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
NCT ID: NCT04687761
Last Updated: 2022-09-08
Study Results
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Basic Information
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UNKNOWN
PHASE1/PHASE2
84 participants
INTERVENTIONAL
2020-11-04
2024-11-30
Brief Summary
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
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.
TREATMENT
NONE
Study Groups
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AZA-Based
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).
Azacitidine
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
Venetoclax
Venetoclax (ramp-up) 400 mg/daily oral days 1 to 28
Quizartinib
Quizartinib 40 mg/daily oral, days, 8 to 28
LDAC-Based
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).
Cytarabine
Low-dose subcutaneous cytarabine (LDAC) 20 mg/m2/daily SC, days 1 to 10
Venetoclax
Venetoclax (ramp-up) 600 mg/daily oral, days 1 to 28
Quizartinib
Quizartinib 40 mg/daily oral, days 8 to 28
Interventions
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Azacitidine
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
Venetoclax
Venetoclax (ramp-up) 400 mg/daily oral days 1 to 28
Quizartinib
Quizartinib 40 mg/daily oral, days, 8 to 28
Cytarabine
Low-dose subcutaneous cytarabine (LDAC) 20 mg/m2/daily SC, days 1 to 10
Venetoclax
Venetoclax (ramp-up) 600 mg/daily oral, days 1 to 28
Quizartinib
Quizartinib 40 mg/daily oral, days 8 to 28
Eligibility Criteria
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Inclusion Criteria
2. Morphological diagnosis of AML (WHO criteria 2008).
3. 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;
* 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)
4. ECOG performance status ≤ 3.
5. 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).
6. 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.
7. 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.
Exclusion Criteria
2. Genetic diagnosis of acute promyelocytic leukemia.
3. 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.
4. 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.
5. Serum creatinine ≥ 2.5 mg/dL or creatinine clearance \< 30 mL/min (unless it is attributable to AML activity).
6. Bilirubin, SGPT or SGOT \> 3 times the upper normal limit (unless it is attributable to AML activity).
7. 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.
8. Contraindications for Quizartinib or Venetoclax.
9. History of known CNS leukemia, including cerebrospinal fluid positive for AML blasts.
10. 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
11. Prior treatment with other FLT3-ITD or BCL-2 inhibitors.
12. Known uncontrolled or significant cardiovascular disease, including any of the following:
1. Bradycardia of less than 50 beats per minute, unless the subject has a pacemaker;
2. QTcF interval \>450 msec;
3. Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome);
4. Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg;
5. History of clinically relevant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes);
6. 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);
7. History of uncontrolled angina pectoris or myocardial infarction within 6 months prior to Screening;
8. History of New York Heart Association Class 3 or 4 heart failure;
9. Known history of left ventricular ejection fraction (LVEF) ≤45% or less than the institutional lower limit of normal;
10. Complete left bundle branch block;
13. Prior therapy for AML (except hydroxiurea).
14. 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.
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. History of hypersensitivity to any excipients in the Quizartinib, Venetoclax or other study medication.
20. Non mutated FLT3-ITD subjects will be considered ineligible during the randomized Phase II after 48 non mutated FLT3-ITD subjects have been randomized.
60 Years
ALL
No
Sponsors
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PETHEMA Foundation
OTHER
Responsible Party
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Principal Investigators
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Pau Montesinos, MD
Role: PRINCIPAL_INVESTIGATOR
Hospital Universitario La Fe
Juan Bergua, MD
Role: PRINCIPAL_INVESTIGATOR
Hospital San Pedro Alcántara
Carmen López-Carrero García
Role: STUDY_CHAIR
Fundación PETHEMA
Locations
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Hospital Universitario Príncipe de Asturias
Alcalá de Henares, , Spain
Hospital Clínic
Barcelona, , Spain
Hospital San Pedro de Alcántara
Cáceres, , Spain
Hospital Universitario de Jerez de La Frontera
Jerez de la Frontera, , Spain
Hospital de León (Complejo Asistencial Universitario de León)
León, , Spain
Hospital Universitari Arnau de Vilanova de Lleida
Lleida, , Spain
Hospital Universitario Infanta Leonor
Madrid, , Spain
Hospital Universitario La Zarzuela
Madrid, , Spain
Hospital Universitario Puerta de Hierro Majadahonda
Majadahonda, , Spain
Hospital de Sant Joan de Deu (Manresa)
Manresa, , Spain
Hospital Clinico Universitario Virgen de La Arrixaca
Murcia, , Spain
Hospital Universitari Son Espases
Palma de Mallorca, , Spain
Hospital Universitario Marques de Valdecilla
Santander, , Spain
Hospital Universitari Mutua de Terrassa
Terrassa, , Spain
Hospital Universitario y Politécnico La Fe
Valencia, , Spain
Countries
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Central Contacts
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Carmen López-Carrero García
Role: CONTACT
Facility Contacts
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Julio García Suárez
Role: primary
Jordi Esteve
Role: primary
Juan Miguel Bergua Burgués
Role: primary
Eusebio Martin Chacón
Role: primary
Fernando Ramos
Role: primary
Antoni García Guiñón
Role: primary
Maria Ángeles Foncillas
Role: primary
Daniel García Belmonte
Role: primary
Guiomar Bautista
Role: primary
Cristina Motlló
Role: primary
Joaquin Antonio Gómez Espuch
Role: primary
Antonia Sampol
Role: primary
Mercedes Colorado Araujo
Role: primary
Ferran Vall-Llovera Calmet
Role: primary
Rebeca Rodríguez Veiga
Role: primary
References
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Other Identifiers
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VEN-A-QUI
Identifier Type: -
Identifier Source: org_study_id
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