Homoharringtonine, Lisaftoclax, and Azacitidine for AML After Venetoclax-Based Therapy Failure

NCT07813390 | Enrolling By Invitation Phase 2

• 1 other identifier: HLA-AML-VENFAIL-2026
• Study Type: interventional
• Target: 73
• Locations: 1 country
• Sites: 1

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.

Conditions

Acute Myeloid Leukemia (AML)

Keywords

Venetoclax treatment failure; Venetoclax resistance; Salvage therapy; Lisaftoclax; Homoharringtonine; Azacitidine; BCL-2 inhibitor; Measurable residual disease

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate After Two Cycles of HLA Therapy

  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.

  At the end of Cycle 2 (each cycle is 28 days; approximately Day 56)

Secondary Outcomes (8)

• Composite Complete Remission Rate

  At the end of Cycle 2 (approximately Day 56)

• Complete Remission Rate

  At the end of Cycle 2 (approximately Day 56)

• Measurable Residual Disease Negativity Rate

  At response assessment after Cycle 2 (up to approximately Day 56)

• Overall Survival

  From initiation of study treatment through study completion (planned follow-up of at least 12 months)

• Relapse-Free Survival

  From the first documented remission through study completion (planned follow-up of at least 12 months)

Study Arms (1)

HLA Regimen

EXPERIMENTAL

Participants will receive homoharringtonine, lisaftoclax, and azacitidine in 28-day salvage-treatment cycles. One or two cycles will be administered according to treatment response and eligibility for allogeneic hematopoietic stem cell transplantation, as described in the protocol.

Drug: Lisaftoclax (APG-2575); Drug: homoharringtonine; Drug: Azacitidine (AZA)

Interventions

Lisaftoclax (APG-2575) DRUG

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.

HLA Regimen

homoharringtonine DRUG

Homoharringtonine will be administered at 1 mg/m\^2 by intravenous infusion once daily on Days 1-7 of each 28-day cycle.

HLA Regimen

Azacitidine (AZA) DRUG

Azacitidine will be administered at 75 mg/m\^2 by subcutaneous injection once daily on Days 1-7 of each 28-day cycle.

HLA Regimen

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of acute myeloid leukemia according to the World Health Organization classification.
• Age 18 years or older.
• 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.
• Creatinine clearance of at least 30 mL/min.
• Alanine aminotransferase less than 5 times the upper limit of normal and bilirubin less than 3 times the upper limit of normal.
• Life expectancy of at least 3 months.
• Able to receive oral lisaftoclax.
• Able to understand and comply with protocol procedures and willing to provide written informed consent.

You may not qualify if:

• Acute promyelocytic leukemia.
• Acute myeloid leukemia with central nervous system involvement.
• Acute myeloid leukemia with FLT3, IDH1/2, or NPM1 mutations or MLL rearrangement for which could be treated with a corresponding targeted inhibitor.
• 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.
• Known hypersensitivity to any study drug.
• Active human immunodeficiency virus infection.
• Pregnant or breastfeeding.
• Any condition that, in the investigator's opinion, makes the patient unsuitable for enrollment.

Sponsors & Collaborators

• Guangdong Second Provincial General Hospital: lead
• Dongguan Kanghua Hospital: collaborator
• Nanfang Hospital, Southern Medical University: collaborator
• Huizhou First Hospital: collaborator
• First Affiliated Hospital of Shantou University Medical College: collaborator
• Guangzhou First People's Hospital: collaborator
• Jiangmen Central Hospital: collaborator

Study Sites (1)

Guangdong Second Provincial General Hospital

Guangzhou, Guangdong, 510317, China

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Neoplasm, Residual

Interventions

Lisaftoclax; Homoharringtonine; Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Harringtonines; Alkaloids; Heterocyclic Compounds; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 4 or More Rings; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Guopan Yu, PhD

  Guangdong Second Provincial General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: All enrolled participants from multi-centers will receive the HLA regimen. There is no concurrent control arm.

Study Record Dates

• First Submitted: September 4, 2026
• First Posted: September 10, 2026
• Study Start: September 1, 2026
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): August 31, 2028
• Last Updated: September 10, 2026

Record last verified: 2026-09

Locations

CN (1)