Study of Quizartinib in Combination With Standard Therapies in Chinese Participants With Newly Diagnosed Acute Myeloid Leukemia (AML)

Study Overview
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Brief Summary
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20 mg or 40 mg of quizartinib will be given to Chinese patients who were just diagnosed with AML. The study drug will be given to them along with standard therapies. The purpose is to find out the highest dose they can stand.

Detailed Description
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This is a Phase 1, multicenter, open-label study to evaluate the safety and pharmacokinetics (PK) of quizartinib in combination with standard induction therapy and consolidation therapy in Chinese patients with newly diagnosed AML. The quizartinib doses will be Level 1: 20 mg and Level 2: 40 mg. No increase in the quizartinib dose will be made in the same subject. Dose-limiting toxicity associated with quizartinib occurring at each level will be assessed, and the maximum tolerated dose (MTD) will be decided using a 3 + 3 design.

Official Title
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A Study to Evaluate the Safety and Pharmacokinetics of Quizartinib in Combination With Standard Induction Therapy and Consolidation Therapy in Chinese Patients With Newly Diagnosed Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: Quizartinib


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Has provided written informed consent for participation in the study Is aged 18 to 70 years at the time of enrollment into the study Has 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) Has Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 at enrollment Has all of the required laboratory test results performed within 14 days prior to enrollment in the study. Is capable of orally taking quizartinib Is capable of being admitted to the hospital during the dose limiting toxicity (DLT) evaluation period If a woman of childbearing potential, has a negative serum pregnancy test upon entry into this study and is 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 (having undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy). If male, is 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: Has 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). Has a diagnosis of AML secondary to prior chemotherapy or radiotherapy for other neoplasms Had 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 or cytokine support Has received prior treatment with any investigational product or device within 30 days prior to enrollment in the study or is currently participating in other investigational procedures Has a history of other malignancies excluding the following: 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 two years Has a past or current history of the following cardiovascular diseases: Heart rate of < 50 beats/min performed with 12-lead ECG within 14 days prior to enrollment in the study (excluding patients using a heart pacemaker) QT interval corrected by Fridericia (QTcF) of ≥ 450 msec performed with 12-lead ECG within 14 days prior to enrollment in the study Congenital long QT syndrome diagnosed or suspected (including family history of long QT syndrome) Systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg measured within 7 days prior to enrollment in the study History of clinically significant ventricular arrhythmias [such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes (TdP)] History of second (Mobitz II) or third-degree heart block (patients 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 enrollment in the study History of heart failure according to New York Heart Association (NYHA) Functional Classification: Class 3 or 4 heart failure Left ventricular ejection fraction (LVEF) of ≤ 45% or lower than the institutional lower limit of normal value per multi-gated acquisition scan (MUGA) or echocardiogram done within 30 days prior to enrollment Complete left bundle branch block Has active acute or chronic systemic fungal, bacterial, or viral infection not well controlled by antifungal, antibacterial, or antiviral therapy Has active clinically relevant liver disease (such as active hepatitis B or active hepatitis C). Has a history of human immunodeficiency virus (HIV). Patients will be tested for HIV prior to enrollment in the study, if required by local regulations or the Ethics Committee. Has a history of hypersensitivity to any excipients in the quizartinib tablets Is a female who is pregnant or breastfeeding Is considered inappropriate for the study by the investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Quizartinib 20 mg<br>Participants receive 20 mg quizartinib in combination with standard induction therapy and consolidation therapy once daily in the fasted state in the morning (at least 1 hour before or two hours after a meal) | Drug: Quizartinib<br>* Quizartinib is provided as 20 mg tablets for oral administration<br>* Other names: AC220;|
| Experimental: Quizartinib 40 mg<br>Participants receive 40 mg quizartinib in combination with standard induction therapy and consolidation therapy once daily in the fasted state in the morning (at least 1 hour before or two hours after a meal) | Drug: Quizartinib<br>* Quizartinib is provided as 20 mg tablets for oral administration<br>* Other names: AC220;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Dose-Limiting Toxicities |  | At the end of induction phase at approximately 56 days | 
| Number of Participants with Adverse Events During the Trial |  | within approximately 19 months | 
| Maximum Concentration (Cmax) | Categories: quizartinib, active metabolite | within 56 days | 
| Time to Cmax (Tmax) | Categories: quizartinib, active metabolite | within 56 days | 
| Area under the Plasma Concentration-Time Curve (AUC) | Categories: quizartinib, active metabolite | within 56 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Response | Categories: Complete remission (CR), CR with incomplete platelet or hematological recovery (CRi), partial remission (PR), no response (NR) | within approximately 19 months | 
| Response Rates | Categories: response rate (CRc + PR), composite CR (CRc: CR + CRi) rate | within approximately 19 months |