Acute Myeloid Leukemia
Conditions
Keywords
Acute Myeloid Leukemia, Gilteritinib, ASP2215
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.
Interventions
DRUGGilteritinib
Participants received gilteritinib oral tablets (10 mg, 40 mg or 100 mg, depending on the dose) once daily without food allowed for at least 2 hours before and 1 hour after dosing starting from day -2 and day of cycle 1, for continuous 28-day cycles.
DRUGVoriconazole
Participants received 200 mg voriconazole tablets daily every 12 hours starting from day 16 of cycle 1 through day 1 of cycle 2.
DRUGMidazolam
Participants received a single oral dose of 2 mg of midazolam syrup on day -1 and day 15 of cycle 1.
DRUGCephalexin
Participants received a single oral dose of 500 mg cephalexin tablet or capsule on day -1 and day 15 of cycle 1.
Sponsors
Astellas Pharma Global Development, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Germany, Italy, United States
Participant flow
Recruitment details
This dose-escalation/dose-expansion study was conducted in sites in the United States, France, Germany and Italy. The study had 7 dose-escalation cohorts with ≥3 participants enrolled at each dose level. Following escalation to the next dose cohort, additional participants were enrolled to the dose-expansion cohorts per protocol-specified criteria.
Pre-assignment details
Participants with acute myeloid leukemia (AML) who relapsed after or were refractory to induction or salvage treatment were selected for this study. Five participants were re-enrolled into the dose-expansion cohorts as they discontinued treatment for reasons other than toxicity or disease progression, as long as they met the eligibility criteria.
Participants by arm
| Arm | Count |
|---|---|
| Gilteritinib 20 mg in Escalation Phase 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. | 5 |
| Gilteritinib 40 mg in Escalation Phase 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. | 3 |
| Gilteritinib 80 mg in Escalation Phase 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. | 3 |
| Gilteritinib 120 mg in Escalation Phase 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. | 3 |
| Gilteritinib 200 mg in Escalation Phase 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. | 3 |
| Gilteritinib 300 mg in Escalation Phase 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. | 3 |
| Gilteritinib 450 mg in Escalation Phase 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. | 3 |
| Gilteritinib 20 mg in Expansion Phase 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. | 12 |
| Gilteritinib 40 mg in Expansion Phase 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. | 13 |
| Gilteritinib 80 mg in Expansion Phase 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. | 21 |
| Gilteritinib 120 mg in Expansion Phase 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. | 66 |
| Gilteritinib 200 mg in Expansion Phase 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. | 100 |
| Gilteritinib 300 mg in Expansion Phase 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. | 17 |
| Total | 252 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 2 | 2 | 5 | 21 | 3 |
| Overall Study | Death | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 2 | 5 | 5 | 19 | 2 |
| Overall Study | Lack of Efficacy | 1 | 2 | 1 | 1 | 0 | 0 | 1 | 3 | 3 | 3 | 16 | 8 | 5 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Miscellaneous | 2 | 1 | 1 | 1 | 0 | 1 | 0 | 1 | 1 | 3 | 12 | 11 | 1 |
| Overall Study | Never Received Study Drug | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 2 | 0 | 2 | 2 | 0 |
| Overall Study | Progressive Disease | 1 | 0 | 1 | 1 | 1 | 2 | 1 | 6 | 5 | 6 | 22 | 31 | 6 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 2 | 6 | 10 | 0 |
Baseline characteristics
| Characteristic | Gilteritinib 20 mg in Escalation Phase | Total | Gilteritinib 300 mg in Expansion Phase | Gilteritinib 200 mg in Expansion Phase | Gilteritinib 120 mg in Expansion Phase | Gilteritinib 80 mg in Expansion Phase | Gilteritinib 40 mg in Expansion Phase | Gilteritinib 20 mg in Expansion Phase | Gilteritinib 450 mg in Escalation Phase | Gilteritinib 300 mg in Escalation Phase | Gilteritinib 200 mg in Escalation Phase | Gilteritinib 120 mg in Escalation Phase | Gilteritinib 80 mg in Escalation Phase | Gilteritinib 40 mg in Escalation Phase |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 65.8 years STANDARD_DEVIATION 6.8 | 59 years STANDARD_DEVIATION 15.1 | 57.7 years STANDARD_DEVIATION 15.9 | 59.8 years STANDARD_DEVIATION 14.6 | 58.3 years STANDARD_DEVIATION 16.7 | 56.3 years STANDARD_DEVIATION 18.1 | 59.6 years STANDARD_DEVIATION 14 | 59.3 years STANDARD_DEVIATION 15.6 | 61.7 years STANDARD_DEVIATION 10.7 | 55.3 years STANDARD_DEVIATION 25 | 64 years STANDARD_DEVIATION 1 | 61.7 years STANDARD_DEVIATION 6 | 61 years STANDARD_DEVIATION 8.7 | 56.7 years STANDARD_DEVIATION 6.7 |
| Duration of Disease (AML) | 19.70 months STANDARD_DEVIATION 24.62 | 13.16 months STANDARD_DEVIATION 14.97 | 12.09 months STANDARD_DEVIATION 17.76 | 10.9 months STANDARD_DEVIATION 9.94 | 12.65 months STANDARD_DEVIATION 11.33 | 16.3 months STANDARD_DEVIATION 9.85 | 10.53 months STANDARD_DEVIATION 11.22 | 11.3 months STANDARD_DEVIATION 6.61 | 7.21 months STANDARD_DEVIATION 4.27 | 19.75 months | 9.46 months STANDARD_DEVIATION 2.23 | 49.53 months STANDARD_DEVIATION 72.17 | 62.46 months STANDARD_DEVIATION 6.97 | 10.81 months STANDARD_DEVIATION 8.58 |
| Ethnicity Hispanic or Latino | 0 Participants | 11 Participants | 0 Participants | 3 Participants | 4 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity Not Hispanic or Latino | 5 Participants | 241 Participants | 17 Participants | 97 Participants | 62 Participants | 20 Participants | 12 Participants | 11 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 3 Participants |
| Local FLT3 Mutation Status Negative | 1 Participants | 58 Participants | 9 Participants | 10 Participants | 13 Participants | 12 Participants | 8 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Local FLT3 Mutation Status Positive | 4 Participants | 194 Participants | 8 Participants | 90 Participants | 53 Participants | 9 Participants | 5 Participants | 11 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 7 Participants | 0 Participants | 4 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 16 Participants | 3 Participants | 4 Participants | 2 Participants | 4 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 16 Participants | 1 Participants | 1 Participants | 6 Participants | 3 Participants | 4 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 213 Participants | 13 Participants | 91 Participants | 57 Participants | 14 Participants | 9 Participants | 10 Participants | 3 Participants | 3 Participants | 1 Participants | 2 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Female | 2 Participants | 123 Participants | 5 Participants | 49 Participants | 37 Participants | 12 Participants | 4 Participants | 8 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 129 Participants | 12 Participants | 51 Participants | 29 Participants | 9 Participants | 9 Participants | 4 Participants | 3 Participants | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 5 | 2 / 3 | 3 / 3 | 3 / 3 | 2 / 3 | 3 / 3 | 3 / 3 | 10 / 12 | 13 / 13 | 21 / 21 | 53 / 66 | 82 / 100 | 16 / 17 |
| other Total, other adverse events | 5 / 5 | 2 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 12 / 12 | 12 / 13 | 20 / 21 | 62 / 66 | 97 / 100 | 16 / 17 |
| serious Total, serious adverse events | 2 / 5 | 2 / 3 | 2 / 3 | 1 / 3 | 2 / 3 | 2 / 3 | 2 / 3 | 8 / 12 | 12 / 13 | 19 / 21 | 52 / 66 | 92 / 100 | 14 / 17 |
Outcome results
Primary
Accumulation Ratio After Multiple Doses of Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Population: The analysis population was the PKAS with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Accumulation Ratio After Multiple Doses of Gilteritinib | 4.259 ratio | Standard Deviation 1.069 |
| Gilteritinib 40 mg in Escalation Phase | Accumulation Ratio After Multiple Doses of Gilteritinib | 9.640 ratio | Standard Deviation 7.754 |
| Gilteritinib 80 mg in Escalation Phase | Accumulation Ratio After Multiple Doses of Gilteritinib | 5.693 ratio | Standard Deviation 1.442 |
| Gilteritinib 120 mg in Escalation Phase | Accumulation Ratio After Multiple Doses of Gilteritinib | 3.290 ratio | Standard Deviation 1.118 |
| Gilteritinib 200 mg in Escalation Phase | Accumulation Ratio After Multiple Doses of Gilteritinib | 9.041 ratio | Standard Deviation 3.693 |
| Gilteritinib 300 mg in Escalation Phase | Accumulation Ratio After Multiple Doses of Gilteritinib | 9.057 ratio | Standard Deviation 3.303 |
Primary
Area Under the Concentration-time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) After Single and Multiple Doses of Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Population: The analysis population was the PKAS with available data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Area Under the Concentration-time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) After Single and Multiple Doses of Gilteritinib | Cycle 1 day -15 | 1030 ng*h/mL | Standard Deviation 984.2 |
| Gilteritinib 20 mg in Escalation Phase | 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 | 303.0 ng*h/mL | Standard Deviation 207.1 |
| Gilteritinib 40 mg in Escalation Phase | 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 | 360.4 ng*h/mL | Standard Deviation 224.1 |
| Gilteritinib 40 mg in Escalation Phase | Area Under the Concentration-time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) After Single and Multiple Doses of Gilteritinib | Cycle 1 day -15 | 1990 ng*h/mL | Standard Deviation 1422 |
| Gilteritinib 80 mg in Escalation Phase | 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 | 1216 ng*h/mL | Standard Deviation 472.6 |
| Gilteritinib 80 mg in Escalation Phase | Area Under the Concentration-time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) After Single and Multiple Doses of Gilteritinib | Cycle 1 day -15 | 7111 ng*h/mL | Standard Deviation 3525 |
| Gilteritinib 120 mg in Escalation Phase | Area Under the Concentration-time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) After Single and Multiple Doses of Gilteritinib | Cycle 1 day -15 | 6943 ng*h/mL | Standard Deviation 3221 |
| Gilteritinib 120 mg in Escalation Phase | 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 | 2480 ng*h/mL | Standard Deviation 1972 |
| Gilteritinib 200 mg in Escalation Phase | 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 | 3024 ng*h/mL | Standard Deviation 846.2 |
| Gilteritinib 200 mg in Escalation Phase | Area Under the Concentration-time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) After Single and Multiple Doses of Gilteritinib | Cycle 1 day -15 | 32248 ng*h/mL | Standard Deviation 22571 |
| Gilteritinib 300 mg in Escalation Phase | 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 | 4181 ng*h/mL | Standard Deviation 3189 |
| Gilteritinib 300 mg in Escalation Phase | Area Under the Concentration-time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) After Single and Multiple Doses of Gilteritinib | Cycle 1 day -15 | 31749 ng*h/mL | Standard Deviation 10090 |
| Gilteritinib 450 mg in Escalation Phase | Area Under the Concentration-time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) After Single and Multiple Doses of Gilteritinib | Cycle 1 day -15 | 35506 ng*h/mL | — |
| Gilteritinib 450 mg in Escalation Phase | 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 | 2544 ng*h/mL | Standard Deviation 1427 |
Primary
Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Population: Pharmacokinetics analysis set (PKAS) - consisted of the subset of the SAF for which sufficient plasma concentration data were available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known. Participants with available data were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib | Day -2 | 302.1 ng*h/mL | Standard Deviation 207 |
| Gilteritinib 20 mg in Escalation Phase | Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib | Cycle 1 Day 15 | 1299 ng*h/mL | Standard Deviation 1006 |
| Gilteritinib 40 mg in Escalation Phase | Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib | Day -2 | 360.0 ng*h/mL | Standard Deviation 223.5 |
| Gilteritinib 40 mg in Escalation Phase | Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib | Cycle 1 Day 15 | 2482 ng*h/mL | Standard Deviation 33.28 |
| Gilteritinib 80 mg in Escalation Phase | Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib | Day -2 | 1216 ng*h/mL | Standard Deviation 472.6 |
| Gilteritinib 80 mg in Escalation Phase | Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib | Cycle 1 Day 15 | 6958 ng*h/mL | Standard Deviation 3273 |
| Gilteritinib 120 mg in Escalation Phase | Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib | Day -2 | 2480 ng*h/mL | Standard Deviation 1972 |
| Gilteritinib 120 mg in Escalation Phase | Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib | Cycle 1 Day 15 | 6943 ng*h/mL | Standard Deviation 3221 |
| Gilteritinib 200 mg in Escalation Phase | Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib | Day -2 | 3022 ng*h/mL | Standard Deviation 843.6 |
| Gilteritinib 200 mg in Escalation Phase | Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib | Cycle 1 Day 15 | 31428 ng*h/mL | Standard Deviation 21412 |
| Gilteritinib 300 mg in Escalation Phase | Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib | Day -2 | 4163 ng*h/mL | Standard Deviation 3178 |
| Gilteritinib 300 mg in Escalation Phase | Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib | Cycle 1 Day 15 | 31005 ng*h/mL | Standard Deviation 10068 |
| Gilteritinib 450 mg in Escalation Phase | Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib | Day -2 | 3324 ng*h/mL | Standard Deviation 221.1 |
| Gilteritinib 450 mg in Escalation Phase | Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib | Cycle 1 Day 15 | 34768 ng*h/mL | — |
Comparison: Dose Proportionality (Single Dose / Day -2) was evaluated using the power model.90% CI: [0.788, 1.19]
Comparison: Dose Proportionality (Multiple Dose / Cycle 1 Day 15) was evaluated using the power model.90% CI: [1, 1.43]
Primary
Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Population: The analysis population was the PKAS with available data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib | Cycle 1 day 15 | 64.64 ng/mL | Standard Deviation 48.77 |
| Gilteritinib 20 mg in Escalation Phase | Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib | Day -2 | 28.13 ng/mL | Standard Deviation 21.49 |
| Gilteritinib 40 mg in Escalation Phase | Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib | Cycle 1 day 15 | 107.6 ng/mL | Standard Deviation 31.92 |
| Gilteritinib 40 mg in Escalation Phase | Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib | Day -2 | 24.98 ng/mL | Standard Deviation 14.58 |
| Gilteritinib 80 mg in Escalation Phase | Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib | Cycle 1 day 15 | 376.4 ng/mL | Standard Deviation 150.5 |
| Gilteritinib 80 mg in Escalation Phase | Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib | Day -2 | 75.29 ng/mL | Standard Deviation 25.22 |
| Gilteritinib 120 mg in Escalation Phase | Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib | Cycle 1 day 15 | 374.2 ng/mL | Standard Deviation 190.1 |
| Gilteritinib 120 mg in Escalation Phase | Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib | Day -2 | 136.7 ng/mL | Standard Deviation 94.37 |
| Gilteritinib 200 mg in Escalation Phase | Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib | Day -2 | 168.2 ng/mL | Standard Deviation 45.34 |
| Gilteritinib 200 mg in Escalation Phase | Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib | Cycle 1 day 15 | 1462 ng/mL | Standard Deviation 815.1 |
| Gilteritinib 300 mg in Escalation Phase | Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib | Day -2 | 204.3 ng/mL | Standard Deviation 136.4 |
| Gilteritinib 300 mg in Escalation Phase | Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib | Cycle 1 day 15 | 1525 ng/mL | Standard Deviation 664.6 |
| Gilteritinib 450 mg in Escalation Phase | Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib | Cycle 1 day 15 | 1528 ng/mL | — |
| Gilteritinib 450 mg in Escalation Phase | Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib | Day -2 | 207.6 ng/mL | Standard Deviation 51.81 |
Comparison: Dose Proportionality (Single Dose / Day -2) was evaluated using the power model.90% CI: [0.629, 0.988]
Comparison: Dose Proportionality (Multiple Dose / Cycle 1 Day 15) was evaluated using the power model.90% CI: [1.02, 1.41]
Primary
Number of Participants With Adverse Events (AEs)
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).
Time frame: 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)
Population: The analysis population was the SAF.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Deaths | 2 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related Serious AEs | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs Leading to Discont. of Study Drug | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Grade 3 or Higher TEAEs | 3 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs | 5 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Serious AEs | 2 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs During On-Study HSCT Period | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs | 3 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs Leading to Discontinuation of Study Drug | 2 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Serious AEs During On-Study HSCT | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs Leading to Discontinuation of Study Drug | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Serious AEs During On-Study HSCT | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs | 3 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related Serious AEs | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Deaths | 2 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs Leading to Discont. of Study Drug | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs | 2 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs During On-Study HSCT Period | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Grade 3 or Higher TEAEs | 2 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Serious AEs | 2 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs Leading to Discontinuation of Study Drug | 1 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Serious AEs During On-Study HSCT | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs | 1 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Deaths | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs | 3 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs During On-Study HSCT Period | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Serious AEs | 2 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Grade 3 or Higher TEAEs | 2 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related Serious AEs | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs Leading to Discont. of Study Drug | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs | 3 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Grade 3 or Higher TEAEs | 1 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Serious AEs | 1 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs Leading to Discontinuation of Study Drug | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs | 3 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Deaths | 1 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs During On-Study HSCT Period | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs Leading to Discont. of Study Drug | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Serious AEs During On-Study HSCT | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related Serious AEs | 1 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Grade 3 or Higher TEAEs | 2 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Deaths | 1 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs Leading to Discont. of Study Drug | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Serious AEs During On-Study HSCT | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Serious AEs | 2 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs | 3 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs Leading to Discontinuation of Study Drug | 1 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related Serious AEs | 1 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs During On-Study HSCT Period | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs | 3 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs Leading to Discont. of Study Drug | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs Leading to Discontinuation of Study Drug | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs | 3 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs During On-Study HSCT Period | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related Serious AEs | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Deaths | 1 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Serious AEs During On-Study HSCT | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs | 2 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Serious AEs | 2 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Grade 3 or Higher TEAEs | 2 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related Serious AEs | 2 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Grade 3 or Higher TEAEs | 3 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Deaths | 1 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Serious AEs During On-Study HSCT | 0 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs Leading to Discont. of Study Drug | 0 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs During On-Study HSCT Period | 0 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs Leading to Discontinuation of Study Drug | 1 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs | 3 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | AEs | 3 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Adverse Events (AEs) | Serious AEs | 2 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Serious AEs | 8 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs During On-Study HSCT Period | 0 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs | 12 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs | 7 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Deaths | 3 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related Serious AEs | 2 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs Leading to Discontinuation of Study Drug | 2 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs Leading to Discont. of Study Drug | 1 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Grade 3 or Higher TEAEs | 9 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Serious AEs During On-Study HSCT | 0 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Grade 3 or Higher TEAEs | 13 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs Leading to Discont. of Study Drug | 1 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Deaths | 4 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related Serious AEs | 1 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs During On-Study HSCT Period | 0 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Serious AEs During On-Study HSCT | 0 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs Leading to Discontinuation of Study Drug | 5 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs | 6 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Serious AEs | 12 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs | 13 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Serious AEs | 19 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Grade 3 or Higher TEAEs | 20 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs During On-Study HSCT Period | 0 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related Serious AEs | 10 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs | 20 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs Leading to Discontinuation of Study Drug | 11 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs Leading to Discont. of Study Drug | 4 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Deaths | 11 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Serious AEs During On-Study HSCT | 0 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs | 17 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs | 64 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs | 52 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs During On-Study HSCT Period | 3 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Serious AEs During On-Study HSCT | 0 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs Leading to Discont. of Study Drug | 5 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs Leading to Discontinuation of Study Drug | 12 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Serious AEs | 52 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related Serious AEs | 19 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Grade 3 or Higher TEAEs | 59 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Deaths | 23 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Deaths | 49 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related Serious AEs | 36 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs Leading to Discont. of Study Drug | 10 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Serious AEs | 92 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Serious AEs During On-Study HSCT | 3 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Grade 3 or Higher TEAEs | 99 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs | 77 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs During On-Study HSCT Period | 7 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs | 100 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs Leading to Discontinuation of Study Drug | 46 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs | 13 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Grade 3 or Higher TEAEs | 14 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Deaths | 7 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs | 17 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Serious AEs During On-Study HSCT | 0 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Serious AEs | 14 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related AEs Leading to Discont. of Study Drug | 3 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | Drug-Related Serious AEs | 4 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs During On-Study HSCT Period | 0 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Adverse Events (AEs) | AEs Leading to Discontinuation of Study Drug | 6 Participants |
Primary
Number of Participants With Dose Limiting Toxicities (DLTs)
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.
Time frame: From first dose up to end of cycle 1 (30 days)
Population: The analysis population was the SAF. Only evaluable participants (defined as participants who received at least 80% of the intended dose during cycle 1 \[received at least 23 daily doses in escalation phase or 22 daily doses in expansion phase during cycle 1\] or participants who developed DLT within cycle 1) were included.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | General disorders & administration site conditions | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Eye disorders | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Metabolism and nutrition disorders | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Investigations | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Cardiac disorders | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Renal and urinary disorders | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Respiratory, thoracic and mediastinal disorders | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Musculoskeletal and connective tissue disorders | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Hepatobiliary disorders | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Reproductive system and breast disorders | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Gastrointestinal disorders | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Any DLT | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Vascular disorders | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Infections and infestations | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Nervous system disorders | 0 Participants |
| Gilteritinib 20 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Blood and lymphatic system disorders | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Any DLT | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | General disorders & administration site conditions | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Infections and infestations | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Hepatobiliary disorders | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Respiratory, thoracic and mediastinal disorders | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Blood and lymphatic system disorders | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Renal and urinary disorders | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Cardiac disorders | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Metabolism and nutrition disorders | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Investigations | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Nervous system disorders | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Eye disorders | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Gastrointestinal disorders | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Reproductive system and breast disorders | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Musculoskeletal and connective tissue disorders | 0 Participants |
| Gilteritinib 40 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Vascular disorders | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Blood and lymphatic system disorders | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Any DLT | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Hepatobiliary disorders | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Infections and infestations | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Metabolism and nutrition disorders | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Musculoskeletal and connective tissue disorders | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Eye disorders | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Nervous system disorders | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Renal and urinary disorders | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Respiratory, thoracic and mediastinal disorders | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Gastrointestinal disorders | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Investigations | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Vascular disorders | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | General disorders & administration site conditions | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Cardiac disorders | 0 Participants |
| Gilteritinib 80 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Reproductive system and breast disorders | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Cardiac disorders | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Blood and lymphatic system disorders | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Reproductive system and breast disorders | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Gastrointestinal disorders | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Nervous system disorders | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | General disorders & administration site conditions | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Eye disorders | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Respiratory, thoracic and mediastinal disorders | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Hepatobiliary disorders | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Any DLT | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Musculoskeletal and connective tissue disorders | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Infections and infestations | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Renal and urinary disorders | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Metabolism and nutrition disorders | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Vascular disorders | 0 Participants |
| Gilteritinib 120 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Investigations | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Infections and infestations | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Investigations | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Any DLT | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Respiratory, thoracic and mediastinal disorders | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Blood and lymphatic system disorders | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Reproductive system and breast disorders | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Renal and urinary disorders | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Gastrointestinal disorders | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Cardiac disorders | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Nervous system disorders | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Eye disorders | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Musculoskeletal and connective tissue disorders | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | General disorders & administration site conditions | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Metabolism and nutrition disorders | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Hepatobiliary disorders | 0 Participants |
| Gilteritinib 200 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Vascular disorders | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | General disorders & administration site conditions | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Musculoskeletal and connective tissue disorders | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Eye disorders | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Investigations | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Hepatobiliary disorders | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Gastrointestinal disorders | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Nervous system disorders | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Cardiac disorders | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Blood and lymphatic system disorders | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Any DLT | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Renal and urinary disorders | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Infections and infestations | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Reproductive system and breast disorders | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Respiratory, thoracic and mediastinal disorders | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Vascular disorders | 0 Participants |
| Gilteritinib 300 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Metabolism and nutrition disorders | 0 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Reproductive system and breast disorders | 0 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Respiratory, thoracic and mediastinal disorders | 0 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Blood and lymphatic system disorders | 0 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Cardiac disorders | 0 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Eye disorders | 0 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Gastrointestinal disorders | 1 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Vascular disorders | 0 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | General disorders & administration site conditions | 0 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Hepatobiliary disorders | 0 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Infections and infestations | 0 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Investigations | 1 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Metabolism and nutrition disorders | 0 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Any DLT | 2 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Musculoskeletal and connective tissue disorders | 0 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Nervous system disorders | 0 Participants |
| Gilteritinib 450 mg in Escalation Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Renal and urinary disorders | 0 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | General disorders & administration site conditions | 0 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Renal and urinary disorders | 0 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Nervous system disorders | 1 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Metabolism and nutrition disorders | 0 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Gastrointestinal disorders | 0 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Vascular disorders | 0 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Reproductive system and breast disorders | 0 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Hepatobiliary disorders | 0 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Infections and infestations | 0 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Musculoskeletal and connective tissue disorders | 0 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Cardiac disorders | 0 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Investigations | 0 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Blood and lymphatic system disorders | 0 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Any DLT | 1 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Respiratory, thoracic and mediastinal disorders | 0 Participants |
| Gilteritinib 20 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Eye disorders | 0 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Renal and urinary disorders | 0 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Blood and lymphatic system disorders | 0 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | General disorders & administration site conditions | 0 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Cardiac disorders | 0 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Reproductive system and breast disorders | 0 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Nervous system disorders | 0 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Investigations | 0 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Any DLT | 1 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Infections and infestations | 1 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Metabolism and nutrition disorders | 0 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Vascular disorders | 0 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Hepatobiliary disorders | 0 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Gastrointestinal disorders | 0 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Musculoskeletal and connective tissue disorders | 0 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Respiratory, thoracic and mediastinal disorders | 0 Participants |
| Gilteritinib 40 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Eye disorders | 0 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Nervous system disorders | 0 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Investigations | 0 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Hepatobiliary disorders | 0 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | General disorders & administration site conditions | 0 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Metabolism and nutrition disorders | 0 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Gastrointestinal disorders | 0 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Eye disorders | 1 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Reproductive system and breast disorders | 0 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Musculoskeletal and connective tissue disorders | 0 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Cardiac disorders | 0 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Vascular disorders | 0 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Blood and lymphatic system disorders | 0 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Renal and urinary disorders | 0 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Any DLT | 2 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Respiratory, thoracic and mediastinal disorders | 0 Participants |
| Gilteritinib 80 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Infections and infestations | 1 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Musculoskeletal and connective tissue disorders | 0 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Vascular disorders | 0 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Eye disorders | 0 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Gastrointestinal disorders | 1 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Reproductive system and breast disorders | 0 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Any DLT | 7 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Renal and urinary disorders | 1 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | General disorders & administration site conditions | 0 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Hepatobiliary disorders | 1 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Metabolism and nutrition disorders | 0 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Nervous system disorders | 0 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Respiratory, thoracic and mediastinal disorders | 1 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Infections and infestations | 0 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Blood and lymphatic system disorders | 0 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Investigations | 2 Participants |
| Gilteritinib 120 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Cardiac disorders | 1 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Eye disorders | 0 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Blood and lymphatic system disorders | 0 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Cardiac disorders | 0 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Any DLT | 15 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Gastrointestinal disorders | 4 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | General disorders & administration site conditions | 1 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Hepatobiliary disorders | 0 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Infections and infestations | 0 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Investigations | 6 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Metabolism and nutrition disorders | 2 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Musculoskeletal and connective tissue disorders | 1 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Nervous system disorders | 3 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Renal and urinary disorders | 0 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Reproductive system and breast disorders | 1 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Respiratory, thoracic and mediastinal disorders | 2 Participants |
| Gilteritinib 200 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Vascular disorders | 2 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Nervous system disorders | 0 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Vascular disorders | 1 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Respiratory, thoracic and mediastinal disorders | 1 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Musculoskeletal and connective tissue disorders | 1 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Metabolism and nutrition disorders | 0 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Investigations | 2 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Infections and infestations | 0 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Hepatobiliary disorders | 0 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | General disorders & administration site conditions | 0 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Gastrointestinal disorders | 1 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Eye disorders | 0 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Cardiac disorders | 0 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Blood and lymphatic system disorders | 1 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Any DLT | 3 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Reproductive system and breast disorders | 0 Participants |
| Gilteritinib 300 mg in Expansion Phase | Number of Participants With Dose Limiting Toxicities (DLTs) | Renal and urinary disorders | 0 Participants |
Primary
Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Population: The analysis population was the PKAS with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib | 62.14 hours | Standard Deviation 17.88 |
| Gilteritinib 40 mg in Escalation Phase | Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib | 151.8 hours | Standard Deviation 129.2 |
| Gilteritinib 80 mg in Escalation Phase | Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib | 86.11 hours | Standard Deviation 24.08 |
| Gilteritinib 120 mg in Escalation Phase | Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib | 45.85 hours | Standard Deviation 18.83 |
| Gilteritinib 200 mg in Escalation Phase | Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib | 141.9 hours | Standard Deviation 61.51 |
| Gilteritinib 300 mg in Escalation Phase | Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib | 142.2 hours | Standard Deviation 55.04 |
Primary
Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Population: The analysis population was the PKAS with available data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib | Day -2 | 2.00 hours |
| Gilteritinib 20 mg in Escalation Phase | Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib | Cycle 1 day 15 | 4.008 hours |
| Gilteritinib 40 mg in Escalation Phase | Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib | Day -2 | 5.983 hours |
| Gilteritinib 40 mg in Escalation Phase | Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib | Cycle 1 day 15 | 3.867 hours |
| Gilteritinib 80 mg in Escalation Phase | Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib | Day -2 | 4.000 hours |
| Gilteritinib 80 mg in Escalation Phase | Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib | Cycle 1 day 15 | 4.333 hours |
| Gilteritinib 120 mg in Escalation Phase | Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib | Day -2 | 2.083 hours |
| Gilteritinib 120 mg in Escalation Phase | Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib | Cycle 1 day 15 | 2.167 hours |
| Gilteritinib 200 mg in Escalation Phase | Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib | Day -2 | 5.233 hours |
| Gilteritinib 200 mg in Escalation Phase | Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib | Cycle 1 day 15 | 6.033 hours |
| Gilteritinib 300 mg in Escalation Phase | Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib | Day -2 | 6.067 hours |
| Gilteritinib 300 mg in Escalation Phase | Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib | Cycle 1 day 15 | 6.050 hours |
| Gilteritinib 450 mg in Escalation Phase | Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib | Day -2 | 5.783 hours |
| Gilteritinib 450 mg in Escalation Phase | Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib | Cycle 1 day 15 | 5.933 hours |
Secondary
Amount of Drug Excreted in Urine (Aelast) of Cephalexin Administered With and Without Gilteritinib
Urine samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)
Population: The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Amount of Drug Excreted in Urine (Aelast) of Cephalexin Administered With and Without Gilteritinib | Cephalexin Alone (Day -1) | 548.9 mg | Standard Deviation 523.7 |
| Gilteritinib 20 mg in Escalation Phase | Amount of Drug Excreted in Urine (Aelast) of Cephalexin Administered With and Without Gilteritinib | Cephalexin + Gilteritinib (Cycle 1 Day 15) | 448.8 mg | Standard Deviation 306.1 |
Comparison: Statistical Assessment of the Effect of Gilteritinib on Cephalexin Pharmacokinetics after Administration of Cephalexin Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between cephalexin alone and cephalexin + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.90% CI: [46.53, 151.39]
Secondary
Apparent Total Systemic Clearance After Single or Multiple Extravascular Dosing (CL/F) of Cephalexin Administered With and Without Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
Population: The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Apparent Total Systemic Clearance After Single or Multiple Extravascular Dosing (CL/F) of Cephalexin Administered With and Without Gilteritinib | Cephalexin Alone (Day -1) | 9.713 L/h | Standard Deviation 3.319 |
| Gilteritinib 20 mg in Escalation Phase | Apparent Total Systemic Clearance After Single or Multiple Extravascular Dosing (CL/F) of Cephalexin Administered With and Without Gilteritinib | Cephalexin + Gilteritinib (Cycle 1 Day 15) | 10.58 L/h | Standard Deviation 2.977 |
Comparison: Statistical Assessment of the Effect of Gilteritinib on Cephalexin Pharmacokinetics after Administration of Cephalexin Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between cephalexin alone and cephalexin + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.90% CI: [85.28, 132.81]
Secondary
Apparent Volume of Distribution During the Terminal Elimination Phase After Single Extravascular Dosing (Vz/F) of Cephalexin Administered With and Without Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
Population: The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Apparent Volume of Distribution During the Terminal Elimination Phase After Single Extravascular Dosing (Vz/F) of Cephalexin Administered With and Without Gilteritinib | Cephalexin Alone (Day -1) | 24.07 liters | Standard Deviation 7.173 |
| Gilteritinib 20 mg in Escalation Phase | Apparent Volume of Distribution During the Terminal Elimination Phase After Single Extravascular Dosing (Vz/F) of Cephalexin Administered With and Without Gilteritinib | Cephalexin + Gilteritinib (Cycle 1 Day 15) | 25.86 liters | Standard Deviation 5.346 |
Secondary
Area Under the Concentration-time Curve From the Time of Dosing Extrapolated to Time Infinity (AUCinf) of Cephalexin Administered With and Without Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
Population: The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Area Under the Concentration-time Curve From the Time of Dosing Extrapolated to Time Infinity (AUCinf) of Cephalexin Administered With and Without Gilteritinib | Cephalexin Alone (Day -1) | 57650 ng*h/mL | Standard Deviation 20386 |
| Gilteritinib 20 mg in Escalation Phase | Area Under the Concentration-time Curve From the Time of Dosing Extrapolated to Time Infinity (AUCinf) of Cephalexin Administered With and Without Gilteritinib | Cephalexin + Gilteritinib (Cycle 1 Day 15) | 51873 ng*h/mL | Standard Deviation 18819 |
Comparison: Statistical Assessment of the Effect of Gilteritinib on Cephalexin Pharmacokinetics after Administration of Cephalexin Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between cephalexin alone and cephalexin + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.90% CI: [75.29, 117.26]
Secondary
AUC24 of Gilteritinib in Co-administration With Voriconazole
Plasma samples were used for pharmacokinetic assessments.
Time frame: Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)
Population: The analysis population was the PKAS, with participants administered 20 mg gilteritinib and voriconazole.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | AUC24 of Gilteritinib in Co-administration With Voriconazole | 919.3 ng*h/mL |
Secondary
AUC24 of Metabolite 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
Population: The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | AUC24 of Metabolite 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib | Midazolam Alone (Day -1) | 20.44 ng*h/mL | Standard Deviation 24.8 |
| Gilteritinib 20 mg in Escalation Phase | AUC24 of Metabolite 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib | Midazolam + Gilteritinib (Cycle 1 Day 15) | 23.10 ng*h/mL | Standard Deviation 21.64 |
Comparison: Statistical Comparison of Midazolam Exposure after Administration of Midazolam Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between 1-hydroxymidazolam alone and 1-hydroxymidazolam + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.90% CI: [74.88, 300.06]
Secondary
AUC24 of Midazolam Administered With and Without Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
Population: The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | AUC24 of Midazolam Administered With and Without Gilteritinib | Midazolam Alone (Day -1) | 66.55 ng*h/mL | Standard Deviation 57.7 |
| Gilteritinib 20 mg in Escalation Phase | AUC24 of Midazolam Administered With and Without Gilteritinib | Midazolam + Gilteritinib (Cycle 1 Day 15) | 81.56 ng*h/mL | Standard Deviation 65.84 |
Comparison: Statistical Comparison of Midazolam Exposure after Administration of Midazolam Alone or Coadministered with Gilteritinib: The difference of least squares (LS) means of log-transformed pharmacokinetic parameters between midazolam alone and midazolam + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.90% CI: [49.82, 240.48]
Secondary
AUClast of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
Population: The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | AUClast of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib | Midazolam Alone (Day -1) | 17.05 ng*h/mL | Standard Deviation 24.7 |
| Gilteritinib 20 mg in Escalation Phase | AUClast of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib | Midazolam + Gilteritinib (Cycle 1 Day 15) | 23.58 ng*h/mL | Standard Deviation 22.07 |
Secondary
AUClast of Cephalexin Administered With and Without Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
Population: The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | AUClast of Cephalexin Administered With and Without Gilteritinib | Cephalexin Alone (Day -1) | 53183 ng*h/mL | Standard Deviation 26877 |
| Gilteritinib 20 mg in Escalation Phase | AUClast of Cephalexin Administered With and Without Gilteritinib | Cephalexin + Gilteritinib (Cycle 1 Day 15) | 54963 ng*h/mL | Standard Deviation 29531 |
Comparison: Statistical Assessment of the Effect of Gilteritinib on Cephalexin Pharmacokinetics after Administration of Cephalexin Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between cephalexin alone and cephalexin + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.90% CI: [74.19, 128.7]
Secondary
AUClast of Gilteritinib in Co-administration With Voriconazole
Plasma samples were used for pharmacokinetic assessments.
Time frame: Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)
Population: The analysis population was the PKAS, with participants administered 20 mg gilteritinib and voriconazole.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | AUClast of Gilteritinib in Co-administration With Voriconazole | 919.3 ng*h/mL |
Secondary
AUClast of Midazolam Administered With and Without Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
Population: The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | AUClast of Midazolam Administered With and Without Gilteritinib | Midazolam Alone (Day -1) | 59.48 ng*h/mL | Standard Deviation 59.49 |
| Gilteritinib 20 mg in Escalation Phase | AUClast of Midazolam Administered With and Without Gilteritinib | Midazolam + Gilteritinib (Cycle 1 Day 15) | 82.44 ng*h/mL | Standard Deviation 64.25 |
Secondary
Cmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
Population: The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Cmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib | Midazolam Alone (Day -1) | 4.562 ng/mL | Standard Deviation 2.858 |
| Gilteritinib 20 mg in Escalation Phase | Cmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib | Midazolam + Gilteritinib (Cycle 1 Day 15) | 5.053 ng/mL | Standard Deviation 3.158 |
Comparison: Statistical Comparison of Midazolam Exposure after Administration of Midazolam Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between 1-hydroxymidazolam/midazolam alone and 1-hydroxymidazolam/midazolam + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.90% CI: [72.41, 210.52]
Secondary
Cmax of Cephalexin Administered With and Without Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
Population: The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Cmax of Cephalexin Administered With and Without Gilteritinib | Cephalexin Alone (Day -1) | 17688 ng/mL | Standard Deviation 6680 |
| Gilteritinib 20 mg in Escalation Phase | Cmax of Cephalexin Administered With and Without Gilteritinib | Cephalexin + Gilteritinib (Cycle 1 day 15) | 16075 ng/mL | Standard Deviation 4606 |
Comparison: Statistical Assessment of the Effect of Gilteritinib on Cephalexin Pharmacokinetics after Administration of Cephalexin Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between cephalexin alone and cephalexin + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.90% CI: [74.6, 112.12]
Secondary
Cmax of Gilteritinib in Co-administration With Voriconazole
Plasma samples were used for pharmacokinetic assessments.
Time frame: Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)
Population: The analysis population was the PKAS, with participants administered 20 mg gilteritinib and voriconazole.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Cmax of Gilteritinib in Co-administration With Voriconazole | 63.79 ng/mL |
Secondary
Cmax of Midazolam Administered With and Without Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
Population: The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Cmax of Midazolam Administered With and Without Gilteritinib | Midazolam Alone (Day -1) | 14.68 ng/mL | Standard Deviation 8.923 |
| Gilteritinib 20 mg in Escalation Phase | Cmax of Midazolam Administered With and Without Gilteritinib | Midazolam + Gilteritinib (Cycle 1 Day 15) | 18.45 ng/mL | Standard Deviation 9.452 |
Comparison: Statistical Comparison of Midazolam Exposure after Administration of Midazolam Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between midazolam alone and midazolam + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.90% CI: [69.54, 179.25]
Secondary
Duration of CRc (DCRc)
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.
Time frame: From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
Population: The analysis population was the FAS. Only participants who achieved CRc were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Duration of CRc (DCRc) | FLT3 Mutation Positive | NA days |
| Gilteritinib 20 mg in Escalation Phase | Duration of CRc (DCRc) | All Participants | NA days |
| Gilteritinib 20 mg in Escalation Phase | Duration of CRc (DCRc) | FLT3 Mutation Negative | NA days |
| Gilteritinib 80 mg in Escalation Phase | Duration of CRc (DCRc) | FLT3 Mutation Negative | 41.0 days |
| Gilteritinib 80 mg in Escalation Phase | Duration of CRc (DCRc) | FLT3 Mutation Positive | NA days |
| Gilteritinib 80 mg in Escalation Phase | Duration of CRc (DCRc) | All Participants | 79.0 days |
| Gilteritinib 120 mg in Escalation Phase | Duration of CRc (DCRc) | FLT3 Mutation Negative | 99.0 days |
| Gilteritinib 120 mg in Escalation Phase | Duration of CRc (DCRc) | FLT3 Mutation Positive | 98.0 days |
| Gilteritinib 120 mg in Escalation Phase | Duration of CRc (DCRc) | All Participants | 99.0 days |
| Gilteritinib 200 mg in Escalation Phase | Duration of CRc (DCRc) | FLT3 Mutation Positive | 191.0 days |
| Gilteritinib 200 mg in Escalation Phase | Duration of CRc (DCRc) | All Participants | 191.0 days |
| Gilteritinib 200 mg in Escalation Phase | Duration of CRc (DCRc) | FLT3 Mutation Negative | NA days |
| Gilteritinib 300 mg in Escalation Phase | Duration of CRc (DCRc) | FLT3 Mutation Positive | NA days |
| Gilteritinib 300 mg in Escalation Phase | Duration of CRc (DCRc) | All Participants | NA days |
Secondary
Duration of CR/CRh (DCRCRh)
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.
Time frame: From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
Population: The analysis population was the FAS. Only participants who achieved CR or CRh were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Duration of CR/CRh (DCRCRh) | NA days |
| Gilteritinib 80 mg in Escalation Phase | Duration of CR/CRh (DCRCRh) | NA days |
| Gilteritinib 120 mg in Escalation Phase | Duration of CR/CRh (DCRCRh) | 307.0 days |
| Gilteritinib 200 mg in Escalation Phase | Duration of CR/CRh (DCRCRh) | 308.0 days |
| Gilteritinib 300 mg in Escalation Phase | Duration of CR/CRh (DCRCRh) | NA days |
Secondary
Duration of CR (DCR)
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.
Time frame: From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
Population: The analysis population was the FAS. Only participants who achieved CR were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Duration of CR (DCR) | FLT3 Mutation Negative | NA days |
| Gilteritinib 20 mg in Escalation Phase | Duration of CR (DCR) | All Participants | NA days |
| Gilteritinib 80 mg in Escalation Phase | Duration of CR (DCR) | FLT3 Mutation Positive | NA days |
| Gilteritinib 80 mg in Escalation Phase | Duration of CR (DCR) | All Participants | NA days |
| Gilteritinib 120 mg in Escalation Phase | Duration of CR (DCR) | FLT3 Mutation Positive | NA days |
| Gilteritinib 120 mg in Escalation Phase | Duration of CR (DCR) | All Participants | NA days |
| Gilteritinib 200 mg in Escalation Phase | Duration of CR (DCR) | FLT3 Mutation Positive | 419.0 days |
| Gilteritinib 200 mg in Escalation Phase | Duration of CR (DCR) | All Participants | 419.0 days |
| Gilteritinib 300 mg in Escalation Phase | Duration of CR (DCR) | All Participants | NA days |
| Gilteritinib 300 mg in Escalation Phase | Duration of CR (DCR) | FLT3 Mutation Positive | NA days |
Secondary
Duration of CRh (DCRh)
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.
Time frame: From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
Population: The analysis population was the FAS. Only participants who achieved CRh were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Duration of CRh (DCRh) | NA days |
| Gilteritinib 80 mg in Escalation Phase | Duration of CRh (DCRh) | NA days |
| Gilteritinib 120 mg in Escalation Phase | Duration of CRh (DCRh) | 64.0 days |
| Gilteritinib 200 mg in Escalation Phase | Duration of CRh (DCRh) | 101.0 days |
| Gilteritinib 300 mg in Escalation Phase | Duration of CRh (DCRh) | NA days |
Secondary
Duration of CRi (DCRi)
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.
Time frame: From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
Population: The analysis population was the FAS. Only participants who achieved CRi were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Duration of CRi (DCRi) | FLT3 Mutation Positive | NA days |
| Gilteritinib 20 mg in Escalation Phase | Duration of CRi (DCRi) | All Participants | NA days |
| Gilteritinib 80 mg in Escalation Phase | Duration of CRi (DCRi) | FLT3 Mutation Negative | 41.0 days |
| Gilteritinib 80 mg in Escalation Phase | Duration of CRi (DCRi) | FLT3 Mutation Positive | NA days |
| Gilteritinib 80 mg in Escalation Phase | Duration of CRi (DCRi) | All Participants | 79.0 days |
| Gilteritinib 120 mg in Escalation Phase | Duration of CRi (DCRi) | FLT3 Mutation Negative | 99.0 days |
| Gilteritinib 120 mg in Escalation Phase | Duration of CRi (DCRi) | FLT3 Mutation Positive | 120.0 days |
| Gilteritinib 120 mg in Escalation Phase | Duration of CRi (DCRi) | All Participants | 120.0 days |
| Gilteritinib 200 mg in Escalation Phase | Duration of CRi (DCRi) | FLT3 Mutation Positive | 191.0 days |
| Gilteritinib 200 mg in Escalation Phase | Duration of CRi (DCRi) | All Participants | 191.0 days |
| Gilteritinib 300 mg in Escalation Phase | Duration of CRi (DCRi) | All Participants | NA days |
| Gilteritinib 300 mg in Escalation Phase | Duration of CRi (DCRi) | FLT3 Mutation Positive | NA days |
Secondary
Duration of CRp (DCRp)
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.
Time frame: From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
Population: The analysis population was the FAS. Only participants who achieved CRp were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 80 mg in Escalation Phase | Duration of CRp (DCRp) | FLT3 Mutation Positive | NA days |
| Gilteritinib 80 mg in Escalation Phase | Duration of CRp (DCRp) | All Participants | NA days |
| Gilteritinib 120 mg in Escalation Phase | Duration of CRp (DCRp) | All Participants | NA days |
| Gilteritinib 120 mg in Escalation Phase | Duration of CRp (DCRp) | FLT3 Mutation Positive | NA days |
| Gilteritinib 200 mg in Escalation Phase | Duration of CRp (DCRp) | FLT3 Mutation Positive | 450.0 days |
| Gilteritinib 200 mg in Escalation Phase | Duration of CRp (DCRp) | All Participants | 450.0 days |
| Gilteritinib 300 mg in Escalation Phase | Duration of CRp (DCRp) | FLT3 Mutation Positive | NA days |
| Gilteritinib 300 mg in Escalation Phase | Duration of CRp (DCRp) | All Participants | NA days |
Secondary
Duration of Response
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 frame: From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
Population: The analysis population was the FAS. Only participants who achieved CRc or PR were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Duration of Response | All Participants | NA days |
| Gilteritinib 20 mg in Escalation Phase | Duration of Response | FLT3 Mutation Negative | NA days |
| Gilteritinib 20 mg in Escalation Phase | Duration of Response | FLT3 Mutation Positive | NA days |
| Gilteritinib 40 mg in Escalation Phase | Duration of Response | All Participants | NA days |
| Gilteritinib 40 mg in Escalation Phase | Duration of Response | FLT3 Mutation Positive | NA days |
| Gilteritinib 80 mg in Escalation Phase | Duration of Response | FLT3 Mutation Positive | 88.0 days |
| Gilteritinib 80 mg in Escalation Phase | Duration of Response | All Participants | 79.0 days |
| Gilteritinib 80 mg in Escalation Phase | Duration of Response | FLT3 Mutation Negative | 41.0 days |
| Gilteritinib 120 mg in Escalation Phase | Duration of Response | FLT3 Mutation Positive | 141.0 days |
| Gilteritinib 120 mg in Escalation Phase | Duration of Response | FLT3 Mutation Negative | 109.5 days |
| Gilteritinib 120 mg in Escalation Phase | Duration of Response | All Participants | 126.0 days |
| Gilteritinib 200 mg in Escalation Phase | Duration of Response | FLT3 Mutation Negative | 85.0 days |
| Gilteritinib 200 mg in Escalation Phase | Duration of Response | FLT3 Mutation Positive | 220.0 days |
| Gilteritinib 200 mg in Escalation Phase | Duration of Response | All Participants | 220.0 days |
| Gilteritinib 300 mg in Escalation Phase | Duration of Response | FLT3 Mutation Positive | 59.0 days |
| Gilteritinib 300 mg in Escalation Phase | Duration of Response | All Participants | 59.0 days |
| Gilteritinib 450 mg in Escalation Phase | Duration of Response | All Participants | NA days |
| Gilteritinib 450 mg in Escalation Phase | Duration of Response | FLT3 Mutation Positive | NA days |
Secondary
Event Free Survival (EFS)
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.
Time frame: 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)
Population: The analysis population was the FAS.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Event Free Survival (EFS) | FLT3 Mutation Positive | 52.0 days |
| Gilteritinib 20 mg in Escalation Phase | Event Free Survival (EFS) | All Participants | 58.0 days |
| Gilteritinib 20 mg in Escalation Phase | Event Free Survival (EFS) | FLT3 Mutation Negative | 58.0 days |
| Gilteritinib 40 mg in Escalation Phase | Event Free Survival (EFS) | All Participants | 55.5 days |
| Gilteritinib 40 mg in Escalation Phase | Event Free Survival (EFS) | FLT3 Mutation Positive | 109.0 days |
| Gilteritinib 40 mg in Escalation Phase | Event Free Survival (EFS) | FLT3 Mutation Negative | 39.0 days |
| Gilteritinib 80 mg in Escalation Phase | Event Free Survival (EFS) | FLT3 Mutation Positive | 93.5 days |
| Gilteritinib 80 mg in Escalation Phase | Event Free Survival (EFS) | FLT3 Mutation Negative | 74.0 days |
| Gilteritinib 80 mg in Escalation Phase | Event Free Survival (EFS) | All Participants | 76.0 days |
| Gilteritinib 120 mg in Escalation Phase | Event Free Survival (EFS) | FLT3 Mutation Positive | 112.0 days |
| Gilteritinib 120 mg in Escalation Phase | Event Free Survival (EFS) | All Participants | 108.0 days |
| Gilteritinib 120 mg in Escalation Phase | Event Free Survival (EFS) | FLT3 Mutation Negative | 85.5 days |
| Gilteritinib 200 mg in Escalation Phase | Event Free Survival (EFS) | FLT3 Mutation Positive | 121.0 days |
| Gilteritinib 200 mg in Escalation Phase | Event Free Survival (EFS) | All Participants | 118.0 days |
| Gilteritinib 200 mg in Escalation Phase | Event Free Survival (EFS) | FLT3 Mutation Negative | 45.0 days |
| Gilteritinib 300 mg in Escalation Phase | Event Free Survival (EFS) | FLT3 Mutation Negative | 43.0 days |
| Gilteritinib 300 mg in Escalation Phase | Event Free Survival (EFS) | FLT3 Mutation Positive | 85.0 days |
| Gilteritinib 300 mg in Escalation Phase | Event Free Survival (EFS) | All Participants | 65.0 days |
| Gilteritinib 450 mg in Escalation Phase | Event Free Survival (EFS) | All Participants | 71.0 days |
| Gilteritinib 450 mg in Escalation Phase | Event Free Survival (EFS) | FLT3 Mutation Negative | 71.0 days |
| Gilteritinib 450 mg in Escalation Phase | Event Free Survival (EFS) | FLT3 Mutation Positive | 86.0 days |
Secondary
Fraction of Drug Excreted Into Urine in Percentage (%Ae) of Cephalexin Administered With and Without Gilteritinib
Urine samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)
Population: The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Fraction of Drug Excreted Into Urine in Percentage (%Ae) of Cephalexin Administered With and Without Gilteritinib | Cephalexin Alone (Day -1) | 109.8 percentage | Standard Deviation 104.7 |
| Gilteritinib 20 mg in Escalation Phase | Fraction of Drug Excreted Into Urine in Percentage (%Ae) of Cephalexin Administered With and Without Gilteritinib | Cephalexin + Gilteritinib (Cycle 1 Day 15) | 89.75 percentage | Standard Deviation 61.21 |
Secondary
Leukemia Free Survival (LFS)
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.
Time frame: 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)
Population: The analysis population was the FAS. Only participants who achieved CRc were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Leukemia Free Survival (LFS) | FLT3 Mutation Positive | 242.0 days |
| Gilteritinib 20 mg in Escalation Phase | Leukemia Free Survival (LFS) | FLT3 Mutation Negative | NA days |
| Gilteritinib 20 mg in Escalation Phase | Leukemia Free Survival (LFS) | All Participants | 242.0 days |
| Gilteritinib 80 mg in Escalation Phase | Leukemia Free Survival (LFS) | FLT3 Mutation Positive | 98.0 days |
| Gilteritinib 80 mg in Escalation Phase | Leukemia Free Survival (LFS) | All Participants | 79.0 days |
| Gilteritinib 80 mg in Escalation Phase | Leukemia Free Survival (LFS) | FLT3 Mutation Negative | 41.0 days |
| Gilteritinib 120 mg in Escalation Phase | Leukemia Free Survival (LFS) | FLT3 Mutation Negative | 99.0 days |
| Gilteritinib 120 mg in Escalation Phase | Leukemia Free Survival (LFS) | All Participants | 98.0 days |
| Gilteritinib 120 mg in Escalation Phase | Leukemia Free Survival (LFS) | FLT3 Mutation Positive | 98.0 days |
| Gilteritinib 200 mg in Escalation Phase | Leukemia Free Survival (LFS) | All Participants | 146.0 days |
| Gilteritinib 200 mg in Escalation Phase | Leukemia Free Survival (LFS) | FLT3 Mutation Negative | 38.0 days |
| Gilteritinib 200 mg in Escalation Phase | Leukemia Free Survival (LFS) | FLT3 Mutation Positive | 146.0 days |
| Gilteritinib 300 mg in Escalation Phase | Leukemia Free Survival (LFS) | FLT3 Mutation Positive | 296.0 days |
| Gilteritinib 300 mg in Escalation Phase | Leukemia Free Survival (LFS) | All Participants | 296.0 days |
Secondary
Overall Survival (OS)
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.
Time frame: 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)
Population: The analysis population was the FAS.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Overall Survival (OS) | All Participants | 149.5 days |
| Gilteritinib 20 mg in Escalation Phase | Overall Survival (OS) | FLT3 Mutation Positive | 123.0 days |
| Gilteritinib 20 mg in Escalation Phase | Overall Survival (OS) | FLT3 Mutation Negative | NA days |
| Gilteritinib 40 mg in Escalation Phase | Overall Survival (OS) | FLT3 Mutation Negative | 71.5 days |
| Gilteritinib 40 mg in Escalation Phase | Overall Survival (OS) | All Participants | 95.0 days |
| Gilteritinib 40 mg in Escalation Phase | Overall Survival (OS) | FLT3 Mutation Positive | 199.5 days |
| Gilteritinib 80 mg in Escalation Phase | Overall Survival (OS) | FLT3 Mutation Positive | 197.5 days |
| Gilteritinib 80 mg in Escalation Phase | Overall Survival (OS) | All Participants | 154.0 days |
| Gilteritinib 80 mg in Escalation Phase | Overall Survival (OS) | FLT3 Mutation Negative | 136.0 days |
| Gilteritinib 120 mg in Escalation Phase | Overall Survival (OS) | All Participants | 216.0 days |
| Gilteritinib 120 mg in Escalation Phase | Overall Survival (OS) | FLT3 Mutation Positive | 246.0 days |
| Gilteritinib 120 mg in Escalation Phase | Overall Survival (OS) | FLT3 Mutation Negative | 144.0 days |
| Gilteritinib 200 mg in Escalation Phase | Overall Survival (OS) | FLT3 Mutation Negative | 67.0 days |
| Gilteritinib 200 mg in Escalation Phase | Overall Survival (OS) | FLT3 Mutation Positive | 214.0 days |
| Gilteritinib 200 mg in Escalation Phase | Overall Survival (OS) | All Participants | 176.0 days |
| Gilteritinib 300 mg in Escalation Phase | Overall Survival (OS) | FLT3 Mutation Positive | 157.0 days |
| Gilteritinib 300 mg in Escalation Phase | Overall Survival (OS) | FLT3 Mutation Negative | 68.0 days |
| Gilteritinib 300 mg in Escalation Phase | Overall Survival (OS) | All Participants | 128.5 days |
| Gilteritinib 450 mg in Escalation Phase | Overall Survival (OS) | All Participants | 89.0 days |
| Gilteritinib 450 mg in Escalation Phase | Overall Survival (OS) | FLT3 Mutation Positive | 204.0 days |
| Gilteritinib 450 mg in Escalation Phase | Overall Survival (OS) | FLT3 Mutation Negative | 89.0 days |
Secondary
Percentage of Participants Who Achieved Transfusion Conversion
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.
Time frame: 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
Population: The analysis population was the FAS. Participants who were transfusion dependent at baseline and had evaluable post-baseline transfusion status were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | All Participants | NA percentage of participants |
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | FLT3 Mutation Negative | NA percentage of participants |
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | FLT3 Mutation Positive | 0 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | FLT3 Mutation Negative | NA percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | FLT3 Mutation Positive | 0 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | All Participants | NA percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | All Participants | 25.0 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | FLT3 Mutation Positive | 37.5 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | FLT3 Mutation Negative | 12.5 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | FLT3 Mutation Negative | 22.2 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | FLT3 Mutation Positive | 27.5 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | All Participants | 26.5 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | FLT3 Mutation Negative | 33.3 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | FLT3 Mutation Positive | 40.4 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | All Participants | 39.7 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | FLT3 Mutation Positive | NA percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | All Participants | NA percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | FLT3 Mutation Negative | NA percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | All Participants | NA percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | FLT3 Mutation Negative | NA percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Conversion | FLT3 Mutation Positive | NA percentage of participants |
Secondary
Percentage of Participants Who Achieved Transfusion Maintenance
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.
Time frame: 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
Population: The analysis population was the FAS. Participants who were transfusion independent at baseline and had evaluable post-baseline transfusion status were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Maintenance | All Participants | 100.0 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Maintenance | FLT3 Mutation Positive | 100.0 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Maintenance | FLT3 Mutation Positive | 75.0 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Maintenance | FLT3 Mutation Negative | 33.3 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Maintenance | All Participants | 57.1 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Maintenance | All Participants | 80.0 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Maintenance | FLT3 Mutation Positive | 80.0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Maintenance | All Participants | 100.0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants Who Achieved Transfusion Maintenance | FLT3 Mutation Positive | 100.0 percentage of participants |
Secondary
Percentage of Participants With Best Response
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.
Time frame: Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
Population: The analysis population was the FAS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With Best Response | All Participants | 18.8 percentage of participants |
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With Best Response | FLT3 Mutation Negative | 50.0 percentage of participants |
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With Best Response | FLT3 Mutation Positive | 14.3 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With Best Response | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With Best Response | FLT3 Mutation Positive | 37.5 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With Best Response | All Participants | 18.8 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With Best Response | All Participants | 41.7 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With Best Response | FLT3 Mutation Positive | 66.7 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With Best Response | FLT3 Mutation Negative | 16.7 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With Best Response | FLT3 Mutation Negative | 14.3 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With Best Response | FLT3 Mutation Positive | 53.6 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With Best Response | All Participants | 45.7 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With Best Response | FLT3 Mutation Negative | 18.2 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With Best Response | FLT3 Mutation Positive | 48.3 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With Best Response | All Participants | 45.0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With Best Response | FLT3 Mutation Positive | 60.0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With Best Response | All Participants | 30.0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With Best Response | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With Best Response | All Participants | 33.3 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With Best Response | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With Best Response | FLT3 Mutation Positive | 50.0 percentage of participants |
Secondary
Percentage of Participants With Complete Remission and Complete Remission With Partial Hematologic Recovery (CR/CRh)
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.
Time frame: Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
Population: The analysis population was the FAS, with participants who were FLT3 mutation positive.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With Complete Remission and Complete Remission With Partial Hematologic Recovery (CR/CRh) | 7.1 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With Complete Remission and Complete Remission With Partial Hematologic Recovery (CR/CRh) | 0 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With Complete Remission and Complete Remission With Partial Hematologic Recovery (CR/CRh) | 25.0 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With Complete Remission and Complete Remission With Partial Hematologic Recovery (CR/CRh) | 23.2 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With Complete Remission and Complete Remission With Partial Hematologic Recovery (CR/CRh) | 19.1 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With Complete Remission and Complete Remission With Partial Hematologic Recovery (CR/CRh) | 30.0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With Complete Remission and Complete Remission With Partial Hematologic Recovery (CR/CRh) | 0 percentage of participants |
Secondary
Percentage of Participants With Complete Remission (CR) During the First 2 Cycles
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.
Time frame: During the first 2 cycles (56 days)
Population: Full analysis set (FAS) - consisted of all participants who were enrolled, took at least 1 dose of study drug and who had at least 1 posttreatment data point. Re-enrolled participants and participants from one site due to concerns with this site's GCP compliance were excluded. Participants were summarized under planned reporting groups in the FAS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | All Participants | 6.3 percentage of participants |
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | FLT3 Mutation Negative | 50.0 percentage of participants |
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | FLT3 Mutation Positive | 0 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | FLT3 Mutation Positive | 0 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | All Participants | 0 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | All Participants | 4.2 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | FLT3 Mutation Positive | 8.3 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | FLT3 Mutation Positive | 3.6 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | All Participants | 2.9 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | FLT3 Mutation Positive | 3.4 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | All Participants | 3.0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | FLT3 Mutation Positive | 10 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | All Participants | 5.0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | All Participants | 0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With Complete Remission (CR) During the First 2 Cycles | FLT3 Mutation Positive | 0 percentage of participants |
Secondary
Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh)
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.
Time frame: Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
Population: The analysis population was the FAS, with participants who were FLT3 mutation positive.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh) | 7.1 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh) | 0 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh) | 8.3 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh) | 10.7 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh) | 7.9 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh) | 20.0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh) | 0 percentage of participants |
Secondary
Percentage of Participants With Composite CR (CRc)
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.
Time frame: Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
Population: The analysis population was the FAS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | FLT3 Mutation Negative | 50.0 percentage of participants |
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | FLT3 Mutation Positive | 7.1 percentage of participants |
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | All Participants | 12.5 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | FLT3 Mutation Positive | 0 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | All Participants | 0 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | All Participants | 29.2 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | FLT3 Mutation Positive | 41.7 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | FLT3 Mutation Negative | 16.7 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | FLT3 Mutation Positive | 46.4 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | FLT3 Mutation Negative | 7.1 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | All Participants | 38.6 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | FLT3 Mutation Positive | 40.4 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | FLT3 Mutation Negative | 9.1 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | All Participants | 37.0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | FLT3 Mutation Positive | 30.0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | All Participants | 15.0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | All Participants | 0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | FLT3 Mutation Positive | 0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With Composite CR (CRc) | FLT3 Mutation Negative | 0 percentage of participants |
Secondary
Percentage of Participants With CR During Treatment
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.
Time frame: Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
Population: The analysis population was the FAS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With CR During Treatment | FLT3 Mutation Negative | 50.0 percentage of participants |
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With CR During Treatment | All Participants | 6.3 percentage of participants |
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With CR During Treatment | FLT3 Mutation Positive | 0 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With CR During Treatment | FLT3 Mutation Positive | 0 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With CR During Treatment | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With CR During Treatment | All Participants | 0 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With CR During Treatment | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With CR During Treatment | FLT3 Mutation Positive | 16.7 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With CR During Treatment | All Participants | 8.3 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With CR During Treatment | All Participants | 10.0 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With CR During Treatment | FLT3 Mutation Positive | 12.5 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With CR During Treatment | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With CR During Treatment | All Participants | 10.0 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With CR During Treatment | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With CR During Treatment | FLT3 Mutation Positive | 11.2 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With CR During Treatment | All Participants | 5.0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With CR During Treatment | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With CR During Treatment | FLT3 Mutation Positive | 10.0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With CR During Treatment | All Participants | 0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With CR During Treatment | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With CR During Treatment | FLT3 Mutation Positive | 0 percentage of participants |
Secondary
Percentage of Participants With CR With Incomplete Hematological Recovery (CRi)
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.
Time frame: Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
Population: The analysis population was the FAS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | All Participants | 6.3 percentage of participants |
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | FLT3 Mutation Positive | 7.1 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | FLT3 Mutation Positive | 0 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | All Participants | 0 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | All Participants | 20.8 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | FLT3 Mutation Positive | 25.0 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | FLT3 Mutation Negative | 16.7 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | FLT3 Mutation Negative | 7.1 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | FLT3 Mutation Positive | 30.4 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | All Participants | 25.7 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | FLT3 Mutation Negative | 9.1 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | FLT3 Mutation Positive | 20.2 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | All Participants | 19.0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | FLT3 Mutation Positive | 10.0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | All Participants | 5.0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | All Participants | 0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) | FLT3 Mutation Positive | 0 percentage of participants |
Secondary
Percentage of Participants With CR With Incomplete Platelet Recovery (CRp)
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.
Time frame: Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
Population: The analysis population was the FAS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | All Participants | 0 percentage of participants |
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | FLT3 Mutation Positive | 0 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | FLT3 Mutation Positive | 0 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | All Participants | 0 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | All Participants | 0 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | FLT3 Mutation Positive | 0 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | FLT3 Mutation Positive | 3.6 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | All Participants | 2.9 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | FLT3 Mutation Positive | 9.0 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | All Participants | 8.0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | FLT3 Mutation Positive | 10.0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | All Participants | 5.0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | All Participants | 0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) | FLT3 Mutation Positive | 0 percentage of participants |
Secondary
Percentage of Participants With Partial Remission (PR)
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 frame: Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
Population: The analysis population was the FAS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | All Participants | 6.3 percentage of participants |
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 20 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | FLT3 Mutation Positive | 7.1 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | FLT3 Mutation Positive | 37.5 percentage of participants |
| Gilteritinib 40 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | All Participants | 18.8 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | All Participants | 12.5 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | FLT3 Mutation Positive | 25.0 percentage of participants |
| Gilteritinib 80 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | FLT3 Mutation Negative | 7.1 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | FLT3 Mutation Positive | 7.1 percentage of participants |
| Gilteritinib 120 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | All Participants | 7.1 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | FLT3 Mutation Negative | 9.1 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | FLT3 Mutation Positive | 7.9 percentage of participants |
| Gilteritinib 200 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | All Participants | 8.0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | FLT3 Mutation Positive | 30.0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | All Participants | 15.0 percentage of participants |
| Gilteritinib 300 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | All Participants | 33.3 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | FLT3 Mutation Negative | 0 percentage of participants |
| Gilteritinib 450 mg in Escalation Phase | Percentage of Participants With Partial Remission (PR) | FLT3 Mutation Positive | 50.0 percentage of participants |
Secondary
Renal Clearance (CLr) of Cephalexin in Administered With and Without Gilteritinib
Urine samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)
Population: The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Renal Clearance (CLr) of Cephalexin in Administered With and Without Gilteritinib | Cephalexin Alone (Day -1) | 8.784 L/h | Standard Deviation 8.727 |
| Gilteritinib 20 mg in Escalation Phase | Renal Clearance (CLr) of Cephalexin in Administered With and Without Gilteritinib | Cephalexin + Gilteritinib (Cycle 1 Day 15) | 11.04 L/h | Standard Deviation 8.43 |
Comparison: Statistical Assessment of the Effect of Gilteritinib on Cephalexin Pharmacokinetics after Administration of Cephalexin Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between cephalexin alone and cephalexin + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.90% CI: [40.25, 170.48]
Secondary
T1/2 of Cephalexin Administered With and Without Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
Population: The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | T1/2 of Cephalexin Administered With and Without Gilteritinib | Cephalexin Alone (Day -1) | 1.822 hours | Standard Deviation 0.5914 |
| Gilteritinib 20 mg in Escalation Phase | T1/2 of Cephalexin Administered With and Without Gilteritinib | Cephalexin + Gilteritinib (Cycle 1 Day 15) | 1.827 hours | Standard Deviation 0.7175 |
Secondary
Time to Best CR/CRh (TTBCRCRh)
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 frame: 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)
Population: The analysis population was the FAS. Participants who achieved CR or CRh were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Time to Best CR/CRh (TTBCRCRh) | 57.0 days |
| Gilteritinib 80 mg in Escalation Phase | Time to Best CR/CRh (TTBCRCRh) | 57.0 days |
| Gilteritinib 120 mg in Escalation Phase | Time to Best CR/CRh (TTBCRCRh) | 63.0 days |
| Gilteritinib 200 mg in Escalation Phase | Time to Best CR/CRh (TTBCRCRh) | 88.0 days |
| Gilteritinib 300 mg in Escalation Phase | Time to Best CR/CRh (TTBCRCRh) | 30.0 days |
Secondary
Time to Best Response (TTBR)
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.
Time frame: 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)
Population: The analysis population was the FAS. Only participants who achieved CR, CRp, CRi, or PR were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Time to Best Response (TTBR) | All Participants | 57.0 days |
| Gilteritinib 20 mg in Escalation Phase | Time to Best Response (TTBR) | FLT3 Mutation Negative | 30.0 days |
| Gilteritinib 20 mg in Escalation Phase | Time to Best Response (TTBR) | FLT3 Mutation Positive | 75.5 days |
| Gilteritinib 40 mg in Escalation Phase | Time to Best Response (TTBR) | All Participants | 57.0 days |
| Gilteritinib 40 mg in Escalation Phase | Time to Best Response (TTBR) | FLT3 Mutation Positive | 57.0 days |
| Gilteritinib 80 mg in Escalation Phase | Time to Best Response (TTBR) | All Participants | 58.0 days |
| Gilteritinib 80 mg in Escalation Phase | Time to Best Response (TTBR) | FLT3 Mutation Positive | 44.0 days |
| Gilteritinib 80 mg in Escalation Phase | Time to Best Response (TTBR) | FLT3 Mutation Negative | 71.5 days |
| Gilteritinib 120 mg in Escalation Phase | Time to Best Response (TTBR) | FLT3 Mutation Negative | 29.5 days |
| Gilteritinib 120 mg in Escalation Phase | Time to Best Response (TTBR) | FLT3 Mutation Positive | 43.5 days |
| Gilteritinib 120 mg in Escalation Phase | Time to Best Response (TTBR) | All Participants | 30.0 days |
| Gilteritinib 200 mg in Escalation Phase | Time to Best Response (TTBR) | FLT3 Mutation Negative | 29.5 days |
| Gilteritinib 200 mg in Escalation Phase | Time to Best Response (TTBR) | FLT3 Mutation Positive | 57.0 days |
| Gilteritinib 200 mg in Escalation Phase | Time to Best Response (TTBR) | All Participants | 56.0 days |
| Gilteritinib 300 mg in Escalation Phase | Time to Best Response (TTBR) | All Participants | 29.0 days |
| Gilteritinib 300 mg in Escalation Phase | Time to Best Response (TTBR) | FLT3 Mutation Positive | 29.0 days |
| Gilteritinib 450 mg in Escalation Phase | Time to Best Response (TTBR) | All Participants | 31.0 days |
| Gilteritinib 450 mg in Escalation Phase | Time to Best Response (TTBR) | FLT3 Mutation Positive | 31.0 days |
Secondary
Time to CRc (TTCRc)
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 frame: 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)
Population: The analysis population was the FAS. Only participants who achieved CRc were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Time to CRc (TTCRc) | FLT3 Mutation Positive | 57.0 days |
| Gilteritinib 20 mg in Escalation Phase | Time to CRc (TTCRc) | All Participants | 43.5 days |
| Gilteritinib 20 mg in Escalation Phase | Time to CRc (TTCRc) | FLT3 Mutation Negative | 30.0 days |
| Gilteritinib 80 mg in Escalation Phase | Time to CRc (TTCRc) | FLT3 Mutation Negative | 71.5 days |
| Gilteritinib 80 mg in Escalation Phase | Time to CRc (TTCRc) | FLT3 Mutation Positive | 56.0 days |
| Gilteritinib 80 mg in Escalation Phase | Time to CRc (TTCRc) | All Participants | 57.0 days |
| Gilteritinib 120 mg in Escalation Phase | Time to CRc (TTCRc) | FLT3 Mutation Negative | 30.0 days |
| Gilteritinib 120 mg in Escalation Phase | Time to CRc (TTCRc) | FLT3 Mutation Positive | 30.0 days |
| Gilteritinib 120 mg in Escalation Phase | Time to CRc (TTCRc) | All Participants | 30.0 days |
| Gilteritinib 200 mg in Escalation Phase | Time to CRc (TTCRc) | FLT3 Mutation Positive | 31.5 days |
| Gilteritinib 200 mg in Escalation Phase | Time to CRc (TTCRc) | All Participants | 31.0 days |
| Gilteritinib 200 mg in Escalation Phase | Time to CRc (TTCRc) | FLT3 Mutation Negative | 30.0 days |
| Gilteritinib 300 mg in Escalation Phase | Time to CRc (TTCRc) | FLT3 Mutation Positive | 28.0 days |
| Gilteritinib 300 mg in Escalation Phase | Time to CRc (TTCRc) | All Participants | 28.0 days |
Secondary
Time to CRi (TTCRi)
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 frame: 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)
Population: The analysis population was the FAS. Only participants who achieved CRi were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Time to CRi (TTCRi) | All Participants | 57.0 days |
| Gilteritinib 20 mg in Escalation Phase | Time to CRi (TTCRi) | FLT3 Mutation Positive | 57.0 days |
| Gilteritinib 80 mg in Escalation Phase | Time to CRi (TTCRi) | All Participants | 64.0 days |
| Gilteritinib 80 mg in Escalation Phase | Time to CRi (TTCRi) | FLT3 Mutation Negative | 71.5 days |
| Gilteritinib 80 mg in Escalation Phase | Time to CRi (TTCRi) | FLT3 Mutation Positive | 57.0 days |
| Gilteritinib 120 mg in Escalation Phase | Time to CRi (TTCRi) | FLT3 Mutation Positive | 57.0 days |
| Gilteritinib 120 mg in Escalation Phase | Time to CRi (TTCRi) | FLT3 Mutation Negative | 30.0 days |
| Gilteritinib 120 mg in Escalation Phase | Time to CRi (TTCRi) | All Participants | 43.5 days |
| Gilteritinib 200 mg in Escalation Phase | Time to CRi (TTCRi) | All Participants | 35.0 days |
| Gilteritinib 200 mg in Escalation Phase | Time to CRi (TTCRi) | FLT3 Mutation Positive | 39.5 days |
| Gilteritinib 200 mg in Escalation Phase | Time to CRi (TTCRi) | FLT3 Mutation Negative | 30.0 days |
| Gilteritinib 300 mg in Escalation Phase | Time to CRi (TTCRi) | FLT3 Mutation Positive | 28.0 days |
| Gilteritinib 300 mg in Escalation Phase | Time to CRi (TTCRi) | All Participants | 28.0 days |
Secondary
Time to CRp (TTCRp)
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.
Time frame: 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)
Population: The analysis population was the FAS. Only participants who achieved CRp were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 80 mg in Escalation Phase | Time to CRp (TTCRp) | FLT3 Mutation Positive | 140.0 days |
| Gilteritinib 80 mg in Escalation Phase | Time to CRp (TTCRp) | All Participants | 140.0 days |
| Gilteritinib 120 mg in Escalation Phase | Time to CRp (TTCRp) | All Participants | 195.0 days |
| Gilteritinib 120 mg in Escalation Phase | Time to CRp (TTCRp) | FLT3 Mutation Positive | 195.0 days |
| Gilteritinib 200 mg in Escalation Phase | Time to CRp (TTCRp) | FLT3 Mutation Positive | 84.5 days |
| Gilteritinib 200 mg in Escalation Phase | Time to CRp (TTCRp) | All Participants | 84.5 days |
| Gilteritinib 300 mg in Escalation Phase | Time to CRp (TTCRp) | FLT3 Mutation Positive | 29.0 days |
| Gilteritinib 300 mg in Escalation Phase | Time to CRp (TTCRp) | All Participants | 29.0 days |
Secondary
Time to CR (TTCR)
TTCR was defined as the time from the first dose of study drug until the date of first CR.
Time frame: 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)
Population: The analysis population was the FAS. Only participants who achieved CR were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Time to CR (TTCR) | FLT3 Mutation Negative | 30.0 days |
| Gilteritinib 20 mg in Escalation Phase | Time to CR (TTCR) | All Participants | 30.0 days |
| Gilteritinib 80 mg in Escalation Phase | Time to CR (TTCR) | FLT3 Mutation Positive | 171.5 days |
| Gilteritinib 80 mg in Escalation Phase | Time to CR (TTCR) | All Participants | 171.5 days |
| Gilteritinib 120 mg in Escalation Phase | Time to CR (TTCR) | FLT3 Mutation Positive | 141.0 days |
| Gilteritinib 120 mg in Escalation Phase | Time to CR (TTCR) | All Participants | 141.0 days |
| Gilteritinib 200 mg in Escalation Phase | Time to CR (TTCR) | FLT3 Mutation Positive | 93.0 days |
| Gilteritinib 200 mg in Escalation Phase | Time to CR (TTCR) | All Participants | 93.0 days |
| Gilteritinib 300 mg in Escalation Phase | Time to CR (TTCR) | All Participants | 56.0 days |
| Gilteritinib 300 mg in Escalation Phase | Time to CR (TTCR) | FLT3 Mutation Positive | 56.0 days |
Secondary
Time to First CR/CRh (TTFCRCRh)
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 frame: 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)
Population: The analysis population was the FAS. Only participants who achieved CR or CRh were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Time to First CR/CRh (TTFCRCRh) | 57.0 days |
| Gilteritinib 80 mg in Escalation Phase | Time to First CR/CRh (TTFCRCRh) | 57.0 days |
| Gilteritinib 120 mg in Escalation Phase | Time to First CR/CRh (TTFCRCRh) | 59.0 days |
| Gilteritinib 200 mg in Escalation Phase | Time to First CR/CRh (TTFCRCRh) | 57.0 days |
| Gilteritinib 300 mg in Escalation Phase | Time to First CR/CRh (TTFCRCRh) | 28.0 days |
Secondary
Time to Response (TTR)
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 frame: 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)
Population: The analysis population was the FAS. Only participants who achieved CRc or PR were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Time to Response (TTR) | All Participants | 30.0 days |
| Gilteritinib 20 mg in Escalation Phase | Time to Response (TTR) | FLT3 Mutation Negative | 30.0 days |
| Gilteritinib 20 mg in Escalation Phase | Time to Response (TTR) | FLT3 Mutation Positive | 61.5 days |
| Gilteritinib 40 mg in Escalation Phase | Time to Response (TTR) | All Participants | 57.0 days |
| Gilteritinib 40 mg in Escalation Phase | Time to Response (TTR) | FLT3 Mutation Positive | 57.0 days |
| Gilteritinib 80 mg in Escalation Phase | Time to Response (TTR) | All Participants | 43.5 days |
| Gilteritinib 80 mg in Escalation Phase | Time to Response (TTR) | FLT3 Mutation Positive | 31.0 days |
| Gilteritinib 80 mg in Escalation Phase | Time to Response (TTR) | FLT3 Mutation Negative | 71.5 days |
| Gilteritinib 120 mg in Escalation Phase | Time to Response (TTR) | FLT3 Mutation Negative | 29.5 days |
| Gilteritinib 120 mg in Escalation Phase | Time to Response (TTR) | FLT3 Mutation Positive | 29.0 days |
| Gilteritinib 120 mg in Escalation Phase | Time to Response (TTR) | All Participants | 29.0 days |
| Gilteritinib 200 mg in Escalation Phase | Time to Response (TTR) | FLT3 Mutation Negative | 29.5 days |
| Gilteritinib 200 mg in Escalation Phase | Time to Response (TTR) | FLT3 Mutation Positive | 29.0 days |
| Gilteritinib 200 mg in Escalation Phase | Time to Response (TTR) | All Participants | 29.0 days |
| Gilteritinib 300 mg in Escalation Phase | Time to Response (TTR) | All Participants | 28.0 days |
| Gilteritinib 300 mg in Escalation Phase | Time to Response (TTR) | FLT3 Mutation Positive | 28.0 days |
| Gilteritinib 450 mg in Escalation Phase | Time to Response (TTR) | All Participants | 31.0 days |
| Gilteritinib 450 mg in Escalation Phase | Time to Response (TTR) | FLT3 Mutation Positive | 31.0 days |
Secondary
Tmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
Population: The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Tmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib | Midazolam Alone (Day -1) | 0.5583 hours |
| Gilteritinib 20 mg in Escalation Phase | Tmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib | Midazolam + Gilteritinib (Cycle 1 Day 15) | 1.00 hours |
Secondary
Tmax of Cephalexin Administered With and Without Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
Population: The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Tmax of Cephalexin Administered With and Without Gilteritinib | Cephalexin + Gilteritinib (Cycle 1 Day 15) | 1.483 hours |
| Gilteritinib 20 mg in Escalation Phase | Tmax of Cephalexin Administered With and Without Gilteritinib | Cephalexin Alone (Day -1) | 1.500 hours |
Secondary
Tmax of Gilteritinib in Co-administration With Voriconazole
Plasma samples were used for pharmacokinetic assessments.
Time frame: Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)
Population: The analysis population was the PKAS, with participants administered 20 mg gilteritinib and voriconazole.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Tmax of Gilteritinib in Co-administration With Voriconazole | 2.08 hours |
Secondary
Tmax of Midazolam Administered With and Without Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Time frame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
Population: The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib 20 mg in Escalation Phase | Tmax of Midazolam Administered With and Without Gilteritinib | Midazolam Alone (Day -1) | 0.5000 hours |
| Gilteritinib 20 mg in Escalation Phase | Tmax of Midazolam Administered With and Without Gilteritinib | Midazolam + Gilteritinib (Cycle 1 Day 15) | 1.00 hours |