Phase II Evaluation of Azacitidine and Low-Dose Venetoclax in Acute Myeloid Leukemia with Multi-Omics and Ex Vivo Drug Screening Integration
- Trial ID
- 2023-510415-19-00
- Sponsor
- Region Hovedstaden
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase II study is to evaluate the **efficacy** of azacitidine in combination with low dose venetoclax in patients with **Acute Myeloid Leukemia** (AML). The efficacy will be measured by the overall response rate (ORR), which includes complete remission (CR), complete remission with partial hematologic recovery (CRh), complete remission with incomplete hematologic recovery (CRi), and morphologic leukemia-free state (MLFS) rate, as well as the composite CR/CRh/CRi rate and partial remission (PR) rate. This is clinically relevant as it aims to determine the potential of this combination therapy to improve treatment outcomes in AML, a condition with limited effective treatment options.
Secondary objectives include:
- Assessing overall survival (OS), duration of response (DOR), and progression-free survival (PFS) in patients with AML, which are critical endpoints for understanding the long-term benefits and durability of the treatment.
- Evaluating the safety of azacitidine in combination with low dose venetoclax, which is essential for determining the risk-benefit profile of the treatment regimen.
Participants
The clinical trial involves participants diagnosed with **Acute Myeloid Leukemia** (AML). The study population includes both male and female subjects, with an age range spanning from 18 to over 75 years. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 for those aged 75 and above, or ≤ 3 for those aged 18 to 74. The trial does not include a vulnerable population. Participants must have adequate renal and liver function, as indicated by specific laboratory criteria. The trial population was selected based on their diagnosis of AML, with specific inclusion criteria for refractory, elderly/unfit, and relapsed AML patients. These criteria include failure to achieve remission after previous therapies, being unfit for standard induction therapy, or having relapsed after prior treatments. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the trial data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **azacitidine** in combination with low-dose **venetoclax** in patients diagnosed with **Acute Myeloid Leukemia** (AML). This is a Phase II, randomized, double-blind, controlled study. The trial aims to assess the overall response rate (ORR), including complete remission (CR), complete remission with partial hematologic recovery (CRh), complete remission with incomplete hematologic recovery (CRi), and morphologic leukemia-free state (MLFS) rates. The study is expected to run until June 2026, with recruitment having commenced in January 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as written informed consent and adequate organ function. The trial includes multiple follow-up visits to monitor treatment response and safety, with assessments of overall survival, duration of response, and progression-free survival. The end-of-study visit will conclude the participant's involvement, summarizing the treatment outcomes and any adverse events experienced.
The expected duration of participant involvement is up to 24 months, corresponding to the maximum treatment period for both **azacitidine** and **venetoclax**. Participants may be subject to early termination from the study if they experience severe adverse events, fail to comply with study protocols, or withdraw consent. The trial's methodology ensures rigorous monitoring and data collection to support the primary and secondary endpoints, contributing to the understanding of the therapeutic potential of the drug combination in AML treatment.
Treatment
The clinical trial involves the administration of **azacitidine**, a chemical compound with the ATC code L01BC07. Azacitidine is provided in a pharmaceutical form identified as PHF00243MIG and is administered via **subcutaneous injection**. The dosage is set at a maximum of 75 mg/m² per day, with the treatment period extending up to 24 weeks. The administration schedule is designed to ensure consistent dosing, and participant compliance is monitored throughout the trial to maintain the integrity of the study data.
In conjunction with azacitidine, the trial also utilizes **venetoclax**, a chemical substance with the ATC code L01XX52. Venetoclax is administered orally in a pharmaceutical form denoted as PHF00082MIG. The maximum daily dose for venetoclax is 400 mg, and similar to azacitidine, the treatment period is capped at 24 weeks. The oral administration of venetoclax is structured to align with the study's dosing schedule, and adherence to the regimen is closely monitored to ensure accurate assessment of the treatment's efficacy.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are employed in this study. The trial's primary objective is to evaluate the efficacy of the combination of azacitidine and venetoclax in patients with **acute myeloid leukemia** (AML), focusing on overall response rates, including complete remission and partial remission rates. The study is designed to integrate explorative multi-omics and ex vivo drug screening data to enhance the understanding of treatment outcomes.
Efficacy
The efficacy of the combination therapy of **azacitidine** and low-dose **venetoclax** in patients with acute myeloid leukemia (AML) will be assessed using several primary and secondary endpoints. The primary endpoint is the overall response rate (ORR), which includes complete remission (CR), complete remission with partial hematologic recovery (CRh), complete remission with incomplete hematologic recovery (CRi), and morphologic leukemia-free state (MLFS) rates. Additionally, the composite rates of CR/CRh/CRi and partial remission (PR) will be evaluated.
Secondary endpoints include overall survival (OS), duration of response (DOR), and progression-free survival (PFS). The frequency and severity of adverse events will also be monitored, focusing on hematologic toxicities of grade 3 or 4, febrile neutropenia, and the time until recovery of neutrophils to ≥ 0.5 x 10^9/L and platelets to ≥ 50 x 10^9/L. Severe adverse events of grade 3 or 4 will be documented.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written informed consent.
- Patients who present with one of the following (except acute promyelocytic leukemia) a. De novo or secondary AML unfit for standard induction therapy (see inclusion criterion 8). b. Relapsed/refractory AML1 (2022 ELN response criteria) after 1-3 lines of prior therapy (see inclusion criterion 9).
- Written informed consent to participate in an exploratory research protocol including biobanking, comprehensive AML profiling (genomics, transcriptomics, proteomics, etc.) and ex vivo drug sensitivity testing to assess venetoclax and other drug sensitivities. (Not applicable for patients enrolled in Sweden).a. All patients are treated with azacytidine + venetoclax irrespective of the ex vivo screening results.
- ECOG Performance Status ≤ 2 for patients ≥ 75 years of age OR ≤ 3 for patients ≥ 18 to 74 years of age
- Leukocyte count < 25 x10E9/l. Hydroxyurea use is permitted to meet this criterion.
- Adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined by the Cockcroft Gault formula.
- Adequate liver function as demonstrated by a. alanine aminotransferase (ALT) ≤ 4.0 × ULN. b. bilirubin ≤ 1.5 × ULN.
- Specific inclusion criteria for elderly/unfit AML patients: a. ≥ 70 years of age OR b. ≥ 18 to 69 years of age and ineligible for intensive chemotherapy meeting at least one of the following criteria: Clinically significant comorbidities, as reflected by at least 1 of the following criteria: o Left ventricular ejection fraction (LVEF) < 50%. o Lung diffusion capacity for carbon monoxide (DLCO) ≤ 65% of expected. o Forced expiratory volume in 1 second (FEV1) ≤ 65% of expected. o Chronic stable angina or congestive heart failure controlled with medication. o Alanine aminotransferase (ALT) 3.0-4.0 × ULN. Other contraindication(s) to anthracycline therapy (must be documented). Adverse risk genetics (2022 ELN risk classification criteria) associated with poor outcome with standard chemotherapy. Patient declines intensive chemotherapy. Secondary AML after previous disease modifying treatment (i.e., HMA/induction chemotherapy and/or allogeneic stem cell transplantation) of clonal myeloid diseases such as MDS, MDS/MPN, or MPN.
- Specific inclusion criteria for relapsed AML patients: a. ≥ 55 years of age with non-CBF AML relapse OR b. ≥ 18 of age and meeting at least one of the following criteria: Not candidate for intensive chemotherapy (see criterion 8). Relapse after chemotherapy, or monotherapy with HMA, or allogeneic stem cell transplantation (note: patients with 4th or higher relapse are excluded). Patient declines intensive chemotherapy.
- Specific inclusion criteria for refractory AML patients: Patients who fail to achieve a complete or partial remission after previous monotherapy with HMA or induction chemotherapy (at least 1 cycle of chemotherapy containing cytarabine or clofarabine, in combination with a topoisomerase II inhibitor (e.g., anthracycline or mitoxantrone).
Exclusion Criteria
- Acute promyelocytic leukemia (APL).
- Patients with 4th or higher AML relapse.
- Blast percentage in peripheral blood < 10% (only applicable for patients in whom DSRT during screening is performed on blood).
- ECOG Performance Status >3 (see also inclusion criteria 4).
- Prior venetoclax treatment for myeloid malignancy.
- AML patients with CNS involvement (note: cerebrospinal fluid or radiological investigations are not required without clinical suspicion).
- HIV infection or active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection that is not controlled with antiviral medication with the definition hereof at the discretion of the investigator.
- 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 palpitations, fatigue, dyspnea, or anginal pain.
- Evidence of clinically significant condition(s), which at the investigator's discretion would adversely affect the patient’s participation in this study (including but not limited to): a. Chronic respiratory disease that requires continuous oxygen use. b. Systemic uncontrolled infection requiring therapy (viral, bacterial or fungal). c. Malabsorption syndrome or other condition that precludes enteral route of administration. d. Uncontrolled GVHD.
- Previous non-myeloid malignancies with the exception of previous malignancy treated successfully with curative intent or indolent/smoldering malignancies (defined at the investigator's discretion).
- Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment).
- Fertile men or women of childbearing potential unless: a. Surgically sterile or ≥ 2 years after the onset of menopause. Willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 3months after the end of study treatment.
- Known hypersensitivity to venetoclax or azacitidine or excipients of any of the drugs.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Recruiting | 06 Jan 2022 | 70 |
 Finland | Recruiting | 06 Jan 2022 | 25 |
 Norway | Recruiting | 06 Jan 2022 | 26 |
 Sweden | Recruiting | 06 Jan 2022 | 26 |
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 | Other | PHF00243MIG | SUBCUTANEOUS INJECTION | 75 | 24 | SCP184620 |
VENETOCLAX | Test | PHF00082MIG | ORAL | 400 | 24 | SCP16272936 |
Inaqovi 35 mg/100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 35 | 24 | PRD10840060 |