A Randomized, Open-label, Controlled, Phase 2 Study of Pevonedistat, Venetoclax, and Azacitidine Versus Venetoclax Plus Azacitidine in Adults With Newly Diagnosed Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 164
- 试验地点
- 57
- 主要终点
- Event-Free Survival (EFS)
研究概览
简要总结
The main aim is to see how the combination of pevonedistat + venetoclax + azacitidine compares to venetoclax + azacitidine in adults recently diagnosed with AML who are unable to be treated with intensive chemotherapy.
Participants will receive either pevonedistat + venetoclax + azacitidine or venetoclax + azacitidine in 28-day treatment cycles. Bone marrow samples (biopsy) will be collected throughout the study. Pevonedistat will be given as an intravenous (IV) infusion and Azacitidine will be given through IV or subcutaneous (under the skin).
Study treatments may continue as long as the participant is receiving benefit from it. Participants may choose to stop treatment at any time.
详细描述
The drug being tested in this study is called Pevonedistat. Pevonedistat is being tested to treat people who have AML. This study will compare the improvement in EFS in Arm A: Pevonedistat + Venetoclax + Azacitidine combination arm group when compared with Arm B: Venetoclax + Azacitidine.
The study will enroll approximately 164 patients. Participants will be randomly assigned in 1:1 ratio to one of the two treatment groups in 28-day treatment cycles and which will remain disclosed to the patient and study doctor during the study:
- Pevonedistat 20 mg/m^2 + Venetoclax 400 mg (ramp-up dose, Cycle 1 only: 100-400mg) + Azacitidine 75 mg/m^2
- Venetoclax 400 mg (ramp-up dose, Cycle 1 only: 100-400 mg) + Azacitidine 75 mg/m^2
This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 3 years. 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 AML (World Health Organization [WHO] criteria 2008). Participants may have newly diagnosed primary de novo AML or secondary AML (sAML), defined as AML after myelodysplastic syndromes (MDS) or myeloproliferative neoplasm (MPN), or therapy-related AML (t-AML) following cytotoxic therapy, and/or radiotherapy for a malignant or nonmalignant disease.
- •Is unfit for treatment with a standard arabinosylcytosine (Ara-C) and anthracycline induction regimen due to age or co-morbidities defined by 1 of the following:
- •≥75 years of age. OR
- •≥18 to <75 years of age with at least one of the following:
- •Eastern Cooperative Oncology Group (ECOG) performance status of 2 or
- •Severe cardiac disorder (e.g., congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina).
- •Severe pulmonary disorder (e.g., carbon monoxide lung diffusion capacity ≤65% or forced expiratory volume in 1 second ≤65%).
- •Creatinine clearance (CrCl) <45 mL/min (but ≥30 mL/min as part of general eligibility criteria).
- •Hepatic disorder with total bilirubin >1.5 times the upper limit of the normal range (ULN).
- •Has clinical laboratory values within the following parameters (repeat within 3 days before the first dose of study drug if laboratory values used for randomization were obtained more than 3 days before the first dose of study drug):
- •Total bilirubin ≤1.5 times the ULN except in participants with Gilbert's syndrome. Participants with Gilbert's syndrome may enroll with direct bilirubin ≤3 times the ULN of the direct bilirubin. Elevated indirect bilirubin due to posttransfusion hemolysis is allowed.
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 times the ULN.
- •Creatinine clearance (CrCl) ≥30 mL/min (calculated by the Modification of Diet in Renal Disease [MDRD] Study equation).
- •Albumin >2.7 g/dL.
- •White blood cell (WBC) count <25 × 10^9/L. Participants who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria before starting therapy.
排除标准
- •Has history of MPN with BCR-ABL1 translocation or AML with BCR-ABL1 translocation.
- •Has genetic diagnosis of acute promyelocytic leukemia.
- •Is eligible for intensive chemotherapy and/or allogeneic stem cell transplantation.
- •Has extramedullary AML without evidence of bone marrow involvement.
- •Had prior treatment with hypomethylating agents for AML (hypomethylating agent treatment for prior MDS is not exclusionary).
- •Has clinical evidence of or history of central nervous system involvement by AML.
- •Had diagnosed or treated for another malignancy (except for adequately treated carcinoma in situ of any organ or nonmelanoma skin cancer) within 1 year before randomization or previously diagnosed with another malignancy and have any evidence of residual disease that may compromise the administration of pevonedistat, venetoclax or azacitidine. Prior MDS is also allowed, but the participant cannot have received treatment for MDS within 14 days before first dose of any study drug.
- •Has a WBC count ≥25 × 10^9/L
- •Has uncontrolled human immunodeficiency virus (HIV) infection. Note: Known HIV positive participants who meet the following criteria will be considered eligible:
- •Cluster difference 4 (CD4) count >350 cells/mm^
- •Undetectable viral load.
- •Maintained on modern therapeutic regimens utilizing non-cytochrome P (CYP)-interactive agents.
- •No history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections.
- •Participant is known to be positive for hepatitis B or C infection, with the exception of those with an undetectable viral load within 3 months (hepatitis B or C testing is not required for eligibility assessment).
- •Has hepatic cirrhosis.
- •Has uncontrolled coagulopathy or bleeding disorder.
- •Has high blood pressure which cannot be controlled by standard treatments.
- •Has prolonged rate QTc interval ≥500 msec, calculated according to institutional guidelines.
- •Has left ventricular ejection fraction (LVEF) <40%, based on echocardiogram or multi gated acquisition (MUGA) scan at screening (data to be available within last 3 months of screening).
- •As infection is a common feature of AML, participants with active infection are permitted to enroll provided that the infection is under control and no signs of systemic inflammatory response beyond low grade fever that makes participant clinically unstable in the opinion of the investigator. Participants with uncontrolled infection shall not be enrolled until infection is treated and brought under control.
研究组 & 干预措施
Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2
Venetoclax 100 mg tablet orally on Day 1; 200 mg on Day 2; thereafter, at 400 mg on Day 3 through Day 28 in Cycle 1 (cycle length= 28 days) and 400 mg on Days 1 through 28 in Cycle 2 and beyond if tolerated. Following the confirmation of remission in Cycle 1 or thereafter, venetoclax 400 mg was administered on Day 1 through 21 or 28 as per Investigator's discretion, plus azacitidine 75 mg/m^2 intravenous (IV) or subcutaneous (SC) dosing on Days 1 through 7 or Days 1 through 5, Days 8, and 9 in each cycle up to primary completion date: 06 September 2022.
干预措施: Venetoclax (Drug)
Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2
Venetoclax 100 mg tablet orally on Day 1; 200 mg on Day 2; thereafter, at 400 mg on Day 3 through Day 28 in Cycle 1 (cycle length= 28 days) and 400 mg on Days 1 through 28 in Cycle 2 and beyond if tolerated. Following the confirmation of remission in Cycle 1 or thereafter, venetoclax 400 mg was administered on Day 1 through 21 or 28 as per Investigator's discretion, plus azacitidine 75 mg/m^2 intravenous (IV) or subcutaneous (SC) dosing on Days 1 through 7 or Days 1 through 5, Days 8, and 9 in each cycle up to primary completion date: 06 September 2022.
干预措施: Azacitidine (Drug)
Pevonedistat 20 mg/m^2 + Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2
Pevonedistat 20 mg/m^2 as a 60-minute IV infusion on Days 1, 3, and 5 in each 28-day cycle plus venetoclax 100 mg tablet orally on Day 1; 200 mg on Day 2; thereafter, at 400 mg on Day 3 through Day 28 in Cycle 1 (cycle length= 28 days) and 400 mg on Days 1 through 28 in Cycle 2 and beyond if tolerated. Following the confirmation of remission in Cycle 1 or thereafter, venetoclax 400 mg was administered on Day 1 through 21 or 28 as per Investigator's discretion, plus azacitidine 75 mg/m^2 IV or SC dosing on Day 1 through 7 or Days 1 through 5, Days 8, and 9 in each cycle up to primary completion date: 06 September 2022.
干预措施: Pevonedistat (Drug)
Pevonedistat 20 mg/m^2 + Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2
Pevonedistat 20 mg/m^2 as a 60-minute IV infusion on Days 1, 3, and 5 in each 28-day cycle plus venetoclax 100 mg tablet orally on Day 1; 200 mg on Day 2; thereafter, at 400 mg on Day 3 through Day 28 in Cycle 1 (cycle length= 28 days) and 400 mg on Days 1 through 28 in Cycle 2 and beyond if tolerated. Following the confirmation of remission in Cycle 1 or thereafter, venetoclax 400 mg was administered on Day 1 through 21 or 28 as per Investigator's discretion, plus azacitidine 75 mg/m^2 IV or SC dosing on Day 1 through 7 or Days 1 through 5, Days 8, and 9 in each cycle up to primary completion date: 06 September 2022.
干预措施: Venetoclax (Drug)
Pevonedistat 20 mg/m^2 + Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2
Pevonedistat 20 mg/m^2 as a 60-minute IV infusion on Days 1, 3, and 5 in each 28-day cycle plus venetoclax 100 mg tablet orally on Day 1; 200 mg on Day 2; thereafter, at 400 mg on Day 3 through Day 28 in Cycle 1 (cycle length= 28 days) and 400 mg on Days 1 through 28 in Cycle 2 and beyond if tolerated. Following the confirmation of remission in Cycle 1 or thereafter, venetoclax 400 mg was administered on Day 1 through 21 or 28 as per Investigator's discretion, plus azacitidine 75 mg/m^2 IV or SC dosing on Day 1 through 7 or Days 1 through 5, Days 8, and 9 in each cycle up to primary completion date: 06 September 2022.
干预措施: Azacitidine (Drug)
结局指标
主要结局
Event-Free Survival (EFS)
时间窗: Up to 22 months
EFS was defined as time from study randomization to date of failure to achieve complete remission (CR)/CR with incomplete blood count recovery (CRi), relapse from CR/CRi, or death. Assessments of disease response based on criteria: European Leukemia Net (ELN) 2017 guidelines. CR was defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC)≥1.0×10\^9/L (1000/µL); platelet count≥100×10\^9/L (100,000/µL). CRi was defined as all CR criteria except for residual neutropenia (\<1.0×10\^9/L \[1000/µL\]) or thrombocytopenia (\<100×10\^9/L \[100,000/µL\]). For participants who achieved CR/CRi, if relapse is not observed by time of analysis, was censored at the date of last disease assessment. If failed to achieve CR/CRi, date of treatment failure was set on day of randomization.
次要结局
- Sixty-day Mortality Rate(Day 60)
- Overall Survival (OS)(Up to 36 months)
- Thirty-day Mortality Rate(Day 30)
- Percentage of Participants With Composite Complete Remission (CCR)(Up to 36 months)
- Percentage of Participants With Leukemia Response(Up to 36 months)
- Percentage of Participants With Complete Remission (CR)(Up to 36 months)
- Percentage of Participants With CR + CRh(Up to 36 months)
- Plasma Concentration of Pevonedistat(At multiple time points pre-dose and post-dose on Days 1, 3 and 5 in Cycle 1 and post-dose on Day 1 in Cycles 2 and 4 (cycle length= 28 days))
- Overall Response Rate (ORR)(Up to 36 months)
- Duration of CR and CRi(Up to 36 months)
- Time to First CR, CRi and PR(Up to 36 months)