Overview
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
Status:
Recruiting
Recruiting
Trial end date:
2024-11-01
2024-11-01
Target enrollment:
0
0
Participant gender:
All
All
Summary
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 IIPhase:
Phase 1/Phase 2Accepts Healthy Volunteers?
NoDetails
Lead Sponsor:
PETHEMA FoundationTreatments:
Azacitidine
Cytarabine
Venetoclax
Criteria
Inclusion Criteria:1. Newly diagnosed AML.
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:
1. Age <60 years.
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.