Acute Myeloid Leukemia (AML)
Conditions
Brief summary
This prospective, open-label, multicenter phase Ib trial will evaluate the safety, tolerability, and RP2D of the VAM regimen (liposomal mitoxantrone + azacitidine \[AZA\] + venetoclax \[VEN\]) in elderly or unfit patients with newly diagnosed AML. A standard 3+3 dose escalation will enroll 12-30 patients, testing liposomal mitoxantrone at 8, 12, 16, and 20 mg/m². VEN duration (9 vs. 14 days) will be determined at the 8 mg/m² dose level, after which only liposomal mitoxantrone will be escalated while AZA and VEN will remain fixed. Induction therapy will consist of up to two 28-day cycles. Responders achieving CR/CRi/MLFS will be eligible for up to 4 consolidation cycles (total ≤6 cycles), after which they will proceed to maintenance with either AZA+VEN or observation.
Interventions
Liposome Mitoxantrone: 8, 12, 16, and 20 mg/m², administered by intravenous drip (ivgtt) on day 1, every 4 weeks
DRUGVenetoclax
Venetoclax(9 days): 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-9, administered orally (po), every 4 weeks Venetoclax(14 days): 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-14, administered orally (po), every 4 weeks
DRUGAzacitidine
Azacitidine: 75 mg/m², administered subcutaneously (sc) on days 1-7, every 4 weeks
Sponsors
Institute of Hematology & Blood Diseases Hospital, China
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Subjects eligible for enrollment in this study must meet all of the following criteria: 1. Diagnosis of acute myeloid leukemia (AML) according to the WHO 2022 or ICC criteria, excluding acute promyelocytic leukemia (APL). 2. No prior therapy for AML, except hydroxyurea for the management of hyperleukocytosis. 3. Meeting at least one of the following criteria: 1. Age ≥ 75 years; 2. Age 18-74 years with at least one of the following conditions precluding suitability for intensive chemotherapy: i. ECOG performance status 2-3; ii. Cardiac dysfunction with left ventricular ejection fraction (LVEF) ≤ 50%; iii. Pulmonary dysfunction with diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 65% or forced expiratory volume in 1 second (FEV1) ≤ 65%; iv. Creatinine clearance 30-45 mL/min; v. Other major organ dysfunction or comorbidities that, in the investigator's judgment, render the patient unsuitable for intensive chemotherapy. 4. ECOG performance status 0-3. 5. Life expectancy ≥ 3 months. 6. Patients of childbearing potential agree to use effective contraception during the treatment period and for at least 6 months after the last dose of study treatment. 7. Voluntary written informed consent provided.
Exclusion criteria
* Subjects who meet any of the following criteria will not be eligible for enrollment in this study: 1. Acute promyelocytic leukemia (APL).. 2. Active central nervous system (CNS) leukemia. 3. Prior targeted therapy or chemotherapy for AML, excluding hydroxyurea. 4. Uncontrolled active infection. 5. Uncontrolled cardiovascular disease: New York Heart Association (NYHA) class III-IV heart failure, myocardial infarction or unstable angina within 6 months before enrollment, or uncontrolled hypertension. 6. Left ventricular ejection fraction (LVEF) \< 40%. 7. Concurrent active malignancy, except for cured non-melanoma skin cancer, carcinoma in situ of the cervix, or localized prostate cancer. 8. Known hypersensitivity to the study drugs or their excipients. 9. Pregnant or breastfeeding women. 10. Any other condition that, in the investigator's judgment, would make the patient unsuitable for study participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-Limiting Toxicity (DLT) | Cycle 1(up to 42 days) | To evaluate the safety, tolerability, and RP2D of the VAM regimen in newly diagnosed elderly/unfit AML patients. |
| Incidence of treatment-related adverse events | From day 1 of treatment to 28 days after the last dose | The safety of the drug was evaluated by NCI-CTC AE 5.0 standard which including hematologic and non-hematologic toxicity |
| Composite complete remission (CRc) rate | Up to approximately eight weeks | Proportion of patients with complete remission (CR), complete remission with incomplete hematologic recovery (CRi) or morphologic leukemia-free state (MLFS) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete remission (CR) rate | Up to approximately eight weeks | Proportion of patients with complete remission (CR) |
| Complete remission with incomplete hematologic recovery (CRi) rate | Up to approximately eight weeks | Proportion of patients with complete remission with incomplete hematologic recovery (CRi) |
| Morphologic leukemia-free state (MLFS) rate | Up to approximately eight weeks | Proportion of patients with morphologic leukemia-free state (MLFS) |
| Event-free survival (EFS) | Up to approximately 5 years | It is defined as the time from the start of study treatment to the occurrence of induction failure or disease progression or death from any cause (whichever occurs first) |
| Overall survival (OS) | Up to approximately 5 years | It is defined as the time from the start of study treatment to the death from any cause |
| Relapse-free Survival (RFS) | Up to approximately 5 years | It is defined as the time from the start of achieving remission to disease progression, death from any cause or the last follow-up |
| Duration of Response (DoR) | Up to approximately 5 years | It is defined as the time from the first documentation of CRc to relapse |
| 30-day postinduction mortality | Up to approximately 30 days | It is defined as death from any cause within 30 days after the start of induction |
| 60-day postinduction mortality | Up to approximately 60 days | t is defined as death from any cause within 60 days after the start of induction |
| Measurable Residual Disease (MRD) negative rate by flow cytometry | Up to approximately eight weeks | Among those who have achieved CR/CRh/CRi after induction, proportion of patients who is MRD-negative by flow cytometry |
| Measurable Residual Disease (MRD) negative rate by molecular testing | Up to approximately eight weeks | Among those who have achieved CR/CRh/CRi after induction, proportion of patients who is MRD-negative by molecular testing |
Outcome results
None listed