A study to compare Venetoclax Azacitidine and Quizartinib Vs Venetoclax and Azacitidine in newly diagnosed acute myeloid leukemia patient´s ineligible for standard induction chemotherapy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion PETHEMA

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

30 Apr 2026 → ongoing

Decision date (initial)

2025-12-04

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Daiichi Sankyo Europe GmbH

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To compare the OS rate between the experimental arm with triple combination of venetoclax, azacitidine and quizartinib vs. standard therapy (venetoclax plus azacitidine)

Secondary objectives 12

1. Key secondary objective: To compare the event-free survival (EFS) rate (failure to achieve CR/CRi/CRh after 4 cycles, death in CR/CRi/CRh or relapse, whichever occurs the first) between the experimental arm with triple combination and standard arm.
2. Key secondary objective: To evaluate the CR/CRi/CRh (composite complete response [CCR]) rate (best response obtained on study).
3. To evaluate the CR/CRi/CRh with negative measurable residual disease (MRD) by next generation sequencing (NGS) after 1, 4 and 9 cycles of standard therapy or experimental arm with quizartinib.
4. To assess safety and tolerability of experimental arm and standard arm.
5. To compare the overall hematologic and non-hematologic toxicity of the standard and experimental arm.
6. To compare the relapse-free survival (RFS) (time to events, death in CR/CRi/CRh or relapse, whichever occurs the first), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) between the experimental and standard arms.
7. Subanalyses on efficacy and safety in different populations (FLT3-ITD, FLT3-TKD, NPM1, IDH, P53, and other).
8. To evaluate early mortality (first 30 and 60 days since randomization).
9. To evaluate the impact on the quality of life, using the EQ5D and the EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30) forms, of standard therapy or experimental arm.
10. To evaluate the impact on the use of medical resources during treatment phase (ie, antibiotics, transfusions, duration of hospitalization, use of triazoles).
11. Safety parameters including changes in clinical laboratory measures (clinical chemistry, hematology, coagulation, urinalysis), vital signs, electrocardiograms (ECGs), the incidence and severity of adverse events (AEs), and the incidence of serious adverse events (SAEs) and deaths.
12. Biomarker plans to gain insight into the mechanism of action of quizartinib in FLT3-ITD negative AML.

Conditions and MedDRA coding

Acute myeloid leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 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.
2. 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.
3. ECOG performance status ≤2 for patients >75 years, ≤3 for patients ≥ 60 to 75 years of age.
4. 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).
5. 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.
6. 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.

Exclusion criteria 20

1. Age <18 years old at screening.
2. Subject has received prior treatment with hypomethylating agent, FLT3 or BCL2 inhibitors.
3. 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.
4. Genetic diagnosis of acute promyelocytic leukemia.
5. 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.
6. 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.
7. Serum creatinine ≥ 2.5 mg/dL or creatinine clearance < 30 mL/min (unless it is attributable to AML activity).
8. Bilirubin >1.5 times, SGPT or SGOT > 3 times the upper normal limit (unless it is attributable to AML activity).
9. WBC >25 x 109/L before randomization.
10. Contraindications for Azacitidine, Quizartinib or Venetoclax (such as history of hypersensitivity to any excipients in Azacitidine, Quizartinib, or Venetoclax).
11. Known central nervous system (CNS) active leukemia, including cerebrospinal fluid positive for AML blasts.
12. 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.
13. 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
14. Prior therapy for AML (except hydroxiurea, or maximum 1 gram/sqm per 2 days of cytarabine allowed to control hyperleukocytosis during the screening period).
15. 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.
16. Active acute or chronic systemic fungal, bacterial, or viral infection not well controlled by antifungal, antibacterial or antiviral therapy at physician discretion.
17. Known active clinically relevant liver disease (eg, active hepatitis B, or active hepatitis C)
18. Known history of human immunodeficiency virus (HIV).
19. 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).
20. Uncontrolled hypothyroidism.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall survival (OS)

Secondary endpoints 14

1. Event-free survival (EFS)
2. Composite CR (CCR) (best response obtained on study)
3. Early mortality (first 30 and 60 days)
4. CR, CRh, and CRi with negative measurable residual disease (MRD) by NGS
5. CR, CRh, CRi and CCR at 1, 4 and 9 cycles of treatment
6. Time to CR, CRh, CRi, CCRCR, CRi, MLFS, PR, PD
7. Relapse-free survival (RFS)
8. Cumulative incidence of relapse (CIR)
9. Duration of response (DoR)
10. Quality of life measurements (from the EuroQoL Group EQ-5D-5L and the EORTC QLQ-C30 instruments)
11. Medical resources during treatement phase
12. Rates of RBC and platelet transfusion independence, duration of RBC transfusion independence and platelet transfusion independence and platelet and RBC transfusion independence
13. Minimal residual disease (MRD) by NGS
14. Separate analyses in secondary AML, CBF, FLT3-ITD, FLT3 other, NPM1, P53, IDH1/IDH2, and subsets

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion PETHEMA

Sponsor organisation

Fundacion PETHEMA

Address

Oficinas 3 4 5, Calle De Santa Balbina 2 Calle De Santa Balbina 2

City

Madrid

Postcode

28023

Country

Spain

Scientific contact point

Organisation

Fundacion PETHEMA

Contact name

Alfonso Santiago

Public contact point

Organisation

Fundacion PETHEMA

Contact name

Alfonso Santiago

Third parties 1

Locations

1 EU/EEA country · 51 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications