FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) (+) acute myeloid leukemia (AML) MedDRA version: 21.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 100000004864
Conditions
Interventions
Product Name: Quizartinib 20mg
Product Code: AC220
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Quizartinib dihydrochloride
CAS Number: 1132827-21-4
Current Sponsor code: AC220
Other d
Sponsors
Daiichi Sankyo, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Must be competent and able to comprehend, sign, and date an Ethics Committee or Institutional Review Board approved Informed Consent Form (ICF) before performance of any study-specific procedures or tests; 2. =18 years or the minimum legal adult age (whichever is greater) and =75 years (at Screening); 3. Newly diagnosed, morphologically documented primary AML or AML secondary to myelodysplastic syndrome or a myeloproliferative neoplasm based on the World Health Organization (WHO) 2008 classification (at Screening); 4. Eastern Cooperative Oncology Group performance status 0-2 (at Screening); 5. Presence of FLT3-ITD activating mutation in bone marrow (allelic ratio of =3% FLT3-ITD/total FLT3); 6. Subject is receiving standard "7+3" induction chemotherapy regimen as specified in the protocol; 7. Adequate renal function defined as: a. Creatinine clearance rate >50 mL/min, as calculated with the modified Cockcroft Gault equation; 8. Adequate hepatic function defined as: a. Total serum bilirubin =1.5 × ULN unless the subject has documented Gilbert`s syndrome or the increase is related to increased unconjugated (indirect) bilirubin due to hemolysis; b. Serum alkaline phosphatase, aspartate transaminase and alanine transaminase =2.5 × ULN; 9. Serum electrolytes within the instruction`s normal limits: potassium, calcium (total calcium, calcium corrected for serum albumin in case of hypoalbuminemia, or ionized calcium) and magnesium. If outside the instruction`s of normal range, subject will be eligible when electrolytes are corrected; 10. If a woman of childbearing potential, must have a negative serum pregnancy test upon entry into this study and must be willing to use highly effective birth control upon enrollment, during the treatment period and for 6 months following the last dose of investigational drug or cytarabine, whichever is later. A woman is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy); 11. If male, must be surgically sterile or willing to use highly effective birth control upon enrollment, during the treatment period, and for 6 months following the last dose of investigational drug or cytarabine, whichever is later. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 268 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 268
Exclusion criteria
Exclusion criteria: 1. Diagnosis of acute promyelocytic leukemia (APL), French-American- British classification M3 or WHO classification of APL with translocation, t(15;17)(q22;q12), or BCR-ABL positive leukemia (ie, chronic myelogenous leukemia in blast crisis); subjects who undergo diagnostic workup for APL and treatment with all-trans retinoic acid (ATRA), but who are found not to have APL, are eligible (treatment with ATRA must be discontinued before starting induction chemotherapy). 2. Diagnosis of AML secondary to prior chemotherapy or radiotherapy for other neoplasms; 3. Prior treatment for AML, except for the following allowances: a. Leukapheresis; b. Treatment for hyperleukocytosis with hydroxyurea; c. Cranial radiotherapy for central nervous system (CNS) leukostasis; d. Prophylactic intrathecal chemotherapy; e. Growth factor/cytokine support; 4. Prior treatment with quizartinib or other FLT3-ITD inhibitors; 5. 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; 6. History of known CNS leukemia, including cerebrospinal fluid positive for AML blasts; lumbar puncture is recommended for subjects with symptoms of CNS leukemia to rule out extramedullary CNS involvement; 7. History of other malignancies, except adequately treated nonmelanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated with no evidence of disease for at least 2 years; 8. 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; 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. Left ventricular ejection fraction (LVEF) =45% or less than the institutional lower limit of normal per multi-gared acquisition scan (MUGA) or echocardiogram done within 30 days prior to randomization; j. Complete left bundle branch block; 9. Active acute or chronic systemic fungal, bacterial, or viral infection not well controlled by antifungal, antibacterial or antiviral therapy; 10. Known active clinically relevant liver disease (eg, active hepatitis B, or active hepatitis C) 11. Known history of human immunodeficiency virus (HIV). Subjects should be tested for HIV prior to Randomization if required by local regulations or EC;
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to compare the effect of quizartinib versus placebo (administered with standard induction and consolidation chemotherapy, then administered as continuation therapy for up to 36 cycles) on the primary endpoint of overall survival (OS) in subjects with newly diagnosed AML with FLT3-ITD mutations. ;Secondary Objective: • Compare the following in subjects treated with quizartinib versus placebo (administered with standard induction and consolidation chemotherapy, then administered as continuation therapy for up to 36 cycles): - Event-free survival (EFS) - Composite complete remission rate (CRc = complete remission (CR) + CR with incomplete neutrophil or platelet recovery [CRi]) after Induction; - Percentage of subjects achieving CRc with FLT3-ITD minimal or measurable residual disease (MRD) negativity after Induction; - Complete remission (CR) rate after Induction; - Percentage of subjects achieving CR with FLT3-ITD MRD negativity after Induction. • Further characterize the safety profile of quizartinib administered with standard Induction and consolidation chemotherapy, then administered as continuation therapy for up to 36 cycles. • Assess the pharmacokinetics (PK) of quizartinib and its metabolite (AC886). ;Primary end point(s): The primary efficacy endpoint is OS. Overall survival is defined as the time from randomization until death from any cause. ;Timepoint(s) of evaluation of this end point: Date of earliest of any of the following: - Refractory disease (or treatment failure) which is determined at the end of the Induction Phase; - Relapse after CR, CRp or CRi; - Death from any cause at any time during the study. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary efficacy endpoints (ie, secondary outcome measures) are: • Event-free survival is defined as the time from Randomization until the date of the earliest of any of the following: - Refractory disease (or treatment failure) which is determined at the end of the Induction Phase; - Relapse after CR or CRi; - Death from any cause at any time during the study. • Composite complete remission rate which is the percentage of subjects achieving CR or CRi after Induction; • Percentage of subjects achieving CRc with FLT3-ITD MRD negativity below a certain cutoff after Induction. Minimal or measurable residual disease is the presence of a small number of leukemic cells in the bone marrow of patients with AML below the level of detection using conventional morphologic assessment. The FLT3-ITD MRD assay by Next Generation Sequencing will be used to detect and quantify residual FLT3-ITD mutations. • Complete remission rate, which is the percentage of subjects achieving CR after Induction; • Percentage of subjects achieving CR with FLT3-ITD MRD negativity following Induction therapy. ;Timepoint(s) of evaluation of this end point: 1. Lost to follow-up 2. Outcome at the end of induction cycle 1 and the induction phase 3. Same as point 2 4. Same as point 2 | — |
Countries
Belgium, Bulgaria, Croatia, Czech Republic, Estonia, Germany, Hungary, Italy, Portugal, Romania, Spain, United Kingdom
Contacts
Public ContactSandra W. Hamelsky
Daiichi Sankyo, Inc.
Outcome results
None listed