A Study of ASP2215 in Combination With Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia.

Phase 1

Completed

Conditions: Acute Myeloid Leukemia
FLT3-mutated Acute Myeloid Leukemia

Interventions: Drug: Gilteritinib
Drug: Idarubicin
Drug: Cytarabine

Registration Number: NCT02310321

Lead Sponsor: Astellas Pharma Inc

Brief Summary: The purpose of phase 1 part in this study was to determine the maximum tolerated dose (MTD) and/or recommended expansion dose (RED) of ASP2215 concomitant with cytarabine/idarubicin as induction chemotherapy based on the status of the onset of dose-limiting toxicity (DLT) in newly diagnosed Acute Myeloid Leukemia (AML) subjects. Phase 1 part also evaluated safety and tolerability and characterized the pharmacokinetic (PK) parameters of ASP2215 concomitant with induction and consolidation chemotherapy as well as evaluated the PK parameters of cytarabine concomitant with ASP2215.

The purpose of phase 2 part was to evaluate efficacy of ASP2215 in combination with induction therapy. Phase 2 cohort also evaluated safety and characterized the PK parameters of ASP2215 in combination with induction and consolidation therapy followed by maintenance therapy in newly diagnosed FLT3-mutated AML subjects.

Detailed Description: This study was composed of Phase 1 part (the dose-evaluation part and the expansion part) and Phase 2 part.

In the dose-evaluation part of Phase 1 part, at least 3 subjects received ASP2215 at each dose (low, middle, and high) for determination of MTD and/or RED. Treatment of AML in Phase 1 part was composed of 3 periods of therapy: remission induction, consolidation, and maintenance. The decision of whether or not to proceed to the next dose was made based on the occurrence of DLT during Cycle 1 of the induction period.

In the expansion part of Phase 1 part, a maximum of 3 subjects received ASP2215 at RED that had been recommended in the dose-evaluation part and the safety was assessed based on the onset of DLTs during Cycle 1 of the induction and consolidation periods.

In Phase 2 part, Subjects received ASP2215 at the recommended dose established in Phase 1 part. The target population was limited to newly diagnosed FLT3-mutated AML.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 97

Inclusion Criteria

[Phase 1 part]

Subject is defined as having previously untreated de novo AML according to the World Health Organization (WHO) criteria (2008) within 28 days prior to study enrollment.
Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
Subject must meet all of the following criteria in the laboratory test at screening:
- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels of ≤ 2.5 × institutional upper limit of normal (ULN)
- Total serum bilirubin level of ≤ 1.5 × institutional ULN
- Serum creatinine level of ≤ 1.5 × institutional ULN or an estimated glomerular filtration rate (eGFR) of > 50 mL/min
Subject is suitable for oral administration of ASP2215.
Female subject falls under the following:
- Of non-childbearing potential:
- ・Post-menopausal (defined as at least 1 year with no menses without a medical reason such as drug administration) at screening, or
- ・Documented surgically sterile or status post-hysterectomy (at least 1 month prior to screening)
- Of childbearing potential:
- ・Has a negative result for the pregnancy test at screening, and
- ・Agrees to use an appropriate contraception starting at screening and throughout the study period and for 60 days after the final study drug administration
Female subject agrees not to breastfeed starting at screening and throughout the study period and for 60 days after the final study drug administration.
Female subject agrees not to donate ova starting at screening and throughout the study period and for 60 days after the final study drug administration.
Male subject and his female spouse/partner who is of childbearing potential agrees to use an appropriate contraception starting at screening and throughout the study period and for 120 days after the final study drug administration.
Male subject agrees not to donate sperm starting at screening and throughout the study period and for 120 days after the final study drug administration.
Subject agrees not to participate in another interventional study while on study treatment.
Subject can be admitted during the induction period.

[Phase 2 part]

Subject has a diagnosis of previously-untreated de novo acute myeloid leukemia (AML) according to World Health Organization (WHO) classification (2017) documented within 28 days prior to enrollment.
Subject is positive for FLT3-ITD and/or TKD mutation in bone marrow or whole blood as determined by the central lab. Registration by the local lab result is not acceptable.
Subject has an ECOG performance status (PS) 0 to 1. Subject who has an ECOG PS 2 is eligible only if the primary disease related symptoms such as pneumonia and febrile neutropenia are the cause of PS score.
Subject is suitable for oral administration of ASP2215.
Female subject is not pregnant and at least 1 of the following conditions apply:
- Not a woman of childbearing potential (WOCBP)
- WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 180 days after final study treatment administration.
Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 60 days after the final study drug administration.
Female subject must not donate ova starting at screening and throughout the study period, and for 180 days after the final study drug administration.
Male subject and their female partners who are of childbearing potential must be using highly effective contraception per locally accepted standards in addition to a barrier method starting at screening and continue throughout the study period and for 120 days after the final study drug administration.
Male subject must not donate sperm starting at screening and throughout the study period and for 120 days after the final study drug administration.
Male subject with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 120 days after the final study treatment administration.
Subject agrees not to participate in another interventional study while on treatment.
Subject must meet the following criteria as indicated on the clinical laboratory tests:
- Serum creatinine ≤ 1.5 × institutional upper limit of normal (ULN), or if serum creatinine outside normal range, then glomerular filtration rate (GFR) > 50 mL/min/1.73m^2 as calculated with the 4-parameter Modification of Diet in Renal Disease (MDRD) equation.
- Serum total bilirubin ≤ 2.5 mg/dL (43 μmol/L), except for subjects with Gilbert's syndrome.
- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN. If liver abnormality by the primary disease is suspected, subject may be pre-registered to initiate the chemotherapy. Prior to registration, AST/ALT values must meet the criteria to continue the study.
- Serum magnesium ≥ institutional lower limit of normal (LLN). Subject may pre-register without magnesium value, but subject must meet the criteria prior to the full registration on Day 8.
- Serum potassium ≥ institutional lower limit of normal (LLN).

Exclusion Criteria

[Phase 1 part]

Subject was diagnosed with acute promyelocytic leukemia (APL).
Subject has breakpoint cluster region-abelson (BCR-ABL)-positive leukemia (chronic myelogenous leukemia in blast crisis).
Subject has active malignant tumors other than AML or myelodysplastic syndrome (MDS).
Subject has received prior AML treatment except for the following:
- Urgent leukapheresis
- Hydroxyurea administration for emergency treatment of hyperleukocytosis (≤ 7 days)
- Administration of retinoic acid before the diagnosis to exclude APL (≤ 7 days)
- Supportive care using growth factors or cytokines
- Steroid administration to treat hypersensitivity or blood transfusion reactions
Subject has clinically active central nervous system leukemia.
Subject has disseminated intravascular coagulation (DIC).
Subject has had major surgery within 28 days prior to the first study drug administration.
Subject has had radiation therapy within 28 days prior to the first study drug administration.
Subject has congestive heart failure of New York Heart Association (NYHA) class 3 or 4, or subject with a past history of congestive heart failure of NYHA class 3 or 4 and in whom echocardiogram (ECHO) or Multiple Gate Acquisition (MUGA) scan performed within 3 months prior to screening or at screening showed a left ventricular ejection fraction (LVEF) of < 45%.
Subject has cardiac impairment or a clinically significant cardiac disease, including any one of the following:
- Complete left bundle branch block
- Obligate use of a cardiac pacemaker
- Long QT syndrome at Screening
- Prolongation of the QTc interval (> 450 ms) on electrocardiogram (ECG) at screening
- Right bundle branch block + left anterior hemiblock (bifascicular block)
- Angina pectoris within 3 months prior to study drug administration
- Acute myocardial infarction within 3 months prior to study drug administration
Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP)3A.
Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of P glycoprotein (P-gp) with the exception of drugs that are considered absolutely essential for the care of the subject.
Subject requires treatment with concomitant drugs that target serotonin 5HT1 or 5HT2B receptors or sigma receptors, with the exception of drugs that are considered absolutely essential for treatment of the subject.
Subject has an active uncontrollable infection.
Subject is known to have human immunodeficiency virus (HIV) infection.
Subject has active hepatitis B or C or other active hepatic disorders.
Subject has any condition that, in the investigator's or sub-investigator's opinion, makes the subject unsuitable for study participation.
Potassium and magnesium levels of below institutional lower limit of normal in the laboratory test at screening.

[Phase 2 part]

Subject was diagnosed with acute promyelocytic leukemia (APL).
Subject has known BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
Subject has therapy-related AML.
Subject has active malignant tumors other than AML.
Subject has received previous therapy for AML, with the exception of the following:
- Emergency leukapheresis
- Emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 10 days
- Preemptive treatment with retinoic acid prior to exclusion of APL ≤ 7 days
- Growth factor or cytokine support
- Steroids for the treatment of hypersensitivity or transfusion reactions.
Subject has QTcF interval > 450 ms (average of triplicate determinations based on central reading).
Subject with long QT syndrome.
Subject has clinically active central nervous system leukemia.
Subject has had major surgery within 4 weeks prior to the first study dose.
Subject has radiation therapy within 4 weeks prior to the first study dose.
Subject has immediate life-threatening, severe complications of leukemia such as severe uncontrolled bleeding and/or severe disseminated intravascular coagulation
Subject is known to have human immunodeficiency virus infection.
Subject has active hepatitis B or C.
Subject has an uncontrolled infection. An infection controlled with an approved or closely monitored antibiotic/antiviral/antifungal treatment is allowed.
Subject has uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia, congestive heart failure New York Heart Association (NYHA) class 3 or 4 or subject has a history of congestive heart failure of NYHA class 3 or 4 and echocardiogram (ECHO) or Multiple Gate Acquisition (MUGA) scan performed within 3 months prior to screening or at screening showed a left ventricular ejection fraction (LVEF) of < 45%.
Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A.
Subject requires treatment with concomitant drugs that target serotonin 5HT2B receptors or sigma nonspecific receptors, with the exception of drugs that are considered absolutely essential for treatment of the subject.
Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of P glycoprotein (P-gp) with the exception of drugs that are considered absolutely essential for the care of the subject.
Subject has prior malignancies, except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent < 5 years previously will not be allowed.
Subject has any condition which makes the subject unsuitable for study participation.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1: Dose Evaluation (DEv)	Gilteritinib	Induction period: Participants received 120 milligrams (mg) gilteritinib (3 tablets of 40 mg) orally, once daily from day 4 to 17 combined with chemotherapy (idarubicin: 12 mg per square meters per day \[mg/m\^2/day\] on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via intravenous (IV) infusion; in cycles (C) 1 and 2 (1 cycle= 42 days). Consolidation period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from day 1 to 14 combined with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in the consolidation period in C1 to 3 (1 cycle= 28 days). Duration of infusion was determined by site clinical practice and local package insert in both induction and consolidation periods.. Maintenance period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 1 to 28 in the maintenance period in C1 to 26 or untill discontinuation criterion is met (1 cycle= 28 days).
Phase 1: Dose Evaluation (DEv)	Idarubicin	Induction period: Participants received 120 milligrams (mg) gilteritinib (3 tablets of 40 mg) orally, once daily from day 4 to 17 combined with chemotherapy (idarubicin: 12 mg per square meters per day \[mg/m\^2/day\] on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via intravenous (IV) infusion; in cycles (C) 1 and 2 (1 cycle= 42 days). Consolidation period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from day 1 to 14 combined with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in the consolidation period in C1 to 3 (1 cycle= 28 days). Duration of infusion was determined by site clinical practice and local package insert in both induction and consolidation periods.. Maintenance period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 1 to 28 in the maintenance period in C1 to 26 or untill discontinuation criterion is met (1 cycle= 28 days).
Phase 1: Dose Evaluation (DEv)	Cytarabine	Induction period: Participants received 120 milligrams (mg) gilteritinib (3 tablets of 40 mg) orally, once daily from day 4 to 17 combined with chemotherapy (idarubicin: 12 mg per square meters per day \[mg/m\^2/day\] on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via intravenous (IV) infusion; in cycles (C) 1 and 2 (1 cycle= 42 days). Consolidation period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from day 1 to 14 combined with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in the consolidation period in C1 to 3 (1 cycle= 28 days). Duration of infusion was determined by site clinical practice and local package insert in both induction and consolidation periods.. Maintenance period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 1 to 28 in the maintenance period in C1 to 26 or untill discontinuation criterion is met (1 cycle= 28 days).
Phase 1: Dose Expansion (DEx)	Gilteritinib	Induction period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 4 to 17 in combination with chemotherapy (idarubicin: 12 mg/m\^2/day on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via IV infusion; in the induction period in C1 and 2 (1 cycle= 42 days). Consolidation period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 1 to 14 in combination with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in the consolidation period in C1 to 3 (1 cycle= 28 days). Duration of infusion was determined based on site clinical practice and the local package insert in both induction and consolidation periods. Maintenance period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 1 to 28 in the maintenance period in C1 to 26 or a discontinuation criterion is met (1 cycle= 28 days).
Phase 1: Dose Expansion (DEx)	Idarubicin	Induction period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 4 to 17 in combination with chemotherapy (idarubicin: 12 mg/m\^2/day on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via IV infusion; in the induction period in C1 and 2 (1 cycle= 42 days). Consolidation period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 1 to 14 in combination with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in the consolidation period in C1 to 3 (1 cycle= 28 days). Duration of infusion was determined based on site clinical practice and the local package insert in both induction and consolidation periods. Maintenance period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 1 to 28 in the maintenance period in C1 to 26 or a discontinuation criterion is met (1 cycle= 28 days).
Phase 1: Dose Expansion (DEx)	Cytarabine	Induction period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 4 to 17 in combination with chemotherapy (idarubicin: 12 mg/m\^2/day on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via IV infusion; in the induction period in C1 and 2 (1 cycle= 42 days). Consolidation period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 1 to 14 in combination with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in the consolidation period in C1 to 3 (1 cycle= 28 days). Duration of infusion was determined based on site clinical practice and the local package insert in both induction and consolidation periods. Maintenance period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 1 to 28 in the maintenance period in C1 to 26 or a discontinuation criterion is met (1 cycle= 28 days).
Phase 2: FLT3-mutated AML	Gilteritinib	Induction period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 8 until blood recovery combined with chemotherapy (idarubicin: 12 mg/m\^2/day on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via IV infusion; in C1 and 2. Each cycle was extended until blood recovery was observed. Consolidation period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 1 until blood recovery combined with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in C1 to 3. Each cycle was extended until blood recovery was observed. Duration of infusion was based on site clinical practice and the local package insert in both induction and consolidation periods. Maintenance period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 1 to 28 in the maintenance period in C1 to 26 or a discontinuation criterion is met (1 cycle= 28 days).
Phase 2: FLT3-mutated AML	Idarubicin	Induction period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 8 until blood recovery combined with chemotherapy (idarubicin: 12 mg/m\^2/day on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via IV infusion; in C1 and 2. Each cycle was extended until blood recovery was observed. Consolidation period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 1 until blood recovery combined with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in C1 to 3. Each cycle was extended until blood recovery was observed. Duration of infusion was based on site clinical practice and the local package insert in both induction and consolidation periods. Maintenance period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 1 to 28 in the maintenance period in C1 to 26 or a discontinuation criterion is met (1 cycle= 28 days).
Phase 2: FLT3-mutated AML	Cytarabine	Induction period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 8 until blood recovery combined with chemotherapy (idarubicin: 12 mg/m\^2/day on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via IV infusion; in C1 and 2. Each cycle was extended until blood recovery was observed. Consolidation period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 1 until blood recovery combined with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in C1 to 3. Each cycle was extended until blood recovery was observed. Duration of infusion was based on site clinical practice and the local package insert in both induction and consolidation periods. Maintenance period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 1 to 28 in the maintenance period in C1 to 26 or a discontinuation criterion is met (1 cycle= 28 days).

Primary Outcome Measures

Name	Time	Method
Phase 1 Part: Maximum Tolerated Dose (MTD) of Gilteritinib	Day 1 up to the end of Induction period cycle 1 (up to 42 days)	The MTD was defined as the highest dose of gilteritinib at which the posterior mean of the DLT incidence during Cycle 1 of induction therapy was estimated to be closest to 33%.
Phase 1 Part: Recommended Expansion Dose (RED) of Gilteritinib	Day 1 up to the end of Induction period cycle 1 (up to 42 days)	RED was the recommended dose used in Phase 2 of the study that was decided by the sponsor's responsible person by comprehensively assessing the data obtained from the study.
Phase 1 Part: Number of Participants With Dose Limiting Toxicities (DLTs) of Gilteritinib	Day 1 up to the end of Consolidation Cycle 1 (approximately up to 4 months)	DLTs were defined as: Any Grade ≥ 3 non-hematologic or extramedullary toxicity with the following exceptions: * Anorexia or fatigue * Grade 3 nausea and/or vomiting if participant did not require tube feeding or total parenteral nutrition, or diarrhea if the events did not require or prolong hospitalization that could be managed to grade ≤ 2 with standard antiemetic or antidiarrheal medications used at prescribed dose within 7 days of onset. * Grade 3 mucositis that resolved to Grade ≤ 2 within 7 days of onset, fever with neutropenia, with or without infection, infection * Grade 4 peripheral neutrophil count \< 500/cubic millimeters (mm\^3) * Platelet count \< 20,000/mm\^3 due to bone marrow hypoplasia * Grade ≥ 3 platelet count \< 50,000/mm\^3 accompanying bleeding * Grade 4 platelet count \< 25,000/mm\^3 requiring platelet transfusion DLT was assessed until cycle 1 of dose evaluation induction period and until cycle 1 of dose expansion consolidation period.
Phase 1 Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs)	From the date of first dose up to 28 days after the last dose (approximately up to 2.6 years)	An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE could therefore be any unfavorable \& unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. TEAE included both serious and non-serious AEs. TEAE for Phase 1 was defined as an AE observed after the date of first dose until 28 days after the last dose.
Phase 2 Part: Complete Remission (CR) Rate: Induction Period	From the date of first dose up to the start of Consolidation (approximately up to 4 months)	Percentage of participants with CR was reported. CR was defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm3 and platelet count of ≥ 100,000/mm3, bone marrow blasts \< 5%. No evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%.

Secondary Outcome Measures

Name	Time	Method
Phase 1 Part: Maximum Concentration (Cmax) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy	Induction period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 4 Consolidation period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 1	Cmax was derived from the PK samples collected. It was planned that standard deviation(SD) would only be calculated if there are more than 3 participants analyzed otherwise, SD was not calculated.
Phase 1 Part: Time to Attain Cmax (Tmax) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy	Induction period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 4 Consolidation period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 1	Tmax was derived from the PK samples collected.
Phase 1 Part: Area Under Plasma Concentration-time Curve From Time 0 to 24 (AUC24) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy	Induction period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 4 Consolidation period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 1	AUC24 was derived from the PK samples collected. It was planned that standard deviation(SD) would only be calculated if there are more than 3 participants analyzed otherwise, SD was not calculated.
Phase 1 Part: Area Under The Concentration-Time Curve From The Time Zero to The Last Measurable Concentration (AUClast) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy	Induction period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 4 Consolidation period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 1	AUClast was derived from the PK samples collected. It was planned that standard deviation(SD) would only be calculated if there are more than 3 participants analyzed otherwise, SD was not calculated.
Phase 1 Part: Plasma Trough Concentration (Ctrough) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy	Induction period: Pre-dose on Cycle 1 Day 8, 11, and 17 Consolidation period: Pre-dose on Cycle 1 Day 6 and 15	Ctrough is the plasma concentration prior to drug administration. It was planned that standard deviation(SD) would only be calculated if there are more than 3 participants analyzed otherwise, SD was not calculated.
Phase 1 Part: Plasma Trough Concentration of Cytarabine Concomitant With Gilteritinib With Induction and Consolidation Period	Induction period: Predose on Cycle 1 Day 1, 3, and 8 Consolidation period: Predose on Cycle 1 Day 2 and 6	Ctrough is the plasma concentration prior to drug administration. It was planned that standard deviation(SD) would only be calculated if there are more than 3 participants analyzed otherwise, SD was not calculated.
Phase 2 Part: Plasma Trough Concentration of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy	Induction period : Predose on Cycle 1 Day 15 and 21 Consolidation period: Predose on Cycle 1 Day 8 and 15	Ctrough is the plasma concentration prior to drug administration.
Phase 2 Part: Overall Survival (OS)	From the date of first dose up to the date of death (maximum duration: approximately 4.4 years)	Overall survival (OS) was defined as the time from the date of first dose of day 1 to the date of death due to any cause. Participants still alive or lost to follow up was censored at the time they were last known to be alive. Kaplan-Meier (KM) estimate was used for analysis.
Phase 2 Part: Event Free Survival (EFS)	From the date of first dose up to the date of documented relapse, treatment failure or death from any cause (maximum duration: approximately 4.4 years)	Event-free survival (EFS): time from date of first dose of study regimen until date of documented relapse, treatment failure or death from any cause, whichever occurred first. KM estimate was used for analysis. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in bone marrow aspirate (BMA)/reappearance of significant numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%. Treatment failure: participants who failed to achieve composite complete remission (CRc) or who discontinued treatment due to "lack of efficacy" without previous response. CRc: rate of all complete \& incomplete remissions i.e. CR + CR with incomplete platelet recovery (CRp) + CR with incomplete hematological recover (CRi). CRp: met all CR criteria at post-baseline visit, except unrecovered platelet count (\< 100,000/mm\^3). CRi: met all CR criteria at post-baseline visit, except unrecovered neutrophil count (\< 1,000/mm\^3). CR: defined in outcome measure #5.
Phase 2 Part: Relapse Free Survival (RFS)	From the date of achievement of first CRc up to the date of documented relapse or death from any cause (maximum duration: approximately 4.4 years)	Relapse-free survival (RFS): time from date of achievement of first CRc until relapse or death from any cause. KM estimate was used for analysis. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in bone marrow aspirate (BMA)/reappearance of significant numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%. CRc: rate of all complete \& incomplete remissions i.e. CR + CR with incomplete platelet recovery (CRp) + CR with incomplete hematological recover (CRi). CRp: met all CR criteria at post-baseline visit, except unrecovered platelet count (\< 100,000/mm\^3). CRi: met all CR criteria at post-baseline visit, except unrecovered neutrophil count (\< 1,000/mm\^3). CR: morphologically leukemia-free state at post-baseline visit, having neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods \& extramedullary leukemia. Blast counts in peripheral blood was ≤ 2%.
Phase 2 Part: CR Rate After Consolidation and Maintenance Period	From the date of first dose up to the end of each period (approximately up to 4.4 years)	Percentage of participants with CR was reported. CR was defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%.
Phase 2 Part: CR Rate Without Minimal Residual Disease (MRD) After Each Treatment Therapy Period	From the date of first dose up to the end of each period (approximately up to 4.4 years)	Percentage of CR without MRD was reported. CR rate without MRD after each treatment therapy was defined similarly as CR rate after each treatment therapy. Responders achieve that the best response is CR and MRD status was negative. CR was defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%.
Phase 2 Part: CR With Partial Hematological Recovery (CRh) Rate After Each Treatment Therapy Period	From the date of first dose up to the end of each period (approximately up to 4.4 years)	Percentage of participants with CRh was reported. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery neutrophil count≥ 500/mm\^3 and platelet count ≥ 50,000/mm\^3, no evidence of extramedullary leukemia and could be classified as CR. The blast counts in peripheral blood was ≤ 2%.
Phase 2 Part: Composite CR (CRc) Rate After Each Treatment Therapy Period	From the date of first dose up to the end of each period (approximately up to 4.4 years)	Percentage of participants with CRc was reported. CRc: rate of all complete \& incomplete remissions i.e. CR + CR with incomplete platelet recovery (CRp) + CR with incomplete hematological recover (CRi). CRp: met all CR criteria at post-baseline visit, except unrecovered platelet count (\< 100,000/mm\^3). CRi: met all CR criteria at post-baseline visit, except unrecovered neutrophil count (\< 1,000/mm\^3). CR: morphologically leukemia-free state at post-baseline visit, having neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods \& extramedullary leukemia. Blast counts in peripheral blood was ≤ 2%.
Phase 2 Part: CR/CRh Rate After Each Treatment Therapy Period	From the date of first dose up to the end of each period (approximately up to 4.4 years)	Percentage of participants with CR/CRh was reported. CR was defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery neutrophil count≥ 500/mm\^3 and platelet count ≥ 50,000/mm\^3, no evidence of extramedullary leukemia and could be classified as CR. The blast counts in peripheral blood was ≤ 2%.
Phase 2 Part: Duration of CR	From the date of achieving CR up to the date of documented relapse (maximum duration: approximately 4.4 years)	Duration of CR was defined as the time from the date of achieving first CR until the date of first documented relapse for participants who achieved CR. KM estimate was used for analysis. CR was defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in BMA/reappearance of numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%.
Phase 2 Part: Duration of CR/CRh	From the date of achieving CR/CRh up to the date of documented relapse (maximum duration: approximately 4.4 years)	Duration of CR/CRh is defined as the time from the date of achieving first CR/CRh until the date of first documented relapse for participants who achieved CR/CRh. KM estimate was used for analysis. CR was defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery neutrophil count≥ 500/mm\^3 and platelet count ≥ 50,000/mm\^3, no evidence of extramedullary leukemia and could be classified as CR. The blast counts in peripheral blood was ≤ 2%. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in BMA/reappearance of numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%.
Phase 2 Part: Duration of CRh	From the date of achieving CRh up to the date of documented relapse (maximum duration: approximately 4.4 years)	Duration of CRh was defined as the time from date of achieving first CRh until date of first documented relapse for participants who achieved CRh. KM estimate was used for analysis. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery neutrophil count≥ 500/mm\^3 and platelet count ≥ 50,000/mm\^3, no evidence of extramedullary leukemia and could be classified as CR. The blast counts in peripheral blood was ≤ 2%. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in BMA/reappearance of numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%.
Phase 2 Part: Duration of CRc	From the date of achieving CRc up to the date of documented relapse (maximum duration: approximately 4.4 years)	Duration of CRc is defined as the time from the date of achieving first CRc until the date of first documented relapse for participants who achieved CRc. KM estimate was used for analysis. CRc: rate of all complete \& incomplete remissions i.e. CR + CR with incomplete platelet recovery (CRp) + CR with incomplete hematological recover (CRi). CRp: met all CR criteria at post-baseline visit, except unrecovered platelet count (\< 100,000/mm\^3). CRi: met all CR criteria at post-baseline visit, except unrecovered neutrophil count (\< 1,000/mm\^3). CR: morphologically leukemia-free state at post-baseline visit, having neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods \& extramedullary leukemia. Blast counts in peripheral blood was ≤ 2%. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in BMA/reappearance of numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%.
Phase 2 Part: Duration of Response (DoR)	From the date of achieving CR, CRp, CRi/PR up to the date of documented relapse (maximum duration: approximately 4.4 years)	DoR: period from first day of achieving CR, CRp, CRi/partial remission (PR) to first day of relapse. KM estimate was used for analysis. CR: morphologically leukemia-free state at post-baseline visit, having neutrophil count of ≥ 1,000/mm\^3 \& platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods \& extramedullary leukemia. Peripheral blood blast counts was ≤ 2%. CRp: met all CR criteria at post-baseline visit, except unrecovered platelet count (\< 100,000/mm\^3). CRi: met all CR criteria at post-baseline visit, except unrecovered neutrophil count (\< 1,000/mm\^3). PR: condition with regeneration of normal hematopoietic cells in bone marrow, no detectable blasts, ≥ 50% decrease of blasts in BMA \& total bone marrow blasts of 5-25%. No evidence of extramedullary leukemia. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in BMA/reappearance of numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%.
Phase 2 Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs)	From the date of first dose up to 30 days after the last dose (approximately up to 4.4 years)	An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE could therefore be any unfavorable \& unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. TEAE for Phase 2 was defined as an AE observed after the date of first dose until 30 days after the last dose. TEAE included both serious and non-serious AEs.

Trial Locations

Locations (55): Site JP81037
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Anjo, Aichi, Japan
Site JP00003
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Nagoya, Aichi, Japan
Site JP81003
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Nagoya, Aichi, Japan
Site JP81038
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Toyohashi, Aichi, Japan
Site JP81027
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Nagoya, Aichi, Japan
Site JP81010
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Narita, Chiba, Japan
Site JP81039
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Matsuyama, Ehime, Japan
Site JP81007
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Yoshida-gun, Fukui, Japan
Site JP00002
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Maebashi, Gunma, Japan
Site JP81001
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Maebashi, Gunma, Japan
Site JP81026
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Fukuyama, Hiroshima, Japan
Site JP81018
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Otake, Hiroshima, Japan
Site JP81014
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Sapporo, Hokkaido, Japan
Site JP81015
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Sapporo, Hokkaido, Japan
Site JP81043
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Himeji, Hyogo, Japan
Site JP00007
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Kobe, Hyogo, Japan
Site JP81006
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Kobe, Hyogo, Japan
Site JP81036
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Mito, Ibaraki, Japan
Site JP81023
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Tsukuba, Ibaraki, Japan
Site JP81020
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Kanazawa, Ishikawa, Japan
Site JP81013
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Isehara, Kanagawa, Japan
Site JP00006
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Yokohama, Kanagawa, Japan
Site JP81005
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Yokohama, Kanagawa, Japan
Site JP81024
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Yokohama, Kanagawa, Japan
Site JP81035
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Sendai, Miyagi, Japan
SIte JP81011
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Omura, Nagasaki, Japan
Site JP81041
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Tenri, Nara, Japan
Site JP81022
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Shimono, Tochigi, Japan
Site JP81040
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Bunkyo-ku, Tokyo, Japan
Site JP00005
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Shinagawa-ku, Tokyo, Japan
Site JP81032
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Shinagawa-ku, Tokyo, Japan
Site JP81029
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Akita, Japan
Site JP81008
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Chiba, Japan
Site JP00001
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Fukuoka, Japan
Site JP81004
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Fukuoka, Japan
Site JP81025
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Fukuoka, Japan
Site JP81031
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Fukushima, Japan
Site JP81030
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Gifu, Japan
Site JP81033
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Kochi, Japan
Site JP81028
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Kumamoto, Japan
Site JP81016
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Kyoto, Japan
Site JP81012
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Nagasaki, Japan
Site JP81009
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Okayama, Japan
Site JP81019
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Osaka, Japan
Site JP81021
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Osaka, Japan
Site KR82005
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Busan, Korea, Republic of
Site KR82002
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Incheon, Korea, Republic of
Site KR82001
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Seoul, Korea, Republic of
Site KR82003
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Seoul, Korea, Republic of
Site KR82004
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Seoul, Korea, Republic of
Site KR82006
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Seoul, Korea, Republic of
Site TW88604
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Kaohsiung, Taiwan
Site TW88602
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Taichung, Taiwan
Site TW88601
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Tainan, Taiwan
Site TW88603
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Taoyuan, Taiwan