Quizartinib With Standard of Care Chemotherapy and as Continuation Therapy in Patients With Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia (AML)

Study Overview
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Brief Summary
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Quizartinib is an experimental drug. It is not approved for regular use. It can only be used in medical research. Adults might be able to join this study after bone marrow tests show they have a certain kind of blood cancer (FLT3-ITD AML). Participants will have an equal chance of receiving quizartinib or placebo along with their chemotherapy.

Detailed Description
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This is a phase 3, randomized, double-blind, placebo-control global study. The purpose of this study 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 overall survival in subjects with FLT3-internal tandem duplication (ITD) positive AML.

Official Title
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A Phase 3, Double-Blind, Placebo-controlled Study of Quizartinib Administered in Combination With Induction and Consolidation Chemotherapy, and Administered as Continuation Therapy in Subjects 18 to 75 Years Old With Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia (QuANTUM First)

Conditions
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Acute Myeloid Leukemia, Leukemia

Intervention / Treatment
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* Drug: Chemotherapy
* Drug: Quizartinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be competent and able to comprehend, sign, and date an Ethics Committee (EC) or Institutional Review Board approved Informed Consent Form (ICF) before performance of any study-specific procedures or tests; Is ≥18 years or the minimum legal adult age (whichever is greater) and ≤75 years (at Screening); 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); Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (at the time the participant signs their first ICF); Presence of FLT3-ITD activating mutation in bone marrow (allelic ratio of ≥3% FLT3-ITD/total FLT3); Participant is receiving standard 7+3 induction chemotherapy regimen as specified in the protocol; Adequate renal function defined as: a. Creatinine clearance >50 mL/min, as calculated with the modified Cockcroft Gault equation Adequate hepatic function defined as: Total serum bilirubin (TBL) ≤1.5 × upper limit of normal (ULN) unless the participant has documented Gilbert's syndrome or the increase is related to increased unconjugated (indirect) bilirubin due to hemolysis; Serum alkaline phosphatase, aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 × ULN; Serum electrolytes within normal limits: potassium, calcium (total, or corrected for serum albumin in case of hypoalbuminemia or ionized calcium) and magnesium. If outside of normal limits, participant will be eligible when electrolytes are corrected; 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); 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. Exclusion Criteria: Diagnosis of acute promyelocytic leukemia (APL), French-American-British classification M3 or WHO classification of APL with translocation, t(15;17)(q22;q12), or breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) positive leukemia (ie, chronic myelogenous leukemia in blast crisis); participants 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). Diagnosis of AML secondary to prior chemotherapy or radiotherapy for other neoplasms; Prior treatment for AML, except for the following allowances: Leukapheresis; Treatment for hyperleukocytosis with hydroxyurea; Cranial radiotherapy for central nervous system (CNS) leukostasis; Prophylactic intrathecal chemotherapy; Growth factor/cytokine support; Prior treatment with quizartinib or other FLT3-ITD inhibitors; 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; History of known CNS leukemia, including cerebrospinal fluid positive for AML blasts; lumbar puncture is recommended for participants with symptoms of CNS leukemia to rule out extramedullary CNS involvement; History of other malignancies, except adequately treated non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated with no evidence of disease for at least 2 years; Uncontrolled or significant cardiovascular disease, including any of the following: Bradycardia of less than 50 beats per minute, unless the participant has a pacemaker; Fridericia's Heart Rate Correction Formula (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 (participants 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; Active acute or chronic systemic fungal, bacterial, or viral infection not well controlled by antifungal, antibacterial or antiviral therapy; Known active clinically relevant liver disease (eg, active hepatitis B, or active hepatitis C); Known history of human immunodeficiency virus (HIV). Participants should be tested for HIV prior to Randomization if required by local regulations or EC; History of hypersensitivity to any excipients in the quizartinib/placebo tablets; Females who are pregnant or breastfeeding; Otherwise considered inappropriate for the study by the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemotherapy plus quizartinib<br>Induction: up to 2 cycles with cytarabine and daunorubicin/idarubicin, followed by the experimental drug quizartinib Consolidation: up to 4 cycles of cytarabine followed by the experimental drug quizartinib and/or hematopoeitic stem cell transplant Continuation: up to 36 cycles with the experimental drug quizartinib | Drug: Chemotherapy<br> <br> * Other names: Idarubicin;Drug: Quizartinib<br> <br> * Other names: Test Product;|
| Active Comparator: Chemotherapy plus placebo<br>Induction: up to 2 cycles with cytarabine and daunorubicin/idarubicin, followed by placebo Consolidation: up to 4 cycles of cytarabine followed by placebo and/or hematopoeitic stem cell transplant Continuation: up to 36 cycles with placebo | Drug: Chemotherapy<br> <br> * Other names: Idarubicin;Drug: Placebo<br> <br> * Other names: Placebo Control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival in Participants With Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia | Overall survival is defined as the time from randomization until death from any cause. | Date of randomization to the date of death due to any cause, up to approximately 3 years after enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival in Participants With Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia | Event-free survival (EFS) is the time from randomization to the earliest date of either refractory disease (or treatment failure [TF]), relapse, or death from any cause. Refractory disease is defined as complete remission never achieved during Induction (CR: >1000 neutrophils, >100,000 platelets, <5% blasts, and other [defined as absence of extramedullary disease [EMD], blasts with rods, and leukemic blasts]). For refractory disease, EFS event date is Day 1 (randomization). Relapse after CR is defined as ≥5% blasts, leukemic blasts, extramedullary leukemia, and presence of rods. This analysis is based on a response assessment with TF defined as not achieving response of CR, using a 42- day window from the start of the last cycle in Induction for CR evaluation. | Date of randomization to the date of refractory disease, relapse, or death, up to approximately 3 years after enrollment | 
| Complete Remission (CR) Rate at the End of Induction in Participants With Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia | Complete remission (CR) rate is defined as the percentage of participants achieving CR, defined as a disappearance of all target lesions, after Induction. | Approximately Cycle 1 Day 21 (Induction) to end of Induction, up to approximately 120 days (each Induction cycle is up to 60 days) | 
| Composite CR Rate at the End of Induction in Participants With Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia | Composite complete remission (CRc) rate is defined as the percentage of participants whose best response is complete remission (CR), defined as a disappearance of all target lesions, or CR with incomplete neutrophil or platelet recovery (CRi) at the end of first Induction cycle. | Approximately Cycle 1 Day 21 (Induction) to end of Induction, up to approximately 120 days (each Induction cycle is up to 60 days) | 
| Number of Participants With Treatment-emergent Adverse Events Occurring in ≥10% Participants With Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia | A treatment-emergent adverse event (TEAE) is defined as an adverse event that occur, having been absent before first dose of quizartinib or placebo, or have worsened in severity after initiating quizartinib or placebo. Adverse events collected more than 30 days after the last dose of quizartinib/placebo will not be considered TEAEs unless they are considered drug-related. | Date of first dose up to 30 days after last dose, up to 36 cycles following continuation (approximately 6 years 11 months, each cycle is 28 days) | 
| Number of Participants Achieving CR With FLT3-ITD Minimal Residual Disease Negativity at the End of Induction in Participants With Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia | Complete remission (CR) is defined as participants achieving CR defined as a disappearance of all target lesions. 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. | Approximately Cycle 1 Day 21 (Induction phase) to end of Induction phase, up to approximately 120 days (each Induction cycle is up to 60 days) | 
| Number of Participants Achieving Composite CR With FLT3-ITD Minimal Residual Disease Negativity at the End of Induction in Participants With Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia | Composite complete remission (CRc) is defined as participants achieving complete remission (CR), defined as a disappearance of all target lesions, or CR with incomplete neutrophil or platelet recovery (CRi). 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. | Approximately Cycle 1 Day 21 (Induction phase) to end of Induction phase, up to approximately 120 days (each Induction cycle is up to 60 days) | 
| Pharmacokinetic Parameter Area Under the Concentration Versus Time Curve at Steady State | AUCss was assessed by population PK analysis during Cycle 1 of each phase. | Induction Cycle 1: Day 8, predose, 2-4 hours (hr) postdose on Days 8, 15, 21; Consolidation Cycle 1: Day 6, predose, 2-4 hr postdose on Days 6, 13, 19; Continuation Cycle 1: 2-4 hr postdose, Days 1, 8, 15; Cycle 2 Days 1 and 15 (each cycle, 28 days) | 
| Pharmacokinetic Parameter Steady State, Maximum Plasma Concentration (Css,Max) | Css,max was assessed by population PK analysis during Cycle 1 of each phase. | Induction Cycle 1: Day 8, predose, 2-4 hours (hr) postdose on Days 8, 15, 21; Consolidation Cycle 1: Day 6, predose, 2-4 hr postdose on Days 6, 13, 19; Continuation Cycle 1: 2-4 hr postdose, Days 1, 8, 15; Cycle 2 Days 1 and 15 (each cycle, 28 days) | 
| Pharmacokinetic Parameter Time to Maximum Plasma Concentration Steady State (Tmax,ss) | Tmax,ss was assessed by population PK analysis during Cycle 1 of each phase. | Induction Cycle 1: Day 8, predose, 2-4 hours (hr) postdose on Days 8, 15, 21; Consolidation Cycle 1: Day 6, predose, 2-4 hr postdose on Days 6, 13, 19; Continuation Cycle 1: 2-4 hr postdose, Days 1, 8, 15; Cycle 2 Days 1 and 15 (each cycle, 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Newly diagnosed Acute Myeloid Leukemia, FLT3-ITD positive, Chemotherapy, Induction chemotherapy, Consolidation chemotherapy, Quizartinib, Feline McDonough sarcoma (FMS)-like tyrosine kinase 3, AC220, FLT3-ITD, AML