DEC3-VEN vs. Venetoclax-Based vs. DA Regimens in Newly Diagnosed AML

Official title

A Prospective, Randomized Controlled Study on the Efficacy and Safety of Venetoclax Combined With 3-Day Decitabine (DEC3-VEN) Versus Venetoclax Combined With "2+6" DA Versus "3+7" DA Regimen in Adult Patients With Newly Diagnosed Acute Myeloid Leukemia

Overview

Protocol Title: A Prospective, Randomized Controlled Study of Venetoclax Plus 3-Day Decitabine (DEC3-VEN) Versus Venetoclax Plus "2+6" DA Versus "3+7" DA Regimen in Adult Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Objective: This is a prospective, open-label, randomized, multicenter, phase II trial designed to compare the efficacy and safety of three induction regimens-Venetoclax plus 3-day Decitabine (DEC3-VEN), Venetoclax plus "2+6" DA, and standard "3+7" DA-in adult patients with newly diagnosed, intensifiable AML. Study Design: The study employs a prospective, randomized, controlled, multicenter design. A total of 291 eligible patients will be enrolled across approximately 10 centers in China and randomized in a 2:2:1 ratio to the three treatment arms. Key Eligibility Criteria: Inclusion: Aged 16-65 with newly diagnosed non-APL AML (excluding favorable CBF-AML), eligible for intensive chemotherapy, ECOG ≤2, and adequate organ function. Exclusion: Prior AML treatment, secondary AML, active severe infection, significant cardiac comorbidity, or known hypersensitivity to the study drugs. Interventions: Induction: Arm A (VEN+"2+6"DA): Venetoclax (D1-8), Daunorubicin (D2-3), Cytarabine (D2-7). Arm B (DEC3-VEN): Venetoclax (D1-14), Decitabine (D4-6). FLT3/ITD+ patients add Sorafenib or Gilteritinib (D8-14). Arm C ("3+7"DA): Daunorubicin (D1-3), Cytarabine (D1-7). Consolidation (2 cycles): Arms A/B: Venetoclax + Intermediate-Dose Cytarabine. Arm C: High-Dose Cytarabine. Consolidation (Subsequent cycles): All arms receive multiple cycles of DA or HA regimens. Maintenance (6-8 cycles): Arms A/B: Venetoclax + Azacitidine. Arm C: Azacitidine. Main Outcome Measures: Primary Endpoint: Composite Complete Remission Rate (CR + CRi) after induction. Secondary Endpoints: Overall Survival (OS), CR rate, MRD-negative rate, Relapse-Free Survival (RFS), Event-Free Survival (EFS), and safety. Keywords: Acute Myeloid Leukemia, Venetoclax, Decitabine, Consolidation Therapy, Maintenance Therapy, Randomized Controlled Trial.

Detailed description

This Phase 3, open-label, randomized controlled trial employs a three-arm parallel design to evaluate the optimal integration of venetoclax into intensive chemotherapy for newly diagnosed AML. The study is designed to address the critical unmet need of balancing high remission rates with tolerability in fit adult AML patients.

Scientific Rationale for Treatment Arms:

Arm A (VEN+"2+6" DA) investigates a modified intensive regimen where daunorubicin exposure is limited to 2 days (vs. conventional 3 days) based on prior institutional data suggesting comparable efficacy with reduced cardiotoxicity. Arm B (DEC3-VEN) explores a novel combination of venetoclax with high-dose decitabine (20 mg/m² every 8 hours for 3 days), a regimen developed to enhance hypomethylating effects while limiting myelosuppression duration to approximately 2 weeks through shortened decitabine exposure. Arm C represents the standard "3+7" DA regimen as the reference arm.

Venetoclax Pharmacological Considerations:

The 100→200→400 mg dose ramp-up over 2-3 days is implemented for tumor lysis syndrome (TLS) prophylaxis, with extended dosing through Day 8 (Arm A) or Day 14 (Arm B) based on the pharmacokinetic principle of sustained BCL-2 inhibition. For FLT3-ITD positive patients in Arm B, sorafenib or gilteritinib is added from Day 8 to target dual oncogenic pathways.

Stratification and Randomization:

Randomization employs block randomization with stratification by study center to ensure balance across the 10 participating sites. The 2:2:1 allocation ratio (Arms A:B:C) prioritizes evaluation of the two experimental venetoclax-containing regimens while maintaining adequate power for the standard arm comparison.

MRD Assessment Methodology:

Measurable residual disease is evaluated by multi-parameter flow cytometry (sensitivity 10-⁴) and, where available, NGS-based sequencing to provide complementary sensitivity for treatment response characterization. MRD assessment is performed at remission confirmation and post-consolidation to evaluate depth of response.

Statistical Considerations:

The primary analysis employs a non-inferiority framework comparing the composite CR rate (CR+CRi) of each experimental arm against the standard arm, with a pre-specified non-inferiority margin of -10%. Hierarchical testing controls for multiplicity, prioritizing Arm A followed by Arm B comparisons. An interim analysis for futility is planned after 50% enrollment to preserve resources if either experimental arm shows \<50% response rate.

Interventions

• Procedure Arm A (VEN+"2+6"DA)
  Venetoclax (Days 1-8), Daunorubicin (Days 2-3), Cytarabine (Days 2-7)
• Procedure Arm B (DEC3-VEN)
  Venetoclax (Days 1-14), Decitabine (Days 4-6). FLT3/ITD-positive patients receive additional Sorafenib or Gilteritinib (Days 8-14).
• Procedure Arm C ("3+7"DA)
  Daunorubicin (Days 1-3), Cytarabine (Days 1-7)

Primary outcome measures

• Composite Complete Remission Rate after Induction Therapy [Time frame: At the end of Cycle 1 (each cycle is 28 days)]

Secondary outcome measures (5)

• Overall Survival (OS) [Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months]
• MRD-negative remission rate [Time frame: At the end of Cycle 1 (each cycle is 28 days)]
• Relapse-Free Survival (RFS) [Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months]
• Event-Free Survival (EFS) [Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months]
• safety profile [Time frame: At the end of Cycle 1 (each cycle is 28 days)]

Eligibility criteria

Inclusion criteria

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Subjects who are suitable for enrollment in this study must meet all of the following criteria:

• Except for APL or carrying t(8) that meet the diagnostic criteria (WHO2022 criteria) of the World Health Organization; 21)/(RUNX1::RUNX1TI)、inv(16)(p13.1q22) 、 t(16; 16) (p13.1q22) 、 t(16; 16)/CBFβ::myh11) and other acute myeloid leukemia other than one of the abnormal karyotypes;
• Except for acute panmyeloproliferative disease with myelofibrosis and myeloid sarcoma, the World Health Organization AML classification is AML without separate classification;
• Newly diagnosed AML patients with male or female, age greater than or equal to 16 years old and less than 65 years old, patients are considered suitable for intensive chemotherapy;
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2 at the time of enrollment;
• The patient has not received previous AML therapy (except for hydroxyurea and Ara-C<1.0g/d for reducing tumor compounds);
• Pass the following laboratory test indicators (performed within 7 days before treatment):

1\) Aspartate aminotransferase (ALT), alanine aminotransferase (AST) and alkaline phosphatase (ALP) ≤3× upper limit of normal (ULN), serum bilirubin ≤2×ULN; Serum cardiac enzymes < 2.0× ULN; Unless it is thought to be a leukemic organ involvement.

Creatinine ≥ 30 mL/min, calculated by the Cockcroft Gault formula or measured by 24-hour urine collection;

7\. Female subjects of childbearing potential must have a negative pregnancy test result within 72 hours before the start of treatment; Not planning to become pregnant during the study and within 6 months after the last dose of study drug, and negative urine or serum pregnancy test results at screening. Men must use a latex condom during any sexual contact with WOCBP, even if they have had a successful vasectomy, and must agree to avoid childbearing (during treatment and for 6 months after the last dose of study drug).

8\. Life expectancy exceeds 2 months;

9\. Informed consent must be signed before the start of all specific study procedures, and the informed consent form must be signed by the patient or his immediate family; Considering the patient's condition, if the patient's signature is not conducive to the treatment of the condition, the legal guardian or the patient's immediate family will sign the informed consent form.

Exclusion criteria

• Subjects who meet any of the following criteria are not eligible for this study:

• AML with BCR-ABL1; or CML sudden change period;
• Treated patients (refers to those who have received induction chemotherapy in the past, regardless of the efficacy);
• Subjects with acute panmyelopathy with myelofibrosis or myelosarcoma as defined by WHO 2016;
• Secondary leukemia (mainly refers to those who belong to the treatment-related AML subcategory of the World Health Organization (WHO 2016) AML classification and those with a history of pre-stage MDS and/or MPD);
• Patients with other hematological diseases (such as hemophilia, myelofibrosis, etc., who are not suitable for inclusion; Those with previous blood picture abnormalities, except for bone marrow examination, MDS and MPD are allowed to be selected);
• Pregnant or lactating patients;
• Those who are allergic to any drugs involved in this study;
• Use of strong or moderate CYP7A inducers within 3 days before the start of study treatment;
• Suffering from malignant tumors of other organs (those who need treatment);
• Obvious abnormal liver and kidney function, exceeding the enrollment criteria;
• Active cardiac disease, defined as one or more of the following:

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• Myocardial infarction less than 6 months from enrollment in the study;
• History of arrhythmias requiring medication or severe clinical symptoms;
• Uncontrolled or symptomatic congestive heart failure (> NYHA Grade 2);
• Uncontrolled or symptomatic angina;
• Left ventricular ejection fraction below the lower limit of the normal range;

12\. Patients with severe infectious diseases (uncured tuberculosis, pulmonary aspergillosis), known infection with human immunodeficiency virus (HIV) or active hepatitis B or C; Subjects with uncontrollable infection.

13\. Subjects with evidence of central nervous system leukemia before treatment;

14\. Subjects with epilepsy, dementia or other abnormal mental states that require medication and cannot understand or follow the protocol;

15\. Restriction of oral drug intake or gastrointestinal absorption;

16\. Those who are not suitable for enrollment in the opinion of the investigator;

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

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• The Second Affiliated Hospital of Kunming Medical University — Kunming

Publications

• Mantzaris I, Goldfinger M, Uriel M, Shastri A, Shah N, Gritsman K, Kornblum NS, Shapiro L, Sica RA, Munoz A, Chambers N, Dhawan A, Verceles JA, Fehn K, Tirone B, Shah L, Clark S, Zhang C, Kim M, Cooper DL, Verma A, Konopleva M, Feldman EJ. Venetoclax plus daunorubicin and cytarabine for newly diagnosed acute myeloid leukemia: results of a phase 1b study. Blood. 2025 Apr 24;145(17):1870-1875. doi: PMID 39919267
• Suo X, Fang Z, Wang D, Zhao L, Liu J, Li H, Ma X, Zhang C, Zhao X, Shi R, Wu Y, Jiao Z, Song J, Zhang L, Li L, Zhang S, Lu X, Yuan L, Gao S, Zhang J, Liu K, Zhao X, Bai G, Mi Y. Venetoclax combined with daunorubicin and cytarabine (2 + 6) in acute myeloid leukemia: Updated results of a phase II trial. Hematol Oncol. 2024 Jul;42(4):e3296. doi: 10.1002/hon.3296. No abstract available. PMID 39041653
• Mei M, Aldoss I, Marcucci G, Pullarkat V. Hypomethylating agents in combination with venetoclax for acute myeloid leukemia: Update on clinical trial data and practical considerations for use. Am J Hematol. 2019 Mar;94(3):358-362. doi: 10.1002/ajh.25369. Epub 2018 Dec 13. PMID 30499168
• Del Poeta G, Venditti A, Del Principe MI, Maurillo L, Buccisano F, Tamburini A, Cox MC, Franchi A, Bruno A, Mazzone C, Panetta P, Suppo G, Masi M, Amadori S. Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML). Blood. 2003 Mar 15;101(6):2125-31. doi: 10.1182/blood-2002-06-1714. Epub 2002 Nov 7. PMID 12424199

Identifiers

NCT: NCT07712848 · 2ndKunmingMC

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗