Phase 3 Evaluation of Venetoclax and Azacitidine Post-Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia Patients
- Trial ID
- 2023-507222-17-00
- Protocol
- M19-063
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the recommended Phase 3 dose of **venetoclax** in combination with **azacitidine** in patients with Acute Myeloid Leukemia (AML) when administered as maintenance therapy following allogeneic stem cell transplantation (SCT). Additionally, the study aims to evaluate the efficacy of this combination in improving overall survival (OS) in AML patients compared to best supportive care (BSC) when used as maintenance therapy post-allogeneic SCT. This is clinically relevant as it seeks to optimize treatment regimens to enhance patient outcomes in a population with limited therapeutic options.
Secondary objectives include:
- Confirming the safety of venetoclax combined with azacitidine post-allogeneic SCT in AML patients.
- Determining the efficacy of the combination as measured by relapse-free survival (RFS).
- Assessing the impact on the frequency and severity of graft-versus-host disease (GvHD).
- Evaluating the effect on Quality of Life (QoL).
- Investigating the impact on minimal residual disease levels.
Participants
The clinical trial involves a total of **304 participants** diagnosed with **Acute Myeloid Leukaemia** (AML), as defined by the World Health Organization (WHO) criteria. The study population includes both male and female subjects, with an age range starting from 12 years for Part 2 and 18 years for Part 1. Participants are required to have undergone or be planning for allogeneic stem cell transplantation. The trial population was selected based on specific health criteria, including adequate renal function and specific blood count thresholds. Participants must not have a known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The study considers lifestyle factors such as the absence of supportive care like growth factors or platelet transfusions for at least 7 days prior to certain assessments. The trial includes a vulnerable population, ensuring careful monitoring and adherence to ethical standards.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the safety and efficacy of **venetoclax** in combination with **azacitidine** following allogeneic stem cell transplantation in subjects with **acute myeloid leukemia** (AML). The trial aims to determine the recommended Phase 3 dose of venetoclax in combination with azacitidine and to assess the efficacy of this combination in improving overall survival (OS) compared to best supportive care (BSC). The trial is expected to conclude by November 30, 2026, with recruitment having commenced on September 8, 2020.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, AML diagnosis, and recent stem cell transplantation. The inclusion criteria specify that participants must be adults aged 18 years or older for Part 1 and at least 12 years old for Part 2, with no active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The screening visit will ensure that participants meet the necessary hematological and renal function thresholds and have a performance status above the specified minimum.
Following the screening, participants will be randomized to receive either the venetoclax and azacitidine combination or BSC. The study will include regular follow-up visits to monitor safety, efficacy, and any adverse events. The primary endpoint for Part I is the frequency of dose-limiting toxicities (DLTs) of the combination therapy, while Part II focuses on overall survival. Secondary endpoints include relapse-free survival, graft-versus-host disease (GvHD) rates, and changes in quality of life measures.
The expected length of participant involvement will vary depending on individual response and tolerance to the treatment, with the maximum treatment period for venetoclax being 40 days and for azacitidine 30 days. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or failure to adhere to the study protocol. Participants will conclude their involvement with an end-of-study visit, where final assessments will be conducted to evaluate the overall outcomes of the treatment regimen.
Treatment
The clinical trial involves the administration of **Azacitidine**, an experimental medication formulated as a powder for suspension for injection. The active substance, azacitidine, is administered either intravenously (IV) or subcutaneously (SC). The dosage is calculated based on body surface area, with a maximum daily dose of 20 mg/m² and a total maximum dose of 600 mg/m² over a treatment period of 30 days. The medication is classified as a chemical substance and is not a pediatric formulation. Compliance with the dosing schedule is monitored throughout the trial.
In addition to azacitidine, the trial includes the administration of **Venetoclax**, a film-coated tablet taken orally. Venetoclax is provided in three different product forms, each with the same active substance and pharmaceutical form. The maximum daily dose for venetoclax is 200 mg, with a total maximum dose of 224,000 mg over a treatment period of 40 days. Venetoclax is also classified as a chemical substance and is not a pediatric formulation. The administration of venetoclax is monitored to ensure adherence to the prescribed dosing regimen.
Both azacitidine and venetoclax are used in combination as part of the study's investigational treatment regimen. The trial aims to evaluate the safety and efficacy of this combination therapy in subjects with acute myeloid leukemia (AML) following allogeneic stem cell transplantation. The study does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance with the treatment protocol is closely monitored to ensure the integrity of the trial data.
Efficacy
The efficacy of the clinical trial evaluating the combination of **Venetoclax** and **Azacitidine** in subjects with Acute Myeloid Leukemia (AML) will be assessed through a series of primary and secondary endpoints. The primary endpoint for Part I of the trial is the frequency of dose-limiting toxicities (DLTs) of Venetoclax in combination with Azacitidine. For Part II, the primary endpoint is overall survival (OS), defined as the time from randomization to death from any cause.
Secondary endpoints include several measures: IRC-assessed morphologic relapse-free survival (RFS), composite relapse-free survival, and GvHD-free, relapse-free survival (GRFS). Additionally, the GvHD rate at 90 days post-randomization or treatment initiation will be evaluated, with higher grade GvHD defined as Grade 2 or higher for acute GvHD and moderate or severe for chronic GvHD, following NIH criteria. Changes from baseline in physical functioning and fatigue at 6 months will be measured using the EORTC QLQ-C30 physical functioning domain and PROMIS Cancer Fatigue SF 7a, respectively. The measurable residual disease (MRD) conversion rate will be calculated among subjects with MRD ≥10⁻³ at baseline, defined as the proportion of subjects converting to MRD <10⁻³ after randomization or treatment initiation. Time to deterioration in Global Health Status/Quality of Life (GHS/QoL) will also be assessed, defined as the time from randomization to death or the first-time deterioration of ≥10 points from baseline in GHS/QoL score, as measured by the EORTC QLQ-C30 Version 3.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adult male or female ≥18 years old for Part 1 and, male or female at least 12 years old for Part 2.
- Subject must be diagnosed with 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 prior to pre-transplant conditioning must be < 10%. Blast count in peripheral blood must be "0" and malignant Blast percentage in bone marrow must be < 5% after transplant within 7 days prior to Cycle 1 Day 1.
- Bilirubin ≤3 × ULN* within 7 days prior to Cycle 1 Day 1. For Part 1: ANC ≥1,500/µL, measured twice at least 2 days apart (approximately 48 hours) and within 1 week prior to Cycle 1 Day 1. Subjects should not have granulocyte-colony stimulating factor (G-CSF) treatment for 7 days before first ANC count. For Part 2: ANC ≥1,000/µL, measured twice at least 2 days apart (approximately 48 hours) and within 1 week prior to Cycle 1 Day 1 or prior to dosing on Cycle 1 Day 1. Subjects should not have granulocyte- colony stimulating factor (G-CSF) treatment for 7 days before first ANC count.
- Part 1: Platelet count ≥80,000/µL measured twice at least 2 days apart (approximately 48 hours) and within 1 week prior to Cycle 1 Day 1. Subjects should not have supportive treatment (e.g., transfusions and/or growth factors) for 7 days before first platelet count. Part 2: Platelet count ≥50,000/µL measured twice at least 2 days apart (approximately 48 hours) and within 1 week prior to Cycle 1 Day 1 or prior to dosing on Cycle 1 Day 1. Subjects should not have supportive treatment (e.g., transfusions and/or growth factors) for 7 days before first platelet count.
- Adequate renal function as demonstrated by a creatinine clearance > 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24- hour urine collection.
- Subjects ≥17 years old must have a Karnofsky Performance Scale (KPS) score > 50 and Subjects 12 to 16 years old must have a Lansky Play- Performance Scale (LPPS) score > 40. Part 2: If a subject is 12 to 16 at the time of screening and turns 17 during the study, the subject will continue with the LPPS.
- Cycle 1 Day 1 administration of 1st dose of the study drug(s) must occur within 28 to 100 days after transplant. Subjects may enter into Screening upon the first instance of meeting the count recovery criteria without the need for supportive care (e.g., growth factors and/or platelet transfusions) for at least 7 days prior. Upon entering screening, subjects must maintain count thresholds on at least 2 occasions (approximately 48 hours apart) in the absence of supportive care (platelet transfusion/G-CSF within 7 days).
- If graft failure occurs during the registration period and a subsequent transplant is planned, the subject can be reconsented for the study.
- (Notes a - b): a) C1D1 must occur within 28 to 100 days of this subsequent transplant date. b) If there is a subsequent (second) graft failure after reconsent during the registration period, the subject will not be permitted to enroll into the study.
- No known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
Exclusion Criteria
- Subjects with favorable cytogenetic risk per NCCN 2016 criteria and in first complete remission prior to transplant are not eligible to enroll in this study.
- 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).
- Known infection with HIV or subjects with active hepatitis B virus (HBV) or hepatitis C virus (HCV) with high viral titers.
- Presence of clinical or laboratory symptoms/signs of extramedullary myeloid malignancy.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 08 Sept 2020 | 19 |
 France | Not Recruiting | 08 Sept 2020 | 7 |
 Germany | Not Recruiting | 08 Sept 2020 | 46 |
 Greece | Not Recruiting | 08 Sept 2020 | 16 |
 Hungary | Not Recruiting | 08 Sept 2020 | 1 |
 Italy | Not Recruiting | 08 Sept 2020 | 8 |
 Spain | Not Recruiting | 08 Sept 2020 | 23 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
AZACITIDINE | Test | — | INTRAVENOUS (IV) OR SUBCUTANEOUS (SC) | 20 | 30 | SUB05624MIG |
Venetoclax | Test | FILM-COATED TABLET | ORAL USE | 200 | 40 | PRD2186236 |
Venetoclax | Test | FILM-COATED TABLET | ORAL USE | 200 | 40 | PRD2186235 |
Venetoclax | Test | FILM-COATED TABLET | ORAL USE | 200 | 40 | PRD2186234 |