given within 8 weeks before the first dose of study drug.
- •Has acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis.
- •Participants with AML with a WBC count >50,000/mcL. Participants who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria.
- •Is eligible for intensive chemotherapy and/or allogeneic stem cell transplantation. The reason a participant is not eligible for intensive chemotherapy and/or allogeneic stem cell transplantation may consist of one or more of the following factors:
- •Comorbidities.
- •Inability to tolerate intensive chemotherapy (e.g., participants with AML with 20%-30% blasts and TRM >=4).
- •Physician decision (e.g., lack of available stem cell donor).
- •The reason a participant is not eligible should be documented in the electronic case report form (eCRF).
- •Has either clinical evidence of or history of central nervous system involvement by AML.
- •Has active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.
- •Is diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease.
- •Has nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection.
- •Has prothrombin time (PT) or aPTT >1.5× upper limit of normal (ULN) or active uncontrolled coagulopathy or bleeding disorder. Participants therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are excluded from enrollment.
- •Has known human immunodeficiency virus (HIV) seropositive.
- •Has known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection. Note: Participants who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load.
- •Has known hepatic cirrhosis or severe preexisting hepatic impairment.
- •Has known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV), and/or myocardial infarction within 6 months before first dose, or severe pulmonary hypertension.
- •Has treatment with strong cytochrome P 3A (CYP3A) inducers within 14 days before the first dose of pevonedistat.
研究组 & 干预措施
Azacitidine 75 mg/m^2
Participants were administered azacitidine 75 milligram per square meter (mg/m^2) intravenous (IV) or subcutaneous (SC) injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
干预措施: Azacitidine (Drug)
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Participants were administered azacitidine 75 mg/m^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
干预措施: Azacitidine (Drug)
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Participants were administered azacitidine 75 mg/m^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
干预措施: Pevonedistat (Drug)
结局指标
主要结局
Event-Free Survival (EFS)
时间窗: From randomization until transformation to acute myeloid leukemia, or death due to any cause: up to approximately 42 months
EFS was defined as the time from randomization to the date of an EFS event. An EFS event was defined as death or transformation to acute myelogenous leukemia (AML) (World Health Organization \[WHO\] classification as a participant having greater than 20 % blasts in the blood or marrow and an increase of blast count by 50%), whichever event occurred first, in participants with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemias (CMML). An EFS event was defined as death in participants with low-blast AML.
次要结局
- Kaplan-Meier Estimates of Six-Month Survival Rate(Month 6)
- Overall Survival (OS)(Up to approximately 6.9 years)
- Kaplan-Meier Estimates of One-Year Survival Rate(Year 1)
- Thirty-Day Mortality Reported as Number of Participants Who Died Up to Day 30(Up to Day 30)
- Sixty-Day Mortality Reported as Number of Participants Who Died Up to Day 60(Up to Day 60)
- Time to Acute Myelogenous Leukemia (AML) Transformation in Higher-Risk Myelodysplastic Syndromes (HR MDS), Higher-Risk Chronic Myelomonocytic Leukemias (HR CMML) and HR MDS/CMML Participants(From randomization until transformation to AML (up to approximately 42 months))
- Number of Participants With Complete Remission (CR) and CR+ Complete Remission With Incomplete Blood Count Recovery (CRi)(From randomization until CR (up to approximately 42 months))
- Number of Participants With CR and Marrow CR(From randomization until CR or marrow CR (up to approximately 42 months))
- Number of Participants With CR, Partial Remission (PR) and Hematologic Improvement (HI)(From randomization until, CR, PR or HI (up to approximately 42 months))
- Number of Participants With CR and Marrow CR and PR(From randomization until CR or Marrow CR and PR (up to approximately 42 months))
- Number of Participants With CR and Marrow CR, PR and Hematologic Improvement (HI)(From randomization until CR, marrow CR, PR or HI (up to approximately 42 months))
- Number of Participants With Overall Response (OR)(From randomization until CR and PR or CR, CRi and PR (up to approximately 42 months))
- Number of Participants With Overall Response 2 (OR2)(From randomization until, CR, PR or HI or CR, CRi or PR (up to approximately 42 months))
- Duration of Complete Remission (CR)(From CR until first documentation of PD or relapse from CR or relapse after CR or PR (up to approximately 42 months))
- Duration of Complete Remission + Complete Remission With Incomplete Blood Count Recovery (CRi)(From CR until first documentation of PD or relapse from CR or relapse after CR or PR (up to approximately 42 months))
- Duration of Overall Response (OR)(Up to approximately 42 months)
- Duration of Overall Response 2 (OR2)(Up to approximately 42 months)
- Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence(Up to approximately 42 months)
- Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence(Up to approximately 42 months)
- Time to First Complete Remission (CR) or Partial Remission (PR) or Complete Remission With Incomplete Blood Count Recovery (CRi)(From randomization until CR or PR (up to approximately 42 months))
- Number of Participants With Hematologic Improvement (HI)(From randomization until HI (up to approximately 42 months))
- Number of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML(From randomization until transformation to AML or until initiation of subsequent therapy (up to approximately 42 months))
- Time to Progressive Disease (PD), Relapse After CR (Low-blast AML), Relapse After CR or PR (HR MDS/CMML), or Death(From randomization until PD, relapse after CR, or relapse after CR or PR, or death due to any cause, whichever occurs first (up to approximately 42 months))
- Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30(Baseline, at approximately 58 months)
- Number of Participants With Overall Response in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group(From randomization until CR, CRi and PR (up to approximately 42 months))
- Event-Free Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group(From randomization until transformation to AML if eligible or death (up to approximately 42 months))
- Overall Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group(From randomization until death (up to approximately 42 months))
- Number of Participants With Overall Response by Cycle 6(Up to Cycle 6 (up to approximately Day 168))