A Clinical Trial to Assess the Efficacy and Safety of the Combination of a Drug Call Quizartinib With Chemotherapy (FLAG-IDA) in Patients With Acute Myeloid Leukemia That Has Not Responded to the First Treatment or That Has Returned After the First Treatment

A Multicenter, Prospective, Non-randomized, Phase I-II Trial to Assess the Efficacy and Safety of the Combination of Oral Quizartinib and the FLAG-IDA Chemotherapy Regimen in First Relapsed/Refractory Acute Myeloid Leukemia (R/R AML) Patients

This is a multicenter, prospective, non-randomized, Phase I-II trial to assess the efficacy and safety of the combination of oral quizartinib and FLAG-IDA chemotherapy schedule (FLAG-QUIDA regimen) in first relapsed/refractory AML (acute myeloid leukemia) patients.

Patients of approximately 20 sites (in Spain and Portugal) will receive FLAG-QUIDA regimen followed by transplantation, when possible, with up to 3 optional consolidation cycles. All patients in CR/CRi (complete remission / complete remission with incomplete hematologic recovery) will receive a maintenance schedule.

A Phase I (dose escalation) will be performed at 40 mg x 14 days of quizartinib in the first 3 patients, and if no dose-limiting toxicity (DLT) is observed, the next cohort of patients will receive 60 mg x 14 days. There is also the possibility of de-escalation cohorts at 60 mg x 7 days and at 40 mg x 7 days. Patients participating in the Phase I will receive the allocated dose level, and therefore, they must not receive strong CYP3A4 inhibitors concomitantly with quizartinib The Phase II will include 68 patients treated at the RP2D (recommended phase 2 dose). A 1-year maintenance schedule starting at 30 mg will be increased to 60 mg/day if appropriate.

Patients will be followed up for a minimum period of 1 year since the first visit of the last patient included.

Inclusion Criteria:

1. Written informed consent in accordance with national, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure. Informed consent form must be signed by the patient and the Investigator.

2. Patients aged ≥ 18 years old and ≤70 years old at the time of screening.

3. First R/R AML defined as:

   • First relapse after frontline intensive chemotherapy (with or without prior alloSCT), irrespectively of the duration of the first CR. Patients previously treated with a FLT3 inhibitor different from quizartinib, can be included.
   • First refractory disease (defined as patients not achieving at least a PR after first induction cycle and/or not achieving CR/CRi after first 2 cycles). Patients previously treated with a FLT3 inhibitor different from quizartinib, can be included.

4. Non-APL AML.

5. Considered for intensive approach as per Investigator judgment.

6. ECOG 0-2.

7. No contraindications for quizartinib.

8. No contraindications for intensive chemotherapy.

9. No severe organ function abnormalities.

10. No active relevant GVHD.

11. For the Phase II, FLT3-ITD patients will represent 50% of the study cohort (FLT3-TKD are not excluded but included in the FLT3-ITD-WT group).

12. Female patients of child-bearing potential must have a negative serum pregnancy test at screening and agree to use reliable methods of contraception upon enrollment, during the treatment period and for 6 months following the last dose of investigational drug or cytarabine, whichever is later.

13. Male patients must use a reliable method of contraception (if sexually active with a female of child-bearing potential) upon enrollment, during the treatment period, and for 6 months following the last dose of investigational drug or cytarabine, whichever is later.

Exclusion Criteria:

1. Patients with genetic diagnosis of acute promyelocytic leukemia.

2. Blastic phase of bcr/abl chronic myeloid leukemia.

3. Patients with other neoplastic disease, for whom the Investigator has clinical suspicion of active disease at the time of enrollment. Note: Patients with adequately treated early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia are eligible for this study. Hormonal or adjuvant therapies will be allowed for breast cancer or prostate cancer if they are on a stable dose for at least 2 weeks prior to first dose.

4. Presence of any severe psychiatric disease or physical condition/comorbidity that, according to the physician´s criteria, contraindicates the inclusion of the patient in the clinical trial

5. Serum creatinine ≥ 250 μmol/l (≥ 2.5 mg/dL) (unless it is attributable to AML activity).

6. Bilirubin, alkaline phosphatase, or SGOT >3 times the upper normal limit (unless it is attributable to AML activity).

7. Uncontrolled or significant cardiovascular disease, including any of the following:

   • Symptomatic bradycardia of less than 50 beats per minute, unless the subject has a pacemaker.
   • QTcF >450 ms at screening. Note: QTcF will be derived from the mean of triplicate readings.
   • Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome)
   • History of clinically relevant ventricular arrhythmias (e.g., 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 6months prior to Screening.
   • History of New York Heart Association Class 3 or 4 heart failure.
   • Complete left bundle branch block.
   • Right bundle branch and left anterior hemiblock (bifascicular block)
   • Infarction (MI) within 3 months.
   • Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥ 110 mmHg
   • A previously known left ventricle ejection fraction <45%

8. Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; however, prophylactic use of these agents is acceptable even if parenteral.

9. Active hepatitis B or hepatitis C infection.

10. Previously known and documented human immunodeficiency virus (HIV) infection (HIV testing is not required as part of this study).

11. Active acute or chronic GVHD requiring prednisone >10 mg or equivalent corticosteroid daily

12. Any patients with known significant impairment in gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of quizartinib

13. History of hypersensitivity to any excipients in the quizartinib tablets.

14. Females who are pregnant or breastfeeding.

15. Isolated extramedullary R/R AML.

16. Only applicable to patients screened after the first cohort of 34 patients of the Phase II has been achieved (e.g., FLT3-ITD negative): patients must have a confirmation of FLT3-ITD status at relapse, and this must correspond to the non-achieved cohort (e.g. FLT3-ITD positive).