Study to Assess Adverse Events and Change in Disease State of Oral Venetoclax in Combination With Subcutaneous (SC) Azacitidine in Newly Diagnosed Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Intensive Chemotherapy in China

Study Overview
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Brief Summary
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Acute myeloid leukemia (AML) is one of the most aggressive blood cancers, with a very low survival rate and few options for participants who are unable to undergo intensive chemotherapy, the current standard of care. This study is to evaluate how safe the combination of azacitidine and venetoclax is and how effective the combination of azacitidine and venetoclax is in adult participants with acute myeloid leukemia (AML), in China. Adverse events and change in disease state will be assessed. The combination of azacitidine and venetoclax is being evaluated in the treatment of acute myeloid leukemia (AML). Participants will receive azacitidine with increasing doses of venetoclax. Adult participants with a diagnosis of AML will be enrolled. Around 40 participants will be enrolled in the study in approximately 30 sites in China. At cycle 1 during ramp-up period, participants will receive venetoclax oral tablets once daily in increasing doses until the study dose is achieved on day 3. Then ventoclax oral tablets will continue once daily thereafter. Azacitidine will be given by subcutaneous injection (SC) for 7 days beginning on Day 1 of each 28-day cycle. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, and checking for side effects.

Official Title
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A Phase 4 Study of Venetoclax in Combination With Azacitidine in Newly Diagnosed Subjects With Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy in China

Conditions
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Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: Venetoclax
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmation of Acute myeloid leukemia (AML) diagnosis by World Health Organization (WHO) criteria, have a projected life expectancy of at least 12 weeks, previously untreated, and ineligible for treatment with intensive chemotherapy. Participant must be considered ineligible for induction therapy defined by the following: >= 75 years of age >=18 to 74 years of age with at least one of the following comorbidities: Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3. Cardiac history of congestive heart failure requiring treatment or ejection fraction <= 50% or chronic stable angina. Diffusing capacity of the lung for carbon monoxide (DLCO) <= 65% or forced expiratory volume during the first second (FEV1) <= 65%. Creatinine clearance >= 30 mL/min to < 45 mL/min. Moderate hepatic impairment with total bilirubin > 1.5 to <= 3.0 × upper limit of normal (ULN). Any other comorbidity that the physician judges to be incompatible with intensive chemotherapy. Must meet the laboratory requirements per the protocol. Must have an ECOG performance status of: 0 to 2 for subject ≥ 75 year of age; or 0 to 3 for subject ≥ 18 to 74 years of age. Female participant must not be pregnant or breastfeeding and is not considering becoming pregnant or donating eggs during the study or for approximately six months after the last dose of study drug. Female participants of childbearing potential must agree to use at least 1 protocol-specified method of birth control and male participants, if sexually active with female partner(s) of childbearing potential, must agree to practice the protocol-specified contraception. Exclusion Criteria: History of any malignancies within 2 years prior to study entry with exception noted in the protocol. Have received any investigational drug 30 days prior to the first dose of study drug. Have received strong and/or moderate CYP3A inducers within 7 days prior to initiation of study treatment. Must not have received treatment with the following: An hypomethylating agent (HMA), venetoclax, and/or any chemotherapeutic agent for myelodysplastic syndrome (MDS). Prior therapy or experimental therapies for MDS or Acute myeloid leukemia (AML). Current participation in another research or observational study. Myeloproliferative neoplasm including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia with or without BCR-ABL1 translocation, and AML with BCR-ABL1 translocation. Participant has acute promyelocytic leukemia. Participant has known active central nervous system (CNS) involvement with AML. Participant has a history of malabsorption syndrome or other condition that precludes enteral route of administration. Participant has known 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. Active hepatitis B virus (HBV) and/or hepatitis C virus (HCV) with high viral titers. Participants with HBV inactive carrier status and/or HCV with low viral titers on antivirals (non-exclusionary medications) are eligible. 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 chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or 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 exhibits evidence of other clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial or fungal).

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Venetoclax in Combination with Azacitidine<br>Participants will receive oral tablet venetoclax dose ramp-up only in Cycle 1 Days 1-3 until target dose is reached. Particpants will then receive oral tablet venetoclax at the target dose every day (QD) on Cycle Days 1 - 28 plus Azacitidine through subcutaneous injection (SC) QD on Cycle Days 1 - 7 (28-day cycle). | Drug: Venetoclax<br>* Tablet: Oral<br>* Other names: Venclexta;Drug: Azacitidine<br>* Subcutaneous Injection (SC)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. Treatment-emergent events (TEAEs) are defined as any event that began or worsened in severity after the first dose of study drug. The investigator assesses the relationship of each event to the use of study. | Up to Approximately 19 Months | 
| Number of Laboratory Abnormalities from Clinical Laboratory Values (Hematology and Chemistry) | Number of Laboratory abnormalities from clinical laboratory values (hematology and chemistry). | Up to Approximately 19 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Composite Complete Remission (CR [Complete Remission] + CRi [Complete Remission with Incomplete Blood Count Recovery]) Based on the Modified International Working Group (IWG) Criteria for Acute Myeloid Leukemia (AML) | CR + CRi is defined as achieving a CR or CRi at any time point during the study prior to the start of post-treatment anti-AML therapies per the modified IWG criteria for AML. CR is defined as absolute neutrophil count (ANC) > 10^3/μL, platelets > 10^5/μL, red cell transfusion independence, and bone marrow with < 5% blasts. Absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRi is defined as all of the criteria for CR except for residual neutropenia <= 10^3/μL (1000/μL) or thrombocytopenia <= 10^5/μL (100,000/μL). Red blood cell (RBC) transfusion dependence is also defined as CRi. | Up to Approximately 19 Months | 
| Percentage of Participants with CR based on the modified IWG criteria for AML | CR is defined as absolute neutrophil count (ANC) > 10^3/μL, platelets > 10^5/μL, red cell transfusion independence, and bone marrow with < 5% blasts. Absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. | Up to Approximately 19 Months | 

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