A Study of Venetoclax in Combination With Azacitidine Versus Azacitidine in Treatment Naïve Participants With Acute Myeloid Leukemia Who Are Ineligible for Standard Induction Therapy

Study Overview
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Brief Summary
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Acute Myeloid Leukaemia (AML) is an aggressive and rare cancer of myeloid cells (a white blood cell responsible for fighting infections). Successful treatment of AML is dependent on what subtype of AML the participant has, and the age of the participant when diagnosed. Venetoclax is an experimental drug that kills cancer cells by blocking a protein (part of a cell) that allows cancer cells to stay alive. This study is designed to see if adding venetoclax to azacitidine works better than azacitidine on its own. This is a Phase 3, randomized, double-blind (treatment is unknown to participants and doctors), placebo controlled study in patients with AML who are >= 18 or more years old and have not been treated before. Participants who take part in this study should not be suitable for standard induction therapy (usual starting treatment). AbbVie is funding this study which will take place at approximately 180 hospitals globally and enroll approximately 400 participants. In this study, 2/3 of participants will receive venetoclax every day with azacitidine and the remaining 1/3 will receive placebo (dummy) tablets with azacitidine. Participants will continue to have study visits and receive treatment for as long as they are having a clinical benefit. The effect of the treatment on AML will be checked by taking blood, bone marrow, scans, measuring side effects and by completing health questionnaires. Blood and bone marrow tests will be completed to see why some people respond better than others. Additional blood tests will be completed for genetic factors and to see how long the drug remains in the body.

Official Title
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A Randomized, Double-Blind, Placebo Controlled Phase 3 Study of Venetoclax in Combination With Azacitidine Versus Azacitidine in Treatment Naïve Subjects With Acute Myeloid Leukemia Who Are Ineligible for Standard Induction Therapy

Conditions
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Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: Azacitidine
* Drug: Venetoclax
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must have confirmation of Acute Myeloid Leukemia (AML) by World Health Organization (WHO) criteria, previously untreated and be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due age or comorbidities. Participant must be >= 18 years of age. Participant must have a projected life expectancy of at least 12 weeks. Participant must be considered ineligible for induction therapy defined by the following: a. >= 75 years of age; or b. >= 18 to 74 years of age with at least one of the following comorbidities: i. Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or 3; ii. Cardiac history of Congestive Heart Failure (CHF) requiring treatment or Ejection Fraction <= 50% or chronic stable angina; iii. Diffusing capacity of the Lung for Carbon Monoxide (DLCO) <= 65% or Forced Expiratory Volume in 1 second (FEV1) <= 65%; iv. Creatinine clearance >= 30 mL/min to < 45 ml/min; v. Moderate hepatic impairment with total bilirubin > 1.5 to <= 3.0 × Upper Limit of Normal (ULN); vi. Any other comorbidity that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the AbbVie Therapeutic Medical Director during screening and before study enrollment. Participant must have an ECOG Performance status: 0 to 2 for Participants >= 75 years of age or 0 to 3 for Participants >= 18 to 74 years of age. Participant must have adequate renal function as demonstrated by a creatinine >= 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection. Participant must have adequate liver function as demonstrated by: aspartate aminotransferase (AST) <= 3.0 x ULN* alanine aminotransferase (ALT) <= 3.0 x ULN* bilirubin <= 1.5 x ULN* * Unless considered to be due to leukemic organ involvement i. Participants who are < 75 years of age may have a bilirubin of <= 3.0 x ULN Female participants must be either postmenopausal defined as: Age > 55 years with no menses for 12 or more months without an alternative medical cause. Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause AND an follicle stimulating hormone (FSH) level >40 international units per liter (IU/L); or Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy); or Women of Childbearing Potential (WOCBP) practicing at least one protocol specified method of birth control, starting at Study Day 1 through at least 90 days after the last dose of study drug. Male participants who are sexually active, must agree, from Study Day 1 through at least 90 days after the last dose of study drug, to practice the protocol specified contraception. Male subjects must agree to refrain from sperm donation from initial study drug administration through at least 90 days after the last dose of study drug. Female participants of childbearing potential must have negative results for pregnancy test performed: At Screening with a serum sample obtained within 14 days prior to the first study drug administration, and Prior to dosing with urine sample obtained on Cycle 1 Day 1, if it has been > 7 days since obtaining the serum pregnancy test results. Participant must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures. Exclusion Criteria: Participant has received treatment with the following: A hypomethylating agent, venetoclax and/or chemo therapeutic agent for Myelodysplastic syndrome (MDS). Chimeric Antigen Receptor (CAR)-T cell therapy. Experimental therapies for MDS or Acute Myeloid Leukemia (AML). Current participation in another research or observational study. Participant has history of myeloproliferative neoplasm (MPN) including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia (CML) with or without BCR-ABL1 translocation and AML with BCR-ABL1 translocation. Participant has the following: a. Favorable risk cytogenetics such as t(8;21), inv(16) or t(16;16) or t(15;17) as per the National Comprehensive Cancer Network (NCCN) Guidelines Version 2, 2016 for Acute Myeloid Leukemia. Participant has acute promyelocytic leukemia Participant has known active central nervous system (CNS) involvement with AML. Participant has known human immunodeficiency virus (HIV) infection (due to potential drug-drug interactions between antiretroviral medications and venetoclax) HIV testing will be performed at Screening, only if required per local guidelines or institutional standards. Participant is known to be positive for hepatitis B or C infection [HCV Ab indicative of a previous or current infection; and/or positive HBs Ag or detected sensitivity on hepatitis B virus (HBV) deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) test for HBc Ab and/or HBs Ab positivity] with the exception of those with an undetectable viral load within 3 months screening. Hepatitis B or C testing is not required. Participant has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment; additional details as described in the protocol. Participant has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment. Participant has a cardiovascular disability status of New York Heart Association Class > 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain. Participant has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, any other medical condition or known hypersensitivity to any of the study medications including excipients of azacitidine that in the opinion of the investigator would adversely affect his/her participating in this study. Participant has a malabsorption syndrome or other condition that precludes enteral route of administration. Participant exhibits evidence of other clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial or fungal). Participant has a history of other malignancies within 2 years prior to study entry, with the exception of: Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast; Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent; requires discussion with TA MD. Participant has a white blood cell count > 25 × 10^9/L. (Hydroxyurea or leukapheresis are permitted to meet this criterion.)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Group 1 and Group 2: Placebo + Azacitidine 75 mg/m^2<br>Participants enrolled under original protocol and enrolled during or after protocol amendment 1 received venetoclax-matching placebo, orally, every day (QD), from Day 1 to Day 28 of each 28 day cycle along with azacitidine 75 mg/m^2, subcutaneously (SC) or intravenously (IV), QD for 7 days from Day 1 of each 28-day cycle until documented disease progression, unacceptable toxicity, withdrawal of consent, or other protocol criteria for discontinuation (whichever occurred first). | Drug: Azacitidine<br>* Solution for subcutaneous or intravenous administration.<br>Drug: Placebo<br>* Matching placebo tablet<br>|
| Active Comparator: Group 1 and Group 2: Venetoclax 100 mg/200 mg/400 mg + Azacitidine 75 mg/m^2<br>Participants enrolled under original protocol and enrolled during or after protocol amendment 1 received venetoclax 100 mg, once orally, on Day 1 of Cycle 1 followed by venetoclax 200 mg, once orally, on Day 2 of Cycle 1 and venetoclax 400 mg, orally, QD, on Day 3 to Day 28 of each 28 day cycle along with azacitidine 75 mg/m^2, SC or IV, QD for 7 days from Day 1 of each 28-day cycle until documented disease progression, unacceptable toxicity, withdrawal of consent, or other protocol criteria for discontinuation (whichever occurred first). | Drug: Azacitidine<br>* Solution for subcutaneous or intravenous administration.<br>Drug: Venetoclax<br>* Tablet<br>* Other names: ABT-199;|
| Active Comparator: Open Label China Cohort: Venetoclax 400 mg + Azacitidine 75 mg/m^2<br>Participants received venetoclax 400 mg, orally, QD, from Day 1 to Day 28 of each 28 day cycle along with azacitidine 75 mg/m^2, SC, QD for 7 days from Day 1 of each 28-day cycle until documented disease progression, unacceptable toxicity, withdrawal of consent, or other protocol criteria for discontinuation (whichever occurred first). | Drug: Azacitidine<br>* Solution for subcutaneous or intravenous administration.<br>Drug: Venetoclax<br>* Tablet<br>* Other names: ABT-199;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the number of days from the date of randomization to the date of death. Log rank test was used to compare the OS distribution between two treatment arms. Cox regression was used to report the hazard ratio. | From the study start up to death or alive or lost to follow-up (up to approximately 4.8 years; data cut off date: 1 December 2021) | 
| Percentage of Participants With Complete Remission (CR) and Complete Remission With Incomplete Marrow Recovery (CRi) | CR and CRi was calculated based on current International Working Group (IWG) criteria. CR is defined as absolute neutrophil count >10^3/ microliter (mcL), platelets >10^5/mcL, red cell transfusion independence, and bone marrow with <5% blasts. CRi is defined as bone marrow with less than 5% blasts, and absolute neutrophils of ≤10^3/mcL or platelets ≤10^5/mcL. Percentages are rounded off to whole number at the nearest decimal. | From the study start up to death (up to approximately 4.8 years; data cut-off date: 1 December 2021) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival (EFS) | EFS will be defined as the number of days from randomization to the date of progressive disease, relapse from CR or CRi, treatment failure or death from any cause. | Measured up to 2 years after the last participant is randomized | 
| Global Health Status/Quality of Life (GHS/QoL) | Improvement in GHS/QoL will be assessed using the Patient Reported Outcomes Measurement Information System (PROMIS) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30). | Measured at participant's Day 1 of Cycle 1 (each cycle is 28 days) and at Day 1 of every Cycle thereafter for up to 2 years following the last subject last visit | 
| Percentage of Participants Achieving Composite Complete Remission (CR or CRi) | This will be calculated based on current International Working Group (IWG) criteria. CR is defined as absolute neutrophil count > 10^3/mcL, platelets > 10^5/mcL, red cell transfusion independence, and bone marrow with < 5% blasts. CRi is defined as bone marrow with less than 5% blasts, and absolute neutrophils of <= 10^3/mcL or platelets <= 10^5/mcL. | Up to 6 months after the first 225 participants are randomized | 
| Complete Remission or Complete Remission With Partial Hematologic Recovery Rate (CR+CRh) | A response of CRh is defined as Bone marrow with <5% blasts, peripheral blood neutrophil count >0.5*10^3/mcL and peripheral blood platelet count >0.5*10^5/mcL. | Measured up to 2 years after the last participant is randomized | 
| Post Baseline Transfusion Independence Rate | Transfusion Independence is defined as a period of 56 days with no transfusion between first dose of study drug and the last dose of study drug + 30 days. The rate of conversion for red blood cells (RBC) and platelets is defined as percentage of participants being post-baseline transfusion independent from baseline transfusion dependence. | Measured up to 2 years after the last participant is randomized | 
| Complete Remission (CR) Rate | The percentage of participants with complete remission (CR) will be calculated based on the modified IWG criteria for AML. | Measured up to 2 years after the last participant is randomized | 
| Fatigue/Quality of Life (QoL) | Fatigue QoL will be assessed using the Patient Reported Outcomes Measurement Information System (PROMIS) Cancer Fatigue Short Form (SF) 7a global fatigue score | Measured at participant's Day 1 of Cycle 1 (each cycle is 28 days) and at Day 1 of every Cycle thereafter for up to 2 years following the last participant last visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, Venetoclax, Treatment Naïve, Azacitidine