A Study Evaluating Safety and Efficacy of Venetoclax in Combination With Azacitidine Versus Standard of Care After Allogeneic Stem Cell Transplantation (SCT) in Participants With Acute Myeloid Leukemia (AML)

Study Overview
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Brief Summary
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The main objective of this study is to evaluate the efficacy of venetoclax in combination with azacitidine to improve Overall Survival (OS) in Acute Myeloid Leukemia (AML) participants compared to Best Supportive Care (BSC) when given as maintenance therapy following allogeneic stem cell transplantation (SCT). This study will have 2 parts: Part 1 (Dose Confirmation), which may include participants who are greater than or equal to 18 years old; Part 2 (Randomization) which may include participants who are greater than or equal to 12 years old. During Part 1, recommended Phase 3 dose of venetoclax in combination with azacitidine will be determined and during Part 2, the efficacy and safety of venetoclax with azacitidine (Part 2 Arm A) will be compared with BSC (Part 2 Arm B).

Official Title
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A Randomized, Open Label Phase 3 Study Evaluating Safety and Efficacy of Venetoclax in Combination With Azacitidine After Allogeneic Stem Cell Transplantation in Subjects With Acute Myeloid Leukemia (AML) (VIALE-T)

Conditions
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Acute Myeloid Leukemia (AML), Cancer

Intervention / Treatment
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* Drug: Venetoclax
* Drug: Azacitidine
* Other: Best Supportive Care (BSC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be at least 18 years old for Part 1 and, at least 12 years old for Part 2. Participant must be diagnosed with Acute Myeloid Leukemia (AML) by World Health Organization (WHO) criteria (2017) and either be planning for allogeneic stem cell transplantation or have received allogeneic stem cell transplantation within the past 60 days. Blast percentage in bone marrow before transplant must be < 10%. Blast count in peripheral blood must be 0 and Blast percentage in bone marrow must be < 5% after transplant. Participant meet adequate renal, hepatic and hematologic criteria as described in the protocol. Participants >= 17 years old must have a Karnofsky Performance Scale (KPS) score > 50 and participants between 12 to 16 years old must have a Lansky Play Performance Scale score > 40. Exclusion Criteria: History of disease progression during prior treatment with venetoclax. History of any other malignancy within 2 years prior to study entry, except for: 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; Myelodysplastic Syndrome, Myeloproliferative neoplasm (only allowed if it transformed to AML and AML should be the indication for marrow transplantation). Participant has known infection with HIV or history of being positive for hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Presence of clinical or laboratory symptoms/signs of extramedullary myeloid malignancy.

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Venetoclax + Azacitidine (AZA) + Best Supportive Care<br>Participants will be administered various doses and dose regiments of venetoclax and AZA. Venetoclax will be administered once daily (QD) (Days 1-28) for up to 24 cycles, AZA QD on Days 1-5 of each 28-day cycle for up to 6 cycles and best supportive care (BSC) for 24 cycles (each cycle = 28 days) | Drug: Venetoclax<br>* Tablet; Oral<br>* Other names: VENCLEXTA;Drug: Azacitidine<br>* Subcutaneous (SC) or intravenous (IV) injection<br>Other: Best Supportive Care (BSC)<br>* BSC is the best supportive care, without AML directed therapy, determined per the investigator and institutional guidelines.<br>|
| Experimental: Part 2: Arm A - Venetoclax + Azacitidine (AZA) + BSC<br>Participants will be administered with venetoclax and AZA at a dose level determined in Part 1 in addition to best supportive care (when required). Venetoclax will be administered once daily (QD) (Days 1-28) for up to 24 cycles, AZA QD on Days 1-5 of each 28-day cycle for up to 6 cycles and best supportive care (BSC) for 24 cycles (each cycle = 28 days). | Drug: Venetoclax<br>* Tablet; Oral<br>* Other names: VENCLEXTA;Drug: Azacitidine<br>* Subcutaneous (SC) or intravenous (IV) injection<br>Other: Best Supportive Care (BSC)<br>* BSC is the best supportive care, without AML directed therapy, determined per the investigator and institutional guidelines.<br>|
| Experimental: Part 2: Arm B - Best Supportive Care (BSC)<br>Participants will receive treatment as prescribed by their physician according to the BSC for up to 24 cycles (1 cycle = 28 days) | Other: Best Supportive Care (BSC)<br>* BSC is the best supportive care, without AML directed therapy, determined per the investigator and institutional guidelines.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-Limiting Toxicities (DLTs) Following Administration of Venetoclax and Azacitidine (Part 1) | DLTs are any of the hematologic, nonhematologic toxicities, adverse events (AEs) occurring following administration of venetoclax and AZA as described in the protocol and evaluated by the Investigator and the sponsor. | Up to the first treatment cycle (28 days) | 
| Overall Survival (OS) (Part 2) | OS is defined as the number of days from the date of randomization to the date of death from any cause. | Up to 45 months after the first participant is randomized | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Morphologic Relapse-Free Survival (RFS) (Part 2) | Morphologic relapse from AML defined as bone marrow blasts of >= 5% or reappearance of blasts in the peripheral blood not attributable to any other cause (e.g., bone marrow regeneration) in at least 2 peripheral blood samples at least one week apart or development of extramedullary disease after achieving a complete remission (CR) or complete remission with incomplete count recovery (CRi); or the date of death from any cause, whichever comes first as determined by Independent Review Committee (IRC). | Up to 39 months after the first participant is randomized | 
| Composite Relapse-Free Survival (RFS) (Part 2) | Morphologic relapse from AML, non-morphologic relapse from AML, which is defined as increase in disease burden determined by standard methods with reappearance or acquisition of new findings with or without change in anti-leukemic treatment per investigator decision due to cytogenetic abnormalities or change in molecular marker or measurable residual disease by multiparameter flow with sensitivity to at least 10^-3; or the date of death from any cause, whichever comes first as determined by IRC. | Up to 39 months after the first participant is randomized | 
| Graft-versus-Host Disease (GvHD)-free, Relapse Free Survival (GRFS) (Part 2) | GRFS is defined as number of days from the date of randomization to occurrence of disease relapse OR incidence of GvHD OR death from any cause. | Up to 39 months after the first participant is randomized | 
| Graft-versus-Host Disease (GvHD) Rate (Part 2) | GvHD rate is defined as grade 2 or higher for acute graft-versus-host disease (aGvHD) and moderate/severe for chronic graft-versus-host disease (cGvHD) assessed by investigator. | Up to 39 months after the first participant is randomized | 
| Change from Baseline in Physical Functioning as Measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) (Part 2) | The EORTC-QLQ-C30 is a 30-item patient-reported questionnaire composed of both multi-item and single scales including 5 functional scales (physical, role, emotional, social, and cognitive), 3 symptom scales (fatigue, nausea and vomiting, and pain), a global health status/QoL scale, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Participantts rate items on a 4-point scale ranging from 1 to 4 (1 = Not at All, 2 = A Little, 3 = Quite a Bit, and 4 = Very Much). | Up to 39 months after the first participant is randomized | 
| Change From Randomization in Fatigue in Adult Participants (Part 2) | Fatigue is measured as Patient Reported Outcome (PRO) using Patient Reported Outcomes Measurement Information System (PROMIS) Cancer Fatigue SF 7a. | Up to 39 months after the first participant is randomized | 
| Measurable Residual Disease (MRD) Response Rate in Participants With MRD >= 10^-3 at Randomization (Part 2) | MRD conversion rate is defined as percentage of participants who convert to MRD < 10^-3 after initiation of treatment. | Up to 39 months after the first participant is randomized | 
| Time to Deterioration in Global Health Status (GHS)/Quality of Life (QoL) in Adult Participants (Part 2) | Time to deterioration defined as number of days from randomization to either deterioration of >= 5 points based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) version 3 or death due to any cause. | Up to 39 months after the first participant is randomized | 
| Change in Patient Reported Signs, Symptoms and Impact of Acute Myeloid Leukemia (AML) as Measured by the European Quality-of-Life-5 Dimensional-5-Level (EQ-5D-5L) | The EQ-5D-5L is a generic preference instrument that has been validated in numerous population and has 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. These dimensions are measured on a 5-point scale: with higher scores representing better functioning/quality of life and greater symptom burden. | Up to 39 months after the first participant is randomized | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia (AML), Venetoclax, Azacitidine, Stem Cell Transplantation (SCT), Best Support Care (BSC), Cancer