Exploratory Study of Venetoclax, Homoharringtonine, Azacitidine Plus G-CSF for Newly Diagnosed AML (VHAG)

Official title

A Prospective, Multicenter, Exploratory Study of Venetoclax, Homoharringtonine, and Azacitidine Combined With G-CSF in Elderly or Unfit Patients With Newly Diagnosed Acute Myeloid Leukemia

Overview

This study is a single-arm, prospective, multi-center exploratory clinical trial. A total of 61 patients with newly diagnosed acute myeloid leukemia (AML) who are not suitable for intensive chemotherapy will be enrolled. The Simon two-stage design will be adopted to control the type I and type II errors, with the minimum acceptable composite remission rate of 65% and a power of 80%. Prior to treatment, subjects will undergo screening within 28 days, including bone marrow aspiration, genetic testing, ECOG performance status assessment, and organ function evaluation. Data will be recorded in Excel and subject to unified quality control. During the treatment period, G-CSF (granulocyte colony-stimulating factor) will be administered subcutaneously as appropriate, and supportive care such as antiemetic and hydration therapy will be provided routinely. For patients who achieve remission, individualized consolidation therapy will be given: those eligible for transplantation will undergo allogeneic hematopoietic stem cell transplantation; those who can tolerate moderate-intensity treatment will receive consolidation with medium-dose cytarabine first, followed by 4 cycles of VHAG regimen consolidation. Patients with FLT3 mutations will receive additional targeted therapy during consolidation. Safety assessment will be conducted in accordance with the NCI-CTCAE Version 5.0. For grade 4 hematological toxicity or severe non-hematological toxicity, the treatment dose will be adjusted or the treatment will be suspended. Severe adverse events will be reported in a timely manner, and all research-related data will be retained for at least 10 years in accordance with relevant regulations.

Detailed description

According to the detailed inclusion and exclusion criteria, first-line induction therapy: VHAG regimen Venetoclax 100 mg on day 2, 200 mg on day 3, 400 mg on days 4-10; Homoharringtonine 1 mg/m² on days 1-7; Azacitidine 75 mg/m² on days 1-7; G-CSF 5 μg/kg subcutaneously starting on day 0;G-CSF to be discontinued if WBC ≥ 30 × 10⁹/L.

One cycle every 4 weeks, for a total of 2 cycles.Patients who achieve CR/CRi/MLFS/PR after the first cycle will receive one additional cycle of the same regimen for consolidation(venetoclax 400 mg on days 1-7 in the second course).

Subsequent treatment After achieving remission, re-evaluate tolerability comprehensively based on age, performance status, comorbidities, and other factors.

Patients eligible for transplantation will undergo allogeneic hematopoietic stem cell transplantation.

Transplant-ineligible patients:

Those tolerable to intensive chemotherapy may receive1-2 courses of intermediate-dose cytarabine consolidation,followed by 4 courses of VHAG consolidation.

Those intolerant to intensive chemotherapy will continue6 courses of VHAG consolidation.

Patients with FLT3 mutations in the intermediate- or high-risk groups may receive combination therapy with a FLT3 inhibitor during consolidation.

Endpoints Primary endpoint: Composite complete remission rate (CRc: CR + CRi)

Secondary endpoints:

Overall response rate (ORR: CR + CRi + MLFS + PR) Overall survival (OS) Relapse-free survival (RFS) Rate of measurable residual disease (MRD) negativity Safety Hematologic and non-hematologic toxicities (NCI CTCAE version 5.0) Exploratory biomarker evaluation

Interventions

• Drug Intervention for Venetoclax
  Oral administration of venetoclax. The starting dose is 100 mg on Day 2, 200 mg on Day 3, and 400 mg once daily from Day 4 to Day 10 of each induction cycle. Dose adjustments may be made per protocol based on tolerability and safety.
• Drug Intervention for Homoharringtonine
  Intravenous infusion of homoharringtonine at a dose of 1 mg/m² daily from Day 1 to Day 7 of each induction cycle.
• Drug Intervention for Azacitidine
  Subcutaneous or intravenous administration of azacitidine at a dose of 75 mg/m² daily from Day 1 to Day 7 of each induction cycle.
• Drug Intervention for G-CSF
  Subcutaneous administration of G-CSF at a dose of 5 μg/kg daily, initiated prior to the start of induction therapy (Day 0). Discontinuation will be per protocol when the white blood cell count (WBC) exceeds 30 × 10⁹/L.

Primary outcome measures

• CRc（CR+CRi） [Time frame: After 2 cycles of induction therapy(each cycle is 28 days; approximately Day 56)]

Secondary outcome measures (5)

• ORR（CR+CRi+MLFS+PR） [Time frame: After 2 cycles of induction therapy(each cycle is 28 days; approximately Day 56)]
• OS [Time frame: 1year]
• RFS [Time frame: 1year]
• MRD [Time frame: After 2 cycles of induction therapy(each cycle is 28 days; approximately Day 56)]
• NCICTCAEv5.0 [Time frame: After 2 cycles of induction therapy(each cycle is 28 days; approximately Day 56)]

Eligibility criteria

Inclusion criteria

• The patient has fully understood the study, voluntarily participated, and signed the informed consent form (ICF).
• Newly diagnosed acute myeloid leukemia (AML) confirmed by bone marrow morphology, immunophenotyping, cytogenetics, and/or molecular biology testing, in accordance with the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (2022 edition).
• No prior systemic therapy for AML (including induction, consolidation, or maintenance therapy).
• Patients judged unfit for standard cytarabine plus anthracycline induction chemotherapy due to age or comorbidities.
• Short-term use of hydroxyurea or low-dose cytarabine before enrollment to control hyperleukocytosis is permitted.
• Age ≥ 75 years, or age 18-74 years with any of the following comorbidities:
• ECOG performance status 2-3
• History of congestive heart failure, left ventricular ejection fraction (LVEF) ≤ 50%, or chronic stable angina
• Diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 65% predicted, or forced expiratory volume in 1 second (FEV1) ≤ 65% predicted
• Creatinine clearance 30-45 mL/min (≥ 30 and < 45)
• Moderate hepatic impairment: total bilirubin > 1.5 × ULN and ≤ 3 × ULN
• Other comorbidities deemed unfit for standard chemotherapy by the investigator
• Estimated survival time ≥ 12 weeks.
• For patients aged ≥ 75 years: ECOG performance status 0-2.
• For patients aged 18-74 years: ECOG performance status 0-3.
• Creatinine clearance ≥ 30 mL/min (calculated by the Cockcroft-Gault formula).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN).
• Total bilirubin ≤ 1.5 × ULN; may be relaxed to ≤ 3 × ULN in patients with leukemic hepatic infiltration.
• For patients < 75 years old, total bilirubin ≤ 3 × ULN.

Exclusion criteria

• Acute promyelocytic leukemia (APL).
• History of prior myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia, myelofibrosis, etc.
• Prior receipt of hypomethylating agents, venetoclax (VEN), or systemic chemotherapy for myelodysplastic syndromes (MDS).
• Prior receipt of any investigational drug or device therapy for MDS/AML.
• Concurrent participation in another clinical trial.
• AML with central nervous system (CNS) involvement confirmed by imaging or cerebrospinal fluid examination.
• Positive HIV antibody during the screening period.
• Positive HBsAg or HCV antibody with a high-sensitivity viral load above the lower limit of detection within 3 months (excluding those who are cured or with persistent low-level replication).
• Ingestion of grapefruit, grapefruit juice, Seville oranges, star fruit, or their products within 72 hours prior to the first dose.
• Chronic respiratory failure requiring long-term oxygen therapy.
• Presence of severe cardiac, hepatic, renal, endocrine, metabolic, immune, neurological, or psychiatric disorders.
• History of hypersensitivity to the study drug (including azacitidine excipients).
• Impaired drug absorption due to malabsorption syndrome, short bowel syndrome, or other conditions affecting oral drug absorption.
• Active tuberculosis or other severe infections requiring intravenous anti-infective therapy for ≥7 days.
• Presence of a second malignancy within 2 years prior to enrollment, excluding cured carcinoma in situ of the cervix or breast, completely resected basal cell carcinoma or localized squamous cell carcinoma of the skin, or localized malignancies cured by surgery and requiring no further follow-up.
• The investigator judges that the patient is otherwise ineligible to participate in this study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University — Hangzhou

Publications

• Yin Z, Gao Y, Bu X, Wang J, Yao Z, Liu Q, Zhang Y, Yu G, Ping B. Homoharringtonine sensitized resistant acute myeloid leukemia cells to venetoclax-induced apoptosis. Leuk Lymphoma. 2024 Dec;65(14):2138-2150. doi: 10.1080/10428194.2024.2400228. Epub 2024 Sep 5. PMID 39235111
• Yu G, Zhang Y, Yu S, Yin Z, Weng G, Xu N, Du X, Lin D, Xiao J, Sun Z, Zhang H, Liang X, Guo Z, Zhao W, Dai M, Fan Z, Xuan L, Liu H, Xu D, Ye J, Jiang X, Shi P, Jin H, Liu Q. Homoharringtonine Added to Venetoclax and Azacitidine Improves Outcome and Mitigates Genetic Impact in Relapsed/Refractory AML: A Multicenter Cohort Study. Clin Cancer Res. 2025 Jan 6;31(1):87-97. doi: 10.1158/1078-0432.CCR-24 PMID 39531539
• DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, Konopleva M, Dohner H, Letai A, Fenaux P, Koller E, Havelange V, Leber B, Esteve J, Wang J, Pejsa V, Hajek R, Porkka K, Illes A, Lavie D, Lemoli RM, Yamamoto K, Yoon SS, Jang JH, Yeh SP, Turgut M, Hong WJ, Zhou Y, Potluri J, Pratz KW. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020 Aug 1 PMID 32786187
• Um HD. Bcl-2 family proteins as regulators of cancer cell invasion and metastasis: a review focusing on mitochondrial respiration and reactive oxygen species. Oncotarget. 2016 Feb 2;7(5):5193-203. doi: 10.18632/oncotarget.6405. PMID 26621844
• Choi JH, Bogenberger JM, Tibes R. Targeting Apoptosis in Acute Myeloid Leukemia: Current Status and Future Directions of BCL-2 Inhibition with Venetoclax and Beyond. Target Oncol. 2020 Apr;15(2):147-162. doi: 10.1007/s11523-020-00711-3. PMID 32319019
• Dombret H, Raffoux E, Gardin C. Acute myeloid leukemia in the elderly. Semin Oncol. 2008 Aug;35(4):430-8. doi: 10.1053/j.seminoncol.2008.04.013. PMID 18692693
• Pollyea DA, Kohrt HE, Medeiros BC. Acute myeloid leukaemia in the elderly: a review. Br J Haematol. 2011 Mar;152(5):524-42. doi: 10.1111/j.1365-2141.2010.08470.x. PMID 21314823
• Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysak D, Minden M, Arthur C. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly PMID 22689805

Identifiers

NCT: NCT07507825 · 2026IIT031-1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗