Leukemia, Myeloid, AcutePhase 1/2NCT04687761

Clinical Trial to Assess the Safety and Tolerability of the Combination of Low-dose Cytarabine or Azacitidine Plus Venetoclax and Quizartinib in Newly Diagnosed AML Patients Aged Equal or More Than 60 Years Old

A Phase 1/2 study testing Azacitidine, Venetoclax and Quizartinib in people with Leukemia, Myeloid, Acute and De Novo, run by PETHEMA Foundation at 15 sites in Spain.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 60 years and older
Conditions the study is for: Leukemia, Myeloid, Acute, De Novo, Age More 60yr
What is being tested?: Azacitidine, Venetoclax and Quizartinib
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 113 participants
Where: 15 sitesSpain
Study dates: 4 Nov 2020to 30 May 2025
Phase: Phase 1/2
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 60 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Newly diagnosed AML.
Morphological diagnosis of AML (WHO criteria 2008).
Patient must be considered be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age or co-morbidities defined by the following criteria: 3.1. ≥ 71 years of age; 3.2. ≥ 60 to 70 years of age with at least one of the following co-morbidities:
ECOG Performance Status of 2 or 3;
Cardiac history of CHF requiring treatment or Ejection Fraction ≤ 55% or chronic stable angina;
DLCO ≤ 65% or FEV1 ≤ 65% or significant history of chronic pulmonary obstructive;

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Creatinine clearance ≥ 30 mL/min to < 50 ml/min
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 Trial Coordinators before study enrollment (e.g, prior MDS or MPS, high-risk cytogenetics)
ECOG performance status ≤ 3.
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 0).
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 4 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) 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.

Who cannot join

Age <60 years.
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, SGPT or SGOT > 3 times the upper normal limit (unless it is attributable to AML activity).

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WBC> 50 x 109/L. Subject should have white blood cell count <50 × 109/L before starting therapy. Patients who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria before starting therapy.
Contraindications for Quizartinib or Venetoclax.
History of known CNS leukemia, including cerebrospinal fluid positive for AML blasts.
Prior treatment with any investigational drug or device within 30 days prior to Randomization (within 2 weeks for investigational or approved immunotherapy) or currently participating in other investigational procedures
Prior treatment with other FLT3-ITD or BCL-2 inhibitors.
Known uncontrolled or significant cardiovascular disease, including any of the following:
Bradycardia of less than 50 beats per minute, unless the subject has a pacemaker;
QTcF interval >450 msec;
Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome);
Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg;
History of clinically relevant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes);
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);
History of uncontrolled angina pectoris or myocardial infarction within 6 months prior to Screening;
History of New York Heart Association Class 3 or 4 heart failure;
Known history of left ventricular ejection fraction (LVEF) ≤45% or less than the institutional lower limit of normal;
Complete left bundle branch block;
Prior therapy for AML (except hydroxiurea).
Subject enrolling into a dose-escalation cohort must not have received a known strong or moderate inducer or inhibitor of cytochrome P450 (CYP) 3A within 7 days before the first Quizartinib or Venetoclax dose. Subject enrolling into a safety expansion cohort must not have received a known strong or moderate inducer or strong inhibitor of CYP3A within 7 days before the first Quizartinib or Venetoclax dose.
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).
History of hypersensitivity to any excipients in the Quizartinib, Venetoclax or other study medication.
Non mutated FLT3-ITD subjects will be considered ineligible during the randomized Phase II after 48 non mutated FLT3-ITD subjects have been randomized.

Trial locations and contacts

15 sites in 1 country.

City, postcode or hospital

15 sites in 1 country

Spain15 sites

Hospital Universitario Príncipe de Asturias
Alcalá de Henares
Hospital Clínic
Barcelona
Hospital San Pedro de Alcántara
Cáceres
Hospital Universitario de Jerez de La Frontera
Jerez de la Frontera
Hospital de León (Complejo Asistencial Universitario de León)
León
Hospital Universitari Arnau de Vilanova de Lleida
Lleida
Hospital Universitario Infanta Leonor
Madrid
Hospital Universitario La Zarzuela
Madrid
Hospital Universitario Puerta de Hierro Majadahonda
Majadahonda
Hospital de Sant Joan de Deu (Manresa)
Manresa
Hospital Clinico Universitario Virgen de La Arrixaca
Murcia
Hospital Universitari Son Espases
Palma de Mallorca
Hospital Universitario Marques de Valdecilla
Santander
Hospital Universitari Mutua de Terrassa
Terrassa
Hospital Universitario y Politécnico La Fe
Valencia

Other trials in Spain

About this study

Official title: A Phase I-II, Multicentre, Open Label Clinical Trial to Assess the Safety and Tolerability of the Combination of Low-dose Cytarabine or Azacitidine, Plus Venetoclax and Quizartinib in Newly Diagnosed Acute Myeloid Leukemia Patients Aged Equal or More Than 60 Years Old Ineligible for Standard Induction Chemotherapy

A phase I-II trial based on the combination of three drugs regimen LDAC or Azacitidine + Venetoclax + Quizartinib that in this population could be well tolerated by a sequential type administration. The first objective is to achieve rapid control of the disease, using two different schemes, one based in Azacitidine and the other in LDAC, by dose escalation in phase I of the trial. The second goal is to prevent relapse through a maintenance schedule. Phase II will study the efficacy and safety of the recommended dose for Phase II

Read the detailed description

The prognosis of AML in elderly patients remain very poor and without significant advances in last decades. AML is a heterogeneous disease in which many altered molecular pathways could contribute to the disease. Thus, curative approaches have been based on highly eradicating regimens using high-dose chemotherapy. However, the low rate of CRs and the high rate of deaths due to toxicity and relapses in elderly patients should stimulate the development of new regimens that overcome these therapeutic obstacles. In recent years, there are a series of new drugs under development that allow the design of sequential combination therapies in this vulnerable population. These drugs have an acceptable toxicity profile and are apparently effective in monotherapy or even in combination, being able to improve the CR rate in this population. The investigators hypothesize that the combination of two targeted drugs that have different mechanisms of action could be capable of breaking the viability of leukemic cells as well as their proliferative qualities, and therefore prolong survival. In this way, the combined action of a pro-apoptotic agent (Venetoclax) and an antiproliferative agent (Quizartinib) could produce a powerful antileukemic effect, preventing the adaptive escape mechanisms of leukemic cells. The investigators have designed a phase I-II trial based on the combination of three drugs regimen LDAC or Azacitidine + Venetoclax + Quizartinib that in this population could be well tolerated by a sequential type administration. The first objective is to achieve rapid control of the disease, using two different schemes, one based in Azacitidine and the other in LDAC, by dose escalation in phase I of the trial. The second goal is to prevent relapse through a maintenance schedule. Phase II will study the efficacy and safety of the recommended dose for Phase II.

Conditions: Leukemia, Myeloid, Acute, De Novo, Age More 60yr
Being tested: Azacitidine, Venetoclax, Quizartinib, Cytarabine
Keywords: Acute myeloid Leukaemia, Newly Diagnosed
Medical subject headings: Leukemia, Myeloid, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

AzacitidineDrug
AZA 75 mg/m2/daily SC days 1 to 7 or on a 5-on/2-off [weekend]/2-on schedule in 28-day cycle
VenetoclaxDrug
Venetoclax (ramp-up) 400 mg/daily oral days 1 to 28
QuizartinibDrug
Quizartinib 40 mg/daily oral, days, 8 to 28
CytarabineDrug
Low-dose subcutaneous cytarabine (LDAC) 20 mg/m2/daily SC, days 1 to 10
VenetoclaxDrug
Venetoclax (ramp-up) 600 mg/daily oral, days 1 to 28
QuizartinibDrug
Quizartinib 40 mg/daily oral, days 8 to 28

Study groups in NCT04687761
Study group	Role	What they receive
AZA-Based	Experimental	Azacitidine 75 mg/m2/daily SC on a 5-on/2-off [weekend]/2-on schedule in 28-day cycle plus Venetoclax (ramp-up) 400 mg/daily oral, days 1 to 28 plus Quizartinib phase I/RP2D mg/daily oral, days 8 to 14-28. If 1 DLT is observed among these 3 patients, additional 3 subjects will receive the level 2 dose, and it will be recommended in the absence of DLT between them. If >1 DLT occurs in these 6 level 2 patients, the dose administered in the level 1 will be the RP2D of the AZA-based schedule. AZA and Venetoclax doses will remain the same in all levels and only the dose of Quizartinib will be modificated according to the following table: Escalation-Quizartinib dose-Quizartinib duration; Level-2 -30 mg/daily-Days 8 to 14; Level-1 -30 mg/daily-Days 8 to 21; Level1-40 mg/daily Days 8 to 28; Level2-60 mg/daily-Days 8 to 28. In phase II, patients randomized to this arm, will receive the recommended phase 2 dose (RP2D) regimen of AZA + Venetoclax + Quizartinib regimen (30 patients). Receives: Drug: Azacitidine; Drug: Venetoclax; Drug: Quizartinib
LDAC-Based	Experimental	Low-dose subcutaneous cytarabine 20 mg/m2/daily SC, days 1 to 10 plus Venetoclax (ramp-up) 600 mg/daily oral, days 1 to 28 plus Quizartinib phase I/RP2D mg/daily oral, days 8 to 14-28. If 1 DLT is observed among these 3 patients, additional 3 subjects will receive the level 2 dose, and it will be recommended in the absence of DLT between them. If >1 DLT occurs in these 6 level 2 patients, the dose administered in the level 1 will be the RP2D of the LDAC-based schedule. LDAC and Venetoclax doses will remain the same in all levels and only the dose of Quizartinib will be modificated according to the following table: Escalation-Quizartinib dose-Quizartinib duration; Level-2 -30 mg/daily-Days 8 to 14; Level-1 -30 mg/daily-Days 8 to 21; Level1-40 mg/daily-Days 8 to 28; Level2-60 mg/daily-Days 8 to 28. In phase II, patients randomized to this arm, will receive the recommended phase 2 dose (RP2D) regimen of LDAC + Venetoclax + Quizartinib regimen (30 patients). Receives: Drug: Cytarabine; Drug: Venetoclax; Drug: Quizartinib

What is being measured

The primary outcome is the main question the study is designed to answer.

Phase I: Recommended phase 2 dose (RP2D)
Recommended phase 2 dose (RP2D) of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules
Measured: Approximately 6 months after first patient first visit (FPFV)
Phase II: CR/Cri rate of AZA based and LDAC based
CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.
Patients will receive 4 consecutive cycles of treatment (approximately every 28 days). After the first 4 cycles, depending on the response and tolerance to treatment, the patient will continue receiving treatment in maintenance cycles until one of these situations occurs: disease progression, lack of clinical benefit, hematological relapse, unacceptable toxicity.
Measured: Aproximatey 3 years after FPFV

Secondary outcomes (23)

CR/CRi rate
To evaluate the CR/CRi rate after 1 and 4 cycles of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.
Measured: After cycle 1 and after cycle 4, being each cycle of 28 days
Overall survival (OS)
Overall survival will be defined as the number of days from the start of treatment to the date of death. Subjects that have not died will be censored at the last known date to be alive. To estimate 1, 2 and 3 years event-free, disease-free, and relapse-free survival, as well as on the cumulative incidence of relapse.
Measured: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
Overall hematologic and non-hematologic toxicity
To evaluate the safety and tolerability of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules (overall hematologic and non-hematologic toxicity).
Measured: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
Event-free survival (EFS)
EFS will be defined as the time from enrollment until the date of progressive disease, relapse from CR or CRi, failure to achieve CR or CRi at 6 months after initiation of treatment, or death from any cause. If a specified event does not occur, subjects will be censored at the date of last disease follow-up. Data for subjects without any disease assessments performed after enrollment will be censored at the date of enrollment.
Measured: 1, 2 and 3 years.
Disease-free survival (DFS)
DFS will be defined as the time from achieving CR or CRi until the date of relapse or death from any cause, whichever occurs first.
Measured: 1, 2 and 3 years.
Relapse-free survival (RFS)
RFS will be defined as the time from achieving CR or CRi until the date of relapse.
Measured: 1, 2 and 3 years.
Cumulative incidence of relapse
Estimation of cumulative incidence of relapse
Measured: 1, 2 and 3 years.
Impact on the quality of life assessed by EuroQoL Group EQ-5D-5L
The impact on the quality of life will be assessed using the EuroQoL Group EQ-5D-5L instrument.
Measured: At the screening, after cycle 2, after cycle 6, and after cycle 12, being each cycle of 28 days; and through study completion, an average of 48 months.
Impact on the quality of life assessed by EORTC QLQ-C30
The impact on the quality of life will be assessed using the EORTC QLQ-C30 instrument.
Measured: at the screening, after 6 cycles, after 12 cycles since start of therapy, being each cycle of 28 days; and through study completion, an average of 48 months
Use of medical resources during treatment phase
To evaluate the impact on the use of medical resources during treatment phase (ie, antibiotics, transfusions, duration of hospitalization, need of central venous line, use of strong or moderate CYP3A inhibitors and moderate CYP3A inducers).
Measured: At the end of treatment phase: after cycle 4, being each cycle of 28 days.
Quality of CR
To evaluate the quality of CR (by study of minimal residual disease percentages in the bone marrow (BM) using multiparametric flow cytometry [MPFC] and NGS-MRD).
Measured: After cycle 1, cycle 4 and then every 3 cycles during the first 2 years after start of the therapy (each cycle of 28 days).
CRh rate
To evaluate the CRh rate in AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.
Measured: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
Early mortality
To evaluate early mortality rate in AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.
Measured: First 30 and 60 days
CR/Cri rate of AZA based and LDAC based, in secondary AML subset
CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.
Measured: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
CR/Cri rate of AZA based and LDAC based, in CBF subset
CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.
Measured: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
CR/Cri rate of AZA based and LDAC based, in FLT3-ITD subset
CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.
Measured: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
CR/Cri rate of AZA based and LDAC based, in NPM1 subset
CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.
Measured: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
CR/Cri rate of AZA based and LDAC based, in P53 subset
CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.
Measured: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
CR/Cri rate of AZA based and LDAC based, in IDH1/IDH2 subset
CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.
Measured: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
MRD negativity rate in the BM
To evaluate the MRD negativity rate in the BM using MPFC and NGS-MRD, as part of analysis of biomarkers.
Measured: After cycle 1, cycle 4 and then every 3 cycles, being each cycle of 28 days.
MRD negativity rate in PB
To evaluate the MRD negativity rate in PB using NGS-MRD, as part of analysis of biomarkers.
Measured: After cycle 1, cycle 4 and then every 3 cycles, being each cycle of 28 days.
Natural Killer (NK) cell phenotypes and functions (immune recovery) analysis.
Natural Killer (NK) substudy to analyse NK cell phenotypes and functions, as part of biomarker analysis.
Measured: At screening and after first and fourth cycles of treatment, being each cycle of 28 days.
Baseline and relapse molecular characterization by NGS.
Baseline and relapse molecular characterization by next generation sequencing (NGS), as part of biomarker analysis.
Measured: At baseline and at through study completion due to relapse/resistance, an average of 48 months.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

4 Nov 202030 May 2025

First posted29 Dec 2020
Study start4 Nov 2020
Primary completion30 Nov 2024
Study completion30 May 2025

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (23)Papers the sponsor has linked to this study.
Other trials for Leukemia, Myeloid, AcuteStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Model description: Phase 1: Study treatment will start at level 1 and therapeutic level will be escalated or descalated depending on the apparition of DLT. DLT will be monitored during cycle 1 and it is defined as any grade 3-4 related extrahematological toxicity or grade 4 neutropenia not recovered on day 56 since C1D1 not attributable to persistent leukemia. Phase I will consist of two parallel dose escalation cohorts, with consecutive assignment to each group (first patient will be assigned to AZA-based schedule, second to LDAC-based, third to AZA-based, etc). Phase II includes two treatment arm groups (AZA-based RP2D vs. LDAC-based RP2D). Patients will be enrolled at diagnosis, within a maximum 28 days screening period, will be assessed for eligibility and therefore randomized to follow the assigned treatment arm (open label design). All screening activities will be performed after patient's informed consent form is signed. Patients will start the assigned regimen 48h maximum after randomization.
Masking: None (open label)
Enrolment: 113 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04687761
Sponsor's protocol ID: VEN-A-QUI
Status last verified: May 2026
First submitted: 17 Nov 2020
Last updated: 13 May 2026
Results posted: No
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No

Publications

Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Lowenberg B, Bloomfield CD. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017 Jan 26;129(4):424-447. doi: 10.1182/blood-2016-08-733196. Epub 2016 Nov 28.
PubMed 27895058
Juliusson G, Antunovic P, Derolf A, Lehmann S, Mollgard L, Stockelberg D, Tidefelt U, Wahlin A, Hoglund M. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood. 2009 Apr 30;113(18):4179-87. doi: 10.1182/blood-2008-07-172007. Epub 2008 Nov 13.
PubMed 19008455
Menzin J, Lang K, Earle CC, Kerney D, Mallick R. The outcomes and costs of acute myeloid leukemia among the elderly. Arch Intern Med. 2002 Jul 22;162(14):1597-603. doi: 10.1001/archinte.162.14.1597.
PubMed 12123403
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010 Feb 1;28(4):562-9. doi: 10.1200/JCO.2009.23.8329. Epub 2009 Dec 21.
PubMed 20026804
Burnett AK, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK, Wheatley K. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007 Mar 15;109(6):1114-24. doi: 10.1002/cncr.22496.
PubMed 17315155
Cortes JE, Kantarjian H, Foran JM, Ghirdaladze D, Zodelava M, Borthakur G, Gammon G, Trone D, Armstrong RC, James J, Levis M. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013 Oct 10;31(29):3681-7. doi: 10.1200/JCO.2013.48.8783. Epub 2013 Sep 3.
PubMed 24002496
Martinelli G, Perl AE, Dombret H, et al. Effect of quizartinib (AC220) on response rates and long-term survival in elderly patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia. J Clin Oncol. 2013;31 (suppl): abstr 7021
Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, Deng X, Zhai D, Shi YX, Sneed T, Verhaegen M, Soengas M, Ruvolo VR, McQueen T, Schober WD, Watt JC, Jiffar T, Ling X, Marini FC, Harris D, Dietrich M, Estrov Z, McCubrey J, May WS, Reed JC, Andreeff M. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006 Nov;10(5):375-88. doi: 10.1016/j.ccr.2006.10.006.
PubMed 17097560
Tsao T, Shi Y, Kornblau S, Lu H, Konoplev S, Antony A, Ruvolo V, Qiu YH, Zhang N, Coombes KR, Andreeff M, Kojima K, Konopleva M. Concomitant inhibition of DNA methyltransferase and BCL-2 protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells. Ann Hematol. 2012 Dec;91(12):1861-70. doi: 10.1007/s00277-012-1537-8. Epub 2012 Aug 15.
PubMed 22893484
Nakayama K, Nakayama K, Negishi I, Kuida K, Sawa H, Loh DY. Targeted disruption of Bcl-2 alpha beta in mice: occurrence of gray hair, polycystic kidney disease, and lymphocytopenia. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3700-4. doi: 10.1073/pnas.91.9.3700.
PubMed 8170972
Yamamura K, Kamada S, Ito S, Nakagawa K, Ichihashi M, Tsujimoto Y. Accelerated disappearance of melanocytes in bcl-2-deficient mice. Cancer Res. 1996 Aug 1;56(15):3546-50.
PubMed 8758925
Lees JA, Weinberg RA. Tossing monkey wrenches into the clock: new ways of treating cancer. Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4221-3. doi: 10.1073/pnas.96.8.4221. No abstract available.
PubMed 10200241
Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006 Apr 10;24(11):1770-83. doi: 10.1200/JCO.2005.03.7689.
PubMed 16603719
Schwartz GK, Shah MA. Targeting the cell cycle: a new approach to cancer therapy. J Clin Oncol. 2005 Dec 20;23(36):9408-21. doi: 10.1200/JCO.2005.01.5594.
PubMed 16361640
Chen YN, Sharma SK, Ramsey TM, Jiang L, Martin MS, Baker K, Adams PD, Bair KW, Kaelin WG Jr. Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists. Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4325-9. doi: 10.1073/pnas.96.8.4325.
PubMed 10200261

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Questions to ask the study team

What is the study trying to find out?
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Could I receive a placebo instead of the treatment?
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Study at a glance

From the registry record, last updated by the sponsor on 13 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase I-II, Multicentre, Open Label Clinical Trial to Assess the Safety and Tolerability of the Combination of Low-dose Cytarabine or Azacitidine, Plus Venetoclax and Quizartinib in Newly Diagnosed Acute Myeloid Leukemia Patients Aged Equal or More Than 60 Years Old Ineligible for Standard Induction Chemotherapy
ClinicalTrials.gov ID: NCT04687761
Acronym / sponsor ID: VEN-A-QUI
Conditions: Leukemia, Myeloid, Acute, De Novo, Age More 60yr
Keywords: Acute myeloid Leukaemia, Newly Diagnosed
Phase: Phase 1/2
Study type: Interventional
Recruitment status: Completed
Enrolment: 113 participants (actual)
Lead sponsor: PETHEMA FoundationUniversity, hospital or other
Study start: 4 Nov 2020 (actual)
Primary completion: 30 Nov 2024 (actual)
Study completion: 30 May 2025 (actual)
First posted: 29 Dec 2020 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 2
Model description: Phase 1: Study treatment will start at level 1 and therapeutic level will be escalated or descalated depending on the apparition of DLT. DLT will be monitored during cycle 1 and it is defined as any grade 3-4 related extrahematological toxicity or grade 4 neutropenia not recovered on day 56 since C1D1 not attributable to persistent leukemia. Phase I will consist of two parallel dose escalation cohorts, with consecutive assignment to each group (first patient will be assigned to AZA-based schedule, second to LDAC-based, third to AZA-based, etc). Phase II includes two treatment arm groups (AZA-based RP2D vs. LDAC-based RP2D). Patients will be enrolled at diagnosis, within a maximum 28 days screening period, will be assessed for eligibility and therefore randomized to follow the assigned treatment arm (open label design). All screening activities will be performed after patient's informed consent form is signed. Patients will start the assigned regimen 48h maximum after randomization.

Arm	Type	Receives
AZA-Based	Experimental	Drug: Azacitidine, Drug: Venetoclax, Drug: QuizartinibAzacitidine 75 mg/m2/daily SC on a 5-on/2-off [weekend]/2-on schedule in 28-day cycle plus Venetoclax (ramp-up) 400 mg/daily oral, days 1 to 28 plus Quizartinib phase I/RP2D mg/daily oral, days 8 to 14-28. If 1 DLT is observed among these 3 patients, additional 3 subjects will receive the level 2 dose, and it will be recommended in the absence of DLT between them. If >1 DLT occurs in these 6 level 2 patients, the dose administered in the level 1 will be the RP2D of the AZA-based schedule. AZA and Venetoclax doses will remain the same in all levels and only the dose of Quizartinib will be modificated according to the following table: Escalation-Quizartinib dose-Quizartinib duration; Level-2 -30 mg/daily-Days 8 to 14; Level-1 -30 mg/daily-Days 8 to 21; Level1-40 mg/daily Days 8 to 28; Level2-60 mg/daily-Days 8 to 28. In phase II, patients randomized to this arm, will receive the recommended phase 2 dose (RP2D) regimen of AZA + Venetoclax + Quizartinib regimen (30 patients).
LDAC-Based	Experimental	Drug: Cytarabine, Drug: Venetoclax, Drug: QuizartinibLow-dose subcutaneous cytarabine 20 mg/m2/daily SC, days 1 to 10 plus Venetoclax (ramp-up) 600 mg/daily oral, days 1 to 28 plus Quizartinib phase I/RP2D mg/daily oral, days 8 to 14-28. If 1 DLT is observed among these 3 patients, additional 3 subjects will receive the level 2 dose, and it will be recommended in the absence of DLT between them. If >1 DLT occurs in these 6 level 2 patients, the dose administered in the level 1 will be the RP2D of the LDAC-based schedule. LDAC and Venetoclax doses will remain the same in all levels and only the dose of Quizartinib will be modificated according to the following table: Escalation-Quizartinib dose-Quizartinib duration; Level-2 -30 mg/daily-Days 8 to 14; Level-1 -30 mg/daily-Days 8 to 21; Level1-40 mg/daily-Days 8 to 28; Level2-60 mg/daily-Days 8 to 28. In phase II, patients randomized to this arm, will receive the recommended phase 2 dose (RP2D) regimen of LDAC + Venetoclax + Quizartinib regimen (30 patients).

Who may qualify

Ages: 60 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (14 listed)

Newly diagnosed AML.
Morphological diagnosis of AML (WHO criteria 2008).
Patient must be considered be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age or co-morbidities defined by the following criteria: 3.1. ≥ 71 years of age; 3.2. ≥ 60 to 70 years of age with at least one of the following co-morbidities:
ECOG performance status ≤ 3.
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 0).

Key exclusion criteria (30 listed)

Age <60 years.
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).

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
AzacitidineAZA 75 mg/m2/daily SC days 1 to 7 or on a 5-on/2-off [weekend]/2-on schedule in 28-day cycle	Drug	AZA-Based
VenetoclaxVenetoclax (ramp-up) 400 mg/daily oral days 1 to 28	Drug	AZA-Based
QuizartinibQuizartinib 40 mg/daily oral, days, 8 to 28	Drug	AZA-Based
CytarabineLow-dose subcutaneous cytarabine (LDAC) 20 mg/m2/daily SC, days 1 to 10	Drug	LDAC-Based
VenetoclaxVenetoclax (ramp-up) 600 mg/daily oral, days 1 to 28	Drug	LDAC-Based
QuizartinibQuizartinib 40 mg/daily oral, days 8 to 28	Drug	LDAC-Based

Primary outcome

Phase I: Recommended phase 2 dose (RP2D)
Time frame: Approximately 6 months after first patient first visit (FPFV)
Recommended phase 2 dose (RP2D) of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules
Phase II: CR/Cri rate of AZA based and LDAC based
Time frame: Aproximatey 3 years after FPFV
CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules. Patients will receive 4 consecutive cycles of treatment (approximately every 28 days). After the first 4 cycles, depending on the response and tolerance to treatment, the patient will continue receiving treatment in maintenance cycles until one of these situations occurs: disease progression, lack of clinical benefit, hematological relapse, unacceptable toxicity.

23 secondary outcomes

CR/CRi rate
Time frame: After cycle 1 and after cycle 4, being each cycle of 28 days
Overall survival (OS)
Time frame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
Overall hematologic and non-hematologic toxicity
Time frame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
Event-free survival (EFS)
Time frame: 1, 2 and 3 years.
Disease-free survival (DFS)
Time frame: 1, 2 and 3 years.
Relapse-free survival (RFS)
Time frame: 1, 2 and 3 years.
Cumulative incidence of relapse
Time frame: 1, 2 and 3 years.
Impact on the quality of life assessed by EuroQoL Group EQ-5D-5L
Time frame: At the screening, after cycle 2, after cycle 6, and after cycle 12, being each cycle of 28 days; and through study completion, an average of 48 months.
Impact on the quality of life assessed by EORTC QLQ-C30
Time frame: at the screening, after 6 cycles, after 12 cycles since start of therapy, being each cycle of 28 days; and through study completion, an average of 48 months
Use of medical resources during treatment phase
Time frame: At the end of treatment phase: after cycle 4, being each cycle of 28 days.
Quality of CR
Time frame: After cycle 1, cycle 4 and then every 3 cycles during the first 2 years after start of the therapy (each cycle of 28 days).
CRh rate
Time frame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
Early mortality
Time frame: First 30 and 60 days
CR/Cri rate of AZA based and LDAC based, in secondary AML subset
Time frame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
CR/Cri rate of AZA based and LDAC based, in CBF subset
Time frame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
CR/Cri rate of AZA based and LDAC based, in FLT3-ITD subset
Time frame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
CR/Cri rate of AZA based and LDAC based, in NPM1 subset
Time frame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
CR/Cri rate of AZA based and LDAC based, in P53 subset
Time frame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
CR/Cri rate of AZA based and LDAC based, in IDH1/IDH2 subset
Time frame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
MRD negativity rate in the BM
Time frame: After cycle 1, cycle 4 and then every 3 cycles, being each cycle of 28 days.
MRD negativity rate in PB
Time frame: After cycle 1, cycle 4 and then every 3 cycles, being each cycle of 28 days.
Natural Killer (NK) cell phenotypes and functions (immune recovery) analysis.
Time frame: At screening and after first and fourth cycles of treatment, being each cycle of 28 days.
Baseline and relapse molecular characterization by NGS.
Time frame: At baseline and at through study completion due to relapse/resistance, an average of 48 months.

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 13 May 2026.
Background: PubMed 27895058Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Lowenberg B, Bloomfield CD. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017 Jan 26;129(4):424-447. doi: 10.1182/blood-2016-08-733196. Epub 2016 Nov 28.
Background: PubMed 19008455Juliusson G, Antunovic P, Derolf A, Lehmann S, Mollgard L, Stockelberg D, Tidefelt U, Wahlin A, Hoglund M. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood. 2009 Apr 30;113(18):4179-87. doi: 10.1182/blood-2008-07-172007. Epub 2008 Nov 13.
Background: PubMed 12123403Menzin J, Lang K, Earle CC, Kerney D, Mallick R. The outcomes and costs of acute myeloid leukemia among the elderly. Arch Intern Med. 2002 Jul 22;162(14):1597-603. doi: 10.1001/archinte.162.14.1597.
Background: PubMed 20026804Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010 Feb 1;28(4):562-9. doi: 10.1200/JCO.2009.23.8329. Epub 2009 Dec 21.
Background: PubMed 17315155Burnett AK, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK, Wheatley K. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007 Mar 15;109(6):1114-24. doi: 10.1002/cncr.22496.
Background: PubMed 24002496Cortes JE, Kantarjian H, Foran JM, Ghirdaladze D, Zodelava M, Borthakur G, Gammon G, Trone D, Armstrong RC, James J, Levis M. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013 Oct 10;31(29):3681-7. doi: 10.1200/JCO.2013.48.8783. Epub 2013 Sep 3.
BackgroundMartinelli G, Perl AE, Dombret H, et al. Effect of quizartinib (AC220) on response rates and long-term survival in elderly patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia. J Clin Oncol. 2013;31 (suppl): abstr 7021
Background: PubMed 17097560Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, Deng X, Zhai D, Shi YX, Sneed T, Verhaegen M, Soengas M, Ruvolo VR, McQueen T, Schober WD, Watt JC, Jiffar T, Ling X, Marini FC, Harris D, Dietrich M, Estrov Z, McCubrey J, May WS, Reed JC, Andreeff M. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006 Nov;10(5):375-88. doi: 10.1016/j.ccr.2006.10.006.
Background: PubMed 22893484Tsao T, Shi Y, Kornblau S, Lu H, Konoplev S, Antony A, Ruvolo V, Qiu YH, Zhang N, Coombes KR, Andreeff M, Kojima K, Konopleva M. Concomitant inhibition of DNA methyltransferase and BCL-2 protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells. Ann Hematol. 2012 Dec;91(12):1861-70. doi: 10.1007/s00277-012-1537-8. Epub 2012 Aug 15.
Background: PubMed 8170972Nakayama K, Nakayama K, Negishi I, Kuida K, Sawa H, Loh DY. Targeted disruption of Bcl-2 alpha beta in mice: occurrence of gray hair, polycystic kidney disease, and lymphocytopenia. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3700-4. doi: 10.1073/pnas.91.9.3700.
Background: PubMed 8758925Yamamura K, Kamada S, Ito S, Nakagawa K, Ichihashi M, Tsujimoto Y. Accelerated disappearance of melanocytes in bcl-2-deficient mice. Cancer Res. 1996 Aug 1;56(15):3546-50.
Background: PubMed 10200241Lees JA, Weinberg RA. Tossing monkey wrenches into the clock: new ways of treating cancer. Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4221-3. doi: 10.1073/pnas.96.8.4221. No abstract available.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Pau Montesinos, MD principal investigator

Hospital Universitario La Fe

Juan Bergua, MD principal investigator

Hospital San Pedro Alcántara

Carmen López-Carrero García study chair

Fundación PETHEMA

15 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Azacitidine, Venetoclax and Quizartinib in people with Leukemia, Myeloid, Acute and De Novo, run by PETHEMA Foundation at 15 sites in Spain.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 May 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 15 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase I: Recommended phase 2 dose (RP2D) (time frame: Approximately 6 months after first patient first visit (FPFV)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04687761, which also lists 23 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 May 2026.