A Study of the Effectiveness of Venetoclax in Combination With Azacitidine or Decitabine in an Outpatient Setting in Patients With Acute Myeloid Leukemia (AML) Ineligible for Intensive Chemotherapy

Study Overview
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Brief Summary
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A study evaluating the effectiveness and safety of venetoclax, in combination with azacitidine or decitabine, in an outpatient setting for treatment-naïve participants with AML who are ineligible for intensive chemotherapy.

Official Title
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A Phase 3b, Single-Arm, Multicenter Open-Label Study of Venetoclax in Combination With Azacitidine or Decitabine in an Outpatient Setting in AML Patients Ineligible for Intensive Chemotherapy

Conditions
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Acute Myeloid Leukemia (AML), Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has confirmation of acute myeloid leukemia (AML) by World Health Organization (WHO) criteria Participant is deemed by the investigator to be an appropriate candidate for outpatient ramp-up of venetoclax Participant is not eligible to receive treatment with standard cytarabine and anthracycline induction regimens Participant has not received prior treatment for AML (treatment naïve) with the exception of hydroxyurea Participant has no evidence of spontaneous tumor lysis syndrome (TLS) at Screening Participant can have progressed from myelodysplastic syndrome (MDS) or be considered to have secondary AML and could have been treated with growth factors or other agents with the exception of hypomethylating agents Participant has adequate kidney, liver, and hematology laboratory values as detailed in the protocol Has an Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 3 Exclusion Criteria: Has a history of the following conditions: Acute promyelocytic leukemia Known active central nervous system involvement with AML Positive for HIV (HIV testing is not required) Positive for hepatitis B or C infection with the exception of those with an undetectable viral load within 3 months Cardiovascular disability status of New York Heart Association Class > 2 Chronic respiratory disease that requires continuous oxygen or any other medical condition that in the opinion of the investigator would adversely affect his/her participating in this study Malabsorption syndrome or other condition that precludes enteral route of administration 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

Ages Eligible for Study
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Minimum Age: 12 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Venetoclax 400 mg + azacitidine 75 mg<br>Participants received venetoclax orally daily for 28-day cycles, for a maximum of 6 cycles, beginning on Cycle 1 Day 1. The venetoclax dosing ramp-up schedule was 100 mg on Cycle 1 Day 1, 200 mg on Cycle 1 Day 2, and 400 mg on Cycle 1 Days 3 -28 and 400 mg daily for each 28-day cycle thereafter. Azacitidine (75 mg/m^2) was administered subcutaneously or intravenously per investigator's choice and institutional practice for 7 days beginning on Day 1 of each 28-day cycle. | Drug: Venetoclax<br>* Venetoclax tablets were to be taken orally once daily with a meal and water in the morning at approximately the same time each day. Tablets were to be swallowed whole and not chewed, crushed, or broken prior to swallowing. On the days that the participant received either azacitidine or decitabine, venetoclax was dosed in clinic and administered prior to these agents.<br>* Other names: VENCLYXTO;Drug: Azacitidine<br>* The azacitidine infusion was prepared and administered per the package insert and given either subcutaneously or intravenously, per institutional practice.<br>* Other names: Vidaza;|
| Experimental: Venetoclax 400 mg + decitabine 20 mg<br>Participants received venetoclax orally daily for 28-day cycles, for a maximum of 6 cycles, beginning on Cycle 1 Day 1. The venetoclax dosing ramp-up schedule was 100 mg on Cycle 1 Day 1, 200 mg on Cycle 1 Day 2, and 400 mg on Cycle 1 Days 3 -28 and 400 mg daily for each 28-day cycle thereafter. Decitabine (20 mg/m^2) was administered intravenously per investigator's choice and institutional practice for 5 days beginning on Day 1 of each cycle. | Drug: Venetoclax<br>* Venetoclax tablets were to be taken orally once daily with a meal and water in the morning at approximately the same time each day. Tablets were to be swallowed whole and not chewed, crushed, or broken prior to swallowing. On the days that the participant received either azacitidine or decitabine, venetoclax was dosed in clinic and administered prior to these agents.<br>* Other names: VENCLYXTO;Drug: Decitabine<br>* The decitabine infusion was prepared and administered per the package insert and given intravenously, per institutional practice.<br>* Other names: Dacogen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR + CRi) | The composite complete remission rate is defined as the percentage of participants with complete remission (CR) or complete remission with incomplete blood count recovery (CRi) at any time during the study as assessed by the investigator. Response was based on bone marrow results and hematology values according to the modified International Working Group (IWG) criteria for AML: CR: Absolute neutrophil count (ANC) > 10^3/μL (1,000/μL), platelets > 10^5/μL (100,000/μL), red blood cell (RBC) transfusion independence, and bone marrow with < 5% blasts CRi: Bone marrow with < 5% blasts, and absolute neutrophils of ≤ 10^3/μL or platelets ≤ 10^5/μL | Assessed at Cycle 1 end, at Cycle 2 end if CR/CRi wasn't achieved at Cycle 1 end, or Cycle 4 end if CR/CRi wasn't achieved at Cycle 2 end. Median treatment duration of venetoclax was 16.1 wks (range 3.9-38.1) and 21.1 wks (range 2.7-40.4), respectively. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Remission (CR) | The complete remission rate is defined as the percentage of participants with complete remission (CR) at any time during the study as assessed by the investigator. Response was based on bone marrow results and hematology values according to the modified International Working Group (IWG) criteria for AML: CR: Absolute neutrophil count (ANC) > 10^3/μL (1,000/μL), platelets > 10^5/μL (100,000/μL), red blood cell (RBC) transfusion independence, and bone marrow with < 5% blasts | Assessed at Cycle 1 end, at Cycle 2 end if CR/CRi wasn't achieved at Cycle 1 end, or Cycle 4 end if CR/CRi wasn't achieved at Cycle 2 end. Median treatment duration of venetoclax was 16.1 wks (range 3.9-38.1) and 21.1 wks (range 2.7-40.4), respectively. | 
| Percentage of Participants With Complete Remission With Incomplete Blood Count Recovery (CRi) | The complete remission with incomplete blood count recovery rate is defined as the percentage of participants with complete remission with incomplete blood count recovery (CRi) at any time during the study as assessed by the investigator. Response was based on bone marrow results and hematology values according to the modified International Working Group (IWG) criteria for AML: CRi: Bone marrow with < 5% blasts, and absolute neutrophils of ≤ 10^3/μL or platelets ≤ 10^5/μL. | Assessed at Cycle 1 end, at Cycle 2 end if CR/CRi wasn't achieved at Cycle 1 end, or Cycle 4 end if CR/CRi wasn't achieved at Cycle 2 end. Median treatment duration of venetoclax was 16.1 wks (range 3.9-38.1) and 21.1 wks (range 2.7-40.4), respectively. | 
| Percentage of Participants With Post-baseline Transfusion Independence | The transfusion independence rate is defined as the percentage of participants with post-baseline transfusion independence, which is defined as a period of at least 56 days with no transfusion after the first dose of study drug and within 30 days of the last dose of study drug, death, or initiation of post-treatment therapy, whichever is earliest. | From the first dose of study drug to the last dose of study drug +30 days, or death, or initiation of post-treatment therapy, whichever occurred earliest. Median time on follow-up was 183.5 days and 195.0 days, respectively. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia (AML), Cancer, Treatment-naïve, Venetoclax, Azacitidine, Decitabine, Outpatient setting