A randomized phase III, global, multicentre, open label clinical trial comparing Venetoclax Azacitidine and Quizartinib vs Venetoclax and Azacitidine in newly diagnosed acute myeloid leukemia patient´s ineligible for standard induction chemotherapy.

Trial ID: 2025-522979-29-00
Protocol: VENP-A-QUI
Sponsor: Fundacion PETHEMA

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Diseases & Conditions

Acute myeloid leukaemia

Objectives

The primary objective of this study is to compare the overall survival (OS) rate between the experimental arm utilizing triple combination therapy with venetoclax, azacitidine, and quizartinib versus standard therapy consisting of venetoclax plus azacitidine in patients with newly diagnosed acute myeloid leukemia who are ineligible for standard induction chemotherapy. This comparison aims to determine whether the addition of quizartinib to the standard doublet regimen confers a survival advantage in this specific patient population.

The secondary objectives include:

• Comparison of event-free survival (EFS) rate, defined as failure to achieve complete response (CR), CR with incomplete hematologic recovery (CRi), or CR with partial hematologic recovery (CRh) after 4 cycles, death in CR/CRi/CRh, or relapse, whichever occurs first, between treatment arms.
• Evaluation of the CR/CRi/CRh (composite complete response) rate as the best response obtained during the study.
• Assessment of CR/CRi/CRh with negative measurable residual disease (MRD) by next generation sequencing (NGS) after 1, 4, and 9 cycles of therapy.
• Evaluation of safety and tolerability of both treatment arms, including comparison of overall hematologic and non-hematologic toxicity.
• Comparison of relapse-free survival (RFS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) between treatment arms.
• Subanalyses of efficacy and safety in specific molecular subgroups including FLT3-ITD, FLT3-TKD, NPM1, IDH, P53, and other mutations.
• Assessment of early mortality at 30 and 60 days post-randomization.
• Evaluation of quality of life impact using EQ5D and EORTC QLQ-C30 questionnaires.
• Assessment of medical resource utilization during treatment, including antibiotics, transfusions, hospitalization duration, and triazole use.
• Comprehensive safety monitoring including clinical laboratory parameters, vital signs, electrocardiograms, and incidence and severity of adverse events, serious adverse events, and deaths.
• Biomarker analyses to elucidate the mechanism of action of quizartinib in FLT3-ITD negative acute myeloid leukemia.

Participants

This clinical trial enrolled a total of **56 participants** diagnosed with **acute myeloid leukemia** who were previously untreated and deemed ineligible for standard intensive chemotherapy. The study population included both **male and female subjects** aged **18 years and older**, with specific focus on individuals aged **75 years or older**, as well as patients aged **18 to 75 years** presenting with significant comorbidities. Participants were selected based on their inability to tolerate standard cytarabine and anthracycline-based induction regimens due to advanced age or the presence of conditions such as reduced cardiac function, impaired pulmonary capacity, moderate renal or hepatic impairment, or **ECOG Performance Status** of 2 or 3. All enrolled subjects were required to have confirmation of acute myeloid leukemia according to 2022 WHO criteria. Male participants who were sexually active were required to use contraception for a specified period, while female subjects of childbearing potential needed to demonstrate negative pregnancy results and agree to use highly effective contraceptive methods throughout the study duration. The trial excluded vulnerable populations and required voluntary informed consent from all participants prior to enrollment.

Plans and Procedures

This is a **randomized**, **phase III**, global, **multicentre**, **open-label clinical trial** evaluating the efficacy and safety of a triple combination regimen in patients with newly diagnosed **acute myeloid leukemia** who are ineligible for standard induction chemotherapy. The trial compares an experimental arm consisting of venetoclax, azacitidine, and **quizartinib** versus a control arm of venetoclax and azacitidine. **Quizartinib dihydrochloride** is administered as a **film-coated tablet** via the **oral route**, functioning as an **antineoplastic agent** and **protein kinase inhibitor**. The maximum daily dose is 60 mg, with a maximum total dose of 80 g over a treatment period of up to 48 months.

The primary objective of the trial is to compare the **overall survival** rate between the experimental triple combination arm and the standard therapy arm. Secondary endpoints include **event-free survival**, **composite complete remission** as the best response obtained during the study, early mortality at 30 and 60 days, achievement of complete remission, complete remission with partial hematologic recovery, and complete remission with incomplete hematologic recovery with negative **measurable residual disease** by **next-generation sequencing**, response rates at specific treatment cycles, time to various response categories, **relapse-free survival**, **cumulative incidence of relapse**, **duration of response**, quality of life measurements using standardized instruments, medical resource utilization during the treatment phase, rates and duration of transfusion independence, minimal residual disease assessment, and separate analyses in specific genetic and disease subsets including secondary acute myeloid leukemia and various molecular markers.

The trial employs a randomized design to allocate participants to either the experimental or control treatment arm. Eligible participants include adults with confirmed acute myeloid leukemia according to 2022 WHO criteria who are previously untreated and deemed ineligible for standard cytarabine and anthracycline-based induction regimens due to age or comorbidities. Specific inclusion criteria encompass patients aged 75 years or older, or patients aged 18 to 75 years with at least one significant comorbidity such as **ECOG Performance Status** of 2 or 3, cardiac conditions including **congestive heart failure** requiring treatment or reduced **left ventricular ejection fraction**, pulmonary impairment, renal insufficiency with **creatinine clearance** between 30 and 50 mL/min, moderate hepatic impairment, or other comorbidities incompatible with intensive chemotherapy as determined by the investigator and approved by the Clinical Trial Coordinator. Patients younger than 60 years require review and approval by the Clinical Trial Coordinator prior to enrollment. Female participants must be postmenopausal, surgically sterile, or **women of childbearing potential** agreeing to use highly effective contraception methods, with negative pregnancy test results and commitment not to breastfeed. Male participants who are sexually active must agree to use protocol-specified contraception from study initiation through at least 120 days after the last dose of study drug. All participants must provide voluntary **informed consent** approved by an Independent Ethics Committee or Institutional Review Board prior to any study-specific procedures.

The estimated recruitment start date is March 23, 2026, with an estimated trial completion date of December 30, 2030. The maximum duration of participant involvement in the treatment phase is 48 months. The trial protocol includes screening procedures to assess eligibility, baseline assessments, randomization to treatment arms, regular follow-up visits during the treatment phase to monitor efficacy and safety parameters, and an end-of-study visit. Throughout the study, participants undergo assessments of disease response, minimal residual disease status, transfusion requirements, quality of life measures, and monitoring for adverse events. Conditions that may lead to early termination from the study include participant withdrawal of consent, disease progression, unacceptable toxicity, investigator decision based on safety concerns, loss to follow-up, or death. The open-label design means that both participants and investigators are aware of the treatment assignment, which is appropriate given the nature of the interventions being compared.

Treatment

The experimental medication utilized in this clinical trial is **Quizartinib** (sponsor product code AC220), which is formulated as a **film-coated tablet** for **oral administration**. The active substance is **quizartinib dihydrochloride**, a chemical entity classified as an **antineoplastic agent** and **protein kinase inhibitor**. The maximum daily dose is 60 mg, with a maximum total dose of 80 g administered over a maximum treatment period of 48 months. Quizartinib is administered in combination with **venetoclax** and **azacitidine** as part of the experimental treatment arm for patients with newly diagnosed **acute myeloid leukemia** who are ineligible for standard induction chemotherapy.

The comparator treatment in this randomized, open-label phase III trial consists of the standard therapy regimen combining venetoclax and azacitidine without quizartinib. This dual combination represents the current standard of care for the target patient population and serves as the control arm against which the triple combination therapy is compared. The primary objective of the trial is to evaluate overall survival rates between the experimental triple combination and the standard dual therapy regimen.

Efficacy

Efficacy will be assessed using overall survival as the primary endpoint. Secondary efficacy endpoints include event-free survival, composite complete remission as best response obtained on study, early mortality at first 30 and 60 days, complete remission, complete remission with partial hematologic recovery, and complete remission with incomplete hematologic recovery with negative measurable residual disease by next-generation sequencing. Additional secondary endpoints comprise complete remission, complete remission with partial hematologic recovery, complete remission with incomplete hematologic recovery and composite complete remission at 1, 4 and 9 cycles of treatment, time to complete remission, complete remission with partial hematologic recovery, complete remission with incomplete hematologic recovery, composite complete remission, complete remission with incomplete hematologic recovery, morphologic leukemia-free state, partial response, and progressive disease. Relapse-free survival, cumulative incidence of relapse, and duration of response will also be evaluated. Quality of life measurements will be assessed using the EuroQoL Group EQ-5D-5L and the EORTC QLQ-C30 instruments. Medical resources during treatment phase, rates of red blood cell and platelet transfusion independence, duration of red blood cell transfusion independence and platelet transfusion independence, and platelet and red blood cell transfusion independence will be monitored. Minimal residual disease by next-generation sequencing will be analyzed. Separate analyses will be conducted in secondary acute myeloid leukemia, core binding factor, FLT3-ITD, FLT3 other, NPM1, P53, IDH1/IDH2, and subsets.

Inclusion and Exclusion Criteria

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Inclusion Criteria

The subject must have confirmation of AML by 2022 WHO criteria, previously untreated and be ineligible for treatment with a standard cytarabine and anthracycline based induction regimen due to age and/or comorbidities.
Patients must be considered ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age or co-morbidities defined by the following criteria: - ≥ 75 years of age; - or ≥ 18 to 75 years of age with at least one of the following co-morbidities: • ECOG Performance Status of 2 or 3; • Cardiac history of cardiac heart failure (CHF) requiring treatment or left ventricular ejection fraction (LVEF) >45% and ≤ 55% or chronic stable angina. • DLCO ≤ 65% or FEV1 ≤ 65% and/or significant history of chronic pulmonary obstructive; • Creatinine clearance ≥ 30 mL/min to < 50 ml/min (see Appendix 7); • Moderate hepatic impairment with total bilirubin, SGPT or SGOT > 1.5 to ≤ 3.0 × ULN; • Non active/controlled prior neoplastic disease; • Any other patient´s comorbidity or disease condition that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the Clinical Trial Coordinator before study enrollment (e.g, prior neoplastic disease, high-risk cytogenetics). All patients aged less than 60 years old must be reviewed and approved by Clinical Trial Coordinator before study enrollment.
ECOG performance status ≤2 for patients >75 years, ≤3 for patients ≥ 60 to 75 years of age.
Male subjects who are sexually active, must agree, from Study Day 1 through at least 120 days after the last dose of study drug, to practice the protocol specified contraception (see Section 7.9).
Female subjects must be either postmenopausal for at least 1 year before screening OR permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) or Women of Childbearing Potential (WOCBP) must agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 7 months after the last dose of study drug (female and male condoms should not be used together), or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception). Female subjects of childbearing potential must have negative results for pregnancy test performed and must not be lactating and breastfeeding.
Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

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Exclusion Criteria

Age <18 years old at screening.
Subject has received prior treatment with hypomethylating agent, FLT3 or BCL2 inhibitors.
Confirmed diagnosis of prior myelodysplastic syndrome (MDS) or a myeloproliferative neoplasm (MPN) or MDS/MPNs including CMML, aCML, JMML and others. This exclusion criterion will not be applicable to patients with with FLT3 (allelic ratio >0.03) or NPM1 mutations (as per technical sensitivity threshold of local and/or central laboratory), who can be enrolled.
Genetic diagnosis of acute promyelocytic leukemia.
Treated (excluding surgery or hormone-therapy) for another malignancy within 6 months before randomization or previously diagnosed with another malignancy and have any evidence of disease which may compromise the administration of investigational treatment schedule.
Presence of any severe psychiatric disease or physical condition that, according to the physician´s criteria, contraindicates the inclusion of the patient into the clinical trial.
Serum creatinine ≥ 2.5 mg/dL or creatinine clearance < 30 mL/min (unless it is attributable to AML activity).
Bilirubin >1.5 times, SGPT or SGOT > 3 times the upper normal limit (unless it is attributable to AML activity).
WBC >25 x 109/L before randomization.
Contraindications for Azacitidine, Quizartinib or Venetoclax (such as history of hypersensitivity to any excipients in Azacitidine, Quizartinib, or Venetoclax).
Known central nervous system (CNS) active leukemia, including cerebrospinal fluid positive for AML blasts.
Prior treatment with any investigational drug or device within 14 days prior to Randomization (within 2 weeks for investigational or approved immunotherapy) or currently participating in other investigational interventional procedures.
Known uncontrolled or significant cardiovascular disease, including any of the following: a) Bradycardia of less than 50 beats per minute, unless the subject has a pacemaker; b) QTcF interval >450 msec in males, >470 in female patients; c) Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome); d) Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg; e) History of clinically relevant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes); f) History of second (Mobitz II) or third degree heart block (subjects with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker); g) History of uncontrolled angina pectoris or myocardial infarction within 6 months prior to Screening; h) History of New York Heart Association Class 3 or 4 heart failure; i) Known history of LVEF ≤45%; j) Complete left bundle branch block; k) Severe aortic stenosis
Prior therapy for AML (except hydroxiurea, or maximum 1 gram/sqm per 2 days of cytarabine allowed to control hyperleukocytosis during the screening period).
Subject must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade-containing Seville oranges), or star fruit within 3 days before anticipated first dose of Venetoclax and must consent not to consume through the last dose of Venetoclax.
Active acute or chronic systemic fungal, bacterial, or viral infection not well controlled by antifungal, antibacterial or antiviral therapy at physician discretion.
Known active clinically relevant liver disease (eg, active hepatitis B, or active hepatitis C)
Known history of human immunodeficiency virus (HIV).
Uncorrected Grade 3 or 4 hypokalemia, hypomagnesemia or hypocalcemia (Subjects with Grade 1 or 2 electrolyte abnormalities can be enrolled while electrolytes are being corrected).
Uncontrolled hypothyroidism.