A Study of Pevonedistat and Venetoclax Combined With Azacitidine to Treat Acute Myeloid Leukemia (AML) in Adults Unable to Receive Intensive Chemotherapy

Takeda164 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

164

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * 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 3. * 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. Exclusion Criteria: * 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\^3. * 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.

Outcomes

Primary Outcomes

Event-Free Survival (EFS)

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.

Time frame: Up to 22 months

Secondary Outcomes

Overall Survival (OS)

OS is defined as time from randomization to death from any cause. Participants without documentation of death at the time of analysis will be censored at the date last known to be alive.

Time frame: Up to 36 months

Thirty-day Mortality Rate

Mortality rate is defined as percentage of participants who survive at most 30 days from the first dose of study drug.

Time frame: Day 30

Sixty-day Mortality Rate

Mortality rate is defined as percentage of participants who survive at most 60 days from the first dose of study drug.

Time frame: Day 60

Percentage of Participants With Complete Remission (CR)

CR rate is defined as the percentage of participants who achieve the CR as evaluated by the investigator. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CR is defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥1.0×10\^9/L (1000/µL); platelet count≥100×10\^9/L (100,000/µL).

Time frame: Up to 36 months

Percentage of Participants With Composite Complete Remission (CCR)

CCR rate is defined as the percentage of participants who achieve the CR + CRi as evaluated by the investigator. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CR is defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥1.0×10\^9/L (1000/µL); platelet count≥100×10\^9/L (100,000/µL). CRi is defined as all CR criteria except for residual neutropenia (\<1.0×10\^9/L \[1000/µL\]) or thrombocytopenia (\<100×10\^9/L \[100,000/µL\]).

Time frame: Up to 36 months

Overall Response Rate (ORR)

ORR is defined as the percentage of participants who achieve the CR + CRi + Partial Remission (PR) as evaluated by the investigator. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CR is defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥1.0×10\^9/L (1000/µL); platelet count≥100×10\^9/L (100,000/µL). CRi is defined as all CR criteria except for residual neutropenia (\<1.0×10\^9/L \[1000/µL\]) or thrombocytopenia (\<100×10\^9/L \[100,000/µL\]). PR is defined as all hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%.

Time frame: Up to 36 months

Percentage of Participants With CR + CRh

CR + CRh rate is defined as the percentage of participants who achieve the CR + CRh as evaluated by the investigator. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CR is defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥1.0×10\^9/L (1000/µL); platelet count≥100×10\^9/L (100,000/µL). CRh is defined as bone marrow with \<5% blasts, peripheral blood neutrophil count \>0.5×10\^3/µL and peripheral blood platelet count \>0.5×10\^5/µL.

Time frame: Up to 36 months

Percentage of Participants With Leukemia Response

Leukemia response rate is defined as the percentage of participants who achieve the CR + CRi + PR + morphological leukemia-free state \[MLFS, marrow CR (mCR)\]) as evaluated by the investigator. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CR is defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥ 1.0×10\^9/L (1000/µL); platelet count≥100×10\^9/L (100,000/µL). CRi is defined as all CR criteria except for residual neutropenia (\<1.0×10\^9/L \[1000/µL\]) or thrombocytopenia (\<100×10\^9/L \[100,000/µL\]). PR is defined as all hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%. MLFS is defined as bone marrow blasts \<5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required.

Time frame: Up to 36 months

Duration of CR and CRi

Duration of CR and CRi is defined as the time from first documentation of CR or CRi to the date of first documentation of PD or relapse from CR or CRi, and will be summarized descriptively using the K-M method based on the responders. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CR is defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥ 1.0×10\^9/L (1000/µL); platelet count≥100×10\^9/L (100,000/µL). CRi is defined as all CR criteria except for residual neutropenia (\<1.0×10\^9/L \[1000/µL\]) or thrombocytopenia (\<100×10\^9/L \[100,000/µL\]).

Time frame: Up to 36 months

Time to First CR, CRi and PR

Time to first CR, CRi, and PR is defined as the time from randomization until the first documented CR, CRi or PR, whichever occurs first, and will be analyzed using the K-M method. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CR is defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥ 1.0×10\^9/L (1000/µL); platelet count≥100×10\^9/L (100,000/µL). CRi is defined as all CR criteria except for residual neutropenia (\<1.0×10\^9/L \[1000/µL\]) or thrombocytopenia (\<100×10\^9/L \[100,000/µL\]). PR is defined as all hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%.

Time frame: Up to 36 months

Plasma Concentration of Pevonedistat

Time frame: 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)

A Study of Pevonedistat and Venetoclax Combined With Azacitidine to Treat Acute Myeloid Leukemia (AML) in Adults Unable to Receive Intensive Chemotherapy

Overview

Conditions

Interventions

Eligibility

Locations (57)

Outcomes

Primary Outcomes

Secondary Outcomes