Acute Myeloid Leukemia (AML), Elderly Patients (60-75 Years)
Conditions
Keywords
Acute Myeloid Leukemia (AML), Elderly Patients
Brief summary
This is a multicenter, open-label, randomized, controlled phase III clinical trial designed to evaluate the efficacy and safety of the combination of Venetoclax, Azacitidine, and Homoharringtonine (VAH) compared to Venetoclax and Azacitidine (VA) alone in newly diagnosed elderly patients with Acute Myeloid Leukemia (AML). A total of 308 treatment-naïve patients aged 60-75 years with AML (non-APL) will be enrolled and randomly assigned in a 1:1 ratio to either the control arm (VA) or the experimental arm (VAH). The study aims to determine if the addition of Homoharringtonine to the standard VA regimen can improve response rates. To mitigate bias in this open-label study, the primary and key secondary efficacy endpoints will be assessed by an Independent Review Committee or central laboratory blinded to treatment allocation.
Interventions
DRUGVenetoclax
Venetoclax: 100 mg orally on Day 1, 200 mg on Day 2, then 400 mg orally on Days 3-28 of a 28-day cycle (dose ramp-up recommended for newly diagnosed patients).
DRUGAzacitidine
Azacitidine: 75 mg/m² subcutaneously or intravenously on Days 1-7.
Homoharringtonine (HHT): 1 mg/m² intravenously on Days 1-7.
Sponsors
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of acute myeloid leukemia (AML), non-APL, according to the 2022 International Consensus Classification (ICC) criteria. * Age 60 to 75 years, inclusive. * Life expectancy of at least 12 weeks. * Eastern Cooperative Oncology Group (ECOG) performance status 0 to 3. * Adequate organ function unless abnormalities are considered due to leukemic organ involvement: Serum creatinine ≤ 1.5 × upper limit of normal (ULN). Oxygen saturation \> 92% on room air. Total bilirubin ≤ 3.0 × ULN. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × ULN. If laboratory abnormalities are considered due to leukemic organ involvement, total bilirubin ≤ 5.0 × ULN and ALT/AST ≤ 5.0 × ULN are permitted. * Female subjects of childbearing potential must be postmenopausal or surgically sterile. Male subjects must agree to use effective contraception or abstain from sperm donation from study start through 90 days after the last dose of study treatment. * Ability to understand and voluntarily sign an informed consent form prior to any study-related procedures.
Exclusion criteria
* Prior treatment with hypomethylating agents for myelodysplastic syndrome (MDS). Prior chemotherapy for AML, except hydroxyurea. Prior CAR-T cell therapy. * Prior investigational therapy for AML. * Documented history of myeloproliferative neoplasm (MPN). * Favorable-risk AML according to 2022 European LeukemiaNet (ELN) criteria. * Known active central nervous system (CNS) involvement of AML. * Known human immunodeficiency virus (HIV) infection. * Active hepatitis B or hepatitis C requiring antiviral therapy. Risk of hepatitis B reactivation (hepatitis B surface antigen positive or hepatitis B core antibody positive without antiviral prophylaxis). * History of another malignancy within 5 years prior to screening, except adequately treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, localized prostate cancer treated with curative intent, or ductal carcinoma in situ treated with curative intent. * Unstable systemic disease including unstable angina, cerebrovascular accident, or transient ischemic attack within 3 months prior to screening. Myocardial infarction within 3 months prior to screening. Congestive heart failure New York Heart Association class III or IV. Recent pacemaker implantation. Severe liver, kidney, or metabolic disease requiring ongoing treatment. Pulmonary arterial hypertension. Clinically significant or uncontrolled arrhythmias including persistent atrial fibrillation or flutter, symptomatic ventricular arrhythmias, QTc ≥ 470 ms in males or ≥ 480 ms in females, second- or third-degree atrioventricular block without pacemaker, or arrhythmias requiring continuous antiarrhythmic therapy. * Malabsorption syndrome or any condition preventing enteral drug administration. Active systemic infection requiring treatment. * Significant neurological or psychiatric disorders requiring treatment including epilepsy grade 2 or higher, paralysis, aphasia, recent cerebral infarction, severe traumatic brain injury, dementia, Parkinson's disease, or schizophrenia. * Fertile males or females of childbearing potential unwilling to use effective contraception during treatment and for 12 months after completion of treatment. * White blood cell count \> 25 × 10⁹/L at screening (hydroxyurea permitted to reduce count to meet eligibility).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Complete Remission Rate (CRc) | Up to approximately 12 weeks (from randomization to initiation of Cycle 4; each cycle is planned as 28 days). | The proportion of randomized participants who achieve complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), according to the 2022 ELN criteria, from randomization up to the initiation of Cycle 4. Participants who are randomized but do not undergo ELN disease assessment within this period will be considered non-responders. CR/CRi rates will be compared between treatment groups using the Cochran-Mantel-Haenszel (CMH) test, stratified by age (60-64, 65-69, 70-75 years) and study center. Two-sided 95% confidence intervals will be calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival (EFS) | up to 36 months | Time from randomization to morphological relapse, initiation of subsequent therapy (while in CR/CRi), or death |
| Overall Survival (OS) | up to 36 months | Time from randomization to death from any cause |
| CR/CRi Rate by Cycle 2 and Cycle 3 | End of Cycle 1 and end of Cycle 2 (each cycle is planned as 28 days; assessments performed prior to initiation of Cycle 2 and Cycle 3) | Proportion of patients achieving CR/CRi prior to the start of Cycle 2 and Cycle 3 |
| Complete Remission (CR) Rate | From randomization through the end of Cycle 3 (approximately 12 weeks). | The proportion of randomized participants who achieve complete remission (CR) according to the 2022 European LeukemiaNet (ELN) criteria. CR is defined as bone marrow blasts \<5%, absence of circulating blasts and extramedullary disease, absolute neutrophil count ≥1.0 ×10⁹/L, and platelet count ≥100 ×10⁹/L. Participants will be evaluated for CR from randomization through the end of Cycle 3. Participants who do not undergo disease assessment within this period will be considered non-responders for this endpoint. |
| Minimal Residual Disease (MRD) Negativity Rate | Up to 2 years after completion of treatment. | The proportion of randomized participants who achieve measurable residual disease (MRD) negativity (\<0.1%), assessed according to protocol-defined methodology. MRD assessments will be performed on Day 14 (±1 day) of Cycle 1, at the end of Cycle 1 (±3 days), at the end of each subsequent treatment cycle (±7 days), and every 3 months during follow-up after achieving CR/CRi, for up to 2 years after completion of treatment. Participants who are randomized but do not undergo MRD assessment will be considered non-responders. MRD negativity rates will be compared between treatment groups using the Cochran-Mantel-Haenszel (CMH) test, stratified by age (60-64, 65-69, 70-75 years) and study center. Two-sided 95% confidence intervals will be calculated. |
| Time to First Composite Complete Remission (CR or CRi) | From randomization until the first documented CR or CRi during study treatment (up to approximately 12 months). | Time to first composite complete remission is defined as the number of days from the date of randomization to the earliest date on which a participant achieves complete remission (CR) or complete remission with incomplete hematologic recovery (CRi). |
Countries
China
Contacts
CONTACTXianmin Song
Outcome results
None listed