Dose Escalation Study Investigating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics of ASP2215 in Patients With Relapsed or Refractory Acute Myeloid Leukemia

Phase 1

Completed

Conditions: Acute Myeloid Leukemia

Interventions: Drug: Gilteritinib
Drug: Cephalexin
Drug: Voriconazole
Drug: Midazolam

Registration Number: NCT02014558

Lead Sponsor: Astellas Pharma Global Development, Inc.

Brief Summary: The objective of this study was to assess the safety and tolerability, including the maximum tolerated dose, of gilteritinib in participants with relapsed or treatment-refractory acute myeloid leukemia (AML). This study also determined the pharmacokinetic (PK) parameters of gilteritinib.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 265

Inclusion Criteria

Subject is defined as morphologically documented primary or secondary AML by the World Health Organization (WHO) criteria (2008) and fulfills one of the following:
- Refractory to at least 1 cycle of induction chemotherapy
- Relapsed after achieving remission with a prior therapy
Subject has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
Subject's interval from prior treatment to time of study drug administration is at least 2 weeks for cytotoxic agents (except hydroxyurea given for controlling blast cells), or at least 5 half-lives for prior experimental agents or noncytotoxic agents.
Subject must meet the following criteria as indicated on the clinical laboratory tests*:
- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 x institutional upper limit normal (ULN)
- Total serum bilirubin < 1.5x institutional ULN
- Serum creatinine < 1.5 x institutional ULN or an estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation.
Subject agrees not to participate in another interventional study while on treatment.

Exclusion Criteria

Subject was diagnosed as acute promyelocytic leukemia (APL).
Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
Subject has active malignant tumors other than AML or Myelodysplastic syndrome (MDS).
Subject has persistent nonhematological toxicities of >= Grade 2 (Common Terminology Criteria for Adverse Events v4), with symptoms and objective findings, from prior AML treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental agents, radiation, or surgery).
Subject has had hematopoietic stem cell transplant (HSCT) and meets any of the following:
- Is within 2 months of transplant from C1D1
- Has clinically significant graft-versus-host disease requiring treatment
- Has >= Grade 2 persistent non-hematological toxicity related to the transplant. Donor lymphocytes infusion (DLI) is not permitted <= 30 days prior to study registration or during the first cycle of treatment on the study in Cohort 1 and first two cycles of the treatment in Cohort 2
Subject has clinically active central nervous system leukemia
Subject has disseminated intravascular coagulation abnormality (DIC)
Subject has had major surgery within 4 weeks prior to the first study dose.
Subject has had radiation therapy within 4 weeks prior to the first study dose
Subject has congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subject with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram performed within 3 months prior to study entry results in a left ventricular ejection fraction that is ≥ 45%
Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of Cytochrome P450-isozyme3A4 (CYP3A4) with the exception of antibiotics, antifungals, and antivirals that are used as standard of care post-transplant or to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the subject
Subject required treatment with concomitant drugs that target serotonin 5HT1R or 5HT2BR receptors or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the subject.
Subject has an active uncontrolled infection
Subject is known to have human immunodeficiency virus infection
Subject has active hepatitis B or C, or other active hepatic disorder

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Gilteritinib 20 mg in Expansion Phase	Gilteritinib	Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2.
Gilteritinib 200 mg in Expansion Phase	Cephalexin	Participants received 200 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.
Gilteritinib 20 mg in Escalation Phase	Gilteritinib	Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Gilteritinib 20 mg in Escalation Phase	Voriconazole	Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Gilteritinib 40 mg in Escalation Phase	Gilteritinib	Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Gilteritinib 120 mg in Escalation Phase	Gilteritinib	Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Gilteritinib 80 mg in Escalation Phase	Gilteritinib	Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Gilteritinib 40 mg in Expansion Phase	Gilteritinib	Participants received 40 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.
Gilteritinib 200 mg in Escalation Phase	Gilteritinib	Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Gilteritinib 300 mg in Escalation Phase	Gilteritinib	Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Gilteritinib 450 mg in Escalation Phase	Gilteritinib	Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Gilteritinib 120 mg in Expansion Phase	Gilteritinib	Participants received 120 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.
Gilteritinib 80 mg in Expansion Phase	Gilteritinib	Participants received 80 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.
Gilteritinib 200 mg in Expansion Phase	Gilteritinib	Participants received 200 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.
Gilteritinib 300 mg in Expansion Phase	Gilteritinib	Participants received 300 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.
Gilteritinib 300 mg in Expansion Phase	Midazolam	Participants received 300 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Dose Limiting Toxicities (DLTs)	From first dose up to end of cycle 1 (30 days)	To determine the maximum tolerated dose, safety was assessed by DLTs, defined as any grade ≥ 3 non-hematologic or extramedullary toxicity that occurred within 30 days starting with the first dose taken on day -2, and included the first treatment cycle in the dose escalation phase and in the first treatment cycle (28 days) in the dose expansion phase, that was considered to be possibly or probably related to study drug. Exceptions to this were the following: (1) Alopecia, anorexia or fatigue, (2) Grade 3 nausea and/or vomiting if not required tube feeding or total parenteral nutrition, or diarrhea if not required or prolonged hospitalization that was managed to grade ≤ 2 with standard antiemetic or antidiarrheal medications used at prescribed dose within 7 days of onset, (3) Grade 3 fever with neutropenia, with or without infection, (4) Grade 3 infection.
Number of Participants With Adverse Events (AEs)	From first dose of study drug up to 30 days after last dose of study drug (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A treatment-emergent AE (TEAE) was defined as an AE observed after starting administration of the study drug up to 30 days after last dose of study drug (for participants who underwent hematopoietic stem cell transplantation \[HSCT\]: defined as AEs observed after starting study drug until the last dose before on study HSCT plus 30 days, and AEs that began after resumption of gilteritinib and within 30 days after the last dose of gilteritinib). AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (1-Mild, 2-Moderate, 3-Severe, 4-LifeThreatening, 5-Death).
Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib	Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose	Plasma samples were used for pharmacokinetic assessments.
Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib	Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose	Plasma samples were used for pharmacokinetic assessments.
Accumulation Ratio After Multiple Doses of Gilteritinib	Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose	Plasma samples were used for pharmacokinetic assessments.
Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib	Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose	Plasma samples were used for pharmacokinetic assessments.
Area Under the Concentration-time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) After Single and Multiple Doses of Gilteritinib	Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose	Plasma samples were used for pharmacokinetic assessments.
Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib	Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose	Plasma samples were used for pharmacokinetic assessments.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Complete Remission (CR) During the First 2 Cycles	During the first 2 cycles (56 days)	CR was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CR when they had bone marrow regenerating normal hematopoietic cells, achieved a morphologic leukemia-free state, had an absolute neutrophil count (ANC) \> 1 x 10\^9/L, platelet count ≥ 100 x 10\^9/L, normal marrow differential with \< 5% blasts, had been red blood cell (RBC) and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion), had no presence of Auer rods and no evidence of extramedullary leukemia, and blast counts in peripheral blood had been ≤ 2%. Exact 95% confidence interval was estimated using binomial distribution.
Percentage of Participants With CR During Treatment	Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	CR was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CR when they had bone marrow regenerating normal hematopoietic cells, achieved a morphologic leukemia-free state, had an absolute neutrophil count (ANC) \> 1 x 10\^9/L, platelet count ≥ 100 x 10\^9/L, normal marrow differential with \< 5% blasts, had been red blood cell (RBC) and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion), had no presence of Auer rods and no evidence of extramedullary leukemia, and blast counts in peripheral blood had been ≤ 2%. Exact 95% confidence interval was estimated using binomial distribution.
Percentage of Participants With CR With Incomplete Platelet Recovery (CRp)	Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	CRp was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CRp when they achieved CR except for incomplete platelet recovery (\< 100 x 10\^9/L). Exact 95% confidence interval was estimated using the binomial distribution.
Percentage of Participants With CR With Incomplete Hematological Recovery (CRi)	Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	CRi was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CRi when they fulfilled all the criteria for CR except for incomplete hematological recovery with residual neutropenia \< 1 x 10\^9/L with or without complete platelet recovery. RBC and platelet transfusion independence were not required. Exact 95% confidence interval was estimated using the binomial distribution.
Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh)	Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	CRh was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CRh when they could not be classified as being in CR and had bone marrow blasts \< 5% and partial hematologic recovery ANC \>= 0.5 x 10\^9/L and platelets \>= 50 x 10\^9/L. There should not be evidence of extramedullary leukemia. Exact 95% confidence interval was estimated using the binomial distribution. CRh was calculated only for participants who were FLT3 mutation positive.
Percentage of Participants With Composite CR (CRc)	Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	CRc was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CRc when they had achieved either CR, complete remission with incomplete platelet recovery (CRp, defined as had achieved CR except for incomplete platelet recovery (\< 100 x 10\^9/L) or complete remission with incomplete hematologic recovery (CRi, defined as had fulfilled all the criteria for CR except for incomplete hematological recovery with residual neutropenia \< 1 x 10\^9/L with or without complete platelet recovery; RBC platelet transfusion independence not required). Exact 95% confidence interval was estimated using the binomial distribution.
Percentage of Participants With Partial Remission (PR)	Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	PR was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in PR when they had bone marrow regenerating normal hematopoietic cells with evidence of peripheral recovery with no (or only a few regenerating) circulating blasts and with a decrease of at least 50% in the percentage of blasts in the bone marrow aspirate with the total marrow blasts between 5% and 25%. A value of less or equal than 5% blasts was also considered a PR if Auer rods were present. There should be no evidence of extramedullary leukemia. Exact 95% confidence interval was estimated using the binomial distribution.
Time to CRp (TTCRp)	From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	TTCRp was defined as the time from the first dose of study drug until the date of first CRp. TTCRp was evaluated for participants who achieved CRp.
Percentage of Participants With Best Response	Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	Best response was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). BR was defined as the best measured response for all visits (in the order of CR, CRp, CRi, and PR) post-treatment. Participants who achieved the best response of CR, CRp, CRi or PR were classified as responders. Participants who did not achieve at least PR were considered as non-responders. Exact 95% confidence interval was estimated using the binomial distribution.
Percentage of Participants With Complete Remission and Complete Remission With Partial Hematologic Recovery (CR/CRh)	Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	Participants with CR/CRh were defined as participants who achieved either CR or CRh. Participants with CR had bone marrow regenerating normal hematopoietic cells, achieved a morphologic leukemia-free state, had an ANC \> 1 x 10\^9/L, platelet count ≥ 100 x 10\^9/L, and normal marrow differential with \< 5% blasts, had been RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). Also, there had been no presence of Auer rods, no evidence of extramedullary leukemia, and blast counts in peripheral blood had been ≤ 2%. Participants with CRh could not be classified as being in CR and had bone marrow blasts \< 5%, partial hematologic recovery ANC \>= 0.5 x 10\^9/L and platelets \>= 50 x 10\^9/L. There should not be evidence of extramedullary leukemia. Exact 95% confidence interval was estimated using the binomial distribution. CR/CRh was calculated only for participants who were FLT3 mutation positive.
Duration of CR (DCR)	From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	DCR was defined as the time from the date of first CR until the date of documented relapse for participants who achieved CR. Participants who died without report of relapse were considered non-events and censored at their last relapse-free disease assessment date. Other participants who did not relapse on study were considered non-events and censored at the last relapse-free disease assessment date. DCR was calculated using Kaplan-Meier method and therefore data are estimated.
Duration of CRp (DCRp)	From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	DCRp was defined as the time from the date of first CRp until the date of documented relapse for participants who achieved CRp. Participants who died without report of relapse were considered non-events and censored at their last relapse-free disease assessment date. Other participants who did not relapse on study were considered non-events and censored at the last relapse-free disease assessment date. DCRp was calculated using Kaplan-Meier method and therefore data are estimated.
Duration of CRi (DCRi)	From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	DCRi was defined as the time from the date of first CRi until the date of documented relapse for participants who achieved CRi. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. DCRi was calculated using Kaplan-Meier method and therefore data are estimated.
Duration of CRh (DCRh)	From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	DCRh was defined as the time from the date of first CRh until the date of documented relapse for participants who achieved CRh but did not have a best response of CR. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. DCRh was calculated using Kaplan-Meier method and therefore data are estimated. DCRh was calculated only for participants who were FLT3 mutation positive.
Duration of CRc (DCRc)	From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	DCRc was defined as the time from the date of first CRc until the date of documented relapse for participants who achieved CRc. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. DCRc was calculated using Kaplan-Meier method and therefore data are estimated.
Duration of CR/CRh (DCRCRh)	From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	DCRCRh was defined as the time from the date of first DCRCRh until the date of documented relapse for participants who achieved CR or CRh. For participants who achieved both CR and CRh, the first CR date or CRh date, whichever occurred first, was used. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. DCRCRh was calculated using Kaplan-Meier method and therefore data are estimated. DCRCRh was calculated only for participants who were FLT3 mutation positive.
Duration of Response	From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	Duration of response was defined as the time from the date of either first CRc or PR until the date of documented relapse of any type for participants who achieved CRc or PR. Participants who died without report of relapse were considered non-events and censored at their last relapse-free disease assessment date. Other participants who did not relapse on study are considered non-events and censored at the last relapse-free assessment date. Duration of response was calculated using Kaplan-Meier method and therefore data are estimated.
Time to CR (TTCR)	From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	TTCR was defined as the time from the first dose of study drug until the date of first CR.
Time to CRi (TTCRi)	From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	TTCRi was defined as the time from the first dose of study drug until the date of first CRi. TTCRi was evaluated for participants who achieved CRi.
Time to First CR/CRh (TTFCRCRh)	From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	TTFCRCRh was defined as the time from the first dose of study drug until the date of first either CR or CRh. TTFCRCRh was evaluated for participants who achieved CR or CRh. For participants who achieve both CR and CRh, the first CR date or CRh date, whichever occurs first was used. TTFCRCRh was calculated only for participants who were FLT3 mutation positive.
Time to Best CR/CRh (TTBCRCRh)	From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	TTBCRCRh was defined as the time from the first dose of study drug until the first date that the best response of CR or CRh was achieved. TTBCRCRh was evaluated for participants who achieved CR or CRh. For participants who achieve both CR and CRh, the first CR date was used. TTBCRCRh was calculated only for participants who were FLT3 mutation positive.
Time to CRc (TTCRc)	From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	TTCRc was defined as the time from the first dose of study drug until the date of first CRc. TTCRc was evaluated for participants who achieved CRc.
Time to Response (TTR)	From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	TTR was defined as the time from the first dose of study drug until the date of either first CRc or PR. TTR was evaluated for participants who achieved CRc or PR.
Time to Best Response (TTBR)	From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)	TTBR was defined as the time from the first dose of study drug until the first disease assessment date when participant achieved best response. TTBR was evaluated in participants who achieved best response of CR, CRp, CRi, or PR.
Overall Survival (OS)	From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days)	The time from the date of first dose of study drug until the date of death from any cause. For a participant who was not known to have died by the end of study follow-up, OS was censored at the date of last contact. OS was calculated using Kaplan-Meier method and therefore data are estimated.
Event Free Survival (EFS)	From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days)	EFS was defined as the time from the date of first dose of study drug until the date of documented relapse, treatment failure or death from any cause, whichever occurred first. For a participant with none of these events, EFS was censored at the date of last relapse-free disease assessment. A participant without post-treatment disease assessment was censored at randomization date. Treatment failure included those participants who discontinued the treatment due to "progressive disease" or "lack of efficacy" without a previous response of CR, CRp, CRi or PR. Treatment failure date referred to the start of new anti-leukemia therapy or the last treatment evaluation date when new anti-leukemia therapy date was not available. For participants who were censored, last relapse-free disease assessment date referred to the participant's last disease assessment date. EFS was calculated using Kaplan-Meier method and therefore data are estimated.
Leukemia Free Survival (LFS)	From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days)	LFS was defined as the time from the date of first CRc until the date of documented relapse or death for participants who achieved CRc. For a participant who was not known to have relapsed or died, LFS was censored on the date of last relapse-free disease assessment date. LFS was calculated using Kaplan-Meier method and therefore data are estimated.
T1/2 of Cephalexin Administered With and Without Gilteritinib	Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)	Plasma samples were used for pharmacokinetic assessments.
Percentage of Participants Who Achieved Transfusion Conversion	Baseline (28 days prior to first dose until 28 days after the first dose) and postbaseline (from 29 days after first dose date until last dose date); median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days	Participants who achieved transfusion conversion were defined as the number of participants who were transfusion dependent at baseline period but became transfusion independent at post-baseline period divided by the total number of participants who were transfusion dependent at baseline period. Participants were considered baseline transfusion dependent if there were RBC or platelet transfusions within the baseline period. Participants were considered post-baseline transfusion independent if they were on treatment \>=84 days, and if there was one consecutive 56 days without any RBC or platelet transfusion within post-baseline period. If participants were on treatment \>28 days but \<84 days, and there was no RBC or platelet transfusion within post-baseline period, or on treatment \<=28 days, post-baseline transfusion status was not evaluable. Exact 95% confidence interval was estimated using the binomial distribution.
Percentage of Participants Who Achieved Transfusion Maintenance	Baseline (28 days prior to first dose until 28 days after the first dose) and postbaseline (from 29 days after first dose date until last dose date); median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days	Participants who achieved transfusion maintenance were defined as the number of participants who were transfusion independent at baseline period and still maintained transfusion independent at post-baseline period divided by the total number of participants who were transfusion independent at baseline period.
AUC24 of Gilteritinib in Co-administration With Voriconazole	Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)	Plasma samples were used for pharmacokinetic assessments.
Cmax of Gilteritinib in Co-administration With Voriconazole	Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)	Plasma samples were used for pharmacokinetic assessments.
AUClast of Gilteritinib in Co-administration With Voriconazole	Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)	Plasma samples were used for pharmacokinetic assessments.
Tmax of Gilteritinib in Co-administration With Voriconazole	Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)	Plasma samples were used for pharmacokinetic assessments.
AUC24 of Midazolam Administered With and Without Gilteritinib	Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)	Plasma samples were used for pharmacokinetic assessments.
AUC24 of Metabolite 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib	Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)	Plasma samples were used for pharmacokinetic assessments.
Cmax of Midazolam Administered With and Without Gilteritinib	Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)	Plasma samples were used for pharmacokinetic assessments.
Cmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib	Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)	Plasma samples were used for pharmacokinetic assessments.
AUClast of Midazolam Administered With and Without Gilteritinib	Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)	Plasma samples were used for pharmacokinetic assessments.
AUClast of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib	Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)	Plasma samples were used for pharmacokinetic assessments.
Tmax of Midazolam Administered With and Without Gilteritinib	Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)	Plasma samples were used for pharmacokinetic assessments.
Tmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib	Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)	Plasma samples were used for pharmacokinetic assessments.
Area Under the Concentration-time Curve From the Time of Dosing Extrapolated to Time Infinity (AUCinf) of Cephalexin Administered With and Without Gilteritinib	Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)	Plasma samples were used for pharmacokinetic assessments.
Cmax of Cephalexin Administered With and Without Gilteritinib	Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)	Plasma samples were used for pharmacokinetic assessments.
AUClast of Cephalexin Administered With and Without Gilteritinib	Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)	Plasma samples were used for pharmacokinetic assessments.
Tmax of Cephalexin Administered With and Without Gilteritinib	Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)	Plasma samples were used for pharmacokinetic assessments.
Apparent Total Systemic Clearance After Single or Multiple Extravascular Dosing (CL/F) of Cephalexin Administered With and Without Gilteritinib	Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)	Plasma samples were used for pharmacokinetic assessments.
Apparent Volume of Distribution During the Terminal Elimination Phase After Single Extravascular Dosing (Vz/F) of Cephalexin Administered With and Without Gilteritinib	Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)	Plasma samples were used for pharmacokinetic assessments.
Amount of Drug Excreted in Urine (Aelast) of Cephalexin Administered With and Without Gilteritinib	Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)	Urine samples were used for pharmacokinetic assessments.
Fraction of Drug Excreted Into Urine in Percentage (%Ae) of Cephalexin Administered With and Without Gilteritinib	Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)	Urine samples were used for pharmacokinetic assessments.
Renal Clearance (CLr) of Cephalexin in Administered With and Without Gilteritinib	Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)	Urine samples were used for pharmacokinetic assessments.

Trial Locations

Locations (26): Site US10018
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Hershey, Pennsylvania, United States
Site US10015
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Chicago, Illinois, United States
Site US10020
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Hackensack, New Jersey, United States
Site US10008
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Los Angeles, California, United States
Site US10001
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Chicago, Illinois, United States
Site US10003
🇺🇸
Baltimore, Maryland, United States
Site US10013
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New York, New York, United States
Site US10023
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Scottsdale, Arizona, United States
Site US10010
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Buffalo, New York, United States
Site US10009
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New York, New York, United States
Site US10019
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New York, New York, United States
Site IT39001
🇮🇹
Bologna, Italy
Site US10012
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Baltimore, Maryland, United States
Site US10002
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Houston, Texas, United States
Site US10022
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Duarte, California, United States
Site US10014
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Cleveland, Ohio, United States
Site US10026
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Fairfax, Virginia, United States
Site US10004
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Philadelphia, Pennsylvania, United States
Site DE49002
🇩🇪
Berlin, Germany
Site DE49004
🇩🇪
Dresden, Germany
Site US10011
🇺🇸
Rochester, Minnesota, United States
Site US10021
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Birmingham, Alabama, United States
Site US10005
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San Francisco, California, United States
Site US10006
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Minneapolis, Minnesota, United States
Site US10017
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Charleston, South Carolina, United States
Site US10007
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Nashville, Tennessee, United States