Acute Myeloid Leukemia (AML)
Conditions
Keywords
Venetoclax treatment failure, Venetoclax resistance, Salvage therapy, Lisaftoclax, Homoharringtonine, Azacitidine, BCL-2 inhibitor, Measurable residual disease
Brief summary
Venetoclax (Ven) resistance is common in the treatment of acute myeloid leukemia (AML). Patients with Ven resistance have poor response and survival, except those with specific targeted therapy. Whether we could use new BCL-2 inhibitors to replace Ven and combine with the agents which have been shown to enhance the antilekeumia effect of BCL-2 inhibitors, to overcome Ven resistance? This is unknown up until now. This multi-center, prospective, open-label, single-arm study will evaluate the efficacy and safety of homoharringtonine combined with lisaftoclax and azacitidine (HLA) as salvage therapy for adults with AML after failure of a Ven-containing regimen. Ven treatment failure is defined as no response after at least two consecutive cycles of a Ven-containing regimen or relapse during continued, protocol-compliant Ven-based therapy after a prior response. The study plans to enroll 73 participants. The primary endpoint is the overall response rate after two treatment cycles. Secondary endpoints include complete remission (CR), CR with incomplete blood count recovery (CRi), measurable residual disease (MRD) negativity, survival and relapse, and treatment-related adverse events.
Detailed description
Venetoclax-based regimens are widely used in acute myeloid leukemia, but patients who do not respond or who relapse during continued venetoclax therapy have poor outcomes and limited low-intensity treatment options. Lisaftoclax is a selective BCL-2 inhibitor with clinical activity in myeloid malignancies, including preliminary activity in patients previously exposed to venetoclax. Prior preclinical and clinical work by the study group suggests that homoharringtonine may enhance the antileukemic activity of BCL-2 inhibitor-based therapy. Participants will receive the HLA regimen in 28-day cycles. Homoharringtonine will be administered at 1 mg/m\^2 by intravenous infusion on Days 1-7. Lisaftoclax will be administered orally at 200 mg on Day 1, 400 mg on Day 2, and 600 mg on Days 3-14. Azacitidine will be administered at 75 mg/m\^2 by subcutaneous injection on Days 1-7. When concomitant use of a strong CYP3A4 inhibitor is required, the lisaftoclax dose will be reduced to 200-400 mg/day. Response will be assessed using blood counts, bone marrow morphology, and measurable residual disease testing. Bone marrow assessment is planned around Day 14 or Day 28 of each salvage cycle. Participants who achieve complete remission, complete remission with incomplete hematologic recovery, or a morphologic leukemia-free state may proceed to allogeneic hematopoietic stem cell transplantation when feasible or receive further protocol-directed therapy. Participants with partial response or no response after the first cycle may receive a second HLA cycle. Participants with no response after reassessment following the second cycle will discontinue study treatment. The study will evaluate overall response after two cycles, additional remission outcomes, measurable residual disease negativity, overall survival, relapse-free survival, duration of response, relapse, and safety. Exploratory whole-genome sequencing, RNA sequencing, targeted next-generation sequencing, and single-cell sequencing will be used to characterize biological correlates of response and investigate mechanisms of venetoclax resistance and response to the HLA regimen.
Interventions
Lisaftoclax will be administered orally on Days 1-14 of each 28-day cycle: 200 mg on Day 1, 400 mg on Day 2, and 600 mg once daily on Days 3-14. If concomitant use of a CYP3A4 inhibitor is required, the protocol specifies a reduced lisaftoclax dose of 200-400 mg/day according to the instruction.
Homoharringtonine will be administered at 1 mg/m\^2 by intravenous infusion once daily on Days 1-7 of each 28-day cycle.
DRUGAzacitidine (AZA)
Azacitidine will be administered at 75 mg/m\^2 by subcutaneous injection once daily on Days 1-7 of each 28-day cycle.
Sponsors
Guangdong Second Provincial General Hospital
Dongguan Kanghua Hospital
Nanfang Hospital, Southern Medical University
Huizhou First Hospital
First Affiliated Hospital of Shantou University Medical College
Guangzhou First People's Hospital
Jiangmen Central Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All enrolled participants from multi-centers will receive the HLA regimen. There is no concurrent control arm.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of acute myeloid leukemia according to the World Health Organization classification. 2. Age 18 years or older. 3. Failure after venetoclax exposure, defined as either no response after at least 2 consecutive cycles of a venetoclax-containing regimen or disease relapse during continued, protocol-compliant treatment with a venetoclax-containing regimen after a prior response. 4. Creatinine clearance of at least 30 mL/min. 5. Alanine aminotransferase less than 5 times the upper limit of normal and bilirubin less than 3 times the upper limit of normal. 6. Life expectancy of at least 3 months. 7. Able to receive oral lisaftoclax. 8. Able to understand and comply with protocol procedures and willing to provide written informed consent.
Exclusion criteria
1. Acute promyelocytic leukemia. 2. Acute myeloid leukemia with central nervous system involvement. 3. Acute myeloid leukemia with FLT3, IDH1/2, or NPM1 mutations or MLL rearrangement for which could be treated with a corresponding targeted inhibitor. 4. Other clinically significant uncontrolled conditions, including but not limited to an uncontrolled or active systemic viral, bacterial, or fungal infection; chronic hepatitis B virus or hepatitis C virus infection requiring treatment; or a concurrent second malignancy requiring active treatment. 5. Known hypersensitivity to any study drug. 6. Active human immunodeficiency virus infection. 7. Pregnant or breastfeeding. 8. Any condition that, in the investigator's opinion, makes the patient unsuitable for enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate After Two Cycles of HLA Therapy | At the end of Cycle 2 (each cycle is 28 days; approximately Day 56) | The proportion of participants who achieve complete remission (CR), complete remission with incomplete hematologic recovery (CRi), partial remission (PR), or morphologic leukemia-free state (MLFS). CR is defined as bone marrow blasts \<5%, no peripheral blood blasts or extramedullary disease, neutrophils \>=1 x 10\^9/L, and platelets \>=100 x 10\^9/L. CRi is defined as meeting the CR criteria except for neutrophils \<1 x 10\^9/L and/or platelets \<100 x 10\^9/L. PR is defined as a \>60% reduction in bone marrow blasts with bone marrow blasts \<20%. MLFS is defined as bone marrow blasts \<5%, no peripheral blood blasts or extramedullary disease, without a requirement for blood-count recovery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite Complete Remission Rate | At the end of Cycle 2 (approximately Day 56) | The proportion of participants who achieve complete remission or complete remission with incomplete hematologic recovery according to the protocol-defined response criteria. |
| Complete Remission Rate | At the end of Cycle 2 (approximately Day 56) | The proportion of participants who achieve complete remission according to the protocol-defined response criteria. |
| Measurable Residual Disease Negativity Rate | At response assessment after Cycle 2 (up to approximately Day 56) | The proportion of responding participants who have a measurable residual disease-negative result according to the standard MRD criteria adopted by the study center with flow cytometry. |
| Overall Survival | From initiation of study treatment through study completion (planned follow-up of at least 12 months) | Time from initiation of study treatment to death from any cause. Participants who are alive at the analysis cutoff will be censored on the last date they are known to be alive. |
| Relapse-Free Survival | From the first documented remission through study completion (planned follow-up of at least 12 months) | Time from the first documented remission to disease relapse or progression, death from any cause, or the last disease assessment. Participants without an event will be censored at the last disease assessment. |
| Duration of Response | From the first documented CR or CRi through study completion (planned follow-up of at least 12 months) | Time from the first documented complete remission or complete remission with incomplete hematologic recovery to loss of that response. Participants without loss of response will be censored at the last valid response assessment. |
| Cumulative Incidence of Relapse | From the first documented remission through study completion (planned follow-up of at least 12 months) | The cumulative incidence of relapse after remission, with death before relapse treated as a competing event. |
| Adverse Events | From the first HLA dose through the protocol-specified 30-day safety follow-up | The number and proportion of participants with treatment-related hematologic or nonhematologic adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 |
Countries
China
Contacts
PRINCIPAL_INVESTIGATORGuopan Yu, PhD
Guangdong Second Provincial General Hospital
Outcome results
None listed